Organic chemistry (Part I, II): textbook 9786010440203

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AL-FARABI KAZAKH NATIONAL UNIVERSITY

B.M. Kudaibergenova

ORGANIC CHEMISTRY PART I, II Educational manual Stereotypical publication

Almaty «Qazaq University» 2020

UDC 541(075) LBC 24.2я73 K 89 Recommended for publication by the decision of the Academic Council of the Faculty of Chemistry and Chemical Technology, Editorial and Publishing Council of Al-Farabi Kazakh National University (Protocol №4 dated 16.04.2019); For students of the specialty 5B060600-Chemistry it is recommended for use in the educational organizations by educational-methodical association of the Republican educational-methodical council under the Al-Farabi KazNU (protocol №1 of March 2, 2019) Rewiers: Doctor of Chemical Sciences, Professor O.A. Almabekov Candidate of Chemical Sciences, Associate Professor M.I. Ilyasova Doctor of Chemical Sciences, Professor G.Sh. Burasheva

Kudaibergenova B.M. K 89 Organic chemistry (Part I, II) / B.M. Kudaibergenova. – Ster. pub. – Almaty: Qazaq university, 2020. – 323 p. ISBN 978-601-04-4020-3 The Organic Chemistry (Part I, II) textbook describes the main classes of organic compounds located in the characteristic groups. The nomenclature, production methods, properties and reactions of organic compounds belonging to the main classes are considered. The textbook is intended to the students specializing in chemistry.

UDC 541(075) LBC 24.2я73 ISBN 978-601-04-4020-3

© Kudaibergenova B.M., 2020 © Al-Farabi KazNU, 2020

Organic chemistry is the study of compounds of the element carbon, compounds which also contain hydrogen and often other non-metal elements like oxygen, nitrogen, the halogens, sulphur, and phosphorus. You might think these ought to be covered by inorganic chemistry just as we learn in inorganic chemistry about compounds formed from sulphur and hydrogen, etc. But there are two reasons for not doing this. The first is historical: in the years before about 1830 it was thought that organic compounds could be made only in plants or animals, that is, in living organisms, and that they contained a mysterious ‘vital force’ in addition to carbon and other chemical elements. Therefore much knowledge was amassed about carbon compounds during that time, but kept separate from knowledge about other compounds. The second reason is practical: carbon forms so many different compounds, often of such complexity, and we now know so much about how they react and what they produce, that we have to study carbon compounds separately. Carbon is singled out because it has a chemical diversity unrivaled by any other chemical element. Its diversity is based on the following:  Carbon atoms bond reasonably strongly with other carbon atoms.  Carbon atoms bond reasonably strongly with atoms of other elements.  Carbon atoms make a large number of covalent bonds (four). Most organic chemicals are covalent compounds, which is why we introduce organic chemistry here. By convention, compounds containing carbonate ions and bicarbonate ions, as well as carbon dioxide and carbon monoxide, are not considered part of organic chemistry, even though they contain carbon. The simplest organic compounds contain only the elements carbon and hydrogen, and are called hydrocarbons. Even though they are composed of only two types of atoms, there is a wide variety of hydrocarbons because they may consist of varying lengths of chains, 3

branched chains, and rings of carbon atoms, or combinations of these structures. In addition, hydrocarbons may differ in the types of carbon-carbon bonds present in their molecules. Some hydrocarbons have only single bonds and appear as a chain (which can be a straight chain or can have branches) of carbon atoms also bonded to hydrogen atoms. Many hydrocarbons are found in plants, animals, and their fossils; other hydrocarbons have been prepared in the laboratory. We use hydrocarbons every day, mainly as fuels, such as natural gas, acetylene, propane, butane, and the principal components of gasoline, diesel fuel, and heating oil. The familiar plastics polyethylene, polypropylene, and polystyrene are also hydrocarbons. We can distinguish several types of hydrocarbons by differences in the bonding between carbon atoms. This leads to differences in geometries and in the hybridization of the carbon orbitals. Nineteenth-century chemists classified hydrocarbons as either aliphatic or aromatic on the basis of their sources and properties. Aliphatic (from Greek aleiphar, “fat”) described hydrocarbons derived by chemical degradation of fats or oils. Aromatic hydrocarbons constituted a group of related substances obtained by chemical degradation of certain pleasant-smelling plant extracts. The terms aliphatic and aromatic are retained in modern terminology, but the compounds they describe are distinguished on the basis of structure rather than origin. The classifications for hydrocarbons are as follows:

In this introductory textbook, we will tell you something of the background of organic chemistry, something of the problems and something of our philosophy of what is important for you to learn so 4

that you will have a reasonable working knowledge of the subject, whether you are just interested in chemistry or plan for a career as a chemist, an engineer, a physician, a biologist, and so on. The subject is very large; more than two million organic compounds have been isolated or prepared and characterized, yet the number of guiding principles is relatively small. You certainly will not learn everything about organic chemistry from this textbook, but with a good knowledge of the guiding principles, you will be able later to find out what you need to know from chemical literature.

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Before structures of molecules could be established, there had to be a means of establishing molecular formulas and for this purpose the key concept was Avogadro's hypothesis, which can be stated in the form "equal volumes of gases at the same temperature and pressure contain the same number of molecules". Avogadro's hypothesis allowed assignment of relative molecular weights from measurements of gas densities. Then, with analytical techniques that permit determination of the weight percentages of the various elements in a compound, it became possible to set up a self-consistent set of relative atomic weights. From these and the relative molecular weights, one can assign molecular formulas. For example, if one finds that a compound contains 22.0% carbon (atomic weight = 12.00), 4.6% hydrogen (atomic weight = 1.008), and 73.4% bromine (atomic weight = 79.90), then the ratios of the numbers of atoms are (22.0/12.00):(4.6/1.008):(73.4/79.90)=1.83:4.56:0.92. Dividing each of the last set of numbers by the smallest (0.92) gives 1.99:4.96:1 2 2:5:1, which suggests a molecular formula of C2H5Br, or a multiple thereof. If we know that hydrogen gas is H, and has a molecular weight of 2 X 1.008 = 2.016, we can compare the weight of a given volume of hydrogen with the weight of the same volume of our unknown in the gas phase at the same temperature and pressure. If the experimental ratio of these weights turns out to be 54, then the molecular weight of the unknown would be 2.01 6 x 54 = 109 and the formula C2H5Br would be correct. Valence. In chemistry, the valence or valency of an element is a measure of its combining power with other atoms when it forms chemical compounds or molecules. The concept of valence was developed in the second half of the 19th century and helped successfully explain the molecular structure of inorganic and organic compounds. 6

Valence of a compound represents the connectivity of the elements, with lines drawn between two elements, sometimes called bonds, representing a saturated valency for each element. The tables below show some examples of different compounds, their valence diagrams, and the valences for each element of the compound.

It will be seen that all the above formulas are consistent if hydrogen atoms and bromine atoms form just one bond (are univalent) while carbon atoms form four bonds (are tetravalent). This may seem almost naively simple today, but a considerable period of doubt and uncertainty preceded the acceptance of the idea of definite valences for the elements that emerged about 1852. If we accept hydrogen and bromine as being univalent and carbon as tetravalent, we can write as a structural formula for C2H5Br.

However, we also might have written

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There is a serious problem as to whether these formulas represent the same or different compounds. All that was known in the early days that every purified sample of C2H5Br, no matter how prepared, had a boiling point of 38 °C and density of 1.460 g ml-l. Furthermore, all looked the same, all smelled the same, and all underwent the same chemical reactions. There was no evidence that C2H5Br was a mixture or that more than one compound of this formula could be prepared. One might conclude, therefore, that all of the structural formulas above represent a single substance even though they superficially, at least, look different. Indeed, because HBr and Br-H are two different ways of writing a formula for the same substance, we suspect that the same is true for

There are, though, two of these structures that could be different from one another, namely

In the first of these, CH3- is located opposite the Br- and the H-'s on the carbon with the Br also opposite to one another. In the second formula, CН3- and Br- are located next to each other as are the H-'s on the same carbon. We therefore have a problem as to whether these two different formulas also represent different compounds.

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Generally, organic compounds are formed by covalent bonds among the constituent atoms. Carbon is tetravalent. It contains four electrons in its valence shell. One carbon atom shares its valence electrons with the other carbon to form the covalent bonds. Methane is the simplest organic compound. One carbon atom shares its four electrons with four atoms of hydrogen forming four covalent bonds.

Modern concept of covalent bonding: Now it is assumed that the covalent bond between two atoms is formed due to overlapping of orbitals. The overlapping orbitals should be half filled and the spins of the electrons in the two overlapping orbitals should be opposite. The overlapping can take place by two ways viz. a) end to end overlapping or b) sidewise or parallel or lateral overlapping. End to end overlapping: This type of bond is formed by overlapping of s-s, p-p and s-p orbitals. A sigma molecular orbital is formed by the end to end (or head-to-head) overlap of atomic orbitals along the internuclear axis. The overlap region is maximum in this bonding. The orbital is symmetrical to rotation about the internuclear axis. Sigma molecular orbital forms a strong bond called sigma () bond. 9

Sidewise or parallel or lateral overlapping: This type of bond is formed by overlapping of p-p orbitals. A covalent bond is formed by lateral or sideways or lateral overlapping of pure orbitals known as pi bond. The pi bond is formed by a lateral overlap of two p orbitals mutually oriented parallel but perpendicular to the internuclear axis.

Sigma bonds are significantly stronger than pi bonds. This is because sigma bonds allow for electron density to be concentrated to a much larger degree between the two nuclei. The lowest energy state for an electron electrostatically attracted to both nuclei is between those two nuclei and as close to each nucleus as possible. In a pi bond the p orbitals overlap above and below the atom, localizing the electrons above and below the plane of the bond–a higher energy state compared to the head-on overlap of a sigma bond. You can also conceptualize that pi bonds are weaker simply because we know those electrons are in a higher-energy state. It is universally true that when a bond is higher in energy it will require less energy to break it. 10

A sigma bond is a covalent bond which is formed by the head on overlap of two atomic orbitals. The combination of overlapping orbitals can be s-s, s-pz or pz-pz. Sigma bonding can be a bonding interaction or an antibonding interaction. Bonding interaction results by the overlapping of two atomic orbitals in the same phase whereas antibonding interaction occurs by the overlapping in opposite phase. A Pi bond is a covalent bond which is formed by the side-to-side overlap of two atomic orbitals. The atomic orbital combinations can be px-px or py-py. Similar to the sigma bonding, a pi bond can be bonding or antibonding.

 

Sigma bonds form between two atoms. Pi bonds form from pp orbital overlapping. Explanation of bonding in organic compounds on the basis of hybridization in carbon: Developed by Linus Pauling, the concept of hybrid orbitals was a theory created to explain the structures of molecules in space. The theory consists of combining atomic orbitals (ex: s, p, d, f) into new hybrid orbitals (ex: sp, sp2, sp3). The hybridization model helps explain molecules with double or triple bonds. Distinguish between sigma bond and pi bond: No. 1 1

Sigma Bond

Pi Bond

2 A covalent bond formed by collinear or coaxial i.e. in a line of internuclear axis overlapping of an atomic orbital is known as a sigma bond.

3 The bond is formed by a lateral overlap of two p orbitals oriented mutually parallel but perpendicular to the internuclear axis is called the pi bond.

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1 2 3 4

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6 7

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2 It is stronger as overlapping takes places to a greater extent. Bond energy is more It results in high electron density between two nuclei on internuclear axis The bond is rotationally symmetrical about the internuclear axis It can be formed between any two orbitals i.e. s-s, s-p or p-p etc. It determines the direction of the bond, internuclear distance, and shape of the molecule Pure and hybrid orbitals can form a this bond

3 It is a weak bond because very little overlapping takes place Bond energy is less It results in high electron density above and below the internuclear axis and not on nuclear axis The bond is not rotationally symmetrical about the internuclear axis It can be formed between p orbitals It does not affect the direction of the bond, internuclear distance, and shape of the molecule Only pure orbitals can form a this bond

sp hybrids: Linear Structures: sp hybrids share characteristics evenly between s and p orbitals. The other unhybridized p orbitals remain the same. The front lobes of the sp orbitals point in opposite directions (at 180°). The back lobes also point in opposite directions. A linear structure is created. In general: The overlap of the lobes of atoms creates bonds; large front lobes overlap more completely, resulting in a relatively stronger bond. sp2 hybrids: Trigonal Structures: The small amount of energy needed to promote an electron from the 2s to one of the 2p levels is compensated by bond formation. The three filled atomic orbitals mix to form three sp2 orbitals-each is of 33% s character and 67% p character. The last p orbital stays the same. The front lobes (and their corresponding back lobes) face in opposite directions (at 120° from each other). Electron repulsion therefore creates a trigonal planar geometry. sp3 hybrids: Tetrahedral structures: The 2s orbital is mixed with all three of the 2p orbitals, creating four hybridized sp3 orbitals. Each of these has 25% s and 75% p character; electron repulsion favors a tetrahedral shape, so the orbitals are 109.5° apart from each other. Hybrid orbitals can overlap with any atomic orbital of a different atom to form a bond; this is seen with the substitution of a chlorine atom in place 2pz of a hydrogen atom in methane. 12

They may also contain lone pairs – this explains the geometry of water, which is sp3 hybridized due to the lone pair, which occupies one of the four hybrid orbitals. Again, the bond angle is slightly distorted due to the electron repulsion of this lone pair. Bond angles are distorted because of these changes; typical bond angles of certain hybridization are often increased or decreased due to the relative electronegativities of atoms in a molecule.

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The increasingly large number of organic compounds identified with each passing day, together with the fact that many of these compounds are isomers of other compounds, requires that a systematic nomenclature system be developed. Just as each distinct compound has a unique molecular structure which can be designated by a structural formula, each compound must be given a characteristic and unique name. As organic chemistry grew and developed, many compounds were given trivial names, which are now commonly used and recognized. Some examples are: Name Formula

Methane Butane CH4

Acetone

Toluene Acetylene

C4H10 CH3COCH3 CH3C6H5

C2H2

Ethyl Alcohol C2H5OH

Such common names often have their origin in the history of science and natural sources of specific compounds, but the relationship of these names to each other is arbitrary, and no rational or systematic principles underly their assignments. The rational nomenclature. The name of rational nomenclature received from the Latin ratio – "mind". This system for the first time allowed to give logical names to organic compounds, based on their belonging to one or another class. She replaced the trivial names, which in no way reflected the structural features of their molecules. The new nomenclature, still called radical or functional, began to take the simplest substances in the homologous series of a class as a basis. And the remaining compounds were considered as substituted derivatives of them. Now let see how we can give names to organic compounds by rational nomenclature. The first or second member of the homologous series of the considered class of organic substances is taken as the starting point 14

of the name. The rest of the hydrocarbon skeleton of the molecule is written down as radicals attached to it. The names of the substituents themselves are formed, based on the homologous series of alkanes, replacing the suffixes -an with -yl, for example, methyl, ethyl, etc.. For example, isopropyl, isobutyl. Another common way to show the branching of substituents is the addition of prefixes sec- and tert-. This entry indicates that there is a free valence at the secondary or tertiary carbon atom. If the free valence is at the end of the unbranched residue of the molecule, then the letter n is added (from the word “normal”), but in fact it is rarely recorded. The IUPAC Systematic nomenclature. A rational nomenclature system should do at least two things. First, it should indicate how the carbon atoms of a given compound are bonded together in a characteristic lattice of chains and rings. Second, it should identify and locate any functional groups present in the compound. Since hydrogen is such a common component of organic compounds, its amount and locations can be assumed from the tetravalency of carbon, and need not be specified in most cases. The IUPAC nomenclature system is a set of logical rules devised and used by organic chemists to circumvent problems caused by arbitrary nomenclature. Knowing these rules and given a structural formula, one should be able to write a unique name for every distinct compound. Likewise, given a IUPAC name, one should be able to write a structural formula. In general, an IUPAC name will have three essential features: • A root or base indicating a major chain or ring of carbon atoms found in the molecular structure. • A suffix or other element(s) designating functional groups that may be present in the compound. • Names of substituent groups, other than hydrogen, that complete the molecular structure. As an introduction to the IUPAC nomenclature system, we shall first consider compounds that have no specific functional groups. Such compounds are composed only of carbon and hydrogen atoms bonded together by sigma bonds (all carbons are sp3 hybridized).

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When we discuss organic compounds, we will focus on differences in how the functional groups were connected to the carbon framework. Differences in connectivity resulted in different chemical compounds with different names. We will learn, for example, that although 1-propanol (n-propanol) and 2-propanol (isopropanol) have the same molecular formula (C3H8O), they have different physical and chemical properties. Just as with metal complexes, compounds that have the same molecular formula but different arrangements of atoms are called isomers. Now, we describe various types of isomers, beginning with those whose three-dimensional structures differ only as the result of rotation about a C–C bond. Conformational Isomers. The C–C single bonds in ethane, propane, and other alkanes are formed by the overlap of an sp3 hybrid orbital on one carbon atom with an sp3 hybrid orbital on another carbon atom, forming a σ bond (Figure 1). Each sp3 hybrid orbital is cylindrically symmetrical (all cross-sections are circles), resulting in a carbon-carbon single bond that is also cylindrically symmetrical about the C–C axis. Because rotation about the carbon–carbon single bond can occur without changing the overlap of the sp3 hybrid orbitals, there is no significant electronic energy barrier to rotation. Consequently, many different arrangements of the atoms are possible, each corresponding to different degrees of rotation. Differences in three-dimensional structure resulting from rotation about a σ bond are called differences in conformation, and each different arrangement is called a conformational isomer (or conformer). The simplest alkane to have a conformational isomer is ethane. Differences between the conformations of ethane are depicted especially clearly in drawings called Newman projections, such as those shown in part (a) in Figure 2. In a Newman projection, the ethane molecule is viewed along the C–C axis, with the carbon that is in 16

front shown as a vertex and the carbon that is in back shown as a circle.

Figure 1. Carbon–Carbon Bonding in Alkanes. Overlapping sp3 hybrid orbitals on adjacent carbon atoms forms a cylindrically symmetrical σ bond. Because rotation about the bond does not affect the overlap of the bonding orbitals, there is no electronic energy barrier to rotation

The three hydrogen atoms nearest to the viewer are shown bonded to the front carbon, and the three hydrogen atoms farthest from the viewer are shown bonded to the circle. In one extreme, called the eclipsed conformation, the C–H bonds on adjacent carbon atoms lie in the same plane.

Figure 2. Eclipsed and Staggered Conformations of Ethane. (a) In a Newman projection, the molecule is viewed along a C–C axis. The carbon in front is represented as a vertex, whereas the carbon that is bonded to it is represented as a circle. In ethane, the C–H bonds to each carbon are positioned at 120° from each other. In the fully eclipsed conformation, the C–H bonds on adjacent carbon atoms are parallel and lie in the same plane. In the staggered conformation, the hydrogen atoms are positioned as far apart as possible. (b) The eclipsed conformation is 12.6 kJ/mol higher in energy than the staggered conformation because of electrostatic repulsion between the hydrogen atoms. An infinite number of conformations of intermediate energy exists between the two extremes

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In the other extreme, called the staggered conformation, the hydrogen atoms are positioned as far from one another as possible. Rotation about the C–C bond produces an infinite number of conformations between these two extremes, but the staggered conformation is the most stable because it minimizes electrostatic repulsion between the hydrogen atoms on adjacent carbons. In a Newman projection, the angles between adjacent C–H bonds on the same carbon are drawn at 120°, although H–C–H angles in alkanes are actually tetrahedral angles of 109.5°, which for chains of more than three carbon atoms results in a kinked structure. Despite this three-dimensional inaccuracy, Newman projections are useful for predicting the relative stability of conformational isomers. As shown in part (b) in Figure 2, the higher energy of the eclipsed conformation represents an energy barrier of 12.6 kJ/mol that must be overcome for rotation about the C–C bond to occur. This barrier is so low, however, that rotation about the C–C bond in ethane is very fast at room temperature and occurs several million times per second for each molecule. Structural Isomers. Unlike conformational isomers, which do not differ in connectivity, structural isomers differ in connectivity, as illustrated here for 1-propanol and 2-propanol. Although these two alcohols have the same molecular formula (C3H8O), the position of the –OH group differs, which leads to differences in their physical and chemical properties.

In the conversion of one structural isomer to another, at least one bond must be broken and reformed at a different position in the molecule. Consider, for example, the following five structures represented by the formula C5H12: 18

Of these structures, (a) and (d) represent the same compound, as do (b) and (c). No bonds have been broken and reformed; the molecules are simply rotated about a 180° vertical axis. Only three–n-pentane (a) and (d), 2-methylbutane (b) and (c), and 2,2-dimethylpropane (e)–are structural isomers. Because no bonds are broken in going from (a) to (d) or from (b) to (c), these alternative representations are not structural isomers. The three structural isomers–either (a) or (d), either (b) or (c), and (e)–have distinct physical and chemical properties. Stereoisomers. Molecules with the same connectivity but different arrangements of the atoms in space are called stereoisomers. There are two types of stereoisomers: geometric and optical. Geometric isomers differ in the relative positions of substituents in a rigid molecule. Simple rotation about a C–C σ bond in an alkene, for example, cannot occur because of the presence of the π bond. The substituents are therefore rigidly locked into a particular spatial arrangement (part (a) in Figure 3). Thus a carbon-carbon multiple bond, or in some cases a ring, prevents one geometric isomer from being readily converted to the other. The members of an isomeric pair are identified as either cis or trans, and interconversion between the two forms requires breaking and reforming one or more bonds. Because their structural difference causes them to have different physical and chemical properties, cis and trans isomers are actually two distinct chemical compounds. Optical isomers are molecules whose structures are mirror images but cannot be superimposed on one another in any orientation. Optical isomers have identical physical properties, although their 19

chemical properties may differ in asymmetric environments. Molecules that are nonsuperimposable mirror images of each other are said to be chiral (pronounced “ky-ral,” from the Greek cheir, meaning “hand”). Examples of some familiar chiral objects are your hands, feet, and ears. As shown in part (a) in Figure 3, your left and right hands are nonsuperimposable mirror images. (Try putting your right shoe on your left foot-it just doesn’t work). An achiral object is one that can be superimposed on its mirror image, as shown by the superimposed flasks in part (b) in Figure 3.

Figure 3. Chiral and Achiral Objects. (a) Objects that are nonsuperimposable mirror images of each other are chiral, such as the left and the right hand. (b) The unmarked flask is achiral because it can be superimposed on its mirror image

Most chiral organic molecules have at least one carbon atom that is bonded to four different groups, as occurs in the bromochlorofluoromethane molecule shown in part (a) in Figure 4. This carbon, often designated by an asterisk in structural drawings, is called a chiral center or asymmetric carbon atom. If the bromine atom is replaced by another chlorine (part (b) in Figure 4), the molecule and its mirror image can now be superimposed by simple rotation. Thus the carbon is no longer a chiral center. 20

In both types of stereoisomer-geometric and optical-isomeric molecules have identical connectivity, but the arrangement of atoms in space differs. Cis and trans isomers exhibit different physical and chemical properties, whereas enantiomers differ only in their interaction with plane-polarized light and reactions in asymmetric environments. Depending on the direction in which they rotate polarized light, enantiomers are identified as (+) or (−). The designations Land D- represent an alternative labeling system.  Isomers can be conformational or structural.  Stereoisomers have the same connectivity but can be optical or geometric isomers.

Figure 4. Comparison of Chiral and Achiral Molecules. (a) Bromochlorofluoromethane is a chiral molecule whose stereocenter is designated with an asterisk. Rotation of its mirror image does not generate the original structure. To superimpose the mirror images, bonds must be broken and reformed. (b) In contrast, dichlorofluoromethane and its mirror image can be rotated so they are superimposable

The categories of stereoisomers are summarized in Figure 5. Isomers are different compounds that have the same molecular formula. For an organic compound, rotation about a σ bond can produce different three-dimensional structures called conformational isomers (or conformers). 21

Figure 5. Classification of Stereoisomers

In a Newman projection, which represents the view along a C–C axis, the eclipsed conformation has the C–H bonds on adjacent carbon atoms parallel to each other and in the same plane, representing one conformational extreme. In the staggered conformation, the opposite extreme, the hydrogen atoms are as far from one another as possible. Electrostatic repulsions are minimized in the staggered conformation. Structural isomers differ in the connectivity of the atoms. Structures that have the same connectivity but whose components differ in their orientations in space are called stereoisomers. Stereoisomers can be geometric isomers, which differ in the placement of substituents in a rigid molecule, or optical isomers, nonsuperimposable mirror images. Molecules that are nonsuperimposable mirror images are chiral molecules. A molecule and its nonsuperimposable mirror image are called enantiomers. These differ in their interaction with plane-polarized light, light that oscillates in only one direction. A compound is optically active if its solution rotates plane-polarized light in only one direction and optically inactive if its rotations cancel to produce no net rotation. A clockwise rotation is called dextrorotatory and is indicated in the compound’s name by (+), whereas a counterclockwise rotation is called levorotatory, designated by (−). The specific rotation is the amount (in degrees) by which the plane of polarized light is rotated when light is passed through a solution containing 1.0 g of solute per 1.0 mL of solvent in a tube 10.0 cm long. A solution that contains equal concentrations of each enantiomer in a pair is a racemic mixture; such solutions are optically inactive. 22

Acid and base properties of organic compounds are the same as the properties of inorganic acids and bases. Organic acids and bases are all weak acids and bases, however, there are strong and weak inorganic acids and bases. Organic acids and bases, thus don’t exhibit the properties strongly. Organic Acids. Organic acids are, in general, weak acids. That is, they do not ionize nearly completely in weak aqueous solutions. Some inorganic acids (also known as mineral acids) are strong acids. That is, they ionize nearly completely in weak aqueous solutions. Some common strong mineral acids are hydrochloric acid, sulfuric acid, and nitric acid. The acid properties listed above are ‘stronger’ or more noticeable for the strong mineral acids than for the weak organic acids. Strong acids (in aqueous solution) will have a pH much lower than 7, will produce many hydrogen ions, and will be very corrosive to the skin. Weak organic acids, on the other hand, will have a pH closer to 7 than a strong acid; will produce some hydrogen ions when dissolved in water, but not as many as a strong acid; and will not be as corrosive to the skin as a strong acid.

Most common organic acids contain a carboxyl group, usually written as – COOH. The structure of the carboxyl group is shown in the diagram at the left. The hydrogen-oxygen bond in the OH is the weakest bond in the carboxyl group, so Hydrogen ions are released from carboxyl 23

 containing organic acids when they are dissolved in water. One of the simpler organic acids is acetic acid (vinegar) with the formula: CH3COOH (or C2 H4O2). An expanded version of the formula, showing the carboxyl group is shown in the diagram at the right. Some other common organic acids are:  propionic acid – CH3CH2COOH (or C3H6O2)  lactic acid – CH3CH(OH)COOH (or C3H6O3)  formic acid – HCOOH (or CH2O2)  oxalic acid – COOHCOOH (or H2C2O4)  citric acid – COOHCH2C(OH)COOHCH2COOH (or C6H8O7) The formulas for each of these organic acids are shown first in a format that emphasizes the functional groups (including COOH at least once in each of them) and then in the more compact, less descriptive format that you will often see. Organic Bases. Organic bases typically do not ionize nearly completely in weak aqueous solutions, so they are classified as weak bases. This is in contrast to strong bases like sodium hydroxide or potassium hydroxide, which do ionize nearly completely in weak aqueous solutions. Just as with the weak and strong acids, the weak organic bases don’t exhibit the properties of bases as ‘strongly’ as strong bases. Organic bases exhibit their basic behavior by having an attraction for hydrogen ions, usually through one or more nitrogen atoms in the molecule. Some common organic bases are:  methyl amine – CH3NH2 (or CH5N)  pyridine – C5H5N  imidazole – C3H4N2  glycine – C2H5NO2 Acid and base properties of organic compounds are much the same as the properties of inorganic acids and bases. There are both strong and weak inorganic acids and bases, however, organic acids and bases are universally weak acids and weak bases. Thus the inorganic acids and bases don’t exhibit the acid and base properties as ‘strongly’ as the strong mineral acids and inorganic bases. 24

An aliphatic compound is an organic compound containing carbon and hydrogen joined together in straight chains, branched chains, or non-aromatic rings. It is one of two broad classes of hydrocarbons, the other being aromatic compounds. These are compounds where the functional group is notattached directly to a benzene ring. Open-chain compounds that contain no rings are aliphatic, whether they contain single, double, or triple bonds. In other words, they may be saturated or unsaturated. Some aliphatics are cyclic molecules, but their rings are not as stable as those of aromatic compounds. While hydrogen atoms are most commonly bound to the carbon chain, oxygen, nitrogen, sulfur, or chlorine atoms might also be present.

6.1. ALKANES Alkanes are organic compounds that consist entirely of singlebonded carbon and hydrogen atoms and lack any other functional groups. Alkanes have the general formula CnH2n+2 and can be subdivided into the following three groups: the linear straight-chain alkanes, branched alkanes, and cycloalkanes. Alkanes are also saturated hydrocarbons. Alkanes are the simplest and least reactive hydrocarbon species containing only carbons and hydrogens. They are commercially very important, being the principal constituent of gasoline and lubricating oils and are extensively employed in organic chemistry; though the role of pure alkanes (such as hexanes) is delegated mostly to solvents. The distinguishing feature of an alkane, making it distinct from other compounds that also exclusively contain carbon and hydrogen, is its lack of unsaturation. That is to say, it contains no double or triple bonds, which are highly reactive 25

in organic chemistry. Though not totally devoid of reactivity, their lack of reactivity under most laboratory conditions makes them a relatively uninteresting, though very important component of organic chemistry. As you will learn about later, the energy confined within the carbon-carbon bond and the carbon-hydrogen bond is quite high and their rapid oxidation produces a large amount of heat, typically in the form of fire. Nomenclature of alkanes. The names of all alkanes end with ane. Whether or not the carbons are linked together end-to-end in a ring (called cyclic alkanes or cycloalkanes) or whether they contain side chains and branches, the name of every carbon-hydrogen chain that lacks any double bonds or functional groups will end with the suffix -ane. Alkanes with unbranched carbon chains are simply named by the number of carbons in the chain. The first four members of the series (in terms of number of carbon atoms) are named as follows: 1. CH4 = methane = one hydrogen-saturated carbon 2. C2H6 = ethane = two hydrogen-saturated carbons 3. C3H8 = propane = three hydrogen-saturated carbons 4. C4H10 = butane = four hydrogen-saturated carbons Alkanes with five or more carbon atoms are named by adding the suffix -ane to the appropriate numerical multiplier, except the terminal -a is removed from the basic numerical term. Hence, C5H12 is called pentane, C6H14 is called hexane, C7H16 is called heptane and so forth. Straight-chain alkanes are sometimes indicated by the prefix n(for normal) to distinguish them from branched-chain alkanes having the same number of carbon atoms. Although this is not strictly necessary, the usage is still common in cases where there is an important difference in properties between the straight-chain and branchedchain isomers: e.g. n-hexane is a neurotoxin while its branched-chain isomers are not. As we explain in previously the simplified IUPAC rules for naming alkanes are as follows. 1. Name alkanes according to the LCC (longest continuous chain) of carbon atoms in the molecule (rather than the total number of carbon atoms). This LCC, considered the parent chain, determines 26

the base name, to which we add the suffix -ane to indicate that the molecule is an alkane. 2. If the hydrocarbon is branched, number the carbon atoms of the LCC. Numbers are assigned in the direction that gives the lowest numbers to the carbon atoms with attached substituents. Hyphens are used to separate numbers from the names of substituents; commas separate numbers from each other. (The LCC need not be written in a straight line; for example, the LCC in the following has five carbon atoms).

3. Place the names of the substituent groups in alphabetical order before the name of the parent compound. If the same alkyl group appears more than once, the numbers of all the carbon atoms to which it is attached are expressed. If the same group appears more than once on the same carbon atom, the number of that carbon atom is repeated as many times as the group appears. Moreover, the number of identical groups is indicated by the Greek prefixes di-, tri-, tetra-, and so on. These prefixes are not considered in determining the alphabetical order of the substituents. For example, ethyl is listed before dimethyl; the di- is simply ignored. The last alkyl group named is prefixed to the name of the parent alkane to form one word. When these rules are followed, every unique compound receives its own exclusive name. The rules enable us not only to name a compound from a given structure but also to draw a structure from a given name. The best way to learn how to use the IUPAC system is to put it to work, not just memorize the rules. It’s easier than it looks. Drawing Hydrocarbons. Recall that when carbon makes four bonds, it adopts the tetrahedral geometry. In the tetrahedral geometry, only two bonds can occupy a plane simultaneously. The other two bonds point in back or in front of this plane. In order to represent the tetrahedral geometry in two dimensions, solid wedges are used to represent bonds pointing out of the plane of the drawing toward the viewer, and dashed wedges are used to represent bonds pointing out 27

of the plane of the drawing away from the viewer. Consider the following representation of the molecule methane:

Two dimensional representation of methane

In the above drawing, the two hydrogens connected by solid lines, as well as the carbon in the center of the molecule, exist in a plane (specifically, the plane of the computer monitor/piece of paper, etc.). The hydrogen connected by a solid wedge points out of this plane toward the viewer, and the hydrogen connected by the dashed wedge points behind this plane and away from the viewer. In drawing hydrocarbons, it can be time-consuming to write out each atom and bond individually. In organic chemistry, hydrocarbons can be represented in a shorthand notation called a skeletal structure. In a skeletal structure, only the bonds between carbon atoms are represented. Individual carbon and hydrogen atoms are not drawn, and bonds to hydrogen are not drawn. In the case that the molecule contains just single bonds (sp3 bonds), these bonds are drawn in a "zig-zag" fashion (A zigzag is a pattern made up of small corners at variable angles, though constant within the zigzag, tracing a path between two parallel lines; it can be described as both jagged and fairly regular). This is because in the tetrahedral geometry all bonds point as far away from each other as possible, and the structure is not linear. Consider the following representations of the molecule propane:

Full structure of propane and skeletal structure of propane

Only the bonds between carbons have been drawn, and these have been drawn in a "zig-zag" manner. Note that there is no repre28

sentation of hydrogens in a skeletal structure. Since, in the absence of double or triple bonds, carbon makes four bonds total, the presence of hydrogens is implicit. Whenever an insufficient number of bonds to a carbon atom is specified in the structure, it is assumed that the rest of the bonds are made to hydrogens. For example, if the carbon atom makes only one explicit bond, there are three hydrogens implicitly attached to it. If it makes two explicit bonds, there are two hydrogens implicitly attached, etc. Note also that two lines are sufficient to represent three carbon atoms. It is the bonds only that are being drawn out, and it is understood that there are carbon atoms (with three hydrogens attached!) at the terminal ends of the structure. Alkyl Groups. Alkanes can be described by the general formula CnH2n+2. An alkyl group is formed by removing one hydrogen from the alkane chain and is described by the formula CnH2n+1. The removal of this hydrogen results in a stem change from -ane to -yl. Take a look at the following examples.

The same concept can be applied to any of the straight chain alkane names provided in the table below (Table 1). Table 1 Simple Alkyl Groups Alkyl Group

Formula

Methyl

CH3–

Ethyl

CH3CH2–

Propyl

CH3CH2CH2–

Butyl

CH3CH2CH2CH2–

Pentyl

CH3CH2CH2CH2CH2–

29

Using common names with alkanes. Certain branched alkanes have common names that are still widely used today. These common names make use of prefixes, such as iso-, sec-, tert-, and neo-. The prefix iso-, which stands for isomer, is commonly given to 2-methyl alkanes. In other words, if there is a methyl group located on the second carbon of a carbon chain, we can use the prefix iso-. The prefix will be placed in front of the alkane name that indicates the total number of carbons. Examples:  isopentane which is the same as 2-methylbutane  isobutane which is the same as 2-methylpropane To assign the prefixes sec-, which stands for secondary, and tert, for tertiary, it is important that we first learn how to classify carbon molecules. If a carbon is attached to only one other carbon, it is called a primary carbon. If a carbon is attached to two other carbons, it is called a secondary carbon. A tertiary carbon is attached to three other carbons and last, a quaternary carbon is attached to four other carbons. Examples:  4-sec-butylheptane  4-tert-butyl-5-isopropylhexane; if using this example, may want to move sec/tert after iso disc The prefix neo- refers to a substituent whose second-to-last carbon of the chain is trisubstituted (has three methyl groups attached to it). A neo-pentyl has five carbons total. Examples:  neopentane  neoheptane Alkoxy Groups. Alkoxides consist of an organic group bonded to a negatively charged oxygen atom. In the general form, alkoxides are written as RO-, where R represents the organic substituent. Similar to the alkyl groups above, the concept of naming alkoxides can be applied to any of the straight chain alkanes provided in the table above.

Three Principles of Naming. 1. Choose the longest, most substituted carbon chain containing a functional group. 30

2. A carbon bonded to a functional group must have the lowest possible carbon number. If there are no functional groups, then any substitute present must have the lowest possible number. 3. Take the alphabetical order into consideration; that is, after applying the first two rules given above, make sure that your substitutes and/or functional groups are written in alphabetical order. The simplest example of a homologous series in organic chemistry is shown in table 2. Table 2 The homologous series of organic componds Name Methane Ethane Propane Butane Pentane Hexane Heptane Octane Nonane Decane Undecane Dodecane Tridecane Tetradecane Pentadecane Hexadecane Heptadecane Octadecane Nonadecane Eicosane

Molecular Formula CH4 C2H6 C3H8 C4H10 C5H12 C6H14 C7H16 C8H18 C9H20 C10H22 C11H24 C12H26 C13H28 C14H30 C15H32 C16H34 C17H36 C18H38 C19H40 C20H42

Condensed Structural Formula CH4 CH3CH3 CH3CH2CH3 CH3(CH2)2CH3 CH3(CH2)3CH3 CH3(CH2)4CH3 CH3(CH2)5CH3 CH3(CH2)6CH3 CH3(CH2)7CH3 CH3(CH2)8CH3 CH3(CH2)9CH3 CH3(CH2)10CH3 CH3(CH2)11CH3 CH3(CH2)12CH3 CH3(CH2)13CH3 CH3(CH2)14CH3 CH3(CH2)15CH3 CH3(CH2)16CH3 CH3(CH2)17CH3 CH3(CH2)18CH3

Physical properties of alkane. The concept of homology. The series of straight-chain alkanes, in which n is the number of carbons in the chain, shows a remarkably smooth gradation of physical properties (Table 3). As n increases, each additional CH, group contributes a fairly constant increment to the boiling point and density, and to a lesser extent to the melting point. This makes it possible to 31

estimate the properties of an unknown member of the series from those of its neighbors. For example, the boiling points of hexane and heptane are 69" and 98", respectively. Thus a difference in the structure of one CH group for these compounds makes a difference in the boiling point of 29"; we would predict the boiling point of the next higher member, octane, to be 98" + 29" = 127", which is close to the actual boiling point of 126". Table 3 The physical properties of alkane

Members of a group of compounds, such as the alkanes, that have similar chemical structures and graded physical properties, and which differ from one another by the number of atoms in the structural backbone, are said to constitute a homologous series. Homology can hardly be overestimated as a practical aid for the organic chemist to cope with the large numbers of compounds with which it works. In the simplest approximation, the members of a homologous series are assumed to have essentially the same pro32

perties, except for increases in the boiling point and melting point for alkanes. This generally will be true, except when the number of carbons is small and when the hydrocarbon chain has polar substituents. To explain briefly, consider compounds such as alcohols, ROH, which have polar O–H groups. Polarity causes molecules to associate with one another, which decreases their volatility, raises melting points, increases solubility in polar liquids, and decreases solubility in nonpolar liquids. This explains why methanol, CH3OH, is much less volatile and much more water-soluble than methane, CH4. But we find that the water-solubility of alcohols falls off rapidly with the length of the carbon chain, certainly faster than expected for a simple homologous series effect. Whereas methanol, CH3OH, and ethanol, CH3CH2OH, ary completely soluble in water, butanol, CH3CH2CH2CH2OH, is only slightly soluble. This illustrates the conflicting properties conferred on molecules by polar groups compared to nonpolar hydrocarbon groups, and points up that large changes in physical properties can be expected in the early part of a homologous series until the hydrocarbon chain is sufficiently long, usually six or more carbons, so that the hydrocarbon parts dominate over the polar parts of the molecules. Chemical properties and reactions of alkanes. Alkanes generally show low reactivity, because their C-C bonds are stable and cannot be easily broken. As they are inert against ionic or other polar substances they are also called "paraffins" (Latin "para + affinis" = = "lacking affinity"). Gaseous alkanes are explosive when mixed with air, the liquid alkanes are highly flammable. The most common reactions occuring with alkanes are reactions involving free radicals (combustion, substitution cracking, and reformation). Reactions with oxygen. All alkanes react with oxygen in a combustion reaction. The general equation for complete combustion is: 2 CnH2n+2 + (3n+1) O2 2(n+1) H2O + 2n CO2 In the absence of sufficient oxygen, carbon monoxide and/or soot can be formed, as shown, for example, for methane: 2CH4 +3O2 CH4 + O2

2CO+4H2O C + 2 H2O 33

Reactions with halogens. The halogenation reactions of alkanes are quite different, depending on the involved halogen. While flourine reacts explosively with alkanes and can hardly be controlled, chlorine and bromine react satisfactorily (bromine much slower than chlorine), and iodine is unreactive. The calculated heats of reaction for the halogenation of hydrocarbons are (kcal/mol): fluorine -116 chlorine -27 bromine -10 iodine

+13

Free halogen radicals are the reactive species and usually lead to a mixture of products. For chlorine and bromine the free radicals have to be created by light and UV radiation, respectively. The fluorination is difficult to control; the only successful direct fluorination of liquid or solid alkanes is performed at low temperatures (on dry ice, -78°C) with highly diluted fluorine (in helium). This procedure yields completely fluorinated compounds. The chlorination of alkanes is a three step process which leads to a mixtue of products. It is shown for the chlorination of methane as an example: 1. Initiation: splitting a chlorine molecule into two chlorine atoms with unpaired electrons (free radical). This step is initiated by ultraviolet radiation (thus chlorination of alkanes does not occur in the dark): 2 Cl·

Cl2

2. Propagation: a hydrogen atom is pulled off from methane resulting in a methyl radical. Then the methyl radical pulls a chlorine atom from the Cl2 molecule, leaving the other chlorine radical. CH4 + Cl· CH3· + Cl2

CH3· + HCl CH3Cl + Cl· 34

This results in the chlorinated product. This created radical will then go on to take part in another propagation reaction causing a chain reaction. 3. Termination: the chain reaction stops if two free radicals recombine: Cl· + Cl· CH3· + Cl· CH3· + CH3·

Cl2 CH3Cl C2H6

Methane and ethane yield randomly distributed products since all hydrogen atoms are equivalent, having an equal chance of being replaced. In higher alkanes the hydrogen atoms of CH2 or CH groups are preferentially replaced. Bromination, though similar to chlorination, occurs rapidly. Iodination is extremely slow and is reversible in nature. Fluorination of alkanes takes place with almost violence to produce fluorinated compounds. It also involves rupture of some C-C bonds in case of higher alkanes. Reaction can be made less violent by dilution of fluorine nitrogen. Sulphonation. Alkanes containing six or more carbon atoms on heating with fuming tetraoxosulphate (VI) acid for several hours yield the corresponding sulphonic acids. Oxidation. Alkanes on burning in air or oxygen get completely oxidised to carbon (IV) oxide and water with emission of a large amount of heat. CH4 + 2O2  CO2 + 2H2O + Heat C4H10 + 13/2 O2 4CO2 + 5H2O +Heat Due to emission of a large amount of heat, during combustion, alkanes are used as fuels. The general chemical equation for combustion of alkanes may be written as:

35

In the presence of insufficient supply of oxygen, alkanes on combustion produce carbon (IV) oxide, which is highly poisonous. Carbon (IV) oxide combines with haemoglobin in the blood to form carboxy haemoglobin and makes it unfit for carrying oxygen. As a result, the person may die due to suffocation. Isomerisation. In this process, n-alkanes on heating with anhydrous aluminium chloride and hydrogen chloride get converted into branched chain alkanes.

Cracking or phyrolisis. Cracking, the most important process for the commercial production of gasoline, breaks up heavy alkane molecules into lighter ones by means of heat and/or pressure and/or catalysts. It yields gasoline and gases such as methane, ethane, ethylene, and propane. The thermal cracking process follows a homolytic mechanism forming (symmetric) pairs of free radicals, whereas the catalytic cracking follows a heterolytic (assymetric) breakage of bonds, resulting in ions (carbocations and hydride ions). The catalysts involved are solid acids, such as silica-alumina and zeolites. As free radicals and carbocations are highly unstable, they quickly undergo C-C cleavage, chain rearrangements and hydrogen transfer. 36

It is a process of decomposing higher hydrocarbons into lower hydrocarbons with low boiling points by strong heating. The process involves the cleavage of carbon-carbon and carbon-hydrogen bonds and results in the formation of lower hydrocarbons and is believed to be a free radical reaction. The types of hydrocarbons formed depend upon the conditions employed for cracking. For example,

Oil gas or petrol gas is prepared by pyrolysis of kerosene oil or petrol. Similarly, gasoline can be prepared by pyrolysis of kerosene oil or fuel oil. For example, dodecane, a constituent of kerosene oil, on heating to 973 K in the presence of platinum, palladium or nickel, gives a mixture of heptane and pentane.

Reforming. Catalytic reforming is used in the petroleum industry to create alicyclic and aromatic compounds from the C6-C10 gasoline fraction. Reforming is based on the heating of alkanes with hydrogen in the presence of catalysts. This finally results in aromatic compounds such as benzene, toluene, and xylenes which form the basis of a whole chemical industry. The IUPAC names of the first five members of this series are given in the following table. The last (yellow shaded) column gives the general formula for a cycloalkane of any size. If a simple unbranched alkane is converted to a cycloalkane, two hydrogen atoms, one from each end of the chain, must be lost. Hence the general formula for a cycloalkane composed of n carbons is CnH2n (table 4). Substituted cycloalkanes are named in a fashion very similar to that used for naming branched alkanes. The chief difference in the rules and procedures occurs in the numbering system. Since all the carbons of a ring are equivalent (a ring has no ends like a chain does), the numbering starts at a substituted ring atom. 37

Table 4 Examples of Simple Cycloalkanes Cyclopropane C3H6 Molecular Formula Structural Formula Name

Cyclobutane C4H8

Cyclopentane C5H10

Cyclohexane C6H12

Cycloheptane C7H14

Cycloalkane CnH2n (CH2)n

Line Formula

IUPAC rules for cycloalkane nomenclature. For a monosubstituted cycloalkane the ring supplies the root name (table above) and the substituent group is named as usual. A location number is unnecessary. If the alkyl sustituent is large and/or complex, the ring may be named as a substituent group on an alkane. 1. If two different substituents are present on the ring, they are listed in alphabetical order, and the first cited substituent is assigned to carbon No.1. The numbering of ring carbons then continues in the direction (clockwise or counter-clockwise) that affords the second substituent the lower possible location number. 2. If several substituents are present on the ring, they are listed in alphabetical order. Location numbers are assigned to the substituents so that one of them is at carbon No.1 and the other locations have the lowest possible numbers, counting in either a clockwise or counter-clockwise direction. 3. The name is assembled, listing groups in alphabetical order and giving each group (if there are two or more) a location number. The prefixes di, tri, tetra etc., used to designate several groups of the same kind, are not considered when alphabetizing. 4. Small rings, such as three and four membered rings, have significant angle strain resulting from the distortion of the sp3 carbon bond angles from the ideal 109.5° to 60° and 90°, respectively. This angle strain often enhances the chemical reactivity of such compounds, leading to ring cleavage products. It is also important to recognize that, with the exception of cyclopropane, cycloalkyl rings 38

are not planar (flat). The three dimensional shapes assumed by the common rings (especially cyclohexane and larger rings) are described and discussed in the Conformational Analysis Section. Configurational stereoisomers of cycloalkanes. Remember, when the group of atoms that make up the molecules of different isomers is bonded together in fundamentally different ways, we refer to such compounds as constitutional isomers. For example, in the case of C5H10 hydrocarbons, most of the isomers are constitutional. Shorthand structures for five of these isomers are shown below with their IUPAC names.

Note that the fifteen atoms that make up these isomers are connected or bonded in very different ways. As is true for all constitutional isomers, each different compound has a different IUPAC name. Furthermore, the molecular formula provides information about some of the structural features that must be present in the isomers (e.g. a ring or a double bond). Among the formulas of the four monocyclic isomers shown here, the last does not unambiguously designate a single unique compound. Two isomers having the constitution of 1,2-dimethylcyclopropane exist; their properties, together with those of the 1,1-dimethyl isomer are listed in the down. Isomer

boiling pt.

Density

1,1-dimethylcyclopropane

20 °C

0.662

1,2-dimethyl–isomer A

37 °C

0.694

1,2-dimethyl–isomer B

28 °C

0.669

To understand the origin of this isomerism it is necessary to think three-dimensionally, and to consider the orientation or configuration of the atoms and groups in space. The three carbons of the 39

cyclopropane ring define a plane, and the substituent atoms or groups bonded to these carbon atoms are directed in space above and below this plane. In the case of the 1,2-dimethyl isomers, the two methyl groups may lie on the same side of the ring, called a cis configuretion, or on opposite sides, a trans configuration, as shown in the following diagram. From the evidence that will not be described here, isomer A has the cis configuration, and isomer B the trans configuration. This configurational isomerism is commonly called stereoisomerization.

Drawing and naming cycloalkane stereoisomers. Stereoisomers are often found in disubstituted (and higher substituted) cyclic compounds.

Chemists use heavy, wedge-shaped bonds to indicate a substituent located above the average plane of the ring (note that cycloalkanes larger than three carbons are not planar), and a hatched line for bonds to atoms or groups located below the average ring plane. As noted above, disubstituted cycloalkane stereoisomers may be 40

designated by the nomenclature prefix cis, if the substituents are bonded on the same side of the ring, or trans for substituents oriented on opposite sides of the ring. The stereoisomeric 1,2-dibromocyclopentanes shown to the right are an example. In general, if any two sp3 carbons in a ring have two different substituent groups (not counting other ring atoms) stereoisomerism is possible. Four other examples of this kind of sterioisomerism in cyclic compounds are shown below. Ring conformations. Although the customary line drawings of simple cycloalkanes are geometrical polygons, the actual shape of these compounds in most cases is very different.

Cyclopropane is necessarily planar (flat), with the carbon atoms at the angles of an equilateral triangle. The 60° bond angles are much smaller than the optimum 109.5° angles of a normal tetrahedral carbon atom, and the resulting angle strain dramatically influences the chemical behavior of this cycloalkane. Cyclopropane also suffers substantial eclipsing strain, since all the carbon-carbon bonds are fully eclipsed. Cyclobutane reduces some bond-eclipsing strain by 41

folding (the out-of-plane dihedral angle is about 25°), but the total eclipsing and angle strain remain high. Cyclopentane has very little angle strain (the angles of a pentagon are 108°), but its eclipsing strain would be large (about 10 kcal/mol) if it remained planar. Consequently, the five-membered ring adopts non-planar puckered conformations whenever possible. Rings larger than cyclopentane would have angle strain if they were planar. However, this strain, together with the eclipsing strain inherent in a planar structure, can be relieved by puckering the ring. Cyclohexane is a good example of a carbocyclic system that virtually eliminates eclipsing and angle strain by adopting non-planar conformations, such as those shown below. Cycloheptane and cyclooctane have greater strain than cyclohexane, in large part due to transannular crowding (steric hindrance by groups on opposite sides of the ring). Some conformations of cyclohexane rings

A planar structure for cyclohexane is clearly improbable. The bond angles would necessarily be 120°, 10.5° larger than the ideal tetrahedral angle. Also, every carbon-carbon bond in such a structure 42

would be eclipsed. The resulting angle and eclipsing strains would severely destabilize this structure. If two carbon atoms on opposite sides of the six-membered ring are lifted out of the plane of the ring, much of the angle strain can be eliminated. This boat structure still has two eclipsed bonds (colored magenta in the drawing) and severe steric crowding of two hydrogen atoms on the "bow" and "stern" of the boat. This steric crowding is often called steric hindrance. By twisting the boat conformation, the steric hindrance can be partially relieved, but the twist-boat conformer still retains some of the strains that characterize the boat conformer. Finally, by lifting one carbon atom above the ring plane and the other below the plane, a relatively strain-free chair conformer is formed. This is the predominant structure adopted by molecules of cyclohexane. Hydrocarbons having more than one ring are common, and are referred to as bicyclic (two rings), tricyclic (three rings) and in general, polycyclic compounds. The molecular formulas of such compounds have H/C ratios that decrease with the number of rings. In general, for a hydrocarbon composed of n carbon atoms associated with r rings the formula is: CnH(2n+2-2r). The structural relationship of rings in a polycyclic compound can vary. They may be separate and independent, or they may share one or two common atoms. Some examples of these possible arrangements are shown in the following table 5. Table 5 Examples of isomeric C8H14 bicycloalkanes Isolated rings No common atoms

Spiro rings One common atom

Fused rings One common bond

Bridged rings Two common atoms

The simple and bigger cycloalkanes are very stable, like alkanes, and their reactions, for example, radical chain reactions, are like alkanes. 43

1,3-dibromopropane

cyclopropane

The small cycloalkanes – in particular, cyclopropane – have a lower stability due to Baeyer strain and ring strain. They react similarly to alkenes, though they do not react in electrophilic addition, but in nucleophilic aliphatic substitution. These reactions are ringopening reactions or ring-cleavage reactions of alkyl cycloalkanes. Cycloalkanes can be formed in a Diels-Alder reaction followed by a catalytic hydrogenation. 44

6.2. ALKENE Alkenes are aliphatic hydrocarbons containing carbon-carbon double bonds and general formula CnH2n. Alkenes are named as if they were alkanes, but the "-ane" suffix is changed to "-ene". If the alkene contains only one double bond and that double bond is terminal (the double bond is at one end of the molecule or another) then it is not necessary to place any number in front of the name. Nomenclature of Alkenes:

If there is more than one double bond in an alkene, all of the bonds should be numbered in the name of the molecule – even terminal double bonds. The numbers should go from lowest to highest, and be separated from one another by a comma. The IUPAC numerical prefixes are used to indicate the number of double bonds. 45

octa-2,4-diene: CH3CH=CHCH=CHCH2CH2CH3 deca-1,5-diene: CH2=CHCH2CH2CH=CHCH2CH2CH2CH3 Note that the numbering of "2-4" above yields a molecule with two double bonds separated by just one single bond. Double bonds in such a condition are called "conjugated", and they represent an enhanced stability of conformation, so they are energetically favored as reactants in many situations and combinations. EZ Notation. Earlier in stereochemistry, we discussed cis/trans notation where cis- means the same side and trans- means the opposite side. Alkenes can present a unique problem, however in that the cis/trans notation sometimes breaks down. The first thing to keep in mind is that alkenes are planar and there's no rotation of the bonds, as we'll discuss later. So when a substituent is on one side of the double-bond, it stays on that side.

The above example is pretty straight-forward. On the left, we have two methyl groups on the same side, so it's cis-but-2-ene. And on the right, we have them on the opposite sides, so we have transbut-2-ene. So in this situation, the cis/trans notation works and, in fact, these are the correct names.

Whenever an alkene has 3 or 4 differing substituents, one must use what's called the EZ nomenclature, coming from the German words, Entgegen (opposite) and Zusammen (same). E: Entgegen, opposite sides of double bond Z: Zusammen, same sides (zame zides) of double bond 46

Let's begin with (Z)-3-methylpent-2-ene. We begin by dividing our alkene into left and right halves. On each side, we assign a substituent as being either a high priority or low priority substituent. The priority is based on the atomic number of the substituents. So on the left side, hydrogen is the lowest priority because its atomic number is 1 and carbon is higher because its atomic number is 6. On the right side, we have carbon substituents on both the top and bottom, so we go out to the next bond. On to the top, there's another carbon, but on the bottom, a hydrogen. So the top gets high priority and the bottom gets low priority. Because the high priorities from both sides are on the same side, they are Zusammen (as a mnemonic, think 'Zame Zide'). Now let's look at (E)-3-methylpent-2-ene. On the left, we have the same substituents on the same sides, so the priorities are the same as in the Zusammen version. However, the substituents are reversed on the right side with the high priority substituent on the bottom and the low priority substituent on the top. Because the High and Low priorities are opposite on the left and right, these are Entgegen, or opposite. The system takes a little getting used to and it's usually easier to name an alkene than it is to write one out given its name. But with a little practice, you'll find that it's quite easy. Comparison of E-Z with cis-trans (Z)-but-2-ene

(E)-but-2-ene

cis-but-2-ene

trans-but-2-ene

To a certain extent, the Z configuration can be regarded as the cis- isomer and the E as the trans- isomers. This correspondence is exact only if the two carbon atoms are identically substituted. In general, cis-trans should only be used if each double-bonded carbon atom has a hydrogen atom (i.e. R-CH=CH-R'). 47

Properties. Alkenes are molecules with carbons bonded to hydrogens which contain at least two sp2 hybridized carbon atoms. That is, to say, at least one carbon-to-carbon double bond, where the carbon atoms, in addition to an electron pair shared in a sigma (σ) bond, share one pair of electrons in a pi (π) bond between them. The general formula for an aliphatic alkene is: CnH2n – e.g. C2H4 or C3H6 Preparation. There are several methods for creating alkenes. Some of these methods, such as the Wittig reaction, we'll only describe briefly in this chapter and instead, cover them in more detail later in the book. For now, it's enough to know that they are ways of creating alkenes. 1. Dehydrohalogenation of Haloalkanes

Synthesis of alkene by dehydrohalogenation

Alkyl halides are converted into alkenes by dehydrohalogenation: elimination of the elements of hydrogen halide. Dehydrohalogenation involves removal of the halogen atom together with a hydrogen atom from the carbon adjacent to the one bearing the halogen. It uses the E2 elimination mechanism that we'll discuss in detail at the end of this chapter The haloalkane must have a hydrogen and halide 180° from each other on neighboring carbons. If there is no hydrogen 180° from the halogen on a neighboring carbon, the reaction will not take place. It is not surprising that the reagent required for the elimination of what amounts to a molecule of acid is a strong base, for example: alcholic KOH. In some cases this reaction yields a single alkene and in other cases yields a mixture. n-butyl chloride, for example, can eliminate hydrogen only from C-2 and hence yields only 1-butene. sec-butyl chloride, on the other hand, can eliminate hydrogen from either C-l or C-3 and hence yields both 1-butene and 2-butene. Where the two alkenes can be formed, 2-butene is the chief product. 48

2. Dehalogenation of Vicinal Dihalides

Synthesis of alkene via debromination of vicinal dihalides using Sodium Iodide

Synthesis of alkene via debromination of vicinal dihalides using Zinc

The dehalogenation of vicinal dihalides (halides on two neighboring carbons, think "vicinity") is another method for synthesizing alkenes. The reaction can take place using either sodium iodide in a solution of acetone, or it can be performed using zinc dust in a solution of either heated ethanol or acetic acid. This reaction can also be performed with magnesium in ether, though the mechanism is different as this actually produces, as an intermediate, a Grignard reagent that reacts with itself and causes an elimination, resulting in the alkene. 3. Dehydration of alcohols

Synthesis of alkene by dehydration of an alcohol

An alcohol is converted into an alkene by dehydration: elimination of a molecule of water. Dehydration requires the presence of an acid and the application of heat. It is generally carried out in either of two ways, heating the alcohol with sulfuric or phosphoric acid to temperatures as high as 200, or passing the alcohol vapor over alu49

mina, Al2O3 , at 350-400, alumina here serving as a Lewis acid. Ease of dehydration of alcohols: 3° > 2° > 1° General reaction:

Example – 1: preparation of ethene from ethyl alcohol (Ethanol):

Example – 2: preparation of propene from n-propyl alcohol (Propan-1-ol):

Example – 3: preparation of propene from iso-propyl alcohol (Propan-2-ol):

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Markovnikov's Rule. Before we continue discussing reactions, we need to take a detour and discuss a subject that's very important in Alkene reactions, "Markovnikov's Rule." This is a simple rule stated by the Russian scientist Vladmir Markovnikov in 1869, as he was showing the orientation of addition of HBr to alkenes. His rule states:"When an unsymmetrical alkene reacts with a hydrogen halide to give an alkyl halide, the hydrogen adds to the carbon of the alkene that has the greater number of hydrogen substituents, and the halogen to the carbon of the alkene with the fewer number of hydrogen substituents" (This rule is often compared to the phrase: "The rich get richer and the poor get poorer." It means that the Carbon with the most Hydrogens gets another Hydrogen and the one with the least Hydrogens gets the halogen). This means that the nucleophile of the electophile-nucleophile pair is bonded to the position most stable for a carbocation, or partial positive charge in the case of a transition state. Markovnikov addition. Markovnikov addition is an addition reaction which follows Markovnikov's rule, producing a Markovnikov product.

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Anti-Markovnikov addition. Certain reactions produce the opposite of the Markovnikov product, yielding what is called antiMarkovnikov product. That is, hydrogen ends up on the more substituted carbon of the double bond. The hydroboration/oxidation reaction, which we'll discuss shortly, is an example of this, as are reactions that are conducted in peroxides. Markovnikov's rule works because of the stability of carbocation intermediates. Experiments tend to reveal that carbocations are planar molecules, with a carbon that has three substituents at 120° to each other and a vacant p orbital that is perpendicular to it in the 3rd plane. The p orbital extends above and below the trisubstituent plane. This leads to a stabilizing effect called hyperconjugation. Hyperconjugation is what happens when there is an unfilled (antibonding or vacant) C-C π orbital and a filled C-H σ bond orbital next to each other. The result is that the filled C-H σ orbital interacts with the unfilled C-C π orbital and stabilizes the molecule. The more highly substituted the molecule, the more chances there are for hyperconjugation and thus the more stable the molecule is. Another stabilizing effect is an inductive effect. There are a few exceptions to the Markovnikov rule, and these are of tremendous importance to organic synthesis. HBr in Hydrogen Peroxide: Due to formation of free radicals, and the mechanism in which it reacts, the alkyl free radical forms at the middle atom, where it is most stable, and a hydrogen attaches itself here. Note here hydrogen addition is the second step, unlike in the above example. Addition reactions Hydroboration. Hydroboration is a very useful reaction in Alkenes, not as an end product so much as an intermediate product for further reactions. The primary one that we'll discuss below is the Hydroboration/Oxidation reaction which is actually a hydroboration reaction followed by a completely separate oxidation reaction. 52

The addition of BH3 is a concerted reaction in that several bonds are broken and formed at the same time. Hydroboration happens in what's called syn-addition because the boron and one of its hydrogens attach to the same side of the alkene at the same time.

Hydroboration mechanism

As you can see from the transition state in the center of the image, this produces a sort of a box between the two alkene carbons and the boron and its hydrogen. In the final step, the boron, along with its other two hydrogens, remains attached to one carbon and the other hydrogen attaches to the adjacent carbon. This description is fairly adequate, however, the reaction actually continues to happen and the -BH2 continues to react with other alkenes giving an R2BH and then again, until you end up with a complex of the boron atom attached to 3 alkyl groups, or R3B. This trialkyl-boron complex is then used in other reactions to produce various products.

B2H6 complex

BH3-THF complex

Borane, in reality, is not as stable as BH3. Boron, in this configuration has only 6 electrons and wants 8, so in its natural state it actually creates the B2H6 complex shown on the left. Furthermore, instead of using B2H6 itself, BH3 is often used in a complex with tetrahydrofuran (THF) as shown in the image on the right. In either situation, the results of the reactions are the same. 53

Hydroboration/Oxidation

With the reagent diborane, (BH3)2, alkenes undergo hydroboration to yield alkylboranes, R3B, which on oxidation give alcohols. The reaction procedure is simple and convenient, the yields are exceedingly high, and the products are ones difficult to obtain from alkenes in anyother way. Diborane is the dimer of the hypothetical BH3 (borane) and, in the reactions that concern us, acts much as though it were BH3. Indeed, in tetrahydrofuran, one of the solvents used for hydroboration, the reagent exists as the monomer, in the form of an acid-base complex with the solvent. Hydroboration involves addition to the double bond of BH3 (or, in the following stages, BH2R and BHR2), with hydrogen becoming attached to one doubly-bonded carbon, and boron to the other. The alkylborane can then undergo oxidation, in which the boron is replaced by -OH. Thus, the two-stage reaction process of hydroboration-oxidation permits, in effect, the addition to the carbon-carbon double bond of the elements of H-OH. Reaction is carried out in an ether, commonly tetrahydrofuran or "diglyme" (diethylene glycol methyl ether, CH3OCH2CH2OCH2 CH2OCH3). Diborane is commercially available in tetrahydrofuran solution. The alkylboranes are not isolated, but are simply treated in situ with alkaline hydrogen peroxide. Oxymercuration/Reduction

Oxymercuration/Reduction of 1-propene

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Alkenes react with mercuric acetate in the presence of water to give hydroxymercurial compounds which on reduction yield alcohols. The first stage, oxymercuration, involves addition to the carboncarbon double bond of -OH and -HgOAc. Then, in reduction, the HgOAc is replaced by -H. The reaction sequence amounts to hydration of the alkene, but is much more widely applicable than direct hydration. The two-stage process of oxymercuration/reduction is fast and convenient, takes place under mild conditions, and gives excellent yields often over 90%. The alkene is added at room temperature to an aqueous solution of mercuric acetate diluted with the solvent tetrahydrofuran. Reaction is generally complete within minutes. The organomercurial compound is not isolated but is simply reduced in situ by sodium borohydride, NaBH4. (Mercury is recovered as a ball of elemental mercury). Oxymercuration/reduction is highly regiospecific, and gives alcohols corresponding to Markovnikov addition of water to the carbon-carbon doublen bond. Oxymercuration involves electrophilic addition to the carbon-carbon double bond, with the mercuric ion acting as electrophile. The absence of rearrangement and the high degree of stereospecificity (typically anti) in the oxymercuration step argue against an open carbonium ion as an intermediate. Instead, it has been proposed that a cyclic mercurinium ion, analogous to the bromonium and chloronium ions involved in the addition of halogens, is formed. In 1971, Olah reported spectroscopic evidence for the preparation of stable solutions of such mercurinium ions. The mercurinium ion is attacked by the nucleophilic solvent water, in the present case to yield the addition product. This attack is back-side (unless prevented by some structural feature) and the net result is anti addition, as in the addition of halogens. Attack is thus of the SN2 type; yet the orientation of addition shows that the nucleophile becomes attached to the more highly substituted carbon as though there were a free carbonium ion intermediate. As we will see, the transition state in reactions of such unstable threemembered rings has much SN1 character. Reduction is generally not stereospecific and can, in certain special cases, be accompanied by rearrangement. Despite the stereo55

specificity of the first stage, then, the overall process is not, in general, stereospecific. Rearrangements can occur, but are not common. The reaction of 3,3-dimethyl-1-butene illustrates the absence of rearrangements that are typical of intermediate carbonium ions. Diels-Alder reaction. The Diels–Alder reaction is a reaction (specifically, a cycloaddition) between a conjugated diene and a substituted alkene, commonly termed the dienophile, to form a substituted cyclohexene system. The reaction can proceed even if some of the atoms in the newly formed ring are not carbon. Some of the Diels–Alder reactions are reversible; the decomposition reaction of the cyclic system is then called the retro-Diels–Alder.

Diels-Alder for 1,3-butadiene-ethylene

The Diels-Alder reaction is generally considered one of the most useful reactions in organic chemistry since it requires very little energy to create a cyclohexene ring, which is useful in many other organic reactions. A concerted, single-step mechanism is almost certainly involved; both new carbon-carbon bonds are partly formed in the same transition state, although not necessarily to the same extent. The Diels-Alder reaction is the most important example of cycloaddition. Since the reaction involves a system of 4 π electrons (the diene) and a system of 2 π it electrons (the dienophile), it is known as a [4 + 2] cycloaddition. Catalytic addition of hydrogen. Catalytic hydrogenation of alkenes produces the corresponding alkanes. The reaction is carried out under pressure in the presence of a metallic catalyst. Common industrial catalysts are based on platinum, nickel or palladium, but for laboratory syntheses, Raney nickel (formed from an alloy of nickel and aluminium) is often employed. 56

The catalytic hydrogenation of ethylene to yield ethane proceeds thusly: CH2=CH2 + H2 + catalyst → CH3-CH3 Electrophilic addition. Most addition reactions to alkenes follow the mechanism of electrophilic addition. An example is the Prins reaction, where the electrophile is a carbonyl group. Halogenation. Addition of elementary bromine or chlorine in the presence of an organic solvent to alkenes yields vicinal dibromoand dichloroalkanes, respectively. The decoloration of a solution of bromine in water is an analytical test for the presence of alkenes: CH2=CH2 + Br2 → BrCH2-CH2Br The reaction works because the high electron density at the double bond causes a temporary shift of electrons in the Br-Br bond causing a temporary induced dipole. This makes the Br closer to the double bond, slightly positive and therefore an electrophile. Hydrohalogenation. Addition of hydrohalic acids like HCl or HBr to alkenes yields the corresponding haloalkanes. An example of this type of reaction is: CH3CH=CH2 + HBr → CH3-CHBr-CH3 If the two carbon atoms at the double bond are linked to a different number of hydrogen atoms, the halogen is found preferentially at the carbon with less hydrogen substituents (Markovnikov's rule). Addition of a carbene or carbenoid yields the corresponding cyclopropane. Oxidation. Alkenes are oxidized with a large number of oxidezing agents. In the presence of oxygen, alkenes burn with a bright flame to form carbon dioxide and water. Catalytic oxidation with oxygen or the reaction with percarboxylic acids yields epoxides. Reaction with ozone in ozonolysis leads to the breaking of the double bond, yielding two aldehydes or ketones: R1-CH=CH-R2 + O3 → R1-CHO + R2-CHO + H2O 57

This reaction can be used to determine the position of a double bond in an unknown alkene. Polymerization of alkenes is an economically important reaction which yields polymers of high industrial value, such as the plastics polyethylene and polypropylene. Polymerization can either proceed via a free-radical or an ionic mechanism. Substitution and elimination reaction mechanisms Nucleophilic substitution reactions. Nucleophilic substitution reactions (SN1 and SN2) are very closely related to the E1 and E2 elimination reactions, discussed later in this section, and it is generally a good idea to learn the reactions together, as there are parallels in reaction mechanisms, preferred substrates, and the reactions sometimes compete with each other. It's important to understand that substitution and elimination reactions are not associated with a specific compound or mixture so much as they're a representation of how certain reactions take place. At times, combinations of these mechanisms may occur together in the same reaction or may compete against each other, with influences such as solvent or nucleophile choice being the determining factor as to which reaction will dominate. Note: In the notation SN1 and SN2, S stands for substitution (something takes the place of something else) N: stands for nucleophilic (a nucleophile displaces another nucleophile) 1: stands for unimolecular (the concentration of only one kind of molecule determines the rate of the reaction) 2: stands for bimolecular (the concentration of two types of molecules determine the rate of the reaction) In nucleophilic substitution, a nucleophile attacks a molecule and takes the place of another nucleophile, which then leaves. The nucleophile that leaves is called the leaving group. Nucleophilic substitutions require 1. a nucleophile (such as a Lewis base) 2. an electrophile with a leaving group A leaving group is a charged or neutral moiety (group) which breaks free. 58

SN1 and SN2. One of the main differences between SN1 and SN2 is that the SN1 reaction is a 2-step reaction, initiated by disassociation of the leaving group. The SN2 reaction, on the other hand, is a 1-step reaction where the attacking nucleophile, because of its higher affinity for and stronger bonding with the carbon, forces the leaving group to leave. These two things happen in a single step. These two different mechanisms explain the difference in reaction rates between SN1 and SN2 reactions. SN1 reactions are dependent on the leaving group disassociating itself from the carbon. It is the rate-limiting step and thus, the reaction rate is a first-order reaction whose rate depends solely on that step. Alternatively, in SN2 reactions, the single step of the nucleophile, coming together with the reactant from the opposite side of the leaving group, is the key to its rate. Because of this, the rate is dependent on both the concentration of the nucleophile as well as the concentration of the reactant. The higher these two concentrations, the more frequent the collisions. Thus the reaction rate is a secondorder reaction, where Nu is the attacking nucleophile. SN2 Reactions. There are primarily 3 things that affect whether an SN2 reaction will take place or not. The most important is the structure. That is whether the alkyl halide is on a methyl, primary, secondary, or tertiary carbon. The other two components, that determine whether an SN2 reaction will take place or not, are the nucleophilicity of the nucleophile and the solvent used in the reaction. Reactivity due to structure of SN2. CH3X > RCH2X > R2CHX >> R3CX The structure of the alkyl halide has a great effect on the mechanism. CH3X and RCH2X are the preferred structures for SN2. R2CHX can undergo the SN2 under the proper conditions (see below), and R3CX rarely, if ever, is involved in SN2 reactions. The reaction takes place by the nucleophile attacking from the opposite side of the bromine atom. Notice that the other 3 bonds are all pointed away from the bromine and towards the attacking nuc59

leophile. When these 3 bonds are hydrogen bonds, there's very little steric hinderance of the approaching nucleophile.

SN2 nucleophilic substitution of bromine with a generic nucleophile

However, as the number of R groups increases, so does the steric hinderance, making it more difficult for the nucleophile to get close enough to the α-carbon, to expel the bromine atom. In fact, tertiary carbons (R3CX) are so sterically hindered as to prevent the SN2 mechanim from taking place at all. In the case of this example, a secondary α-carbon, there is still a great deal of steric hinderance and, whether the SN2 mechanism will happen, will depend entirely on what the nucleophile and solvent are. SN2reactions are preferred for methyl halides and primary halides. Another important point to keep in mind, and this can be seen clearly in the example above, during the SN2 reaction, is that the molecule undergoes an inversion. The bonds attached to the α-carbon are pushed away as the nucleophile approaches. During the transition state, these bonds become planar with the carbon and, as the bromine leaves and the nucleophile bonds to the α-carbon, the other bonds fold back away from the nucleophile. This is particularly important in chiral or pro-chiral molecules, where an R configuration will be converted into an S configuration and vice versa. As you'll see below, this is in contrast to the results of SN1reactions. Examples: OH- + CH3 – Cl → HO – CH3 + ClOH- is the nucleophile, Cl is the electrophile, HOCH3 is the product, and Cl- is the leaving group or, Na+I- + CH3-Br → I-CH3 + Na+Br60

The above reaction, taking place in acetone as the solvent, sodium and iodide disassociate almost completely in the acetone, leaving the iodide ions free to attack the CH-Br molecules. The negatively charged iodide ion, a nucleophile, attacks the methyl bromide molecule, forcing off the negatively charged bromide ion and taking its place. The bromide ion is the leaving group. Nucleophilicity is the rate at which a nucleophile displaces the leaving group in a reaction. Generally, nucleophilicity is the stronger, the larger, more polarizable, and/or the less stable the nucleophile is. No specific number or unit of measure is used. All other things being equal, nucleophiles are generally compared to each other in terms of relative reactivity. For example, a particular strong nucleophile might have a relative reactivity of 10,000 that of a particular weak nucleophile. These relationships are generalities as things like solvent and substrate can affect the relative rates, but they are generally good guidelines for which species make the best nucleophiles. All nucleophiles are Lewis bases. In SN2 reactions, the preferred nucleophile is a strong nucleophile that is a weak base. Examples of these are N3-, RS-, I-, Br-, and CN-. Alternatively, a strong nucleophile that's also a strong base can also work. However, as mentioned earlier in the text, sometimes reaction mechanisms compete and in the case of a strong nucleophile that's a strong base, the SN2 mechanism will compete with the E2 mechanism. Examples of strong nucleophiles that are also strong bases include RO- and OH-. List of descending nucleophilicities I > Br- > Cl- >> F- > -SeH > -OH > H2O SN1 Reactions the SN1 mechanism is very different from the SN2 mechanism. In some of its preferences, it is exactly the opposite and, in some cases, the results of the reaction can be significantly different. Like in the SN2 mechanism, the structure plays an important role in the SN1 mechanism. The role of the structure in the SN1 mechanism, however, is quite different and because of this, the reactivity of structures is more or less reversed. 61

Reactivity due to structure of SN1 CH3X < RCH2X HC ≡ CR > HNH2 > H2C = CH2 > CH3-CH3 Relative basic nature: OH- ≈ OR- < C ≡ CR < NH2 < CH = CH2 < CH2-CH3 Acidity of Alkynes. The hydrogens in terminal alkynes are relatively acidic. Acetylene itself has a pKa of about 25. It is a far weaker acid that water (pKa 15.7) or the alcohols (pKa 16-19), but it is much more acidic than ammonia (pKa 34). A solution of sodium amide in liquid ammonia readily converts acetylene and other terminal alkynes into the corresponding carbanions. RC ≡ CH + NH2– → RC ≡ C– + NH3 This reaction does not occur with alkenes or alkanes. Ethylene has a pKa of about 44 and methane has a pKa of about 50. From the foregoing pK'as we see that there is a vast difference in the stability of the carbanions RC ≡ C–, CH2 = CH–, and CH3–. This difference may readily be explained in terms of the character of the orbital occupied by the lone-pair electrons in the three anions. Methyl anion has a pyramidal structure with the lone-pair electrons in an orbital that is approximately sp3(1/4 s and ¾ p). In vinyl anion the lone-pair electrons are in an sp2- (1/3 s and 2/3 p) orbital. In acetylide ion the lone pair is in an sp-orbital (1/2 s and 1/2 p).

Electrons in s-orbitals are held, on the average, closer to the nucleus than they are in p-orbitals. This increased electrostatic attraction means that s-electrons have lower energy and greater stability than p72

electrons. In general, the greater the amount of s-character in a hybrid orbital containing a pair of electrons, the less basic is that pair of electrons, and the more acidic is the corresponding conjugate acid.

Of course, the foregoing argument applies to hydrogen cyanide as well. In this case, the conjugate base, NºC—, is further stabilized by the presence of the electronegative nitrogen. Consequently, HCN is sufficiently acidic (pKa 9.2) that it is converted to its salt with hydroxide ion in water. HCN + OH— ⇔ CN— + H2O Alkynes are also quantitatively deprotonated by alkyllithium compounds, which may be viewed as the conjugate bases of alkane: CH3(CH2)3CºCH + n-C4H9Li → CH3(CH2)3C≡CLi + n-C4H10 The foregoing transformation is simply an acid-base reaction, with l-hexyne being the acid and n-butyllithium being the base. Since the alkyne is a much stronger acid than the alkane (by over 20 pK units), equilibrium lies essentially completely to the right. Terminal alkynes give insoluble salts with a number of heavy metal cations such as Ag+ and Cu+. The alkyne can be regenerated from the salt, and the overall process serves as a method for purifying terminal alkynes. However, many of these salts are explosively sensitive when dried and should always be kept moist. CH3(CH2)3CºCH + AgNO3 ⇔ CH3(CH2)3C≡CAg + HNO3 Addition reactions of alkynes. Nucleophilic pi electrons of alkynes add electrophiles in reactions similar to additions to alkenes. Alkynes can add two moles of reagent but are less reactive (except to H2) than alkenes.

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1. Hydrogenation of alkynes. Addition of two molecules of H2 takes place on alkyne.

However the addition of 2nd H2 molecule can be checked if Lindlar catalyst is used. Dialkyl acetylenes may be catalytically reduced to a mixture of cis and trans alkenes, the former is formed predominantly if Lindlar catalyst is used.

However, reduction with sodium in liq. NH3 or by LiAIH4 produces trans alkene. 2. Electrophilic addition. Acetylenic bond in alkyne is a combination of one sigma bond and two Π bonds. Like alkenes, alkynes also show characteristic electrophilic addition reactions which take place in two stages involving the formation of olefinic intermediate. Thus alkynes show addition of two molecules of addendum.

However, the rate of electrophilic addition in acetylene is rather slow than that of ethene in spite of the fact that alkynes have an 74

excess of pi electron. This result is also supported by the fact that in many of electrophilic addition reactions, the presence of catalyst such as Hg2+ ions is needed. The low reactivity of acetylene is not yet clear. 3. Addition of halogens.

a. Western and westrosol are good industrial solvents for rubber, fats and varnishes. Westerns also have some insecticidal action. b. The rate of reaction increases in the presence of light. c. The reactivity order for halogens is: CI2 > Br2 > I2 CH ≡ CH + Br2 → CHBr = CHBr (only) CH ≡ CH + Br2 → CHBr2-CHBr2 in CCI4

d. Direct combination of acetylene with chlorine may be accompanied with explosions, but it is prevented by the presence of metallic chloride as a catalyst. e. The predominant product during addition of one molecule of halogen on alkyne in trans isomer.

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4. Addition of halogen acids. CH ≡ CH + HX

CH2 = CHX

CH3-CHX2

vinyl halide

ethylidene dihalide

The reactivity order is: HI > HBr > HCI Acetylene reacts with dil HCI in the presence of Hg2+ at 65 oC to give vinyl chloride, used in preparation of poly vinyl chloride, a synthetic polymer.

Note: 1. Peroxides have the same effect on the addition of HBr to asymmetrical alkynes as they have on alkenes. 2. Because of -I effect of the bromine atom, the availability of the Π electrons during the second molecule addition becomes much slower than ethylene. 5. Addition of hypohalous acids.

Note: Presence of two or more OH groups on one carbon atom makes it unstable and the molecule loses H2O molecule. However, there are two exceptions to this rule; one is chloral hydrate CCI3CH(OH)2 and the other is carbonic acid.

Chloral

hydrate is extra stable in spite of two OH groups on one carbon atom due to H-bonding.

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6. Addition of AsCI3.

chlorovinyl dichloroarsenic (Lewsite), A poisonous gas, more poisonous than mustard gas

7. Addition of HCN.

Vinyl cyanide or acrylonitrile

8. Addition of acetic acid.

9. Addition of CO and H2O.

10. Polymerisation or self addition. Alkynes undergo polymerization yielding different types of polymeric compounds under different conditions. a) Cyclic polymerization:

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b) Linear polymerisation:

Vinyl acetylene on reaction with HCI forms 2-chloro, 1, 3-butadiene (or chloroprene) which on exposure to air polymerizes to give synthetic rubber neoprene

Note: Acetylene on heating with spongy copper or its oxide gives a cork like substance used in manufacture of linoleum. 11. Addition of H2SO4. CH≡CH + H2SO4 → CH2=CHHSO4 → CH3CH(HSO4)2

The above reaction can also be made as:

Vinyl alcohol CH2=CHOH, which is rapidly converted into an equilibrium mixture that is almost CH3CHO is an example of ketoenol tautomerism.

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Note: Only C2H2 on addition of H2O gives aldehyde, all other alkynes give ketone. 12. H2O (Hydration to carbonyl compounds). When passed into dilute sulphuric acid at 60oC in the presence of mercuric sulphate as a catalyst, acetylene adds on one molecule of water to form acetaldehyde. The mechanism of this hydration takes place via the formation of vinyl alcohol as an intermediate.

The homologues of acetylene form ketone when hydrated, for example, propyne gives acetone

13. Addition of boron hydride.

with dialkylacetylenes, the products of hydrolysis and oxidation are cis-alkenes and ketones, respectively. 79

Ozonolysis

Addition of O3 on alkynes gives their monoozonides, which on hydrolysis form dicarbonyl compounds which are further oxidized to carboxylic acids. In alkenes two molecules of carbonyl compounds are formed during ozonolysis and in alkyne one molecule of dicarbonyl compound is formed which is further oxidized to two acids. Oxidation of alkynes 1. Combustion: CnH2n-2 + (3n-1)/2O2 → nCO2 + (n-1)H2O; ΔH = -ve 2. Oxidation by alkaline KMnO4:

R-C≡CH + 4[O] → RCOOH + HCOOH 80

3. Oxidation by H2CrO4 or acidified K2Cr2O7: CH≡CH + O + H2O → CH3COOH R-C≡CH + O + H2O → RCH2COOH 4. Oxidation by acidified KMnO4: CH≡CH + 3[O] + H2O → 2HCOOH R-C≡CH

H2O + CO2

RCOOH + HCOOH

5. Oxidation by selenium dioxide:

CH3-C≡CH

CH3COCHO 2-ketopropanal

Isomerization of alkynes

Action of N2 on alkynes:

Formation of heterolytic compounds

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Nucleophilic addition Acetylene undergoes nucleophilic addition with CH3OH in the presence of CH3ONa.

Substitution reaction Acetylene on passing through sodium hypochlorite solution at 0 °C in the absence of light shows substitution of H by a chlorine atom. 1. Formation of sodium acetylide or alkynides:

2. Formation of acetylenic grignard reagent: CH ≡ CH + R MgX → CH ≡ CMgX 3. Formation of copper alkynides: on passing alkynes through ammoniacal cuprous chlorides solution, a red precipitate of cuprous alkynide is obtained. 82

4. Formation of silver alkynides: On passing alkynes through ammoniacal silver nitrate solution (Tollens reagent) a white precipitate of silver alkynides is obtained CH≡CH + 2AgNO3 + 2NH4OH → AgC≡CAg + 2NH4NO3 + 2H2O silver acetylide

RC≡CH + AgNO3 + NH3OH → RC≡CAg + NH4NO3 + H2O Note: 1. These alkynides are ionic in nature 2. Alkynides are generally explosive and unstable when dry. 3. Copper and silver alkynides are very sensitive to shock when dry and may explode 4. These alkynides are easily converted to original alkynes when treated with dilute acids. NaC ≡ CNa + 2HNO3 → HC ≡ CH + 2NaNO3 5. Acidic nature of alkyne can be utilized to separate, purify and identify alkyne-1 from other hydrocarbons. Uses of alkynes 1. Among alkynes, acetylene has got wide applications in industries. 2. As oxy-acetylene flame for welding. 3. As illuminating agent in hawker's lamps and light houses. 4. In artificial ripening of fruits. 5. In preparation of monomeric unit (vinyl chloride, vinyl cyanide, vinyl cyanide, vinyl acetate, vinyl acetylene, etc.) to get polymers (PVC, PVA, chloroprene, Buna-S etc.) widely used in textile, plastic, shoe and rubber industries. 6. In preparation of poisonous gas, Lewiste. 7. In preparation of solvents such as westron, westrosol and other useful chemicals e.g., C6H6, acetaldehyde, acetone, etc. 8. It is used as general anesthetic under the name Naracylene. 83

6.4. ALKYL HALIDES These are the organic compounds containing halogen atoms as a substituent. Organic compounds containing C-X bonds are of the following types: 1. Alkyl halides or haloalkanes (R–X): The halogen atom is bonded to an alkyl group (R). They form a homologous series represented by CnH2n+1X. 2. Allylic halides: The halogen atom is bonded to an sp3-hybridised carbon atom next to carbon-carbon double bond (C=C) i.e. to an allylic carbon. 3. Vinylic halides: The halogen atom is bonded to an sp2 – hybridised carbon atom of a carbon-carbon double bond Haloalkanes (also known as halogenoalkanes or alkyl halides) are a group of chemical compounds, consisting of alkanes, such as methane or ethane, with one or more halogens linked, such as chlorine or fluorine, making them a type of organic halide. They are a subset of halocarbons, similar to haloalkenes and haloaromatics. They are known under many chemical and commercial names. As flame retardants, fire extinguishants, refrigerants, propellants and solvents they have or had wide use. Some haloalkanes (those containing chlorine or bromine) have been shown to have negative effects on the environment such as ozone depletion. The most widely known family within this group is the chlorofluorocarbons (CFCs). Structure and nomenclature of alkyl halides: Alkyl halides are commonly designated by the formulas R-X, where R is a simple alkyl or substituted alkyl group. For example,

84

Substituted alkyl halides undergo, of course, the reactions characteristic of their other functional groups: nitration of benzyl chloride, oxidation of ethylene bromohydrin, addition to allyl bromide but as halides they react very much like ethyl or isopropyl or-tertbutyl halides. Compounds in which a halogen atom is attached directly to an aromatic ring (aryl halides, e.g., bromobenzene) differ so much from the alkyl halides in their preparation and properties that they will be discussed separately. Classification of haloalkanes: Alkyl Halides is classified as mono, di, or polyhalogen (tri-,tetra-, etc.) compounds depending on the number of halogen atoms in their structures. For example

Physical properties of alkyl halides. Because of greater molecular weight, haloalkanes have considerably higher boiling points than alkanes with the same number of carbons. For a given alkyl group, the boiling point increases with increasing atomic weight of the halogen, so that fluoride has the lowest boiling point, and iodide – the highest boiling point. In spite of polarity alkyl halides are insoluble in water, probably because of their inability to form hydrogen bonds. They are soluble in typical organic solvents. Preparation of alkyl halides 1. From alcohols (Replacement of OH by X)

Examples:

85

2. Halogenation of hydrocarbons

Examples

3. Addition of hydrogen halides to alkenes

4. Addition of halogens to alkenes and alkynes

86

5. Halide exchange

An alkyl iodide is often prepared from the corresponding bromide or chloride by treatment with a solution of sodium iodide in acetone; the less soluble bromide or sodium chloride precipitates from the solution and can be removed by filtration.A halide ion is an extremely weak base. Its reluctance to share its electrons is shown by its great tendency to release a hydrogen ion, that is, by the high acidity of the hydrogen halides. When attached to carbon, halogen can be readily displaced as halide ion by other, stronger bases. These bases have an unshared pair of electrons and are seeking a relatively positive site, i.e., are seeking a nucleus with which to share their electrons.Alkyl halides are nearly always prepared from alcohols, which are available commercially or are readily synthesized. Although certain alcohol tend to undergo rearrangement during replacement of -OH by -X, this tendency can be minimized by use of phosphorus halides.Certain halides are best prepared by direct halogenation. The most important of these preparations involves substitution of -X for the unusually reactive allylic or benzylic hydrogens.

Basic, electron rich reagents are called nucleophilic reagents. The typical reaction of alkyl halides is nucleophilic substitution. 87

Reactions of alkyl halides 1. Nucleophilic substitution Reaction RX + -OH → ROH + XRX + H2O→ ROH 2RX + Na→ R-R + 2NaX RX + -OR' → R OR'

Product formed Alcohol Alcohol Alkane (Wurtz reaction) Ether (Williamson synthesis) Alkyne Alkyl iodide Nitrile Ester Thioether (sulfide) Thiol (mercaptan) Tertiary amine Secondary amine Primary amine Alkyl benzene (Friedel Craft reaction)

RX + -C CR' → R-CºCR' RX + I- → RI RX + -CN → RCN RX + R'COO- → R'CO-OR RX + :SR' → RSR' RX + SH- → RSH RX + :NH R'R" → RNR'R'' RX + :NH2R' → RNHR' RX + :NH3 → RNH2 RX + ArH + AlCl3 → Ar R

Malonic ester synthesis

Acetoacetic ester synthesis

Hydrolysis: RX + OH– → ROH + X– Williamson synthasis: R-ONa +R'X → R-R' + NaX Reaction with dry silver oxide: 2R-X + Ag2O → R-O-R 88

Reaction with sodio-alkynides: R-C≡C-Na +X-R→ R-C=C-R +NaX Reaction with potassium-cyanide: KCN+X-R→ RCN +KX Reaction with silver-cyanide: AgCN+X-R→ RNC +AgX Reaction with silver-nitrite: AgNO2+X-R→ RNO2 +AgX Reaction with potassium-nitrite: KNO2+X-R→ R-O-N=O +KX Fridal Craft reaction: R-X + C6H6 + AlCl3→C6H5-R Malonic ester synthasis: R-X + -CH(CO2C2H5)2 →R-CH(CO2C2H5)2 +HX Acetoacetic ester synthasis: R-X + -CH(CO2CH3)2 →R-CH(CO2CH3)2 +HX Reaction with ammonia: R-X +NH3→ R-NH2 +HX Wurtz reaction: 2R-I+ 2Na →R—R + 2NaI Dehydrohalogenation: CH3CH2CH2Br+alco.KOH→CH3–CH=CH2+KBr+H2O Reaction with alcoholic AgNO3: R-X +AgNO3 → R + AgX↓+HNO3 2. Dehydrohalogenation Elimination.

3. Preparation of Grignard reagent

4. Reduction RX + M + H+ → RH + M+ + XExamples: CH3)3C Cl

(CH3)3C MgCl 89

(CH3)3CD

Characteristic reaction chart for alkyl halides

Dihalides. Two H atoms of alkanes are replaced by two halogen atoms to form dihalides. The General formula of dihalides is CnH2nX2. Dihalides are classified as: a) Gem dihalides: The term gem has been derived from geminal meaning “the same position”. The two similar halogen atoms are attached to the same carbon atom, e.g. Formula of Gemhalides CH3CHX2 CH3CH2CHX2 (CH3)2CX2

IUPAC Name ethylidene dihalide or 1, 1-dihaloehtane propylidene dihalide or 1, 1-dihalopropane isopropylidene dihalide or 2, 2-dihalopropane

b) vic dihalides: The term vic has been derived from vicinal meaning for adjacent carbon atoms.The two halogens are attached to each other on adjacent carbon atoms, e.g. Vic dihalides CH2XCH2X CH3CHXCH2X

IUPAC Name ethylene dihalide or 1, 2-dihaloethane propylene dihalide or 1, 2-diahlopropane

c) α-ω diahlides: In these compounds halogen atoms are attached to terminal carbon atoms and are separated by three or more carbon atoms. They are also known as polymethylene halides, e.g. 90

CH2X-CH2-CH2-CH2X tetra methylene dichloride or 1, 4-dihalobutane

d) vic and gem diahalides are position isomers to each other. Preparation of dihalides 1) By alkenes and alkynes: CH2=CH2 + X2 → XCH2-CH2X vicinal dihalide

CH≡CH + 2HX → CH3-CHX2 geminal dihalide

2) By the action of PCI5:

Chemical properties of dihalides. Lower members are colourless, oily liquids with sweat smell. Higher members are solid. The reactivity of gem dihalides is lesser than alkyl halides, which might be due to the fact that in the presence of one halogen atom (with a strong attracting effect i.e. -I effect), the other cannot be so easily replaced. However, vic dihalides have the same order of reactivity as alkyl halides. Thus, the reactivity order: vic dihalides > gem dihalides. These are heavier than water. The relative density of CH2I2 is 3.325 g/ml which is the 2nd heaviest liquid known after Hg. Some of the important reactions of dihalides are given below. a) Action of KOHalc: Both vic and gem dihalides give the same products CH2X - CH2X or CH3-CHX2 + alcoho. KOH → CH≡CH +2HX 91

b) Acton of Zn dust: Both vic and gem dihalides give the same products CH2CHX2 or XH2C-CH2X + Zn dust → CH2=CH2 c) Action of KOHaq. It is a distinction test for gem and vic dihalides.

A gem dihalide gives either aldeyde or ketone on hydrolysis by KOHaq; A vicinal dihalide gives 1, 2-diol. d) Action of KCN followed with hydrolysis and heating. A distinction test for geminal and vicinal dihalides. A geminal dihalide gives acid, whereas vicinal dihalide gives anhydride if subjected to the action of KCN followed with hydrolysis and heating.

92

Note: -CN gp on acid hydrolysis always converts to -COOH. Two -COOH gps on one carbon atom on heating always lose CO2 to form mono carboxylic acid. Two -COOH gps on vicinal carbon atom, on heating always lose H2O to form anhydride of acid. General methods of preparation of trihalides 1) The trihalogen derivatives of alkanes are prepared by replacement of three hydrogen atoms by three halogen atoms. 2) Their general formula is CnH2n-1 X3: 3) The trihalogen derivative of methane is also known as haloform Haloform or trihalo methane CHX3 vis a vis chloroform (CHCI3) Preparation: Lab method and industrial method: By the distillation of ethyl alcohol or acetone with bleaching Powder: Bleaching powder on hydrolysis gives slaked lime and CI2, which acts as an oxidizing agent as well as a chlorinating agent. CaOCI2 + H2O → Ca (OH)2 + CI2 By ethanol: CI2 + CH3CH2OH → CH3CHO + 2HCI (CI2 acts as oxidant) CH3CHO + 3CI2 → CCI3CHO + 3HCI (CI2 acts as substituent) 2CCI3CHO + Ca (OH)2 → 2CHCI3 + (HCOO)2Ca (hydrolysis) chloroform Ca formate

By acetone: CH3COCH3 + 3CI2 → CCI3COCH3 + 3HCI (CI2 acts as substituent) 2 CCI3COCH3 + Ca (OH)2 → 2 CHCI3 + (CH3COO)2Ca (hydrolysis) Chloroform is collected with water in the lower layer. It is washed with dilute alkali and dried over CaCI2 and then redistilled at 60-65oC. The yield is better if acetone is used. 93

By haloform reaction: Acetaldehyde and all methyl ketones (2-ones) or carbonyl compounds having CH3CO- units as well as alcohols [primary (only ethanol) and secondary (only 2-ol), which produce this unit on oxidation by halogen, undergo haloform reaction on heating with halogen and NaOH to give haloform. If I2 + NaOH is used, the haloform reaction yields yellow solid as precipitate confirming the presence of CH3CO- unit or CH3CH-OH in the molecule attached to C or H. This is known as iodoform test for confirming the presence of acetaldehyde, methyl ketones and alcohols (which produce CH3COunit on oxidation), e.g. Reactants which give iodoform test because of CH3CO- unit or producing this unit during oxidation:

In general, acetaldehyde, 2-one, ethanol and sec alcohols (2-ol) give the idoform test. Also pyruvic acid CH3COCOOH, lactic acid CH3CHOHCOOH and acetophenone C6H5COCH3 give this test.The reactions are: By ethanol CH3CH2OH + X2 → CH3CHO + 2HX CH3CHO + 3X2 → CX3CHO + 3HX CX3CHO + NaOH → CHX3 + HCOONa 5HX + 5NaOH → 5NaX + H2O CH3CH2OH + 4X2 + 6 → CHX3 + HCOONa + 5NaX + 5H2O 94

By ethanal: CH3CHO + 3X2 → CX3CHO + 3HX CX3CHO + NaOH → CHX3 + HCOONa 3HX + 3NaOH → 3NaX + 3H2O CH3CHO + 3X2 + 4NaOH → CHX3 + HCOONa + 3NaX + 3H2O Note: (a) Ethyl acetoacetate (CH3COCH2COOC2H5) does not give iodoform test, although it contains (CH3CO-gp) attached to carbon (methylene gp). This is due to the active nature of the methylene group at which iodination occurs and not on the methyl group of (CH3CO-) unit; (b) Some quinines, quinols and m-dihydric phenols also give positive iodoform test. Pure chloroform is obtained by heating chloral hydrate with concentrated sodium hydroxide solution. CCI3CH(OH)2 + NaOH

CHCI3 + HCOONa + H2O

By chlorination of methane: CH4 + CI2

CHCI3 + 3HCI

By CCI4 in a commercial method: Commercially it is obtained by the partial reduction of CCI4 with iron fillings and water (steam). This chloroform is not pure and is used only as solvent. CCI4 + 2H

CHCI3 + HCI

Note: Iodoform is commercially obtained by electrolysis of a solution containing ethanol, Na2CO3 and KI. The liberated I2 during electrolysis brings in iodoform reaction with C2H5OH in the presence of Na2CO3. Properties of trihalides. Pure chloroform and bromoform are colourless liquids, and iodoform is yellow solids. All are heavier than 95

water and soluble in organic solvents, but insoluble in water. CHCI3 brings temporary unconsciousness when vapours are inhaled for sufficient time and thus used as anaesthetic agent. CHCI3 is non inflammable but like other halides its vapours when ignited on Cu wire burn with green edge flame. (Beilstein test). Chemical properties of trihalides 1. Oxidation: On exposure to air and sunlight, chloroform is slowly oxidized to a poisonous gas carbonyl chloride i.e. phoszene

Therefore purity of chloroform should be checked before its use as anaesthetic agent. Pure CHCI3 does not give white ppt. of AgCI with AgNO3. Also pure chloroform neither turns blue litmus to red nor gives black colour on shaking with H2SO4 conc. Also, the following precautions are necessary to store CHCI3 to be used as anaesthetic agent. It is kept in brown or blue coloured bottles which are filled upto the brim in order to protect from the action of light and air. 1% ethanol is also added, which acts as a negative catalyst for oxidation of CHCI3 as well as converts carbonyl chloride into harmless ethyl carbonate. 2. Reduction: CHCI3 + 2H

CH2CI2 + HCI

CHCI3 + 4H

CH2CI2 + 2HCI

CHCI3 + 6H

CH4 + 3HCI

3. Hydrolysis or action of KOHaq: CHCI3 + 4KOH → HCOOK + 3KCI + 2H2O 4. Chlorination: CHCI3 + CI2

CCI4 + HCI

96

5. Action of Ag powder:

6. Action of HNO3: The H atom of CHCI3 is replaced by -NO2 group if heated with conc. HNO3.

7. Condensation with acetone:

8. Reaction with sodium ethoxide

9. Riemer - Tiemann reacton: (see phenol)

10. Carbylamine reaction: All primary amines (may be aliphatic R-NH2 or aromatic Ar-NH2) on warming with CHCI3 and KOHalc. undergo carbylamne reaction giving an offensive or unpleasant odour of isonitrile or carbylamines. 97

Uses: 1. CHCI3, an anaesthetic agent; CHI3 as antiseptic due to liberation of I2. 2. CHCI3 as solvent for fat, waxes, rubbers, resins etc. 3. In preparation of chlorotone (drug, a hypnotic agent) and nitrochloroform (an insecticide). 4. CHCI3 as preservative for anatomical specimens 5. As laboratory reagent to identify primary amines and other analytical tests. Note: Iodoform on heating with AgNO3 gives yellow AgI whereas chloroform does not give this test because of stable nature. 1. Iodoform has antiseptic properties because of coming in contact with organic matter of skin it decomposes to give free iodine which acts as an antiseptic. 2. Halothane, CF3-CHCIBr, is used as a general anaesthetic which has replaced diethyl ether. Methods of preparation of tetrachloromethane Manufacture: 1) From methane: Chlorination of methane with excess of chlorine at 400oC yields impure carbon tetrachloride.

Methane used in this process is obtained from natural gas. 2) From carbon disulphide: Chlorine reacts with carbon disulphide in the presence of catalysts like iron, iodine, aluminium chloride or antimony pentachloride. CS2 + 3CI2 → CCI4 + S2CI2 98

S2CI2 further reacts with CS2 to form more of carbon tetrachloride. CS2 + 2S2CI2 → CCI4 + 6S CCI4 is washed with NaOH solution and then distilled to get a pure sample. 3) By the action of chlorine on chloroform. CHCI3 + CI2 → CCI4 + HCI Chemical properties of tetrachloromethane Properties: It is a colourless, non inflammable, poisonous liquid with characteristic smell. Insoluble in water but soluble in ethanol and ether. It is a good solvent for oils, fats and greases. Chemical nature: Less reactive than other halogen derivatives. 1. Oxidation or reaction with steam:

2. Reduction: most iron fillings reduce CCI4 to CHCI3

3. Hydrolysis (action of aqueous KOH): CCI4 + 6KOH(aq.) → 4KCI + K2CO3 + 3H2O Freon-12 (dichlorodifluoromethane) is widely used as a refrigerant and propellant in aerosol sprays of all kinds. 4. Action of hydrogen fluoride in the presence of SbF5. CCI4 + 2HF

CCI3F2 + 2HCI

5. Reaction with phenol and alkali (Reimer-Tiemann reaction). 99

Uses: Carbon tetrachloride is used 1) as a fire extinguisher under the name pyrene. Then dense, non combustile vapours over the burning substances prevent oxygen from reaching them. However, since CCI4 forms phosgene, after the use of pyrene to extinguish a fire the room should be well ventilated. 2) as a laboratory reagent 3) as a solvent for oils, fats, resins, iodine and in dry-cleaning. 4) as a fumigant 5) in medicine for elimination of hookworms as helmenthicide due to antihelminthic nature. Some useful halogen derivatives 1. Freons: The chloro fluoro derivatives of methane and ethane are called freons. Some of the derivatives are: CHF2CI (monochlorodifluoromethane), CF2CI2 (dichloro difluro methane), HCF2CHCI2 (1, 1-dichloro 2, 2-difluoroethane). These are non-inflammable, colourless, non-toxic and low boiling liquids. These are stable up to 550oC. The most important and useful derivative is CF2CI2 which is commonly known as Freon on Freon-12. Freon or freon-12 (CF2CI2) is prepared by treating carbon tetrachloride with antimony trifluoride in the presence of antimony penta chloride (a catalyst). 3CCI4 + 2SbF3

3CCI2F2 + 2SbCI3

or by reacting carbon tetrachloride with hydrofluoric acid in the presence of antimony penta fluoride.

CCI4 + 2HF

CCI2F2 + 2HCI 100

Under normal conditions Freon is a gas (b.pt. - 29.8 °C). It can easily be liquefied. It is chemically inert and is used in air-conditioning and in domestic refrigerators. Note: Freon-14 is CF4, Freon-13 is CF3CI, Freon-11 is CFCI3. All these are used as refrigerants. 2. Teflon: A plastic-like substance produced by the polymerizetion of tetrafluoroethylene (CF2 = CF2). Tetrafluoroethylene is formed when chloroform is treated with antimony trifluoride and hydrofluoric acid. On polymerization, tetrafluoro ethylene forms a plastic-like material which is called teflon. nCF2=CF2 → tetrafluoro ethylene

(CF2-CF2)n Teflon

Teflon is a chemically inert substance. It is not affected by strong acids and even by boiling aquaregia. It is stable at high temperature and thus, used for electrical insulation and preparation of gasket materials. 3. Acetylene tetrachloride (Westron), CHCI2CHCI2: Acetylene tetrachloride is also known as sym. tetrachloroethane. It is prepared by the action of chlorine on acetylene in the presence of a catalyst such as ferric chloride, aluminium chloride, iron, quartz or kieselguhr. CH≡CH + 2CI2 → CHCI2CHCI2 In the absence of a catalyst, the reaction between chlorine and acetylene is highly explosive producing carbon and HCI. The reaction is less violent in the presence of a catalyst. It is a heavy, non-inflammable toxic liquid with a smell like CHCI3. It is insoluble in water but soluble in organic solvents. On further chlorination, it forms penta and hexachloroethane. On heating with lime (calcium hydroxide), it is converted into a useful product westrosol (CCI2=CHCI) 2C2H2CI4 + Ca(OH)2 → 2CHCI2=CCI2 + CaCI2 + 2H2O 101

6.5. ALCOHOL In chemistry, an alcohol is an organic compound in which a hydroxyl group (-OH) is bound to a carbon atom of an alkyl or substituted alkyl group. The general formula for a simple acyclic alcohol is CnH2n+1OH. In common terms, the word alcohol refers to ethanol, the type of alcohol found in alcoholic beverages. Ethanol is a colorless, volatile liquid with a mild odor which can be obtained by the fermentation of sugars. (Industrially, it is more commonly obtained by ethylene hydration-the reaction of ethylene with water in the presence of phosphoric acid.) Ethanol is the most widely used depressant in the world, and has been used for thousands of years. This sense underlies the term alcoholism (addiction to alcohol). Other alcohols are usually described with a clarifying adjective, as in isopropyl alcohol (propan-2-ol) or wood alcohol (methyl alcohol, or methanol). The suffix -ol appears in the "official" IUPAC chemical name of all alcohols. There are three major subsets of alcohols: primary (1°), secondary (2°) and tertiary (3°), based upon the number of carbon atoms the C-OH group's carbon is bonded to. Ethanol is a simple 'primary' alcohol. The simplest secondary alcohol is isopropyl alcohol (propan-2-ol), and a simple tertiary alcohol is tert-butyl alcohol (2-methylpropan-2-ol). Structure of alcohol. Alcohols are compounds of the general formula ROH, where R is any alkyl or substituted alkyl group. The group may be primary, secondary, or tertiary; it may be open-chain or cyclic; it may contain a double bond, a halogen atom, or an aromatic ring. For example,

102

All alcohols contain the hydroxyl (-OH) group, which, as the functional group, determines the properties characteristic of this family. Variations in the structure of the R group may affect the rate at which the alcohol undergoes certain reactions, and even, in a few cases, may affect the type of reaction. Compounds in which the hydroxyl group is attached directly to an aromatic ring are not alcohols; they are phenols, and differ so markedly from the alcohols that we shall consider them separately. Classification of alcohol. Monohydric alcohols: Containing two OH gp e.g. CH3OH methyl alcohol Dihydric alcohols: Containing two OH gp e.g. HO-CH2-OH Polyhydric alcohols: Containing more than two OH gp, e.g. CH2OHCHOHCH2OH Note: If two or more hydroxyl groups are attached to the same carbon atom, the compound is usually unstable and loses a molecule of water to give a stable and therefore two or more hydroxyl groups must be present on different carbon atoms. We classify a carbon atom as primary, secondary, or tertiary according to the number of other carbon atoms attached to it. An alcohol can further be classified according to the kind of carbon that bears the -OH group:

One reaction, oxidation, which directly involves the hydrogen atoms attached to the carbon bearing the -OH group, takes an entirely different course for each class of alcohol. Usually, however, alcohols of different classes differ only in rate or mechanism of reaction, and in a way are consistent with their structures. Certain substituents may affect reactivity in such a way as to make an alcohol of one class 103

resemble the members of a different class. Benzyl alcohol, for example, though formally a primary alcohol, often acts like a tertiary alcohol. We shall find that these variations, too, are consistent with the structures involved. Allylic alcohols: In these alcohols, the —OH group is attached to a sp3 hybridised carbon next to the carbon-carbon double bond, that is to an allylic carbon. For example,

Benzylic alcohols: In these alcohols, the -OH group is attached to a sp3-hybridised carbon atom next to an aromatic ring. For example,

Vinylic alcohols: These alcohols contain -OH group bonded to a carbon-carbon double bond, i.e., to a vinylic carbon or to an aryl carbon.

Structure of alcohols: In alcohols carbon as well as oxygen both show sp3 hybridization. In carbon all the four sp3 hybridized orbitals have an electron in each orbital whereas in oxygen two of the four sp3 hybridized orbitals have one electron and the other two orbitals have an electron pair in each. These two completely filled orbitals in the oxygen atom do not take part in bonding and give rise to contraction in the bond angles due to the lone pair effect and therefore the bond angle C-O-H is 105o, which is lesser than the normal tetrahedral structure. 104

Nomenclature of alcohol. For the simpler alcohols the common names, are most often used. These consist simply of the name of the alkyl group followed by the word alcohol. For example:

We should notice that similar names do not always mean the same classification; for example, isopropyl alcohol is a secondary alcohol, whereas isobutyl alcohol is a primary alcohol. Finally, there is the most versatile system, the IUPAC. The rules are: 1. Select as the parent structure the longest continuous carbon chain that contains the -OH group; then consider the compound to have been derived from this structure by replacement of hydrogen by various groups. The parent structure is known as ethanol, propanol, butanol, etc., depending upon the number of carbon atoms; each name is derived by replacing the terminal -e of the corresponding alkane name by -ol. 2. Indicate by a number the position of the -OH group in the parent chain, generally using the lowest possible number for this purpose. 3. Indicate by numbers the positions of other groups attached to the parent chain.

105

Alcohols containing two hydroxyl groups are called glycols. They have both common names and IUPAC names.

Nomenclature:

Common name CH3OH methyl alcohol CH3CH2OH ethyl alcohol CH3CH2CH2OH n-propyl alcohol CH3CHOHCH3 isopropyl alcohol CH3CH2CH2CH2OH n-butyl alcohol (CH3)2CHCH2OH isobutyl alcohol CH3CH2CHOHCH3 sec.butyl alcohol (CH3)3COH t-butyl alcohol

Carbinol name

IUPAC name

carbinol methyl carbinol ethyl carbinol

Methanol Ethanol propanol-1

dimethyl carbinol

propanol-2

propyl carbinol isopropyl carbinol

butanol-1 2-methylpropanol-1

ethylmethylcarbinol

butan-2-ol

trimethyl carbinol

2-methylpropan-2-ol

6.6. ETHERS Ethers are compounds of the general formula R–O–R, Ar–O–R, or Ar–O–Ar. To commonly name ethers we usually name the two groups that are attached to oxygen, and follow these names by the word ether:

106

If one group does not have a simple name, the compound may be named as an alkoxy derivative:

If the two groups are identical, the ether is said to be symmetrical (e.g., diethyl ether, diphenyl ether), if different, unsymmetrical (e.g., methyl tert-butyl ether, anisole). Nomenclature: Ethers are supposed to have no functional group and thus IUPAC nomenclature does not provide their suffix name. These are named (in IUPAC) as alkoxy alkane, the smaller alkyl group along with oxygen is called alkoxy substituent. Formula CH3OCH3 CH3OCH2CH3 CH3OCH2CH2CH3

CH3CH2OCH2CH3

Trivial Name Dimethyl ether Methyl ethyl ether Methyl propyl ether

IUPAC Name Methoxymethane Methoxyethane 1-Methoxypropane

Methyl isopropyl ether

2-Methoxypropane

Diethyl ether

Ethoxyethane

Isomerism of ethers. Ethers show functional isomerism with alcohols. CH3OCH3 and CH3CH2OH Ethers with at least four carbon atoms show metamerism due to different alkyl gps attached on bivalent O atom.

107

Structure of ether. In CH3OCH3, the central oxygen atom is sp3 hybridized with two completely filled sp3 orbitals having a lone pair of electrons and two half filled sp3 hybridized orbitals. Also carbon atoms are sp3 hybridized and both the half filled sp3orbitals of O atom from strong s (C-O) bonds with half filled sp3 orbitals of two adjacent carbon atoms of alkyl groups. The C-O-C bond angle is about 110 °C which is quite closer to 109° 28' of sp3 hybridized nature, in spite of the fact that the lone pair of electrons must result in contraction in bond angles. This is because of the fact that the presence of alkyl gps on O atom counterbalances the repulsion between the lone pair – bond pair electrons and leads to the bond angle nearer to 109° 28'. Preparations: Alcohols. Alcohols can be prepared by the hydration of alkenes or by the reduction of aldehydes, ketones, acids, and esters. Williamson synthesis

Hydroboration-oxidation

Reduction of aldehydes and ketones

108

Reduction of carboxylic acids

Reduction of esters

Grignard reagent with aldehydes and ketones

Reactions of alcohols. Alcohols are capable of being converted to metal salts, alkyl halides, esters, aldehydes, ketones, and carboxylic acids. Metal salt formation. Alcohols are only slightly weaker acids than water, with a K a value of approximately 1 × 10 −16. The reaction of ethanol with sodium metal (a base) produces sodium ethoxide and hydrogen gas.

109

This reaction is identical to the reaction of sodium metal with water.

However, the latter reaction occurs faster because of the increased acidity of water (Ka value of 1 × 10 −15). Likewise, similar reactions occur with potassium metal. The acidity of alcohols decreases while going from primary to secondary to tertiary. This decrease in acidity is due to two factors: an increase of electron density on the oxygen atom of the more highly‐substituted alcohol, and steric hindrance (because of the alkyl groups, which inhibit solvation of the resulting alkoxide ion). Both of these situations increase the activation energy for proton removal. The basicity of alkoxide ions increases while going from primary to tertiary. This increase in basicity occurs because the conjugate base of a weak acid is strong. The weaker the acid, the stronger the conjugate base. Alkyl halide formation. Alcohols are converted to alkyl halides by SN1 and SN2 reactions with halogen acids.

Primary alcohols favor S N2 substitutions while S N1 substitutions occur mainly with tertiary alcohols. A more efficient method of preparing alkyl halides from alcohols involves reactions with thionyl chloride (SOCl2).

This reaction is rapid and produces few side reaction products. In addition, the sulfur dioxide and hydrogen chloride formed as by110

products are gasses and therefore easily removed from the reaction. Mechanistically, the alcohol initially reacts to form an inorganic ester.

The chloride ion produced by this reaction, acting as a nucleophile, attacks the ester in an S N2 fashion to yield molecules of sulfur dioxide, hydrogen chloride, and an alkyl halide.

Because the reaction proceeds mainly by an S N2 mechanism, the alkyl halide produced from an optically active alcohol will have the opposite relative configuration from the alcohol from which it was formed.

Because thionyl bromide is relatively unstable, alkyl bromides are normally prepared by reacting the alcohol with phosphorous tribromide (PBr3). 111

This reaction proceeds via a two‐step mechanism. In the first step, the alcohol reacts with the phosphorous tribromide.

The second step is an S N1 or S N2 substitution in which the bromide ion displaces the dibromophosphorous group.

In a similar manner, alkyl iodides are prepared by reacting an alcohol with phosphorous triiodide. Ester formation. Esters are compounds that are commonly formed by the reaction of oxygen‐containing acids with alcohols. The ester functional group is the

Alcohols can be converted to esters by means of the Fischer Esterification Process. In this method, an alcohol reacts with a carboxylic acid in the presence of an inorganic acid catalyst. Because the reaction is an equilibrium reaction, in order to receive a good yield, one of the products must be removed as it forms. Doing this drives the equilibrium to the product side.

112

The mechanism for this type of reaction consists of seven steps: 1. The mechanism begins with the protonation of the acetic acid.

2. The π electrons of the carboxyl group,

, migrate to pick

up the positive charge.

3. The oxygen of the alcohol molecule attacks the carbocation.

4. The formed oxonium ion loses a proton.

5. One of the hydroxyl groups is protonated to form an oxonium ion.

113

6. An unshared pair of electrons on another hydroxy group reestablishes the carbonyl group, with the loss of a water molecule.

7. The oxonium ion loses a proton, which leads to the production of the ester.

Alkyl sulfonate formation. Alcohols may be converted to alkyl sulfonates, which are sulfonic acid esters. These esters are formed by reaction of an alcohol with an appropriate sulfonic acid. For example, methyl tosylate, a typical sulfonate, is formed by reacting methyl alcohol with tosyl chloride.

Other sulfonyl halides that form alkyl sulfonates include:

114

These groups are much better leaving groups than the hydroxy group because they are resonance stabilized. Alcohol molecules that are going to react by SN1 or SN2 mechanisms are often first converted to their sulfonate esters to improve both the rate and yield of the reactions. Formation of aldehydes and ketones. The oxidation of alcohols can lead to the formation of aldehydes and ketones. Aldehydes are formed from primary alcohols, while ketones are formed from secondary alcohols. Several examples of the oxidation of primary alcohols:

Because ketones are more resistant to further oxidation than aldehydes, you may employ stronger oxidizing agents and higher temperatures. Secondary alcohols are normally converted to ketones by reaction with potassium dichromate (K2Cr2O7), potassium permanganate (KMnO4), or chromium trioxide in acetic acid (CrO3/CH3COOH). Several examples of the oxidation of secondary alcohols: 115

Carboxylic acid formation. Upon oxidation with strong oxidezing agents and high temperatures, primary alcohols completely oxidize to form carboxylic acids. The common oxidizing agents used for these conversions are concentrated potassium permanganate or concentrated potassium dichromate. Here are several examples of this type of oxidation:

Carbonyl compounds Carbonyl Compounds are the organic compounds containing carbon-oxygen double bond (> C = 0). > C = O is the most important functional group of organic chemistry. Carbonyl compounds in which carbonyl group is bonded to a carbon and hydrogen are known as aldehydes. 116

Carbonyl compounds in which carbonyl group is bonded to carbon atoms are known as ketons. The carbonyl compounds in which carbonyl group is bonded to oxygen are known as carboxylic acids, and their derivatives (e.g. esters, anhydrides) Carbonyl compounds where carbon is attached to nitrogen are called amides. Carbonyl compounds where carbon is attached to haligen are called acyl halides.

6.7. ALDEHYDES AND KETONE Aldehydes are the compounds which have general formula RCHO, ketones are compounds having general formula RR’CO. The groups R and R’ may be aliphatic or aromatic, similar or different alkyl groups. Both aldehydes and ketones contain the carbonyl group, >C = O, and are often referred to collectively as carbonyl compounds. It is the carbonyl group that mainly governs the chemistry of aldehydes and ketones.

117

The melting points, boiling points, and water solubilities of some representative ketones and aldehydes. Although pure ketones and aldehydes cannot be engaged in hydrogen bonding with each other, they have lone pairs of electrons and can act as hydrogen bond acceptors with other compounds having O – H or N – H bonds. For example, the – OH of water or an alcohol can form a hydrogen bond with the unshared electrons on a carbonyl oxygen atom. We will discuss aldehydes and ketones in detail in the following topics. Nomenclature of aldehydes and ketones. Ketones are named by replacing the -e in the alkane name with -one. The carbon chain is numbered so that the ketone carbon, called the carbonyl group, gets the lowest number. For example, would be named 2-butanone because the root structure is butane and the ketone group is on the number two carbon. Alternatively, functional class nomenclature of ketones is also recognized by IUPAC, which is done by naming the substituents attached to the carbonyl group in alphabetical order, ending with the word ketone. The above example of 2-butanone can also be named ethyl methyl ketone using this method.  If two ketone groups are on the same structure, the ending dione would be added to the alkane name, such as heptane-2, 5-dione.  Aldehydes replace the -e ending of an alkane with -al for an aldehyde. Since an aldehyde is always at the carbon that is numbered one, a number designation is not needed. For example, the aldehyde of pentane would simply be pentanal.  The -CH=O group of aldehydes is known as a formyl group. When a formyl group is attached to a ring, the ring name is followed by the suffix "carbaldehyde". For example, a hexane ring with a formyl group is named cyclohexanecarbaldehyde. 118

The common name of aldehydes is derived from the names of the corresponding carboxylic acids by replacing -ic acid by -aldehyde.

The IUPAC names of aldehydes follow the usual pattern. The longest chain containing the –CHO group is considered the parent structure and named by replacing -e of the corresponding alkane by -al. The position of the substituent is indicated by a number, the carbonyl carbon always being considered C-1. Here, as with the carbonyl acids, the C-2 of the IUPAC name corresponds to alpha of the common name. The simple aliphatic ketone has the common name acetone. For most other aliphatic ketones we name the two groups that are attached to carbonyl carbon and follow these names by the word ketone. A ketone in which the carbonyl group is attached to a benzene ring is named as a-phenone, all illustrated below. According to IUPAC system, the longest chain carrying the carbonyl group is considered the parent structure, and is named by replacing –e of the corresponding alkane with one. The positions of various groups are indicated by numbers.

Physical properties. Polarization of the carbonyl group creates dipole - dipole interactions between the molecules of ketones and aldehydes, resulting in higher boiling points than for hydrocarbons and ethers of similar molecular weights. Ketones and aldehydes have no O – H or N – H bonds, so they cannot form hydrogen bonds with each other. The following compounds of molecular weight 58 or 119

60 are ranked in order of increasing boiling point. The ketones and the aldehyde are more polar and have higher boiling points than the ether and the alkane, but lower boiling points than the hydrogenbonded alcohol.

The melting points, boiling points, and water solubilities of some representative ketones and aldehydes. Although pure ketones and aldehydes cannot engage in hydrogen bonding with each other, they have lone pairs of electrons and can act as hydrogen bond acceptors with other compounds having O – H or N – H bonds. For example, the – OH of water or an alcohol can form a hydrogen bond with the unshared electrons on a carbonyl oxygen atom.

Because of this hydrogen bonding, ketones and aldehydes are good solvents for polar hydroxylic substances such as alcohols. They are also remarkably soluble in water. That acetaldehyde and acetone are miscible (soluble in all proportions) with water, and other ketones and aldehydes with up to four carbon atoms are appreciably soluble in water. These solubility properties are similar to those of ethers and alcohols, which also engage in hydrogen bonding with water. Formaldehyde and acetaldehyde are the most common aldehydes. Formaldehyde is a gas at room temperature, so it is often stored and used as a 40 percent aqueous solution called formalin. When dry formaldehyde is needed, it can be generated by heating one of the solid derivatives of formaldehyde, usually trioxane units. Parafor120

maldehyde is a linear polymer, containing many formaldehyde units. These solid derivatives form spotaneously when a small amount of acid catalyst is added to pure formaldehyde.

Acetaldehyde boils near room temperature, and it can be handled as a liquid. Acetaldehyde is also used as a trimer (paraldehyde) and a tetramer (metaldehyde), formed from acetaldehyde under acid catalysis. Heating either of these compounds provides dry acetaldehyde. Paraldehyde is used in medicines as a sedative, and metaldehyde is used as a bailt and poison for snails and slugs. Chemical properties of aldehydes and ketone Oxidation

Tollen’s reagent A specific oxidant for RCHO is Ag(NH3)2+

Tollen’s test is chiefly used for the detection of aldehydes. Tollen’s reagent does not attack carbon-carbon double bonds. 121

Strong oxidants: Ketones resist mild oxidation, but with strong oxidants at high temperature they undergo cleavage of C – C bonds on either sides of the carbonyl gorup.

Haloform reaction. CH3COR are readily oxidised by NaOI (NaOH + I2) to iodoform, CHI3, and RCO2Na. Example:

Reduction of aldehydes and ketones. a) Reduction to alcohols

Aldehydes → 1° alcohols; Ketones → 2°alcohols

Example:

b) Reduction to hydrocarbons 122

Addition reactions of carbonyl compounds. The C of the carbonyl group is electrophilic

and initially forms a bond with the nucleophile

a) Addition of cyanide

123

b) Addition of bisulfite

Example

c) Addition of derivative of ammonia

Product H2N – NH2 H2N – NH – C6H5 H2N – NH – C – NH2 || O

H2N – G Hydrazine Phenylhydrazine Semicarbazide

Product > C = N – NH2 > C = N – NHC6H5 > C = N –NHCONH2

2, 4Dinitrophenyl hydrazine

H2N – G Hydrazone Phenylhydrazone Semicarbazone

2, 4 dinitrophenylhydra zone (bright orange or yellow precipitate used for identifying aldehydes and ketones

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d) Addition of Grignard reagent

e) Addition of hydroxylamine

f) Addition of alcohols; acetal formation

In H3O+, RCHO is regenerated because acetals undergo acid catalyzed cleavage much more easily than do ethers. Since acetals are stable in neutral or basic media, they are used to protect the – CH = O group. Halogenation of ketones

125

Conversion to dihalides

Acidity of a-hydrogens. Carbonyl group largely determines the chemistry of aldehydes and ketones. The carbonyl group strengthens the acidity of hydrogen atoms attached to the a-carbon and by doing this gives rise to a whole set of chemical reactions.

Aldol condensation. Substrate aldehyde or ketone containing hydrogen Reagent Dilute Base Product ß-hydroxyaldehyde or b-hydroxyketone Under the influence of a dilute base or a dilute acid, two molecules of an aldehyde or ketone may combine to form a b-hydroxy aldehyde or ketone. The a-carbanion generated by the base from one molecule of aldehyde or ketone adds to the carbonyl carbon of the other molecule, and the two molecules condense and form b-hydroxy aldehyde or ketone. Let us consider the mechanism for the OH catalysed aldol condensation of acetaldehyde:

126

Aldol condensations are reversible, and with ketones the equilibrium is unfavourable for the condensation product. b-hydroxycarbonyl compounds are readily dehydrated to give a-b-unsaturated carbonyl compounds. With Ar on b-carbon, only dehydrated product is isolated. Crossed aldol condensation. An aldol condensation between two different carbonyl compounds so called crossed aldol condensation – is not always useful as a mixture of four different possible products may be obtained. Under certain conditions, a good yield of a single product can be obtained from a crossed aldol condensation. One reactant contains no a-hydrogens and therefore is uncapable of condensing with itself (eg. Aromatic aldehydes or formaldehyde).

Cannizzaro reaction. Discussion: In the presence of concentrated alkali, aldehydes containing no – a-hydrogens undergo self-oxidation and reduction to yield a mixture of an alcohol and a salt of a carboxylic acid. This reaction is known as Cannizzaro – reaction. Two successive additions are involved. a) Addition of a hydroxide ion in the first step b) Addition of a hydride ion in the next step 127

This explains the Crossed Cannizzario reaction involving formaldehyde to take place in the way that it does. ArCHO + HCHO → HCO2Na+ + ArCH2OH On both electronic and steric grounds, step 1 is faster for HCHO.

Perkin condensation

128

Ester can be condensed with aromatic aldehydes in the presence of alkoxides; thus benzaldehyde and ethylacetate in the presence of sodium ethoxide give ethyl cinnamate C6H5CH = CHCOOC2H5.

Halogenation of ketones

Examples

The Haloform Test depends upon the fact that the three hydrogens on the same carbon atom are successively replaced by halogen. Taking acetone as an example we see that the carbon that suffers the initial substitution to the preferred site undergoes further substitution. 129

Electron withdrawal by halogen makes hydrogens on the carbon to which halogen has already been attached more acidic and hence more readily removed by the base to give further substitution.

Electron withdrawal by three halogens makes –CX3 comparatively weakly basic (for a carbanion) and hence acts as a good leaving group. Thus both essential aspects of the haloform reaction – regiospecificity of halogenation, and cleavage – are controlled by the factor; stabilization of a carbanion through electron withdrawal. Claisen condensation, formation of β-Keto esters. An α-hydrogen in an ester, like an α -hydrogen in an aldehyde or ketone, is weakly acidic, because, the carbonyl group helps to accommodate the negative charge of the carbanion. When ethyl acetate is treated with sodium ethoxide, and the resulting mixture is acidified ethyl 3-oxobutanoate, generally known as ethyl acetoacetate or acetoacetate or acetoacetic ester is obtained.

130

Ethyl accetoacetate is the ester of a β-Keto acid; its preparation illustrates the reaction known as the Claisen condensation.

Crossed Claisen condensation Examples:

Ketones (but not aldehydes) undergo a crossed Claisen Condensation with ester. Example:

Decarboxylation of β-Keto acids. β-Keto esters are normally prepared by Claisen condensation. Hydrolysis of the β-keto ester gives the β-keto acids which can be very easil decarboxylated simply by heating. Decarboxylation of free acetoacetic acid involves transfer of the acidic hydrogen to the keto-group followed by loss of carbondioxide via a cyclic 6-membered. 131

Addition of ammonia. Aldehydes react with ammonia to form aldehyde ammonia

The aldehyde ammonia is unstable and loses water immediately to form aldimine. The dehydration product is not usually obtained because, in most cases, it immediately polymerises to form cyclic trimers.

When treated with ammonia, formaldehyde does not form an aldehyde – ammonia, but gives instead hexamethylenetetramine, used in medicine as a urinary antiseptic under the name Urotoropine.

132

Ketones also give ketone-ammonia but these cannot be isolated. Acetone reacts slowly with ammonia to form acetone ammonia and then a complex compound.

Acetone upon treatment with ammonia at higher temperature gives acetoneammonia.

Aldimines, Schiff’s bases or azomethines are formed when aldehydes react with aliphatic primary amines, which are removed by slow distillation. Meerwein – Ponndorf – Verley reduction The carbonyl compound is heated with aluminium isopropoxide in isopropanol solution, the isopropoxide is oxidised to acetone, which is removed by slow distillation.

133

The reducing agent is specific for the carbonyl group, and so may be used for reducing aldehydes and ketones containing the other functional group that is reducible e.g., a double bond or a nitro group.

Pinacol-Pinacolone rearrangement (1, 2-methyl shift) upon treatment with hot H2SO4, pinacol undergoes a rearrangement and dehydration to give a methyl ketone.

Tischenko reaction. All aldehydes can be made to undergo the Cannizzaro reaction by treatment with aluminium ethoxide. Under these conditions the acids and alcohols are combined as the ester, and the reaction is then known as the Tischenko reaction; e.g., acetaldehyde gives ethyl acetate, and propionaldehyde gives propyl propionate

134

Benzoin condensation: When refluxed with aqueous ethanolic potassium cyanide benzaldehyde forms benzoin.

Sommelet's reaction. Benzaldehyde is produced when benzyl chloride is refluxed with hexamethylenetetramine in aqueous ethanolic solution followed by acidification and steam distillation. C6H5CH2Cl + (CH2)6N4→ C6H5CHO Analysis of aldehydes and ketones. Aldehydes and ketones are characterized through the addition to the carbonyl group of nucleophilic reagents, especially derivatives of ammonia. All aldehyde or ketone will, for example, react with 2, 4-dinitrophenylhydrazine to form an insoluble yellow or red solid. Aldehydes are characterized, and in particular are differentiated from ketones through their ease of oxidation: aldehydes give a positive test with Tollen's reagent; ketones do not. Aldehydes are also, of course, oxidized by many other oxidizing agents: by cold, dilute, neutral KMnO4 and by CrO3 in H2SO4. A highly sensitive test for aldehydes is the Schiff’s test. 135

Aldehydes and ketones are generally identified through the melting points of derivatives like 2, 4-dinitrophenylhydrazones, oximes, and semicarbazones. Methyl Ketones are characterized through the iodoform test. Aldehydes can be oxidised by Fehling's solution. Fehling's solution, an alkaline solution of cupric ion complexed with a tartarate ion (or Benedict's solution, in which complexing is with a citrate ion); the deep-blue colour of the solution is discharged, and red cuprous oxide precipitates. Fehling's solution is made by mixing, Fehling A solution contains copper sulphate. Fehling B solution contains sodium hydroxide and Rochelle salt (Sodium Potassium Tartarate). During the oxidation of aldehydes to acids, the cupric ions are reduced to cuprous ions which are precipitated as red cuprous oxide. RCHO + 2Cu2+ + 3-OH → R-CO-2 + 2Cu+ + 2H2O 2Cu+ + 2-OH → Cu2O¯ + H2O 6.8. CARBOXYLIC ACIDS AND ITS DERIVATIVES Of the organic compounds that show appreciable acidity, by far the most important are the carboxylic acids. These compounds contain the carboxyl group attached to hydrogen (HCOOH) an alkyl group (RCOOH), or an aryl group (ArCOOH). These are also named as fatty acids because of some higher members, particularly, palmitic and stearic acids, occur in natural fats. The general formula of the carboxylic acids is CnH2nO2. Only the hydrogen atom of the carboxyl group is replaceable by a metal, therefore the fatty acids are mono-basic. Carboxylic acids are characterized by the presence of carboxyl group. The COOH group which itself is made up of a carbonyl group (C=O) and a hydroxyl group (¾OH) is called carboxyl group (carb from carbonyl and oxyl from hydroxyl).

136

Carboxylic acids may be aliphatic or aromatic

Comparison of resonating structures of carboxylic group and carbonyl group. Carbonyl group has two resonance structures (I and II)

However, for a carboxyl group, three resonance structures (A, B and C) can be written.

In both structures (A) and (C), the C – atom and the two O – atoms have eight electrons in their respective valence shells while in structure (B), the C – atom has only six electrons. Therefore, structure (B) is less stable than structure (C), in other words the two important resonance structures of carboxyl group are structures (A) and (C). In both these structures, carboxyl carbon is electrically neutral. However, in case of aldehydes and ketones, only one structure i.e. I is electrically neutral. As a result, the carboxyl carbon of the resonance hybrid is less positive and hence less electrophilic than the carbonyl carbon of aldehydes and ketones. However, it may be noted that like carbonyl group, carboxyl group is also polar due to resonance structures (B) and (C) 137

Nomenclature of carboxylic acids. The aliphatic carboxylic acids are commonly known by their initial names, which have been derived from the source of the particular acid. Examples: Carboxylic Acid HCOOH CH3COOH CH3–CH2–COOH CH3(CH2)2COOH CH3(CH2)3COOH CH3(CH2)14COOH CH3(CH2)16COOH

Common Name Formic acid [Latin: Fermica = ant] Acetic acid [Latin: acetum = vinegar] Propionic acid Butyric acid Valeric acid Palmitic acid Stearic acid

Another system of nomenclature, except Formic acid considers acids as acid derivatives of acetic acid Example: CH3 – CH2 – COOH Methyl acetic acid (CH3)3C – COOH Trimethyl acetic acid According to the IUPAC system of nomenclature, the suffix of the monocarboxylic acid is ‘oic acid’, which is added to the name of the alkane corresponding to the longest carbon chain containing the carboxyl group, e.g. HCOOH methanoic acid CH3 – CH2 – CH2 – COOH butanoic acid The positions of side-chains (or substituents) are indicated by numbers, the carboxyl group is always given number I.

Naming of acyl groups; acid chlorides and acid anhydrides. The group obtained from a carboxylic acid by the removal of the hydroxyl portion is known as an acyl group. The name of an acyl 138

group is created by changing the 'ic' at the end of the name of the carboxylic acid to 'yl', examples:

Acid chlorides are named systematically as acyl chlorides.

An acid anhydride is named by substituting anhydride for acid in the name of the acid from which it is derived.

Naming salts and esters. The name of the cation (in the case of a salt) or the name of the organic group attached to the oxygen or the carboxyl group (in the case of an ester) preceeds the name of the acid. The 'ic acid’ part of the name of the acid is converted to 'ate'

139

Name of amides and imides. The names of amides are formed by replacing -oic acid (or -ic acid for common names) by amide or -carboxylic acid by carboxamide.

If the nitrogen atom of the amide has any alkyl group as a substituent, the name of the amide is prefixed by the capital letter N; to indicate substitution on nitrogen, followed by the name(s) of alkyl group(s).

If the substituent on the nitrogen atom of an amide is a phenyl group, the ending for the name of the carboxylic acid is changed to anilide. Some dicarboxylic acids form cylic amides in which two acyl groups are bonded to the nitrogen atom. The suffix imide is given to such compounds.

Physical properties of carboxylic acids. The molecules of carboxylic acids are polar and exhibit hydrogen bonding. The first four are miscible with water. The higher acids are virtually insoluble. The simplest aromatic acid, benzoic acid, contains too many carbon atoms to show appreciable solubility in water. Carboxylic acids are soluble in less polar solvents like ether, alcohol, benzene, etc. 140

Carboxylic acids have higher boiling points than alcohols. These very high boiling points are due to the fact that a pair of carboxylic acid molecules is held together not by one but by two hydrogen bonds and exists as dimer. The first three fatty acids are colourless pungent smelling liquids. A study of nitrated spectra of formic acid in the liquid and solid states has provided evidence that this acid, unlike most of the other carboxylic acids, is not dimeric in these states, but is associated as a polymer. Acidity of carboxylic acids. The acidity of a carboxylic acid is due to the resonance stabilization of its anion

Because of the resonance, both carbon oxygen bonds in the carboxylate anion have identical bond length. In the carboxylic acid, these bond lengths are no longer identical. The acidity of the carboxylic acid depends very much on the substituent attached to –COOH group. Since acidity is due to the resonance stabilization of anion, the substituent causing stabilization of the anion increases acidity whereas the substituent causing destabilization of the anion decrease acidity. For example, electron withdrawing a group disperses the negative charge of the anion and hence makes it more stable causing an increase in the acidity of the corresponding acid, on the other hand, the electron-releasing group increa141

ses the negative charge on the anion and hence makes it less stable causing a decrease in the acidity. In the light of this, the following are the orders of a few substituted carboxylic acids. a) Increase in the number of halogen atoms on α-position increases the acidity, e.g. Cl3CCOOH > Cl2CHCOOH > ClCH2COOH > CH3COOH b) Increase in the distance of halogen from COOH decreases the acidity e.g.

This is due to the fact that the inductive effect decreases with increasing distance. c) Increase in the electro negativity of halogen increases the acidity. FCH2COOH > BrCH2COOH > ICH2COOH Preparation of carboxilic acids. Oxidation is a direct method most commonly used for preparation of carboxylic acids. Direct oxidation of alcohols, ketons, aldehydes, alkenes and alkyl benzene results in formation of carboxylic acids. Oxidation of primary alcohols and aldehydes. Primary alcohols on oxidation give aldehydes, the reaction does not stop here and the oxidation continues to give carboxylic acids as a final product.

Primary alcohol Aldehyde

Carboxylic

or

142

Acid

Example:

2-Metyl-1-butanol

2-Metyl-1-butanoic acid

Oxidation of alkyl benzenes. Strong oxidation of alkyl benzenes also results in formation of carboxylic acids

Example

Grignard synthesis of carboxylic acid. Grignard synthesis has the advantage of increasing the length of carbon chain and thus it is useful for extending the range of available materials.

CO2(g) is bubbled into ether solution of grignard reagent which results in addition of grignard reagent to the C=O bond to form magnesium slats of the carboxylica cids from which carboxylic acids are produced by treatement with mineral acids

This method is useful for converting alkyl halides into corresponding carboxylic acids having one carbon atom more than that present in alkyl halides (ascending the series). Oxidation of alkenes. Strong oxidation of alkenes results in formation of carboxylic acids. Alkenes can be oxidized to carboxylic acids with hot alkaline KMnO4

143

Example: 2-Butene

Ethanoic

Acid

Hydrolysis of nitriles (Cyanides). Just like Grignard synthesis, nitrile synthesis also increases the length of carbon chain. Aliphatic nitriles are prepared by treatment of alkyl halides with sodium cyanide in a solvent that will dissolve both reactants. In dimethyl sulfoxide (DMSO), reaction occurs rapidly and exothermically at room temperature. The resulting nitrile is then hydrolysed to the acid by boiling with aqueous alkali or acid.

Example:

This synthetic method is generally limited to the use of primary alkyl halides. Aryl halides (except for those with ortho and para nitro groups) do not react with sodium cyanide. Hydrolysis of trihalogen derivatives. Trihalogen derivatives in which the three halogen atoms are all attached to the same carbon atom yields carboxylic acid on hydrolysis

CH3CCl3 + KOH → CH3CO2 + H2O Oxidation of methyl ketone. Methyl ketone can be converted to carboxylic acids via the haloform reaction.

144

Koch reaction. A recent method for manufacturing fatty acids is to heat an olefin with carbon monoxide and steam under pressure at 300-400° C in the presence of a catalyst, e.g. phosphoric acid. CH2 = CH2 + CO + H2O → CH3 – CH2 – COOH Heating gem dicarboxylic acids

The most convenient laboratory preparation for formic acid is to heat glycerol with oxalic acid at 100 – 110° C.

Hydrolysis of acyl halides and anhydrides. Acid chlorides on hydrolysis give carboxylate ions which on acidification provide corresponding carboxylic acids. Acid Anhydrides, on the other hand, give the corresponding acid on hydrolysis. Acid Chloride

Carboxylic acid

Acid Chloride

Carboxylic acid Benzoic anhydride

145

Benzoic Acid

Hydrolysis of esters. Acidic hydrolysis of esters gives directly carboxylic acids while basic hydrolysis gives carboxylates, which on acidification gives carboxylic acids

Ethyl Benzoate

Benzoic Acid

Chemical properties of carboxilic acids The characteristic chemical behavior of carboxylic acids is, of course, determined by their functional group, carboxyl, –COOH. This group is made up of a carbonyl group (C = O) and a hydroxyl group (–OH). As we will see, it is the –OH that actually undergoes nearly every reaction. Loss of H+, or replacement by another group is done in a way that is possible only because of the effect of the C = O. Acidity of carboxylic acids. Carboxylic acids are weak acids and their carboxylic anions are strong conjugate bases, which are slightly alkaline due to the hydrolysis of carboxylate anion compared to other species, the order of acidity and basicity or corresponding conjugate bases are as follows: Acidity RCOOH > HOH > ROH > HC ≡ CH > NH3 > RH Basicity RCOO– < HO– < RO– < HCC– < NH2-< R– Reaction of carboxylic acids with metals. The carboxylic acids react with metals to liberate hydrogen and are soluble in both NaOH and NaHCO3 solutions. For example, 2CH3COOH + 2Na → 2CH3COO–Na+ + H2 CH3COOH + NaOH → CH3COO–Na+ + H2O CH3COOH + NaHCO3 → CH3COO–Na+ + H2O + CO2 The carboxylic acids react with metals to liberate hydrogen and are soluble in both NaOH and NaHCO3 solutions. Carboxylic acids dissociate in water to give resonance stabilised carboxylate anions and a hydronium ion. For example,

146

Ionization of carboxylic acids, acidity constant. In aqueous solution, the carboxylic acids undergo self ionization and exist in equilibrium with the carboxilate anion and the hydrogen ion or hydronium ion. RCOO- + H3O+

RCOOH + H2O

The equilibrium constant for the reaction would be Keq = [RCOO-][ H3O+]/[H2O][RCOOH] Here water is a solvent, so its concentration would remain almost the same throughout the reaction. Thus, Keq = [RCOO-] [H3O+]/[RCOOH] Ka = Keq [H2O] Where Keq, is the equilibrium constant and Ka is the acid dissociation constant. For convenience, the strength of an acid is generally indicated by its pKa value rather than its Ka value. pKa = – log Ka  The smaller the pKa, the stronger the acid. Strong acids have pKa values < 1,  The acids with pKa values between 1 and 5 are considered to be moderately strong acids,  Weak acids have pKa values between 5 and 15,  Extremely weak acids have pKa values >15. Carboxylic acids are weaker than mineral acids, but stronger acids than alcohols and many simple phenols 147

Effect of substituents on the acidity of carboxylic acids

Any factor that stabilizes the anion more than it stabilizes the acid would increase the acidity of carboxylic acids. While any factor that decreases the stability of anion would decrease the acidity of carboxylic acids. Electron withdrawing groups disperse the negative charge and thus stabilize the anion, which results in an increase in acidity of the carboxylic acids. Electron donating groups intensify the negative charge and destabilize the anion, which results in a decrease in acidity of carboxylic acid. Carboxylic acids HCOOH CH3COOH ClCH2COOH Cl2CHCOOH Cl3CCOOH CH3CH2CH2COOH CH3CH2CHClCOOH

Ka Value 17.7×10-5 1.75×10-5 136×10-5 5530×10-5 23200×10-5 1.52×10-5 1.52×10-5

From the table it is clear that the electron-withdrowing halogen increases the acidity of carboxylic acids. For example, Chloroacetic acid is about 100 times stronger than acetic acid. Conversion of carboxylic acids into functional derivatives. Carboxylici acids can be convered into a number of other compounds (known as derivatives of carboxylic acids or simply acid derivatives) by replacement of its –OH group by a Cl, OR or NH2.  Replacement of -OH by -Cl forms acid chlorides.  Replacement of -OH by -OR forms ester.  Replacement of -OH by -NH2 forms amide. 148

Carboxylic acid can be recovered simply by hydrolysis of the acid derivatives or one can say that the functional derivatives are all readily reconverted into the acid by simple hydrolysis. Conversion of carboxylic acids into esters (Esterification). Carboxylic acids are esterified with alcohols or phenols in the presence of a mineral acid such as concentrated H2SO4 or HCl gas as a catalyst.

This reaction is reversible and has the same catalyst, hydrogen ion, that catalyzes the forward reaction, i.e. esterification necessarily catalyzes the reverse reaction i.e. hydrolysis. The equilibrium is particularly unfavorable when phenols (ArOH) are used instead of alcohol; yet if water is removed during the reaction, phenolic esters (RCOOAr] are obtained in high yield. The presence of a bulky group near the site of the reaction, whether in alcohol or in the acid, slows down esterification (as well as its reverse, hydrolysis). Reactivity CH3OH > 1° > 2° > 3° Conversion of carboxylic acids into amides. Reaction of carboxylic acids with ammonia results in formation of ammonium salt, which on further heating at high temperature gives amides.

Conversion of carboxylic acids into acid anhydrides. Lower monocarboxylic acid on heating with dehydrating agent (say P2O5) forms anhydrides

Note: Anhydride of formic acid is not known, it gives CO and H2O on heating with conc. H2SO4. 149

HCOOH + Conc. H2SO → H2O + CO Reduction of carboxylic acids to alcohols. Lithium aluminium hydride can reduce an acid to an alcohol; the initial product is an alkoxide from which the alcohol is liberated by hydrolysis. 4 R–COOH + 3LiAlH4 → 4H2 + 2LiAlO2 + (RCH2O)4 AlLi + H2 Hydrolysis of (RCH2O)4 → alcohols Halogenation of aliphatic carboxylic acids (Hell-VolhardZelinsky reaction). In the presence of phosphorus, aliphatic carboxylic acids react smoothly with chlorine or bromine to yield a compound in which a-hydrogen has been replaced by halogen.

The function of the phosphorus is ultimately to convert a little of the acid into acid halide so it is the acid halide, not the acid itself, that undergoes this reaction.

The halogen of this halogenated acid undergoes nucleophilic displacement and elimination much as it does in the simple alkyl halides. Halogenation is therefore the first step in the conversion of a carboxylic acid into many important substituted carboxylic acids.

150

Reaction of carboxylic acids with PCl5, PCl3 and SOCl2. The hydroxyl group of carboxylic acids is replaced by a chlorine atom on treating with PCl5, PCl3 or SOCl2. Thionyl chloride (SOCl2) is used for this reaction because the other two products are gaseous and escape the reaction mixture and we get a pure product RCOOH +PCl5 → RCOCl + POCl3 +HCl RCOOH +PCl3 → 3RCOCl + H3PO3 RCOOH +SOCl2 → RCOCl + SO2 + HCl Here is the summary of all the reactions of carboxylic acids

Carboxylic acid derivatives are formed by substitution of -OH group of carboxylic acids by -X, -OR or -NH2. So, there are four carboxylic acid derivatives. These are generally represented as R – C – Z, where Z is halogen (usually Cl), OCOR', OR' or NH2 (or NHR' or NR2'). 6.8.1. ESTERS Esters are the derivatives of carboxylic acids which are formed by substitution of -OH group of carboxylic acid by -OR. Carboxylic acids are esterified with alcohols or phenols in the presence of a mineral acid such as concentrated H2SO4 or HCl gas as a catalyst. The process of conversion of carboxylic acids into ester by its reaction with alcohols in the presence of mineral acids is known as esterification or esterification reaction. 151

Esterification reaction is reversible and uses the same catalyst, hydrogen ion, that catalyzes the forward reaction, i.e. esterification necessarily catalyzes the reverse reaction i.e. hydrolysis. Reactivity of alcohols for esterification reaction follows the order CH3OH > 1° > 2° > 3°. The equilibrium is particularly unfavorable when phenols (ArOH) are used instead of alcohol; yet if water is removed during the reaction, phenolic esters (RCOOAr] are obtained in high yield. The presence of a bulky group near the site of reaction, whether in alcohol or in the acid, slows down esterification (as well as its reverse, hydrolysis). And that is why the order of reactivity of carboxylic acids for esterification reaction is HCOOH > CH3COOH > RCH2COOH > R2CHCOOH > R3CCOOH The mechanism of esterification reaction. The steps in the mechanism for the formation of an ester from an acid and an alcohol are the reverse of the steps for the acid-catalyzed hydrolysis of an ester, the reaction can go in either direction depending on the conditions used. A carboxylic acid does not react with an alcohol unless a strong acid is used as a catalyst, protonation makes the carbonyl group more electrophilic and enables it to react with the alcohol, which is a weak nucleophile.

Transesterification. An alcohol is capable of displacing another alcohol from an ester. This alcoholysis (cleavage by an alcohol) of an 152

ester is called transesterification. In other words one can say that it is the process of exchanging the organic group R of an ester with the organic group R’ of an alcohol. R-OH+ R-COOR → R-OH + RCOOR Alcohol

Ester

Transesterification is often catalysed by acid (H2SO4 or dry HCl) or base (usually alkoxide ion). Transesterification is an equilibrium reaction. To shift the equilibrium to the right, it is necessary to use a large excess of the alcohol.

The difference in the boiling points of the alcohols allows the equilibrium to be shifted toward the higher molecular weight ester by distilling the methanol out of the reaction mixture. Saponification. Esters are hydrolysed by acids or alkalis. Acidic hydrolysis is reversible and hence the mechanism for hydrolysis is also taken in the opposite direction of the mechanism for esterification.

When hydrolysis is carried out with alkali the carboxylic acid is obtained as its salt. This reaction is essentially irreversible, since a resonance-stabilized carboxylate anion shows little tendency to react with an alcohol. Since the alkali salts of the higher acids are soaps, alkaline hydrolysis is known as saponification; Saponification is far more rapid than acid hydrolysis. If an ester is hydrolyzed in a known 153

amount of base (taken in excess), the amount of base used up can be measured and used to give the saponification equivalent; the equivalent weight of the ester, which is similar to the neutralization equivalent of an acid.

Mechanism of saponification. Esters also undergo base-promoted hydrolysis. This reaction is known as saponification, because it is the way most of the soaps are manufactured. Refluxing an ester with aqueous NaOH produces an alcohol and the sodium salt of the acid.This reaction is essentially irreversible because the carboxylate ion is inert towards nucleophilic substitution.

If an ester is hydrolysed in a known amount of the base (taken in excess), the amount of the base used up can be measured and used to calculate the saponification equivalent; the equivalent weight of the ester, which is similar to the neutralization equivalent of an acid. Reduction of esters 1) Catalytic hydrogenation:

154

2) Chemical reduction is carried out by the use of sodium metal and alcohol, or more usually by the use of lithium aluminium hydride.

Claisen Condensation. When ethyl acetate reacts with sodium ethoxide, it undergoes a condensation reaction. After acidification, the product is a b - keto ester, ethyl aceto acetate (commonly known as – aceto acetic ester)

Condensation of this type is known as Claisen condensation. For esters, it is the exact counterpart of the Aldol condensation. Like the Aldol condensation, the Claisen condensation involves nucleophilic attack by a carbanion on an electron – deficient carbonyl compound. In the Aldol Condensation, nuclephilic attack leads to addition (the typical reaction of aldehydes and ketones). In the Claisen condensation, nucleophilic attack leads to substitution (the typical reaction of acyl compounds). Mechanism of Claisen condensation

155

This step is highly favourable and draws the overall equilibrium toward the product formation

When planning a claisen condensation with an ester it is important to use the alkoxide ion that has the same alkyl group as the alkoxyl group of the ester. This is to avoid the possibility of trancesterification. An intramolecular claisen condensation is called Dieckmann condensation. In general, the Dieckmann condensation is useful only for the preparation of five and six membered rings.

Hydrolysis of esters. Esters are hydrolysed by acids or alkalis. Acidic hydrolysis is reversible and hence the mechanism for hydrolysis is also taken in the opposite direction of the mechanism for esterification.

156

When hydrolysis is carried out with alkali the carboxylic acid is obtained as its salt. This reaction is essentially irreversible, since a resonance-stabilized carboxylate anion shows little tendency to react with an alcohol. Since the alkali salts of the higher acids are soaps, alkaline hydrolysis is known as saponification; Saponification is far more rapid than acid hydrolysis. If an ester is hydrolyzed in a known amount of base (taken in excess), the amount of base used up can be measured and used to give the saponification equivalent; the equivalent weight of the ester, which is similar to the neutralization equivalent of an acid.

Reduction of esters 1) Catalytic hydrogenation:

2) Chemical reduction is carried out by the use of sodium metal and alcohol, or more usually by the use of lithium aluminium hydride.

6.8.2. ACID CHLORIDES Acid chlorides are prepared from the corresponding acids by reaction with thionyl chloride or phosphorus pentachloride, Acid chlorides are the most reactive of the derivatives of carboxylic acids. 157

RCOOH +PCl5 → RCOCl + POCl3 +HCl RCOOH +PCl3 → 3RCOCl + H3PO3 RCOOH +SOCl2 → RCOCl + SO2 + HCl Acyl halides are more reactive than alkyl halides in nucleophilic substitution because the nucleophilic attack on the tetrahedral carbon of RX involves a hindered transition state. Also, to permit the attachment of the nucleophile a bond must be partly broken. In CH3COCl, the nucleophile attack on > C = O involving a relatively unhindered transition of acyl halides occurs in two steps. The first step is similar to addition to carbonyl compound and the second involves the loss of chlorine in this case.

Acylation. Acid Chlorides are important acylating agents for compounds having –OH, –SH, –NH2 and –NHR group. During acylation, hydrogen atom of this group is replaced by RCO–group. Acetylation is an example of acylation and is carried out by acetyl chloride. CH3COCl + HOH → CH3COOH + HCl Acetyl chloride

Acetic acid

CH3COCl + HOC2H5 → CH3COOH + HCl Acetyl chloride

Ethyl acetate

Reaction of acetyl chloride with olefins. Acetyl chlorides add on to the double bond of an olefin in the presence of a catalyst e.g., 158

zinc chloride or aluminium chloride, to form a chloro ketone which, on heating, eliminates a molecule of hydrogen chloride to form an unsaturated ketone.

Conversion of acid chlorides into acid derivatives. Amides and esters are usually prepared from the acid itself. Both the preparation of the acid chloride and its reaction with ammonia or an alcohol are rapid, essentially irreversible reactions.

Note: Formyl chloride is present in the form of carbon monoxide and hydrogen chloride at ordinary temperature.

6.8.3. AMIDES In the laboratory amides are prepared by the reaction of ammonia with acid chlorides or acid anhydrides. In industry they are often made by heating the ammonium salts of carboxylic acids. Hydrolysis of amides. It involves nucleophilic substitution, in which the NH2 group is replaced by –OH. Under acidic conditions hydrolysis involves attack by water on the protonated amide. 159

Under alkaline conditions hydrolysis involves attack by the strongly nucleophilic hydroxide ion on the amide itself.

Basic character of amides. Amides are very feebly basic and form unstable salts with strong inorganic acids. e.g. RCONH2.HCl. The structure of these salts may be I or II Acidic character of amides. Amides are also feebly acidic; e.g. they dissolve mercuric oxide to form covalent mercury compound in which the mercury is probably linked to the nitrogen. 2RCONH2 + HgO→ (RCONH)2Hg + H2O Reduction of amides. Amides are reduced by sodium ethanol, catalytically, or by lithium aluminium hydride to a primary amine.

Reaction of amides with phosphorus pentoxide. When heated with P2O5, amides are dehydrated to alkyl cyanides.

160

Alkyl cyanides are also formed when the amides of the higher fatty acids are heated in the presence of ammonia.

Amides may also be converted into cyanides by phosphorus pentachloride. Reaction of amides with nitrous acid. When amides are treated with nitrous acid, nitrogen is evolved and the acid is formed. RCONH2 + HNO2 → RCO2H + N2 + H2O

6.9. AMINES Amines play a vital role in medicinal chemistry. As our body has a lot of amino acids, these amines help in the regulation of our body. It is also believed that, vitamins were named keeping vitalamines in mind (though many vitamins don't have nitrogen at all). Similarly to produce several synthetic dyes, pigments the amines are used. Therefore, the amines are very important in our everyday life. Structure of amines. Amines are the alkyl (or) aryl derivatives of NH3.

The general formula of amine is R3N, where R is an alkyl (or) aryl group or hydrogen. In amines one or more Hydrogen atoms of ammonia are replaced by Alkyl or aryl groups. Here the nitrogen atom of amines is like that of NH3, it is sp3 hybridised. The three Alkyl groups (or hydrogen atoms) occupy corners of a tetrahedron, one of sp3 orbital occupying the unshared electron pair directed towards the other corner. We say the shape of amine as “Trigonal Pyramidal”. 161

Amines are classified as primary, secondary (or) tertiary according to the number of groups attached to the nitrogen atom. If one alkyl group has replaced one hydrogen atom of ammonia, it is primary amine (amine group or amine functional group of primary amine is – NH2). Similarly, if two hydrogens are replaced, it is secondary amine and if all the three are replaced, it is tertiary amine (e.g. trimethyl amine). NH3

RNH2

R2NH

R3N

Ammonia 1o

Amine 2o

Amine 3o

Amine

Nomenclature of amines. Nomenclature of amines is quite simple. Aliphatic amines are named by naming the alkyl group (or) groups attached to nitrogen, and following that by the word amine, for example, alkyl amine (methyl amine, ethyl amine) & benzyl amine.

162

More complicated amines are often named as prefixing amino (or-N-methylamino -, N-N, diethyl amino -, etc) to the name of the parent chain.

Aromatic amines – those in which nitrogen is attached to an aromatic ring – are generally named as derivatives of the simplest aromatic amine, aniline.

Salts of amines are generally named by replacing – amine by – ammonium (or – aniline by – anilinium), and adding the name of the anion.

Physical properties of amine. Amines are moderately polar substances; they have boiling points that are higher than those of alkanes but generally lower than alcohols of comparable molecular weight. Molecules of primary and secondary amines can form strong 163

hydrogen bonds to each other and to water. Molecules of tertiary amines cannot form hydrogen bonds to each other, but they can form hydrogen bonds to molecules of water or other hydroxylic solvents. As a result, tertiary amines generally boil at lower temperatures than primary and secondary amines of comparable molecular weight. Therefore, the order of boiling points of isomeric amines is as follows. Primary > Secondary > Tertiary

Boiling points of amines, alcohols and alkanes are almost the same. Basicity of amine. Aliphatic bases. As increasing strength in nitrogenous bases is related to the readiness with which they are prepared to take up protons, and therefore, to the availability of the unshared electron pair on nitrogen, we might expect to see an increase in basic strength on going: NH3, RNH2, R2NH, R3N, due to the increasing inductive effect of successive alkyl groups making the nitrogen atom more negative. An actual series of amines was found to have related values as follows, however:

164

It will be seen that the introduction of an alkyl group into ammonia increases the basic strength markedly as expected. The introduction of a second alkyl group further increases the basic strength, but the net effect of introducing the second alkyl group is very much less marked than with the first. The introduction of a third alkyl group to yield a tertiary amine, however, actually decreases the basic strength in both the series quoted. This is due to the fact that the basic strength of an amine in water is determined not only by electron availability on the nitrogen atom, but also by the extent to which the cation, formed by uptake of a proton, can undergo solvation, and so become stabilized. The more hydrogen atoms attached to nitrogen in the cation, the greater the possibilities of powerful solvation via hydrogen bonding between these and water:

Thus on going along the series, NH3, RNH2, R2NH, R3N, the inductive effect will tend to increase the basicity, but progressively less stabilisation of the cation by hydration will occur which will tend to decrease the basicity. The net replacing effect of introducing successive alkyl groups thus becomes progressively smaller, and an actual changeover takes place on going from a secondary to a tertiary amine. If this is the real explanation, no such changeover should be observed if measurements of basicity are made in a solvent in which hydrogen - bonding cannot take place; it has, indeed, been found that in chlorobenzene the order of basicity of the butylamines is BuNH2 < Bu2NH < Bu3N Tetralkylammonium salts, e.g. R4NÅ I-, are known, on treatment with moist silver oxide, AgOH, to yield basic solution comparable in strength with the mineral alkalis. This is readily understandable for 165

the base so obtained, R4N+ –OH, is bound to be completely ionised as there is no possibility, as with tertiary amines, etc., R3NH++ -OH → R3N: + H2O of reverting to an unionised form.

The effect of introducing electron withdrawing groups, e.g. Cl, NO2, close to the basic center is to decrease the basicity, due to their electron withdrawing inductive effect. Thus the amine is found to be virtually non-basic, due to the three powerful electron withdrawing CF3 groups. This can well be explained on the basis of more ‘s’ character on the lone pair of N. The change is also pronounced with C=O, for not only is the nitrogen atom, with its electron pair, bonded to an electron withdrawing group through an sp2 hybridised carbon atom but an electron withdrawing mesomeric effect can also operate:

Thus amides are found to be only very weakly basic in water [pKa for ethanamide(acetamide) is » 0.5], and if two C=O groups are present the resultant imides, far from being basic, are often sufficiently acidic to form alkali metal salts, e.g. benzene – 1, 2 – dicarboximide:

166

Aromatic bases: (Aromatic amines)

The exact reverse of the above is seen with aniline, which is a very weak base (pKa = 4.62) compared with ammonia (pKa = 9.25) or cyclohexylamine (pKa = 10.68). In aniline the nitrogen atom is again bonded to a sp2 hybridised carbon atom but, more significantly, the unshared electron pair on nitrogen can interact with the delocalised p orbitals of the nucleus. If aniline is protonated, any such interaction, with resultant stabilisation, in the anilinium cation is prohibited, as the electron pair on N is no longer available.

The aniline molecule is thus stabilised with respect to the anilinium cation, and it is therefore ‘energetically unprofitable’ for aniline to take up a proton; it thus functions as a base with the utmost reluctance (pKa=4.62, compared with cyclohexylamine, pKa=10.68). The base weakening effect is naturally more pronounced when further phenyl groups are introduced on the nitrogen atom; thus diphenylamine, Ph2NH, is an extremely weak base (pKa=0.8), while triphenylamine, Ph3N, is by ordinary standards not basic at all. Introduction of alkyl, e.g. Me groups, on to the nitrogen atom of aniline results in a small increase in pKa: C6H5NH2 C6H5NHMe C6H5NMe2 MeC6H4NH2 4.62 4.84 5.15 o-4.38 m-4.67 p-5.10 167

Unlike such introduction in aliphatic amines, this small increase is progressive: suggesting that cation stabilisation through hydrogen bonded solvation, responsible for the irregular behavior of aliphatic amines, here has less influence on the overall effect. The major determinant of basic strength in alkyl-substituted anilines remains mesomeric stabilisation of the aniline molecule with respect to the cation; borne out by the irregular effect of introducing Me groups into the o-, m- and p-positions in aniline. A group with a more powerful (electron – withdrawing) inductive effect, e.g. NO2 is found to have rather more influence. Electron withdrawal is intensified when the nitro group is in the o- or p-position, for the interaction of the unshared pair of the amino nitrogen with the delocalised p orbital sytsem of the benzene nucleus is then enhanced. The neutral molecule is thus stabilised even further with respect to the cation, resulting in further weakening as a base. Thus the nitro – anilines are found to have related pKa values:

The extra base-weakening effect, when the substituent is in the o-position, is due in part to the short distance, over which its inductive effect is operating, and also to direct interaction, both steric and by hydrogen bonding, with the NH2 group. o-Nitroaniline is such a weak base that its salts are largely hydrolysed in aqueous solution, while 2, 4 – dinitroaniline is insoluble in aqueous acids, and 2, 4, 6 – trinitroaniline resembles an amide; it is indeed called picramide and readily undergoes hydrolysis to picric acid (2, 4, 6 – trinitrophenol). With substituents such as OH and OMe that have unshared electron pairs, an electron – donating, i.e. base strengthening, mesomeric effect can be exerted from the o- and p-, but not from the m-position, with the result that the p-substituted aniline is a stronger base than the corresponding m-compound. The m-compound is a weaker base 168

than aniline itself, due to the electron – withdrawing inductive effect exerted by the oxygen atom in each case. As so often, the effect of the o – substituent remains somewhat anomalous, due to the interaction with the NH2 group by both steric and polar effects. The substituted anilines are found to have related pKa values. Preparation of amine Ammonolysis of alkyl halides. Many organic halogen compounds are converted into amines by treatment with aqueous (or) alcoholic solution of ammonia. This reaction is generally carried out either by allowing the reactants to stay together at room temperature (or) by heating them under pressure. Displacement of halogen by NH3 yields the amine salt, from which free amine can be liberated with hydroxide ion. CH3Cl + NH3 → CH3NH3Cl

CH3NH2 + Cl– + H2O

The above reaction is a class of substitution reaction, which we know as nucleophilic substitution.

Ammonia can act as a nucelophile and it can also act as a base. If ammonia acts as a nucleophile, substitution takes place CH3CH2CH2Br + NH3 → CH3CH2CH2NH2 + HBr And, if ammonia acts as a base, elimination takes place. (CH3)3CCl + NH3 → (CH3)2C=CH2 It is evident that primary alkyl halides undergo substitution more easily than tertiary alkyl halides, which undergo elimination very easily. Reaction with alkyl halide, yield a mixture of primary, secondary and tertiary amines and also a quaternary ammonium salt (which caannot be considered as amine): 169

This is because the primary amine formed again acts as a base and keeps on reacting with the alkyl halide untill the hydrogen atoms of amine are replaced with alkyl groups. However, primary amine is obtained as a major product by taking large excess of ammonia. Reduction of nitro compounds. Nitro alkanes can be reduced quantitatively to their corresponding amines

Nitro compound can be reduced in two general ways: (A) by catalytic hydrogenation using molecular hydrogen, or (B) by chemical reduction, usually by a metal and an acid. This method cannot be used when the molecule also contains some other easily hydrogenated group, such as a Carbon carbon double bond. Chemical reduction is most often carried out by adding hydrochloric acid to a mixture of the nitro compound and metal, usually granulated tin or iron.

Reduction of nitriles. Alkyl and aryl cyanides (nitriles) can be reduced to their corresponding primary amines using lithium aluminium hydride (LiAlH4) or catalytic hydrogenation.

170

This reaction is used for ascent of amine series, i.e. for preparation of amines containing one carbon atom more than the starting nitrile. Reduction of amides. Amides can directly be converted into their corresponding amines. This reaction is carried out by treating the amide with a mixture of base and bromine (KOH + Br2). This reaction is called Hofmann Bromamide reaction. The reaction is as follows, RCONH2 + Br2 + 4KOH → RNH2 + K2CO3 + 2KBr + 2H2O Here we can see that the amine formed has one carbon less than that of the corresponding amide. Due to the loss of carbon atom, this reaction is also called Hofmann degradation of amides. The mechanism of the reaction is as follows:

171

Apart from this, amides can be dehydrated by P2O5 to their corresponding nitriles and nitriles can then be reduced.

By this method you are retaining the number of carbon atoms in both amide and the amine. Action of ammonia on alcohol

This method yields a mixture of 1o, 2o, 3o amines and 4o salts which are separated from each other by means of Hinsberg method, Hofmann method and fractional distillation. However, amines can be prepared in a good yield by using the excess of ammonia.

From carbonyl compounds. While studying carbonyl compounds we have seen that carbonyl compounds can be converted into any other functional group. How are we converting carbonyl group into amino group? See, the following sequence,

The reactions are clear and simple so that, we can get an amine from carbonyl compound just by reductive amination (amination and reduction). Using this reductive amination we can go from 1° amine to 2° amines. Look at the following reaction. 172

Curtius reaction. Amines can be prepared by treating acid chloride with sodium azides, the isocyanate thus formed is decomposed with treatment by water, and amines are obtained.

Schmidt reaction. Hydrozoic acid reacts with carboxylic acid in the presence of a mineral acid to give amines. RCOOH +NH3

RNH2 + CO2

Gabriel phthalimide synthesis. This method is used for the preparation of primary amines. Phthalimide on treatment with ethanolic potassium hydroxide forms potassium salt of phthalimide, which on heating with alkyl halide followed by alkaline hydrolysis produces the corresponding primary amine.

173

Aromatic primary amines cannot be prepared by this method because aryl halides do not undergo nucleophilic substitution with the anion formed by phthalimide. Methods yielding primary amine only 1. By reduction of nitroalkanes: C2H5NO2 + 6[H]

C2H5NH2 + 2H2O

C6H5NO2 + 6[H]

C6H5NH2 + 2H2O

2. Mendius reduction of alkyl cyanides: CH3CN + 4H

CH3CH2NH2

Reduction of alkyl isocyanides with Na/C2H5OH gives 2o amines e.g. CH3NC CH3CHCH3 3. By reduction of amides and oximes: ROCONH2

Cyclohexanone

RCH2NH2

Cyclohexanoxime

Cyclohexylamine

4. By Hofmann bromamide reaction: CH3CONH2 + Br2 + 4KOH ——> ——> CH3NH2 + 2KBr + K2CO3 + 2H2O C6H5CONH2 + Br2 + 4KOH ——> ——> C6H5NH2 + 2KBr + K2CO3 + 2H2O 174

5. By Gabriel phthalimide reaction: Potassium phthalimide formed after reaction of phthalimide with KOH, on heating with alkyl halide gives N – alkyl phthalimide. This on hydrolysis with 20% hydrochloric acid under pressure gives 1° amine.

6. By action of chloramine on Grignard’s reagent:

7. By decarboxylation of amino acids: H2NCH2COOH

H2NCH3

Glycine Methylamine

8. By Wurtz method:

CH3 – N = C = O + 2KOH ———> CH3NH2 + K2CO3 Methyl isocyanate

9. Schmidt reaction: CH3COOH + HN3

CH3NH2 + CO2 + N2

Hydrazoic acid Methylamine

Methods giving secondary amines only 1. By reduction of alkyl isocyanide with sodium and ethanol 175

CH3NC + 4H

CH3NHCH3

2. By heating an alcoholic solution of 1o amine with alkyl halide C2H5NH2 + IC2H5 ————> (C2H5)2 NH Diethylamine 3. By hydrolysis of p – nitroso dialkyl aniline with boiling alkali

Methods giving tertiary amine only 1. By heating alcoholic solution of NH3 with excess of alkyl halide – 3CH3I + NH3 → (CH3)3 N + 3HI Trimethylamine

2. By decomposition of tetra – alkyl ammonium hydroxide

(CH3)4 N+ OH–

(CH3)3 N + CH3OH

Chemical Properties of Amines Basic Nature of Amines. Like ammonia, amines are converted into their salts by aqueous mineral acids and are liberated from their salts by aqueous hydroxides. Thus, like ammonia, amines are more basic than water and less basic than hydroxide ions. Amines turn red 176

litmus blue and also combine with water and mineral acids to form corresponding salts.

When the amine salts are treated with strong bases like NaOH, the parent amines are regenerated. RN+H3Cl– + OH– → RNH2 + H2O + Cl– Amine salt Amine (Soluble is water) (Insoluble in water)

Further, due to the basic character amines react with auric and platinic chlorides in the presence of HCl to form double salts. RNH2 +PtCl4+2HCl  (RNH3)2+PtCl62Chloroplatinic acid

These double salts decompose on ignition to pure metal, therefore, the formation and decomposition of the double salts is used for determining the molecular weight of amines. Alkylation of amines. Like ammonia, an amine can react with alkyl halide to form next higher class of amine. Here, again it is the presence of an electron pair on nitrogen which makes amine to behave as nuclephile and alkyl halide thus undergo nucleophilic substitution reaction. RNH2

RNHCH3

RN(CH3)2

RN+(CH3)3I

10 amine 20 amine 30 amine Quaternary ammonium iodide

Quarternary ammonium salts are useful in synthetic organic chemistry as phase-transfer catalysts and in the preparation of alkenes. 177

Halogenation of amines

In order to introduce only one halogen atom, the activating effect of the –NH2 group must be lowered using acetylation.

Nitration of amines. Direct nitration of aniline with nitric acid gives a complex mixture of mono – di and trinitro compounds and oxidation products. If however, NH2 group is protected by acety-lation, the main product of nitration is p – nitro derivative. 178

Sulphonation of amines. Aniline reacts with conc. H2SO4 to form the salt anilinium hydrogen sulphate which on heating at 455 – 475 K gives sulphanilic acid (p – amino benzene sulphonic acid).

Sulphanilic acid exists as Zwitter ion i.e. a dipolar ion which exists in the form of an internal salt structure. Such an ion has positive as well as negative charge within the same molecular structure. Acylation of amines. The reaction refers to the reaction of amines with acyl chlorides or acid anhydrides. Primary and secondary amines can react with acid chlorides or acid anhydrides to form substituted amides. RNH2 + R’COCl → R’CO NHR an N-substituted amide R2NH + R’COCl → R’CO NR2 an N,N disubstituted amide Benzoylation of amines (Schotten Baumann reaction). Primary amine reacts with benzoyl chloride to give the acylated product. 179

R-NH2 + Cl – COC6H5 + NaOH → R-NH-COC6H5 + HCl (Benzoyl chloride)

Benzoyl alkyl amine

Carbylamine reaction. This reaction is given only by primary amines. Primary amines when heated with chloroform and alcoholic caustic potash give isocynaides (carbylamines) having very unpleasant smell, which can be easily detected C2H5NH2 + CHCl3 + 3KOH → C2H5NC + 3KCl + 3H2O Ethylamine

Ethyl isocyanide

C6H5 NH2 + CHCl3 + 3KOH → C6H5NC + 3KCl + 3H2O Aniline

Phenyl isocyanide

Action with aldehyde and ketone. Primary amines add as nucleophile to the carbonyl group of an aldehyde or a ketone to form carbinoamines, which are then dehydrated to form imines which are also known as Schiff’s bases as the final product. C2H5NH2 + CH3CHO → C2H5NH-CH(CH3)-OH → → C2H5N = CHCH3 + H2O Ethylamine Acetaldehyde Ethylidene ethylamine (Schiff’s base)

Both the addition and elimination phase of the reaction are accelerated by acid catalysis. Secondary amines add to aldehydes and ketones to form carbinoamines which can be dehydrated to a stable product leading to a carbon-carbon double bond. (C2H5)2NH + CH3CHO → (C2H5)2N-CH(CH3)-OH → → C2H5N-CH=CH2 + H2O Enamine

Hofmann Mustard oil reaction. Primary amines when warmed with alcoholic carbon disulphide followed by heating with excess of mercuric chloride form isothiocyanates having pungent smell similar to mustard oil. 180

Secondary amines also react with CS2 to form dithiocarbamic acids, but the latter do not react with mercuric chloride R2NH + S = C = S → S = C(SH)NR2

No. Reaction

Tertiory amines do not react with carbon disulphide. Reaction of amindes with carbonyl chloride. This reaction is given only by primary amines. C2H5 – NH2 + COCl2 → C2H5NCO + 2HCl Ethylisocyanate

Hofmann Elimination. When a quaternary ammonium hydroxide is heated strongly (125° or higher) it decomposes to yield water, a tertiary amine and an alkene. This reaction is called the Hofmann elimination. The formation of quaternary ammonium salts followed by an elimination of the kind just described and identification of the alkene and tertiary amine formed was once used in the determination of the structure of complicated amines.

181

Diazonium salts of amines. What are diazonium salts? Let us look at the name. The name suggests that, the compound has two nitrogen atoms (diazo) and the whole group has a positive charge (ium). There is also an anion to balance it (It is a salt). So, the possible structure can be: RN2+X-. The preparation is quite simple if we adhere to the experimental conditions. These diazonium salts are prepared by treating a primary amine with NaNO2 in the presence of con. HCl, the temperature being 0°C. (Here the temperature has to be taken care of and if the temperature exceeds 5°C, the reaction will not take place).

Mechanism for Diazotization Step 1:

Step 2:

The diazonium salts of aliphatic amines are generally unstable and they decompose to give different products. 182

Mechanism ArN2+ Cl– + H3PO2 reaction takes place through free radical pathway. Chain initiation ArN2+Cl– + H3PO2 = HCl + ArN2PH (O) OH ArN2PH (O) OH → ArH + N2 + .PH (O)OH Chain propagation Ar× + H2PO2 → ArH + PH (O) OH ArN2+ + .PH (O) OH → ArN2· + P+H (O)OH ArN2· → Ar. + N2 P+H (O) OH + H2O → H3PO3 + H+ Reaction of tertiary and secondary amines with nitrous acid. When a tertiary aliphatic amine is mixed with nitrous acid, an equilibrium is established among the tertiary amine, its salt, and an N-Nitrosoammonium compound. Tertiary arylamines react with nitrous acid to form C-nitroso aromatic compound. Nitrosation takes place almost exclusively at the para position if it is open and if not, at 183

the ortho position. The reaction is another example of electrophilic aromatic substitution.

N-nitrosoamines are very powerful carcinogens (cancer causing substances). Secondary amines, both aryl and alkyl, react with nitrous acid to yield N-nitrosoamines. N-nitrosoamines usually separate from the reaction mixture as oily yellow liquid.

Coupling reactions of arene diazonium salts. Arenediazonium ions are weak electrophiles; they react with highly reactive aromatic compounds with phenols and tertiary arylamines to yield azo compound. This electrophilic aromatic substitution is called a diazo coupling reaction occurring mainly at p-position. 184

Couplings between arenediazonium cations and phenols take place most rapidly in slightly alkaline solution. If the solution is too alkaline (pH > 10), however, the arenediazonium salt itself reacts with hydroxide ion to form a relatively unreactive diazohydroxide or diazotate ion.

Hydrazo compounds are also made as follows: Ph-NO2

Ph- NH-NH-Ph

Diaryl hydrazo compounds undero the benzidine rearrangement

185

Mechanism:

Ring substitution in aromatic amines. The –NH2, – NHR and –NR2 are benzene activating groups through resonance effect of nitrogen, where the lone pair of electrons of nitrogen is shifted to the benzene ring making ortho and para position available for electrophilic attack.

The carbocation formed as intermediate is

The group – NHCOCH3 is less powerful ortho and para director because the electron-withdrawing character of oxygen makes nitrogen a poor source of electrons. This fact is used in preparing mono substituted aniline. The –NH2 group is such a powerful activator, that 186

substitution occurs at all available ortho and para positions of aniline. If, however, –NH2 group is converted to –NHCOCH3, the molecule becomes less powerful activator. Hence, only mono substitution products are obtained. Finally – NHCOCH3 is converted back to –NH2 by hydrolyzing with acid. This technique is especially used while nitrating aniline as strong oxidizing agent destroys the highly reactive ring.

Oxidation of amines. Amines are usually oxidised at N, rather than at C. Primary and secondary aliphatic amines are although oxidisable, in most cases useful products are not obtained. Complicated side reaction often occurs, causing the formation of complex mixtures.

Aniline -X rearrangement

Such compounds are not much stable so the group X migrates mainly at p-position. 187

1. Fisher-Hepp rearrangement

2. Phenylhydroxylamine - p-aminophenol rearrangement.

Mechanism

Nucleophilic attack by H2O at p – position.

Separation of a mixture of amines Hinsberg’s method. Treating a mixture of 3 amines with Hinsbergs reagent (benzene sulfonyl chloride) and finally treating the product formed with NaOH can separate the third class of amines. 188

Primary amine: RNH2 + C6H5SO2Cl → C6H5– SO2 – NH – R + HCl C6H5– SO2 – NH – R : N-alkyl benzene sulfonamides Dissolves in NaOH due to acidic H-attached to Nitrogen Secondary amine:

Tertiary amine: Tertiary amines do not react with Hinsberg’s reagent.After reacting with NaOH the aqueous layer and the second layer (Secondary and Tertiary) can be separated by ether. Aqueous layer Hydrolysed with conc. HCl gives primary amine. The ether layer is distilled and tertiary amine is distilled over. Residue hydrolysed with conc. HCl to recover secondary amine Hofmann’s Method: The mixture of amines is treated with diethyloxalate, which forms a solid oxamide with primary amine, a liquid oxime ester with secondary amine. The tertiary amine does not react.

Test for amines. Primary amine is treated with a strong base in the presence in chloroform, an isocyanide is formed and this isocyanide thus formed has a very foul smell. 189

Here attacking electrophile is the dichlorocarbene (:CCl2). The primary amine can be identified by its foul smell. Secondary amine is converted into nitrosoamine by treating the amine with nitrous acid. The resultant solutions warmed with phenol and concentrated H2SO4, a brown or red colour is formed at first soon it changes to blue and then to green. The colour changes to red on dilution and further changes to greenish blue on treating with alkali. Tertiary arylamines react with nitrous acid to form o-nitroso aromatic compound. Nitro and cyno compounds. Nitro alkanes are derivatives of alkanes. They are isomeric to nitrites (esters) classified as primary, secondary and tertiary depending on the nature of carbon atom to which nitro group is linked.

Primary nitro alkane Secondary nitro alkane Tertiary nitro alkane

-NO2 group is an ambident group. If it attacks through nitrogen, it is called nitro and if it attacks through oxygen atom, it is called nitrite. Hence, nitrites and nitro compounds are isomers. What are ambident nucleophiles? Nucleophiles which can attack from two sites such as CN-, NO2- are called ambident nucleophiles. Evidences show that nitrogen is attached to one of the oxygen atoms by a double bond and to the other by a dative bond. The resonance hybrid is shown as an example which confirms the spectroscopic evidence that both nitrogen – oxygen bonds have the same bond length.

Resonating forms

Hyrbid structure

190

Out of three hybrid orbitals of nitrogen one overlaps with alkyl group and two with oxygens while the unhybridized p orbital of N – atom containing a pair of electrons and lying perpendicular to the plane of hybrid orbitals overlaps sideway with half filled 2 p – orbitals of two oxygen atoms. This forms π-bond above and below the plane of molecule. Preparation of nitro compounds From alkyl halides: Alkyl halides react with silver nitrite in ethanolic solution to give nitro compounds. Alkyl nitrite is formed in minor quantity. This reaction is used to prepare 1o nitro compounds primarily while 2oand 3o halides give major proportion of alkenes due to β – elimination. Contrary to this alkali nitrites give alkyl nitrites as the major product. This is due to ionic nature of alkali nitrite. But if the reaction is carried out in solvents like DMF or DMSO, then even NaNO2 or KNO2 give good yield (about 60%) of nitro compound. Reactions: R–I + AgNO2 ——> RNO2 + AgI C2H5l + AgNO2 ——> C2H5NO2 + AgI Nitroethane

Nitration: Nitro derivatives of aromatic compounds like nitrobenzene are produced when benzene is allowed to react with nitrating mixture. (conc. HNO3/conc.H2SO4).

191

Mechanism: Generation of nitronium ion. Attack of NO2 on benzene molecule.

Loss of proton:

Nitrobenzene

Direct nitration of alkane involves vapour phase nitration at high temperature. R — H + HONO2 ———> R — NO2 + H2O 675 K low yield The problem faced in the method is that at such high temperature, a mixture of nitro alkanes is formed due to C – C cleavage. 192

e.g. CH3CH2CH3 + HNO3 ——> ——> CH3CH2CH2NO2 + CH3CH2NO2 + CH3NH2 + other products From amines: 3o nitroalkanes can be produced as follows:

3o butylamine (83% yield) Distinguish test between nitroalkanes and alkyl nitrites. 1. Nitroalkanes on reduction with H2/Ni produce 1o amines while alkyl nitrites produce alcohols and NH3 CH3CH2NO2

CH3CH2NH2 + H2O 1o amine

CH3CH2 — O — N = O

CH3CH2OH + NH3 + H2O

Ethyl nitrite

2. Nitroalkanes do not get hydrolysed in basic conditions while nitrites produce alcohols

CH3 O – N = O + NaOH ——> CH3OH + NaNO2

6.10. CYANIDES AND ISOCYANIDES Both alkyl cyanides (RCN) and alkyl isocyanides (RNC) are organic derivatives of hydrocyanic acid HCN. Alkali cyanides are ionic and cyanide ion is ambident in nature (can form covalent 193

bond either from carbon or nitrogen). AgC = N is covalent, hence, a lone pair on nitrogen is mainly available for covalent bond formation, resulting in predominant formation of isocyanides. Illustration. How would you account for the fact that alkyl cyanides are soluble in water but alkyl isocyanides are insoluble in water? Solution: Alkyl cyanides possess the tendency to form H – bonding with water which is absent with isocyanides

Methods of preparation of Cyanides 1. Dehydration of amides:

High molecular weight acid amides are dehydrated to the corresponding cyanide by heat alone. CH3(CH3)6 OCNH2

CH3(CH2)6 CN

2. From RX: RX + KCN ——> RCN + KX This method is satisfactory only if R is 1o or 2o group. If it is 3o group, then it is converted into alkene. CH3CH2Cl + KCN → CH3CH2CN + KCl

194

3. By Grignard’s reagent and Cyanogen chloride reaction: RMgCl + CICIN → RCN + MgCl2 This is best method for preparing 3o alkyl cyanides. (CH3)3CMgCl + CICN → (CH3)3 CCN + MgCl2 4. From diazonium salt

Methods of preparation of isocyanides 1. By heating an alkyl iodide with AgCN in aqueous ethanolic solution RI + AgCN → RNC + AgI C2H5I + AgCN → C2H5NC + AgI Ethylisocyanide 2. By carbylamine reaction Heating a mixture of 1o amine and chloroform with ethanolic potassium hydroxide RNH2 + CHCl2 + 4KOH ——> RNC + 3KCl + 3H2O

Mechanism proceeds via intermediate formation of dichloromethylene or, dichloro carbene produced from chloroform in alkaline solution. (Via a-elimination) 195

CHCl3 + KOH ———>KCl + H2O + : CCl2

Properties of isocyanides 1. Alkyl isocyanides are poisonous, unpleasant smelling, with lower boiling points than isomeric cyanides. 2. RNCs are not very soluble in water, nitrogen atom not having a lone pair of electrons available for hydrogen bonding. Reactions: 1. Hydrolysis: RNC + 2H2O

RNH2 + HCO2H

CH3NC + 2H2O

CH3NH2 + HCO2H

RNCs are not hydrolysed by alkalis. 2. Reduction: RNC

R NHCH3 2 amine o

CH3NC CH3NHCH3 Methyl isocyanide Dimethyl amine 3. When alkyl isocyanides are heated for a long time, they arrange to form cyanide RNC → R CN CH3CH2NC → CH3CH2CN 4. With non metals: RNC + X2 ———> RNCX2 CH3NC + Cl2 ——> CH3NCCl2 196

RNC + S ———> RNCS Alkyl isothiocyanates

CH3NC + S ———> CH3NCS 5. Oxidation with HgO: RNC + HgO → RNCO + Hg Akyl isocyanates

CH3NC + HgO → CH3NCO + Hg

197

Definition of biomolecules. A Biomolecule is any molecule present in living organisms including large macromolecules such as carbohydrates, proteins, nucleic acids and lipids, and the small molecules such as primary and secondary metabolites and natural products. 4 types of biomolecules that make up the living organisms. They include proteins, lipids, carbohydrates and nucleic acids. Most of the biomolecules are composed of oxygen, hydrogen, nitrogen and carbon. 7.1. PROTEINS AND AMINO ACID Proteins are biomolecules that are essential for the survival of living organisms. Amino acids are the building blocks of the proteins. There are 22 naturally occurring amino acids. Amino acid is composed of amino group, carboxyl group, hydrogen atom and R group (alkyl group). The R group is variable, that is, varies with different amino acids. These 4 groups are attached to the single carbon atom known as Alpha-Carbon.

Structure of Amino Acid The simplest amino acid is glycine. In glycine, the R group is replaced by hydrogen atom. The bond between the two amino acids is peptide bond. 198

Amino Acid Sequence-Protein Structure of protein. The protein exists most commonly in four different forms: Primary Structure: The sequence of amino acids is called the primary structure of a protein. The left end is represented by the first amino acid, while the right end is represented by the last amino acid. The first amino acid is also called N-terminal amino acid. The last amino acid is called C-terminal amino acid. Secondary Structure: The protein is not a linear chain of amino acids rather the chain would bend at some places and even form helices. Regularly repeating local structures give secondary structure to protein.

Structure of Protein 199

Tertiary Structure: The overall shape of a protein molecule and the spatial relationship of the secondary structures to one another is called tertiary structure of protein. In other words, the various folds which give three dimensional appearances to protein form its tertiary structure. Quaternary Structure: The manner in which the individual folded polypeptides are arranged with respect to each other is called quaternary structure of protein Enzyme is a type of biomolecules. Enzyme belongs to protein. All enzymes are proteins except ribonucleases. Amino acids are molecules, which contain two functional groups, one is carboxylic group and another is amino group. Amino acids are derivatives of carboxylic acids in which one hydrogen atom of carbon chain is substituted by amino group. Amino group may be at alpha, beta or gamma position with respect to carboxylic group.

Formula of amino acid H2N-CH2 - COOH CH3 - CH (NH2) - COOH H2N - CH2 - CH2 -COOH H2N - CH2 - (CH2)2 - COOH

Name of amino acids Amino acetic acid, or Glycine α – Amino propionic acid or Alanine β – Amino propionic acid γ – Amino butyric acid

Some amino acids contain a second carboxyl group or a potential carboxyl group in the form of carboxamide: these are called acidic amino acid, some contain a second basic group which may be an amino group, these are called basic amino acids. Physical properties of amino acids. Although the amino acids are commonly shown as containing an amino group and a carboxyl group, certain properties are not consistent with this structure. In contrast to amines and carboxylic acids, the amino acids are non200

volatile solids, which melt at fairly high temperatures. They are insoluble in organic solvents [i.e. non polar solvents] and are highly soluble in water.Their aqueous solution is neutral.Their aqueous solutions behave like solutions of substances of high dipole moment. Acidity and basicity constants are ridiculously low for - COOH and – NH2 groups. In the physical properties, melting points, solubility, and high dipole moment are just what would be expected of such a salt. The acid base properties also become understandable when it is realized that the measured Ka actually refers to the acidity of an ammonium ion, RNH3+

and Kb actually refers to the basicity of a carboxylate ion, RCOO–

When the solution of an amino acid is made alkaline, the dipolar ion (I) is converted to the anion (II); the stronger base, hydroxide ion, removes a proton from the ammonium ion and displaces the weaker base, the amine. +

H3N ¾ CHRCOO– + OH– H2N CHRCOO– + H2O (I) (II) Stronger Stronger Weaker Weaker acid base base acid

When the solution of an amino acid is made acidic; the dipolar ion I is converted into the cation (III); the stronger acid H3O+, gives up a proton to the carboxylate ion, and displaces the weaker carboxylic acid.

201

+

H3N CHRCOO– + H3O+ (I) Stronger base

+

H3N CHRCOOH + H2O (III)

Stronger acid

Weaker acid

Weaker base

In summary, the acidic group of a simple amino acid like glycine is –NH3+, not –COOH, and the basic group is –COO-, not –NH2. Classification of amino acid. Amino acid with non – polar side chain

Acidic amino acid: These amino acids contain a second carboxyl group or a potential carboxyl group in the form of carboxamide. Basic amino acids: These contain a second basic group which may be an amino group. Essential and non-essential amino acids. Those amino acids which must be supplied to our diet as they are not synthesized in the body are known as essential amino acids. Some of them are Valine, Leucine, Isoelucine, Phenylalanine, Arganine, Threonine, Tryptophan, Methionine, Lysine, Arginine, Histadine. Note: Histidine and arginine are essential i.e. can be synthesized but not in quantities sufficient to permit normal growth. 202

Those amino acids which are synthesized in the body are nonessential amino acids. Some of them ar. Glycine, Alanine, Tyrosine, Serine, Cystine, Proline, Hydroxyprocine, Cysteine, Aspartic acid, Glutonic acid. Zwiter ion. Amino acids contain both an acidic carboxyl group (COOH) and a basic amino group in the same molecules. In aqueous solution, the acidic carboxyl group can lose a proton and the basic amino group can gain a proton in a kind of internal acid – base reaction. The product of this internal reaction is called a Dipolar or a Zwitter ion. The Zwitter ion is dipolar, charged but overall electrically neutral and contains both a positive and negative charge. Amino acid in the dipolar ion form is amphoteric in nature. Depending upon the pH of the solution, the amino acid can donate or accept a proton.

Iso electric point of amino acids. When an ionized form of amino acid is placed in an electric field, it will migrate towards the opposite electrode. Depending upon the pH of the medium the following three things may happen. 1. In acidic medium, the cation moves towards the cathode. 2. In basic medium, the anion moves towards the anode. 3. The Zwitter ion does not move towards any of the electrodes. At a certain pH (i.e. H+ concentration), the amino acid molecules show no tendency to migrate towards any of the electrodes and exist as a neutral dipolar ion when placed in electric field, which is known as isoelectric point. All amino acids do not have the same isoelectric point, it depends upon the nature of R – linked to α-carbon atom. 203

Amino acids Neutral amino acids Glycine Alanine Valine Serine Threonine Acidic amino acids Aspartic acid Glutamic acid Basic amino acids Lysine Arginine

Isoelectric point (pH 5.5 to 6.3) 5.7 6.1 6.0 5.7 5.6 (pH » 3) 2.8 3.2 (pH » 10) 9.7 10.8

Amino acids have minimum aqueous solubility at isoelectric point.

Synthesis of α-amino acids 1. Protein can be hydrolyzed by refluxing with dilute hydrochloric acid to give a mixture of α-amino acids. The resulting mixture can be separated by fractional crystallization. 2. Fractional distillation of their ester followed by hydrolysis (Fischer’s method) 3. Selective precipitation as salt with phosphotungstic and picric acids. 4. Distribution of amino acid between n – butanol saturated with water (Dakin’s method). 5. Column, paper and gas chromatography. 6. Electrophoresis. 204

By amination of α-halo acid

By Strecker synthesis 1)

2)

Note: Usually, the aldehyde is treated with a mixture of ammonium chloride and potassium cyanide in aqueous solution

Chemical properties of amino acids. Amino acids show the following characteristic reactions. 1. Reaction of the carboxyl group. 2. Reaction of the amino group. 3. Reaction involving both the carboxyl and the amino group. 205

Reaction of the carboxyl group. Reaction with the base

Esterification

Note: HCl first converts the dipolar ion into an acid which is subsequently esterified. Decarboxylation

206

Reduction

Reaction with a strong acid Acetylation

Reaction with nitrous acid

207

Note: 1. This reaction forms the basis of the “van slyke method” for the estimation of amino acids. 2. The nitrogen is evolved (one half comes from the amino acid) quantitatively and its volume is measured. Reaction with Nitrosyl halide 1. This reaction forms the basis of the “van slyke method” for the estimation of amino acids. 2. The nitrogen is evolved (one half comes from the amino acid) quantitatively and its volume is measured. Reaction with nitrosyl halide

Reaction with 2, 4 – Dintrofluorobenzene (DNFB)

Reaction involving both the carboxyl & the amino group Effect of heat. α-amino acids undergo dehydration on heating (200°C) to give diketo piperazines

208

7.2. LIPIDS Lipids are usually insoluble in water. They are fatty acid esters. They are the principal component of cell membranes. Lipids can be simple fatty acids and some lipids have phosphorous and phosphorylated organic compounds in them. Lipids, containing phosphorus; are called phospholipids. A fatty acid has a carboxyl group attached to an R group.

Structure of phospholipids The R group can be a methyl or ethyl or higher number of CH2 group (1 carbon to 19 carbons). There are mainly two types of fatty acids- Saturated and unsaturated fatty acids. Saturated fatty acids do not contain any double bond between the carbon atoms. For Example, Butyric acid. Unsaturated fatty acids contain double bonds between the carbon atoms. For Example, Linoleic acid. 209

7.3. CARBOHYDRATES Carbohydrates are made up of carbon, hydrogen and oxygen atoms. It includes sugars, cellulose and starch. The simplest carbohydrate is glucose. The bond between two sugar molecules is known as glycosidic bond.

Structure of Glucose Carbohydrates made up of a single sugar molecule are known as monosaccharides. For Example, glucose. Monosaccharides made up of more than one unit of sugar molecule are known as oligosaccharides. For Example, fructose.

The long chains of sugars are called polysachharides. If a polysaccharide is made up of similar monosaccharides, it is called 210

Homopolymer, e.g. cellulose. If a polysaccharide is made up of different monosachharides, it is called heteropolymer. The right end of a polysaccharide chain is called the reducing end and the left end is called the Non-Reducing end. Reducing and non-reducing ends in maltose. Starch is a homopolymer of glucose. It is the major storage sugar in plants. Similarly, in animals, the storage form of sugar is glycogen. This is stored in liver. When the body needs glucose at the time of starvation or fast, glycogen breaks down into glucose to meet the energy requirement of the body. The sugar present in DNA is deoxyribose whereas in RNA, the sugar is ribose. Nucleic acids. Nucleic Acids are organic molecules present in living cells. Nucleic acids are polymers of nucleotides. There are three chemically distinct components in a nucleotide. These are as follows – Phosphate group, sugar known as deoxyribose and nitrogenous bases. There are two types of nitrogenous bases- Purines and Pyrimidines. Purines include adenine and guanine whereas pyrimidines include thymine and cytosine. DNA contains all 4 bases, that is, adenine, guanine, thymine and cytosine. But in RNA, thymine is replaced by uracil. Type of biomolecules is DNA. DNA is a nucleic acid biomolecules.

Structure of Nitrogenous Bases

Classification of carbohydrates. The carbohydrates are divided into three major classes depending upon whether or not they undergo hydrolysis, and if they do, on the number of products formed. 211

Monosaccharides. The monosaccharides are polyhydroxy aldehydes or polyhydroxy ketones which cannot be decomposed by hydrolysis to give simpler carbohydrates. Examples are glucose and fructose, both of which have molecular formula, C6H12O6.

The monosaccharides are the basis of carbohydrate chemistry since all carbohydrates are either monosaccharides or are converted into monosaccharides on hydrolysis. The monosaccharides are polyhydroxy aldehydes or polyhydroxy ketones. There are, therefore, two main classes of monosaccharides. 1. The Aldoses, which contain an aldehyde group 2. The Ketoses, which contain a ketone group The aldoses and ketoses are further divided into sub-groups on the basis of the number of carbon atoms in their molecules, as trioses, tetroses, pentoses, hexoses, etc. To classify a monosaccharide completely, it is necessary to specify both, the type of the carbonyl group and the number of carbon atoms present in the molecule. Thus monosaccharides are generally referred to as aldotrioses, aldotetro212

ses, aldopentoses, aldohexoses, ketohexoses, etc. The aldoses and ketoses may be represented by the following general formulas.

Glucose and fructose are specific examples of an aldose and a ketose.

Carbon Atoms 3 4 5 6 7

General Terms Triose Tetrose Pentose Hexose Heptose

Aldehydes Aldotriose Aldotetrose Aldopentose Aldohexose Aldoheptose

Ketones Ketotriose Ketotetrose Ketopentose Ketohexose Ketoheptose

Oligosaccharides. The oligosaccharides (Greek, oligo, few) are carbohydrates which yield a definite number (2-9) of monosaccharide molecules on hydrolysis. They include disaccharides which yield two monosaccharide molecules on hydrolysis. Examples are 213

sucrose and maltose, both of which have molecular formula, C12H22O11.

Trisaccharides, which yield three monosaccharide molecules on hydrolysis. Example is raffinose, which has molecular formula, C18H32O16.

Tetrasaccharides, etc. Disaccharides. Carbohydrates which upon hydrolysis give two molecules of the same or different monosaccharides are called disaccharides. Their general formula is C12H22O11. The three most important disaccharides are sucrose, maltose, and lactose. Each one of these on hydrolysis with either an acid or an enzyme gives two molecules of the same or different monosaccharides as shown below:

Disaccharides may also be considered to be formed by a condensation reaction between two molecules of the same or different monosaccharides with the elimination of a molecule of water. This reaction involves the formation of an acetal from a hemiacetal and an alcohol – in which one of the monosaccharides acts as the hemiacetal while the other acts as the alcohol. 214

Sucrose. It is formed by condensation of one molecule of glucose and one molecule of fructose. Unlike maltose and lactose, it is a non-reducing sugar since both glucose (C1-α) and fructose (C2-β) are connected to each other through their reducing centres. Its structure is shown below: Hydrolysis: (Invert Sugar or Invertose). Hydrolysis of sucrose with hot dilute acid yields D-glucose and D-fructose.

Sucrose is dextrorotatory, its specific rotation being +66.5%, Dglucose is also dextrorotatory, [α]D = +53°, but D-fructose has a large negative rotation, [α]D = -92°. Since D-fructose has a greater specific rotation than D-glucose, the resulting mixture is laevorotatory. Because of this the hydrolysis of sucrose is known as the inversion of sucrose, and the equimolecular mixture of glucose and fructose is known is invert sugar or invertose.

Polysaccharides. The polysaccharides are carbohydrates of high molecular weight which yield many monosaccharide molecules on hydrolysis. Examples are starch and cellulose, both of which have molecular formula, (C6H10O5)n.

215

In general, the monosaccharides and oligosaccharides are crystalline solids, soluble in water and sweet to taste. They are collectively known as sugars. The polysaccharides, on the other hand, are amorphous, insoluble in water and tasteless. They are called non-sugars. The carbohydrates may also be classified as either reducing or non-reducing sugars. All those carbohydrates which have the ability to reduce Fehling’s solution and Tollen’s reagent are referred to as reducing sugars, while others are non-reducing sugars. All monosaccharides and the disaccharides other than sucrose are reducing sugars. Polysaccharides are formed when a large number (hundreds to even thousands) of monosaccharide molecules join together with the elimination of water molecule. Thus, polysaccharides may be regarded as condensation polymers in which the monosaccharides are joined together by glycosidic linkages. Some important polysaccharides are: 1. Cellulose 2. Starch 3. Glycogen 4. Gums and 5. Pectins 6. Starch It is a polymer of glucose. Its molecular formula is (C6H10O5)n where the value of n (200 – 1000) varies from source to source. It is the chief food reserve material or storage polysaccharide of plants and is found mainly in seeds, roots, tubers, etc. Wheat, rice, potatoes, corn, bananas etc., are rich sources of starch. Starch is not a single compound but is a mixture of two components – amylose (10 to 20%) and amylopectin (20 to 80%). Both amylose and amylopectin are polymers of α-D-glucose. Amylose is a linear polymer of α-Dglucose. It contains about 200 glucose units which are linked to one another through α-linkage involving C1 of one glucose unit with C4 of the other as shown below:

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Amylopectin, on the other hand, is a highly branched polymer. It consists of a large number (several branches) of short chains each containing 20-25 glucose units which are joined together through αlinkages involving C1 of one glucose unit with C4of the other. The C1 of terminal glucose unit in each chain is further linked to C6 of the other glucose unit in the next chain through C1 – C6 α-linkage. This gives amylopectin a highly branched structure as shown below.

Hydrolysis: Hydrolysis of starch with hot dilute acids or by enzymes gives dextrins of varying complexity, maltose and finally Dglucose. Starch does not reduce Tollen’s reagent and Fehling’s solution. Uses: It is used as a food. It is encountered daily in the form of potatoes, bread, cakes, rice etc. It is used in coating and sizing paper to improve the writing qualities. Starch is used to treat textile fibres before they are woven into cloth so that they can be woven without breaking. It is used in manufacture of dextrins, glucose and ethyl alcohol. Starch is also used in manufacture of starch nitrate, which is used as an explosive. The carbohydrates are divided into three major classes depending upon whether or not they undergo hydrolysis, and if they do, on the number of products formed. Monosaccharides. Monosaccharides are the simplest form of sugars (carbohydrates) which cannot be further hydrolysed into simpler compounds. Glucose & fructose are the two examples of monosaccharides. Monosacharaides can further be classified into aldose & ketose. If the monosaccharide contains an aldehyde group (-CHO), it is known as aldose, e.g., glucose. Monosacharide which contains a ketone group (>C=O) is known as ketoses. E.g., fructose. 217

All the monosaccharides are reducing sugars as all of them have a free functional group which can reduce Tollen’s reagent. Monosaccharides are also classified on the basis of the number of carbon atoms present in its chain. Carbon Atoms 3 4 5 6 7

General Terms Triose Tetrose Pentose Hexose Heptose

Aldehydes Aldotriose Aldotetrose Aldopentose Aldohexose Aldoheptose

Ketones Ketotriose Ketotetrose Ketopentose Ketohexose Ketoheptose

Aldotriose. D and L Terminology: The simplest of all carbohydrates that fit the definition we have given for carbohydrates are the trioses, glyceraldehyde and dihydroxyacetone. Glyceraldehyde is aldotriose, and dihydroxyacetone is a ketotriose.

Glyceraldehyde contains one asymmetric carbon atom (marked by an asterisk) and can thus exist in two optically active forms, called the D-form and the L-form. Clearly, the two forms are mirror images that cannot be superimposed, that is they are enantiomers. 218

The two forms of glyceraldehyde are especially important because the more complex monosaccharides may be considered to be derived from them. They serve as a reference point for designating and drawing all other monosaccharides. In carbohydrate chemistry, the Fischer projection formulas are always written with the aldehyde or ketone groups at the top of the structure. By definition, if the hydroxyl group on the asymmetric carbon atom farthest from aldehyde or ketone group projects to the right, the compound is a member of the D-family. If the hydroxyl group on the farthest asymmetric carbon projects to the left, the compound is a member of the L-family. The maximum number of optical isomers of a sugar is related to the number of asymmetric carbon atoms in the molecule and may be calculated by the following simple equation. The maximum number of optical isomers=2n, where n is the number of asymmetric carbon atoms. Since glyceraldehyde contains only one asymmetric carbon atom, the number of optical isomer is 2. We know that we have seen that there are indeed two different glyceraldehydes. All of its valences are saturated by different functional groups, which raises the possibility of two optical isomers. One of the isomers deviates polarized light clockwise, it is dextrorotatory and designated with the letter d before its name. Both compounds are enantiomers, one being the mirror image of the other. 219

Aldotetrose: A monosaccharide having both an aldehyde (an aldose) and three carbons (a triose). If we examine the general formula of an aldotetrose, we see that they contain two asymmetric carbon atoms (marked by asterisks). This means that 4 optical isomers are possible. They may be represented as the following two pairs

All four isomers have been prepared synthetically. The D- and L-erythrose are mirror images, that is, they are enantiomers. They have exactly the same degree of rotation but in opposite directions. Equal amounts of the two would constitute a racemic mixture, that is, a mixture that would allow a plane-polarised light to pass through the solution unchanged but could be separated into detrorotatory and laevorotatory isomers. The same comments hold for D- and Lthreose. However, D-erythrose and L-threose are not images, that is, they are diastereomers (optical isomers that are not mirror images are called diastereomers), and the degree of rotation of each would probably differ. Aldopentoses: If we examine the general formula of an aldopentose, we see that they contain three asymmetric carbon atoms. This means that 23 or 8 optical isomers are possible. These are:- D(–) lyxose, L(+)-lyxose, D(–) xylose, L(–)xylose, D(–) arabinose, L(+)arabinose, D(–)-ribose, L(+)-ribose 220

Aldohexoses: If we examine the general formula of aldohexose, we see that it contains four asymmetric carbon atoms. This means that 24 or 16 optical isomers are possible: D and L forms of altrose, allose glucose, mannose, galactose, talose, arabinose and idose. Only three of the sixteen possible aldohexoses are found in nature (all sixteen isomers have been prepared synthetically). They are D-glucose, D- mannose, and D-galactose. No one of these three optical iosmers is a mirror image of any of the others, so all three are diastereomers of each other.

Cyclic form of monosaccharide. Aldoses (and ketoses) react with alcohols to give first hemiacetals (and hemiketals) and then acetals (and ketals), i.e.,

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Since monosaccharides contain a number of hydroxyl groups and an aldehyde or a keto group, therefore, any one of the –OH groups (usually C4 or C5 in aldohexoses and C5 or C6 in ketohexoses) may combine with the aldehyde or the keto group to form intramo-

lecular hemiacetal or hemiketal. As a result, the open chain formulae do not represent the actual structures of the monosaccharides. Their actual structures are cyclic involving five or six membered rings containing an oxygen atom. The five-membered ring containing one oxygen atom because of its similarity with furan is called the furanose form and the six-membered ring containing one oxygen atom because of its resemblance with pyran is called the pyranose form. In nut shell, all the monosaccharides (pentoses and hexoses) in the freestate always exist in the pyranose form. However, in the combined state some monosaccharides such as ribose, 2-deoxyribose, fructose etc., usually exist in the furanose form.

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Cyclic structure of glucose – anomers

We have discussed above that monosaccharides have cyclic hemiacetal or hemiketal structures. To illustrate, let us first consider the example of D-glucose. During hemiacetal formation C5 – OH of glucose combines with the C1 – aldehydic group. As a result, C1 becomes chiral or asymmetric and thus has two possible arrangements of H and OH groups around it. In other words, D-glucose exists in two stereoisomeric forms, i.e., a-D-glucose and b-D-glucose as shown below: In a-D-glucose, the OH group at C1 is towards right while in bD-glucose, the OH group at C1 is towards left. Such a pair of stereoisomers which differ in configuration only around C1 is called anomers and the C1 carbon is called Anomeric carbon (or glycosidic carbon). The cyclic structures of monosaccharides can be better represented by Haworth Projection formulae. To get such a formula for any monosaccharide (say a-and b-D-glucose), draw a hexagon with its oxygen atom at the upper right hand corner. Place all the groups (on C1, C2, C3 and C4) which are present on the left hand side in structures I and II, above the plane of the ring and all those groups on the right hand side below the plane of the ring. The terminal – CH2OH group is always placed above the plane of the hexagon ring (in D-series). Following the above procedure, Haworth Projection Formulae for a-D-glucose (I) and b-D-glucose (II) are obtained as shown below: 223

Cyclic structure of fructose. Like glucose, fructose also has a cyclic structure. Since fructose contains a keto group, it forms an intramolecular hemiketal. In the hemiketal formation, C5– OH of the fructose combines with C2-keto group. As a result, C2 becomes chiral and thus has two possible arrangements of CH2OH and OH group around it. Thus, D-fructose exists in two stereoisomeric forms, i.e., a-D-fructopyranose and b-D fructopyranose. However, in the combined state (such as sucrose), fructose exists in furanose form as shown below:

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Mutarotation. The two stereoisomeric forms of glucose, i.e., αD-glucose and β-D-glucose exist in separate crystalline forms and thus have different melting points and specific rotations. For example, α-D-glucose has a m.p. of 419 K with a specific rotation of +112° while β-D-glucose has a m.p. of 424 K and has a specific rotation of +19°. However, when either of these two forms is dissolved in water and allowed to stand, it gets converted into an equilibrium mixture of α-and β-forms through a small amount of the open chain form.

As a result of this equilibrium, the specific rotation of a freshly prepared solution of α-D-glucose gradually decreases from of +112° to +52.7° and that of β-D-glucose gradually increases from +19° to +52.7°.

This change in specific rotation of an optically active compound in solution with time, to an equilibrium value, is called mutarotation. During mutarotation, the ring opens and then recloses either in the inverted position or in the original position giving a mixture of αand-β-forms. All reducing carbohydrates, i.e., monosaccharides and disaccharides (maltose, lactose etc.) undergo mutarotation in aqueous solution. Reactions of glucose a) With HI/P: It undergoes reduction to form n-hexane while with sodium amalgam it forms sorbitol.

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b) With H2O: It forms neutral solution c) With hydroxylamine (NH2OH)

d) With HCN: It forms addition product cyanohydrin

e) Oxidation: Glucose on oxidation with Br2 gives gluconic acid which on further oxidation with HNO3 gives glucaric acid

f) With Tollen reagent and Fehling solution: Glucose forms silver mirror and red ppt. of Cu2O respectively. g) With acetic anhydride. In the presence of pyridine glucose forms pentaacetate.

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h) With phenylhydrazine: it forms glucosazone

j) Glycoside formation: When a small amount of gaseous HCl is passed into a solution of D (+) glucose in methanol, a reaction takes place that results in the formation of anomeric methyl acetals.

i) With conc. HCl acid: Glucose gives laevulinic acid

Carbohydrate acetals are generally called glycosides and an acetal of glucose is called glucoside. An example to solve: Glucose and fructose give the same osazone. One may therefore conclude that 1. glucose and fructose have identical structures 2. glucose and fructose are anomers 3. the structures of glucose and fructose have mirror – image relationship 227

4. the structures of glucose and fructose differ only in those carbon atoms which take part in asazone formation. Kiliani – Fischer synthesis. This is a method of lengthening the carbon chain of an aldose. To illustrate, we take synthesis of D-threose and D-erythrose (Aldotetroses) from D-glyceraldehyde (an aldotriose). Addition of HCN to glyceraldehyde produces two epimeric cyanohydrins because the reaction creates a new stereocenter. The cyanohydrins can be separated easily (as they are diastereomers) and each can be converted to an aldose through hydrolysis, acidification and lactonisation, and reduction with Na-Hg in the presence of H2SO4. One cyanohydrin ultimately yields D-erythrose and Dthreose.

Here we can see that both sugars are D-sugars because the starting compound is D-glyceraldehyde and its stereocentrer is unaffected by its synthesis. Ruff degradation. It is opposite to Kiliani Fischer synthesis that can be used to shorten the chain by a similar unit. The ruff degradation involves (i) Oxidation of the aldose to an aldonic acid using Bromine water. (ii) Oxidative decarboxylation of the aldonic acid to the next lower aldose using H2O2 and Fe2 (SO4)3. D-ribose, for example, can be reduced to D-erythrose.

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Disaccharides. Carbohydrates which upon hydrolysis give two molecules of the same or different monosaccharides are called disaccharides. Their general formula is C12H22O11. The three most important disaccharides are sucrose, maltose, and lactose. Each one of these on hydrolysis with either an acid or an enzyme gives two molecules of the same or different monosaccharides as shown below:

Disaccharides may also be considered to be formed by a condensation reaction between two molecules of the same or different monosaccharides with the elimination of a molecule of water. This reaction involves the formation of an acetal from a hemiacetal and an alcohol – in which one of the monosaccharides acts as the hemiacetal while the other acts as the alcohol. 229

Maltose (C12H22O11). Maltose or malt sugar is formed by condensation of two molecules of glucose joined with an α bond. Maltose is a reducing sugar. It reduces Tollens’ and Fehling’s reagent. It reacts with phenylhydrazine to yield hydrazone. It is oxidized by bromine water to maltobinoic acid. On hydrolysis it gives two glucose units.

Maltose can be hydrolysed by enzyme maltase. Sucrose (C12H22O11)

It is formed by condensation of one molecule of glucose and one molecule of fructose. Unlike maltose and lactose, it is a non-reducing sugar since both glucose (C1 - α) and fructose (C2 -β) are connected to each other through their reducing centres. Its structure is shown below: Hydrolysis of sucrose (Invert Sugar or Invertose) with hot dilute acid yields D-glucose and D-fructose.

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Sucrose is dextrorotatory, its specific rotation being +66.5%, D-glucose is also dextrorotatory, [α]D = +53°, but D-fructose has a large negative rotation, [α]D = -92°. Since D-fructose has a greater specific rotation than D-glucose, the resulting mixture is laevorotatory. Because of this the hydrolysis of sucrose is known as the inversion of sucrose, and the equimolecular mixture of glucose and fructose is known is invert sugar or invertose.

Lactose (C12H22O11)

Lactose or milk sugar is formed by condensation of one molecule of galactose and one molecule of glucose. Maltose is a reducing sugar. It reduces Tollens’ and Fehling’s reagent. It reacts with phenylhydrazine to yield hydrazone. Lactose exists in alpha and beta forms which undergo mutarotation. It makes up about 5% of human milk and of cow’s milk. Milk sours when lactose in converted to lactic acids by bacterial (e.g. Lactobacillus bulgaricus). Acidic hydrolysis of lactose converts it into equal amounts of D- glucose and Dgalactose.

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Cellobiose (C12H22O11)

Cellobiose consists of two glucose molecules linked by a β bond. Octaacetate of cellobiose is obtained by treatement of cellulose with sulfuric acid. Alkaline hydrolysis of octaacetate yeilds cellobiose. Cellobiose is also a reducing sugar just like maltose. It forms osazone and exists in alpha and beta forms that undergo mutarotation. Cellobiose can be hydrolysed to two molecules of D-Glucose. Cellobiose differs from amtose in respect of enzyme which causes hydrolysis. Cellobiose is hydrolysed by emulsion and not be maltase. Polysaccharides. Polysaccharides are formed when many hundreds or even thousands of monosaccharide units join together with the elimination of water molecule. Thus, polysaccharides may be regarded as condensation polymers in which the monosaccharides are joined together by glycosidic linkages. The most important polysacharides are cellulose and starch. Both are obtained from plants. These are synthesised by plants using water and carbondioxide through photosynthesis. Both cellulose and starch are made up of Dglucose units. Hence, their general formula is (C6H12O6)n, where n is the natural number and it denotes the number of glucose units present in the polysaccharide. Polysccharide Cellulose Starch Glycogen Pectin

Monosaccharide units Glucose nits linked together by beta-linkages. Glucose nits linked together by alpha-linkages. Glucoses units linked together linearly by α(1→4) glycosidc bonds 1,4-linkedα-D-galactosyluronic acid

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Starch. It is a polymer of glucose. Its molecular formula is (C6H10O5)n where the value of n (200 – 1000) varies from source to source. It is the chief food reserve material or storage polysaccharide of plants and is found mainly in seeds, roots, tubers, etc. Wheat, rice, potatoes, corn, bananas etc., are rich sources of starch. Starch is not a single compound but a mixture of two components – amylose (10 to 20%) and amylopectin (20 to 80%). Both amylose and amylopectin are polymers of α-D-glucose. Amylose is a linear polymer of α-Dglucose. It contains about 200 glucose units which are linked to one another through α-linkage involving C1 of one glucose unit with C4 of the other as shown below:

Amylopectin, on the other hand, is a highly branched polymer. It consists of a large number (several branches) of short chains each containing 20-25 glucose units which are joined together through αlinkages involving C1 of one glucose unit with C4 of the other. C1 of the terminal glucose unit in each chain is further linked to C6 of the other glucose unit in the next chain through C1 – C6 α-linkage. This gives amylopectin a highly branched structure as shown below.

Hydrolysis of starch with hot dilute acids or by enzymes gives dextrins of varying complexity, maltose and finally D-glucose. Starch does not reduce Tollen’s reagent and Fehling’s solution. Uses of Starch: It is used as food. It is encountered daily in the form of potatoes, bread, cakes, rice, etc. It is used in coating and 233

sizing paper to improve the writing qualities. Starch is used to treat textile fibres before they are woven into cloth so that they can be woven without breaking. It is used in manufacture of dextrins, glucose and ethyl alcohol. Starch is also used in manufacture of starch nitrate, which is used as an explosive.

Cellulose

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Cellulose is a polysaccharide made up of D-glucose units condensed through β(1→4)-glycosidic bonds. It is a straight chain polymer: unlike starch, no coiling occurs. Cellulose is found primarily in the cell wall of plants and it is hydrophilic in nature i.e. insoluble in water.Complete hydrolysis of cellulose yields d- glucose units. It is the major component of wood and plant fibers like cotton. Cellulose is a non-reducing sugar. Its molecular weight is very high (250000 to 1000000 or more). There are about 1500 glucose units per molecule of cellulose.

7.4. PEPTIDE AND PROTEINS Proteins are formed by joining the carboxyl group of one amino to the α – amino group of another acid. The bond formed between two amino acids by the elimination of water molecules is called peptide linkage.

The product formed by linking amino acid molecules through peptide linkage -CO - NH- is called a peptite. When two amino acids are combined in this way the resulting product is called a dipeptide.

Peptides are further designated as tri, tetra or penta peptides, accordingly, as they contain three, four or five amino acid molecules, the same or different. In the peptide the amino acid that contains the free amino group is called the N – terminal residue (written as 235

L.H.S). The amino acid that contains the free carboxyl group is called the C – terminal residue (written as R.H.S).

If a large number of α-amino acids (100 to 1000) are joined by peptide bonds the resulting polyamide is called a polypeptide.

A peptide having a molecular mass more than 10,000 is called a protein. Structure of proteins

Primary structure of protien  This type of structure was given by Friedrich Sanger in 1953 in Insulin.  Primary structure is conformed by a single polypeptide chain in a linear manner.  All amino acids are attached in a straight chain by peptide bond. 236

Secondary structure of protein  The fixed configuration of polypeptide skeleton is referred to as the secondary structure of protein.  It gives information about the manner in which the protein chain is folded and bent and also about the nature of the bond which stabilizes this structure.  This structure of protein is mainly of two types

A) α-Helix  The chain of α-amino acids coiled as a right handed screw (called α-helix) because of the formation of a hydrogen bond.  The spiral is held together by H-bonds between N–H and C = O groups vertically adjacent to one another.  X-Ray studies have shown that there are approximately 3.6 amino acid units for each turn in helix.  Such proteins are elastic, i.e. they can be stretched.  On stretching weak H-bonds break up and the peptide acts like a spring.  The hydrogen bonds are reformed on releasing the tension.  e.g. Myosin, Keratin, Tropomysin. B) Beta-pleated sheet  Polypeptide chains are arranged side by side.  The chains are held together by a very large number of hydrogen bonds between C = O and NH of different chains.  These sheets can slide over each other to form a three dimensionnal structure called a beta pleated sheet, e.g. silk has a beta pleated structure. It refers to the arrangement and interrelationship of the twisted chain of protein into specific layer or fibres.  This tertiary structure is maintained by weak interatomic forces such as, H-bonds, hydrophobic bond, van der Waals’ force and disulphide bonds (e.g. Insulin), e.g. Protein of tobacco mosaic virus (TMV); Myoglobin; Hemoglobin. 237

Tertiary structure of protein

Quarternary structure of protein  When two or more polypeptide chain are united by the force other than covalent bond i.e., peptide and disulphide bonds.

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 It refers to final three dimensional shapes that result from twisting bonding and folding of the protein helix.  It is the most stable structure.

Classification of proteins There are two methods for classifying proteins.  Classification according to Composition  Classification according to Functions Classification according to composition. Simple proteins. Simple proteins are those which yield only α-amino acids upon hydrolysis. Simple proteins are composed of chain of amino acid units only joined by peptide linkage. Examples are: Egg (albumin); Serum (globulins); Wheat (Glutelin); Rice (Coryzenin) Conjugated proteins. Conjugated proteins are those which yield α – amino acids plus a non-protein material on hydrolysis. The non-protein material is called the prosthetic group. Example: Casein in milk (prosthetic group is phosphoric acid); Hemoglobin (prosthetic group is nucleic acid); Chlolesterol (prosthetic group – lipid). According to molecular shape, proteins are further classified into two types. A) Fibrous protein a) These are made up of polypeptide chains parallel to the axis that are held together by strong hydrogen and disulphide bonds. b) They can be stretched & contracted like a thread. c) They are usually insoluble in water. Example: Keratin (hair, wool, silk and nails); Myosin (muscle) B) Globular Proteins a) These have more or less spherical shape (compact structure). b) α – amino helix are tightly held bonding; H – bonds, disulphide bridges, ionic or salt bridges: Examples: Albumin (egg) Classification according to Functions. The functional classification includes the following groups. Structural proteins. These are the fibrous proteins such as collogen (skin, cartilage and bones) which holds living system together. Blood proteins. The major proteins constituent of the blood are albumin hemoglobin and fibrinogen. a) Their presence contributes to maintenance of osmotic pressure, oxygen transport system and blood coagulation, respectively. 239

Chemical tests for protein. Biuret test. On adding a dilute of copper sulphite to alkaline solution of protein, a violet colour is developed. This test is due to the presence of peptide (-CO-NH-) linkage.

Millon’s test. Millon’s reagent consists of mercury dissolved in nitric acid (forming a mixture of mercuric & mercurous nitrates). When millon’s reagent is added to the protein, a white ppt is formed, which turns brick red on heating. This test is given by protein which yields tyrosine on hydrolysis (due to the presence of phenolic group). Nihydrin test. This test is given by all proteins. When protein is boiled with a dilute solution of ninhydrin, a violet colour is produced.

Uses of Proteins:  Proteins constituting as essential part of our food, meat, eggs, fish, cheese provide protein to human beings.  Casein (a milk protein) is used in the manufacture of artificial wool & silk.  Amino acids needed for medicinal use & feeding experiment, are prepared by hydrolysis of proteins.  Gelatin is used in desserts, salads, candies, bakery goods, etc.  Leather is obtained by tanning the protein of animal hides. 240

 Hemoglobin present in blood is responsible for carrying oxygen and CO2.  Hormones control various processes.  Enzymes are the proteins produced by living system & catalyse specific biological reaction. Examples:  Ureases (Urea → CO2 + NH2)  Pepsin (Protein → Amino acid)  Trypsin (Protein → Amino acid)  Carbonic anhydride (H2CO3 → H2O + CO2)  Nuclease (RNA, DNA → Nucleotides)

7.5. NUCLEIC ACIDS Definition of nucleic acid. Nucleic acids are large, organic molecules present in living cells. DNA and RNA are nucleic acids. They are the polymers of nucleotides. There are three chemically distinct components in a nucleotide. These are as follows-Phosphate group, sugar known as Deoxyribose or Ribose and nitrogenous bases. There are two types of nitrogenous bases – Purines and Pyrimidines. Purines include adenine and guanine, whereas pyrimidines include thymine and cytosine. DNA contains all 4 bases, that is, adenine, guanine, thymine and cytosine. But in RNA, thymine is replaced by uracil.

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Nitrogenous bases DNA contains deoxyribose sugar whereas RNA contains ribose sugar.

Structure of Deoxyribose and Ribose Sugar Structure of the DNA. DNA is a double helix formed by twisting of two polynucleotide chains around each other. Watson and Crick proposed the DNA structure using X-ray diffraction studies. The two strands are antiparallel to each other. The bases are stacked inside the helix. The two helices are bonded together via hydrogen bond. Adenine forms two hydrogen bonds with thymine and cytosine forms three hydrogen bonds with guanine.

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Hydrogen Bonding in DNA DNA is negatively charged due to the presence of phosphate groups. This negative charge is stabilized by basic proteins known as histone proteins. Structure of the RNA. RNA exists as a single stranded structure. In RNA, thymine is replaced by uracil. There are 3 major classes of RNA found:  Messenger RNA is a sequence of nucleotides that codes for proteins. In messenger RNA, nucleotides are arranged in the form of codons.  Transfer RNA is used during protein synthesis. It is found in the cytoplasm.  Ribosomal RNA is also found in cytoplasm and is the most abundant RNA found in cells. Denaturation of DNA. DNA exists in a double stranded form. When two DNA strands separate from each other, DNA is said to be denatured. Heating or alkaline pH denatures the DNA. The temperature at which DNA double strands can be separated is known as melting Temperature. Breakage of G-C base pairs needs high temperature as compared to breakage of A-T base pairs due to triple bond in G-C base pairs. But if denaturing agents are removed, the DNA will regain its structure and it is said to be renatured. Boiled eggs become hard because egg proteins and DNA gets denatured. A classic example of denaturing in proteins comes from egg whites, which are typically largely egg albumins in water. Fresh from the eggs, egg whites are transparent and liquid. Cooking the thermally unstable whites turns them opaque, forming an interconnected solid mass. Quantification of DNA content is performed using Absorption at 260nm. Importance of nucleic acids/functions of nucleic acids. Deoxyribonucleic acids and ribonucleic acids are the key components which control almost all the metabolic activities in the organism.  DNA is necessary for transferring genes from parents to offspring.  DNA stores all the information of a cell.  Loss of DNA content is associated with lots of diseases.  DNA samples are used to identify the suspect or father of an unidentified child. 243

 DNA sequence helps in studying relationship between the two organisms such as which organism originates from which ancestor.  Without DNA, no protein synthesis will occur.  RNA is essential for protein synthesis. RNA and DNA help to understand the diseases and to find the cure of genetic diseases.

GENERAL PROBLEMS 1. The hydrocarbons listed below give a name for IUPAC and rational nomenclatures, specify how many primary, secondary, tertiary and quaternary carbon atoms are contained in the alkane. Isomer of which hydrocarbon of normal structure is this hydrocarbon? Write the gross formula (CnH2n + 2) and give the name.

2. Write the structural formulas and name the IUPAC nomenclature. a) ethyldiisopropyl-sec-butylmethane b) ethyldi-sec-butylmethane c) trimethylisopropylmethane d) tripropylisopropylmethane e) methylethyl t-butylmethane f) methylisopropylisobutyl-t-amylmethane g) ethyl isobutyl-sec-butylmethane 244

3. Write the structural formulas of the alkanes and name them according to the rational nomenclature. a) 2,2,3,4-tetramethylpentane b) 2,3,6-trimethyl-3-ethylheptane c) 2,4-dimethyl-3-ethylheptane d) 4-t-Butyl-3-methyloctane e) 2,2,3,3,4,4-hexamethylhexane f) 3-isopropyl-2,4-dimethyl-3-ethylhexane g) 2,2,3,3,6-pentamethylheptane 4. Obtain the following compounds from compounds with the same number, with a smaller number and with a greater number of carbon atoms. The starting materials and reaction products are named for all nomenclatures. a) butane b) 2,3-Dimethylbutane c) 2,3,4,5-tetramethylhexane d) 2,5-dimethylhexane e) ethane f) 2,3,6,7-tetramethyloctane g) 3,4,5,6-tetramethyloctane h) 2,7-dimethyloctane i) 2,3,4,7,8,9-hexamethyldecane g) 2,4-dimethylhexane 5. Write the structural formulas and name the IUPAC nomenclature. a) methylpropyl isobutyl-t-butylmethane b) dimethylpropylisoamyl methane c) methyldiisopropyl-t-butylmethane d) methylisobutylisoamyl methane e) methyl-sec-butyl-t-butylmethane f) dimethylisopropyl-sec-butylmethane g) methylethyl-sec-butyl-t-amylmethane

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6. Write the equations for the monobromination reactions for the hydrocarbons listed below with an indication of a possible reaction mechanism. The source and end products are given. b)

c)

d)

7. In the process of oxidation of saturated hydrocarbons, hydroperoxidesare formed as intermediates. Indicate what chemical transformations will occur with the listed hydroperoxides. What class are the compounds obtained? 8. Write the structural formulas and name the IUPAC nomenclature. a) dimethylisopropyl-sec-butylmethane b) methylethyl-sec-butyl-t-amylmethane c) methylisopropylisobutyl-t-butylmethane d) dimethyltert-butyl isoamyl methane e) dimethyl-sec-butyl-sec-isoamyl methane f) methyldiethylisobutylmethane g) methylethyl-sec-butyl-t-butylmethane 9. Write the structural formula of the organic substance of the composition of C5H10, if it is known that during its bromination, a predominantly tertiary bromine derivative is obtained, and when nitrating with Konovalov, a tertiary nitro compound is obtained. Explain why the substitution most easily occurs in the tertiary hydrocarbon atom. 10. Write the structural formula of the hydrocarbon C6H14, which forms only two monobromo derivatives with bromination. 246

c) Establish the structure of hydrocarbon C6H14, with monobromination of which a tertiary bromine derivative of the composition C6H13Br is formed; the hydrocarbon C6H14 can be obtained by the Würz process without by-products. 11. Write the structural formulas of the alkanes and name them according to the rational nomenclature. a) 2,2,5,5-tetramethylhexane b) 4-isopropyl-2-methylheptane c) 3,5-Dimethyl-4-ethylheptane d) 4-sec-Butyl-3-methylnonane e) 2,3,5,5-tetramethyl-3-ethylhexane f) 3-isopropyl-2,2,3,4-tetramethylpentane g) 2,4,4,5-tetramethylheptane 12. Obtain ethylene hydrocarbons by dehydration of the following alcohols. Specify the conditions and mechanism of the reactions. Name the alkenes.

13. The following alkenes will be obtained from the corresponding alcohols. Specify the conditions and mechanism of the reactions. a) trimethylethylene e) 1,2-dimethyl-1-ethylethylene b) simmethylisopropylethylene f) 1-Methyl-1,2-diethylethylene c) asymmet-dimethylethylene g) 1-Methyl-2-t-butyl-ethylene d) cyclohexene h) 2,3-dimethylethylcyclohexene 14. Which olefins are formed by the action of alcoholic alkali solution on the following halogenated derivatives? a) 2-bromopentane e) 2-chloro-3-methylhexane b) 2-iodobutane f) 2-bromopentane 247

c) 2,3-dimethyl-2-bromobutane g) 2-iodoheptane d) 2-chloro-2-methylbutane h) 2-chloro-3-isopropylheptane 15. Obtain the following olefins from the corresponding monohalogen derivatives. Indicate the conditions for the reaction. a) 2-hexene e) 2,3-dimethyl-2-hexene b) 3-methyl-2-heptene f) sim-dicyclopropylethylene c) 3,4-dimethyl-2-hexene g) 2-methylcyclopentene d) 3-methyl-2-pentene h) simdicyclohexylethylene 16. For the listed alkenes, form reaction equations for the reaction with bromine, reflecting the mechanism of radical and electrophilic addition of halogen. The starting alkene and the resulting compound are named according to the IUPAC nomenclature. a) propylene e) ethylvinylmethane b) methylvinyl methane f) vinyl t-butylmethane c) butylene g) cyclohexene d) propenylmethane h) vinyl propylmethane 17. Which compounds are obtained by the interaction of the lower alkenes with hydrogen bromide in the absence and presence of hydrogen peroxide? Write the equations of reactions, reflecting their mechanism. Name the substances obtained by the IUPAC nomenclature. a) 3-methyl-1-butene b) 2-methyl-1-butene c) 2-methyl-1-pentene d) 3-methyl-1-pentene e) propene f) 1-butene g) 2-methyl-2-pentene h) trimethylethylene 18. Write the equations of the reactions of water addition to alkenes. Specify the conditions and mechanism of the reactions. Name the obtained substances, name the IUPAC nomenclature. a) tert-butylethylene b) propylethylene c) neo-pentylethylene d) methylethylene e) isoamylethylene f) ethylethylene g) 1,1-dimethyl-2-ethyl-ethylene h) 1,1-dimethyl-2-propylethylene 248

19. By hydration of which alkenes, the following alcohols can be obtained? Write the reaction equations, reflecting the conditions and mechanism of the process, the initial and the obtained substances, name the IUPAC nomenclature: a)

b)

c) d) e)

g)

f)

h)

20. Draw up a scheme of reactions and reflect the mechanism of the addition of hypochlorous acid to: a) propylene e) butylene b) isobutylene f) isopropylethylene c) trimethylethylene g) 1-pentene d) isobutylethylene h) 2-methyl-2-butene 21. Draw up a scheme of reactions and reflect the mechanism of sulfuric acid addition to: a) ethylene e) propylene ethylene b) 2-methyl-2-butene, f) 2-methyl-1-butene c) propylene g) 1-butene d) dimethylethylene h) 2-butene 22. For the following alkenes, write the oxidation reactions: a) dilute aqueous solution of KMnO4 (Wagner reaction); b) with a concentrated aqueous solution of KMnO4. a) 2-Methyl-1-pentene e) 3-Methyl-1-pentene 249

b) 3-methyl-1-butene c) 2-Methyl-1-butene d) trimethyl-ethylene

f) 1-butene g) 3-Octene h) 3,4-dimethyl-2-hexene

23.Write the equation of the reaction between an excess of alcohol solution of alkali and the following dihalides. Name the products of reaction according to IUPAC and rational nomenclatures. a) 1,1-dibromo-3-methylbutane b) 2,2-dibromobutane c) 1,2-dibromo-3-methylbutane d) 1,2-dibromobutane e) 2,2-dichloropropane f) 2,3-dichloro-4-methylhexane g) 1,2-dibromo-3,3-dimethylbutane h) 1,2-dichloro-4,4-dimethylpentane 24. Obtain from the corresponding dihalogen derivatives the following alkynes and name them according to another nomenclature: a) isopropylacetylene b) 3,4-dimethyl-1-pentine c) t-butylacetylene d) ethyl acetylene e) propylacetylene f) dimethylacetylene g) methylisopropylacetylene h) 1-butyne 25. With the help of what reagents and in what conditions it is possible to carry out the following transformations: a) 1-pentene to propylacetylene b) 3-methyl-1-butene to 3-methyl-1-butyne c) 1-hexene to butylacetylene d) 3,3-dimethyl-1-butene in 3,3-dimethyl-1-butyne e) 1-butyne to 2-butyne f) 1-pentine in 2-pentine g) 4-methyl-1-pentene to 4-methyl-2-pentene h) butyl bromide in 1-butyne 26. Using as starting materials acetylene, sodium amide and the corresponding alkyl halide, get the following homologues of acetylene. What type of chemical transformation is each stage of synthesis? a) diethylacetylene b) butylacetylene c) di-sec-butylacetylene d) di-t-butylacetylene 250

e) isoamyl acetylene f) tert-amyl acetylene g) methylethylacetylene h) ethylisopropylacetylene 27. What homologues of acetylene need to be taken in order to obtain the following ketones from the Kucherov reaction? Write the reaction equations, specify their conditions. Explain why ketones are produced, not unsaturated alcohols. a) 3-Methyl-2-hexanone b) 3-heptanone c) methyl isobutyl ketone d) methyl isopropyl ketone e) 3,4-Dimethyl-2-pentanone f) methyl-sec-butyl ketone g) methyl ethyl ketone h) methylisoamyl ketone 28. What reactions will enable us to distinguish the following compounds from each other? Use qualitative reactions, ozonation reactions, oxidation. a) ethyl acetylene from dimethylacetylene and butane b) 1-butyne from 2-butyne c) 2-pentine from 1-pentyne d) neopentylacetylene from methyl-t-butylacetylene e) 2,5-dimethyl-3-hexyne from 3,5-dimethyl-1-hexyne f) dimethylethylacetylenylmethane from ethylisopropylacetylene g) trimethylacetylenylmethane from diethylacetylene h) isopropylacetylene from methylethylacetylene 29. Write the interaction reaction on Peppe in the presence of copper acetylide between the following compounds and name the reaction products: a) acetylene and 1 mole formaldehyde b) acetylene and 2 moles of formaldehyde c) acetylene and 1 mole of acetaldehyde d) acetylene and 2 moles of acetaldehyde e) methyl acetylene and formaldehyde 251

f) ethyl acetylene and formaldehyde g) acetylene and 1 mole propanal h) acetylene and 2 moles propanal 30.Using the Favorsky condensation reaction between acetylene or 1-alkynes and ketones, synthesize the following alcohols: a) dimethylacetylenylcarbinolf) diethylacetylenylcarbinol b) methylethylacetylenylcarbinol g) 2-methyl-3-pentyn-2-ol c) 3-methyl-4-hexyn-2-ol h) methylisopropylacetylenylcarbinol d) 2,5-Dimethyl-3-hexyn-2-ol e) 3,6-Dimethyl-4-heptin-3-ol 31. Write the structural formula of a hydrocarbon with a molecular weight of 68 if it is known that it reacts with bromine, with an ammonia solution of silver oxide, and when hydrated, it gives methyl isopropyl ketone. Write all the reactions. 32. Hydrocarbon composition C6H10 adds two molecules of bromine, with an ammonia solution of cuprous chloride gives a precipitate, during oxidation gives isopropylacetic and carbonic acid. Determine the structure of the hydrocarbon and write the equations for these reactions. 33. Determine the structure of the hydrocarbon C5H8, if it is known that it does not react with the ammonia solution of cuprous chloride, with an incomplete reduction forms an alkene. Write all the reactions. 34. Name the final product of the following transformations:

35. Call the final product of the following transformation:

36. Dimethylacetylene has restored to olefin (Na/NH3), and then the product has oxidised on Wagner. What alcohol has turned out? 252

37. Name the В product

38. Show the halogenalkyl which hydrolysis goes on the mechanism SN2 а) CH3Cl; b) C2H5Cl; c) CH3– (CH2)-CH2Cl; d) C6 H5 CH2 Cl; e) (CH3)3CCl 39. What of carbonyl connections is formed from 4-oxyheptanon-2 in conditions of aldol condensation? 40. Specify the reaction mechanism of nitration of alkanes 41. Write the reaction of interaction of 3-nitrobutane acid with SOCl2 tionil chloride 42. Show the final product of the following transformations:

43. What acid is formed as a result of transformations: CH3-CH-COOH NH2

HNO2

........

P2O5 - H2O

..?

44. Show the final product of the following transformations СН3-СН(Br)-СООН

0

2 O ,t  ? H  ….. NaOH

45. What is the acid formed by the action of sodium acetate on CH3COONa sulfuric acid? 46. Specify the reaction mechanism of nitration of alkanes 47. Write the reaction when 3-nitro-butanoic acid reacts with thionyl chloride SOCl2 253

48. Which compound is formed when heated  -aminopropionic (H2NCH2CH2COOH) acid, write the reaction. 49. Write the reaction of glycine (NH2CH2COOH) reacting with benzoic acid chloride. 50. What -amino acid is produced by transformation of C2H5-CN

Cl2

Cl H2O, H+ CH3CHCN .......

254

NH3

?

The term aromatic (Greek; aroma means fragrance) was first used for compounds having pleasant odour although the structure was not known. Now the term aromatic is used for a class of compounds having a characteristic stability despite having unsaturation. These may have one or more benzene rings (benzenoid) or may not have a benzene ring (non-benzenoid). Benzenoid compounds include benzene and its derivatives having aliphatic side chains (arenes) or polynuclear hydrocarbons, e.g. naphthalene, anthracene, biphenyl, etc. Structure of benzene. Benzene has been known since 1825 when it was first isolated by Michel Faraday. Form elemental analysis and molecular mass determination, it was found that the molecular formula of benzene is C6H6 indicating high unsaturation. However, benzene does undergo addition reactions in contrast to unsaturated hydrocarbons, although it mainly undergoes substitution reactions. In 1865 Friedrich August Kekule proposed a ring structure for benzene. However, many alternative structures have been proposed from time to time by different workers. Then the main objection against the Kekule structure was that it should yield two ortho disubstituted products when it reacts with bromine. However, experimentally benzene was found to yield only one product. Kekule removed this objection by proposing that the double bonds in benzene are continuously oscillating back and forth between two adjacent positions. Since positions of double bonds are not fixed, only one product is formed. This structure came to be known as Kekule’s dynamic formula, which formed the basis for the present electronic structure of benzene. Finally Kekule proposed that the equivalent structures with oscillating double bonds averaged out the single and double bonds so that the compounds were indistinguishable. 255

All the carbon atoms in an aromatic ring are sp2sp2 hybridized which gives an idea that each of the carbon atoms can form three sigma bonds (σσ) and one pie (ππ) bond. The single bonds that are present are sigma bonds (σσ) while each of the double bonds consist of one sigma bond (σσ) and one pie bond (ππ).

The double bonds are shorter than the single bonds and the aromatic structure would be deformed with longer single bonds as compared to shorter double bonds.

A benzene ring consists of 6 carbon atoms bonded to each other to form a regular hexagon with a carbon atom at each vertex of the hexagon. The carbon – carbon – carbon bond angle is 120o. The hydrogen atom attached to each carbon atom giving benzene the molecular formula of C6H6. There is a carbon and hydrogen bonding at each vertex in the aromatic ring structure. The circle or lines inside the benzene or aromatic ring represent some of the electrons involved in carbon – carbon bonding. These electrons are in orbitals that extend above and below the plane of the aromatic ring. These electrons circulate around inside the aromatic ring and are not part of any specific carbon – carbon bond. These electrons are delocalized and the C-C bond order in aromatic ring is somewhere between the single bond of an alkane and the double bond of an alkene. 256

Stability of benzene (Resonance). Benzene resists addition whereas it readily undergoes substitution reactions, like nitration, halogenation, etc. This indicates that benzene is more stable than the hypothetical cyclohexatriene molecule. This has been proved by the fact that the enthalpies of hydrogenation and combustion of benzene are lower than expected. Enthalpy of hydrogenation is the change in enthalpy when one mole of an unsaturated compound is hydrogenated. It has been found experimentally that enthalpy of hydrogenation for disubstituted alkenes, R-CH=CH-R varies between 117-125 kJ mol-1. Accordingly, the values for cyclohexene and cyclohexa-1, 3-diene and hypothetical cyclohexa-1, 3, 5-triene were calculated compared with their experimental values. While the experimental values of enthalpy of hydrogenation for cyclohexene are similar to the expected values, the variation in the case of cyclohexa-1, 3-diene is small and is due to delocalization. The expected value of enthalpy of hydrogenation of benzene is much higher than the corresponding calculated value for hypothetical cyclohexa-1, 3, 5-triene indicating that benzene does not have this type of structure. X-ray studies show that it is a planar molecule and that all six C-C bonds in benzene are of equal length (139 pm), intermediate between C-C single bond (154 pm) and C=C (134 pm). All six carbons are sp2 hybridized and all bond angles are 120o. Benzene is a hybrid of various resonating structures, the two Kekule structures A and B, being the main contributing forms. Aromaticity in benzene and related systems. After the structure of benzene was established, the term aromatic was adapted for such compounds which despite having p bonds (unsaturation) resist addition and instead undergo substitution. The aromaticity in benzene is attributed to the six delocalized pi electrons in the coplanar carbon hexagon. When a bonding orbital is not restricted to two atoms but is spread over more than two atoms, e.g. six in benzene, such bonding orbitals are said to be delocalized. Delocalisation results in greater stability. The modern theory of aromaticity was advanced by Eric Huckel 1931. Aromaticity is a function of electronic structure. Any polynuclear compound, heterocyclic rings or cyclic ions may be aromatic if 257

these have a specific electronic structure. The important features of the theory are: 1. Delocalization: Complete delocalization of p-electron cloud of the ring system is a necessary requirement for aromatic character. 2. Planarity: Complete delocalization of p-electron cloud is possible only if the ring is planar. This is the reason that benzene is aromatic but cyclooctatetraene is not, since the latter is not a planar molecule. Huckel’s rule or (4n + 2)p electron rule: The rule states that in a conjugated, planar, cyclic system if the number of delocalized p-electrons is (4n + 2) where n is an integer, i.e., 1, 2, 3 etc., benzene, naphthalene, anthracene and phenanthrene are aromatic as they contain (4n + 2)p electrons i.e. 6, 10, 14, p electrons in a conjugated cyclic system. The cyclopentadiene and cyclooctatetraene are nonaromatic as instead of (4n + 2)p e-these have 4n p e-. Moreover, they are non-planar.

Now, we can check if it follows Huckel's Rule:

Benzene is aromatic; it follows Huckels Rule Simple benzene naming. Some common substituents, like NO2, Br, and Cl, can be named this way when it is attached to a phenyl 258

group. Long chain carbons attached can also be named this way. The general format for this kind of naming is: (positions of substituents (if >1)- + (di, tri, ...) + substituent)n + benzene. For example, chlorine (Cl) attached to a phenyl group would be named chlorobenzene (chloro + benzene). Since there is only one substituent on the benzene ring, we do not have to indicate its position on the benzene ring (as it can freely rotate around and you would end up getting the same compound).

Example of simple benzene naming with chlorine and NO2 as substituents.

Ortho-, Meta-, Para- (OMP) nomenclature for disubstituted benzenes. Instead of using numbers to indicate substituents on a 259

benzene ring, ortho- (o-), meta- (m-), or para (p-) can be used in place of positional markers when there are two substituents on the benzene ring (disubstituted benzenes). They are defined as follow:  ortho- (o-): 1,2- (next to each other in a benzene ring)  meta- (m): 1,3- (separated by one carbon in a benzene ring)  para- (p): 1,4- (across from each other in a benzene ring) Using the same example as above in Figure 9a (1,3-dichlorobenzene), we can use the ortho-, meta-, para- nomenclature to transform the chemical name into m-dichlorobenzene, as shown in the figure below.

Transformation of 1,3-dichlorobenzene into m-dichlorobenzene. Here are some other examples of ortho-, meta-, para- nomenclature used in context:

However, the substituents used in ortho-, meta-, para- nomenclature do not have to be the same. For example, we can use chlorine and a nitro group as substituents in the benzene ring.

In conclusion, these can be pieced together into a summary diagram, as shown below: 260

Base name nomenclature. In addition to simple benzene naming and OMP nomenclature, benzene derived compounds are also sometimes used as bases. The concept of a base is similar to the nomenclature of aliphatic and cyclic compounds, where the parent for the organic compound is used as a base (a name for its chemical name. For example, the following compounds have the base names hexane and cyclohexane, respectively. See Nomenclature of Organic Compounds for a review on naming organic compounds.

Benzene, similar to these compounds shown above, also has base names from its derived compounds. Phenol (C6H5OH), as introduced previously in this article, for example, serves as a base when other substituents are attached to it. This is best illustrated in the diagram below.

An example showing phenol as a base in its chemical name Note how benzene no longer serves as a base when an OH group is added to the benzene ring. 261

Alternatively, we can use the numbering system to indicate this compound. When the numbering system is used, the carbon, where the substituent is attached on the base, will be given the first priority and named as carbon #1 (C1). The normal priority rules then apply in the nomenclature process (give the rest of the substituents the lowest numbering as you could).

The naming process for 2-chlorophenol (o-chlorophenol). Note that 2-chlorophenol = o-chlorophenol. Below is a list of commonly seen benzene-derived compounds. Some of these mono-substituted compounds (labeled in red and green), such as phenol or toluene, can be used in place of benzene for the chemical's base name.

Common benzene derived compounds with various substituents

262

Aromatic Hydrocarbons are compounds having sigma bonds as well as delocalized pi electrons in between the carbon atoms present in the ring form. Refer to see the different examples of aromatic compounds containing a benzene ring. A hydrocarbon can be an aromatic compound if it follows the Huckel Rule. According to this rule, a compound can be aromatic if it has the following distinct properties:  Planarity  Delocalization of the pi-electrons in the carbon ring entirely  A compound having (4n + 2) π electrons in its structure, where n is an integer. Substituted benzene. Replacement of one hydrogen atom from benzene and addition of another atom results in the substitution of benzene. The compounds are known as substituted benzenes. Depending on the number of the substituents, the compounds can either be monosubstituted benzene, disubstituted benzene, and trisubstituted benzene.

Isomerism of aromatic hydrocarbons. If we consider any “disubstituted benzene”, there is a possibility of the formation of three different position isomers on the basis of substituent’s position in relation to the other. Thus, we use ortho-position to indicate the position of two substituents (1,2-). Similarly, meta-position will represent the relative position (1,3-) and para-position will represent the relative position (1,4-). Let’s take the example of xylene. Refer to the diagram below to observe the different isomers of xylene (dimethylbenzene) depending on the position.

263

IUPAC system. Rule 1: As per IUPAC nomenclature system, it is important to place the substituent’s name before the name of the compound as a prefix in any substituted aromatic hydrocarbon. For example, nitrobenzene where the benzene ring is present along with a nitro group.

Rule 2: You have to attach Greek numerical prefixes such as di, tri, and tetra to indicate similar substituents group in case of compounds with more than one substituent group present in the benzene ring. For instance, a benzene ring with two bromo groups present on the adjacent carbon atoms of the benzene ring refers to as 1,2-di-bromobenzene.

Rule 3: If different substituent groups are present in the aromatic compounds, it is important to assign number one position to the substituent of the base. Furthermore, the numbering direction for the rest of the compound is chosen in such a manner that the next substituent will have the lowest numbering position. Moreover, we have to use alphabetical order for the naming of the substituent. For example, if a benzene consists of a chloro group as well as a nitro group, then we start with the chloro group and then the nitro groups on the basis of the alphabetical order. 264

Nomenclatura of aromatic hydrocarbon Rule 4: In case of aromatic compounds with more than one substituents, it is necessary to use terms such as ortho, meta, and para as prefixes to represent the relative positions like 1,2-; 1,3-; 1,4-. For instance, we can rewrite 1,2 di-bromo-benzene as o-di-bromo-benzene. Rule 5: If an organic compound consists of an alkane with a functional group and aromatic compound, then the aromatic compound will act as a substituent instead of the parent group. For instance, when there is a benzene ring joined with an alkane and a functional group, then the aromatic group is known as phenyl (Ph-). Diagrams representing Nomenclature of Aromatic Hydrocarbons

Common systematic (IUPAC) nomenclature. Phenol, benzaldehyde, and benzoic acid are some of the common names that are retained in the IUPAC (systematic) nomenclature. Other names such as 265

toluene, styrene, naphthalene, or phenanthrene can also be seen in the IUPAC system in the same way. While the use of other common names is usually acceptable in IUPAC, their use is discouraged in the nomenclature of compounds. Nomenclature for compounds, which has such discouraged names, will be named by the simple benzene naming system. An example of this would include toluene derivatives like TNT. (Note that toluene by itself is retained by the IUPAC nomenclature, but its derivatives, which contain additional substituents on the benzene ring, might be excluded from the convention). For this reason, the common chemical name 2,4,6-trinitrotoluene, or TNT, as shown in down, would not be advisable under the IUPAC (systematic) nomenclature. To correctly name TNT under the IUPAC system, the simple benzene naming system should be used:

Systematic (IUPAC) name of 2,4,6-trinitrotoluene (common name), or TNT. Note that the methyl group is individually named due to the exclusion of toluene from the IUPAC nomenclature.

The common name 2,4-dibromophenol, is shared by the IUPAC systematic nomenclature. Only substituents phenol, benzoic acid, and benzaldehyde share this commonality. Since the IUPAC nomenclature primarily relies on the simple benzene naming system for the nomenclature of different benzene 266

derived compounds, the OMP (ortho-, meta-, para-) system is not accepted in the IUPAC nomenclature. For this reason, the OMP system will yield common names that can be converted to systematic names by using the same method as above. For example, o-Xylene from the OMP system can be named 1,2-dimethylbenzene by using simple benzene naming (IUPAC standard). The phenyl and benzyl groups. As mentioned previously, the phenyl group (Ph-R, C6H5-R) can be formed by removing a hydrogen from benzene and attaching a substituent to where the hydrogen was removed. To this phenomenon, we can name compounds formed this way by applying this rule: (phenyl + substituent). For example, a chlorine attached in this manner would be named phenyl chloride, and a bromine attached in this manner would be named phenyl bromide (See the diagram below).

Naming of Phenyl Chloride and Phenyl Bromide While compounds like these are usually named by simple benzene type naming (chlorobenzene and bromobenzene), the phenyl group naming is usually applied to benzene rings where a substituent with six or more carbons is attached, such as in the diagram below.

Although the diagram above might be a little daunting to understand at first, it is not as difficult as it seems after careful analysis of the structure is made. By looking for the longest chain in the com267

pound, it should be clear that the longest chain is eight (8) carbons long (octane, as shown in green) and that a benzene ring is attached to the second position of this longest chain (labeled in red). As this rule suggests that the benzene ring will act as a function group (a substituent) whenever a substituent of more than six (6) carbons is attached to it, the name "benzene" is changed to phenyl and is used the same way as any other substituents, such as methyl, ethyl, or bromo. Putting it all together, the name can be derived as: 2-phenyloctane (phenyl is attached at the second position of the longest carbon chain, octane). The benzyl group. The benzyl group (abbv. Bn), similar to the phenyl group, is formed by manipulating the benzene ring. In the case of the benzyl group, it is formed by taking the phenyl group and adding a CH2 group to where the hydrogen was removed. Its molecular fragment can be written as C6H5CH2-R, PhCH2-R, or BnR. Nomenclature of benzyl group based compounds is very similar to the phenyl group compounds. For example, a chlorine attached to a benzyl group would simply be called benzyl chloride, whereas an OH group attached to a benzyl group would simply be called benzyl alcohol.

Benzyl Group Nomenclature Additionally, other substituents can attach on the benzene ring in the presence of the benzyl group. An example of this can be seen in the figure below:

268

Nomenclature of 2,4-difluorobenzyl chloride. Similar to the base name of the nomenclature system, the carbon, in which the base substitutent is attached on the benzene ring, is given the first priority and the rest of the substituents are given the lowest number order possible. Similar to the base name of the nomenclature system, the carbon in which the base substituent is attached on the benzene ring is given the first priority and the rest of the substituents are given the lowest number order possible. Under this consideration, the above compound can be named: 2,4-difluorobenzyl chloride. Physical properties Boiling points. In benzene, the only attractions between the neighbouing molecules are the van der Waals dispersion forces. There is no permanent dipole on the molecule. Benzene boils at 80°C, which is higher than other hydrocarbons of similar molecular size (pentane and hexane, for example). The higher boiling point is presumably due to the ease with which temporary dipoles can be set up involving the delocalized electrons. Methylbenzene boils at 111°C. Methylbenzene is a larger molecule, thus, the van der Waals dispersion forces will be increased. Methylbenzene also has a small permanent dipole; thus, there will be dipole-dipole attractions as well as dispersion forces. The dipole is due to the CH3 group's tendency to "push" electrons away from itself. This also affects the reactivity of methylbenzene (see below). Melting points. You might have expected that methylbenzene's melting point would be higher than benzene's as well, but it isn't - it is much lower! Benzene melts at 5.5°C; methylbenzene at -95°C. Molecules must pack efficiently in the solid if they are to optimize their intermolecular forces. Benzene is a tidy, symmetrical molecule and packs very efficiently. The methyl group that protrudes from the methylbenzene structure tends to disrupt the closeness of the packing. If the molecules are not as closely packed, the intermolecular forces don't work as well, causing the melting point to decrease. Solubility in water. The arenes are insoluble in water. Benzene is quite large compared with a water molecule. For benzene to dis269

solve, it would have to break a significant number of the existing hydrogen bonds between the water molecules. In addition, the quite strong van der Waals dispersion forces between the benzene molecules would require breaking; both of these processes require energy. The only new forces between the benzene and the water would be van der Waals dispersion forces. These forces are not as strong as hydrogen bonds (or the original dispersion forces in the benzene), therefore, only a limited amount of energy is released when they form. It simply isn't energetically profitable for benzene to dissolve in water. It would, of course, be even worse for larger arene molecules. Reactivity. Benzene is resistant to addition reactions. Adding something new to the ring would require that some of the delocalized electrons form bonds with the substituent being added, resulting in a major loss of stability because the delocalization is broken. Instead, benzene primarily undergoes substitution reactions – replacing one or more of the hydrogen atoms with a new substituent, preserving the delocalized electrons as they were. The reactivity of a compound like methylbenzene must be considered in two distinct parts:

Preparation of aromatic hydrocarbons One of the important commercial preparation methods of benzene is by isolation of coal tar. However, the laboratory techniques for preparation of aromatic hydrocarbons are different. Cyclic polymerization of alkynes. Alkynes undergo polymerization reaction similar to alkenes. It can undergo two types of polyme270

rization reaction- linear and cyclic. However, only cyclic polymerization can yield ethyne. Cyclic polymerization of ethyne results in the formation of aromatic hydrocarbons. It is one of the important chemical reactions in alkynes. Ethyne undergoes reaction by passing it from the red-hot iron tube at a very high temperature of 873K to form benzene. This reaction is cyclic polymerization of ethyne. Refer to the example below

Aromatic hydrocarbons by decarboxylation of aromatic acids. The sodium salt of benzoic acid and soda lime react under heating conditions to produce benzene.

Aromatic hydrocarbon by reduction of phenol. Phenol vapours undergo reduction reaction by passing extremely heated zinc dust. This reaction results in the formation of benzene.

271

Catalytic reforming. Reforming takes straight chain hydrocarbons in the C6 to C8 range from the gasoline or naphtha fractions and rearranges them into compounds containing benzene rings. Hydrogen is produced as a by-product of the reactions. For example, hexane, C6H14, loses hydrogen and turns into benzene. As long as you draw the hexane bent into a circle, it is easy to see what is happening.

Similarly, methylbenzene (toluene) is made from heptane:

The process. The feedstock: The feedstock is a mixture of the naphtha or gasoline fractions and hydrogen. The hydrogen is there to help prevent the formation of carbon by decomposition of the hydrocarbons at the high temperatures used. The carbon would otherwise contaminate the catalyst. The catalyst: A typical catalyst is a mixture of platinum and aluminium oxide. With a platinum catalyst, the process is sometimes described as "platforming". Temperature and pressure: The temperature is about 500°C, and the pressure varies either side of 20 atmospheres. Converting methylbenzene into benzene. Methylbenzene is much less commercially valuable than benzene. The methyl group can be removed from the ring by a process known as "dealkylation". The methylbenzene is mixed with hydrogen at a temperature of between 550 and 650 °C, and a pressure of between 30 and 50 272

atmospheres, with a mixture of silicon dioxide and aluminium oxide as catalyst.

Reactions of aromatic compounds o Aromatic compounds or arenes undergo substitution reactions, in which the aromatic hydrogen is replaced with an electrophile, hence their reactions proceed via electrophilic substitution. o Arenes contain double bonds just like alkenes but they do not undergo electrophilic addition because this would result in their loss of ring aromaticity. o The order of substitution on aromatic compounds is governed by the nature of substituents present in the aromatic ring. o In electrophilic aromatic substitution reactions, a carbocation is generated while in nucleophilic aromatic substitutions, a carboanion is generated. o Hydrogenation reactions convert aromatic compounds into saturated compounds. o Metal cross-coupling such as Suzuki reaction allows formation of carbon-carbon bonds between two or more aromatic compounds. Terms  Nucleophile. A compound or functional group that is attractive to centers of positive charge and donates electrons; donates an electron pair to an electrophile to form a bond.  Hydrogenation. The chemical reaction of hydrogen with another substance, especially with an unsaturated organic compound, and usually under the influence of temperature, pressure, and catalysts.  Electrophile. A compound or functional group that is attractive to, and accepts electrons; accepts an electron pair from a nucleophile to form a bond. The benzene ring is frequently noted for the stability it gains from its aromaticity. However, aromatic compounds can participate in a variety of chemical reactions, including a range of substitution, 273

coupling, and hydrogenation reactions. The electrons in the pi system of the benzene ring are responsible for the reactivity observed. While aromatic compounds are best represented by a continuous electron density evenly distributed around the aromatic core, the alternating single and double bonds that are commonly drawn are very useful when predicting the reactivity of aromatic compounds. Many reactions common to alkenes (carbon-carbon double bonds) also function in a similar fashion with the “double bonds” in aromatic compounds, though generally the activation barrier is higher due to the stabilizing force of aromaticity (36 kcal/mol). There are three nucleophilic substitution mechanisms commonly encountered with aromatic systems, the SNAr (addition-elimination) mechanism, the benzyne mechanism and the free radical SRN1 mechanism. The most important of these is the SNAr mechanism, where electron withdrawing groups activate the ring towards nucleophilic attack, for example, if there are nitro functional groups positioned ortho or para to the halide leaving group. It is not generally necessary to discuss these types in detail within the context of an introductory organic chemistry course. Nucleophilic aromatic substitution. A nucleophilic substitution is a substitution reaction in organic chemistry in which the nucleophile displaces a good leaving group, such as a halide on an aromatic ring. In order to understand this type of reaction, it is important to recognize which chemical groups are good leaving groups and which are not. A nucleophilic aromatic substitution is a substitution reaction in organic chemistry in which the nucleophile displaces a good leaving group, such as a halide, on an aromatic ring. There are 6 nucleophilic substitution mechanisms encountered with aromatic systems:  the SNAr (addition-elimination) mechanism

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

the aromatic SN1 mechanism encountered with diazonium



the benzyne mechanism

salts



the free radical SRN1 mechanism The most important of these is the SNAr mechanism, where electron withdrawing groups activate the ring towards nucleophilic attack, for example if there are nitro functional groups positioned ortho or para to the halideleaving group. SNAr reaction mechanism. The following is the reaction mechanism of a nucleophilic aromatic substitution of 2,4-dinitrochlorobenzene in a basic aqueous solution. In this sequence the carbons are numbered clockwise from 1–6 starting with the 1 carbon at 12 o'clock, which is bonded to the chloride. Since the nitro group is an activator toward nucleophilic substitution, and a meta director, it allows the benzene carbon to which it is bonded to have a negative charge. In the Meisenheimer complex, the nonbonded electrons of the carbanion become bonded to the aromatic pi system which allows the ipso carbon to temporarily bond with the hydroxyl group (-OH). In order to return to a lower energy state, either the hydroxyl group leaves, or the chloride leaves. In solution both processes happen. 275

A small percentage of the intermediate loses the chloride to become the product (2,4-dinitrophenol), while the rest return to the reactant. Since 2,4-dinitrophenol is in a lower energy state it will not return to form the reactant, so after some time has passed, the reaction reaches chemical equilibrium that favors the 2,4-dinitrophenol. The formation of the resonance-stabilized Meisenheimer complex is slow because it is in a higher energy state than the aromatic reactant. The loss of the chloride is fast, because the ring becomes aromatic again. Aryl halides cannot undergo the classic SN2 reaction. The carbon-halogen bond is in the plane of the ring because the carbon atom has a trigonal planar geometry. Backside attack is blocked and this reaction is therefore not possible. An SN1 reaction is possible but very unfavourable. It would involve the unaided loss of the leaving group and the formation of an aryl cation. The nitro group is the most commonly encountered activating group, other groups are the cyano and the acyl group. The leaving group can be a halogen or a sulfide. With increasing electronegativity, the reaction rate for nucleophilic attack increases. Nucleophilescan be amines, alkoxides, sulfides and stabilized carbanions. Nucleophilic aromatic substitution reactions. Some typical substitution reactions on arenes are listed below.  In the Bamberger rearrangement N-phenylhydroxylamines rearrange to 4-aminophenols. The nucleophile is water. 276

 In the Sandmeyer reaction and the Gattermann reaction diazonium salts react with halides.  The Smiles rearrangement is the intramolecular version of this reaction type. Nucleophilic aromatic substitution is not limited to arenes, however; the reaction takes place even more readily with heteroarenes. Pyridines are especially reactive when substituted in the aromatic ortho position or aromatic para position because then the negative charge is effectively delocalized at the nitrogen position. One classic reaction is the Chichibabin reaction (Aleksei Chichibabin, 1914) in which pyridine is reacted with an alkali-metal amide such as sodium amide to form 2-aminopyridine. In the compound methyl 3-nitropyridine-4-carboxylate, the meta nitro group is actually displaced by fluorine with caesium fluoride in DMSO at 120 °C.

Asymmetric nucleophilic aromatic substitution. With carbon nucleophiles such as 1,3-dicarbonyl compounds the reaction has been demonstrated as a method for the asymmetric synthesis of chiral molecules. First reported in 2005, the organocatalyst (in a dual role with that of a phase transfer catalyst) is derived from cinchonidine (benzylated at N and O).

Electrophilic Aromatic Substitution. Electrophiles are particles with a deficiency of electrons. Therefore they are likely to react with substances that have excess electrons. Aromatic compounds have increased electron density in the form of delocalized π-orbitals. 277

Step 1: Formation of a π-complex. At first, the electrophile interacts with the delocalized orbitals of the aromatic ring and a πcomplex is formed.

No chemical bonds are formed at this stage. Evidence of the formation of a π-complex as an intermediate state has been found for some reactions, but not for all, since the chemical interaction in πcomplexes is very weak. Step 2: Formation of a σ-complex. After the π-complex is formed, in the presence of an electron acceptor another complex is formed – the σ-complex. It is a cationic species, an intermediate that lacks aromatic properties, but its four π-electrons are delocalized across the ring, which stabilizes the cation somewhat, sometimes allowing its isolation. An example would be the salt mesityl fluoroborate, which is stable at low temperatures, and is prepared by the reaction of mesitylene (1,3,5-trimethylbenzene) with fluoroboric acid (BF3/HF); the cation of this salt is protonated mesitylene. σ-complexes are also known as Wheland intermediates. Step 3: Formation of a Substituted product. At the next stage the σ-complex decomposes, freeing a hydrogen cation and forming the product of substitution.

Electrophilic aromatic halogenation

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Another important reaction of benzene is the electrophilic substitution of halides, a specific type of electrophilic aromatic substitution. These reactions are very useful for adding substituents to an aromatic system. The rates of the reactions increase with the electrophilicity of the halogen: hence, fluorination in this manner is too rapid and exothermic to be practical, whereas iodine requires the most vigorous conditions. Chlorination and bromination are the most often practiced in the lab of the four possible halogenations. Halobenzenes are used for pesticides, as well as the precursors to other products. Many inhibitors contain halobenzene subunits. Some highly activated aromatic compounds, such as phenol and aniline, are reactive enough to undergo halogenation without a catalyst, but for typical benzene derivatives (and benzene itself), the reactions are extremely slow at room temperature in the absence of a catalyst. Usually, Lewis acids are used as catalysts, which work by helping to polarize the halogen-halogen bond, thus decreasing the electron density around one halogen atom, making it more electrophilic. The most common catalysts used are either Fe or Al, or their respective chlorides and bromides (+3 oxidation state). Iron (III) bromide and iron (III) chloride lose their catalytic activity if they are hydrolyzed by any moisture present, including atmospheric water vapor. Therefore, they are generated in situ by adding iron fillings to bromine or chlorine. Iodination is carried out under different conditions: periodic acid is often used as a catalyst. Under these conditions, the I+ ion is formed, which is sufficiently electrophilic to attack the ring. Iodination can also be accomplished using a diazonium reaction. Fluorination is most often done using this technique, as the use of fluorine gas is inconvenient and often fragments organic compounds. Halogenation of aromatic compounds differs from the additions to alkenes or the free-radical halogenations of alkanes, which do not require Lewis acid catalysts. The formation of the arenium ion results in the temporary loss of aromaticity, the overall result being that the reaction's activation energy is higher than that of halogenations of aliphatic compounds. Halogenation of phenols is faster in polar solvents due to the dissociation of phenol, because the phenoxide (-O-) group is more strongly activating than hydroxyl itself. 279

Electrophilic aromatic sulfonation. Aromatic sulfonation is an organic reaction in which a hydrogen atom on an arene is replaced by a sulfonic acid functional group in an electrophilic aromatic substitution. The electrophile of such a reaction is sulfur trioxide (SO3), which can be released from oleum (also known as fuming sulfuric acid), essentially sulfuric acid in which gaseous sulfur trioxide has been dissolved. In contrast to aromatic nitration and other electrophilic aromatic substitutions, aromatic sulfonation is reversible. Sulfonation takes place in strongly acidic conditions, and desulfonation can occur on heating with a trace of acid. This also means that thermodynamic, rather than kinetic, control can be achieved at high temperatures. Hence, directive effects are not expected to play a key role in determining the proportions of isomeric products of hightemperature sulfonation. Aromatic sulfonic acids can be intermediates in the preparation of dyes and many pharmaceuticals. Sulfonation of aniline produces p-aminobenzenesulfonic acid or sulfanilic acid, which is a zwitterionic compound with an unusually high melting point. The amide of this compound and related compounds form a large group of sulfa drugs (a type of antibiotic). Overall reaction: ArH + SO3 → ArSO3H Electrophilic aromatic nitration. Nitration occurs with aromatic organic compounds via an electrophilic substitution mechanism involving the attack of the electron-rich benzene ring by the nitronium (nitryl) ion. Benzene is commonly nitrated by refluxing with a mixture of concentrated sulfuric acid and concentrated nitric acid at 50°C. The sulfuric acid is regenerated and hence acts as a catalyst. Selectivity is always a challenge in nitrations. Fluorenone nitration is selective and yields a tri-nitro compound or tetra-nitro compound by tweaking reaction conditions just slightly. Another example of trinitration can be found in the synthesis of phloroglucinol. Other nitration reagents include nitronium tetrafluoroborate which is a true nitronium salt. This compound can be prepared from hydrogen fluoride, nitric acid and boron trifluoride. Aromatic nitro compounds are important intermediates for anilines; the latter may be readily prepared by the action of a reducing agent. Overall reaction: ArH + HNO3 → ArNO2 + H2O 280

Friedel-Crafts alkylation

The Friedel-Crafts reaction, discovered by French alkaloid chemist Charles Friedel and his American partner, James Crafts, in 1877, is either the alkylation or acylation of aromatic compounds catalyzed by a Lewis acid. They are very useful in the lab for formation of carbon-carbon bonds between an aromatic nucleus and a side chain. Source of electrophile. Friedel-Crafts alkylation is an example of electrophilic substitution in aromatic compounds. The electrophile is formed in the reaction of an alkyl halide with a Lewis acid. The Lewis acid polarizes the alkyl halide molecule, causing the hydrocarbon part of it to bear a positive charge and thus become more electrophilic. CH3—Cl + AlCl3 → CH3+ + AlCl4− or CH3Cl + AlCl3 → CH3δ+Cl+Al−Cl3 (The carbon atom has a slight excess of positive charge, as the electronegative chlorine atom draws electron density towards itself. The chlorine atom has a positive charge, as it has formed a subordinate bond with the aluminium atom. In effect, the Cl atom has lost an electron, while the Al atom has gained an electron. Therefore, the Al atom has a negative charge.) Mechanism of alkylation. The polarized, electrophilic molecule then seeks to saturate its electron deficiency and forms a π-complex with the aromatic compound that is rich in π-electrons. Formation a π-complex does not lead to loss of aromaticity. The aromaticity is lost, however, in the σ-complex that is the next stage of reaction. The positive charge in the σ-complex is evenly distributed across the benzene ring. 281

C6H6 + CH3+ → C6H6+Br → C6H5Br + H+ The σ-complex C6H6+Br can be separated (it is stable at low temperatures), while the π-complex cannot. Restrictions. Deactivating functional groups, such as nitro (-NO2), usually prevent the reaction from occurring at any appreciable rate, so it is possible to use solvents such as nitrobenzene for Friedel-Crafts alkylation.  Primary and secondary carbocations are much less stable than tertiary cations, so rearrangement typically occurs when one attempts to introduce primary and secondary alkyl groups onto the ring. Hence, Friedel-Crafts alkylation using n-butyl chloride generates the n-butylium cation, which rearranges to the t-butyl cation, which is far more stable, and the product is exclusively the t-butyl derivative. This may, in some cases, be circumvented through the use of a weaker Lewis acid.  The Friedel-Crafts reaction cannot be used to alkylate compounds which are sensitive to acids, including many heterocycles.  Another factor that restricts the use of Friedel-Crafts alkylation is polyalkylation. Since alkyl groups have an activating influence, substituted aromatic compounds alkylate more easily than the original compounds, so that the attempted methylation of benzene to give toluene often gives significant amounts of xylene and mesitylene. The usual workaround is to acylate first (see the following sections) and then reduce the carbonyl group to an alkyl group. Friedel-Crafts acylation

Friedel-Crafts acylation, like Friedel-Crafts alkylation, is a classic example of electrophilic substitution. 282

Source of electrophile. Reacting with Lewis acids, anhydrides and chloranhydrides of acids become strongly polarized and often form acylium cations. RCOCl + AlCl3 → RC+O + AlCl4Mechanism of acylation. The mechanism of acylation is very similar to that of alkylation. C6H6 + RC+O → C6H6–CO–R + H+ The ketone that is formed then forms a complex with aluminum chloride, reducing its catalytic activity. C6H6–CO–R + AlCl3 → C6H6–C+(R)–O–Al−Cl3 Therefore, a much greater amount of catalyst is required for acylation than for alkylation. Restrictions  Although no isomerisation of cations happens, due to the reasonance stabilization provided by the acylium ion, certain cations may lose CO and alkylation will occur instead of acylation. For example, an attempt to add pivalyl (neopentanoyl) to an aromatic ring will result in loss of CO from the cation, which then results in the t-butyl derivative being formed.  Acidophobic aromatic compounds, such as many heterocycles can't exist in the presence of both Lewis acids and anhydrides.  Formyl chloride is unstable and cannot be used to introduce the formyl group onto a ring through Friedel-Crafts acylation. Instead, the Gattermann-Koch reaction is often used. Applications. Friedel-Crafts acylation is used, for example, in the synthesis of anthraquinone from benzene and phtalic anhydride. In laboratory synthesis Friedel-Crafts acylation is often used instead of alkylation in cases where alkylation is difficult or impossible, such as synthesis of monosubstituted alkylbenzenes. Coupling Reactions. Coupling reactions are reactions involving a metal catalyst that can result in the formation of a carbon-carbon 283

bond between two radicals. Coupling reaction in organic chemistry is a general term for a variety of reactions where two hydrocarbon fragments are joined together with the aid of a metal catalyst. In one important reaction type a main group organometallic compound of the type RM (R = organic fragment, M = main group centre) reacts with an organic halide of the type R'X with formation of a new carbon-carbon bond in the product R-R'

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Hydrogenation. Hydrogenation can be used to create a fully saturated ring system. This is similar to the hydrogenation of an alkene to form an alkane, albeit more difficult due to the stability of the aromatic system. Hydrogenation of aromatic compounds: introduction

Reaction principle. Compared to the hydrogenation of alkenes and alkynes, the catalytic hydrogenation of aromatic compounds succeeds only under harsh conditions because the aromatic conjugation has to be broken in the first step. Subsequent hydrogenation to fully saturated cycloalkanes is fast. Preferred catalysts for the hydrogenation are platinum, palladium, rhenium and Raney nickel. Examples:

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Phenols are aromatic compounds containing hydroxyl group directly attached to the nucleus. Phenols are compounds of the general formula ArOH, where Ar is phenyl, substituted phenyl, or some other aryl group (e.g., naphthyl). Phenols differ from alcohols in having the OH group attached directly to an aromatic ring. Both phenols and alcohols contain the –OH group, and as a result the two families resemble each other to a limited extent. In most of their properties, however, and in their preparations, the two kinds of compounds differ so greatly that they well deserve to be classified as different families. Physical properties of phenols. The simplest phenols are liquids or low-melting solids; because of hydrogen bonding, they have quite high boiling points. Phenol itself is somewhat soluble in water, most other phenols are essentially insoluble in water. When the physical properties of the isomeric nitrophenols are compared, onitrophenol is found to have low b.p. and much lower solubility in water than its isomers. It is the only one of the three that is readily steam – distillable. Steam distillation depends upon a substance having an appreciable vapour pressure at the boiling point of water. In the ortho isomer, the intramolecular hydrogen bonding takes the place of intermolecular hydrogen bonding with other phenol molecules and with water molecules; therefore o-nitrophenol does not have the low volatility of an associated liquid, nor does it have the solubility characteristic of a compound that forms hydrogen bonds with water. Nomenclature of phenols and phenyl ethers. Compounds having a hydroxyl group directly attached to a benzene ring are called phenols. The term phenol is also used for the parent compound, 286

hydroxybenzene. Hydroxybenzene, may be regarded as an enol, as implied by the name phenol, from phenyl + enol. However, unlike simple ketones, which are far more stable than their corresponding enols, the analogous equilibrium for phenol lies far on the side of the enol form. The reason for this difference is the resonance energy of the aromatic ring, which provides an important stabilization of the enol form.

Since the functional group occurs as suffix in phenol, many compounds containing hydroxyl group are named as derivatives of the parent compound phenol, as illustrated by the IUPAC names.

Suffix groups such as sulfonic acid and carboxylic acid take priority, and when these groups are present the hydroxyl group is used as a modifying prefix.

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Phenyl ethers are named in the IUPAC system as alkoxyarenes, although the ether nomenclature is used for some compounds.

Phenols and their ethers are widespread in nature, and, as is usual for such compounds, trivial names abound.

Salts of phenols. Phenols are fairly acidic compounds, and in this respect, markedly differ from alcohols, which are even more weakly acidic than water. Aqueous hydroxides convert phenols into 288

their salts, aqueous mineral acid converts the salts back into the free phenols.

Most phenols have Ka values in the neighbourhood of 10–10 and are thus weaker acids than the carboxylic acids (Ka values about 10–5). Most phenols are weaker than carbonic acid and hence unlike carboxylic acids do not dissolve in aqueous bicarbonate solution. Preparation of phenols. Industrial methods for preparation of phenols 1. By benzyne mechanism

2. From cumene hydroperoxide

Laboratory methods for preparation of phenols 3. Alkali fusion of aryl sulphonate salts Phenols may be prepared by fusion of sodium arylsulphonates with sodium hydroxide 4. Aromatic nucleophilic substitution of nitro aryl halides Phenols are formed when compounds containing an activated halogen atom are heated with aqueous sodium hydroxide, e.g. pnitrophenol from p-chloronitrobenzene. 289

5. Hydrolysis of diazonium salts When a diazonium sulphate solution is steam distilled, a phenol is produced

6. Distillation of phenolic acids with soda-lime produces phenols, e.g. sodium salicylate

Chemical properties of phenols 1. Reactions of H of the OH group Acidity of Phenols. Phenols are weak acids (pKa = 10). They form salts with aqueous NaOH but not with aqueous NaHCO3.The considerably greater acid strength of PhOH (pKa = 10) than that of ROH (pKa = 18) can be accounted for as the negative charge on the alkoxide anion, RO-, cannot be delocalized, but on PhO– the negative charge is delocalized to the ortho and para ring positions as indicated by the starred sites in the resonance hybrid.

PhO– is therefore a weaker base than RO–, and PhOH is a stronger acid. The effect of a. electron – attracting and b. electron – releasing substituents on the acid strength of phenols 290

Electron – attracting substituents disperse negative charges and therefore stabilize ArO– and increase acidity of ArOH. Electron – releasing substituents concentrate the negative charge on O destabilizes ArO– and decreases acidity of ArOH

In terms of resonance and inductive effects we can account for the following relative acidities. a) p-O2NC6H4OH > m – O2NC6H4OH > C6H5OH b) m – ClC6H4OH > p-ClC6H4OH > C6H5OH The –NO2 is electron – withdrawing and acid – strengthening. Its resonance effect, which occurs only from para and ortho positions, predominates over its inductive effect, which occurs also from the meta position. Other substituents in this category are

c. Cl is electron – withdrawing by induction. This effect diminishes with increasing distance between Cl and OH. The meta is closer than the para positions and m-Cl is more acid – strengthening than the p-Cl. Other substituents in this category are F, Br, I, +NR3. We can assign numbers from 1 for LEAST, 2 for MOST to indicate the relative acid strengths in the following groups: a) phenol, m-chlorophenol, m-nitrophenol, m-cresol; 2, 3, 4, 1. Because

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Has + on N, it has a greater electron – withdrawing inductive effect than Cl. The decreasing order of relative acid strengths: Benzoic acid > carbonic acid > p-nitrophenol > phenol b) phenol, benzoic acid, p-nitrophenol, carbonic acid 1,4,2,3 The decreasing order of relative acid strengths: Benzoic acid > carbonic acid > p-nitrophenol > phenol c) phenol, p-chlorophenol, p-nitrophenol, p-cresol 2,3,4,1. The resonance effect of p-NO2 exceeds the inductive effect of p-Cl p-CH3 is electron releasing. The decreasing order of relative acid strengths p-nitrophenol > p-chlorophenol > phenol > p-cresol d) phenol, o-nitrophenol, m-nitrophenol, p-nitrophenol 1,3,2,4 Intramolecular H-bonding makes the o-isomer weaker than the p-isomer. The increasing order of relative acids strengths: p-nitrophenol > o – nitrophenol > m – nitrophenol > phenol e) phenol, p-chlorophenol, 2,4,6 – trichlorophenol, 2,4 – dichlorophenol The decreasing order of relative acids strengths: 2,4,6 – trichlorophenol > 2,4, - dichlorophenol > p-chlorophenol > phenol f) phenol, benzyl alcohol, benzenesulfonic acid, benzoic acid 2,1,4,3 The decreasing order of relative acid strengths: Acid > benzoic acid > phenol > benzyl alcohol Formation of ethers from phenols: a) Williamson synthesis

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b) Aromatic nucleophilic substitution

Formation of esters from phenols. Phenyl esters (RCOOAr) are not formed directly from RCOOH. Instead, acid chlorides or anhydrides are reacted with ArOH in the presence of a strong base (CH3CO)2O + C6H5OH + NaOH → → CH3COOC6H5 + CH3COO–Na+ + H2O Phenyl acetate C6H5COCl + C6H5OH + NaOH → → C6H5COOC6H5 + Na+Cl– + H2O Phenyl benzoate OH– converts ArOH to the more nucleophilic ArO– and also neutralizes the acids formed. Phenyl acetate undergoes the Fries rearrangement with AlCl3 to form ortho and para hydroxyacetophenone. The ortho isomer is separated from the mixture due to its volatility with steam.

The ortho isomer has higher vapour pressure because of chelation, O–H---O = and is steam volatile. In the para isomer there is 293

intermolecular H– bonding with H2O. The para isomer (rate controlled product) is the exclusive product at 25 °C because it has a lower DH and is formed more rapidly. Its formation is reversible, unlike that of the ortho isomer which is stabilized by chelation. Although it has a higher DH, the ortho isomer (equilibrium – controlled product) is the chief product at 165°C because it is more stable. Displacement of OH group. Phenols resemble aryl halides in that the functional group resists displacement. Unlike ROH, phenols do not react with HX, SOCl2, or phosphorus halides. Phenols are reduced to hydrocarbons, but the reaction is used for structure proof and not for synthesis. ArOH + Zn

ArH + ZnO (poor yields)

Reactions of the benzene ring 1. Hydrogenation of phenols

2. Oxidation of phenols to quinones

3. Electrophilic substitution reactions of phenols The –OH and even more so the –Oph are strongly activating and o, p directing 294

Special mild conditions are needed to achieve electrophilic monosubstituion in phenols because their high reactivity favors both polysubstitution and oxidation. a. Halogenation of phenols

Monobromination is achieved with nonpolar solvents such as CS2 to decrease the electrophilicity of Br2 and also to minimize phenol ionization

b. Nitrosation of phenols

c. Nitration of phenols Low yields of p- nitrophenol are obtained from direct nitration of PhOH because of ring oxidation. A better synthesis method is 295

d. Sulfonation of phenols

e. Diazonium salt coupling to form azophenols. Coupling (G in ArG is an electron – releasing group) ArN2+ + C6H5G → p-G —C6H4 — N = N — Ar (G = OH, NR2, NHR, NH2) f. Mercuration of phenols. Mercuricacetate cation, +HgOAC, is a weak electrophile which substitutes in ortho and para positions of phenols. This reaction is used to introduce an I on the ring.

g. Ring alkylation of phenols

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RX and AlCl3 give poor yields because AlCl3 coordinates with O. h. Ring acylation of phenols. Phenolic ketones are best prepared by the Fries rearrangement (Discussed earlier) i. Kolbe synthesis of phenolic carboxylic acids

Phenoxide carbanion adds at the electrophilic carbon of CO2. j. Reimer – Tiemann synthesis of phenolic aldehydes

Phenol can be used to synthesize (a) aspirin (acetylsalicylic acid) (b) oil of wintergreen (methyl salicylate)

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k. Condensations with carbonyl compounds; phenol – formaldehyde resin. Acid or base catalyzes electrophilic substitution of carbonyl compounds in ortho and para positions of phenols to form phenol alcohols (Lederer – Manasse reaction).

Acid catalyzed

Phenols are soluble in NaOH but not in NaHCO3. With Fe3+ they produce complexes whose characteristic colors are green, red, blue and purple.

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This page looks at the structure and physical properties of phenylamine – also known as aniline or aminobenzene. Phenylamine has an -NH2 group attached directly to a benzene ring. The structure of phenylamine. Phenylamine is a primary amine – a compound in which one of the hydrogen atoms in an ammonia molecule has been replaced by a hydrocarbon group. However, in comparison with simple primary amines like methylamine, the properties of phenylamine are slightly different. This is because the lone pair on the nitrogen atom interacts with the delocalised electrons in the benzene ring. The simplest way to draw the structure of phenylamine is:

There is an interaction between the delocalised electrons in the benzene ring and the lone pair on the nitrogen atom. The lone pair overlaps with the delocalised ring electron system.

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Giving a structure rather like this:

The donation of the nitrogen's lone pair into the ring system increases the electron density around the ring. That makes the ring much more reactive than it is in benzene itself. It also reduces the availability of the lone pair on the nitrogen to take part in other reactions. In particular, it makes phenylamine much more weakly basic than primary amines where the -NH2 group isn't attached to a benzene ring. That will be explored elsewhere in this section. (See the phenylamine menu - link at the bottom of this page.) Physical properties. Pure phenylamine is a colourless liquid, but it darkens rapidly on exposure to light and air. It is normally a brown oily liquid. Melting and boiling points. It is useful to compare phenylmine's melting and boiling points with those of methylbenzene (toluene). Both molecules contain a similar number of electrons and have a very similar shape. That means that the intermolecular attractions due to van der Waals dispersion forces are going to be very similar. C6H5NH2 C6H5CH3

melting point (°C) -6.2 -95.0

boiling point (°C) 184 111

The reason for the higher values for phenylamine is in part due to permanent dipole-dipole attractions due to the electronegativity of the nitrogen - but is mainly due to hydrogen bonding. 300

Hydrogen bonds can form between a lone pair on a nitrogen on one molecule and the hydrogen on the -NH2 group of one of its neighbours. Solubility in water. Phenylamine is slightly soluble in water about 3.6 g (depending on where you get the data from!) of phenylamine will dissolve in 100 g of water at 20°C. Mixtures containing more phenylamine than this separate into two layers, with the phenylamine forming the bottom one. Phenylamine is somewhat soluble in water because of its ability to form hydrogen bonds with water. However, the benzene rings in the phenylamine break more hydrogen bonds between water molecules than are reformed between water and the -NH2 groups. The water molecules also disrupt fairly strong van der Waals attractions between the phenylamine molecules. Both of these effects mean that dissolving phenylamine in water isn't very energetically profitable, and so stop the phenylamine from being very soluble. MAKING PHENYLAMINE. Now looks at the preparation of phenylamine (also known as aniline or aminobenzene) starting from benzene. The benzene is first converted to nitrobenzene which is in turn reduced to phenylamine. Benzene to nitrobenzene. Benzene is nitrated by replacing one of the hydrogen atoms on the benzene ring by a nitro group, NO2. The benzene is treated with a mixture of concentrated nitric acid and concentrated sulphuric acid at a temperature not exceeding 50°C. The mixture is held at this temperature for about half an hour. Yellow oily nitrobenzene is formed.

You could write this in a more condensed form as:

The concentrated sulphuric acid is acting as a catalyst and so isn't written in the equations. The temperature is kept relatively low to prevent more than one nitro group being substituted onto the ring. 301

Nitrobenzene to phenylamine. The conversion is made in the two main stages: Stage 1: conversion of nitrobenzene into phenylammonium ions. Nitrobenzene is reduced to phenylammonium ions using a mixture of tin and concentrated hydrochloric acid. The mixture is heated under reflux in a boiling water bath for about half an hour. Under the acidic conditions, rather than getting phenylamine directly, you instead get phenylammonium ions formed. The lone pair on the nitrogen in the phenylamine picks up a hydrogen ion from the acid. The electron-half-equation for this reaction is:

The nitrobenzene has been reduced by gaining electrons in the presence of the acid. The electrons come from the tin, which forms both tin(II) and tin(IV) ions.

Stage 2: conversion of the phenylammonium ions into phenylamine. All you need to do is to remove the hydrogen ion from the NH3+ group. Sodium hydroxide solution is added to the product of the first stage of the reaction.

The phenylamine is formed together with a complicated mixture of tin compounds from reactions between the sodium hydroxide solution and the complex tin ions formed during the first stage. The 302

phenylamine is finally separated from this mixture. The separation is long, tedious and potentially dangerous - involving steam distillation, solvent extraction and a final distillation.

PHENYLAMINE AS A PRIMARY AMINE. Here we can see at reactions of phenylamine (also known as aniline or aminobenzene) where it behaves as a fairly straightforward primary amine. It explains why phenylamine is a weaker base than other primary amines, and summarises its reactions with acyl chlorides (acid chlorides), acid anhydrides and halogenoalkanes (haloalkanes or alkyl halides). Before you read each section on this page, you should follow the link to the corresponding page about aliphatic amines (those not based on benzene rings). In most cases, the reactions are the same, and this page only really looks in detail at the differences in the phenylamine case. Phenylamine as a base. Amines are bases because the lone pair of electrons on the nitrogen atom can accept a hydrogen ion - in other words, for exactly the same reason that ammonia is a base. With phenylamine, the only difference is that it is a much weaker base than ammonia or an amine like ethylamine - for reasons that we will explore later. The reaction of phenylamine with acids. Phenylamine reacts with acids like hydrochloric acid in exactly the same way as any other amine. Despite the fact that the phenylamine is only a very weak base, with a strong acid like hydrochloric acid the reaction is completely straightforward. Phenylamine is only very slightly soluble in water, but dissolves freely in dilute hydrochloric acid. A solution of a salt is formed phenylammonium chloride. If you just want to show the formation of the salt, you could write:

303

or if you want to emphasise the fact that the phenylamine is acting as a base, you could most simply use:

Getting the phenylamine back from its salt. To get the phenylamine back from the phenylammonium ion present in the salt, all you have to do is to take the hydrogen ion away again. You can do that by adding any stronger base. Normally, you would choose sodium hydroxide solution.

The phenylamine is formed first as an off-white emulsion - tiny droplets of phenylamine scattered throughout the water. This then settles out to give an oily bottom layer of phenylamine under the aqueous layer. The reaction of phenylamine with water. This is where it is possible to tell that phenylamine is a much weaker base than ammonia and the aliphatic amines like methylamine and ethylamine. Phenylamine reacts reversibly with water to give phenylammonium ions and hydroxide ions.

The position of equilibrium lies well to the left of the corresponding ammonia or aliphatic amine equilibria, which means that not many hydroxide ions are formed in the solution. The effect of this is that the pH of a solution of phenylamine will be quite a bit lower than a solution of ammonia or one of the aliphatic amines of the same concentration. For example, a 0.1 M phenylamine solution has a pH of about 9 compared to a pH of about 11 for 0.1 M ammonia solution. Amines are bases because they pick up hydrogen ions on the lone pair on the nitrogen atom. In phenylamine, the attractiveness of the lone pair is lessened because of the way it interacts with the ring electrons. The lone pair on the nitrogen touches the delocalised ring 304

electrons and becomes delocalised with them. That means that the lone pair is no longer fully available to combine with hydrogen ions. The nitrogen is still the most electronegative atom in the molecule, and so the delocalised electrons will be attracted towards it, but the electron density around the nitrogen is nothing like it is in, say, an ammonia molecule. The other problem is that if the lone pair is used to join to a hydrogen ion, it is no longer available to contribute to the delocalisation. That means that the delocalisation would have to be disrupted if the phenylamine acts as a base. Delocalisation makes molecules more stable, and so disrupting the delocalisation costs energy and won't happen easily. Taken together – the lack of intense charge around the nitrogen, and the need to break some delocalisation – means that phenylamine is a very weak base indeed. The acylation of phenylamine. The reactions with acyl chlorides and with acid anhydrides. These are reactions in which the phenylamine acts as a nucleophile. There is no essential difference between these reactions and the same reactions involving any other primary amine. We'll take ethanoyl chloride as a typical acyl chloride, and ethanoic anhydride as a typical acid anhydride. The important product of the reaction of phenylamine with either of these is the same. Phenylamine reacts vigorously in the cold with ethanoyl chloride to give a mixture of solid products – ideally white, but usually stained brownish. A mixture of N-phenylethanamide (old name: acetanilide) and phenylammonium chloride is formed. The overall equation for the reaction is:

With ethanoic anhydride, heat is needed. In this case, the products are a mixture of N-phenylethanamide and phenylammonium ethanoate.

The main product molecule (the N-phenylethanamide) is often drawn looking like this: 305

If you stop and think about it, this is obviously the same molecule as in the equation above, but it stresses the phenylamine part of it much more. Looking at it this way, notice that one of the hydrogens of the NH2 group has been replaced by an acyl group - an alkyl group attached to a carbon-oxygen double bond. You can say that the phenylamine has been acylated or has undergone acylation. Because of the nature of this particular acyl group, it is also described as ethanoylation. The hydrogen is being replaced by an ethanoyl group, CH3CO-. The reaction of phenylamine with halogenoalkanes. This is another reaction of phenylamine as a nucleophile, and again there is no essential difference between its reactions and those of aliphatic amines. Taking bromoethane as a typical halogenoalkane, the reaction with phenylamine happens in the same series of complicated steps as with any other amine. We'll just look at the first step. On heating, the bromoethane and phenylamine react to give a mixture of a salt of a secondary amine and some free secondary amine. In this case, you would first get Nethylphenylammonium bromide:

but this would instantly be followed by a reversible reaction in which some unreacted phenylamine would take a hydrogen ion from the salt to give some free secondary amine: N-ethylphenylamine.

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The reaction wouldn't stop there. You will get further reactions to produce a tertiary amine and its salt, and eventually a quaternary ammonium compound. If you want to explore this further, refer to the last link just up the page, and trace the sequence of equations through using phenylamine rather than ethylamine. MAKING DIAZONIUM SALTS FROM PHENYLAMINE This page looks at the reaction between phenylamine (also known as aniline and aminobenzene) and nitrous acid - particularly its reaction at temperatures of less than 5°C to produce diazonium salts. If you want to know about the reactions of the diazonium ions formed, you will find a link at the bottom of the page. The reactions of phenylamine with nitrous acid. Nitrous acid (also known as nitric (III) acid) has the formula HNO2. It is sometimes written as HONO. Nitrous acid decomposes very readily and is always made in situ. In the case of its reaction with phenylamine, the phenylamine is first dissolved in hydrochloric acid, and then a solution of sodium or potassium nitrite is added. The reaction between the hydrochloric acid and the nitrite ions produces the nitrous acid. You get the reaction:

Because nitrous acid is a weak acid, the position of equilibrium lies well the right. Phenylamine reacts with nitrous acid differently depending on the temperature. The reaction on warming. If the mixture is warmed, you get a black oily product which contains phenol (amongst other things), and nitrogen gas is given off.

The reaction at low temperatures. The solution of phenylamine in hydrochloric acid (phenylammonium chloride solution) is 307

stood in a beaker of ice. The sodium or potassium nitrite solution is also cooled in the ice. The solution of the nitrite is then added very slowly to the phenylammonium chloride solution - so that the temperature never goes above 5°C. You end up with a solution containing benzenediazonium chloride:

The positive ion, containing the -N2+ group, is known as a diazonium ion. The "azo" bit of the name refers to nitrogen. The ionic equation for the reaction is:

Notice that the chloride ions from the acid aren't involved in this in any way. If you use hydrochloric acid, the solution will contain benzenediazonium chloride. If you used a different acid, you would just get a different salt - a sulphate or hydrogensulphate, for example, if you used sulphuric acid. The reactions of a diazonium salt are always carried out with a freshly prepared solution made in this way. The solutions are not kept. Diazonium salts are very unstable and tend to be explosive as solids. REACTIONS OF DIAZONIUM SALTS This page looks at some typical reactions of diazonium ions, including examples of both substitution reactions and coupling reactions. If you have come straight to this page from a search engine and want to know about the preparation of the diazonium ions, you will find a link at the bottom of the page. 308

Substitution reactions of diazonium ions. Diazonium ions are present in solutions such as benzenediazonium chloride solution. They contain an -N2+ group. In the case of benzenediazonium chloride, this is attached to a benzene ring. Benzenediazonium chloride looks like this:

In this set of reactions of the diazonium ion, the -N2+ group is replaced by something else. The nitrogen is released as nitrogen gas. Substitution by an -OH group. To get this reaction, all you need to do is to heat the benzenediazonium chloride solution. The diazonium ion reacts with the water in the solution and phenol is formed – either in solution or as a black oily liquid (depending on how much is formed). Nitrogen gas is evolved.

This is the same reaction that you get if you make a reaction of phenylamine with nitrous acid in the warm. The diazonium ion is formed first and then immediately reacts with the water in the solution to give phenol. Substitution by an iodine atom. This is a good example of the use of diazonium salts to substitute things into a benzene ring which are otherwise quite difficult to attach. (That's equally true of the previous reaction, by the way.) If you add potassium iodide solution to the benzenediazonium chloride solution in the cold, nitrogen gas is given off, and you get oily droplets of iodobenzene formed. There is 309

a simple reaction between the diazonium ions and the iodide ions from the potassium iodide solution.

Coupling reactions of diazonium ions. In the substitution reactions above, the nitrogen in the diazonium ion is lost. In the rest of the reactions on this page, the nitrogen is retained and used to make a bridge between two benzene rings. The reaction with phenol. Phenol is dissolved in sodium hydroxide solution to give a solution of sodium phenoxide.

The solution is cooled in ice, and cold benzenediazonium chloride solution is added. There is a reaction between the diazonium ion and the phenoxide ion and a yellow-orange solution or precipitate is formed. The product is one of the simplest of those known as azo compounds, in which two benzene rings are linked by a nitrogen bridge.

The reaction with naphthalen-2-ol. Naphthalen-2-ol is also known as 2-naphthol or beta-naphthol. It contains an -OH group attached to a naphthalene molecule rather than to a simple benzene ring. Naphthalene has two benzene rings fused together. The reaction is done under exactly the same conditions as with phenol. The naphthalen-2-ol is dissolved in sodium hydroxide solution to produce an ion just like the phenol one. This solution is cooled and mixed with 310

the benzenediazonium chloride solution. An intense orange-red precipitate is formed - another azo compound.

The reaction with phenylamine (aniline). Some liquid phenylamine is added to a cold solution of benzenediazonium chloride, and the mixture is shaken vigorously. A yellow solid is produced.

These strongly coloured azo compounds are frequently used as dyes known as azo dyes. The one made from phenylamine (aniline) is known as "aniline yellow" (amongst many other things - see the note above). Azo compounds account for more than half of modern dyes. The use of an azo dye as an indicator - methyl orange. Azo compounds contain a highly delocalised system of electrons which takes in both benzene rings and the two nitrogen atoms bridging the rings. The delocalisation can also extend to things attached to the benzene rings. If white light falls on one of these molecules, some wavelengths are absorbed by these delocalised electrons. The colour you see is the result of the non-absorbed wavelengths. The groups which contribute to the delocalisation (and thus to the absorption of light) are known as chromophores. Modifying the groups present in the molecule can have an effect on the light absorbed, and thus on the colour you see. You can take an advantage of these indicators. Methyl orange is an azo dye which exists in two forms depending on the pH: As the hydrogen ion is lost or gained there is a shift in the exact nature of the delocalisation in the molecule, and that causes a shift in the wavelength of light absorbed. Obviously it means that you see a 311

different colour. When you add acid to methyl orange, a hydrogen ion attaches to give the red form. Methyl orange is red in acidic solutions (in fact, solutions of pH less than 3.1). If you add an alkali, hydrogen ions are removed and you get the yellow form. Methyl orange is yellow at pH's greater than 4.4. In between, at some point there will be equal amounts of the red and yellow forms and so methyl orange looks orange.

The directing effect of the -NH2 group. The -NH2 group has more activating effect on some positions around the ring than others. That means that incoming groups will go into some positions much faster than they will into others. The net effect of this is that the -NH2 group has a 2, 4-directing effect. That means that incoming groups will tend to go into the 2- position (next door to the -NH2 group) or the 4- position (opposite the -NH2 group). You will get hardly any of the 3- isomer formed - it is produced too slowly. The reaction with bromine water. If bromine water is added to phenylamine, the bromine water is decolourised and a white precipitate is formed. This is exactly like the reaction which happens with phenol. The precipitate is 2,4,6-tribromophenylamine.

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Notice the multiple substitutions around the ring - into all the activated positions. (The 6- position is, of course, just the same as the 2- position. Both are next door to the -NH2 group.) GENERAL PROBLEMS 1. What homologues of benzene are obtained with catalytic aromatization of the following limit hydrocarbons? Write the reaction, its conditions, name the obtained arens. a) heptane b) ethyldipropylmethane c) octane d) 2,5-dimethylhexane e) 2-methylhexane f) 3-methylhexane g) 2,3-dimethylhexane h) 2,4-dimethylhexane 2. Write the reactions of getting the following arens from the corresponding cycloparaffins. Specify the reaction conditions, name the starting materials: a) ethylbenzene b) p-dimethylbenzene c) Toluene d) o-dimethylbenzene e) m-dimethylbenzene f) propylbenzene g) isopropylbenzene h) sim-trimethylbenzene 3. It is known that a benzene ring can be formed in the result of trimerization of acetylene. What homologues of benzene can be expected with a similar cyclotrimerization of the following alkynes? Write the reaction and name the homologue of benzene: a) methyl acetylene b) ethyl acetylene c) dimethylacetylene d) diethylacetylene e) phenylacetylene f) diphenylacetylene g)isopropylacetylene h) 1-butene 4. Which hydrocarbons are produced by the action of metallic sodium on a mixture of halogenated derivatives? a) bromobenzene and isopropyl bromide b) benzyl chloride and ethyl chloride c) n-bromotoluene and ethyl bromide d) chlorobenzene and isobutyl chloride e) m-bromotoluene and propyl bromide 313

f) o-bromotoluene and butyl bromide g) bromobenzene and benzyl bromide h) bromobenzene and butyl bromide 5. Write the following alkylation reactions. Enter the conditions of the reaction, reflect the role of the catalyst in the formation of an electrophile and the reaction mechanism. Take into account the peculiarity of the alkylation reaction, associated with the isomerization of the alkyl cation. a) benzene + ethyl chloride (catalyst - aluminum chloride) b) benzene + isobutyl bromide (catalyst - aluminum bromide) c) benzene + isopropyl alcohol (catalyst - sulfuric acid) d) benzene + propylene (the catalyst is protic acid) e) benzene + 1-methyl-2-chlorobutane (catalyst - aluminum chloride) f) benzene + isobutylene (the catalyst is protic acid) g) benzene + propyl chloride (catalyst - aluminum chloride) h) benzene + propyl alcohol (the catalyst is protic acid) 6. Write the following reactions of electrophilic substitution in aromatic core, describe the reaction conditions, the role of the catalyst in the formation of an electrophile and the reaction mechanism: a) nitration of toluene b) nitration of ethylbenzene c) chlorination of benzene d) bromination of benzene e) acetylation of benzene by Friedel-Crafts f) bromination of toluene g) sulfonation of benzene h) sulfonation of toluene 7. Homologues of benzene have two reaction centers: the nucleus and the lateral chain. Depending on the conditions of the halogenation processes and nitration, substitution occurs in one of them. For reactions of substitution in the side chain, give the reaction mechanism: a) bromination of isobutylbenzene b) chlorination of isobutyl-benzene 314

c) nitration of propylbenzene d) nitration of toluene e) bromination of isopropylbenzene f) nitration of ethylbenzene g) chlorination of cumene h) nitration of isobutylbenzene 8. Arrange the following aromatic compounds in a row on the weakening of their reactivity in reactions of electrophilic substitution. Give an explanation on the basis of electron-donor or electronwithdrawing influence of substituents: a) acetanilide, aniline, nitrobenzene, chlorobenzene b) phenol, benzoic acid, benzonitrile, phenylacetylene c) benzaldehyde, toluene, m-dihydroxybenzene, phenol d) m-xylene, chlorobenzene, m-dichlorobenzene, toluene e) nitrobenzene, m-dinitrobenzene, n-nitroaniline, aniline f) Benzotrichloride, toluene, methoxybenzene, bromobenzene g) iodobenzene, phenol, toluene, benzoic acid h) dimethylphenylammonium, dimethylaniline, cumene, nitrobenzene 9. One of the benzene homologues of the composition C8H10 during ozonation and ozonid splitting gives three products: glyoxal, methylglyoxal and dimethylglyoxal. What is the structural formula of this hydrocarbon? 10. Hydrocarbon of composition С9H12 at oxidation gives one of isomersbenzene tricarboxylic acids. Define its structural formula, considering that with electrophilic substitution it gives. 11. Name the following connection for the IUPAC nomenCOOH clature: OH 12. Indicate the reagents of the reactions to obtain ethyl benzoate from toluene C6H5CH3

?

...

? 315

C6H5COOC2H5

13. What compound is formed by the reaction of benzoyl chloride and sodium benzoate? 14. What kind of acid is formed during the oxidation of oxylene, write the reaction. 15. Write the reaction: what compound will be obtained by oxidation of propylbenzene? 16. What substance is formed during the decomposition of the hydrazone of phenylethyl ketone according to Kizner-Wolff: C6H5-C--CH2 -CH3 N-NH2

KOH to

?

17. How does benzaldehyde react with the following oxidant C6H5-C=O H

Ag(NH 3)2OH

?

18. What kind of compound is obtained by catalytic dehydrogenation of the following alcohol: OH CH3 -CH-CH-C6H5 CH3

19. Indicate the final product of the following transformations: CH3--C=O Cl C6H6 AlCl 3

...

LiAlH 4

...

C2H5 -C=O Cl

20. Call the product of the following interactions

316

?

21. What is the connection in the following diagram: Cl OH NaOH ?

?

Cu

22. Establish the structure of the compound C8H10O, which gives a color reaction with iron (III) chloride, is methylated with dimethyl sulphate in an alkaline medium, oxidation of the methylation product yields p-methoxybenzoic acid 23. Give an example for the strongest orientant in the ortho- and para- position 24. From the scheme of transformations, name the substance C Br

Mg

H2O, H+

A

Br2 B

C

FeBr3

25. What is formed during the oxidation of benzene in the presence of a catalyst - V2O5? Write the reaction. 26. What is formed during the catalytic reforming of heptane? Write the reaction. 27. Which substituent is a meta-orientant. Give the example. 28. Write an anion, which is aromatic according to Hückel's rule 29. Write an example, which is anti-aromatic by the Hückel rule 30. Write a cation, which is aromatic according to Hückel's rule 31. Complete the following reaction: NHCOCH3

+ HNO3 A

H

, kat

H2SO4

317

X B

32. The product of the following transformation

33. The product of the following transformation

34. Write the product of the following transformation

35. Write the following transformation C6H5Br

KCN

...

H2O H+

..

PCl5

?

36. Name the products of the following transformation

37. Name the substance B: +C2H5Br AlBr 3

A

[O]

B

38. By Huckel’s law, what conditions should be presented for true being of aromatic compounds? Write some examples.

318

39. Which structure has a compound of composition C6H6OS that forms an oxime, but does not interact with an ammoniacal solution of silver oxide? 40. Which diazo and azo components should be used to obtain the following azo dye:

(CH3)2N-

-N=NCOOH Write the reaction.

41. Which of the following products is formed as a result of the following transformations NO2

Zn (NH4Cl)

?

H2SO4

?

42. What will be formed in the result of the following transformation?

43. Indicate the final product of the following transformations: C6H5CH3 [O]

..

PCl5

NH2-NH2 ...

?

44. What kind of acid is formed as a result of the following transformations: C6H5CH=C=O

C2H5OH

319

...

H2O H+

?

45. Establish the structure of the substance of the composition C8H8O2, if it is known that when the phosphorus chloride (V) acts, it becomes a substance of the composition C8H7OCl, and when fused with caustic soda it turns into toluene. Write the reaction. 46. What compound is formed if phosphorus chloride (V) acts on benzoic acid and the resulting compound is treated with ammonia? Write the reaction. 47. Which acid is formed during the oxidation of p-ethyltoluene? Write the reaction. 48. What is formed by the interaction of phenylacetic aldehyde with alcohol C6H5 -CH2--C=O H

+ 2 C2H5OH

H+

?

49. Which carbonyl compound is formed by the following reaction: C6H5COCl + (CH3)2Cd 50. Draw the structures of the following substances: 4-chlorobut-1-ene, 1,2-dimethyl-4-ethylcyclohexane and 1-isopropyl-2-secbutyl acetylene

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1. Solomon’s J.W. Organic Chemistry. – 9th ed. / John Wiley. – 2008. 2. Sergienko V.I. and others. Renewable chemical raw materials: comprehensive recycling rice and buckwheat // Russian Chemical Journal. – 2004. – № 3. – P. 116-124. 3. Robert V. Hoffman. Organic Chemistry: аn intermediate text. – 2004. – 489 p. 4. Laurie S. Starkey. Introdution to strategies for Organic Synthesis. – 2012. – 360 p. 5. Carmelo J. Rizzo. Advanced Organic Reactions. – 2002. – 194 p. 6. Traven V.F. Organic Chemistry. – M.: Akademkniga, 2004. – 1, 2. 7. Organic Chemistry. William H. Brown. – 2008. – 1230 p. 8. Falcons R.S. Chemical technology. – M.: "Vlados", 2003. – Volume 2. 9. Morrison, R., R. Boyd. Organic Chemistry. – Wiley, HS, 1990. 10. Shabarov Y.S. Organic Chemistry. – M.: Chemistry, 1994. – Vol. 1, 2. 11. Neyland OJ. Organic Chemistry. – M.: Higher School, 1990. 12. John S. Carey, David Laffan, Colin Thomson and Mike T. Williams. Analysis of the reactions used for the preparation of drug candidate molecules // Org. Biomol. Chem. – 2006. – 4. – 2337-2347. 13. Robert H. Crabtree. The Organometallic Chemistry of the Transition Metals. – Wiley, 2005. – P. 560.

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INTRODUCTION ..................................................................................... 3 1. DETERMINATION OF MOLECULAR FORMULAS ..................... 6 2. BONDING IN ORGANIC COMPOUNDS ........................................ 9 3. NAMING ORGANIC COMPOUNDS ............................................... 14 4. ISOMERS OF ORGANIC COMPOUNDS ........................................ 16 5. ACID AND BASE PROPERTIES ...................................................... 23 6. ALIPHATIC COMPOUNDS.............................................................. 25 6.1. ALKANE ................................................................................... 25 6.2. ALKENE ................................................................................... 45 6.3. ALKYNE ................................................................................... 68 6.4. ALKYL HALIDES. .................................................................. 84 6.5. ALCOHOL ................................................................................ 102 6.6. ETHERS .................................................................................... 106 6.7. ALDEHYDES AND KETONE ................................................. 117 6.8. CARBOXYLIC ACIDS AND ITS DERIVATIVES ................. 136 6.8.1. ESTERS..................................................................................... 151 6.8.2. ACID CHLORIDES .................................................................. 157 6.8.3. AMIDES .................................................................................... 159 6.9. AMINES .................................................................................... 161 6.10. CYANIDES AND ISOCYANIDES .......................................... 193 7. BIOMOLECULES .............................................................................. 198 7.1. PROTEINS AND AMINO ACID ................................................ 198 7.2. LIPIDS ......................................................................................... 209 7.3. CARBOHYDRATES ................................................................... 210 7.4. PEPTIDE AND PROTEINS ........................................................ 235 7.5. NUCLEIC ACIDS ....................................................................... 241 GENERAL PROBLEMS .................................................................... 244 8. AROMATIC HYDROCARBONS ..................................................... 255 9. PHENOLS .......................................................................................... 286 10. PHENYLAMINE ................................................................................ 299 GENERAL PROBLEMS .................................................................... 313 REFERENCE ............................................................................................ 321

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Еducational issue

Kudaibergenova Bates Malikovna ORGANIC CHEMISTRY PART I, II Educational manual Stereotypical publication Editor L.E. Strautman Typesetting G. Kaliyeva Cover design Y. Gorbunov Cover design used photos from sites www.art-2026066_1280.com

IB №13064 Signed for publishing 16.09.2020. Format 60x84 1/16. Offset paper. Digital printing. Volume 20,18 printer’s sheet. 100 copies. Order №5950. Publishing house «Qazaq university» Al-Farabi Kazakh National University KazNU, 71 Al-Farabi, 050040, Almaty Printed in the printing office of the «Kazakh University» publishing house.

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«ҚАЗАҚ УНИВЕРСИТЕТІ» баспа үйінің жаңа кітаптары Seilkhanova G.A. Chemical technology of glass: educational manual / G.A. Seilkhanova. – Almaty: Qazaq university, 2017. – 64 p. ISBN 978-601-04-2997-0 The educational manual presents the theoretical foundations of glass production, its physico-chemical properties, discusses in detail the basic technological stages of obtaining glassware. The textbook contains laboratory works for determining some characteristics of the glass. In order to improve the learning of theoretical material, and also for the control of the students’ knowledge, there are test questions in the textbook. The textbook can be used during the study of the subjects «Chemical technology of silicate materials», «Chemical technology of glass and ceramics». The educational manual is designed for the students enrolled in the chemi-caltechnological specialties, and can also be used by the lecturers and staff working in the field of producing silicate materials. Қоқaнбaев Ә.Қ. Коллоидтық химияның есептері мен жaттығулaры: оқу-­ әдістемелік құрaлы / Ә.Қ. Қоқaнбaев, Д.М-К. Aртыковa, М.Ж. Керім­ құловa. – Aлмaты: Қaзaқ университеті, 2017. – 192 б. ISBN 978-601-04-3053-2 Оқу-әдістемелік құралда коллоидтық химияның есептері мен жаттығулары осы пәннің жеті негізгі тараулары: «Беттік керілу, беттік құбылыстар және коллоидтық бетті-активтік заттар», «Әртүрлі фазалардың жанасу беттеріндегі адсорбциялар», «Коллоидтық жүйелердегі электр­ кинетикалық құбылыстар», «Дисперстік жүйелердің молекулалық-ки­нетикалық қасиеттері», «Дисперстік жүйелердің оптикалық қа­сиет­тері», «Коллоидтық жүйелердің тұрақтылығы және коагуля­циясы», «Дисперстік жүйелердің құрылымдық-механикалық (реологиялық) қасиеттері» бойынша түзілген. Әр тараудың басында тип­тік есептердің шығару жолдары және студенттердің өз бетімен орындауға арналған есептері берілген. Оқу-әдістемелік құрал коллоидтық химия пәнін оқитын ЖОО-ның «Химия», «Бейорганикалық заттардың химиялық технологиясы», «Орга­ никалық заттардың химиялық технологиясы» мамандықтарының сту­ денттеріне арналған. Ospanova A.K. Chemical technology of glass: еducational manual / A.K. Ospa­ nova, G.A. Seilkhanova. – Almaty: Qazaq university, 2017. – 136 p. ISBN 978-601-04-3046-4 In the еducational manual presents the theoretical and practical aspects of chemical kinetics and electrochemistry. Much attention is paid to the important section on the problems of catalysis. Modern views on the nature of homogeneous and heterogeneous catalysis are considered. And the features of the influence of the catalyst on the rate of chemical reactions are given. The problems of the theory of solutions of strong and weak electrolytes, the thermodynamics of electrochemical processes are considered. The еducational manual is intended for students studying in chemical and chemical-technical specialties, and can also be used by undergraduates, doctorants, teachers of higher educational institutions of the Republic of Kazakhstan. Кітаптарды сатып алу үшін «Қазақ университеті» баспа үйінің маркетинг және сату бөліміне хабарласу керек. Байланыс тел: 8(727) 377-34-11. E-mail: [email protected], cайт: www.read.kz, www.magkaznu.com