Biphasic chemistry and the solvent case 9781786305091, 1781801851, 1786305097

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Biphasic Chemistry and The Solvent Case

Eco-compatibility of Organic Synthesis Set coordinated by Max Malacria

Volume 3

Biphasic Chemistry and The Solvent Case

Edited by

Jean-Philippe Goddard Max Malacria Cyril Ollivier

First published 2020 in Great Britain and the United States by ISTE Ltd and John Wiley & Sons, Inc.

Apart from any fair dealing for the purposes of research or private study, or criticism or review, as permitted under the Copyright, Designs and Patents Act 1988, this publication may only be reproduced, stored or transmitted, in any form or by any means, with the prior permission in writing of the publishers, or in the case of reprographic reproduction in accordance with the terms and licenses issued by the CLA. Enquiries concerning reproduction outside these terms should be sent to the publishers at the undermentioned address: ISTE Ltd 27-37 St George’s Road London SW19 4EU UK

John Wiley & Sons, Inc. 111 River Street Hoboken, NJ 07030 USA

www.iste.co.uk

www.wiley.com

© ISTE Ltd 2020 The rights of Jean-Philippe Goddard, Max Malacria and Cyril Ollivier to be identified as the authors of this work have been asserted by them in accordance with the Copyright, Designs and Patents Act 1988. Library of Congress Control Number: 2019951189 British Library Cataloguing-in-Publication Data A CIP record for this book is available from the British Library ISBN 978-1-78630-509-1

Contents

Chapter 1. Solid-phase Supported Chemistry . . . . . . . . . . . Géraldine GOUHIER 1.1. Introduction . . . . . . . . . . . . . . . . . . . 1.2. Principle of solid-phase chemistry . . . . . . 1.3. Advantages . . . . . . . . . . . . . . . . . . . 1.4. Safety and environment . . . . . . . . . . . . 1.5. Disadvantages and limitations . . . . . . . . 1.6. Evolution . . . . . . . . . . . . . . . . . . . . . 1.7. Supports: linear skeletons . . . . . . . . . . . 1.8. Three-dimensional resins . . . . . . . . . . . 1.8.1. Macroporous resins . . . . . . . . . . . . 1.8.2. Gel resins . . . . . . . . . . . . . . . . . . 1.9. Characteristics of gel supports . . . . . . . . 1.9.1. Functionalization rate . . . . . . . . . . . 1.9.2. Swelling properties . . . . . . . . . . . . 1.9.3. Size of the beads . . . . . . . . . . . . . . 1.9.4. Influence of cross-linking on swelling . 1.9.5. Diffusion effect. . . . . . . . . . . . . . . 1.9.6. Influence of cross-linking on diffusion . 1.9.7. Influence of steric bulk . . . . . . . . . . 1.9.8. Influence of agitation . . . . . . . . . . . 1.9.9. Proximity and pseudodilution effects . . 1.9.10. Proximity effect. . . . . . . . . . . . . . 1.9.11. Pseudodilution effect . . . . . . . . . . 1.9.12. Availability and costs . . . . . . . . . . 1.10. Functionalization of the solid support . . .

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1 1 2 4 4 5 6 6 7 7 8 10 10 10 12 12 13 13 14 14 14 15 15 16 17

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Biphasic Chemistry and The Solvent Case

1.10.1. Spacer arms. . . . . . . . . . . . . . . . . . . 1.10.2. Linkers . . . . . . . . . . . . . . . . . . . . . 1.10.3. Influence of functionalization . . . . . . . . 1.11. Analytical methods and reaction monitoring . 1.11.1. Centesimal analyses . . . . . . . . . . . . . . 1.11.2. Colorimetric dosages . . . . . . . . . . . . . 1.11.3. Indirect analyses . . . . . . . . . . . . . . . . 1.11.4. Infrared spectroscopy . . . . . . . . . . . . . 1.11.5. Nuclear magnetic resonance spectrometry 1.11.6. Mass spectrometry . . . . . . . . . . . . . . 1.12. Solid-phase syntheses . . . . . . . . . . . . . . . 1.12.1. Supported reagents . . . . . . . . . . . . . . 1.12.2. Supported chiral catalysts . . . . . . . . . . 1.12.3. Scavengers . . . . . . . . . . . . . . . . . . . 1.13. Innovative applications and processes . . . . . 1.13.1. Examples . . . . . . . . . . . . . . . . . . . . 1.13.2. Parallel syntheses on a solid support . . . . 1.14. Activation on solid phase . . . . . . . . . . . . . 1.14.1. Microwave reactions . . . . . . . . . . . . . 1.14.2. Reactions under high pressure . . . . . . . . 1.14.3. Reactions under ultrasound . . . . . . . . . 1.14.4. Supported electrochemical reactions . . . . 1.14.5. Reactions in ionic liquid . . . . . . . . . . . 1.15. Industrial applications and prospects . . . . . . 1.16. Conclusion. . . . . . . . . . . . . . . . . . . . . . 1.17. References . . . . . . . . . . . . . . . . . . . . . .

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17 18 19 20 20 22 23 23 24 29 29 29 32 34 35 35 37 40 40 42 42 43 43 45 45 45

Chapter 2. Fluorous Tags and Phases for Synthesis and Catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jean-Marc VINCENT

57

2.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Structures and properties of fluorous tags and phases . 2.2.1. History of fluorous chemistry . . . . . . . . . . . . . 2.2.2. Fluorous tags. . . . . . . . . . . . . . . . . . . . . . . 2.2.3. Fluorous solvents . . . . . . . . . . . . . . . . . . . . 2.2.4. Solid fluorous phases . . . . . . . . . . . . . . . . . . 2.3. Separation/recycling methodologies using fluorous tags and phases . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.1. Application for catalysis . . . . . . . . . . . . . . . . 2.3.2. Application for synthesis . . . . . . . . . . . . . . .

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57 58 58 59 60 62

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Contents

vii

2.4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

90 90

Chapter 3. Chemistry In and On Water . . . . . . . . . . . . . . . . Marie-Christine SCHERRMANN

99

3.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. Presentation and history. . . . . . . . . . . . . . . . 3.1.2. Position in the context of green chemistry . . . . . 3.2. General: origin of reactivity in and on water . . . . . . 3.2.1. Water structure and properties . . . . . . . . . . . . 3.2.2. Chemistry in water: the hydrophobic effect . . . . 3.2.3. Origin of reactivity on water . . . . . . . . . . . . . 3.3. Limitations of the method . . . . . . . . . . . . . . . . . 3.4. Reactivity in and on water . . . . . . . . . . . . . . . . . 3.4.1. Pericyclic reactions . . . . . . . . . . . . . . . . . . 3.4.2. Addition reactions of carbonyl derivatives . . . . 3.4.3. Coupling reactions catalyzed by transition metals 3.4.4. Radical reactions . . . . . . . . . . . . . . . . . . . . 3.4.5. Oxidation and reduction reactions. . . . . . . . . . 3.5. Multistep syntheses . . . . . . . . . . . . . . . . . . . . . 3.6. Industrial applications . . . . . . . . . . . . . . . . . . . 3.7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . 3.8. References . . . . . . . . . . . . . . . . . . . . . . . . . .

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99 99 100 100 100 102 106 107 107 107 121 127 135 136 142 143 144 145

Chapter 4. Solvent-free Chemistry . . . . . . . . . . . . . . . . . . . Thomas-Xavier MÉTRO, Xavier BANTREIL, Jean MARTINEZ and Frédéric LAMATY

169

4.1. Introduction . . . . . . . . . . . . . . . . . . . . . 4.2. General information on solvent-free synthesis: why use a solvent? . . . . . . . . . . . . . . . . . . . . 4.3. Working without solvents . . . . . . . . . . . . . 4.4. Limitations of the technique . . . . . . . . . . . 4.5. In practice: methods and reactivity . . . . . . . 4.5.1. Methods and equipment. . . . . . . . . . . . 4.5.2. Examples . . . . . . . . . . . . . . . . . . . . 4.5.3. Scaling up: industrial applications . . . . . 4.6. Mortar and pestle . . . . . . . . . . . . . . . . . . 4.6.1. Methods and equipment. . . . . . . . . . . . 4.6.2. Examples . . . . . . . . . . . . . . . . . . . . 4.6.3. Scaling up: industrial applications . . . . . 4.7. Ball-mills . . . . . . . . . . . . . . . . . . . . . . .

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Biphasic Chemistry and The Solvent Case

4.7.1. Methods and equipment . . . . . . . 4.7.2. Examples . . . . . . . . . . . . . . . . 4.7.3. Scaling up: industrial applications . 4.8. Extruders . . . . . . . . . . . . . . . . . . 4.8.1. Methods and equipment . . . . . . . 4.8.2. Examples . . . . . . . . . . . . . . . . 4.9. Microwave irradiation. . . . . . . . . . . 4.9.1. Methods and equipment . . . . . . . 4.9.2. Examples . . . . . . . . . . . . . . . . 4.9.3. Scaling up: industrial applications . 4.10. Photochemistry . . . . . . . . . . . . . . 4.10.1. Methods and equipment . . . . . . 4.10.2. Examples . . . . . . . . . . . . . . . 4.10.3. Scaling up: industrial applications 4.11. Comparison of techniques . . . . . . . 4.12. Conclusion. . . . . . . . . . . . . . . . . 4.13. References . . . . . . . . . . . . . . . . .

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178 180 185 190 190 191 192 192 194 196 198 198 199 201 204 206 206

List of Authors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

217

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

219

1 Solid-phase Supported Chemistry

1.1. Introduction Since Merrifield’s pioneering work in solid-phase peptide synthesis, which won him the Nobel Prize in 1963, supported organic synthesis has enjoyed constant popularity and development. The solid phase was first applied to the oligomeric synthesis of natural products such as polypeptides, polysaccharides and oligonucleotides. It was the work of Fréchet and Leznoff in the late 1970s that initiated its use in the synthesis of small molecules by performing organic reactions in which a substrate, reagent or catalyst was grafted onto an insoluble solid polymer. Another application is the purification of reaction mixtures by trapping agents attached to solid supports: scavengers. A significant number and diversity of organic reactions have been successfully transferred to the solid phase and were the beginning of the development of combinatorial synthesis in the 1990s and then parallel synthesis. Solid-phase chemistry limits the use of toxic, flammable solvents, thus reducing their production and elimination, since it simplifies the purification steps to simple solid/liquid filtration. The polymer is recyclable, which reduces waste. Chemical syntheses are less dangerous and harmful due to the high chemical and physical stability of the substrates. Microwave, ultrasound and high pressure activations

Chapter written by Géraldine GOUHIER.

Biphasic Chemistry and The Solvent Case,First Edition. Edited by Jean-Philippe Goddard, Max Malacria and Cyril Ollivier. © ISTE Ltd 2020. Published by ISTE Ltd and John Wiley & Sons, Inc.

2

Biphasic Chemistry and The Solvent Case

and the positive influence of green solvents, such as ionic liquids, have been demonstrated. Finally, the toxicity or volatility of the grafted compounds is minimal, which helps to prevent accidents, diseases, explosions and fires. For all these reasons, solid-phase chemistry has found its place in the concept of green chemistry. 1.2. Principle of solid-phase chemistry When a reagent is attached to a polymer, the process is usually a single step. Reagents in solution A and B react with the supported entity, which may be, for example, a catalyst (Figure 1.1 and section 1.12). The resulting AB compound is isolated in the filtrate by simply filtering the regenerated polymer.

Figure 1.1. Use of a supported reagent

When a supported trapping agent (section 1.12.3) is used, excess reagents or unwanted by-products (denoted C) present in the reaction medium are fixed to the solid phase and then removed by simple filtration (Figure 1.2).

Figure 1.2. Using a scavenger

Solid-phase Supported Chemistry

3

The use of a supported substrate requires prior functionalization and a succession of filtration (Figure 1.3). The first step involves grafting of a functionalized spacer arm (called linkers, section 1.10.2) of variable length onto the polymer, then incorporating a substrate (denoted A) at its end. As this grafted polymer is generally solid and insoluble in all solvents, the residual compound A is removed by simple filtration and washing. In order to obtain quantitative conversions, reactions can be repeated. This is usually necessary for processing large quantities. This grafted polymer is then used in conventional chemical reactions. Thus, a substrate (denoted B) reacts on the supported active site A to form the compound AB. The reaction by-products and residual reagent present in the filtrate (liquid phase) are removed by simple filtration. The polymer (AB) is thus purified and then the bond between the spacer arm (linker) and the AB molecule is broken (cleavage) by the action of a reagent C (often an acid). This cleavage step can, in some cases, also be a chemical transformation step (e.g. cyclization). The AB molecule is thus obtained with high purity and the initial polymer is regenerated.

Figure 1.3. General diagram of solid phase synthesis

4

Biphasic Chemistry and The Solvent Case

1.3. Advantages Many advantages have contributed to the use of polymers in organic synthesis and justify the green chemistry name: – simplification of product isolation and purification steps. The resin is separated from the liquid phase by simple filtration, thus avoiding separation problems (chromatography, distillation, crystallization, etc.). This saves a lot of time and energy; – possible use of excess reagents. The yields are then optimized without increasing the reaction treatment; the excess remains in the liquid phase and is therefore easily removable and recyclable. In addition, each step can be repeated for maximum performance; – polymer regeneration by simple washing and filtration; particularly useful in the case of expensive chiral substrates or delicate synthetic substrates; – remarkable reduction in toxicity and odors due to the nonvolatility of the grafted molecules, particularly desirable in the chemistry of sulfur, selenium or tin; – strong stabilization of the supports, allowing reactions to proceed under a wide range of reaction conditions (temperature, acidobasicity, etc.) without physicochemical degradation of the polymer. Moreover, resins rarely require special storage conditions (refrigeration, inert gas), which also simplify their handling; – intramolecular cyclization facilitated by pseudodilution (section 1.9.9) due to the heterogeneous medium (solid/liquid) reducing direct contact between reaction sites; – automation of multistep reactions possible and use in combinatorial chemistry and parallel synthesis allowing the rapid development of libraries of potentially active molecules with several thousand analogues (section 1.13.2). 1.4. Safety and environment The use of solid phase in a synthesis strategy reduces the risk of intoxication and contamination since direct contact with the

Solid-phase Supported Chemistry

5

compounds by air and skin is avoided. The remarkable stability of these supports avoids drastic storage conditions that are costly in terms of energy (low temperature) and the use of inert gas. Finally, the purification steps are reduced to simple filtration and washing, thus avoiding long chromatographies that consume flammable toxic solvents or costly distillations. Safety is therefore improved and environmental risks and costs are reduced. 1.5. Disadvantages and limitations This technique, although very practical and effective, has some limitations: – two additional steps are required compared to solution synthesis (grafting and cleavage). These steps must not generate by-products. However, they can be integrated into the synthesis strategy (traceless linker, section 1.13.2); – significant volumes of solvents are required during washing for the large-scale production of a product. However, they remain lower than those used for chromatographic column purification; – the ratio of atoms used to atoms engaged is not optimal. Indeed, the functionalization of the resins used may be low and, consequently, a large amount of polymer must be used. The atom economy principle is far from being respected here. However, the medium is recycled during the synthesis; – the adaptation of organic reactions to solid-phase synthesis generally requires further development because the reactivity of supported substrates may, in some cases, be different (diffusion and site accessibility issues, section 1.9.5). In addition, the bonds with the polymer must be sufficiently stable with respect to all reagents used; – reaction monitoring and/or solid support analyses (quantification of loading and determination of the structure of the grafted product) are more time consuming (section 1.11).

6

Biphasic Chemistry and The Solvent Case

1.6. Evolution Solid-phase chemistry underwent significant development in the 1990s with the advent of automation and combinatorial chemistry. Fifteen years later, this synthesis strategy refocused on the development of parallel synthesis in order to produce smaller targeted libraries. A wide range of supported scavengers, or catalysts, as well as a wide range of synthesis, extraction and purification automatons are now commercially available. Finally, the transfer to the solid phase of new methodologies, reagents and concepts developed in solution is necessary for the development of pharmaceutical and agrochemical industries that use these synthetic tools for the production and screening of innovative chemical libraries. 1.7. Supports: linear skeletons Linear skeleton polymers are soluble in certain organic solvents, thus allowing reactions to be carried out in a homogeneous medium without diffusion problems, with equal accessibility of all supported reaction sites and kinetics similar to the same reaction under conventional conditions. In addition, immobilized substrates can be characterized by standard analytical techniques. Finally, precipitation by adding a non-solvent to the polymer makes it possible to filter it. However, it is not always complete and selective, sometimes causing separation and purification issues. The most commonly used linear polymers in organic synthesis are polyethylene glycol (PEG) 1, monomethyl ether polyethylene glycol (MPEG) 2 and linear polystyrene (PSl) 3 (Figure 1.4). H

O PEG

O x

H

Me

O

O x

H

MPEG Figure 1.4. Soluble polymer structures

Ph

x PSl

Solid-phase Supported Chemistry

7

The molecular weight of PEGs is generally 20,000, so the number of grafting sites is very low (around 0.1 meq./g). PEGs precipitate in diethyl ether or tert-butylmethyl ether, but since these solvents are not very polar, impurities that are too polar sometimes precipitate with the polymer. The use of isopropanol helps to overcome this disadvantage. On the other hand, due to their insolubility at low temperatures in THF and their chelating potential for metal cations, PEGs are excluded from organometallic chemistry. In this case, the PSls are chosen. In addition, the latter can be functionalized at a rate higher than PEGs (up to 6 or 7 meq./g). However, too much functionalization can lead to intrapolymeric secondary reactions resulting in undesirable and irreversible cross-linking that modifies the structure and therefore the reactivity of the resin (section 1.9.10). 1.8. Three-dimensional resins Three-dimensional skeleton polymers are in the form of small beads and are insoluble in almost all solvents. These are cross-linked polymers generally derived from polystyrene. Their cross-linking rate is an important characteristic leading to very different physical properties depending on its degree (section 1.9.4). Two subgroups can be distinguished, macroporous resins and gel resins. 1.8.1. Macroporous resins These are characterized by a high rate of cross-linking (≥20%). As this cross-linking is not homogeneous, polymers have permanent pores of different sizes. The largest cavities (about 0.1 μm) are accessible by the molecules in solution without diffusion issues. This high cross-linking considerably limits the mobility and accessibility of reaction sites; therefore, high grafting rates can be achieved without fear of possible interpolymeric interactions between supported sites (section 1.9.10). The reaction sites are distributed over the surface of the pores and are therefore accessible. The reactivity of these polymers does not depend on their swelling in solvents because it is a surface reactivity inside the pores (>500 m2/g). They are therefore

8

Biphasic Chemistry and The Solvent Case

interesting supports for reactions developing very polar, even ionic intermediates. However, these resins are physically very fragile and prolonged agitation in a reactor or high temperatures can cause irreversible damage. Therefore, they are often used for solid–liquid extraction (SPE: solid-phase extraction) due to the presence of supported trapping agents (section 1.12.3) or as ion exchange resins. Some examples of functionalized macroporous polystyrenes (MPs) are illustrated in Figure 1.5. 2

NEt3,(CO3)1/2 MP-Carbonate

HN NH2 S O

OH NH2 MP-NH2

S O O MP-TsOH

O MP-TsNHNH2

Figure 1.5. Functionalized macroporous polystyrenes

MP-carbonate resin is chosen to trap amine hydrochlorides, carboxylic acids or phenols. The MP-NH2 polymer is a trapping agent for electrophiles such as acids and sulfonyl chlorides or isocyanates. Para-toluenesulfonic acid grafted onto MP, MP-TsOH, marketed as Amberlyst A-15, is generally used as a trapping agent for basic species and particularly amines. The supported hydrazines, MP-TsNHNH2, trap ketones and aldehydes. 1.8.2. Gel resins These are weakly cross-linked polymers (0.5–2%). The crosslinking rate is an important characteristic that leads to polymers with different physical properties depending on their degrees (section 1.9.4). Styrene and its functionalized derivatives are monovinyl compounds generally used to form the skeleton of gel resins. Paradivinylbenzene (DVB) is the most common bifunctional monomer used to create low cross-linking within the matrix. For example, Merrifield (chloromethylated) resin is obtained either by copolymerization of styrene, DVB and para-chloromethylstyrene, or

Solid-phase Supported Chemistry

9

by functionalization of polystyrene by a Friedel–Craft reaction (Figure 1.6).

Figure 1.6. Two ways of synthesizing Merrifield polymer

The control and reproductibility of polymerization reactions require specific know-how. These reactions allow the preparation of highly functionalized polymers (rate higher than 50%); however, all the sites created are not accessible because they are enclosed in the polymeric mesh. Organic chemists generally directly functionalize the previously formed polystyrene skeleton. However, this method has drawbacks. Firstly, because of the accessibility of the reaction sites being lower than in the homogeneous phase, due to the size of the matrix, the reactivity is reduced. It is therefore important to use solvents that allow the resin to swell optimally (section 1.9.2). Secondly, at the end of the reaction, it is impossible to purify the polymer. Therefore, the functionalization reactions of the substrate must be quantitative and chemoselective in order to avoid the presence of undesirable sites. Finally, this method allows access to maximum functionalization rates of 30%; however, in this case, all the sites created are actually active. As this second approach has been widely used, many reactions meet these criteria and this method is therefore the most commonly used. Since the early 1980s, Fréchet et al. have been developing various functionalizations of polystyrene (Figure 1.7).

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Biphasic Chemistry and The Solvent Case

Figure 1.7. Functionalization of polystyrene

1.9. Characteristics of gel supports 1.9.1. Functionalization rate The functionalization or loading rate is an important parameter. It determines the number of functionalized benzene rings in relation to the total number of aromatic rings of the polymer. For example, in the case of Merrifield resin (Figure 1.6), this parameter is expressed as the percentage by weight of chlorine (%Cl) or as the number of milliequivalents of chlorine per gram of resin (nCl). The correspondence between these different units is shown in Table 1.1. nCl (mmol/g)

0.8

2.1

4.3

%Cl

2.84%

7.46%

15.27%

Functionalization rate

9%

32%

56%

Table 1.1. Variation in the functionalization rate of Merrifield polymer

1.9.2. Swelling properties The resins can, in suitable solvents, swell up to 10 times their dry volume. This property limits the diffusion issues of the reagents

Solid-phase Supported Chemistry

11

present in solution and increases the accessibility of the supported reaction sites. If the reaction solvent does not allow the polymeric mesh to expand, the mobility of the chains and the accessibility of the reaction sites are greatly reduced. As a result, the reactivity of the resin is limited and the conversion rate and reaction rate may be lower. The swelling of a polymer in a given solvent is very strongly dependent on its cross-linking, loading and functionalization. The lower the cross-linking, the better the polymer’s swelling properties. In general, polar solvents do not promote mesh expansion and the addition of a suitable co-solvent improves the swelling of the polymer (Table 1.2). Solvents

-

Water

MeOH

MeCN

DMSO

THF/Water

Et2O

THF

Vpolymer (mL.g–1)

1.5

1.5

1.8

1.8

1.8

3.1

3.3

7.7

Table 1.2. Swelling volumes for Merrifield resin 1% DVB

In the absence of a solvent, the volume of the polymer is minimal because the chains are entangled and the pores are not expanded, while in the presence of a suitable solvent, the solvation of the chains causes the mesh to expand and the pores to be reconstituted (Figure 1.8).

Figure 1.8. Evolution of polymeric meshes in a solvent. For a color version of this figure, see www.iste.co.uk/malacria/biphasic.zip

The chains then become mobile, varying the volume and site of the pores. Consequently, when the diffusion issues of non-grafted

12

Biphasic Chemistry and The Solvent Case

reagents are overcome by a good swelling of the resin, the reactivity of polymer gels tends to approach the homogeneous phase conditions. 1.9.3. Size of the beads During their formation by suspension polymerization, polymers form beads of sizes ranging from 50 µm to 1 mm in diameter. To ensure a homogeneous reactivity of the resins, the beads are sieved and grouped according to their size. The analysis of these homogeneous batches makes it possible to determine the number of active sites carried by a single bead (Table 1.3). Size of the beads(µm) 35–75 (200–400 mesh) 75–150 (100–200 mesh) 75–150 (100–200 mesh) 150–300 (50–100 mesh) 150–300 (50–100 mesh)

Functionalization rate (meq./g)

Beads (mg)

Loading a bead (nmol)

1.0

8,000– 16,000

0.06–0.12

1.0

1,000–2,000

0.5–1.0

2.0

1,000–2,000

1.0–2.0

2.0

125–250

8–16

4.0

125–250

16–32

Table 1.3. Influence of bead size

The number of meshes corresponds to the mesh size of the sieve. As the size of the beads decreases, the finer the sieve is and the higher the number of meshes. On the one hand, the size of the beads increases as loading increases. On the other hand, for the same loading, the more the size of the beads decreases, the more the number of active sites per bead decreases. 1.9.4. Influence of cross-linking on swelling The swelling (measured in mL/g) of Merrifield resin, cross-linked at 1% or 2% DVB, was compared in four solvents (Table 1.4).

Solid-phase Supported Chemistry

Solvent

MeOH

Ether

DCM

THF

V1% DVB (mL/g)

1.8

3.3

7.4

7.7

V2% DVB (mL/g)

1.6

2.5

5.2

5.9

13

Table 1.4. Influence of cross-linking on swelling

The lower the percentage of DVB, the better the swelling properties of the polymer. Pore size is therefore inversely proportional to the rate of cross-linking. 1.9.5. Diffusion effect Reactions on solid supports are often compared to those performed in solution. However, this analogy is not always obvious to establish because a heterogeneous system brings additional parameters that do not have an equivalence in the homogeneous phase. First of all, the kinetics of reactions are difficult to set in equation. Indeed, electronic or steric interactions between the polystyrene backbone and the substrate in solution can significantly affect the concentration of the reagent in solution in the vicinity of the supported active site. In addition, depending on the nature of the solvent that regulates the swelling of the polymer, the cross-linking of the solid support and the mode of agitation of the reaction medium, diffusion issues of the substrate through the mesh can greatly alter the contact between the two reagents and thus affect the reaction kinetics. 1.9.6. Influence of cross-linking on diffusion Diffusion is dependent on the cross-linking of the threedimensional skeleton. Two supported triphenyl phosphines with 0.5% and 2% cross-linking were tested in a Wittig reaction to convert aldehydes to olefins (Heitz and Michels 1972). It appears that the more cross-linked the polymer (2%), the more restricted the mobility of the sites and the more limited the interactions between sites; the reaction, in this case, is more difficult.

14

Biphasic Chemistry and The Solvent Case

1.9.7. Influence of steric bulk For the same polymer, diffusion is affected by the size of the substrate in solution and by the reaction solvent used. For example, the hydrogenation of alkenes in ethanol catalyzed by a supported Wilkinson catalyst analogue showed that the hydrogenation rate of a cyclic alkene decreased if the size of the ring increased, while this effect is not linear in solution (Grubbs and Kroll 1971). The reaction rate with the supported catalyst can be seven times slower for a cyclic alkene than for a linear disubstituted alkene with the same carbon number. In addition, a series of reactions was carried out in a benzene/ethanol mixture, allowing the mesh to expand. In this condition, the lower the proportion of ethanol (a solvent not very favorable to swelling), the faster the hydrogenation. 1.9.8. Influence of agitation Different agitation techniques were tested in order to obtain, first, a correct diffusion of the substrates in solution and, second, a good homogeneity of reaction on the different polymer beads by an infrared spectroscopy study (section 1.11.4) conducted on each polymer bead and by fluorescence spectroscopy of the filtrate during a condensation reaction (Li and Yan 1997). Thus, it has been demonstrated that orbital or rotational agitation (180°) homogenizes the reactivity of the reaction sites but is not sufficient for good diffusion. Vigorous agitation is therefore necessary (magnetic, 360°, nitrogen bubbling) both for the homogeneity of the reaction and for obtaining good yields. 1.9.9. Proximity and pseudodilution effects The nature of microenvironmental effects is difficult to assess because it depends on many factors. Depending on the characteristics of the polymer backbone (cross-linking rate and grafting rate), the distribution, mobility and nature of the substrates, but also on the solvent used (by playing on the swelling properties), it is possible to observe either a proximity effect of the grafted substrates or a pseudodilution effect (Figure 1.9) (Scott et al. 1977; Crowley and Rapoport 2007; Shi et al. 2007).

Solid-phase Supported Chemistry

Proximity effect

15

Pseudodilution effect

Figure 1.9. Microenvironmental effects

1.9.10. Proximity effect Supported substrates have reduced mobility involving forced proximity that can lead to electronic interactions and influence reaction kinetics. As a result, high loading polymers will be highly subject to this type of interaction. Intrapolymeric reactions are often side reactions that need to be avoided but could be promoted by the forced proximity of the supported reaction sites. A common example of this type of reaction involves benzyl chlorines in Merrifield resin (Figure 1.10). In contact with a reducing agent, such as zinc, or in the presence of a Lewis acid, such as aluminum trichloride, intrapolymeric reactions are observed, favored by proximity effects. An additional cross-linking is then created, modifying the structure of the resin and thus its reactivity (Figure 1.10).

Figure 1.10. Proximity effect: cross-linking

1.9.11. Pseudodilution effect The pseudodilution effect is the opposite of the proximity effect (Scott et al. 1977; Crowley and Rapoport 2007; Shi et al. 2007). It

16

Biphasic Chemistry and The Solvent Case

depends on the distance of the reaction sites from each other. The more a polymer is cross-linked, the more restricted the mobility of sites is and the more difficult the interactions between supported sites are. Similarly, the lower the loading, the further away the sites are from each other and therefore intrapolymeric reactions are limited. This effect can be illustrated by the formation of supported titanocene complexes (Figure 1.11).

Figure 1.11. Proximity and pseudodilution effects

In the presence of a 2% cross-linked polymer, the cyclopentadienyl titanium trichloride complex leads to titanocene with bispolymeric ligands. On the other hand, with the highly cross-linked resin, the complex obtained has only one polymeric ligand. 1.9.12. Availability and costs A very wide choice of variously functionalized resins is commercially available and generally classified according to their specific uses. However, for regular and consistent use, it is preferable to functionalize your own supports from more affordable basic supports (Rink (amino), Merrifield (chlorinated), Wang (alcohol), etc.). Finally, most syntheses allow the solid phase to be recycled, either directly after filtration and washing or after a simple acidobasic treatment. Saving time, energy and solvents with this synthesis strategy is also a financial parameter to be taken into account.

Solid-phase Supported Chemistry

17

1.10. Functionalization of the solid support Before grafting the desired substrate onto a solid support, it is often advisable to introduce a spacer arm and/or linker (Figure 1.12).

Figure 1.12. General diagram of a supported substrate

Indeed, if the active site is grafted directly onto the polymer skeleton, its accessibility, and therefore its reactivity, can be reduced by the sterically hindered matrix. 1.10.1. Spacer arms The introduction of a spacer arm moves the supported reaction site away from the polymeric mesh. It is usually a functionalized linear chain that must be compatible with solvents, allowing the polymer mesh to expand, and chemically inert to the desired reactions (Figure 1.13).

Figure 1.13. Influence of a spacer arm

The spacer arm can also physicochemical properties of the structures swell only in aprotic limiting factor for the chemistry

be introduced to modify the resin. Polymers with polystyrene solvents, which is sometimes a considered. The introduction of

18

Biphasic Chemistry and The Solvent Case

polyethylene glycol arms on the polystyrene skeleton (Figure 1.14) makes the resin compatible with polar solvents. These polystyrene/ DVB/polyethylene glycol (PS-DVB-PEG) copolymers are resins known as “TentaGel”. They allow NMR spectra of 1H and 13C of grafted substrates with good resolutions.

Figure 1.14. Structure of TentaGel polymers

1.10.2. Linkers A linker is a bisfunctional group. One of the two functions allows grafting on the polymer by a chemically stable covalent bond (carboncarbon, ether, thioether, etc.). The second is used to immobilize the substrate to the resin and allows the modified substrate to be cleaved, while resisting chemical transformations (Figure 1.15). Thus, the linker is considered, in part, as a supported protective group.

Figure 1.15. Use of a linker in supported chemistry

It can also modify the reactivity of the substrate by acting as an activating group, or by inducing stereoselectivity of the reaction in asymmetric synthesis. There is a wide variety of linkers adapted to the type of chemistry being considered. Initially developed for peptide synthesis, Wang, Trityl and Rink linkers are the most widely used in organic synthesis (Figure 1.16).

Solid-phase Supported Chemistry

19

Figure 1.16. Structures of Wang, Trityl and Rink resins

1.10.3. Influence of functionalization The swelling of the mesh varies according to the nature of the groups grafted onto the polystyrene skeleton. Table 1.5 illustrates these variations (measured in mL/g) between cross-linked polystyrene (PS-1% DVB) and cross-linked polystyrenes functionalized by polyethylene glycol arms (PS-DVB-PEG) at different rates (nPEG) (Santini et al. 1998). Polystyrene with a non-polar structure has good swelling properties in aprotic solvents, while protic polar solvents cause almost no mesh expansion. TentaGel PS-DVB-PEG resins consist of an apolar skeleton and protic polar grafts. Water, methanol and ethanol allow, for these resins, a correct expansion of the chains. Solvents Water V PS– 1%DVB (mL/g) V PS-

MeOH

EtOH

DCM Toluene DMF

MeCN

THF

Ether

1.6

1.7

8.3

8.5

5.6

3.2

8.8

4.0

4.2

4.2

2.1

5.1

5.3

5.4

5.1

5.8

1.9

3.1

3.6

3.5

5.7

4.1

4.6

3.9

4.2

2.4

DVB-PEG

(mL/g) nPEG = 0.3 mmol/g V PSDVB-PEG

(mL/g) nPEG = 0.6 mmol/g

Table 1.5. Influence of functionalization on swelling

20

Biphasic Chemistry and The Solvent Case

Therefore, during multistage functionalization on solid substrates, the choice of solvent is variable and influenced, on the one hand, by the structure of the polymer backbone itself and, on the other hand, by the nature of the grafted groups. 1.11. Analytical methods and reaction monitoring Methods of analysis and reaction monitoring of supported organic chemistry have long been insufficient, particularly for insoluble threedimensional polymers. Some classical techniques are adapted to the solid phase (elemental analysis, infrared spectroscopy, assays, colorimetric tests). However, not all these methods are quantitative and generally provide little structural information. The rise of solid phase synthesis has therefore required the development of new technologies adapted to the direct analysis of insoluble polymers. The appearance and development of specialized equipment now makes it possible to carry out direct structural analysis of resins. These high-tech devices provide access to direct supported reaction monitoring, solid phase step performance, and better understanding of secondary or side reactions that may occur within the polymer. Other techniques, such as infrared microspectroscopy, magic-angle spinning NMR spectrometry (MAS-NMR) or matrix-assisted laser desorption ionization, time-of-flight (MALDI-TOF) mass spectrometry, can quickly and efficiently analyze solid media, but these devices are less readily available. 1.11.1. Centesimal analyses Given the mass importance of the polymeric skeleton, the percentages of carbon or hydrogen do not provide much information. In addition, the oxygen dosage is very sensitive to the presence of water and air, making its accuracy sometimes questionable. It is therefore because of the presence of heteroatoms that centesimal analysis makes it possible to calculate yields. As an example, in the case where group A, containing the heteroatom a (or the heteroatom a, itself), is substituted by a molecule B with a heteroatom b, the

Solid-phase Supported Chemistry

21

conversion ratio τ is evaluated using the following equations (Figure 1.17): τ=

nb n b max

×100

where n b max = and n a =

na 1 + n [ MM(A) − MM(B) ] a

and n b =

%b /100 MA(b) /1, 000

%a /100 MA(a) / 1,000

where: – na and nb are the number of equivalent atoms a and b per gram, respectively (in mol/g) ; – nbmax is the theoretical maximum number of milliequivalents of b expected at the end of the reaction; – MM(A) and MM(B) are the molecular weights of the groups A and B, respectively (in g/mol); – MA(a) and MA(b) are the atomic mass of elements a and b, respectively (in g/mol); – %a and %b are the mass percentage in a and b, respectively, given by the elemental analysis.

Figure 1.17. Elemental analysis: examples of reactions

In the case where substrate B is grafted onto the already present group A, the yield is simply equal to (nb/na). However, this technique is destructive and requires about 10 mg of resin for the mass

22

Biphasic Chemistry and The Solvent Case

determination of each atom. In addition, this method of analysis is not fast enough for reaction monitoring. 1.11.2. Colorimetric dosages Most of the dosages on supports are performed by back titration. An excess of reagent is stirred with the polymer, then, after filtration, the filtrate titer is measured. 1.11.2.1. Acidobasic assays Acid or basic functions can be determined by acid-base reactions. For instance, it is possible to quantify the nitrogen level by the protonation reaction of a secondary amine supported by hydrochloric acid (Figure 1.18). After filtering the resin, the excess acid is back titrated. Finally, this technique is not destructive since the hydrochlorinated polymer is easily neutralized in the presence of triethylamine to regenerate the starting resin.

Figure 1.18. Acidobasic determination

1.11.2.2. Colorimetric tests Many colorimetric tests have been implemented during the development of peptide syntheses. The Nα-fluorenylmethoxycarbonyl (Fmoc) method has been widely used and has proven its universality and effectiveness. This group is cleaved rapidly under mild conditions in the presence of piperazine in DMF (Figure 1.19). The concentration of N-Fmoc-piperazine is measured at 301 nm (ε = 7,800 M–1⋅cm–1) and reflects the level of supported amino groups.

Solid-phase Supported Chemistry

HN

HN NH

NH

23

+

N

NH2

O

O O

O

301 nm

Figure 1.19. UV dosing of a solid phase

1.11.3. Indirect analyses Solid-phase reactions can also be monitored indirectly by analyzing the reagents in solution. This technique is not destructive and has the advantage of both qualitative and quantitative methods. Moreover, it is only applied for the grafting (disappearance of the substrate) or cleavage (appearance of the product in solution) stages. In addition, it does not provide information on secondary or side reactions that could occur at the polymer level. Another commonly used method is to cleave the resin and then analyze the filtrate. However, this process is destructive for the polymer and is not always fast enough to allow optimal reaction monitoring. In addition, it requires the optimization of the cleavage conditions, which must then be quantitative. Finally, this methodology is not applicable to all synthesis steps because some reaction intermediates are unstable with respect to cleavage conditions. 1.11.4. Infrared spectroscopy Infrared spectroscopy of polymers in potassium bromide (powder or pellets) allows us to observe the appearance or disappearance of vibrations characteristic of a functional group involved in the chemical modification of the resin. Since the polymeric backbone has intense absorption bands, the vibrations of the functional groups grafted onto the matrix are attenuated by the dilution effect. It is therefore wise to realize the spectra by the difference between the functionalized resin and the polymer matrix. This considerably simplifies their analysis and highlights the specific vibrations of the

24

Biphasic Chemistry and The Solvent Case

grafted substrates. However, the absorption bands are not always well resolved and can make it difficult to evaluate the transformations carried out on the resin. In addition, this technique is not very suitable for reaction monitoring, because it requires at least 10 mg of resin that must be washed and dried before a spectrum can be recorded. 1.11.4.1. Infrared microspectroscopy of a resin bead By coupling a microscope to an optical bench, infrared spectra with better resolutions can be obtained from a single flattened bead. This technique makes it possible to reach very low detection thresholds, approximately 100 picomoles (10–10 mol). A study showed that a bead taken from the reaction medium was representative of the entire mass introduced in reaction (Yan et al. 1995). This method is often compared to thin layer chromatography because it is fast and very sensitive. Thus, reaction monitoring is possible by comparing the evolution of the relative intensity of characteristic absorption bands. 1.11.4.2. Near infrared spectroscopy The use of near infrared spectroscopy (NIR) in fine chemistry is increasingly being used through the development of principal component analysis (PCA) equipment and processing software essential for extracting information from spectra (Troy and Tran 2001). The observed bands are wider than in the mid-infrared region and the spectra are much more complex. The solids are analyzed in solution, by diffuse reflection, using an optical fiber directly immersed in the heterogeneous mixture. 1.11.5. Nuclear magnetic resonance spectrometry Conventional NMR spectrometry of 13C, 19F and 31P is a very good tool for reaction monitoring because it uses standard equipment. TentaGel resins, unlike polystyrene gel resins, swell instantly in an almost homogeneous manner and can be easily analyzed by NMR (Luo et al. 2007). Indeed, the grafted substrate is very far from the polymeric matrix, its mobility is comparable to a substrate in homogeneous phase. It is sometimes necessary to prepare, in a

Solid-phase Supported Chemistry

25

homogeneous phase, molecules with a structure similar to that of grafted substrates, in order to facilitate the interpretation of the NMR spectra of resins. Three-dimensional gel polymers (insoluble solids), after swelling in a suitable solvent, have an intermediate appearance between the liquid state and the solid, therefore pseudohomogeneous. It is therefore essential to homogenize the resin samples (50 mg of resin in CDCl3 and 15 min of swelling). 1.11.5.1. Carbon 13 NMR 13

C NMR spectrometry was tested on insoluble three-dimensional cross-linked polystyrene resins; the carbons in the polymeric matrix relax quickly. Indeed, a relaxation delay, D1 of 0.7 s, allows us to obtain well-resolved spectra. In addition, the complete relaxation of the carbons belonging to the grafted species is longer. The signals specific to the polystyrene matrix are between 120 and 140 ppm for aromatics and between 40 and 46 ppm for aliphatic carbons in polymer chains. For example, the synthesis of chiral epoxides grafted on Merrifield resin in the presence of sodium hydride was followed by 13 C NMR spectrometry (Figure 1.20) (Vidal-Ferran et al. 1998).

Figure 1.20. Monitoring of a grafting reaction in 13C NMR

The reaction is completed after 48 h of contact and the polymer spectrum perfectly matches with the benzylated liquid model substrate. In addition, the authors showed that the width of the midheight signals could be refined by recording the spectra at 50°C. Indeed, at 25°C, the width at half height (H1/2) varies from 0.5 to 1.5 ppm, due to the anisotropy of the gel obtained and the low mobility of the chains, while at 50°C the signals become finer. The

26

Biphasic Chemistry and The Solvent Case

further away a carbon is from the matrix, the greater its mobility and the more its signal is resolved and vice versa. Therefore, 13C NMR spectrometry provides information not only on the structure, but also on the mobility of the grafted substrates. 1.11.5.2. Phosphorus 31 NMR 31

P NMR solid-phase spectrometry has been more widely used for peptide or oligonucleotide synthesis. However, only the monitoring of PEG resins is reported. For example, a Horner–Wadworth–Emmons reaction was performed using a phosphoacetamide grafted onto a TentaGel Cbz-threonine resin via a phosphonic ester bond (Figure 1.21) (Johnson and Zhang 1995). With this approach, the formation of the olefin and the release of the product in solution take place in a single step.

Figure 1.21. Follow-up of a

31

P NMR reaction

Monitoring using 31P NMR spectrometry allows us to observe the disappearance of the 24 ppm signal corresponding to the initial polymer and the appearance of two signals corresponding to the expected diester phosphate and the phosphonate monoester monoanion. Thus, the use of 31P NMR spectrometry in this case revealed the existence of a parasitic reaction. 1.11.5.3. Fluorine 19 NMR Since fluorine has a wide spectral range, chemical transformations carried out at positions relatively far from this fluorinated nucleus

Solid-phase Supported Chemistry

27

have an impact on its chemical displacement. The use of TentaGel resins for solid phase reaction monitoring was developed in 1996. The use of conventional 19F NMR spectrometry for cross-linked threedimensional insoluble polystyrene resins was first reported in 2003. In both cases, fluorinated linkers were used as markers. For instance, a monitoring and optimization of a multistep synthesis is described in Figure 1.22 (Hourdin et al. 2005). Thus, the spectrum obtained during cleavage of an aromatic methoxy group presents two distinct signals, one at –136.0 ppm corresponding to the methoxylated substrate, the other at –140.5 ppm attributed to phenolic fluorine, respectively 40:60 (Figure 1.22, spectrum A). A second sample of the polymer collected after 16 hours of reaction showed that 90% of the methoxyl groups had been cleaved (Figure 1.22, spectrum B). The reaction was quantitative after 24 hours of heating. A significant increase in signal width was observed, probably due to the creation of a hydrogen bond between fluorine and acid proton of phenol. The resolution of the signal is therefore dependent on the chemical environment of the 19F nucleus. The grafting of a chiral amine by Mitsunobu reaction modifies the signal at –135 ppm. It then appears as a poorly resolved doublet due to the presence of the nitrogen protecting group, which has two rotamer forms. Finally, after cleavage of the carbamate, the chemical displacement remains unchanged but refines into a singlet, highlighting the limits of this technique. 19

F NMR spectrometry typically makes it possible to monitor reactions on an insoluble solid support in a few minutes. It is a quantitative analysis tool to evaluate the conversion rate of the reaction. However, it has limitations because the fluorinated “marker” must not be too far from the reaction site (maximum five to six bonds).

28

Biphasic Chemistry and The Solvent Case

Figure 1.22. 19F NMR reaction monitoring

1.11.5.4. Magic-angle NMR Solids, even in the gel form, are media with anisotropic physicochemical properties. As a result, the magnetic field undergoes a discontinuity at the interface between the polymer bead and the solvent that allows swelling. This is why the signals obtained in gel NMR are wider and the spectra area less well resolved than for soluble substrates. The rotation of the sample around an axis inclined to the magnetic field compensates this inhomogeneity and consequently improves the quality of the spectra, the sensitivity of the nuclei and reduces the acquisition time. This angle has been nicknamed the magic angle and is equal to half the tetrahedral angle or 54.7°. Standard probes can be equipped with a magic angle rotation system, but there are also probes designed with materials specially adapted for high resolution called nanoprobes.

Solid-phase Supported Chemistry

29

Magic angle NMR improves resolution and increases signal sensitivity, making it possible, for example, to visualize quaternary carbons and thus to perform structural analysis of solid supports. It is a technique that is being increasingly used, but which requires specific equipment and requires particular expertise. NMR analysis of 13C is also useful for determining the grafting rate of the polymer (Hany et al. 2001). 1.11.6. Mass spectrometry MALDI-TOF technique is a soft ionization method for determining the molecular weight of the substrate (Aubagnac et al. 2003). The resin beads are exposed, before analysis, to trifluoroacetic acid vapors for acid cleavage linkers to release the substrate. Other techniques involve carrying out this dissociation by photolysis using a photosensitive linker (Gerdes and Waldmann 2003) or by thermal degradation of a benzyl group (Chavez et al. 2003). Mass spectrometry is a very sensitive analytical method, requiring only a small amount of resin. 1.12. Solid-phase syntheses Since the early 1990s, the popularity of supported chemistry has been applied to combinatorial techniques in pharmaceutical and agrochemical research for molecular recognition, catalysis and the “construction” of new molecules. A very large number of organic chemistry reactions have been successfully transposed to solid-phase synthesis. Many reviews trace the different uses of polymers and their applications in synthesis. Some selected examples are reported here to illustrate the use of supported reagents, auxiliaries and chiral catalysts. 1.12.1. Supported reagents The Mitsunobu reaction was, like many others, applied to the solid phase. Triphenylphosphine is then supported on polystyrene, thus avoiding the delicate chromatography step in the presence of

30

Biphasic Chemistry and The Solvent Case

triphenylphosphine oxide (Figure 1.23) (Guino and Hii 2007; Tunoori et al. 2015). The pure ether is then obtained by simply filtering and washing the polymer. The formed by-product remains fixed on the support. The grafting of supported reagents generates good regioselectivities during cyclization reactions giving access to aminooxadiazole derivatives (Figure 1.24) (Yang et al. 2015).

Figure 1.23. Mitsunobu reaction: supported reagent

Figure 1.24. Cyclisation of a supported thiosemicarbazide

1.12.1.1. Supported chiral reagents The principle of deracemization was applied to the solid phase by using a supported chiral proton donor derived from (R)-mandelate (Figure 1.25) (Cavelier et al. 1994).

Solid-phase Supported Chemistry

31

Figure 1.25. Supported enantioselective protonation

Protonation takes place in 30 min and allows one to obtain an excellent enantiomeric excess at −40°C. In solution, no selectivity is observed at this temperature. Finally, the protonant agent is easily recyclable, without reducing asymmetric induction. 1.12.1.2. Supported chiral inductors The advantages of the solid phase are particularly applicable to asymmetric synthesis. A supported chiral inductor can be very easily separated from the reaction medium by simple filtration, then regenerated and recycled. In addition, due to the steric clutter of the polymeric skeleton, the relative rigidity of the mesh and the reduced mobility of the grafted entities, the chiral substrate fixed on the resin can be assimilated to an enzymatic structure and lead to high stereoselectivities. There is a very wide variety of supported chiral inductors. Among the most well known are derivatives of natural alkaloids or amino acids, but also many systems with binaphthyl nuclei and Salen ligands. The first use of a chiral auxiliary on a solid support was described by Leznoff (Figure 1.26). An enantiopure primary amine, derived from natural (S)-alanine, grafted onto Merrifield resin, was used for the preparation of optically active 2-methylcyclohexanone (McArthur et al. 1982; Worster et al. 1982). These results highlight the advantage of the solid phase: higher optical yields than in the liquid phase, ambient temperature favorable to selectivity and possible recycling without loss of diasterelectivity (7% decrease in efficiency).

32

Biphasic Chemistry and The Solvent Case

∗

Amine

NH2

O

H+

O

O

Solid phase Liquid phase Solid phase Liquid phase

Rdt = 87%, ee = 94%

O

N

N

O

1) LDA, 0°C 2) MeI

T

Rdt

ee

20°C

87% 94%

20°C

62% 49%

−78°C

72% 98%

−78°C

58% 85%

Figure 1.26. Use of a supported chiral inductor

1.12.2. Supported chiral catalysts Progress in the study and optimization of chemical and optical yields now makes it possible to match the enantioselectivities obtained in the homogeneous phase. The use of Cinchona alkaloid derivatives and proline is most often reported. 1.12.2.1. Organometallic catalyst The α-substituted pyrrolidine structural unit is widely used in asymmetric synthesis because it leads to good enantioselectivities. The addition of diethylzinc to benzaldehyde in the presence of an aminoalcohol grafted onto polystyrene via a tetrahydropyran linker provides access to an enantiomeric excess of 89% close to that obtained in the homogeneous phase (94%) (Figure 1.27) (Castellnou et al. 2005; Liu and Ellman 2016). O

O

O

O H

2-5% mol.

Ph Ph N Me

OH

OH Et

Et2Zn, 0°C Conversion = 100% ee = 89% Figure 1.27. Supported organometallic catalyst

Solid-phase Supported Chemistry

33

Asymmetric oxidation reactions catalyzed by vanadium complexes have been developed in the presence of hydrogen peroxide as a primary oxidant. Greater activation and selectivity efficiency is observed and can be explained by the positive influence of the ligand and the matrix (Figure 1.28) (Pessoa and Maurya 2016).

Figure 1.28. Supported chiral vanadium complex

1.12.2.2. Organic catalysis Cinchona alkaloids have been widely used in organic catalysis (Figure 1.29). O O 5

O N

H HO

OMe

CO2Me O

N

+ O

10%

CO2Me O

Rdt = 85%, ee = 87%

O

Figure 1.29. Supported organic catalysis

The influence of the spacer arm on induction was investigated during the Michael reaction between 2-carbomethoxyindan-1-one and methyl vinyl ketone (Alvarez et al. 1999). The results obtained with the catalyst comprising a flexible chain with five carbon atoms

34

Biphasic Chemistry and The Solvent Case

constitute the best excess reported in the literature for this reaction, whether in the homogeneous or solid phase. Supported phase transfer catalysts have also been developed during asymmetric alkylation of αamino acids (Thierry et al. 2001). 1.12.3. Scavengers The role of so-called scavenger polymers is to trap by-products, excess reagents and even substrates and thus to facilitate their removal from the reaction medium by simple filtration (Figure 1.2). They do not interfere in the reaction mechanism, but make it possible to avoid the restrictive purification steps. It is therefore the simplest way to use the solid phase because a wide range of scavengers is commercially available: electrophiles, nucleophiles, radical inhibitors and metal couplings (Table 1.6). NCO

SO2-NH-NH2

Amines I and II

Aldehydes Ketones

NH2

Acyl halides

CHO

Amines I

N

N H

NH2

Sulfonyl halides Isocyanates

SO3H

Amines

NEt3+ (CO32-)0,5

Aniline

SO2Cl

Aniline Alcohols

P(Ph)2

Halogenated derivatives

Carboxylic acids Phenol, HOBt

O SH

N H

Halogenated derivatives Alkylating agents

OH

N OH

Titanium Boronic acids

Table 1.6. Examples of scavengers – trapped chemical functions

Solid-phase Supported Chemistry

35

Figure 1.30. Successive use of two scavengers

In general, they are used in excess (3–5 equivalents) and two sequential reactions are sometimes reported. Thus, an excess benzylamine reacts with benzoyl chloride in the presence of supported DIEA to form an amide (Figure 1.30). The hydrochloric acid released is trapped by the nucleophilic scavenger. A second isocyanate-based scavenger extracts the excess amine that can be regenerated by hydrolysis of the urea formed. These trapping/release steps are also called catch and release. 1.13. Innovative applications and processes Many books and journals summarize the possible applications of supported chemistry. A few original examples have been chosen here to illustrate the potential of this methodology. With regard to the development of innovative processes, the advantages of using the solid phase in parallel synthesis will be demonstrated. The effects of microwave, ultrasonic and high-pressure activations, known in the liquid phase, were evaluated for the solid phase. Finally, reactions carried out electrochemically or in the presence of ionic liquid were also tested. 1.13.1. Examples The synthesis of a phalloidine was developed on a solid phase by two intramolecular macrocyclic reactions via peptide synthesis

36

Biphasic Chemistry and The Solvent Case

(Figure 1.31) (Anderson et al. 2016). The final compound is a mixture of two natural and unnatural atropoisomers. Tmse

O

O

O Ns-HN

O

S

N O

N H

O N H

O

N HO

O O

N H

N H

H N OtBu

O

N H

HN

NH

S

O

O

O Ns-HN

O

O

N H

HN O

Tmse

O

O

HN H N OtBu

O

HN

NH

HN O

O

Fmoc

OAllyl

O N

O

O O

NH

S O

O

N H

N H

H N

O

OtBu

Figure 1.31. Supported intramolecular macrocyclizations

The overall efficiency of this supported synthesis, i.e. 18 steps, is 1.3%, i.e. an average of 79% per step, which is comparable to that obtained in solution. Such strategies also provide access to new libraries of biologically active cyclic peptides (Shi et al. 2016). A multistep synthesis described by Schreiber clearly demonstrates the extent of solid-phase chemistry applications (Figure 1.32) (Lee et al. 2000). Indeed, a complex structure with five cycles was obtained in four steps with excellent stereo control of the five chiral centers from a silylated polystyrene by using a multicomponent reaction, an intramolecular Diels–Alder reaction, a bis-allylation and finally a cycle opening and closing by metathesis.

Solid-phase Supported Chemistry

37

NHFmoc HO Pri

Si

Si

iPr OTf

Si

1) lutidine

O NH2

2) piperidine CN

OTf

MeOH / THF

3)

H N

HO2C OHC

O

O

N H

HN

O H N

O O

Br

Br

HN

O H

HN

4) KHMDS

O

O

Si H N

O

O

H

Si

H O

O Br

N

O H

O

N

Br

O H N

O

O

Si

N Mes Mes N Cl Ru 5) Cl Ph PCy3

H

N

CH2Cl2, 40°C, 48h Br

OH

O

6) HF-pyridine

N O

O H

O

H N

Br

Figure 1.32. Total supported synthesis

It was therefore possible to obtain a single stereoisomer without any chromatography. 1.13.2. Parallel syntheses on a solid support Synthesis on a solid support is a very practical technique in terms of handling (Gooding 2004). Only sequences of reagent introduction, washing and filtration follow one another. It is therefore easily automated and therefore very well suited for parallel synthesis. The libraries of compounds (chemical libraries) produced in this way are then subjected to automated biological tests. This synthesis technique involves simultaneously carrying out n reactions in n reactors. Unlike

38

Biphasic Chemistry and The Solvent Case

combinatorial chemistry, where mixtures of products are obtained, and where the identification of a biologically active molecule is often difficult, this technique allows the production of compounds isolated from each other, in each reactors. Parallel synthesis can first be useful for optimizing a reaction by varying a parameter in each reactor (the nature of the solvent, the concentration, the temperature or the catalyst, etc.). It can then be used to produce diverse compounds by varying the nature of the reagents (Figure 1.33).

Figure 1.33. Principle of parallel synthesis on solid phase

Many manual, semiautomated or automated automatons dedicated to parallel synthesis are currently on the market. For example, the semiautomated synthesis of five aminobisarynes by the Suzuki reaction is shown in Figure 1.341. The substitution of bromobenzyl with four secondary amines was performed in the presence of an electrophilic scavenger, which traps the hydrobromic acid formed. After automatic filtration of the resin, the filtrate is transferred by cannula into a second series of parallel reactors containing boronic acids and reagents. After the reaction, the reaction media is extracted, then the organic compounds, dried on an LSE cartridge (liquid–solid extraction), transferred to five new reactors, evaporated and then passed on a SEP cartridge (solid extraction phase). Impurities are removed by washing with methanol using a nucleophilic scavenger 1 Argonaut Technologies, application note for QUEST, 2005.

Solid-phase Supported Chemistry

39

that traps the formed amine. The addition of ammonia releases the five amines (catch and release), which are obtained with a purity of 97% and a yield of 67%.

Figure 1.34. Semiautomated parallel synthesis

Nicolaou developed six chemistry libraries (Irori macrokans) using the structure of 2,2-dimethylbenzopyran, called a scaffold, with four potential diversity sites (Figure 1.35) (Nicolaou et al. 2000a, 2000b, 2000c). The originality of the approach is to use a traceless linker; the trace of the grafting on the solid support disappears after cleavage. The grafting and cleavage steps are therefore optimized because they are quantitative and functional. This concept is perfectly applicable to selenium chemistry, since oxidation of selenium, followed by synelimination, results in its removal from the support and the formation of unsaturation. In addition, the toxicity risks associated with this atom are greatly reduced.

40

Biphasic Chemistry and The Solvent Case

Figure 1.35. Use of a traceless linker by synelimination

Diversification is achieved by modifying the four aromatic positions by glycosylation reactions, addition, annulation and condensation. Thus, from these methodologies, libraries of 10,000 compounds could be developed. A very wide range of linkers is described in the literature. Supported ligands that occur only during the chemical reaction and disappear completely after cleavage are the most requested (Figure 1.36) (Okorochenkov et al. 2015).

Figure 1.36. Supported hydrazone: example of traceless linker. For a color version of this figure, see www.iste.co.uk/malacria/biphasic.zip

1.14. Activation on solid phase 1.14.1. Microwave reactions The use of microwave irradiation in functionalized indole synthesis via alkynylanilide cyclization increases the rate of intramolecular

Solid-phase Supported Chemistry

41

cyclization, decreases reaction time and limits impurity formation (Figure 1.37, Table 1.7) (Dai et al. 2003; Sun and Dai 2006).

Figure 1.37. Intramolecular cyclization under microwave irradiation

Activation

Thermal

Microwave ovens

Temperature

80°C

200°C

Reaction time

5h

10 min

Yield

85%

82%

Purity

75%

99%

Table 1.7. Influence of microwave activation on a reaction

The choice of resin and solvent are important parameters during this activation and can be optimized for the synthesis of a library of molecules (Tullberg et al. 2006). Radical cyclizations are also possible under microwave activation (Figure 1.38). DMF appears to be the solvent of choice by inducing a local concentration effect in the carrier (Akamatsu et al. 2004).

Figure 1.38. Radical reaction under microwave activation

42

Biphasic Chemistry and The Solvent Case

1.14.2. Reactions under high pressure A three-component tandem [4 + 2]/[3 + 2] reaction between an enol ether, nitrostyrene and supported acrylate was carried out in one pot under a pressure of 15 kbar (Figure 1.39) (Kuster and Scheeren 1998).

Figure 1.39. Multicomponent synthesis under high pressure

A total of control and yields ranging from 33 to 52% are reported. Finally, nitroso acetal is released from the Wang resin by a transesterification reaction. The resin does not undergo any modification at this pressure. This activation accelerates the reaction and prevents Lewis acid catalysis. 1.14.3. Reactions under ultrasound Ultrasonic activation was used to graft a diamine linked by a polyethylene glycol (PEG) chain onto a paramagnetic chloromethyl support (Figure 1.40) (Sucholeiki et al. 2001). It facilitates the diffusion of the high molecular weight arm through the matrix and thus increases the rate of substitution. An improvement of 30–40% in the functionalization rate was observed.

Solid-phase Supported Chemistry

43

Figure 1.40. Ultrasonic activation

Ultrasound replaces mechanical agitation and facilitates washing (Perez et al. 2000). This support is obtained by polymerization of styrene around a magnetic core with a high degree of cross-linking, then by polymerization of chloromethylstyrene (1–2% DVB). The polymer is separated, no longer by filtration but by magnetization. The development of this magnetic carrier has made it possible to automate the synthesis and purification by the simple catch and release of polysaccharides (Calin et al. 2013). 1.14.4. Supported electrochemical reactions Indirect electrolysis is described on a solid support using a redox catalyst such as bromide ion as a mediator (Figure 1.41) (Nad and Breinbauer 2004, 2005; Mentel and Breinbauer 2007). Thus, the 2,5dimethoxylation of a furan is described from a platinum anode that oxidizes bromide to bromine, which in turn oxidizes the solid phase. OH O N H

O 4

O

Pt anode O

2

O

NH4+Br-, MeOH

N H

O 4

O

2

O

O

O

LiOH O

O

O

Figure 1.41. Supported electrochemical reaction

A cis/trans mixture, after cleavage and filtering the polymer, is obtained with yields of 63% and purity greater than 97%. 1.14.5. Reactions in ionic liquid The use of ionic liquid in solid-phase synthesis can also provide additional activation. Thus, the coupling of Suzuki-Miyaura was performed in a 1/1 mixture of ionic liquid and DMF (Figure 1.42)

44

Biphasic Chemistry and The Solvent Case

(Revell and Ganesan 2002). The addition of this co-solvent speeds up the reaction and increases the yield. The reaction is not observed in the ionic liquid when used alone. Finally, the ionic liquid and the solid phase are recyclable. I O

1) 5% mol Pd(PPh3)4 bmim BF4 / DMF 110°C, 2h 2) Na2CO3 aq, 110°C, 2h R (HO)2B

R HO

Solvent Time Rdt

DMF 24 h 56%

DMF/LI 2h 74%

3) TFA 5% / CH2Cl2, 1h

Figure 1.42. Supported synthesis in the presence of ionic liquid

Ionic liquids supported on the solid phase are also used as organocatalysts (Figure 1.43) (Li et al. 2008).

Figure 1.43. Supported ionic liquid catalyst

A supported pyrrolidine (cat 1, Figure 1.43) on a chiral ionic liquid allows Michael addition reactions between ketones or aldehydes and nitrostyrene. Yields are quantitative and excellent enantioselectivities and disastereoselectivities are observed in the absence of a solvent. After eight recyclings, the catalyst properties are preserved.

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1.15. Industrial applications and prospects The discovery of new drugs in the pharmaceutical industry requires constant innovation and ever-increasing efficiency. In the 1990s, combinatorial chemistry infiltrated academic and industrial laboratories and the solid phase was used for the synthesis of large libraries. In the 2000s, after enormous investment efforts, combinatorial chemistry had not produced the expected results. Screening libraries with 1,000–10,000 molecules is not a guarantee of success in discovering new active substances. The strategy is now focused on the greater exploration of target molecules, improved synthesis and process optimization. Applications are now oriented toward flow chemistry (Baxendale et al. 2006a, 2006b). This technique uses reagents, catalysts and supported scavengers packaged in ready-to-use columns or cartridges that can be used in parallel or in series and recycled to access libraries of compounds with high purities by simple evaporation of the solvent, thus avoiding long and costly purification processes. 1.16. Conclusion Because of the use of supported reagents and commercial scavengers, solid-phase syntheses are now available to all. The new syntheses developed in the liquid phase are generally transposed in parallel with the solid phase. With the development of new and ever more efficient linkers, the transfer to organometallic chemistry and multicomponent reactions is booming in view of the increasing number of journals and books. However, although present for years in industrial environments, the use of synthetic automatons remains quite marginalized in universities. In any case, the use of solid-phase synthesis is still a current issue for the development of chemical libraries. 1.17. References Ahluwalia, V.K., Aggarwal, R. (2001). Organic Synthesis Special Techniques. Alpha Science, Pangbourne.

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Akamatsu, H., Fukase, K., Kusumoto, S. (2004). Solid-phase synthesis of indol-2-ones by microwave-assisted radical cyclisation. Synlett, 6, 1049– 1053. Akdar, U., Shin, D.-S., Schneider, E., Dordick, J.S., Clark, D.S. (2010). Twostep enzymatic modification of solid-supported bergenin in aqueous and organic media. Tetrahedron Lett., 51, 1220–1225. Al-Obeidi, F., Austin, R.E., Okonya, J.F., Bond, D.R.S. (2003). Microwaveassisted solid-phase synthesis (MASS): Parallel and combinatorial chemical library synthesis. Mini Rev. Med. Chem., 3, 449–460. Alvarez, R., Hourdin, M.-A., Cavé, C., D’angelo, J., Chaminade, P. (1999). New polymer-supported catalysts derived from Cinchona alkaloids: Their use in the asymmetric Michael reaction. Tetrahedron Lett., 40, 7091– 7094. Anderson, M.O., Shelat, A.A., Guy, R.K. (2016). A solid-phase approach to the phallotoxins: Total synthesis of [ala7]-phalloidin. J. Org. Chem., 70, 4578–4584. Aubagnac, J.-L., Enjalbal, C., Subra, G., Bray, A.M., Combarieu, R., Martinez, J. (1998). Application of time-of-flight secondary ion mass spectrometry to in situ monitoring of solid-phase peptide synthesis on the multipin system. J. Mass. Spec., 33, 1094–1103. Banfi, L., Riva, R., Basso, A. (2007). Multicomponent reactions in solidphase synthesis. Curr. Opin. Drug. Discov. Devel., 10, 704–714. Bannwarth, W., Felder, A. (2008). Combinatorial Chemistry. A Pratical Approach. Wiley-VCH, Weinheim. Bannwarth, W., Hinzen, B. (2006). Combinatorial Chemistry. Wiley-VCH, Weinheim. Baudelle, R. (2000). Chimie combinatoire. Techniques de l’ingénieur. The TI reference is P3270v1. Baxendale, I.R., Deeley, J., Griffiths-Jones, C.M., Ley, S.V., Saaby, S., Tranmer, G.K. (2006a). A flow process for the multistep synthesis of the alkaloid natural product oxomaritidine: A new paradigm for molecular assembly. Chem. Commun., 2566–2568. Baxendale, I.R., Ley, S.V., Smith, C.D., Tranmer, G.K. (2006b). A flow reactor process for the synthesis of peptides utilizing immobilized reagents, scavengers and catch and release protocols. Chem. Commun., 4835–4837.

Solid-phase Supported Chemistry

47

Blaney, P., Grigg, R., Sridharan, V. (2002). Traceless solid-phase organic synthesis. Chem. Rev., 102, 2607–2624. Bochet, C.G. (2002). Photolabile protecting groups and linkers. J. Chem. Soc., Perkin Trans. 1, 2, 125–142. Bräse, S. (2007). Combinatorial Chemistry on Solid Supports. Topics in Current Chemistry. Springer-Verlag, Berlin-Heidelberg. Bräse, S., Dahmen, S. (2000). Traceless linkers – only disappearing links in solid-phase organic synthesis? Chem. A Eur. J., 6, 1899–1905. Bräse, S., Lauterwasser, F., Ziegert, R.E. (2003). Recent advances in asymmetric C-C and C-heteroatom bond forming reactions using polymer-bound catalysts. Adv. Synth. Catal., 345, 869–929. Buchmeiser, M.R. (2003). Polymeric Materials in Organic Synthesis and Catalysis. Wiley-VCH, Weinheim. Buchmeiser, M.R. (2006). Polymeric Materials in Organic Synthesis and Catalysis. Wiley-VCH, Weinheim. Bunin, A. (1998). The Combinatorial Index B. Academic Press, New York. Burgess, K. (2000). Solid-Phase Organic Synthesis. John Wiley & Sons, Texas A&M University, New York, College Station. Calin, O., Eller, S., Seeberger, P.H. (2013). Automated polysaccharide synthesis: Assembly of a 30mer mannoside. Angew. Chem. Int. Ed., 52, 5862–5865. Carboni, B., Carreaux, F., Pilard, J.-F. (2000). La chimie combinatoire. Actualité Chim., 234, 4–68. Castellnou, D., Fontes, M., Jimeno, C., Font, D., Sola, L., Verdaguer, X., Pericas, M.A. (2005). Polystyrene-supported amino ligands for the heterogeneous asymmetric addition of phenyl zinc reagents to aldehydes. Tetrahedron, 61, 12111–12120. Cavelier, F., Gomez, S., Jacquier, R., Verducci, J. (1994). A first approach to asymmetric protonation via a polymer supported chiral proton donor. Tetrahedron Lett., 35, 2891–2894. Chavez, D., Madrigal, O.D., Castillo, M., Espinoza, K., Gonzalez, T., Velez, E., Melendez, J., Garcia, J.D., Rivero, I.A. (2003). Method for analysis of polymer-supported organic compounds using mass spectrometry direct insertion. J. Comb. Chem., 5, 149–154.

48

Biphasic Chemistry and The Solvent Case

Chorghade, M.S. (2007). Drug Discovery Development. John Wiley & Sons, Hoboken. Cin, M.D., Davalli, S., Marchioro, C., Passarini, M., Perini, O., Provera, S., Zaramella, A. (2002). Analytical methods for the monitoring of solid phase organic synthesis. Il Farmaco, 57, 497–510. Clapham, B., Reger, T.S., Janda, K.D. (2001). Polymer-supported catalysis in synthetic organic chemistry. Tetrahedron, 57, 4637–4662. Comely, C.A., Gibson, S.E. (2001). Tracelessness unmasked: A general linker nomenclature. Angew. Chem. Int. Ed., 40, 1012–1032. Congreve, M.S., Steven, S.V., Scicinski, J.J. (2002). Analytical construct of analysis of solid-phase chemistry. Chem. A Eur. J., 8, 1768–1776. Crowley, J.I., Rapoport, H. (1976). Solid-phase organic synthesis: Novelty or fundamental concept? Acc. Chem. Res., 9, 135–144. Dai, W.-M., Guo, D.-S., Sun, L.-P., Huang, X.-H. (2003). Microwaveassisted solid-phase organic synthesis (MASPOS) as a key step for an indole library construction. Org. Lett., 5, 2919–2922. Dai, W.-M., Shi, J. (2007). Diversity-oriented synthesis and solid-phase organic synthesis under controlled microwave heating. Combinatorial Chem. High Throughput Screening, 10, 837–856. De la Hoz, A., Diaz-Ortiz, A., Moreno, A., Sanchez-Migallon, A., Prieto, P., Carillo, J.R., Vasquez, E., Gomez, V., Herrero, A. (2007). Microwaveassisted reactions in heterocyclic compounds with applications in medicinal and supramolecular chemistry. Comb. Chem. High Throughput Screen., 10, 877–902. Dolle, R.E. (2000). Comprehensive survey of combinatorial library synthesis: 1999. J. Comb. Chem., 2, 383–433. Dolle, R.E. (2001). Comprehensive survey of combinatorial library synthesis: 2000. J. Comb. Chem., 3, 477–517. Dolle, R.E. (2002). Comprehensive survey of combinatorial library synthesis: 2001. J. Comb. Chem., 4, 369–418. Dolle, R.E. (2003). Comprehensive survey of combinatorial library synthesis: 2002. J. Comb. Chem., 5, 693–753. Dolle, R.E. (2004). Comprehensive survey of combinatorial library synthesis: 2003. J. Comb. Chem., 6, 623–679.

Solid-phase Supported Chemistry

49

Dolle, R.E. (2005). Comprehensive survey of combinatorial library synthesis: 2004. J. Comb. Chem., 7, 739–798. Dolle, R.E., Nelson, K.H. (1999). Comprehensive survey of combinatorial library synthesis: 1998. J. Comb. Chem., 1, 235–282. Dolle, R.E., Le Bourdonnec, B., Goodman, A.J., Morales, G.A., Moriarty, K.J., Salvino, J.M. (2006). Comprehensive survey of combinatorial library synthesis: 2005. J. Chem. Comb., 8, 597–635. Dolle, R.E., Le Bourdonnec, B., Morales, G.A., Moriarty, K.J., Salvino, J.M., Zhang, W. (2007). Comprehensive survey of chemical libraries for drug discovery and chemical biology: 2006. J. Chem. Comb., 9, 855–902. Dörwald, F.Z. (2000). Organic Synthesis on Solid Phase. Wiley-VCH, Weinheim. Dörwald, F.Z. (2002). Organic Synthesis on Solid Phase: Support, Linkers, Reactions. Wiley-VCH, Weinheim. Eames, J., Watkinson, M. (2001). Polymeric scavenger reagents in organic synthesis. Eur. J. Org. Chem., 7, 1213–1224. Eifler-Lima, V.L., Graebin, C.S., de Toni Uchoa, F., Duarte, P.D., Correa, A.G. (2010). Highlights in the solid-phase organic synthesis of natural products and analogues. J. Braz. Chem. Soc., 21, 1401–1423. Epton, R. (2004). Innovation and Perspectives in Solid Phase Synthesis & Combinatorial Libraries, Collected Papers. Mayflower Worldwide, Kingswinford. Espinosa, J.F. (2011). High resolution magic angle spinning NMR applied to the analysis of organic compounds bound to solid supports. Current Topics Med. Chem., 11, 74–92. Gerdes, J.M., Waldmann, H. (2003). Direct mass spectrometric monitoring of solid phase organic syntheses. J. Comb. Chem., 5, 814–820. Gooding, O.X. (2004). Process optimization using combinatorial design principles: Parallel synthesis and design of experiment methods. Curr. Opin. Chem. Biol., 8, 297–304. Grubbs, R.H., Kroll, L.C. (1971). Catalytic reduction of olefins with a polymer-supported rhodium(I) catalyst. J. Am. Chem. Soc., 73, 3062– 3063. Gu, Y., Li, G. (2009). Ionic liquids-based catalysis with solids: State of the art. Adv. Synth. Catal., 351, 817–847.

50

Biphasic Chemistry and The Solvent Case

Guiller, F., Orain, D., Bradley, M. (2000). Linkers and cleavage strategies in solid-phase organic synthesis and combinatorial chemistry. Chem. Rev., 100, 2091–2157. Guino, M., Hii, K.K. (2007). Applications of phosphine-functionalised polymers in organic synthesis. Chem. Soc. Rev., 36, 608–617. Hany, R., Rentsch, D., Dhanapal, B., Obrecht, D. (2001). Quantitative determination of resin loading in solid-phase organic synthesis using 13C MAS NMR. J. Comb. Chem., 3, 85–89. Heitz, W., Michels, R. (1972). Polymeric wittig reagents. Angew. Chem. Int. Ed. Engl., 11, 298–299. Hourdin, M., Gouhier, G., Gautier, A., Condamine, E., Piettre, S.R. (2005). Development of cross-linked polystryrene-supported chiral amines featuring a fluorinated linker for gel-phase 19F NMR spectrometry monitoring of reactions. J. Comb. Chem., 7, 285–297. Hulme, C., Lee, Y.-S. (2008). Emerging approaches for the synthesis of bicyclic imidazo-[1,2-x]-heterocycles. Mol. Divers., 12, 1–15. Ilia, G., Iliescu, S., Popa, A. (2015). Polymer-supported phase transfer catalysts in green organic syntheses. Curr. Green Chem., 2, 264–273. Jacob, J. (2012). Microwave assisted reactions in organic chemistry: A review of recent advances. Int. J. Chem., 4, 29–43. Johnson, R.J., Zhang, B. (1995). Solid phase synthesis of alkenes using the Horner-Wadsworth-Emmons. Reaction and monitoring by gel phase 31P NMR. Tetrahedron Lett., 51, 9253–9256. Jung, G. (2008). Combinatorial Chemistry. Synthesis, Analysis, Screening. Wiley-VCH, Weinheim. Kappe, C.O., Stadler, A., Dallinger, D. (2013). Microwaves in Organic and Medical Chemistry. Wiley-VCH, Weinheim. Kennedy, J.P., Williams, L., Bridges, T.M., Daniels, R.N., Weaver, D., Lindsley, C.W. (2008). Application of combinatorial chemistry science on modern drug discovery. J. Comb. Chem., 10, 345–354. Kirschining, A., Monenschein, H., Wittenberg, R. (2000). The “resin-capture – release” hybrid technique: A merger between solid- and solution-phase synthesis. Chem. Eur. J., 6, 4445–4450.

Solid-phase Supported Chemistry

51

Kirschning, A., Monenschein, H., Wittenberg, R. (2001). Functionalized polymers – emerging versatile tools for solution-phase chemistry and automated parallel synthesis. Angew. Chem. Int. Ed., 40, 650–679. Kuster, G.J., Scheeren, H.W. (1998). High pressure promoted tandem [4+2]/[3+2] cycloadditions on the solid phase. Tetrahedron Lett., 39, 3613–3616. Larsen, K., Thygesen, M.B., Guillaumie, F., Willats, W.G.T., Jensen, K.J. (2006). Solid-phase chemical tools for glycobiology. Carbohydr. Res., 341, 1209–1234. Lee, D., Sello, J.K., Schreiber, S.L. (2000). Pairwise use of complexitygenerating reactions in diversity-oriented organic synthesis. Org. Lett., 2, 709–712. Lee, T., Gong, Y.-D. (2012). Solid-phase parallel synthesis of drug-like artificial 2H-benzopyran libraries. Molecules, 17, 5467–5496. Ley, S.V., Baxendale, I.R., Brusotti, G., Caldarelli, M., Massi, A., Nesi, M. (2002). Solid-supported reagents for multi-step organic synthesis: Preparation and application. Il Framaco, 57, 321–330. Li, P., Wang, L., Wang, M., Zhang, Y. (2008). Polymer-immobilized pyrrolidine-based chiral ionic liquids as recyclable organocatalysts for asymmetric Michael additions to nitrostyrenes under solvent-free reaction conditions. Eur. J. Org. Chem., 7, 1157–1160. Li, W., Yan, B. (1997). A direct comparison of the mixing efficiency in solid-phase organic synthesis by single bead IR and fluorescence spectroscopy. Tetrahedron Lett., 38, 6485–6488. Liu, G., Ellman, J.A. (1995). A general solid-phase synthesis strategy for the preparation of 2-pyrrolidinemethanol ligands. J. Org. Chem., 60, 7712– 7713. Luo, J., Pardin, C., Zhu, X.X. (2007). Poly(vinyl alcohol)-graft-poly(ethylen glycol)resins and their use in solid-phase synthesis and supported TEMPO catalysis. Chem. Commun., 21, 2136–2138. Martinez-Ceron, M.C., Giudicessi, S.L., Saavedra, S.L., Gurevich-Messina, J.M., Erra-Balsells, R., Albericio, F., Cascone, O., Camperi, S.A. (2016). Latest advances in OBOC peptide libraries. Improvements in screening strategies and enlarging the family from linear to cyclic libraries. Current Pharm. Biotechnol., 17, 449–457.

52

Biphasic Chemistry and The Solvent Case

McArthur, C.R., Worster, P.M., Jiang, J., Leznoff, C.C. (1982). Polymer supported enantioselective reactions. II. α-Methylation of cyclohexanone. Can. J. Chem., 60, 1836–1841. McGhee, A.M., Procter, D.J. (2006). Radical chemistry on solid support. Topics Curr. Chem., 264, 93–134. Mentel, M., Breinbauer, R. (2007). Electrons as a reagent in solid-phase organic synthesis. Eur. J. Org. Chem., 26, 4283–4292. Mirizzi, D., Pulici, M. (2011). From polymer to small organic molecules: A tight relationship between radical chemistry and solid-phase organic synthesis. Molecules, 16, 3252–3314. Mishra, K.P., Ganju, L., Banerjee, P.K., Sawhney, R.C. (2008). A review of high throughput technology for the screening of natural product. Biomed. Pharmacother., 62, 94–98. Muthyala, M.K., Velisetti, K., Parang, K., Kumar, A. (2014). Advances in functionalized ionic liquids as reagents and scavengers in organic synthesis. Current Org. Chem., 18, 2530–2554. Nad, S., Breinbauer, R. (2004). Electroorganic synthesis on the solid phase using polymer beads as supports. Angew. Chem. Int. Ed., 43, 2297–2299. Nad, S., Breinbauer, R. (2005). Electroorganic synthesis of 2,5-dialkoxydihydrogurans and pyridazines on solid phase using polymer beads as supports. Synthesis, 20, 3654–3665. Nandy, J.P., Prakesch, M., Khadem, S., Reddy, P.T., Sharma, U., Arya, P. (2009). Advances in solution- and solid-phase synthesis toward the generation of natural product-like libraries. Chem. Rev., 109, 1999–2060. Nicolaou, K.C., Pfefferkorn, J.A., Roecker, A.J., Cao, G.-Q., Barluenga, S., Mitchell, H.J. (2000a). Natural product-like combinatorial libraries based on privileged structures. 1. General principles and solid-phase synthesis of benzopyrans. J. Am. Chem. Soc., 122, 9939–9953. Nicolaou, K.C., Pfefferkorn, J.A., Mitchell, H.J., Roecker, A.J., Barluenga, S., Cao, G.-Q., Affleck, R.L., Lillig, J.E. (2000b). Natural product-like combinatorial librairies based on privileged structures. 2. Construction of a 10 000-membered benzopyran library by directed split-and-pool chemistry using nanokans and optical encoding. J. Am. Chem. Soc., 122, 9954–9967.

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Nicolaou, K.C., Pfefferkorn, J.A., Barluenga, S., Mitchell, H.J., Roecker, A.J., Cao, G.-Q. (2000c). Naturel product-like combinatorial libraries based on privileged structures. 3. The “libraries from libraries” principle of diversity enhancement of benzopyran libraries. J. Am. Chem. Soc., 122, 9968–9976. Nielsen, T.E., Schreiber, S.L. (2008). Towards the optimal screening collection. A synthesis strategy. Angew. Chem. Int. Ed., 47, 48–56. Obrecht, D., Villalgordo, J.M. (1998). Solid-Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Librairies. Tetrahedron Organic Chemistry Series, vol. 17. Pergamon, Totowa, NJ. Okorochenkov, S., Burglova, K., Popa, I., Hlavac, J. (2015). Solid-supported hydrazone of 4-(4’-formyl-3’-methoxyphenoxy)butyric acid as a new traceless linker for solid-phase synthesis. Org. Lett., 17, 180–183. Orain, D., Ellard, J., Bradley, M. (2002). Protecting groups in solid-phase organic synthesis. J. Comb. Chem., 4, 1–16. Patil, S., Patil, R., Miller, D.D. (2009). Solid phase synthesis of biologically important indoles. Curr. Med. Chem., 16, 2531–2565. Perez, J.M., Wilhem, E.J., Sucholeiki, I. (2000). The use of power ultrasound coupled with magnetic separation for the solid phase synthesis of compound libraries. Bioorg. Med. Chem. Lett., 10, 171–174. Pessoa, J.C., Maurya, M.R. (2017). Vanadium complexes supported on organic polymers as sustainable systems for catalytic oxidations. Inorg. Chim. Acta, 455, 415–428. Pignatoro, B. (2012). New Strategies in Chemical Synthesis and Catalysis. John Wiley-VCH, Weinheim. Rademann, J., Grotli, M., Meldal, M., Bock, K. (1999). SPOCC: A resin for solid-phase organic chemistry and enzymatic reactions on solid phase. J. Am. Chem. Soc., 121, 5459–5466. Ragozin, E., Redko, B., Tuchinsky, E., Rozovsky, A., Albeck, A., Grynszpan, F., Gellerman, G. (2016). Biolabile peptidyl delivery systems toward sequential drug release. Peptide Sci., 106, 119–132. Reents, R., Jeyaraj, D., Waldmann, H. (2003). Biocatalyzed reactions on polymeric supports: Enzyme-labile linker groups. Polymeric Mat. Org. Syn. Cat., 445–466.

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Revell, J.D., Ganesan, A. (2002). Ionic liquid acceleration of solid-phase Suzuki-Miyaura cross-coupling reactions. Org. Lett., 4, 3071–3073. Salimi, H., Rahimi, A., Pourjavadi, A. (2007). Applications of polymeric reagents in organic synthesis. Monatshefte für Chemie., 138, 363–379. Santini, R., Griffith, M.C., Qi, M. (1998). A measure of solvent effects on swelling of resins for solid phase organic synthesis. Tetrahedron Lett., 39, 8951–8954. Scicinski, J.J., Congreve, M.S., Kay, C., Ley, S.V. (2002). Analytical techniques for small molecule solid phase synthesis. Curr. Med. Chem., 9, 2103–2127. Scott, P. (2009). Linker Strategies in Organic Synthesis. John Wiley & Sons, Chichester. Scott, P., Steel, P.G. (2006). Diversity linker units for solid-phase organic synthesis. Eur. J. Org. Chem., 2251–2268. Scott, L.T., Rebek, J., Ovsyanko, L., Sims, C.L. (1977). Organic chemistry on the solid phase. Site-site interactions on functionalized polystyrene. J. Am. Chem. Soc., 99, 625–626. Seeberger, P.H. (2008). Automated oligosaccharide synthesis. Chem. Soc. Rev., 37, 19–28. Shi, R., Wang, F., Yan, B. (2007). Site-site isolation and site-site interaction – two sides of the same coin. Int. J. Pept. Res. Therapeutics, 13, 213–219. Shi, Y., Teng, T., Sang, P., She, F., Wei, L., Cai, J. (2016). γ−AApeptides: Design, structure, and applications. Acc. Chem. Res., 49, 428–441. Skoda-Foldes, R. (2014). The use of supported acidic ionic liquids in organic synthesis. Molecules, 19, 8840–8884. Solinas, A., Taddei, M. (2007). Solid-supported reagents and catch-andrelease techniques in organic synthesis. Synthesis, 16, 2409–2453. Sucholeiki, I., Perez, J.M., Owens, P.D. (2001). New polyoxyalkyleneaminegrafted paramagnetic supports for solid-phase synthesis and bioapplications. Tetrahedron Lett., 42, 3279–3282. Sun, L.-P., Dai, W.-M. (2006). An engineered linker capable of promoting on-resin reactions for microwave-assisted solid-phase organic synthesis. Angew. Chem. Int. Ed., 45, 7255–7258.

Solid-phase Supported Chemistry

55

Thierry, A., Plaquevent, J.-C., Cahard, D. (2001). New polymer-supported chiral phase-transfer catalysts in the asymmetric synthesis of α-amino acids: The role of a spacer. Tetrahedron, 12, 983–986. Toy, P.H., Yulin, L. (2012). Solid-Phase Organic Synthesis: Concepts, Strategies, and Application. John Wiley & Sons, Hoboken. Trojanowicz, M. (2016). Flow chemistry vs flow analysis. Talanta, 146, 621– 640. Troy, A., Tran, C.D. (2001). Near-infrared spectrometric determination of di and tripeptides synthesized by a combinatorial solid-phase method. Anal. Chem., 73, 1062–1067. Tulla-Puche, J., Albericio, F. (2009). The Power of Functional Resins in Organic Synthesis. Wiley-VCH Verlage GmbH & Co. KGaA, Weinheim. Tullberg, M., Luthman, K., Grotli, M. (2006). Microwave-assisted solidphase synthesis of 2,5-diketopiperazines: Solvent and resin dependence. J. Comb. Chem., 8, 915–922. Tunoori, A.R., Dutta, D., Georg, G.I. (1998). Polymer-bound triphenylphosphine as traceless reagent for Mitsunobu reactions in combinatorial chemistry: Synthesis of aryl ethers from phenols and alcohols. Tetrahedron Lett., 39, 8751–8754. Verma, A., Ram, Y.M., Giridha, R., Prajapati, N., Tripathi, C.A., Saraf, K.S. (2013). Nitrogen containing privileged structures and their solid phase combinatorial synthesis. Comb. Chem. High Throughput Screen., 16, 345–393. Vidal-Ferran, A., Bampos, N., Moyano, A., Pericas, M.A., Riera, A., Sanders, J.K.M. (1998). High catalytic activity of chiral amino alcohol ligands anchored to polystryrene resins. J. Org. Chem., 63, 6309–6318. Worster, P.M., McArthur, C.R., Leznoff, C.C. (1979). Asymmetric synthesis of 2-alkylcyclohexanones on solid phases. Angew. Chem., 18, 221–222. Yan, B., Kumaravel, G., Anjaria, H., Wu, A., Petter, R.C., Jewell, C.F., Wareing, J.R. (1995). Infrared spectrum of a single resin-bead for realtime monitoring of solid-phase reactions. J. Org. Chem., 60, 5736–5738. Yang, S.-J., Choe, J.-H., Abdildinova, A., Gong, Y.-D. (2015). A highly efficient diversification of 2-amino/amido-1,3,4-oxadiozole and 1,3,4thiadiazole derivatives via reagent-based cyclization of thiosemicarbazide intermediate on solid-phase. ACS Comb. Sci., 17, 732–741.

2 Fluorous Tags and Phases for Synthesis and Catalysis

2.1. Introduction The development of more efficient, rapid and environmentally friendly synthesis processes, whether for the production of hightonnage compounds, pharmaceutical compounds or on a laboratory scale, is an important objective of this study. Most research efforts focus on optimizing the activity of existing reagents or catalysts or discovering new reactions. However, in a synthesis process, the purification step should not be neglected, as the isolated product yield and the overall energy cost of synthesis depend strongly on the nature and efficiency of the latter (Curran 1998). Methodologies for easily separating or recycling a catalyst, reagent or by-product from a reaction medium are to be encouraged in the context of sustainable chemistry. Ideally, as far as possible, these methods should make it feasible to avoid chromatographic purifications that consume large amounts of organic solvents, and if possible, distillations, which are costly in terms of energy and can lead to catalyst degradation. The use of liquid (perfluorocarbons [PFCs]) or solid (perfluorinated silicas or Teflon) perfluorinated phases is fully in line with this approach. PFCs, such as n-perfluorohexane (C6F14), are liquids with extreme physicochemical properties. They are chemically inert, non-toxic and

Chapter written by Jean-Marc VINCENT.

Biphasic Chemistry and The Solvent Case,First Edition. Edited by Jean-Philippe Goddard, Max Malacria and Cyril Ollivier. © ISTE Ltd 2020. Published by ISTE Ltd and John Wiley & Sons, Inc.

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are the most non-polar liquids available. They are both hydrophobic and lipophobic, so they form liquid/liquid two-phase systems at room temperature with most organic solvents. The principle of fluorous chemistry consists of increasing the affinity of catalysts, reagents or substrates for liquid or solid perfluorinated phases, i.e. increasing their fluorophilicity. This is achieved by modifying catalysts, reagents or substrates with perfluoroalkyl fragments called fluorous tags (F-tags). As we will see later, fluorous compounds present in a reaction medium can then be easily separated from non-fluorous products by liquid/liquid or solid/liquid separation techniques that are simple to use, fast and effective. 2.2. Structures and properties of fluorous tags and phases 2.2.1. History of fluorous chemistry Although the physicochemical properties (chemical and thermal stability, hydrophobicity, low coefficient of friction, etc.) of perfluorinated polymers, such as Teflon, have been recognized and exploited since the 1950s for various industrial and domestic applications, surprisingly the use of perfluorinated phases for catalysis and synthesis has only recently developed. In 1994, Horváth and Rábai (1994) first described, in the journal Science, the use of a PFC/hydrocarbon (HC) biphasic system to facilitate the separation and recycling of a catalyst. These two researchers, who were then working for Exxon, demonstrated the relevance of their approach by applying it to a very important industrial reaction, alkene hydroformylation. To do this, they have developed a rhodium catalyst that is extremely fluorophilic and therefore soluble only in PFCs. In this founding article, they introduced the term fluorous that would make it possible to define a new field of chemistry. The term fluorous was proposed by analogy with the term aqueous. Their article clearly shows that, in addition to aqueous and organic media, perfluorinated media should be considered for separation and recycling applications. Fluorous chemistry was born. Since this pioneering work, the extensive research carried out in this field has considerably increased the fields of application of fluorochemistry applied to synthesis (Gladysz et al.

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2004b). In this chapter, we will focus on the field of fluorous chemistry with a broad synthetic focus, i.e. the methodologies developed to facilitate the recycling of catalysts and the purification of reaction products. 2.2.2. Fluorous tags In fluorous chemistry, the physicochemical properties of molecules (catalysts, substrates, reagents) whose affinity for fluorous phases will be increased by the presence of mixed alkylperfluoroalkyl chains (-(CH2)n(CF2)mCF3,), known as fluorous tags (F-tags) (Gladysz 2004), are used. The most commonly used perfluoroalkyl moiety is the perfluorooctyl group -(CF2)7CF3 (symbolized by -Rf8). The fluorine atom is the most electronegative element of the periodic table (3.98 on the Pauling scale compared to 2.20 for the hydrogen atom and 2.50 for the carbon atom). The role of the alkyl fragment, known as a spacer, is to isolate the coordinating atom of a ligand or the active center of a reagent from the strong electron-attractor effect of the perfluoroalkyl fragment (Jiao et al. 2002). Spacers with two or three -CH2- are the most commonly used. Ligands, catalysts and fluorous reagents will therefore have the same properties, in terms of affinity for a metal or reactivity, as their non-fluorous analogs. Fluorous compounds are classified into two categories: light fluorous compounds, which generally have only one F-tag, and heavy fluorous compounds modified with at least three F-tags. The light fluorous compounds are lipophilic and weakly fluorophilic. They will be used under the usual conditions of organic synthesis, and will be separated/recycled by elution on fluorous silica gel. Heavy fluorous compounds are generally extremely fluorophilic and lipophobic, and therefore very poorly soluble in conventional organic solvents. In a two-phase liquid/liquid PFC/HC system, these compounds will partition exclusively into PFC, which will allow them to be efficiently recovered by simple decantation. In all cases, fluorous catalysts, reagents and substrates are soluble molecular compounds, therefore easily characterized and whose reactivity is similar to that of their non-fluorinated analog.

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2.2.3. Fluorous solvents Fluorous solvents are used in fluorochemistry to form biphasic or triphasic systems with organic phases. These multiphase systems are used to separate/recycle highly fluorophilic catalysts and reaction products by simple decantation. They can also be used as a vanishing phase in some reactions. Due to the high stability of the C-F bond (CF3-F binding energy of 130.5 kcal/mol compared to 105 kcal/mol for a CH3-H bond) and its low polarizability, these solvents are chemically inert, very thermally stable and non-toxic, making them particularly interesting compounds for applications in industrial environments. The most commonly used solvents are perfluoroalkanes, perfluorinated trialkylamines and perfluorinated ethers/polyethers (Table 2.1) (Gladysz and Emnet 2004, p. 11). Fluorous solvents are very dense and therefore always form the lower phase of two-phase systems with other solvents (density CHCl3 1.492 g/mL). It should also be noted that boiling points (boiling temperature n-octane 126 °C) and surface tensions are significantly lower than those of their hydrogenated analogs, reflecting their low cohesion energy. Solvent

Formula

Boiling point (°C)

Melting point (°C)

Density (g/mL)

Psa

Perfluoro hexane

C6F14

57.1

–90

1.669

0.00 (2.56)

Perfluoro octane

C8F18

103–104

–25

1.766

0.55 (2.86)

Perfluoro methylcyclo hexane

CF3C6F11

76.1

–37

1.787

0.58 (3.34)

Perfluoro decalin

C10F18

142

–10

1.908

0.99 (4.07)

Perfluoro tributylamine

C12F17N

178

–

1.883

0.68 (3.93)

Fluorous Tags and Phases for Synthesis and Catalysis

Perfluoro tripentylamine

C15F33N

212-218

–

1.93

–

Perfluoro-2butyltetrahydrof uran

C8F16O

99-107

–

1.77

–

61

a

Spectral polarity index; the number in brackets corresponds to the Ps of the hydrogenated analog. Table 2.1. Examples of “common” fluorous solvents and some physicochemical characteristics

The main property of perfluorinated solvents used in fluorous chemistry is their very low polarity, which is linked to the very low polarizability of the C-F bond, limiting Van der Waals intermolecular interactions. These are the only solvents that are both hydrophobic and lipophobic. The measurement of polarity is expressed by the spectral polarity index, Ps, determined by studying the solvatochromic properties of fluorophilic dyes. At the end of the hydrophobic and lipophobic scale is perfluorohexane. In comparison, the Ps of isopropanol is 7.85. The other perfluoroalkanes are slightly more polar but remain significantly less polar than their hydrogenated analogs. As a result, PFCs form two-phase systems at room temperature with their HC analogs. On the other hand, by increasing the temperature, a single-phase medium is obtained, while the two-phase system is reformed at room temperature. This thermomorphic property will be used for the separation and recycling of catalysts. Due to the very low cohesion energy of PFCs, the formation of cavities in these solvents, allowing gas dissolution, is much more favorable than for other solvents, particularly water, whose extreme cohesion energy is linked to the three-dimensional network of hydrogen bonds. As a result, PFCs can solubilize larger quantities of gases than organic solvents, and particularly water. For comparison, the solubilities of O2 in perfluoromethylcyclohexane (PFMC), tetrahydrofuran and water are 23.2, 10.0 and ~1 mM, respectively, at 37 °C. This exceptional oxygen solubility has been used for the clinical development of blood substitutes in the form of PFC emulsions. For catalysis or synthesis applications, however, the

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difference in solubility compared to organic solvents is not large enough to expect an increase in reaction rates, when one of the reagents is a gas (O2, H2, CO, etc.). The relative solubility of fluorous compounds in PFCs is an important parameter when considering a liquid/liquid separation of PFC/HC. This relative solubility is expressed by the partition coefficient of the fluorous compound between two liquids, the most commonly used being PFMC and toluene (Table 2.2) (Gladysz et al. 2004a, p. 56). Comparison of the data from inputs 2 and 6 shows that, besides the percentage of fluorine by mass, it is the number of F-tags per molecule that will make a partition very favorable to PFC. Partitions > 99.5: < 0.5 in favor of PFC are preferred in separation/recycling processes by liquid/liquid separation. Solute

Fluorine by mass %

C6F13(CH2)3OH C10F21(CH2)3OH C10F21I

65.32 69.01 61.76

PFMC partition: toluene 44:56 80.5:19.5 94.5:5.5

55.93

40:60

70.61 68.31

>99.7:10 mmol), the ester is recovered pure after settling, without adding toluene. The effectiveness of this methodology has been demonstrated by

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performing 10 reaction cycles (reaction/separation/recycling) on a 10 mmol scale. For each cycle, the isolated ester yield is >99.5%, and 95% of the initial catalyst is recovered after the 10th cycle. The extreme efficiency of the methodology is related to the very low solubility of water in the PFC, which allows the equilibrium to be shifted toward ester formation without using dehydration methods, an excess of alcohol or an acid activation step. This biphasic system is therefore close to an ideal esterification method.

Figure 2.4. Esterification in fluorous biphasic medium (adapted from Xiang et al. 2002)

The potential of fluorous biphasic catalysis for industry has been clearly established by Nishikido et al. (2003) who developed and used a semi-industrial continuous flow process to easily recycle the very expensive solvent and fluorous catalyst. The principle of the continuous flow process is shown in Figure 2.5. The assembly consists of a reactor (mechanical agitator) connected to a decanter that continuously separates the products and recycles the catalyst. Using a semi-industrial pilot assembly (500 mL reactor, introduction of reagents into a 6 L of toluene solution at a rate of 0.967 mL min−1), an acetylation reaction of cyclohexanol (200.32 g, 2 mol) with acetic anhydride (245.02 g, 2.4 mol) catalyzed by a ytterbium (III) complex Yb[N(SO2-n-Rf8)2]3 (2.584 g, 0.83 mmol in solution in 250 ml of a PFC) was carried out at 40 °C continuously for 500 h. Yields were maintained >90% throughout the process, representing ~10,000 catalytic cycles. Very low contamination of cyclohexyl acetate by

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ytterbium (≤2 ppm) was measured, demonstrating the high efficiency of the recycling step.

Figure 2.5. Principle of a semi-industrial continuous flow process for recycling fluorous catalysts (adapted from Yoshida et al. 2003). For a color version of this figure, see www.iste.co.uk/malacria/biphasic.zip

Corrêa da Costa and Gladysz (2006) published very interesting results in 2006 showing that fluorous phases can be used in an innovative way, i.e. not to facilitate the separation of the catalyst, but to activate it. This new concept of catalyst activation by fluorous phase transfer activation has been applied to the metathesis of alkenes. The activation principle is shown in Figure 2.6. Second-generation fluorous Grubbs catalysts have been prepared. Since fluorous phosphines have a high affinity for PFCs, it has been hypothesized

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that they can be effectively sequestered in the fluorous phase, thus activating a non-fluorophilic catalyst essentially present in the organic phase containing the reactants. It has been shown that reaction rates are indeed much faster when performed in the presence of a fluorous solvent. For example, in the presence of perfluoro-2butyltetrahydrofuran, cyclopentene (Figure 2.6) was formed with a yield of 74% in 2 hours, compared to 6% using only DCM.

rt

2.5 mol% CH2Cl2 fluorous solvent

Figure 2.6. Principle of catalyst activation by fluorous phase transfer activation applied to the alkene metathesis (adapted from Corrêa da Costa and Gladysz 2006)

Fluorous ligands are also very useful for carrying out reactions in supercritical fluids, in particular supercritical carbon dioxide (CO2sc). Indeed, fluorous compounds are generally very soluble in these nonpolar environments. For example, using a fluorous phosphine, Koch and Leitner (1998) were able to perform rhodium catalyzed hydroformylation reactions in sCO2 very effectively, while bipyridine (5) was used by Matyjaszewskiand et al. (1999) to perform copper catalyzed atom transfer radical polymerization (ATRP) reactions in sCO2.

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PFCs have also been used as solvents for enzymatic reactions to develop simple purification procedures for biocatalytic processes (Hobbs and Thomas 2007). The liquid/liquid PFC/hexane system is particularly interesting because (1) the enzymes retain their activity in hexane at a rather high temperature (40–60 °C); (2) this solvent combination is biphasic below 20–25 °C but becomes monophasic at slightly higher temperatures. In 2002, Beier and O'Hagan (2002) reported for the first time that fluorous biphasic catalysis could be applied to biocatalysis. Transesterification between esters and fluorous alcohols catalyzed by Candida rugosa lipase (CRL) was performed at 40 °C in a hexane/perfluorohexane monophasic system while the enzyme was used as a heterogeneous catalyst (Figure 2.7). After a conversion of about 50%, the reactions were stopped, the enzyme was removed by filtration and the reaction mixture was cooled to 0 °C, allowing the enantioenriched (R) acid to be recovered in the organic phase, while the fluorous ester (S) was essentially found in perfluorohexane. Interestingly, increased stereoselectivity has been observed compared to previous studies conducted in hexane alone. In addition, it has been shown that this biphasic process can be applied on a preparatory scale. From 6 g racemic acid, 1.97 g (66%) of the acid (S) (ee 96%) was isolated after hydrolysis of the corresponding ester, while 1.81 g (57%) of unreacted acid (R) (ee 79%) was obtained.

Figure 2.7. Kinetic resolution of a racemic acid catalyzed by Candida Rugosa lipase (CRL) using a fluorous biphasic system (adapted from Beier and O'Hagan 2002)

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71

In 2007, Thomas and his collaborators demonstrated that enzymatic reactions could be effectively carried out in a fluorous and completely homogeneous environment using a soluble enzyme. Proteins such as cytochrome c or α-chymotrypsin (CMT) have been effectively transferred from an aqueous phase to PFMC by creating hydrophobic ion pairs using a carboxylate (KDP 4606) and a carboxylic acid (Krytox 157 FSL), both highly fluorophilic (Figure 2.8). Concentrated and clear solutions of proteins in PFC were obtained (up to 20 mg cytochrome c per mL). The transesterifications are then carried out at 40 °C in a completely homogeneous hexane/PFMC solution. At the end of the reaction, lowering the temperature separates the two phases and allows the enzyme to be recycled. It has been shown that under these conditions the enzyme retains its activity during four reaction cycles.

KDP 4606 (mw ~ 1400; n ~ 9)

Krytox 157 FSL (mw ~ 2500; n ~ 17)

Figure 2.8. Structures of carboxylate KDP 4606 and carboxylic acid Krytox 157 FSL

2.3.1.2. Solid/liquid phase separation As PFCs are expensive solvents and present a risk of persistence in the environment due to their extreme chemical stability, many efforts have been made to develop separation methodologies that limit their use. As Curran et al. have shown, molecules modified by a single F-tag known as “light fluorous compounds” are very effectively separated from non-fluorous compounds by fluorous solid-phase extraction (FSPE). Non-fluorous compounds are eluted first typically by using a mixture of MeOH/H2O (10/1) as eluent, while fluorous compounds are eluted with more fluorophilic mobile phases such as pure MeOH.

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Biphasic Chemistry and The Solvent Case

This approach has the advantage of using catalysts containing less fluorine and therefore having a similar solubility in conventional solvents and a reactivity comparable to reference catalysts. In addition, this approach does not require the use of PFCs. Using this methodology, Stuart et al. (2003) were able to thrice recycle the catalyst [Ni{Rf6C(O)CHC(O)Rf6}2] used as a Lewis acid in reactions between β-diketones and ethyl cyanoformate. Matsugi and Curran (2005) prepared the fluorous analogs (10) and (11) of Grubbs– Hoveyda first and second-generation metathesis catalysts. These catalysts have the same reactivity as the original complexes and are used under standard conditions, as shown in the reaction in Figure 2.9, which provides an intermediate in the synthesis of an anti-cancer agent, dictyostatin (Moura-Letts and Curran 2007). The product is easily separated from the catalyst by fluorous silica chromatography by eluting with MeOH/H2O (9/1) and then pure THF to elute the catalyst. After evaporation of the fraction containing the catalyst and subsequent recrystallization, 1.0 g (77%) of (11) could be recovered.

Figure 2.9. Light fluorous Grubbs–Hoveyda metathesis catalysts of first (10) and second (11) generations

Other examples of recycling of light fluorous catalysts by FSPE have been described, in particular for recycling chiral catalysts (Takeuchi and Nakamura 2004).

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73

Adsorption (physisorption) of fluorous catalysts on solid fluorous substrates such as fluorous silica or Teflon is another very interesting strategy for efficient and easy recycling of catalysts under conditions that do not require PFCs. Tzschucke et al. (2002) and Biffis et al. (2003) were, independently, the first to show that fluorous catalysts were effectively adsorbed to the fluorous silica surface. These catalysts can then be used as conventional supported catalysts under heterogeneous conditions, with the advantage of being separable by simple filtration or decantation. This methodology has been applied to Suzuki and Sonogashira couplings catalyzed by fluorous Pd– phosphine complexes (Tzschucke et al. 2002), and to alcohol silylation catalyzed by Rh–carboxylate complexes (Biffis et al. 2003). The supported catalysts retain a high reactivity associated with a low contamination of the final product by the metal (~2%). Matsugi and Curran (2005) showed that these supported catalysts could be desorbed from silica and then re-adsorbed by modifying the polarity of the solvent. For example, the catalyst (11) adsorbed onto the silica, due to its hydrophobic nature, does not desorb when suspended in a MeOH/H2O mixture (8/2). On the other hand, the catalyst is completely desorbed when a more lipophilic solvent such as DCM is used. Metathesis reactions can therefore be performed under homogeneous DCM reflux catalysis conditions in the presence of the “supported” catalyst (5 mol%). After reaction, the DCM is evaporated and the residue returns to MeOH/H2O and is filtered to separate the product from the supported catalyst. The complex thus recovered was reused five times without any sign of loss of activity. With the aim of making this type of recycling even more practical, Dinh and Gladysz (2005) discovered that Teflon, in particular Teflon tapes used in plumbing (Teflon tape) or Gore-Tex-type Teflon fibers, could be used as a fluorous carrier to allow, when necessary, adsorption/desorption of catalysts, while facilitating their handling at low load. When a homogeneous solution of the fluorous rhodium complex (12) (7 mg, 4 mol, 0.15 mol%) in dibutyl ether at 55 °C containing a piece of Teflon tape (50 × 12 mm) is cooled, the complex adsorbs to the surface rather than precipitating. The hydrosilylation of ketones was thus performed using the reaction sequence shown in Figure 2.10. The catalyst adsorbed on Teflon was used for three

74

Biphasic Chemistry and The Solvent Case

reaction cycles without observing a significant decrease in catalytic activity (yields >96% and similar reaction rates). More recently, Siedel and Gladysz (2008) have shown that Teflon fibers (trade name “Gore-Rastex”) are a powerful carrier for this methodology.

Figure 2.10. Recycling of fluorine catalysts by physisorption on Teflon tape. For a color version of this figure, see www.iste.co.uk/malacria/biphasic.zip

Heavy fluorous catalysts, due to their low solubility in conventional organic solvents at room temperature, can be separated from the reaction medium by precipitation and therefore recovered by simple filtration. In addition, the variation in solubility as a function of temperature is very important, which makes it possible to carry out reactions under homogeneous catalysis conditions by heating the reaction medium and to precipitate the catalyst by lowering the temperature. These thermomorphic properties were exploited by Sheldon et al. (1999) to recycle perfluoroheptadecan-9-one (C8F17C(O)C8F17) used as an organic epoxidation catalyst in the presence of H2O2. The reactions are carried out at reflux in an EtOAc/1,2-dichloroethane mixture, cooling the reaction medium in an ice bath, leading to the crystallization of the catalyst that is isolated by filtration with a 92% yield. These thermomorphic properties of fluorous compounds, in particular the large variation in solubility with temperature, were established by Gladysz et al. (Wende et al. 2001; Rocaboy and Gladysz 2002; Wende and Gladysz 2003). For example, a solubility change by a factor ~600 was measured in n-octane between −20°C and 80 °C for phosphine P[(CH2)2(CF2)7CF3]3 (Wende and Gladysz 2003). This type of phosphine was used as an alcohol addition catalyst on methyl propiolate under homogeneous conditions

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75

at 65 °C and recovered by filtration with yields of 90–95% after precipitation at −30 °C (Figure 2.11). Yamamoto et al. (2001, 2002) have also demonstrated the utility of this concept for fluorous acid catalyzed acetylation and aldolization reactions.

Figure 2.11. Thermomorphism of heavy fluorous compounds applied to catalyst recycling (phosphine)

This approach has also been used for the recycling of metal complexes. Contel et al. (2005) carried out oxidation reactions of benzyl alcohols catalyzed by Cu(II)-carboxylate complexes such as (13) in the presence of TEMPO/O2. Using the conditions shown in Figure 2.12, aldehyde conversions >90% were obtained while 85–90% of the catalyst is recovered by filtration.

Figure 2.12. Thermomorphism of heavy fluorous compounds applied to catalyst recycling (copper complex) For a color version of this figure, see www.iste.co.uk/malacria/biphasic.zip

2.3.2. Application for synthesis The development of automated parallel syntheses has grown considerably over the past 20 years and they are now part of the

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current techniques used in research and development laboratories. The advantage of this type of synthesis is to be able to quickly obtain a wide variety of molecules in sufficient quantities and purity to be tested on biological targets, generally by high-throughput screening methods. The rise of these automated techniques is linked to the development of operating modes using “simple”, fast and efficient reaction conditions and purifications that can be performed by robots on small quantities. Reagents, substrates and trapping agents immobilized on solid supports, most often cross-linked polystyrene beads, are by far the most widely used because they allow, in most cases, the purification stage to be reduced to a simple filtration. Nevertheless, chemistry on solid support, due to heterogeneous conditions, has major disadvantages such as longer reaction times and the difficulty of characterizing the grafted products or monitoring the progress of reactions by typical techniques (thin film or gas chromatography, NMR, etc.). The fluorous chemistry applied to synthesis, known as fluorous synthesis, offers a very interesting alternative to chemistry on solid support since it allows the combination of an optimal reactivity in homogeneous condition with the simplicity of the separation step. The potential of fluorous synthesis to facilitate the preparation of synthetic compounds or natural products has been demonstrated by the pioneering work of Curran and Hadida (1996) and Curran (2008). As Wei Zhang (2004) pointed out in a review on fluorous synthesis for heterocyclic preparation, the main characteristics of fluorous synthesis compared to those of traditional solution synthesis or solid phase synthesis are as follows: 1) the reactions are done in homogeneous conditions with optimal kinetics; 2) fluorous molecules can be purified/separated by fluorous or traditional separation techniques (chromatography, distillation, recrystallization, etc.); 3) fluorous reactions can be monitored by traditional analytical methods (CCM, HPLC, IR, NMR);

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4) fluorous tags are chemically stable and have little effect on the reactivity of the molecules on which they are grafted; 5) the solubility of fluorous compounds in organic solvents can be adjusted according to temperature and the amount of fluorine; 6) the use of a large excess of reagent is not necessary to achieve complete reactions; 7) unlike solid-phase supported reagents, several fluorous reagents can be used in the same reaction; 8) adapting the reaction conditions in literature is less problematic than for the supported reagents; 9) fluorous synthesis can be combined with other methods such as microwave reactions, in supercritical CO2 and solid phase synthesis; 10) fluorous compounds can be recovered and reused after separation using a solid or liquid fluorine phase. 2.3.2.1. Light fluorous synthesis 2.3.2.1.1. Substrates and fluorous protecting groups The general principle of light fluorous synthesis is to use, in a synthesis, a substrate or reagent modified by a single F-tag. After reaction, the fluorous product or by-product is separated by solidliquid extraction on fluorous silica (FSPE). The principle of the methodology using fluorous substrates is presented in Figure 2.13. Zhang and Hiu-Tung Chen (2003) have developed a fluorous molecular analog (14) (FluorMarTM) of the Marshall resin (15) widely used in solid phase synthesis, particularly for the preparation of amides. An example of the application of a group of amides to the synthesis is shown in Figure 2.14.

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Figure 2.13. Light fluorous synthesis. For a color version of this figure, see www.iste.co.uk/malacria/biphasic.zip

P

S 15

OH

2

3

19{1,1}, 75%

19{1,2}, 100%

19{1,3}, 70%

19{2,1}, 78%

19{2,2}, 92%

19{2,3}, 62%

1

R1

R2

Figure 2.14. Example of application to the synthesis of a group of amides

Compounds 17{1-2} are prepared under standard conditions in DMF using 2 equivalents of diisipropylcarbodiimide (DIC) and 1 equivalent of (dimethylamino) pyridine (DMAP). They are purified by flash chromatography on non-fluorous silica. The addition of amines (18) leads to the six amides (19) and the release of (14). Separation is carried out by F-SPE, the amides being recovered pure in the MeOH/H2O fraction, while the FluorMar tag (14) is recovered pure in

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the MeOH fraction with a yield of 65–70%. This approach has been successfully used to prepare libraries of heterocyclic compounds such as hydantoins and thiohydantoins (Zhang and Lu 2003), disubstituted pyrimidines (Zhang 2003) or polysubstituted indoles (McCormick et al. 2006). Fluorous protective groups for amine, alcohol or ketone functional groups have also been developed. In addition to the traditional role of protective groups, fluorous derivatives will facilitate the purification of protected molecules. Some representative examples of protective groups are presented in Figure 2.15 (Curran 2001; Luo et al. 2001a, 2001b; Curran and Furukawa 2002; Curran et al. 2003; Curran and Ogoe 2006; Matsugi et al. 2006). These protective groups have the same reactivity as their non-fluorous analogs and allow the protected compounds to be purified very effectively by FSPE. Examples of important applications include the purification of oligonucleotides (up to 100-mers) (de Visser et al. 2003) or synthetic peptides (Pearson et al. 2005).

Figure 2.15. Examples of protective groups

2.3.2.1.2. Fluorous trapping agents In parallel syntheses on solid support, the use of scavengers immobilized on resin is extremely useful to facilitate the elimination of a soluble reagent used in excess. Some examples of fluorous trapping agents are shown in Figure 2.16 (Zhang et al. 2002a, 2003; Werner and Curran 2002; Lu and Zhang 2006).

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For example, thiol Rf6(CH2)2SH has been used to trap excess αbromoketones used in secondary amine alkylation reactions (Figure 2.17). Many amines have thus been obtained after purification by F-SPE with yields between 75% and 95% and purities between 80% and 95% (determined by CPLH).

Figure 2.16. Examples of fluorous trapping agents

Figure 2.17. Trapping of excess alpha-bromoketones during secondary amine alkylation reactions

2.3.2.1.3. Fluorous reagents Two examples of light fluorous reagents are shown in Figure 2.18. These fluorous reagents are the diethylazodicarboxylate (DEAD) and Lawesson reagent analogs used for Mitsunobu (Dandapani and Curran 2002) and carbonyl thionylation reactions, respectively (Zoltán et al. 2006). By using these compounds, excess reagent and fluorous byproducts are easily removed by F-SPE chromatography. In the case of the Mitsunobu reaction, Curran et al. (2002) used a fluorinated triphenylphosphine as co-reagent, which eliminates the

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two by-products, triphenylphosphine oxide and hydrazine, during the separation step on fluorinated silica.

Figure 2.18. Examples of light fluorous reagents

2.3.2.1.4. Fluorous mixture synthesis The authors used the ability of high-performance liquid chromatography combined with fluorous silica to very effectively separate molecules modified by F-tags of different perfluoroalkyl chain lengths to develop the first homogeneous solution mixture synthesis methodology that isolates each product from the “library” (Luo et al., 2001a; Zhang et al. 2002b). The general principle of the methodology and amplification principle is presented in Figure 2.19.

Figure 2.19. Fluorous mixture synthesis (adapted from Zhang 2004). For a color version of this figure, see www.iste.co.uk/malacria/biphasic.zip

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Compounds of the same family are individually modified by F-tags whose perfluoroalkyl fragment length varies (C3F7, C4F9, C5F11, etc.). The resulting compounds, three in the case presented, are then mixed and can be reacted with a fourth product to produce a mixture of three new products. The mixture can be split in two, then each mixture is reacted with a different product, resulting in two mixtures containing three different products, or six products. The key step will be to carry out a separation on each mixture by means of a preparative fluorous HPLC, to isolate each “tagged” product. The products obtained must then be “detached” and the F-tag eliminated by F-SPE. One of the advantages of this approach is that at each step the mixtures can be analyzed by fluorous HPLC and, if necessary, purified by nonfluorous silica chromatography. The relevance and efficacy of fluorous mixture synthesis has been demonstrated by the preparation of a “library” of 560 (S)-mappicine (20) and its analog (21), natural products with biological activity against the human herpes virus and cytomegalovirus (Figure 2.20) (Zhang et al. 2002b).

Figure 2.20. Structures of (S)-mappicine (20) and its analog (21)

The synthesis pathway and protocol used are shown in Figure 2.21. The 7 pyridines 22{1-7} are prepared individually. To each substituent R1 corresponds an F-tag, C3F7 for Me, C4F9 for Pr, etc. The 7 pyridines 22{1-7} are mixed in equimolar quantities and reacted with ICl and BBr3 to produce the product mixture 23{1-7}. Note that a standard silica gel purification step is performed on this mixture. On standard silica, the 7 fluorinated products 23{1-7} will migrate together. The mixture is divided into 8, and each new mixture is reacted with one of the 8 propargyl bromides (24), resulting in 8 mixtures of 7 pyridones 25{1-7,1-8}, or 56 different products. Each of the 8 mixtures is

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divided into 10, and each of the mixtures obtained is reacted with one of the 10 isonitriles (26), resulting in 80 mixtures each containing 7 tagged mappicines 27{1-7, 1-8,1-10} or 560 compounds. Each of the 80 mixtures is then “demixed” by preparative fluorine HPLC, which allows the 560 products 27{1-7,1-8,1-10} to be isolated. An example of “demixing” on a semi-preparatory scale for tagged mappicines 27{1-7,6,2} is shown in Figure 2.22. All products are perfectly separated, the order of elution always following the increasing order of the total fluorine content. Treatment with HF-pyridine eliminates the silylated protective group and each reaction medium is then processed via chromatography on reverse phase silica gel, allowing the 560 mappicines to be recovered with a purity >90%. The quantities of mappicine obtained by weight are as follows: 1–2 mg for 315 samples (56%), less than 1 mg for 180 samples (32%) and more than 2 mg for 65 samples (12%).

Figure 2.21. Fluorous mixture synthesis for the preparation of 560 mappicine analogs (adapted from Zhang 2004)

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27{1-7,6,2}

R1 Rf

A Me C3F7

B Pr C4F9

C Et C6F10

D s-Bu C7F15

E i-Pr C8F17

F c-C6H11 C9F19

G CH2CH2-c-C6H11 C10F21

Figure 2.22. Semi-preparatory HPLC chromatogram corresponding to the separation (demixing) of the product mixture 27{1-7,6,2}

This concept of fluorous mixture synthesis was subsequently extended to the preparation of stereoisomer “libraries” of natural products such as passiflorin (28) (Figure 2.23) (Curran et al. 2006). Compared to linear synthesis, this approach significantly reduces the number of chemical reactions that allow access to these compounds.

Figure 2.23. Structure of passiflorin

2.3.2.1.5. Fluorous chemistry for the preparation of microarrays In the field of biotechnology, the development of biochips (or bioarrays) is undergoing considerable growth. A biochip consists of a small support (typically a glass slide with a surface area of one to a few cm2) on which very small quantities of a set of DNA molecules (DNA microarray), proteins (protein microarray), oligosaccharides (sugar microarray) or other molecules are fixed on a surface in an

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ordered and precise manner. These techniques, which are now routinely used, make it possible to identify and study the interactions between biomolecules. The grafting of molecules on the surface is generally done by creating a covalent bond, which avoids losses or migrations on the surface during the hybridization steps. The grafting is carried out by reacting a nucleophilic group already present on the molecule to be grafted or added via a tag, onto an electrophilic group present on the surface. This strategy, although effective, generates many problems related to selectivity, the development of reaction conditions and reproducibility. An important breakthrough was described in 2005 by Pohl et al. (2005) who showed that it was possible to effectively immobilize monosaccharides non-covalently by exploiting the solvophobic effects generated by F-tags. The general principle of fluorous microarrays is shown in Figure 2.24. The validity of this approach was tested by immobilizing monosaccharides or disaccharides tagged with a C8F17 group and showing that it was possible to detect, by fluorescence, the formation of complexes between some of these sugars and proteins (lectins modified by fluorescent tags). Extended incubation periods and extensive washing to remove non-hybrid proteins do not affect the stability of fluorous microarrays (Mamidyala et al. 2006). It was then shown that this type of approach could be used to quantify the binding strength between sugars and proteins by measuring the variation in fluorescence intensity as a function of the protein concentration of incubation solutions (Jaipuri et al. 2008). 2.3.2.2. Heavy fluorous synthesis The first fluorous methodologies developed for synthesis, as early as 1996 by Curran and Hadida (1996), concerned so-called “heavy fluorous” techniques because the reagents used were modified by at least three F-tags, thus giving them a high solubility in PFCs. The products, by-products or excess reagent are then removed by liquid/liquid HC/PFC extraction.

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Figure 2.24. Fluorous microarrays. For a color version of this figure, see www.iste.co.uk/malacria/biphasic.zip

In 1997, the authors developed a fluorous synthesis for the multicomponent condensation of Ugi and Biginelli to obtain functionalized diamides and pyrimidines, respectively (Studer et al. 1997a, 1997b). An example of Ugi fluorous synthesis is shown in Figure 2.25 (Studer et al. 1997b). A heavy fluorous carboxylic acid (15 mol) is reacted for 48 hours at 90°C in trifluoroethanol (TFE, CF3CH2OH) in the presence of a large excess (17 equivalents each) of amine, aldehyde and isonitrile. The solvent is evaporated, the residue is taken up in benzene and extracted three times by FC-72, which allows the selective and quantitative extraction of fluorous

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compounds. Desilylation is carried out by tetrabutylammonium fluoride (TBAF) and leads to the formation of desired diamides and fluorosilane, which are separated by benzene/FC-72 extraction. The approach is conceptually very interesting and effective. Nevertheless, the use of very expensive solvents (TFE, FC-72) or toxic solvents (benzene) has disadvantages that have led to the development of light fluorous techniques.

Figure 2.25. Fluorous synthesis of Ugi

Inazu et al. (2003) have developed an original approach based on the use of the heavy fluorous “molecular support” F-OH (Figure 2.26) with a dendrimeric structure with 6 F-tags -C8F17. This extremely fluorophilic acid has been successfully used for the solution synthesis of oligopeptides (Mizuno et al. 2003) and oligosaccharides (Miura et al. 2003; Mizuno et al. 2006). The preparation of a biologically active tripeptide (thyrotropin-releasing hormone) was first carried out by grafting a trialkoxybenzhydryl linker commonly used in peptide synthesis on resin. The synthesis uses the Fmoc strategy with deprotection/coupling cycles performed in solution using the usual conditions. Note that for the coupling step, a partially fluorinated ether is used as a co-solvent to promote substrate solubility. A liquid/liquid extraction DMF/FC72 allows the product to be selectively and quantitatively extracted after deprotection. The products obtained after coupling are separated by MeOH/FC72 extractions. The removal of the “molecular support” is carried out in an acidic medium, and the peptide is isolated in the aqueous phase after the three-phase extraction with toluene, H2O and FC72. The HPLC chromatogram of the aqueous phase shows that the purity of the crude peptide is very satisfactory. After purification of the aqueous phase by reverse phase HPLC, the peptide is obtained with a yield of 62% for seven steps and a single purification by chromatography.

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Figure 2.26. Use of a heavy fluorous molecular carrier, F-OH, for the synthesis of a tripeptide. For a color version of this figure, see www.iste.co.uk/malacria/biphasic.zip

Finally, the authors developed the concept of reversible extraction of pyridine tag molecules between an organic phase and a PFC, which could be used to facilitate the purification of substrate/products during the multi-step synthesis of a hydantoin (El Bakkari et al. 2002; El Bakkari and Vincent 2004). The principle of the liquid/liquid extraction-release system is shown in Figure 2.27. The bis-monopyridyl tag (29) has a benzyl alcohol function allowing a substrate to be grafted in a manner similar to a Merrifield or Wang type resin. The reaction sequence used for hydantoin synthesis (33) is described in Figure 2.28. Intermediates (30) and (32) are quantitatively extracted from the reaction medium at the end of the reaction by adding a perfluorodecalin solution containing the heavy fluorous copper dimer (34) soluble only in PFC. After settling, removal of the CH2Cl2 phase, (30) and (32) are released into chloroform by the addition of THF. In the last step, the hydantoin and the tag are obtained in equimolar proportions; the addition of the perfluorodecalin solution containing (34) enables isolation of (33) with an overall yield for the four steps of 86% (El Bakkari and Vincent 2004).

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Figure 2.27. Concept of the reversible phase transfer process between an organic solvent and a perfluorocarbon applied to organic synthesis. For a color version of this figure, see www.iste.co.uk/malacria/biphasic.zip

Figure 2.28. Reaction scheme used for the synthesis of hydantoin (33)

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2.4. Conclusion Twenty-five years after their appearance in literature, fluorous techniques offer a very wide range of methodologies to facilitate the purification of complex reaction mixtures. The combination of fluorous molecules and liquid or solid fluorous phases offers an ideal compromise in terms of ease of process implementation, reactivity, efficiency and simplicity of purification. When in a chemical reaction, the purification step is considered a key step in the process; fluorous techniques are now to be considered a credible and viable alternative to solid support chemistry. For catalysis applications, fluorous biphasic catalysis is the technique of choice for highly efficient catalyst recycling and has a high potential for industrial applicability. Environmental persistence and therefore the risk of bioaccumulation of PFCs in the environment is a potential problem with these compounds, which must therefore be perfectly contained to avoid any risk of contamination. It should be noted, however, that PFCs are, along with water, the only solvents that are not toxic and can be ingested in large quantities. For synthesis applications, light fluorous techniques are particularly well suited to the preparation of compound libraries via automated parallel syntheses. In general, these techniques save time, reduce the use of reagents and significantly reduce the number of chemical reactions required to obtain the target compounds, compared to existing techniques. Since 2005, fluorous techniques have successfully entered the field of biotechnology, a rapidly expanding field in which the exceptional physicochemical properties of perfluorinated tags and phases will continue to be exploited. 2.5. References Beier, P., O’Hagan, D. (2002). Enantiomeric partitioning using fluorous biphase methodology for lipase-mediated (trans)esterifications. Chem. Commun., 1680–1681. Betzemeier, B., Lhermitte, F., Knochel, P. (1998). Wacker oxidation of alkenes using a fluorous biphasic system. A mild preparation of polyfunctional ketones. Tetrahedron Lett., 39, 6667–6670.

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Biffis, A., Zecca, M., Basato, M. (2003). A green protocol for the silylation of alcohols using bonded fluorous phase catalysis. Green Chem., 5, 170– 173. Cavazzini, M., Manfredi, A., Montanari, F., Quici, S., Pozzi, G. (2001). Asymmetric epoxidation of alkenes in fluorinated media, catalyzed by second‐generation fluorous chiral (salen)manganese complexes. Eur. J. Org. Chem., 4639–4649. Contel, M., Villuendas, P.R., Fernández-Gallardo, J., Alonso, P.J., Vincent, J.-M., Fish, R.H. (2005). Fluorocarbon soluble copper(II) carboxylate complexes with nonfluoroponytailed nitrogen ligands as precatalysts for the oxidation of alkenols and alcohols under fluorous biphasic or thermomorphic modes:  Structural and mechanistic aspects. Inorg. Chem., 44, 9771–9778. Corrêa da Costa, R., Gladysz, J.A. (2006). Fluorous phase-transfer activation of catalysts: Application of a new rate-enhancement strategy to alkene metathesis. Chem. Commun., 2619–2621. Crich, D., Zhou, Y. (2004). Recyclable oxidation reagents. In Handbook of Fluorous Chemistry, Gladysz, J.A., Curran, D.P., Horváth, I.T. (eds). Wiley-VCH, Weinheim, 202–222. Croxtall, B., Hope, E.G., Stuart, A.M. (2003). Separation, recovery and recycling of a fluorous-tagged nickel catalyst using fluorous solid-phase extraction. Chem. Commun., 2430–2431. Curran, D.P. (1998). Strategy‐level separations in organic synthesis: From planning to practice. Angew. Chem. Int. Ed., 37, 1174–1196. Curran, D.P. (2008). Fluorous chemistry in Pittsburg: 1996-2008. J. Fluor. Chem., 129, 898–902. Curran, D.P., Amatore, M., Guthrie, D., Campbell, M., Go, E., Luo, Z. (2003). Synthesis and eractions of fluorous carbobenzyloxy (FCBZ) derivatives of α-amino acids. J. Org. Chem., 68, 4643–4647. Curran, D.P., Furukawa, T. (2002). Simultaneous preparation of four truncated analogues of discodermolide by fluorous mixture synthesis. Org. Lett., 4, 2233–2235. Curran, D.P., Hadida, J. (1996). Tris(2-(perfluorohexyl)ethyl)tin hydride:  A new fluorous reagent for use in traditional organic synthesis and liquid phase combinatorial synthesis. J. Am. Chem. Soc., 118, 2531–2532.

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Curran, D.P., Hadida, S., He, M. (1997). Thermal allylations of aldehydes with a fluorous allylstannane. Separation of organic and fluorous products by solid phase extraction with fluorous reverse phase silica gel. J. Org. Chem., 62, 6714–6715. Curran, D.P., Moura-Letts, G., Pohlman, M. (2006). Solution-phase mixture synthesis with fluorous tagging en route: Total synthesis of an eightmember stereoisomer library of passifloricins. Angew. Chem. Int. Ed., 45, 2423–2426. Curran, D.P., Oderaotoshi, Y. (2001). Thiol additions to acrylates by fluorous mixture synthesis: Relative control of elution order in demixing by the fluorous tag and the thiol substituent. Tetrahedron, 57, 5243–5253. Curran, D.P., Ogoe, C. (2006). A new fluorous methoxymethyl (FMOM) protecting group for alcohols. QSAR Comb. Sci., 25, 732–735. Dandapani, S., Curran, D.P. (2002). Fluorous Mitsunobu reagents and reactions. Tetrahedron, 58, 3855–3864. de Visser, P.C., van Helden, M., Filippov, D.V., van der Marel, G.A., Drijfhout, J.W., van Boom, J.H., Noort, D., Overkleeft, H.S. (2003). A novel, base-labile fluorous amine protecting group: Synthesis and use as a tag in the purification of synthetic peptides. Tetrahedron Lett., 44, 9013– 9016. de Wolf, E., Speets, E.A., Deelman, B.-J., Van Koten, G. (2001). Recycling of rhodium-based hydrosilylation catalysts: A fluorous approach. Organometallics, 20, 3686–3690. Dinh, L.V., Gladysz, J.A. (2005). “Catalyst-on-a-tape”-Teflon: A new delivery and recovery method for homogeneous fluorous catalysts. Angew. Chem. Int. Ed., 44, 4095–4097. El Bakkari, M., McClenaghan, N., Vincent, J.-M. (2002). The pyridyl-tag strategy applied to the hydrocarbon/perfluorocarbon phase-switching of a porphyrin and a fullerene. J. Am. Chem. Soc., 124, 12942–12943. El Bakkari, M., Vincent, J.-M. (2004). Fluorous phase-switching of pyridyltagged substrates/products. Org. Lett., 6, 2765–2767. Gladysz, J.A. (2004). Ponytails: Structural and electronic properties. In Handbook of Fluorous Chemistry, Gladysz, J.A., Curran, D.P., Horváth, I.T. (eds). Wiley-VCH, Weinheim, 41–55.

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93

Gladysz, J.A., Emnet, C. (2004). Fluorous solvents and related media. In Handbook of Fluorous Chemistry, Gladysz, J.A., Curran, D.P., Horváth, I.T. (eds). Wiley-VCH, Weinheim, 11–23. Gladysz, J.A., Curran, D.P., Horváth, I.T. (eds) (2004b). Handbook of Fluorous Chemistry. Wiley-VCH, Weinheim. Gladysz, J.A., Emnet, C., Rábai, J. (2004a). Partition coefficients involving fluorous solvents. In Handbook of Fluorous Chemistry, Gladysz, J.A., Curran, D.P., Horváth, I.T. (eds). Wiley-VCH, Weinheim, 56–100. Hobbs, H.R., Kirke, H.M., Poliakoff, M., Thomas, N.R. (2007). Homogeneous biocatalysis in both fluorous biphasic and supercritical carbon dioxide systems. Angew. Chem. Int. Ed., 46, 7860–7863. Hobbs, H.R., Thomas, N.R. (2007). Biocatalysis in supercritical fluids, in fluorous solvents, and under solvent-free conditions. Chem. Rev., 107, 2786–2820. Hope, E.G., Stuart, A.M. (2004). Synthesis of perfluoroalkylated phosphines. In Handbook of Fluorous Chemistry, Gladysz, J.A., Curran, D.P., Horváth, I.T. (eds). Wiley-VCH, Weinheim, 247–256. Horváth, I.T., Kiss, G., Cook, R.A., Bond, J.E., Stevens, P.A., Rábai, J., Mozeleski, E. (1998). Molecular engineering in homogeneous catalysis: One-phase catalysis coupled with biphase catalyst separation. The fluorous-soluble HRh(CO) {P[CH2CH2(CF2)5CF3]3}3 hydroformylation system. J. Am. Chem. Soc., 120, 3133–3143. Horváth, I.T., Rábai, J. (1994). Facile catalyst separation without water: Fluorous biphase hydroformylation of olefins. Science, 266, 72–75. Ishihara, K., Hasegawa, K., Yamamoto, H. (2002). A fluorous super Brønsted acid catalyst: Application without fluorous solvents. Synlett, 1299–1301. Ishihara, K., Kondo, S., Yamamoto, H. (2001). 3,5Bis(perfluorodecyl)phenylboronic acid as an easily recyclable direct amide condensation catalyst. Synlett, 1371–1374. Jaipuri, F.A., Collet, B.Y.M., Pohl, N.L. (2008). Synthesis and quantitative evaluation of Glycero-D-manno-heptose binding to concanavalin A by fluorous-tag assistance. Angew. Chem. Int. Ed., 47, 1707–1710.

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Jiao, H., Le Stang, S., Soós, T., Meier, R., Kowski, K., Rademacher, P., Jafarpour, L., Hamard, J.-B., Nolan, P., Gladysz, J.A. (2002). How to insulate a reactive site from a perfluoroalkyl group:  Photoelectron spectroscopy, calorimetric, and computational studies of long-range electronic effects in fluorous phosphines P((CH2)m(CF2)7CF3)3. Am. Chem. Soc., 124, 1516–1523. Juliette, J.J.J., Rutherford, D., Horváth, I.T., Gladysz, J.A. (1999). Transition metal catalysis in fluorous media: Practical application of a new immobilization principle to rhodium-catalyzed hydroborations of alkenes and alkynes. J. Am. Chem. Soc., 121, 2696–2704. Klemet, I., Lütjens, H., Knochel, P. (1997). Transition metal catalyzed oxidations in perfluorinated solvents. Angew. Chem. Int. Ed. Engl., 36, 1454–1456. Ko, K.-S., Jaipuri, F.A., Pohl, N.L. (2005). Fluorous-based carbohydrate microarrays. J. Am. Chem. Soc., 127, 13162–13163. Koch, D., Leitner, W.J. (1998). Rhodium-catalyzed hydroformylation in supercritical carbon dioxide. J. Am. Chem. Soc., 120, 13398–13404. Lu, Y., Zhang, W. (2006). Fluorous 2,4-Dichloro-1,3,5-triazines (F-DCTs) as nucleophile scavengers. QSAR Comb. Sci., 25, 728–731. Luo, Z., Zhang, Q., Odearotoshi, Y., Curran, D.P. (2001a). Fluorous mixture synthesis: A fluorous-tagging strategy for the synthesis and separation mixtures of organic compounds. Science, 291, 1766–1769. Luo, Z., William, J., Read, R.W., Curran, D.P. (2001b). Fluorous Boc (FBoc) carabamates: New amine protecting groups for use in fluorous synthesis. J. Org. Chem., 66, 4261–4266. Maillard, D., Pozzi, G., Quici, S., Sinou, D. (2002). Asymmetric hydrogen transfer reduction of ketones using chiral perfluorinated diimines and diamines. Tetrahedron, 58, 3971–3976. Mamidyala, S.K., Ko, K.-S., Jaipuri, F.A., Park, G., Pohl, N.L. (2006). Noncovalent fluorous interactions for the synthesis of carbohydrate microarrays. J. Fluor. Chem., 127, 571–579. Matsugi, M., Curran, D.P. (2005). Synthesis, reaction, and recycle of light fluorous Grubbs-Hoveyda catalysts foe alkene metathesis. J. Org. Chem., 70, 1636–1642.

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Matsugi, M., Yamanaka, K., Inomata, I., Takekoshi, N., Hasegawa, M., Curran, D.P. (2006). Synthesis of fluorous-FMOC reagents and purification of protected dipeptides with fluorous solid phase extraction. QSAR Comb. Sci., 25, 713–715. McCormick, R.A., James, K.M., Willets, N., Procter, D.J. (2006). Developing new cleavage strategies in a fluorous phase Pummerer cyclative-capture approach for the synthesis of N-heterocycles. QSAR Comb. Sci., 25, 709–712. Miura, T., Goto, K., Hosaka, D., Inazu, T. (2003). Oligosaccharide synthesis on a fluorous support. Angew. Chem. Int. Ed., 42, 2047–2051. Mizuno, M., Goto, K., Miura, T., Hosaka, D., Inazu, T. (2003). A novel peptide synthesis using fluorous chemistry. Chem. Commun., 972–973. Mizuno, M., Goto, K., Miura, T., Inazu, T. (2006). Rapid oligosaccharide and peptide synthesis on a recyclable fluorous support. QSAR Comb. Sci., 25, 742–752. Moura-Letts, G., Curran, D.P. (2007). Selective synthesis of (2Z,4E)-dienyl esters by ene-diene cross metathesis. Org. Lett., 9, 5–8. Nakamura, Y., Takeuchi, S., Okumura, K., Ohgo, Y., Curran, D.P. (2002a). Recyclable fluorous chiral ligands and catalysts: Asymmetric addition of diethylzinc to aromatic aldehydes catalyzed by fluorous BINOL-Ti complexes. Tetrahedron, 58, 3963–3969. Nakamura, Y., Takeuchi, S., Zhang, S., Okumura, K., Ohgo, Y. (2002b). Preparation of a fluorous chiral BINAP and application to an asymmetric Heck reaction. Tetrahedron Lett., 43, 3053–3056. Pearson, W.H., Berry, D.A., Stoy, P., Jung, K.-Y., Sercel, A.D. (2005). Fluorous affinity purification of oligonucleotides. J. Org. Chem., 70, 7114–7122. Pozzi, G., Montanari, F., Quici, S. (1997). Cobalt tetraarylporphyrincatalyzed epoxidation of alkenes by dioxygen and 2-methylpropanal under fluorous biphasic conditions. Chem. Commun., 69–70. Pozzi, G., Quici, S. (2004). Fluorous nitrogen ligands for oxidation reactions. In Handbook of Fluorous Chemistry, Gladysz, J.A., Curran, D.P., Horváth, I.T. (eds). Wiley-VCH, Weinheim, 290–298.

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Richter, B., Spek, A.L., Van Koten, G., Deelman, B.-J. (2000). Fluorous versions of Wilkinson’s catalyst. Activity in fluorous hydrogenation of 1alkenes and recycling by fluorous biphasic separation. J. Am. Chem. Soc., 122, 3945–3951. Rocaboy, C., Gladysz, J.A. (2002). Highly active thermomorphic fluorous palladacycle catalyst precursors for the Heck reaction; Evidence for a palladium nanoparticle pathway. Org. Lett., 4, 1993–1996. Siedel, F.O., Gladysz, J.A. (2008). Catalysis of intramolecular Morita-BaylisHillman and Rauhut-Currier reactions by fluorous phosphines; facile recovery by liquid/solid organic/fluorous biphase protocols involving precipitation, Teflon® tape, and Gore‐Rastex® fiber. Adv. Synth. Catal., 350, 2443–2449. Studer, A., Hadida, S., Ferritto, S., Kim, Y., Jeger, P., Wipf, P, Curran, D.P. (1997a). Flurous synthesis: A fluorous-phase strategy for improving separation efficiency in organic synthesis. Science, 275, 823–826. Studer, A., Jeger, P., Wipf, P., Curran, D.P. (1997b). Fluorous synthesis:  Fluorous protocols for the Ugi and Biginelli multicomponent condensations. J. Org. Chem., 62, 2917–2924. Takeuchi, S., Nakamura, Y. (2004). Enantioselective catalysis in nonbiphasic conditions. In Handbook of Fluorous Chemistry, Gladysz, J.A., Curran, D.P., Horváth, I.T. (eds). Wiley-VCH, Weinheim, 316–322. Tzschucke, C.C., Markert, C., Glatz, H., Bannwarth, W. (2002). Fluorous biphasic catalysis without perfluorinated solvents: Application to Pdmediated Suzuki and Sonogashira couplings. Angew. Chem. Int. Ed., 41, 4500–4503. Van Vliet, M.C.A., Arends, I.W.C.E., Sheldon, R.A. (1999). Perfluoroheptadecan-9-one: A selective and reusable catalyst for epoxidations with hydrogen peroxide. Chem. Commun., 263–264. Vincent, J.-M., Lastécouères, D., Contel, M., Laguna, M., Fish, R.H. (2004). Synthesis of fluorous nitrogen ligands and their metal complexes as precatalysts for applications in alkane, alkene, and alcohol oxidation, and atom transfer radical reactions. In Handbook of Fluorous Chemistry, Gladysz, J.A., Curran, D.P., Horváth, I.T. (eds). Wiley-VCH, Weinheim, 298–305.

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Vincent, J.-M., Rabion, A., Yachandra, V.K., Fish, R.H. (1997). Fluorous biphasic catalysis: Complexation of 1,4,7-[C8F17(CH2)3]3-1,4,7triazacyclononane with [M(C8F17(CH2)2CO2)2] (M = Mn, Co) to provide perfluoroheptane-soluble catalysts for alkane and alkene functionalization in the presence of t-BuOOH and O2. Angew. Chem. Int. Ed. Engl., 36, 2346–2349. Wende, M., Gladysz, J.A. (2003). Fluorous catalysis under homogeneous conditions without fluorous solvents:  A “Greener” catalyst recycling protocol based upon temperature-dependent solubilities and liquid/solid phase separation. J. Am. Chem. Soc., 125, 5861–5872. Wende, M., Meier, R., Gladysz, J.A. (2001). Fluorous catalysis without fluorous solvents:  A friendlier catalyst recovery/recycling protocol based upon thermomorphic properties and liquid/solid phase separation. J. Am. Chem. Soc., 123, 11490–11491. Werner, S., Curran, D.P. (2003). Fluorous dienophiles are powerful diene scavengers in Diels-Alder reactions. Org. Lett., 5, 3293–3296. Xia, J., Johnson, T., Gaynor, S.G., Matyjaszewski, K., DeSimone, J. (1999). Atom transfer radical polymerization in supercritical carbon dioxide. Macromolecules, 32, 4802–4805. Xiang, J., Orita, A., Otera, J. (2002). Fluorous biphasic esterification directed towards ultimate atom efficiency. Angew. Chem. Int. Ed., 41, 4117–4119. Yoshida, A., Hao, X., Nishikido, J. (2003). Development of the continuousflow reaction system based on the Lewis acid-catalyzed reactions in a fluorous biphasic system. Green Chem., 5, 554–557. Zhang, W. (2003). Fluorous synthesis of disubstituted pyrimidines. Org. Lett., 5, 1011–1013. Zhang, W. (2004). Fluorous synthesis of heterocyclic systems. Chem. Rev., 104, 2531–2556. Zhang, W., Curran, D.P. (2006). Synthetic applications of fluorous solidphase extraction (F-SPE). Tetrahedron, 62, 11837–11865. Zhang, W., Curran, D.P., Hiu-Tung Chen, C. (2002a). Use of fluorous silica gel to separate fluorous thiol quenching derivatives in solution-phase parallel synthesis. Tetrahedron 58, 3871–3875.

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Zhang, W., Luo, Z., Hiu-Tung Chen, C., Curran, D.P. (2002b). Solutionphase preparation of a 560-compound library of individual pure mappicine analogues by fluorous mixture synthesis. J. Am. Chem. Soc., 124, 10443–10450. Zhang, W., Hiu-Tung Chen, C. (2003). FluoMar, a fluorous version of the Marshall resin for solution-phase library synthesis. Org. Lett., 5, 1015– 1017. Zhang, W., Hiu-Tung Chen, C., Nagashima, T. (2003). Fluorous electrophilic scavengers for solution-phase parallel synthesis. Tetrahedron Lett., 44, 2065–2068. Zhang, W., Lu, Y. (2003). Fluorous synthesis of hydantoins and thiohydantoins. Org. Lett., 5, 2555–2558. Zoltán, K., Tárkányi, G., Gömöry, A., Kálmán, F., Nagy, T., Soós, T. (2006). Synthesis and application of a fluorous Lawesson’s reagent: Convenient chromatography-free product purification. Org. Lett., 8, 1093–1095.

3 Chemistry In and On Water

3.1. Introduction 3.1.1. Presentation and history Water is the solvent in which nature carries out all the chemical transformations associated with life. The organic chemist, on the other hand, has tended to avoid this environment and work in anhydrous conditions. This is due to several reasons, the main one being that most organic molecules are poorly soluble, or even insoluble, in this medium, and many reagents are not stable in water; researchers then abandoned the idea of developing syntheses in an aqueous medium. This has not always been the case. Indeed, the early stages of organic synthesis attributed to the German chemist Wöhler consist of the preparation of urea by heating an aqueous solution of ammonium isocyanate. This was done in 1828. Water remained a solvent for the transformations of organic molecules until the beginning of organometallic chemistry, which imposed anhydrous conditions. Breslow’s work, published in 1980, marked the beginning of a new era for chemistry in water. He showed that the Diels-Alder reaction was considerably accelerated in this environment and also more selective in favor of the endo isomer. Since then, water use has increased significantly, including for reactions involving organometallic

Chapter written by Marie-Christine SCHERRMANN.

Biphasic Chemistry and The Solvent Case,First Edition. Edited by Jean-Philippe Goddard, Max Malacria and Cyril Ollivier. © ISTE Ltd 2020. Published by ISTE Ltd and John Wiley & Sons, Inc.

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compounds, and industrial processes have been developed (Joó and Kathó 2010; Mori and Kobayashi 2012). 3.1.2. Position in the context of green chemistry Solvents are generally the most important part of the mass of a reaction medium. They are used to facilitate mass and heat transport during synthesis but also to carry out workup, separations and purifications. Analysis of the materials used to produce an active ingredient in the pharmaceutical industry revealed that solvents represent 56% of the mass used (Henderson et al. 2011). They therefore contribute significantly to the environmental impact of chemical processes and, according to the recommendations of the fifth of the twelve principles of green chemistry (Anastas and Warner 1998), safer solvents should be used. Various methods have been proposed to assess the greenness of solvents (Koller et al. 2000) and to guide the choice made by the chemist (Prat et al. 2016; Clarke et al. 2018). In the pharmaceutical fine chemicals sector, it is clearly recommended to substitute organic solvents with water when possible (Prat et al. 2016; Clarke et al. 2018). Indeed, aqueous phase synthesis represents an alternative to processes generally developed in organic solvents. Water is a very abundant solvent, cheap, non-toxic and nonflammable, qualities that are currently very much in demand, for good reason. In this medium, reactions can generally be carried out under mild conditions by improving yields and selectivities compared to organic solvents. 3.2. General: origin of reactivity in and on water 3.2.1. Water structure and properties The distribution of molecules in a fluid is governed by the interaction energy between them. The nature of these interactions depends on molecular geometry and charge distribution. In the case of water, hydrogen bonds, with an average force of 20 kJ/mol, primarily contribute to the interaction energy.

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Neutron diffraction experiments have shown a radial distribution function with two maxima (at 0.28 and 0.45 nm), which are very close to those of ice. By integrating this distribution function up to the first maximum, we obtain the number of nearest neighbors of a water molecule, 4.4. This number, slightly higher than that of ice, led to the formulation of a model according to which liquid water would result from the equilibrium between two types of water (Figure 3.1): – ordered low entropy water, whose structure is similar to that of ice; – dense, disordered, high entropy water, where each molecule has more than four neighbors.

Dense water

Ordered water

Figure 3.1. Equilibrium between dense and ordered water. For a color version of this figure, see www.iste.co.uk/malacria/biphasic.zip

The position of this equilibrium can be influenced by pressure, temperature, solutes, etc. This arrangement is responsible for the unique physicochemical properties of liquid water such as: – high cohesive energy density; – very high calorific capacity, which is halved in the vapor or solid state; – high surface tension;

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– low compressibility; – a decrease in viscosity with pressure; – a strong and abnormal dependence of the thermal expansion coefficient with a maximum density at 4°C. 3.2.2. Chemistry in water: the hydrophobic effect The transfer of a hydrophobic molecule into water is a thermodynamically unfavorable process (ΔtrG > 0) due to a strong decrease in entropy (ΔtrS < 0), which corresponds to a loss of the degrees of freedom of the water molecules surrounding the solute (first solvation sphere). When two hydrophobic molecules are placed in water, they will tend to aggregate in such a way as to reduce unfavorable interactions with the solvent; this phenomenon partially compensates for hydrophobic solvation. This entropic aggregation of apolar molecules in water (or apolar centers of the same molecule) is at the origin of reactivity in an aqueous medium. This aggregation, corresponding to a destabilization of the initial state of the reaction, is not sufficient to explain the accelerations observed in an aqueous environment; it is also necessary that the transition state be less destabilized than the initial state. This is true if the activation volume of the reaction is negative. This dynamic process was called the “enhanced hydrophobic effect” by Blokzijl and Engberts (1993). The hydrophobic effect is still the subject of many studies, in the attempt to fully understand its mechanisms (Kronberg 2016; Liu et al. 2016; Shrinidhi 2016). It is clear that if charges are developed in the transition state of the reaction, the polarity effect is added to the hydrophobic effect. The entropy of an initial state of reaction between apolar molecules will therefore be lower in water than in an organic solvent due to hydrophobic solvation and hydrophobic interactions. Transition state entropy will also be lower in water, but its level will be lower than in the initial state because it will only undergo hydrophobic solvation (Figure 3.2) (Scherrmann et al. 2005).

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S EIorg ΔS#org ETorg

EIwater

Hydrophobic solvation + hydrophobic interaction

ΔS#water ETwater

Hydrophobic solvation

ΔS#org< ΔS#water< 0 Figure 3.2. Entropic diagram of a reaction between hydrophobic substrates. EIorg, ETorg: initial state and transition state of the reaction in an organic solvent; EIwater, ETwater: initial state and transition state of the reaction in water. For a color version of this figure, see www.iste.co.uk/malacria/biphasic.zip

The effect of water polarity on a reaction in which charges (total or partial) are developed in the transition state occurs at the enthalpy level (Figure 3.3). As a result of these different effects, a reaction between hydrophobic water-soluble substrates can be accelerated in an aqueous medium (Figure 3.4): – by the reinforced hydrophobic effect, which corresponds to a destabilization of the initial state, more than the transition state; – by the polarity effect, which corresponds to a stabilization of the transition state; – by the effects of hydrogen bonds with substrates and the transition state.

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H ETorg ΔH#org EIorg

Stabilization of the charged transition state

ETwater ΔH#water EIwater

ΔH#org> ΔH#water> 0 Figure 3.3. Enthalpic diagram of a reaction with the development of charges in the transition state. Effect of water polarity. Notations, see Figure 3.2 (here org = non-polar organic solvent). For a color version of this figure, see www.iste.co.uk/malacria/biphasic.zip

G ETwater

ETorg

ETwater

ΔG#org EIorg

Transition state with the development of charges

ΔG#water

ΔG#water

EIwater

EIwater

ΔG#org> ΔG#water> 0 Figure 3.4. Energy diagram. Comparison of the organic solvent and water reaction for a reaction between hydrophobic substrates, without and with the development of charges in the transition state. For a color version of this figure, see www.iste.co.uk/malacria/biphasic.zip

The hydrophobic effect can be increased or decreased by adding various compounds to the reaction medium and the effect of such additives on the rate of reactions is often used as evidence of the involvement of the hydrophobic effect (Breslow 1991; Breslow and Rizzo 1991; Breslow et al. 1998; Butler et al. 2002; Chandler 2005; Nagare et al. 2015; Murakami et al. 2017; Van der Vegt and Nayar 2017).

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Breslow showed that lithium chloride (salting-out agent) increased the rate of the Diels-Alder reaction between cyclopentadiene 1 and methylvinyl ketone 2, while guanidinium salt (salting-in agent) slightly decreased it (Rideout and Breslow 1980; Breslow and Zhu 1995) (Figure 3.5 and Table 3.1).

Figure 3.5. Diels-Alder cycloaddition between cyclopentadiene and methylvinyl ketone

Solvent MeOH HCONH2 H2O H2O-LiCl 4.86 M H2O-(NH2)3CCl 4.86 M

105 k (M−1s−1) 75.5 318 4,400 10,800 4,300

Endo/exo 8.5 8.9 25 28 22

Table 3.1. Rate constants and selectivities of the cycloaddition between cyclopentadiene and methylvinyl ketone at 20°C

Similarly, the addition of non-polar co-solvents accelerates the Diels-Alder reaction and this acceleration is due to an increase in the hydrophobic effect: in the presence of such co-solvents, water becomes more structured by the formation of hydration spheres around the non-polar molecules, as a result, hydrophobic interactions are entropically more favorable. The problem of low solubility generally observed for organic compounds has been solved by the use of water-miscible co-solvents, biphasic media and/or surfactants (La Sorella et al. 2015) and many reactions have been performed under these conditions, while continuing to benefit from the effect of water. Another approach consists of grafting charged or uncharged hydrophilic side groups (carboxylates, ammoniums, sugars, etc.) that provide solubility while

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allowing hydrophobic interactions on the rest of the molecule (Keana et al. 1983; Yoshida and Grieco 1985; Grieco et al. 1986; Lubineau et al. 1994). 3.2.3. Origin of reactivity on water In the case of insoluble reagents, the reaction can take place “on water”. While reactions in water between hydrophobic substrates that are at least slightly soluble in water (solubilities greater than 10−2 mol/L) can be accelerated and sometimes lead to cleaner products than in organic solvents, when they are insoluble, the reaction can take place “on water” as shown by Sharpless and co-workers in 2005. In this case, the effects occur with the reagents and the transition state at the interphase (Jung and Marcus 2007; Zuo and Qu 2014). A striking example is the cycloaddition between quadricyclane 4 (solubility in water at room temperature: 5.7 mmol/L) and dimethyl azodicarboxylate 5 (solubility in water at room temperature: 110 mmol/L) to give 1,2-diazetidine 6 (Figure 3.6). This reaction required 48 h at 23°C without a solvent, while vigorous agitation of the two reagents in the presence of water led to the product in 10 min at the same temperature. In this particular case, the reaction product being poorly soluble in water (48 mmol/L), it was recovered by simple decantation or filtration, which makes the process particularly green.

Figure 3.6. Cycloaddition reaction between quadricyclane and dimethyl azodicarboxylate

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3.3. Limitations of the method Reactions involving water-sensitive reagents obviously cannot be performed in or on this solvent. We have seen above the conditions that benefit from using water as a solvent: substrates with at least one hydrophobic moiety, charge development in the transition state to take advantage of the polarity of water, or transition states that can be stabilized by hydrogen bonding. For “on-water” conditions, at least one of the two reagents must be liquid for the interface activation process to take place, an example will be described below. In the context of green chemistry, the benefits of using water as a solvent can be counterbalanced by treatments and/or purifications involving organic solvents (Brogan et al. 2006; Blackmond et al. 2007), which often require more material than in reactions (Butler and Coyne 2010; Pessel et al. 2016a, 2016b). To overcome these disadvantages, syntheses using only water or biphasic systems allowing easy recycling have been developed, as we will illustrate below. 3.4. Reactivity in and on water 3.4.1. Pericyclic reactions Pericyclic reactions are reactions with total atom economy, so they are particularly suitable for green syntheses (Klijn and Engberts 2010). 3.4.1.1. Diels-Alder and hetero Diels-Alder reactions As previously mentioned, the study of the Diels-Alder reaction has been strongly involved in the development of the use of water as a solvent for organic synthesis (Otto and Engberts 2000). In fact, Diels and Alder (1931) carried out the cycloaddition between furan and maleic anhydride into water as early as 1931. A few cases of cycloadditions in aqueous media appeared in the literature until the Breslow paper in 1980, which was the first to study the reaction kinetics in various solvents and to observe a remarkable acceleration of the cycloaddition in water between cyclopentadiene 1 and methylvinyl ketone 2 (Figure 3.5, Table 3.2) (Rideout and Breslow 1980).

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It also showed that the major compound resulted from the endo transition state (the most compact). The study of the thermodynamic parameters of this reaction confirmed the hypothesis of the entropic origin of this acceleration (Table 3.2). Solvent H2O MeOH nPrOH

ΔG≠ (kJ.mol−1) 80.0 89.8 90.3

ΔH≠ (kJ.mol−1) 38.0 ± 1.7 38.0 ± 1.0 45.1 ± 0.7

ΤΔS≠ (kJ.mol−1) –42.0 ± 1.5 –51.8 ± 1.0 –45.3 ± 0.7

Table 3.2. Thermodynamic parameters of cycloaddition between cyclopentadiene 1 and methylvinyl ketone 2 at 25°C

In addition to studies on the hydrophobic effect, the Diels-Alder reaction was also carried out in water for preparatory purposes. An example that fits perfectly into the framework of green chemistry is the transformation of furfural, a compound derived from biomass, into polysubstituted aromatic compounds through a one-pot procedure involving the formation of a dimethyl hydrazone 8, Diels-Alder cycloaddition and subsequent dehydration (Figure 3.7) (Higson et al. 2016). This synthesis is remarkable in terms of green chemistry because the atom economy of the sequence was high, the number of equivalents of the reagents used was relatively low (1.2–1.3 eq. of dimethyl hydrazine and 1–2 eq. of maleimide 9), the pure products were isolated by simply filtering the aqueous mixture.

Figure 3.7. Transformation of furfurals by a three-step “one pot” method in water

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Several catalysts have been shown to be effective, such as the use of complexing agents such as Co(NO3)2, Ni(NO3)2, Cu(NO3)2 or Zn(NO3)2. Catalysis was effective only if the cation formed a chelate with the dienophile (Otto and Engberts 1995). The use of a Lewis acid (Fringuelli et al. 2001) in the presence of micelles led to exceptionally efficient catalysis (Manabe et al. 1999): the Diels-Alder reaction performed in the presence of copper didodecyl sulfate micelles showed an acceleration of 1.8 × 106 compared to the reaction performed in nitromethane (Otto et al. 1998). The use of metallo-vesicles was also efficient and allowed lower additive concentrations to be used than metallo-micelles (Rispens and Engberts 2001). Other catalysts such as artificial metallo-enzymes have also been successfully prepared and used to perform the reaction in aqueous media (Talbi et al. 2010). The search for catalysts to control the enantioselectivity of cycloaddition has also been an important research topic (Kitanosono et al. 2018). As early as 1995, the Engberts team carried out the first enantioselective Diels-Alder cycloaddition in an aqueous medium, catalyzed by copper(II) chelated with amino acids (Otto and Engberts 2000) (Figure 3.8).

Figure 3.8. Influence of solvent on the enantioselectivity of the Diels-Alder reaction between 2-azachalcone 12 and Cu(II)catalyzed cyclopentadiene 1 in the presence of N-methyltryptophan

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Following this concept, other systems capable of chelating copper(II) were developed (Reymond and Cossy 2008). These include a triazacyclophane platform with three histidine amino acid residues (Bauke et al. 2011), or catalysts using BSA (Reetz and Jiao 2006) or DNA as a chirality source (Roelfes and Feringa 2005; Park et al. 2015). In order to easily recover the catalyst, the copper chelating DNA was impregnated on ammonium functionalized silica 14 (Figure 3.9). This insoluble catalyst could be used for the asymmetric DielsAlder reaction between 2-azachalcone and cyclopentadiene in the presence of copper(II) in water for 10 cycles with yields greater than 93% and enantioselectivity ranging from 94 to 89% (Park et al. 2013).

Figure 3.9. Ammonium functionalized silica used as a support for copper chelating DNA used to catalyze the Diels-Alder reaction. For a color version of this figure, see www.iste.co.uk/malacria/biphasic.zip

Various chiral and aqueous stable Lewis acids have been described to catalyze, among other things, the Diels-Alder reaction (Kitanosono and Kobayashi 2017). The organocatalytic approach was also applied to this cycloaddition (Jimeno 2016). McMillan described the use of chiral amines to activate α-β-unsaturated ketones such as 15 (Figure 3.10) in regio-, enantio- and diastereoselective reactions with a wide range of dienes and dienophiles (Northrup and MacMillan 2002). A recent example concerns the cycloaddition of α−β unsaturated aldehydes catalyzed by a diarylprolinol salt 21 (Shibatomi et al. 2015). The reaction took place on water and was accelerated compared to toluene. The procedure did not require any organic solvents, including for the purification step, since the cycloadducts were distilled directly from the reaction mixture (Figure 3.11).

Chemistry In and On Water

Figure 3.10. Organocatalyzed Diels-Alder reaction in water

Figure 3.11. Cycloaddition of unsaturated aldehyde 18 catalyzed by a diarylprolinol salt

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The hetero-Diels-Alder reaction has also been extensively studied in aqueous media. Thus, glyoxylic acid 10 gave rise to cycloadditions in water with various dienes (Lubineau et al. 1991) while the carbonyl function was almost entirely in hydrate form. Catalysis by lanthanide triflates increased reactivity. Similarly, imines or nitroso compounds, gave rise to efficient cycloadditions in aqueous media. Nitroso derivatives, which are generally unstable in water, could be effectively generated in situ by oxidation (Naruse et al. 1996) (Figure 3.12).

Figure 3.12. Examples of a hetero Diels-Alder reaction in aqueous medium

This approach involving phosphorylated nitroso-alkenes 27 and enol 28 ethers was used for the preparation of 1,2-oxazines 29 and 30 (Figure 3.13) (de los Santos et al. 2014).

Figure 3.13. Preparation of oxazines by cycloaddition in aqueous medium

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The reaction on water gave better results compared to solvent-free or organic solvent conditions. This superiority was also illustrated during the synthesis of dipyrromethanes by reacting azo and nitrosoalkene hetero-Diels-Alder with a pyrrole (Pereira et al. 2014). Another interesting example from a green chemistry perspective is the intramolecular aza-Diels-Alder cycloaddition to construct tetracyclic compounds 32 (Lezana et al. 2016). The reaction was carried out without a catalyst with microwave heating and, in most cases, the product of the reaction precipitated, meaning organic solvent could not be used for the extraction and purification steps (Figure 3.14).

Figure 3.14. aza-Diels-Alder reaction

3.4.1.2. 1,3-Dipolar cycloadditions 1,3-Dipolar cycloadditions easily afford five-atom heterocycles such as pyrroles, pyrrolidines, isoxazoles, pyrazoles, pyrazolines, triazoles, triazolines and tetrazoles. The Engberts group studied the kinetics of cycloadditions between benzonitrile oxide 33 and various dipolarophiles (Figure 3.15), and showed that reactions involving electron-rich dipolarophiles were accelerated in water while those involving electron-poor dipolarophiles proceeded slower (Van Mersbergen et al. 1998). Nitrones can also be used effectively in aqueous media. The reaction of C,N-phenylnitrone 36 with dibutyl fumarate 37 was accelerated by a factor of 125 when switching from ethanol to water. The effect of structuring (LiCl) and destructuring (urea) compounds is

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consistent with acceleration due to the hydrophobic effect (Gholami and Yangjeh 1999) (Figure 3.16).

Figure 3.15. Relative rates of 1,3-dipolar cycloadditions: influence of the solvent and the nature of the dipolarophile

Figure 3.16. Effect of solvent and additives for the cycloaddition of a nitrone

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Azomethine ylides, such as 40 (Figure 3.17), generated by condensation reaction between aqueous formaldehyde and amino acid derivatives, gave rise to 1,3-dipolar cycloaddition reactions in an aqueous medium leading to pyrrolidines 42 (Lubineau et al. 1995; Molteni et al. 2000).

Figure 3.17. Generation and reaction of azomethine ylides in water

A very interesting example showed that, depending on the “on” or “in” water conditions, different selectivities could be obtained for 1,3 dipolar cycloadditions: when reactions were carried out in water, the proportion of adducts from the endo transition state was increased compared to the reaction in acetonitrile while on water, this increase associated with the hydrophobic effect was reduced showing that the effects involved are different. Indeed, acrylic ester 44a with a water solubility of 0.46 M at 20°C gave rise to a reaction in water and the endo/exo ratio increased from 8.1/1 in acetonitrile to 9.8/1 for the reaction in water. With derivative 44b, which is poorly soluble in an aqueous medium (0.031 M at 20°C), the reaction took place on water and the endo/exo ratio of 5.3/1 in acetonitrile was 3.6/1 when water was used as the reaction medium (Figure 3.18) (Butler et al. 2013). As noted in the section on method limitations, for water chemistry conditions to be effective, at least one of the two reagents must be

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liquid in order to have a liquid organic phase in contact with the aqueous phase. Thus, the cycloaddition reaction between 44 (solid; Tmelting = 252–254°C; water solubility < 5 × 10−6 M) occurred only above the melting temperature of dipolarophile 47 (solid; Tmelting= 58– 62°C; water solubility 1.2 × 10−4 M) (Figure 3.19) (Butler et al. 2007).

Figure 3.18. Reaction in water for 44a and on water for 44b, difference in endo/exo ratios compared to the reaction in CH3CN

Figure 3.19. Temperature effect for a reaction between solid substrates for a cycloaddition reaction on water

1,3-Dipolar cycloadditions involving azides are part of click chemistry (Kolb et al. 2001), where most reactions can be performed in water. Copper-catalyzed azide alkyne cycloaddition is certainly one

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of the simplest and most effective methods for covalently assembling even very complex molecules to form a 1,4-disubstituted 1,2,3 triazole (Figure 3.13). This reaction has been applied in organic synthesis, medicinal chemistry, molecular biology and materials chemistry (Wu and Fokin 2007). The reaction is catalyzed by Cu(I) that can be introduced directly using salts (CuI, CuBr), or generated in situ by reducing Cu(II) (copper sulfate or acetate) with sodium ascorbate. Many studies are aimed at developing stable and effective copper(I) catalysts in aqueous environments (Özçubukçu et al. 2009; Ali et al. 2014; Zhou et al. 2015). Surfactants or phase transfer agents have also been used (Dwars et al. 2005; Holmberg 2007; Shin et al. 2012; Lipshutz et al. 2013; Lipshutz and Ghorai 2014; Tasca et al. 2015). Recently, it has been shown that the use of betaine as a simple zwiterionic surfactant allows cycloaddition with very small amounts of copper (2.5–200 ppm) (Figure 3.20) (Shin et al. 2017).

Figure 3.20. Synthesis of 1,4 disubstituted 1,2,3 triazoles 52 by azide alkyne cycloaddition

The triazole unit is present in many commercial pharmaceutical compounds (Baumann et al. 2011), particularly in rufinamide 56 (Figure 3.21) used in the treatment of epilepsy. One of the syntheses, developed by Novartis, consists of a [3+2] cycloaddition followed by an aromatization by HCl elimination. As this acid catalyzes the polymerization of the acrylic derivative, the triazole yield is impacted. In order to avoid this secondary reaction, conditions on water have been developed: triazole was obtained in the organic phase consisting of the reagents while the hydrochloric acid formed was solubilized in water minimizing the side polymerization reaction (Portmann 1998).

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Figure 3.21. Synthesis of rufinamide 56, advantage of the on-water conditions for the cycloaddition

Synthesis of 1,5-disubstituted regioisomers using water as the solvent has been described either from substituted vinyl sulfone in an “on water” procedure that did not require a catalyst (Dey et al. 2011) (Figure 3.22), or from azides and alkynes using a nickel catalyst (Kim et al. 2017). Access to substituted 5-amido derivatives has also been described using an iridium catalyst (Song and Zheng 2017).

Figure 3.22. Synthesis of 1,5-disubstituted 1,2,3 triazoles 58 by azide-vinyl sulfone cycloaddition

The cycloaddition in water between azide anion and different nitriles in the presence of zinc bromide provides convenient access to the 1H-tetrazoles 60 (Demko and Sharpless 2001) (Figure 3.23). Bismuth chloride has been shown to be a good catalyst for this reaction in aqueous media (Coca et al. 2015).

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Figure 3.23. Synthesis of 1-H tetrazoles by cycloaddition of sodium azide and nitriles in water

3.4.1.3. [4+3] cycloadditions The cycloaddition of α-α’ dihalogen ketones 61 with furan or cyclopentadiene has been described in the presence of Fe2(CO)9 in benzene. These absolutely non-green conditions have been advantageously replaced by water and iron powder. The oxyallyl cations thus generated could be trapped by dienes to give the cycloadducts with almost quantitative yields. These cations could also be obtained from α-monohalogen ketones using an aqueous base (Lubineau and Bouchain 1997; Lautens and Bouchain 2003). The increase in rate, efficiency and stereoselectivity was explained by the high cohesive energy and polarity of water (Figure 3.24).

Figure 3.24. [4+3] cycloadditions in aqueous medium

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3.4.1.4. Claisen rearrangement Claisen rearrangement is also a reaction with a negative activation volume that is accelerated in water. The uncatalyzed conversion of chorismate 64 to prephenate 65 was 100 times faster in water than in methanol (Figure 3.25) (Repasky et al. 2003).

Figure 3.25. Uncatalyzed rearrangement of chorismate to prephenate

On-water conditions can also be much better compared to conventional organic solvents (Narayan et al. 2005) (Figure 3.26). Numerous studies have been done to rationalize the accelerations observed in and on water (Grieco et al. 1989; Acevedo and Armacost 2010).

Figure 3.26. Claisen transposition

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3.4.2. Addition reactions of carbonyl derivatives 3.4.2.1. Aldolization-type reactions While condensation between a silylated enol ether and an aldehyde mainly led to the anti adduct when carried out in an anhydrous medium in the presence of a stoichiometric amount of titanium tetrachloride (Mukayiama conditions), it preferentially gave the syn hydroxy ketone in an aqueous medium (Lubineau 1986). This selectivity, similar to that obtained under high pressure, was explained by considering that the most compact transition state is favored in water. The reaction yield was significantly improved by the use of catalysts such as water-stable Lewis acids developed by the Kobayachi group, lanthanide triflates or salts of Fe(II), Cu(II) etc., which accelerate the condensation compared to the competitive hydrolysis reaction of silylated ether and that can often be recycled (Kobayashi and Ogawa 2006; Kobayashi et al. 2007). In particular, catalyst recycling was facilitated by immobilizing scandium triflate on silica gel. The aldolization reaction was performed in water with this catalyst in the presence of ionic liquids, the latter creating a hydrophobic environment that promoted reactivity (Gu et al. 2006). Examples of enantioselective reactions using chiral ligands of these water-stable Lewis acids have also been described (Hamada et al. 2003; Jankowska et al. 2007; Mei et al. 2012; Ollevier and Plancq 2012; Woyciechowska et al. 2012); however, in most cases, reactions were conducted in mixtures of aqueous solvents (e.g. EtOH/ H2O, 91). More recently, metallo-enzyme systems have been proposed (Kitanosono and Kobayashi 2015) to catalyze the direct aldol condensation of formaldehyde with various ketones in water. The use of organocatalysts in the presence of metals also allowed the reaction to be carried out without pre-synthesizing the enol ether (Mlynarski and Bas 2014). Examples include the combination of zinc (II) and proline (Darbre and Machuqueiro 2003; Fernandez-Lopez et al. 2005) or scandium triflate and proline derivatives (Mase et al. 2006), but the most important efforts are related to the use of metalfree organocatalytic systems (Jimeno 2016). Such supported organocatalysts have been developed to allow recycling (Figure 3.27)

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(Font et al. 2006, 2008; Gruttadauria et al. 2008; Huerta et al. 2013; Llanes et al. 2016; Xu et al. 2016).

Figure 3.27. Examples of polystyrene (PS) supported organocatalysts for the aldolization reaction

Another approach for effective recycling of organocatalysts is to graft them onto surfactants to make them water soluble. Thus, compound 70 (Figure 3.28) formed micelles and catalyzed the aldol condensation of water-soluble or insoluble substrates and the catalyst was easily recycled because it remained in the aqueous phase, while the products were extracted with an organic solvent (Lipshutz and Ghorai 2012).

Figure 3.28. Surfactant-grafted organocatalyst to facilitate recycling

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Other reactions, such as the Henry reaction (Ballini and Bosica 1997; Jammi and Punniyamurthy 2009; Chintala et al. 2011; Karmakar et al. 2014) (reaction between nitroalkane and aldehyde), and the Mannich reaction (Hamada et al. 2004; Song et al. 2007; Bae et al. 2016) (condensation of ketones with secondary amines in the presence of formaldehyde) were effectively performed in aqueous media. Although involving a dehydration step, the Knoevenagel reaction could be performed in an aqueous medium (Deba and Bhuyan 2005; Bigi and Quarantelli 2012; Yu and Wang 2012; He et al. 2016). This reaction, applied to unprotected sugars (Scherrmann 2010; Queneau et al. 2011), provided simple and efficient access to C-glycosides (Riemann et al. 2002; Hersant et al. 2004; Bragnier and Scherrmann 2005; Graziani et al. 2005). The reaction products depend on the acidic or basic conditions used: in the presence of cerium chloride (Misra and Agnihotri 2004) or indium chloride (Yadav et al. 2007), D-glucose 71 and pentanedione 72 led to C-furyl glucoside 73 while β-C-glucoside 74 ketone was obtained under basic conditions (Figure 3.29) (Rodrigues et al. 2000).

Figure 3.29. Knoevenagel reactions between d-glucose and pentanedione under acidic or basic conditions

This condensation, applied to xylose 75, a sugar widely present in inedible plant biomass, was used in an industrial process to prepare Pro-Xylane® 77, an anti-aging compound (Cavezza et al. 2009). Conditions have been optimized to reduce the environmental factor (E = waste mass/product mass) (Sheldon 1992) of the process (Leseurre et al. 2014) (Figure 3.30).

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Figure 3.30. Synthesis of Pro-Xylane® (L’Oréal), process improvement to reduce the environmental factor

3.4.2.2. Michael-type reactions The effect of water on the Michael reaction between nitroalkanes and methylvinyl ketone has been observed during the transition from non-polar solvents to water. This reaction took place in water without addition of a base, whereas it did not take place without a catalyst in an aprotic solvent or in neat conditions (Lubineau and Augé 1992). The first asymmetric version of this type of reaction in an aqueous medium was described by the Kobayashi group (Kobayashi et al. 2001) (Figure 3.31).

Figure 3.31. Addition of asymmetric Michael in water

Since then, many catalysts for carrying out enantioselective reactions in aqueous media have been proposed (Coquière et al. 2007; Dijk et al. 2010; Mao et al. 2010; Zheng et al. 2010; Resch et al.

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2013; Rogozińska-Szymczak and Mlynarski 2015), and mechanistic studies to understand the role of water have been conducted (Świderek et al. 2018). An example that fits well into the field of green chemistry is the synthesis of the enantiomers of warfarin 84 (Kucherenko et al. 2018) (Figure 3.32). Catalysts (S,S)-83 and (R,R)-83 were used in the presence of (R)or (S) mandelic acid ((R)-MA or (S)-MA), respectively, for the synthesis of the two enantiomers of warfarin 84 (Figure 3.32). The purification technique used consists of precipitation and crystallization and has enabled this anticoagulant to be obtained with enantiomeric excesses greater than 99%. The catalytic system could be recycled five times. Also for recycling purposes, organocatalysts supported on polystyrene (Alza et al. 2007) or DNA (Dey et al. 2017) have been prepared and used to catalyze the Michael reaction in aqueous media in an enantioselective and efficient manner.

Figure 3.32. Synthesis of warfarin enantiomers

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The Baylis–Hillman reaction, which involves the conjugated addition of a tertiary amine to acrylonitrile, was also accelerated in aqueous media (Figure 3.33) (Augé et al. 1994; Yu et al. 2001; Krishna et al. 2003; Roy and Sunoj 2008).

Figure 3.33. Baylis–Hillman reaction

3.4.2.3. Barber-type allylation reactions Allylation of carbonyl derivatives in aqueous media can be performed in the presence of tin, zinc, antimony, bismuth, cobalt, gallium, iron, magnesium, mercury manganese and indium (Li 2005, 2007). Since it does not require prior protection of hydroxyl functional groups, it has been widely used to modify unprotected sugars (Scherrmann et al. 2010). Indium is stable in water, resistant to air oxidation and has a very low initial ionization potential (5.8 eV). The α-hydroxyaldehydes 90 are the most reactive compounds and gave a syn selectivity due to chelation in the reaction intermediate. Oxygenated aldehydes, such as 92, also gave a chelated intermediate that led to anti-selectivity (Figure 3.34) (Tan et al. 2003).

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Figure 3.34. Selectivity of addition reactions of allyl bromide in the presence of indium on α and β-hydroxy aldehydes

The reaction involving γ-substituted allylic bromides leads to γ isomers except in the case of silylated substituents or in the case of a tertiary butyl substituent. Anti compounds were mainly obtained (Figure 3.35).

Figure 3.35. Selectivity of addition reactions of γ-substituted allylic bromides

3.4.3. Coupling reactions catalyzed by transition metals Organometallic catalysis in aqueous media has undergone significant development (Sinou 2002; Leseurre et al. 2010; Li and Dixneuf 2013). There are many benefits of the use of water in this

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area: products are easily separated, costs are reduced, safety is increased and catalysts are more easily recycled. Reactions are most often catalyzed by metals chelated by water-soluble ligands bearing ionic groups, including triphenylphosphine trisulfonate (tppts) 59, which is certainly the most widely used, or neutral polar groups and supported ligands, in such a way that the catalysts could be easily recovered (Figure 3.36) (Lamblin et al. 2010).

Figure 3.36. Some examples of water-soluble ligands and polystyrene (PS) supported catalysts

3.4.3.1. Formation of carbon-carbon bonds 3.4.3.1.1. The Heck reaction The Heck reaction forms a carbon–carbon bond by ethynylation or arylation of alkenes in the presence of a palladium catalyst. The reaction of aryl halides with acrylic acid or its esters, or acrylonitrile, took place in water in the presence of palladium acetate and a base with good yields. The use of water-soluble ligands allowed this reaction to be carried out in a few hours under mild conditions (Uozumi and Watanabe 1999; Botella and Nájera 2004, 2005; Arvela et al. 2007). Recently, it has been shown that Pd(PPh3)4 could also be used to carry out the coupling reaction, the catalyst being recycled 10 times by a simple procedure (Figure 3.37) (Jadhav and Rode 2017).

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Figure 3.37. Heck coupling

3.4.3.1.2. The Sonogashira reaction Similarly, the coupling of terminal alkynes with aromatic or vinyl halides was possible in an aqueous medium (Lopez-Deber et al. 2001). In this case too, the catalyst was palladium and the addition of copper increased the reactivity of the system (Sonogashira reaction). This reaction could also be carried out on water using insoluble catalysts (Soberats et al. 2009). For example, iodobenzene 108 reacted with phenyl acetylene 109 in the presence of Pd(PPh3)4 and CuI to synthesize the coupling product 110 in good yield (Bhattacharya and Sengupta 2004) (Figure 3.38).

Figure 3.38. Sonogashira reaction

Alkynylation could also be performed using only palladium, referred to as Heck alkynylation or Sonogashira coupling in the absence of copper (Zhou et al. 2014). 3.4.3.1.3. Suzuki, Negishi and Stille coupling The Suzuki reaction takes place between aryl halides or triflates and boronic acids or esters in the presence of a base and Pd(0). The reaction in aqueous medium (Chatterjee and Ward 2016) has been described without ligands. In this case, the use of tetrabutylammonium bromide in a stoichiometric quantity makes it possible to obtain coupling products under very mild conditions in good yields (Figure 3.39) (Badone et al. 1997).

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Other catalysts have been developed to allow recycling (Liu et al. 2011; Hao et al. 2015; Mpungose et al. 2017; Wang et al. 2017; Dadras et al. 2018).

Figure 3.39. Suzuki coupling reaction

Negishi coupling involves the reaction of a halogenated derivative on an organozinc compound, usually in the presence of palladium (0). It is only recently that this reaction has been successfully carried out in an aqueous medium. The use of a non-ionic amphiphilic derivative (PTS, Figure 3.40) has allowed cross-coupling between alkyl and alkenyl bromides in the presence of zinc powder in water at room temperature to give the coupled products with good yields without prior organozinc reagent formation (Krasovskiy et al. 2010).

Figure 3.40. Negishi coupling with in situ organozinc formation

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The coupling reaction involving organostannanes (Stille reaction) also took place in an aqueous solution using palladium catalysts (Coelho et al. 2007). In the context of green chemistry, however, this reaction should be avoided since it involves tin derivatives, which are generally toxic. 3.4.3.1.4. Tsuji–Trost allylation π-Allylpalladium complexes can react with multiple nucleophiles to create carbon–carbon or carbon–heteroatom bonds (Tsuji–Trost reaction). The Sinou group described allyl derivative substitution reactions (Sigismondi and Sinou 1997), where the use of a biphasic medium allowed the products of the reaction to be easily separated and the catalyst recycled (Figure 3.41).

Figure 3.41. Tsuji-Trost reaction in a water–acetonitrile medium

In some cases, a different selectivity is observed when the reaction is carried out in an organic solvent compared to biphasic conditions. For example, the reaction of uracil 119 with E-cinnamyl acetate 120 in the presence of Pd(PPh3)4 in THF gave a mixture of mono and diallylated products while in the water-acetonitrile system in the presence of Pd(OAc)2 and TPPTS, only the monoallylated product at N1 121 is obtained in good yield (Goux et al. 1996) (Figure 3.42).

Figure 3.42. Tsuji–Trost reaction of uracil

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Other catalysts, such as palladium nanoparticles (Llevot et al. 2017) or supported catalysts (Lamblin et al. 2010), can be used and recycled efficiently. In some cases, the reaction may also take place in an aqueous medium in the absence of a metal catalyst (Chevrin et al. 2003; Ghorpade et al. 2018). The use of chiral ligands allows the stereochemical control of the reaction. Some chiral ligands supported on polystyrene–polyethylene glycol resin allowed enantiomeric excesses of up to 98% for Tsuji– Trost reactions of cyclic and acyclic compounds in an aqueous medium. The catalyst could easily be recovered and recycled without a decrease in yield (Uozumi and Shibatomi 2001). The allylation reaction could also be performed via transmetallation of π−allylpalladium in an aqueous medium (Franke et al. 2012). 3.4.3.1.5. Carbonylation, hydroformylation of alkenes The hydroformylation reaction of alkenes in aqueous media is an important industrial process (section 3.6). This reaction could be carried out in a biphasic medium with rhodium catalysts in the presence of tppts. The water-soluble catalyst could easily be separated from the products by decantation and recycled (Fontana et al. 2005). 3.4.3.1.6. Olefin metatheses The metathesis reaction (Figure 3.43) could be performed in an aqueous medium (Tomasek and Schatz 2013) using either insoluble catalysts, possibly in the presence of surfactants (Davis and Sinou 2002; Lipshutz et al. 2008), ultrasound (Gułajski et al. 2008) or watersoluble catalysts (Gallivan et al. 2005; Hong and Grubbs 2006; Jordan and Grubbs 2007; Samanta et al. 2008) (Figure 3.44).

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Figure 3.43. Ring-closing reaction by metathesis in water

Figure 3.44. Examples of water-soluble catalysts for the metathesis reaction

3.4.3.1.7. Cyclopropanation Rhodium(II) complexes are used in cyclopropanation reactions. Generally, this reaction should be conducted under anhydrous conditions in order to avoid the competitive hydroxyl insertion reaction leading to 129 (Figure 3.45). The cyclopropanation reaction is likely to occur due to its heterogeneous nature. The hydrophobic catalyst migrates in the “alkene” phase. Ethyldiazoacetate 128 being quite soluble in water, it diffuses slowly in the alkene phase leading preferentially to the formation of cyclopropanes (Wurz and Charette 2002).

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Figure 3.45. Rh(II)-catalyzed cyclopropanation in an aqueous medium

3.4.3.2. Formation of carbon–nitrogen bonds 3.4.3.2.1. Buchwald–Hartwig amination reactions The Buchwald–Hartwig reaction is a palladium-catalyzed coupling between aryl halides (or triflates) and primary or secondary amines. This reaction could be performed in an aqueous medium in the presence of surfactants (Lipshutz et al. 2011; Isley et al. 2014; Wagner et al. 2014) (Figure 3.46).

Figure 3.46. Buchwald–Hartwig reaction in the presence of surfactant TGPS750-M, recycling of catalyst for four cycles

3.4.3.2.2. Ullmann amination reactions Ullmann-type reactions are catalyzed by copper, they consist of an aromatic nucleophilic substitution of aryl halides by various

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nucleophiles including amines. These N-arylation reactions have been described in water and a recent example describes micellar conditions for performing the reaction under mild conditions (ambient temperature or 50°C) in the presence of D-glucose whose role is to reduce Cu(II) to Cu(I) during the catalytic cycle (Bollenbach et al. 2016) (Figure 3.47).

Figure 3.47. Ullmann N-arylation in the presence of d-glucose and under micellar conditions

3.4.4. Radical reactions Water is also the solvent of choice for carrying out some radical reactions, and remarkable results have been obtained (Yorimitsu and Oshima 2002; Postigo and Nudelman 2011). The cyclization reaction of iodoacetates 136 was significantly more effective in aqueous media than in organic solvents (Yorimitsu et al. 2000) (Figure 3.48).

Figure 3.48. Solvent effect for the radical cyclization reaction

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In the case of particularly hydrophobic molecules, the use of watersoluble radical initiators and surfactants has made it possible to carry out radical cyclizations with good yields (Nambu et al. 2002). Intermolecular radical couplings of α brominated carbonyl derivatives on alkenes (Yorimitsu et al. 2001) or on allylgallium derivatives were also effectively carried out in water Similarly, alkyl radicals generated by indium (Miyabe et al. 2002), triethylborane or zinc (Ueda et al. 2005) gave rise to an addition to imines in aqueous medium, whereas this reaction did not occur in dichloromethane (Figure 3.49) (Miyabe et al. 2000). On-water conditions are also effective for radical reactions such as copper-catalyzed trimethylation of acrylamide (Yang et al. 2014) or addition on C=N bonds of hydrazones (Nam and Jang 2018).

Figure 3.49. Solvent effect for the addition reaction of the propyl radical

3.4.5. Oxidation and reduction reactions 3.4.5.1. Oxidation Potassium permanganate, sodium or calcium hypochlorite and chromic acid are conventionally used in aqueous media but are not green oxidants. Much effort has been made to use oxygen, or hydrogen peroxide, which only generates water as a by-product, in oxidation reactions (Bryliakov 2017). Among the many methods for epoxidizing alkenes with hydrogen peroxide (Clark et al. 2003), the two-phase method using

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tetraalkylammonium bisulfate as a phase transfer agent in the presence of sodium tungstate (Noyori et al. 2003) is an example (Figure 3.50). The same system is effective for the direct oxidation of cyclohexene to adipic acid (Sato et al. 1998).

Figure 3.50. Epoxidation of alkenes with aqueous H2O2

Recently, a recyclable yolk-shell catalyst system has been proposed to perform the epoxidation reaction with oxygen on water (Nabid et al. 2014). This catalyst consists of a magnetic core and a porous carbon shell derived from chitosan, covered with tiny nanoparticles with a silver-coated copper core, these nanoparticles being retained in the porous carbon layer (Figure 3.51). This catalyst was easily recovered from the reaction medium by “magnetic extraction” and could be recycled eight times without loss of activity.

Figure 3.51. Epoxidation of styrene by O2 in the presence of a magnetic core catalyst. For a color version of this figure, see www.iste.co.uk/malacria/biphasic.zip

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Efforts have also been made to develop asymmetric versions of this reaction using chiral organometallic catalysts (Colladon et al. 2007; Malkov et al. 2009; Sgarbossa et al. 2012; Ballistreri et al. 2016). Epoxidation of α,β-unsaturated carbonyl derivatives has been described in an aqueous medium in the presence of a phase transfer catalyst (Fioroni et al. 2003) or hydrotrope (Sela et al. 2017) and in asymmetric version in the presence of pyrrolidine 146 as an organocatalyst (Zhuang et al. 2005). Epoxy-aldehydes 145 were obtained with enantiometric excesses between 85 and 96% and modest yields (Figure 3.52).

Figure 3.52. Asymmetric epoxidation of α,β-unsaturated aldehydes in the presence of an organocatalyst

The oxidation of alcohols with oxygen or hydrogen peroxide has also been studied in aqueous media (Sheldon 2015). The system using sodium tungstate in the presence of a phase transfer agent is used to oxidize secondary alcohols to ketones by H2O2. The efficiency is such that 0.002 mol% of the catalyst and phase transfer agent was sufficient to give excellent oxidation yields of various alcohols with 1.1 equivalent of hydrogen peroxide (Maheswari et al. 2005) (Figure 3.53).

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Figure 3.53. Oxidation of alcohols by H2O2

Primary alcohols can be oxidized by hydrogen peroxide in the presence of a Fe(III) catalyst made water-soluble by an ammonium ligand (Yan et al. 2017) (Figure 3.54).

Figure 3.54. Oxidation of a primary alcohol by H2O2 in the presence of Fe(III)

Oxidations catalyzed by palladium in aqueous media are numerous. The oxidation of ethylene to acetaldehyde in water by

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oxygen in the presence of palladium and copper(II), allowing palladium to be reoxidized at the end of the catalytic cycle, is well known as the Wacker process (Hintermann 2008). Bayer–Villiger oxidation with soluble (persuccinic) (Meziane et al. 1998) or insoluble (meta-chloroperoxybenzoic acid) peracids is very rapid in water, however, the atom economy of reactions using such oxidants is low. Oxidation of cyclobutanones by Bayer–Villiger was carried out with hydrogen peroxide under micellar conditions in the presence of cobalt-salt complexes (Bianchini et al. 2009) or Pt(II) (Cavarzan et al. 2009, 2010). Amine oxidation reactions could be carried out in aqueous media to give oximes 154 with oxygen in the presence of alkoxyamine 152 and acetaldehyde 153 (Yu et al. 2015) or imines by oxidation with sodium hypochlorite (de Souza et al. 2017) (Figure 3.55).

Figure 3.55. Oxidation of amines to oximes 154 or imines 155

3.4.5.2. Reductions The hydrogenation reaction was one of the first transition metal catalyzed reactions to be studied in an aqueous medium. The hydrogenation of various unsaturated substrates was carried out in

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water or in a biphasic medium using rhodium, ruthenium (Dwars and Oehme 2002) or palladium (Callis et al. 2007) catalysts. Ruthenium or rhodium complexes associated with chiral watersoluble ligands gave enantioselectivities similar to those obtained in organic media (Tóth et al. 1990) (Figure 3.56).

Figure 3.56. Asymmetric reduction in aqueous medium

Other hydrogen sources such as sodium formate could be used (Wei et al. 2015) or Hantzsch esters (Rueping and Theissmann 2010) as in the case of the enantioselective reduction of quinolein 158 by hydrogen transfer catalyzed by the Brønsted acid 160 (Figure 3.57).

Figure 3.57. Hydrogen transfer by Hantzsch ester 159 catalyzed by chiral Brønsted acid 160

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Hydrogen transfer was also used for the enantioselective reduction of carbonyl derivatives. Different catalysts have been described, based on iridium(III), rhodium(III) or ruthenium(II) (Wu et al. 2008, 2010; Ariger and Carreira 2012; Yang et al. 2017). Another strategy is based on the use of chiral surfactants (Li et al. 2012, 2017). 3.5. Multistep syntheses As illustrated above, examples of reactions in aqueous environments are numerous and techniques have been developed to avoid using organic solvents for the isolation and purification steps. Examples of multistep syntheses in water are still rare. Various tetrahydro-1,3-oxazines were prepared via a Baylis–Hillman reaction, a Michael addition followed by cyclization with formaldehyde. The use of water for most synthesis and purification steps was possible using an approach in which substrate 162 was covalently bound to polyethylene glycol to ensure the solubility of the compounds and allow ultrafiltration separations from aqueous media. This multistep synthesis was also carried out using microreactors used in continuous flow (Prosa et al. 2012) (Figure 3.58), a technique recently recognized as a green chemistry tool because it allows efficient mass and heat transfers and small volumes of reaction media, which improves process safety.

Figure 3.58. Synthesis of tetrahydro-1,3-oxazines

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A multistep synthesis of Ranolazin 171 (Figure 3.59), used in the treatment of angina, has been described in three steps in water, this, as well as the intermediate compounds 169 and 170, being isolated pure by simple filtration from aqueous media (Kommi et al. 2013).

Figure 3.59. Synthesis of Ranolazin 171

3.6. Industrial applications The benefits of using water as a solvent in the industry are numerous. Water is the cheapest solvent; it is non-toxic, nonflammable and processes carried out in aqueous media often allow easy separation of products by simple decantation. The most remarkable example of industrial development using water as a reaction medium is certainly the hydroformylation process developed by Ruhrchemie/Rhône-Poulenc, which produces more than 11,000,000 tons per year. It concerns the transformation of propene into n and iso-butyraldehyde or butene into valeraldehyde (Figure 3.60). The catalyst (HRh(CO) (TPPTS)3) is prepared by mixing a Rhodium salt with an aqueous solution of tppts. At the end of the

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reaction, the products are recovered by decantation, the catalyst solution remaining almost entirely in the reactor. This process produces butanals with yields of 99% and n/iso selectivity of 98:2 (Wiebus and Cornils 2007).

Figure 3.60. Hydroformylation of propene

Other processes using water as a solvent have been developed industrially (Joó and Kathó 2010; Mori and Kobayashi 2012). These include the hydrodimerization of butadiene and water to 2,7-ocadienol (Kuraray process), the hydrocyanation of butadiene or the Wacker process. In addition to the reactions catalyzed by transition metals, other applications are developing. In particular, L’Oréal uses the condensation of a β-diketone on unprotected xylose in an aqueous medium in the first stage of preparation of Pro-Xylane (Dalko and Breton 2002; Philippe and Semeria 2002). 3.7. Conclusion The work of many teams has demonstrated that water is a solvent of choice for most organic synthesis reactions. Very often, particular selectivities are obtained in this medium and the effects on the thermodynamics of the reactions make it possible to operate at lower temperatures, which is a way of saving energy. The implementation of such reactions in the laboratory is obviously much simpler than those requiring anhydrous conditions. Green chemistry includes biotransformations. Because of the development of biotechnologies allowing the production of stable enzymes and various activities, these catalysts used are commercially available and are an important tool for chemistry in aqueous media.

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Remarkable advances in the field of transition metal catalysis have made it possible to develop industrial processes in which the aqueous phase is completely recycled, reducing the amount of waste. The advantages of using water as a synthetic solvent are therefore numerous. Research in this area will certainly lead to further reactions, the discovery of new mechanisms, the invention of effective reagents and catalysts, and innovation in separation and recycling techniques. Although already used for large tonnage production, efforts still need to be made to transfer chemical advances in and on water in the industrial field. 3.8. References Acevedo, O., Armacost, K. (2010). Claisen rearrangements: Insight into solvent effects and “on water” reactivity from QM/MM simulations. J. Am. Chem. Soc., 132, 1966–1975. Ali, A.A., Chetia, M., Saikia, P.J., Sarma, D. (2014). (DHQD)2PHAL ligandaccelerated Cu-catalyzed azide-alkyne cycloaddition reactions in water at room temperature. RSC Adv., 4, 64388–64392. Alza, E., Cambeiro, X.C., Jimeno, C., Pericàs, M.A. (2007). Highly enantioselective Michael additions in water catalyzed by a PS-supported pyrrolidine. Org. Lett., 9(19), 3717–3720. Anastas, P.T., Li, C.-J. (eds) (2010). Handbook of Green Chemistry. Vol. 5: Green Solvents, Reactions in Water. Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. Anastas, P.T., Warner, J.C. (1998). Green Chemistry: Theory and Practise. Oxford University Press, New York. Ariger, M.A., Carreira, E.M. (2012). pH-independent transfer hydrogenation in water: Catalytic, enantioselective reduction of β-Keto esters. Org. Lett., 14, 4522–4524. Arvela, R.K., Pasquini, S., Larhed, M. (2007). Highly regioselective internal heck arylation of hydroxyalkyl vinyl ethers by aryl halides in water. J. Org. Chem., 72, 6390–6396. Augé, J., Lubin, N., Lubineau, A. (1994). Acceleration in water of the BaylisHillman reaction. Tetrahedron Lett., 35, 7947–7948.

146

Biphasic Chemistry and The Solvent Case

Badone, D., Baroni, M., Cardamone, R., Ielmini, A., Guzzi, U. (1997). Highly efficient palladium-catalyzed boronic acid coupling reactions in water: Scope and limitations. J. Org. Chem., 62, 7170–7173. Bae, H.Y., Kim, M.J., Sim, J.H., Song, C.E. (2016). Direct catalytic asymmetric Mannich reaction with dithiomalonates as excellent Mannich donors: Organo-catalytic synthesis of (R)-sitagliptin. Angew. Chem., Int. Ed., 55, 10825–10829. Ballini, R., Bosica, G. (1997). Nitroaldol reaction in aqueous media: An important improvement of the Henry reaction. J. Org. Chem., 62, 425– 427. Ballistreri, F.P., Gangemi, C.M.A., Pappalardo, A., Tomaselli, G.A., Toscano, R.M., Sfrazzetto, G.T. (2016). (Salen)Mn(III) Catalyzed asymmetric epoxidation reactions by hydrogen peroxide in water: A green protocol. Int. J. Mol. Sci., 17, 1112. Bauke, A.H., Rosati, F., Coquière, D., Roelfes, G., Liskamp, R.M.J. (2011). Enantioselective CuII-catalyzed Diels-Alder and Michael addition reactions in water using bio-inspired triazacyclophane-based ligands. Eur. J. Org. Chem., 9, 1714–1720. Baumann, M., Baxendale, I.R., Ley, S.V., Nikbin, N. (2011). An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals. Beilstein J. Org. Chem., 7, 442–495. Bhattacharya, S., Sengupta, S. (2004). Palladium catalyzed alkynylation of aryl halides (Sonogashira reaction) in water. Tetrahedron Lett., 45, 8733– 8736. Bianchini, G., Cavarzan, A., Scarso, A., Strukul, G. (2009). Asymmetric Baeyer-Villiger oxidation with Co(Salen) and H2O2 in water: Striking supramolecular micelles effect on catalysis. Green Chem., 11, 1517– 1520. Bigi, F., Quarantelli, C. (2012). The Knoevenagel condensation in water. Curr. Org. Synth., 9, 31–39. Blackmond, D.G., Armstrong, A., Coombe, V., Wells, A. (2007). Water in organo-catalytic processes: Debunking the myths. Angew. Chem. Int. Ed., 46, 3798–3800. Blokzijl, W., Engberts, J.B.F.N. (1993). Hydrophobic effects. Opinions and facts. Angew. Chem. Int. Ed., 32, 1545–1579.

Chemistry In and On Water

147

Bollenbach, M., Wagner, P., Aquino, P.G.V., Bourguignon, J.-J., Bihel, F., Salom, C., Schmitt, M. (2016). D-Glucose: An efficient reducing agent for a Copper(II)-mediated arylation of primary amines in water. ChemSusChem, 9, 3244–3249. Botella, L., Nájera, C. (2004). Synthesis of methylated resveratrol and analogues by Heck reactions in organic and aqueous solvents. Tetrahedron, 60, 5563–5570. Botella, L., Nájera, C. (2005). Mono- and β,β-double-Heck reactions of α,βunsaturated carbonyl compounds in aqueous media. J. Org. Chem., 70, 4360–4369. Bragnier, N., Scherrmann, M.-C. (2005). One step synthesis of β-Cglycosidic ketones in aqueous media: The case of 2-acetamido sugars. Synthesis, 5, 814–818. Breslow, R. (1991). Hydrophobic effects on simple organic reactions in water. Acc. Chem. Res., 1991, 24, 159–164. Breslow, R., Rizzo, C.J. (1991). Chaotropic salt effects in a hydrophobically accelerated Diels-Alder reaction. J. Am. Chem. Soc., 113, 4340–4341. Breslow, R., Zhu, Z. (1995). Quantitative antihydrophobic effects as probes for transition state structures. 2. Diels-Alder reactions. J. Am. Chem. Soc., 117(39), 9923–9924. Breslow, R., Groves, K., Mayer, M.U. (1998). The hydrophobic effect as a mechanistic tool. Pure Appl. Chem., 70(10), 1933–1938. Brogan, A.P., Dickerson, T.J., Janda, K.D. (2006). Enamine-based aldol organo-catalysis in water: Are they really “all wet”? Angew. Chem. Int. Ed., 45, 8100–8102. Bryliakov, K.P. (2017). Catalytic asymmetric oxygenations with the environmentally benign oxidants H2O2 and O2. Chem. Rev., 117, 11406– 11459. Butler, R.N., Coyne, A.G. (2010). Water: Nature’s reaction enforcers comparative effects for organic synthesis “in-water” and “on-water”. Chem. Rev., 110, 6302. Butler, R.N., Coyne, A.G., Cunningham, W.J., Burke, L.A. (2002). Kinetic and synthetic influences of water and solvent-free conditions on 1,3dipolar cycloaddition reactions: The phthalazinium and pyridazinium dicyanomethanide 1,3-dipoles: surprisingly successful synthetic methods. J. Chem. Soc. Perkin Trans. 2, 1807–1815.

148

Biphasic Chemistry and The Solvent Case

Butler, R.N., Coyne, A.G., Moloney, E.M. (2007). Organic synthesis in water: 1,3-Dipolar cycloaddition reactions at ambient temperature with aqueous suspensions of solid reactants. Tetrahedron Lett., 48, 3501. Butler, R.N., Coyne, A.G., Cunningham, W.J., Moloney, E.M. (2013). Water and organic synthesis: A focus on the in-water and on-water border. Reversal of the in-water Breslow hydrophobic enhancement of the normal endo-effect on crossing to on-water conditions for Huisgen cycloadditions with increasingly insoluble organic liquid and solid 2π-dipolarophiles. J. Org. Chem., 78, 3276–3291. Callis, N.M., Thiery, E., Le Bras, J., Muzart, J. (2007). Palladium nanoparticles-catalyzed chemoselective hydrogenations, a recyclable system in water. Tetrahedron Lett., 48, 8128–8131. Cavarzan, A., Bianchini, G., Sgarbossa, P., Lefort, L., Gladiali, S., Scarso, A., Strukul, G. (2009). Catalytic asymmetric Baeyer-Villiger oxidation in water by using PtII catalysts and hydrogen peroxide: Supramolecular control of enantioselectivity. Chem. Eur. J., 15, 7930–7939. Cavarzan, A., Scarso, A., Sgarbossa, P., Michelin, R.A., Strukul, G. (2010). Green catalytic Baeyer-Villiger oxidation with hydrogen peroxide in water mediated by PtII catalysts. ChemCatChem, 2, 1296–1302. Cavezza, A., Boule, C., Guéguiniat, A., Pichaud, P., Trouille, S., Ricard, L., Dalko-Csiba, M. (2009). Synthesis of Pro-XylaneTM: A new biologically active C-glycoside in aqueous media. Bioorg. Med. Chem. Lett., 19, 845– 849. Chandler, D. (2005). Interfaces and the driving force of hydrophobic assembly. Nature, 437, 640–647. Chatterjee, A., Ward, T.R. (2016). Recent advances in the palladium catalyzed Suzuki-Miyaura cross-coupling reaction in water. Catalysis Lett., 146(4), 820. Chevrin, C., Bras, J.L., Hénin, F., Muzart, J. (2003). Water-mediated transition-metal-free Tsuji-Trost-type reaction. Tetrahedron Lett., 44, 8099–8102. Chintala, P., Ghosh, S.K., Long, E., Headley, A.D., Nia, B. (2011). The application of a recyclable organocatalytic system to the asymmetric domino Michael/Henry reaction in aqueous media. Adv. Synth. Catal., 353, 2905–2909.

Chemistry In and On Water

149

Clark, J.H., Elings, J.A., Grigoropoulou, G. (2003). Recent developments on the epoxidation of alkenes using hydrogen peroxide as an oxidant. Green Chem., 5, 1–7. Clarke, C.J., Tu, W.-C., Levers, O., Bröhl, A., Hallett, J.P. (2018). Green and sustainable solvents in chemical processes. Chem. Rev., 118(2), 747–780. Coca, A., Feinn, L., Dudley, J. (2015). Microwave synthesis of 5-substituted 1 H-tetrazoles catalyzed by Bismuth chloride in water. Synth. Commun., 45, 1023–1030. Coelho, A.V., de Souza, A.L.F., de Lima, P.G., Wardell, J.L., Antunes, O.A.C. (2007). Ligand-free stille cross-coupling reaction using Pd/CaCO3 as catalyst reservoir. Tetrahedron Lett., 48, 7671–7674. Colladon, M., Scarso, A., Strukul, G. (2007). Towards a greener epoxidation method: Use of water-surfactant media and catalyst recycling in the platinum-catalyzed asymmetric epoxidation of terminal alkenes with hydrogen peroxide. Adv. Synth. Catal., 349, 797–801. Coquière, D., Feringa, B.L., Roelfes, G. (2007). DNA-based catalytic enantioselective Michael reactions in water. Angew. Chem. Int. Ed., 46, 9308–9311. Cornils, B., Herrmann, W.A., Horvath, I.T., Leitner, W., Mecking, S., Olivier-Bourbigou, H., Vogt, D. (eds) (2005). Multiphase Homogeneous Catalysis, 2 vol. Wiley-VCH, Weinheim. Dadras, A., Naimi-Jamal, M.R., Moghaddam, F.M., Ayati, S.E. (2018). Suzuki-Miyaura coupling reaction in water in the presence of robust palladium immobilized on modified magnetic Fe3O4 nanoparticles as a recoverable catalyst. Appl. Organometal. Chem., 32, 3993. Dalko, M., Breton, L. (2002). Novel C-glycoside derivatives and use thereof, WO 2002051828. Chem. Abstr., 137, 79179. Darbre, T., Machuqueiro, M. (2003). Zn-Proline catalyzed direct Aldol reaction in aqueous media. Chem. Commun., 34, 1090–1091. Davis, K.J., Sinou, D. (2002). Ring closing metathesis in water with or without surfactants in the presence of RuCl2(PPh3)2(CHPh). J. mol. Catal. A: Chem., 177, 173–178. Deba, M.L., Bhuyan, P.J. (2005). Uncatalysed Knoevenagel condensation in aqueous medium at room temperature. Tetrahedron Lett., 46, 6453–6456.

150

Biphasic Chemistry and The Solvent Case

Demko, Z.P., Sharpless, K.B. (2001). Preparation of 5-substituted 1Htetrazoles from nitriles in water. J. Org. Chem., 66, 7945–7950. Dey, S., Datta, D., Pathak, T. (2011). A metal-free, aqueous and general route to 1,5-disubstituted-1,2,3-triazoles: “Reversed regioisomeric” 1,3-dipolar cycloaddition of azides and vinyl sulfones. Synlett, 17, 2521–2524. Dey, S., Rühl, C.L., Jäschke, A. (2017). Catalysis of Michael additions by covalently modified G-quadruplex DNA. Chem. Eur. J., 23, 12162– 12170. Diels, O., Alder, K. (1931). Synthesen in der hydroaromatischen Reihe. XII. Mitteilung. (“Dien-Synthesen” sauerstoffhaltiger Heteroringe. 2. DienSynthesen des Furans.). Ann. Chem., 490, 243–247. Dijk, E.W., Boersma, A.J., Feringa, B.L., Roelfes, G. (2010). On the role of DNA in DNA-based catalytic nantioselective conjugate addition reactions. Org. Biomol. Chem., 8, 3868–3873. Dixneuf, P.H., Cadierno, V. (eds) (2013). Metal-Catalyzed Reactions in Water. Wiley-VCH, Weinheim. Dwars, T., Oehme, G. (2002). Complex-catalyzed hydrogenation reactions in aqueous media. Adv. Synth. Cat., 344, 239–260. Dwars, T., Paetzold, E., Oehme, G. (2005). Reactions in micellar systems. Angew. Chem., Int. Ed., 44, 7174–7199. Fernandez-Lopez, R., Kofoed, J., Machuqueiro, M., Darbre, T. (2005). A selective direct aldol reaction in aqueous media catalyzed by zinc-proline. Eur. J. Org. Chem., 24, 5268–5276. Fioroni, G., Fringuelli, F., Pizzo, F., Vaccaro, L. (2003). Epoxidation of α,βunsaturated ketones in water. An environmentally benign protocol. Green Chem., 5, 425–428. Font, D., Jimeno, C., Pericàs, M.A. (2006). Polystyrene-supported hydroxyproline: An insoluble, recyclable organocatalyst for the asymmetric Aldol reaction in water. Org. Lett., 8, 4653–4655. Font, D., Sayalero, S., Bastero, A., Jimeno, C., Pericàs, M.A. (2008). Toward an artificial aldolase. Org. Lett., 10, 337–340. Fontana, G., Lubineau, A., Scherrmann, M.-C. (2005). Investigation of the aqueous transmetalation of pi-allylpalladium with indium salt: The use of the Pd(OAc)2-TPPTS catalyst. Org. Biomol. Chem., 3, 1375–1380.

Chemistry In and On Water

151

Franke, R., Selent, D., Börner, A. (2012). Applied hydroformylation. Chem. Rev., 112, 5675–5732. Fringuelli, F., Piermatti, O., Pizzo, F., Vaccaro, L. (2001). Recent advances in Lewis acid catalyzed Diels-Alder reactions in aqueous media. Eur. J. Org. Chem., 3, 439–455. Gallivan, J.P., Jordan, J.P., Grubbs, R.H. (2005). A neutral, water-soluble olefin metathesis catalyst based on an N-heterocyclic carbene ligand. Tetrahedron Lett., 46, 2577–2580. Gholami, M.R., Yangjeh, A.H. (1999). Hydrophobic effect in 1,3-dipolar cycloaddition of C,N-diphenylnitrone with dibutyl fumarate in aqueous solution. J. Chem. Res. (S), 3, 226–227. Ghorpade, S.A., Sawant, D.N., Makki, A., Sekar, N., Eppinger, J. (2018). Water promoted allylic nucleophilic substitution reactions of (E)-1,3 diphenylallyl acetate. Green Chem., 20(2), 425–430. Goux, C., Sigismondi, S., Sinou, D., Moreno-Mañas, M., Pleixats, R., Villaroya, M. (1996). Palladium(0)-catalysed allylation of uracils and thiouracils. Influence of the solvent on the regioselectivity of the allylation. Tetrahedron, 52, 9521–9534. Graziani, A., Amer, H., Zamyatina, A., Hofinger, A., Kosma, P. (2005). Synthesis of C-glycosides related to glycero-β-D-manno-heptoses. Tetrahedron: Asymmetry, 16, 167–175. Grieco, P.A., Galatsis, P., Spohn, R.F. (1986). Aqueous intermolecular DielsAlder chemistry. Reaction of (E)-2,4-pentadienyl ammonium chloride and related ammonium salts with dienophiles in water. Tetrahedron, 42, 2847–2853. Grieco, P.A., Brandes, E.B., McCann, S., Clark, J.D. (1989). Water as a solvent for the Claisen rearrangement: Practical implications for synthetic organic chemistry. J. Org. Chem., 54(25), 5849–5851. Gruttadauria, M., Giacalone, F., Marculescu, A.M., Noto, R. (2008). Novel prolinamide-supported polystyrene as highly stereoselective and recyclable organocatalyst for the Aldol reaction. Adv. Synth. Catal., 350, 1397–1405. Gu, Y., Ogawa, C., Kobayashi, J., Mori, Y., Kobayashi, S. (2006). A heterogeneous silica-supported scandium/ionic liquid catalyst system for organic reactions in water. Angew. Chem., Int. Ed., 45, 7217–7220.

152

Biphasic Chemistry and The Solvent Case

Gułajski, Ł., Sledz, P., Lupa, A., Grela, K. (2008). Olefin metathesis in water using acoustic emulsification. Green Chem., 10, 271–274. Hamada, T., Manabe, K., Ishikawa, S., Nagayama, S., Shiro, M., Kobayashi, S. (2003). Catalytic asymmetric Aldol reactions in aqueous media using chiral bis-pyridino-18-crown-6-rare earth metal triflate complexes. J. Am. Chem. Soc., 125, 2989–2996. Hamada, T., Manabe, K., Kobayashi, S. (2004). Enantio- and diastereoselective, stereospecific Mannich-type reactions in water. J. Am. Chem. Soc., 126, 7768–7769. Hao, Y., Jiang, J., Wang, Y., Jin, Z. (2015). An efficient and recyclable thermore-gulated phosphine-palladium catalyst for the carbonylative Suzuki coupling of aryl halides with arylboronic acids in water. Catal. Commun., 71, 106–110. He, T., Shi, R., Gong, Y., Jiang, G., Liu, M., Qian, S., Wang, Z. (2016). Base-promoted cascade approach for the preparation of reduced Knoevenagel adducts using Hantzsch esters as reducing agent in water. Synlett, 27, 1864–1869. Henderson, R.K., Jimenez-Gonzalez, C., Constable, D.J.C., Alston, S.R., Inglis, G.G.A., Fisher, G., Sherwood, J., Binks, S.P., Curzons, A.D. (2011). Expanding GSK’s solvent selection guide – embedding sustainability into solvent selection starting at medicinal chemistry. Green Chem., 13, 854–862. Hersant, Y., Abou-Jneid, R., Canac, Y., Lubineau, A., Philippe, M., Semeria, D., Radisson, X., Scherrmann, M.-C. (2004). One step synthesis of β-Cglycolipid derivatives from unprotected sugars. Carbohydr. Res., 339, 741–745. Higson, S., Subrizi, F., Sheppard, T.D., Hailes, H.C. (2016). Chemical cascades in water for the synthesis of functionalized aromatics from furfurals. Green Chem., 2016, 18, 1855. Hintermann, L. (2008). Wacker-Type Oxidations. In Transition Metals for Organic Synthesis, 2nd ed., Beller, M., Bolm, C. (eds). Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, 379–388. Holmberg, K. (2007). Organic reactions in microemulsions. Eur. J. Org. Chem., 5, 731–742. Hong, S.H., Grubbs, R.H. (2006). Highly active water-soluble olefin metathesis catalyst. J. Am. Chem. Soc., 128, 3508–3509.

Chemistry In and On Water

153

Huerta, E., Stals, P.J.M., Meijer, E.W., Palmans, A.R.A. (2013). Consequences of folding a water-soluble polymer around an organocatalyst. Angew. Chem., Int. Ed., 52, 2906–2910. Isley, N.A., Dobarco, S., Lipshutz, B.H. (2014). Installation of protected ammonia equivalents onto aromatic and heteroaromatic rings in water enabled by micellar catalysis. Green Chem., 16, 1480–1488. Jadhav, S.N., Rode, C.V. (2017). An efficient palladium catalyzed MizorokiHeck cross-coupling in water. Green Chem., 19(24), 5958. Jammi, S., Punniyamurthy, T. (2009). Synthesis, structure and catalysis of tetranuclear copper(II) open cubane for Henry reaction on water. Eur. J. Inorg. Chem., 17, 2508–2511. Jankowska, J., Paradowska, J., Rakiel, B., Mlynarski, J. (2007). Iron(II) and zinc(II) complexes with designed pybox ligand for asymmetric aqueous Mukaiyama-Aldol reactions. J. Org. Chem., 72, 2228–2231. Jimeno, C. (2016). Water in asymmetric organocatalytic systems: A global perspective. Org. Biomol. Chem., 14, 6147–6164. Joó, F., Kathó, Á., (2010). Water as a green solvent for bulk chemicals. In Handbook of Green Chemistry, vol. 5, Anastas, P.T. (ed.). Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, 385–408. Jordan, J.P., Grubbs, R.H. (2007). Small-molecule N-heterocyclic-carbenecontaining olefin-metathesis catalysts for use in water. Angew. Chem., Int. Ed., 46, 5152–5155. Jung, Y., Marcus, R.A. (2007). On the theory of organic catalysis “on water”. J. Am. Chem. Soc., 129, 5492–5502. Karmakar, A., Hazra, S., Guedes da Silva, M.F.C., Pombeiro, A.J.L. (2014). Synthesis, structure and catalytic applications of amidoterephthalate copper complexes in the diastereoselective Henry reaction in aqueous medium. New J. Chem., 38, 4837. Keana, J.F.W., Guzikowski, A.P., Morat, C., Volwerk, J.J. (1983). Detergents containing a 1,3-diene group in the hydrophobic segment. Facile chemical modification by a Diels-Alder reaction with hydrophobic dienophiles in aqueous solution. J. Org. Chem., 48, 2661–2666.

154

Biphasic Chemistry and The Solvent Case

Kim, W.G., Kang, M.E., Lee, J.B., Jeon, M.H., Lee, S., Lee, J., Choi, B., Cal, P.M.S.D., Kang, S., Kee, J.-M., Bernardes, G.J.L., Rohde, J.-U., Choe, W., Hong, S.Y. (2017). Nickel-catalyzed azide-alkyne cylcoaddition to access 1,5-disubstituted 1,2,3-triazoles in air and water. J. Am. Chem. Soc., 139, 12121–12124. Kitanosono, T., Kobayashi, S. (2015). Toward chemistry-based design of the simplest metalloenzyme-like catalyst that works efficiently in water. Chem. Asian J., 10, 133–138. Kitanosono, T., Kobayashi, S. (2017). Water-compatible chiral Lewis acids. In Chiral Lewis Acids in Organic Synthesis, Mlynarski, J. (ed.). WileyVCH Verlag GmbH & Co. KGaA, Weinheim. Kitanosono, T., Masuda, K., Xu, P., Kobayashi, S. (2018). Catalytic organic reactions in water toward sustainable society. Chem. Rev., 118(2), 679. Klijn, J.E., Engberts, J.B.F.N. (2010). Pericyclic reactions in water. Towards green chemistry. In Handbook of Green Chemistry, vol. 5, Green Solvents. Reactions in Water, Anastas, P., Li, C.-J. (eds). Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, 229–271. Kobayashi, S. (ed.) (2012). Water in Organic Synthesis. Thieme, Stuttgart. Kobayashi, S., Ogawa, C. (2006). New entries to water-compatible Lewis acids. Chem. Eur. J., 12, 5954–5960. Kobayashi, S., Kakumoto, K., Mori, Y., Kei, M. (2001). Chiral Lewis acidcatalyzed enantioselective Michael reactions in water. Isr. J. Chem., 41, 247–249. Kobayashi, S., Manabe, K., Nagayama, S. (2007). Activation of carbonyl and related compounds in aqueous media. In Modern Carbonyl Chemistry, Otera, J. (ed.). Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. Kolb, H.C., Finn, M.G., Sharpless, K.B. (2001). Click chemistry: Diverse chemical function from a few good reactions. Angew. Chem. Int. Ed., 40, 2004–2021. Koller, G., Fischer, U., Hungerbühler, K. (2000). Assessing safety, health, and environmental impact early during process development. Ing. Eng. Chem. Res., 39, 960. Kommi, D.N., Kumar, D., Chakraborti, A.K. (2013). “All water chemistry” for a concise total synthesis of the novel class anti-anginal drug (RS), (R), and (S)-ranolazine. Green Chem., 15, 756–767.

Chemistry In and On Water

155

Krasovskiy, A., Duplais, C., Lipshutz, B.H. (2010). Stereoselective Negishilike couplings between alkenyl and alkyl halides in water at room temperature. Org. Lett., 12, 4742–4744. Krishna, P.R., Kannan, V., Sharma, G.V.M., Ramana Rao, M.H.V. (2003). Diastereoselective Baylis-Hillman reaction: Use of sugar derived aldehydes as chiral electrophiles. Synlett, 34, 888–890. Kronberg, B. (2016). The hydrophobic effect. Current Opinion in Colloid & Interface Science, 22, 14–22. Kucherenko, A.S., Kostenko, A.A., Zhdankina, G.M., Kuznetsova, O.Y., Zlotin, S.G. (2018). Green asymmetric synthesis of Warfarin and Coumachlor in pure water catalyzed by quinoline-derived 1,2-diamines. Green Chem., 20, 754. La Sorella, G., Strukul, G., Scarso, A. (2015). Recent advances in catalysis in micellar media. Green Chem., 17, 644. Lamblin, M., Nassar-Hardy, L., Hierso, J.-C., Fouquet, E., Felpin, F.-X. (2010). Recyclable heterogeneous palladium catalysts in pure water: Sustainable developments in Suzuki, Heck, Sonogashira and Tsuji-Trost reactions. Adv. Synth. Catal., 352, 33–79. Lautens, M., Bouchain, G. (2003). [4 + 3] Cycloaddition in water. Synthesis of 2,4-endo, endo-dimethyl-8-oxabicyclo[3.2.1]oct-6-en-3-one. Org. Synth., 79, 251–256. Leseurre, L., Genêt, J.-P., Michelet, V. (2010). Coupling reactions in water. In Handbook of Green Chemistry, vol. 5, Green Solvents. Reactions in Water, Anastas, P., Li, C.-J. (eds). Wiley-VCH, Weinheim, 151–191. Leseurre, L., Merea, C., Duprat de Paule, S., Pinchart, A. (2014). Ecofootprint: A new tool for the “made in Chimex” considered approach. Green Chem., 16, 1139–1148. Lezana, N., Matus-Pérez, M., Galdámez, A., Lührb, S., Vilches-Herrera, M. (2016). Highly stereoselective and catalyst-free synthesis of annulated tetrahydropyridines by intramolecular imino-Diels-Alder reaction under microwave irradiation in water. Green Chem., 18, 3712. Li, C.-J. (2005). Organic reactions in aqueous media with a focus on carboncarbon bond formations:  A decade update. Chem. Rev., 105, 3095–3165.

156

Biphasic Chemistry and The Solvent Case

Li, C.-J. (2007). Metal-mediated C-C bond formations in aqueous media in organic reactions. In Organic Reactions in Water: Principles, Strategies and Applications, Lindström, U.M. (ed.). Blackwell Publishing, Oxford, 92–145. Li, C.-J., Chan, T.-H. (2007). Comprehensive Organic Reactions in Aqueous Media. Wiley-Interscience, Hoboken. Li, B., Dixneuf, P.H. (2013). sp2 C-H bond activation in water and catalytic cross-coupling reactions. Chem. Soc. Rev., 42(13), 5744–5767. Li, J., Tang, Y., Wang, Q., Li, X., Cun, L., Zhang, X., Zhu, J., Li, L., Deng, J. (2012). Chiral surfactant-type catalyst for asymmetric reduction of aliphatic ketones in water. J. Am. Chem. Soc., 134, 18522–18525. Li, J., Lin, Z., Huang, Q., Wang, Q., Tang, L., Zhu, J., Deng, J. (2017). Asymmetric transfer hydrogenation of aryl ketoesters with a chiral double-chain surfactant-type catalyst in water. Green Chem., 19, 5367– 5370. Lindström, U.M. (ed.) (2007). Organic Reactions in Water: Principles, Strategies and Applications. Blackwell Publishing, Oxford. Lipshutz, B.H., Ghorai, S. (2014). Transitioning organic synthesis from organic solvents to water. What’s your E Factor? Green Chem., 16, 3660– 3679. Lipshutz, B.H., Bošković, Z., Crowe, C.S., Davis, V.K., Whittemore, H.C., Vosburg, D.A., Wenzel, A.G. (2013). “Click” and olefin metathesis chemistry in water at room temperature enabled by biodegradable micelles. J. Chem. Educ., 90, 1514. Lipshutz, B.H., Ghorai, S. (2012). Organocatalysis in water at room temperature with in-flask catalyst recycling. Org. Lett., 14, 422–425. Lipshutz, B.H., Aguinaldo, G.T., Ghorai, S., Voigtritter, K. (2008). Olefin cross-metathesis reactions at room temperature using the nonionic amphiphile “PTS”:  Just add water. Org. Lett., 10, 1325–1328. Lipshutz, B.H., Ghorai, S., Abela, A.R., Moser, R., Nishikata, T., Duplais, C., Krasovskiy, A., Gaston, R.D., Gadwood, R.C. (2011). TPGS-750-M: A second-generation amphiphile for metal-catalyzed cross-couplings in water at room temperature. J. Org. Chem., 76, 4379–4391. Liu, N., Liu, C., Yan, B., Jin, Z. (2011). Thermoregulated ligand-palladiumcatalyzed Suzuki reaction in water. Appl. Organometal. Chem., 25, 168– 172.

Chemistry In and On Water

157

Liu, F., Yang, Z., Mei, Y., Houk, K.N. (2016). QM/QM’ direct molecular dynamics of water-accelerated Diels-Alder reaction. J. Phys. Chem. B, 120, 6250–6254. Llanes, P., Sayalero, S., Rodríguez Escrich, C., Pericàs, M.A. (2016). Asymmetric cross- and self-Aldol reactions of aldehydes in water with a polystyrene-supported triazolylproline organocatalyst. Green Chem., 18, 3507–3512. Llevot, A., Monney, B., Sehlinger, A. Behrens, S., Meier, M.A.R. (2017). Highly efficient Tsuji-Trost allylation in water catalyzed by Pdnanoparticles. Chem. Commun., 53, 5175–5178. Lopez-Deber, M.P., Castedo, L., Granja, J.R. (2001). Synthesis Of N-(3arylpropyl)amino acid derivatives by Sonogashira types of reaction in aqueous media. Org. Lett., 3, 2823–2826. Lubineau, A. (1986). Water promoted organic reactions: Aldol reaction under neutral conditions. J. Org. Chem., 51, 2142–2144. Lubineau, A., Augé, J., Lubin, N. (1991). Hetero Diels-Alder reaction in water. synthesis of α-hydroxy-γ-lactones. Tetrahedron Lett., 32, 7529– 7530. Lubineau, A., Augé, J. (1992). Water-promoted organic-reactions – Michael addition of nitroalkanes to methylvinylketone under neutral conditions. Tetrahedron Lett., 33, 8073–8074. Lubineau, A., Bienaymé, H., Queneau, Y., Scherrmann, M.-C. (1994). Aqueous cycloadditions using glyco-organic substrates. Thermodynamics of the reaction. New J. Chem., 18, 279–285. Lubineau, A., Bouchain, G., Queneau, Y. (1995). Reactivity of the carbonyl group in water. Generation of azomethine Ylides from aqueous formaldehyde: Michael addition versus dipolar trapping. J. Chem. Soc. Perkin Trans 1, 2433–2437. Lubineau, A., Bouchain, G. (1997). Water-promoted reactions: Generation of oxyallyl intermediates and their [4+3] cycloadditions with furan and cyclopentadiene. Facile access to Bridged-cycloheptenones. Tetrahedron Lett., 38(46), 8031–8032. Maheswari, P.U., de Hoog, P., Hage, R., Gamez, P., Reedijk, J. (2005). A Na2WO4/H2WO4-based highly efficient biphasic catalyst towards alkene epoxidation, using dihydrogen peroxide as oxidant. Adv. Synth. Catal., 347, 1759–1764.

158

Biphasic Chemistry and The Solvent Case

Malkov, A.V., Czemerys, L., Malyshev, D.A. (2009). Vanadium-catalyzed asymmetric epoxidation of allylic alcohols in water. J. Org. Chem., 74, 3350–3355. Manabe, K., Mori, Y., Kobayashi, S. (1999). Effects of Lewis acidsurfactant-combined catalysts on Aldol and Diels-Alder reactions in water. Tetrahedron, 55, 11203–11208. Mao, Z., Jia, Y., Li, W., Wang, R. (2010). Water-compatible iminium activation: Highly enantioselective organocatalytic Michael addition of malonates to α,β-unsaturated enones. J. Org. Chem., 75, 7428–7430. Mase, N., Nakai, Y., Ohara, N., Yoda, H., Takabe, K., Tanaka, F., Barbas, C.F. (2006). Organocatalytic direct asymmetric Aldol reactions in water. J. Am. Chem. Soc., 128, 734–735. Mei, Y., Averill, D.J., Allen, M.J. (2012). Study of the lanthanide-catalyzed, aqueous, asymmetric Mukaiyama Aldol reaction. J. Org. Chem., 77, 5624–5632. Meziane, S., Lanteri, P., Longeray, R., Arnaud, C. (1998). Emploi de l’acide mono-persuccinique (PSA) dans l’eau comme agent d’oxydation dans la réaction de Baeyer-Villiger appliquée aux cétones cycliques. C. R. Acad. Sci. Paris, t. 1, Serie IIc, 1, 91–94. Misra, A.K., Agnihotri, G. (2004). Preparation of polyhydroxyalkyl- and Cglycosylfuran derivatives from free sugars catalyzed by cerium(III) chloride in aqueous solution: An improvement of the Garcia González reaction. Carbohydr. Res., 339, 1381–1387. Miyabe, H., Ueda, M., Naito, T. (2000). Free-radical reaction of imine derivatives in water. J. Org. Chem., 65, 5043–5047. Miyabe, H., Ueda, M., Nishimura, A., Naito, T. (2002). Indium-mediated intermolecular alkyl radical addition to electron-deficient C=N bond and C=C bond in water. Org. Lett, 4, 131–134. Mlynarski, J., Bas, S. (2014). Catalytic asymmetric aldol reactions in aqueous media – a 5 year update. Chem. Soc. Rev., 43, 577. Molteni, G., Orlandi, M., Broggini, G. (2000). Nitrilimine cycloadditions in aqueous media. J. Chem. Soc. Perkin Trans 1, 3742–3745. Mori, Y., Kobayashi, S. (2012). Industrial applications other than hydroformylation. In Science of Synthesis, Water in Organic Synthesis, Kobayashi, S. (ed.). Georg Thieme Verlag, Stuttgart, 831–854.

Chemistry In and On Water

159

Mpungose, P.P., Sehloko, N.I., Maguire, G.E.M., Friedrich, H.B. (2017). PdCuCeO-TPAB: A new catalytic system for quasi-heterogeneous Suzuki-Miyaura cross-coupling reactions under ligand-free conditions in water. New J. Chem., 41(22), 13560–13566. Murakami, S., Hayashi, T., Kinoshita, M. (2017). Effects of salt or cosolvent addition on solubility of a hydrophobic solute in water: Relevance to those on thermal stability of a protein. J. Chem. Phys., 146, 055102. Nabid, M.R., Bide, Y., Abuali, M. (2014). Coppercore silvershell nanoparticleyolk/shell Fe3O4@chitosan-derived carbon nanoparticle composite as an efficient catalyst for catalytic epoxidation in water. RSC Adv., 4, 35844– 35851. Nagare, A.S., Manna, A., Sonawane, P.D., Kumar, A. (2015). The waterpromoted Diels-Alder reaction in quaternary ammonium salts. J. Phys. Org. Chem., 28, 665–673. Nam, T.K., Jang, D.O. (2018). Radical “on water” addition to the C=N bond of hydrazones: A synthesis of isoindolinone derivatives. J. Org. Chem., 83 (14), 7373–7379. Nambu, H., Anilkumar, G., Matsugi, M., Kita, Y. (2002). An efficient methodology for the C-C bond forming radical cyclization of hydrophobic substrates in water: Effect of additive on radical reaction in water. Tetrahedron, 59, 77–85. Narayan, S., Muldoon, J., Finn, M.G., Fokin, V.V., Kolb, H.C., Sharpless, K.B. (2005). “On water”: Unique reactivity of organic compounds in aqueous suspension. Angew. Chem. Int. Ed., 44, 3275–3279. Naruse, M., Aoyagi, S., Kibayashi, C. (1996). Stereoselective total synthesis of (–)-pumiliotoxin C by an aqueous intramolecular acylnitroso DielsAlder approach. J. Chem. Soc., Perkin Trans. 1, 1113–1124. Northrup, A.B., MacMillan, D.W.C. (2002). The first general enantioselective catalytic Diels-Alder reaction with simple α,βunsaturated ketones. J. Am. Chem. Soc., 124, 2458–2460. Noyori, R., Aoki, M., Sato, K. (2003). Green oxidation with aqueous hydrogen peroxide. Chem. Commun., 1977–1986. Ollevier, T., Plancq, B. (2012). Highly enantioselective Mukaiyama aldol reaction in aqueous conditions using a chiral iron(II) bipyridine catalyst. Chem. Commun., 48, 2289–2291.

160

Biphasic Chemistry and The Solvent Case

Otto, S., Engberts, J.B.F.N. (1995). Lewis-acid catalysis of a Diels-Alder reaction in water. Tetrahedron Lett., 36, 2645–2648. Otto, S., Engberts, J.B.F.N. (2000). Diels-Alder reactions in water. Pure Appl. Chem., 72, 1365–1372. Otto, S., Engberts, J.B.F.N., Kwak, J.C.T. (1998). Million-Fold acceleration of a Diels-Alder reaction due to combined Lewis acid and micellar catalysis in water. J. Am. Chem. Soc., 120, 9517–9525. Özçubukçu, S., Ozkal, E., Jimeno, C., Pericàs, M.A. (2009). A highly active catalyst for Huisgen 1,3-dipolar cycloadditions based on the tris(triazolyl) methanol-Cu(I) structure. Org. Lett., 11, 4680–4683. Park, S., Ikehata, K., Sugiyama, H. (2013). Solid-supported DNA for asymmetric synthesis: A stepping-stone toward practical applications. Biomater. Sci., 1, 1034–1036. Park, S., Okamura, I., Sakashita, S., Yum, J.H., Acharya, C., Gao, L., Sugiyama, H. (2015). Development of DNA metalloenzymes using a rational design approach and application in the asymmetric Diels-Alder reaction. ACS Catal., 5(8), 4708–4712. Pereira, N.A.M., Lopes, S.M.M., Lemos, A., Pinho e Melo, T.M.V.D. (2014). On-water synthesis of dipyrromethanes via bis-hetero-Diels-Alder reaction of azo- and nitrosoalkenes with pyrrole. Synlett, 25, 423–427. Pessel, F., Billault, I., Scherrmann, M.-C. (2016a). Total synthesis of triazolelinked C-glycosyl flavonoids in alternative solvents and environmental assessment in terms of reaction, workup and purification. Green Chem., 18, 5558–5568. Pessel, F., Augé, J., Billault, I., Scherrmann, M.-C. (2016b). The weight of flash chromatography: A tool to predict its mass intensity from thin-layer chromato-graphy. Beilstein J. Org. Chem., 12, 2351–2357. Philippe, M., Semeria, D. (2002). Novel C-glycoside derivatives and use thereof, brevet WO 2002051803. Chem. Abstr., 137, 63422. Portmann, R. (1998). Process for preparing 1-substituted 4-cyano-1,2,3triazoles, WO 98.02423, CAN 128:140707. Postigo, A., Nudelman, N.S. (2011). Synthetically useful metal-mediated radical transformations in water and aqueous media. Coord. Chem. Rev., 255, 2991–3030.

Chemistry In and On Water

161

Prat, D., Wells, A., Hayler, J., Sneddon, H., McElroy, C.R., Abou-Shehada, S., Dunn, P.J. (2016). CHEM21 selection guide of classical- and less classicalsolvents. Green Chem., 18, 288. Prosa, N., Turgis, R., Piccardi, R., Scherrmann, M.-C. (2012). Soluble polymer-supported flow synthesis: A green process for the preparation of heterocycles. Eur. J. Org. Chem., 11, 2188–2200. Queneau, Y., Pinel, C., Scherrmann, M.-C. (2011). Some chemical transformations of carbohydrates in aqueous medium. C. R. Chimie, 14, 688–699. Reetz, M.T., Jiao, N. (2006). Copper-phthalocyanine conjugates of serum albumins as enantioselective catalysts in Diels-Alder reactions. Angew. Chem. Int. Ed., 45, 2416–2419. Repasky, M.P., Guimarães, C.R.W., Chandrasekhar, J., Tirado-Rives, J., Jorgensen, W.L. (2003). Investigation of solvent effects for the claisen rearrangement of chorismate to prephenate: Mechanistic interpretation via near attack confor-mations. J. Am. Chem. Soc., 125(22), 6663–6672. Resch, V., Seidler, C., Chen, B.-S., Degeling, I., Hanefeld, U. (2013). On the Michael addition of water to α,β-unsaturated ketones using amino acids. Eur. J. Org. Chem., 34, 7697–7704. Reymond, S., Cossy, J. (2008). Copper-catalyzed Diels-Alder reactions. Chem. Rev., 108, 5359–5406. Rideout, D.C., Breslow, R. (1980). Hydrophobic acceleration of Diels-Alder reactions. J. Am. Chem. Soc., 102, 7816–7817. Riemann, I., Papadopoulos, M.A., Knorst, M., Fessner, W.-D. (2002). Cglycosides by aqueous condensation of β-dicarbonyl compounds with unprotected sugars. Aust. J. Chem., 55, 147–154. Rispens, T., Engberts, J.B.F.N. (2001). Efficient catalysis of a Diels-Alder reaction by Metallo-Vesicles in aqueous solution. Organic Lett., 3, 941– 943. Rodrigues, F., Canac, Y., Lubineau, A. (2000). A convenient, one-step, synthesis of β-C-glycosidic ketones in aqueous media. Chem. Commun., 20, 2049. Roelfes, G., Feringa, B.L. (2005). DNA-based asymmetric catalysis. Angew. Chem. Int. Ed., 44, 3230–3232.

162

Biphasic Chemistry and The Solvent Case

Rogozińska-Szymczak, M., Mlynarski, J. (2015). Unmodified primary amine organo-catalysts for asymmetric Michael reactions in aqueous media. Eur. J. Org. Chem., 27, 6047–6051. Roy, D., Sunoj, R.B. (2008). Water catalysis in the Morita-Baylis-Hillman reaction: A mechanistic perspective. Chem. Eur. J., 14, 10530–10534. Rueping, M., Theissmann, T. (2010). Asymmetric Brønsted acid catalysis in aqueous solution. Chem. Sci., 1, 473–476. Samanta, D., Kratz, K., Zhang, X., Emrick, T. (2008). A synthesis of PEGand phosphorylcholine-substituted pyridines to afford water-soluble ruthenium benzylidene metathesis catalysts. Macromolecules, 41, 530– 532. de los Santos, J.M., Ignacio, R., Es Sbai, Z., Aparicio, D., Palacios, F. (2014). Hetero-Diels-Alder reaction of phosphorylated nitroso alkenes with enol ethers on water: A clean approach toward 1,2-oxazine derivatives. J. Org. Chem., 79, 7607–7615. Sato, K., Aoki, M., Noyori, R. (1998). A “green” route to adipic acid: Direct oxidation of cyclohexenes with 30 percent hydrogen peroxide. Science, 281, 1646–1647. Scherrmann, M.-C. (2010). Knoevenagel reaction of unprotected sugars. Top. Curr. Chem., 295, 1–18. Scherrmann, M.-C., Norsikian, S., Lubineau, A. (2005). Solvophobic activation in organic synthesis. In Advances in Organic Synthesis, vol. 1, Atta-ur-Rahman (ed.), Bentham Science Publishers, Hilversun. Scherrmann, M.-C., Lubineau, A., Queneau, Y. (2010). Functionalization of carbo-hydrates in water. In Handbook of Green Chemistry, vol. 5, Green Solvents. Reactions in Water, Anastas, P., Li, C.J. (eds). Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, 291–330. Sela, T., Lin, X., Vigalok, A. (2017). Concentrated aqueous sodium tosylate as green medium for alkene oxidation and nucleophilic substitution reactions. J. Org. Chem., 82, 11609–11612. Sgarbossa, P., Scarso, A., Strukul, G., Michelin, R.A. (2012). Platinum(II) complexes with coordinated electron-withdrawing fluoroalkyl and fluoroaryl ligands: Synthesis, reactivity, and catalytic activity. Organometallics, 31, 1257–1270. Sheldon, R.A. (1992). Organic synthesis – past, present and future. Chem. Ind., 23, 903–906.

Chemistry In and On Water

163

Sheldon, R.A. (2015). Recent advances in green catalytic oxidations of alcohols in aqueous media. Catalysis Today, 247, 4–13. Shibatomi, K., Kawasaki, Y., Iwasa, S. (2015). Organocatalytic enantioselective Diels-Alder reaction of 4,4,4-trifluorocrotonaldehyde. J. Fluorine Chem., 179, 77–82. Shin, J.-A., Lim, Y.-G., Lee, K.-H. (2012). Copper-catalyzed azide-alkyne cyclo-addition reaction in water using cyclodextrin as a phase transfer catalyst. J. Org. Chem., 77, 4117–4122. Shin, J.-A., Oh, S.-J., Lee, H.Y., Lim, Y.G. (2017). An efficient Cu-catalyzed azide-alkyne cycloaddition (CuAAC) reaction in aqueous medium with a zwitterionic ligand, betaine. Catal. Sci. Technol., 7, 2450–2456. Shrinidhi, A. (2016). Diels-Alder reaction with hydrophilic dienes and dienophiles. ChemistrySelect, 1(12), 3016–3021. Sigismondi, S., Sinou, D. (1997). Palladium(0)-catalyzed substitution of allylic substrates in an aqueous-organic medium. Influence of various parameters on the selectivity of the reaction. J. Mol. Cat. A: Chemical., 116, 289–296. Sinou, D. (2002). Asymetric organometallic-catalyzed reactions in aqueous media. Adv. Synth. Cat., 344, 221–237. Soberats, B., Martínez, L., Vega, M., Rotger, C., Costa, A. (2009). Conventional Tetrakis(triphenylphosphine)palladium-Copper(I) Iodidecatalyzed Sonogashira coupling of free and BOC-protected propargylic amines “on water”. Adv. Synth. Catal., 351, 1727–1731. Song, W., Zheng, N. (2017). Iridium-catalyzed highly regioselective azideynamide cycloaddition to access 5-amido fully substituted 1,2,3-triazoles under mild, air, aqueous, and bioorthogonal conditions. Org. Lett., 19, 6200–6203. Song, J., Shih, H.W., Deng, L. (2007). Asymmetric Mannich reactions with in situ generation of carbamate-protected imines by an organic catalyst. Org. Lett., 9, 603–606. de Souza, G.F.P., Von Zuben, T.W., Salles, A.G. (2017). “On water” metalcatalyst-free oxidative coupling-amidation of amines to access imines and amides. ACS Sustainable Chem. Eng., 5, 8439–8446.

164

Biphasic Chemistry and The Solvent Case

Świderek, K., Nödling, A.R., Tsai, Y.-H., Luk, L.Y.P., Moliner, V. (2018). Reaction mechanism of organocatalytic Michael addition of nitromethane to cinnamaldehyde: A case study on catalyst regeneration and solvent effects. J. Phys. Chem. A, 122, 451–459. Talbi, B., Haquette, P., Martel, A., Montigny, F.D., Fosse, C., Cordier, S., Roisnel, T., Jaouen, G., Salmain, M. (2010). (η6-Arene) ruthenium(II) complexes and metallo-papain hybrid as Lewis acid catalysts of Diels−Alder reaction in water. Dalton Trans., 39(24), 5605–5607. Tan, K.-T., Chng, S.-S., Cheng, H.-S., Loh, T.-P. (2003). Development of a highly-regioselective metal-mediated allylation reaction in aqueous media: New mechanistic proposal for the origin of homoallylic alcohol. J. Am. Chem. Soc., 125, 2958–2963. Tasca, E., La Sorella, G., Sperni, L., Strukul, G., Scarso, A. (2015). Micellar promoted multi-component synthesis of 1,2,3-triazoles in water at room temperature. Green Chem., 17, 1414–1422. Tomasek, J., Schatz, J. (2013). Olefin metathesis in aqueous media. Green Chem., 15, 2317–2338. Tóth, I., Hanson, B.E., Davis, M.E. (1990). Novel chiral water soluble phosphines II. applications in catalytic asymmetric hydrogenation. Tetrahedron, 1, 895–912. Ueda, M., Miyabe, H., Sugino, H., Naito, T. (2005). Zinc-mediated carbon radical addition to glyoxylic imines in aqueous media for the synthesis of α-amino acids. Org. Biomol. Chem., 3, 1124–1128. Uozumi, Y., Shibatomi, K. (2001). Catalytic asymmetric allylic alkylation in water with a recyclable amphiphilic resin-supported P,N-chelating palladium complex. J. Am. Chem. Soc., 123, 2919–2920. Uozumi, Y., Watanabe, T. (1999). Green catalysis:  Hydroxycarbonylation of aryl halides in water catalyzed by an amphiphilic resin-supported phosphine-palladium complex. J. Org. Chem., 64, 6921–6923. Van der Vegt, N.F.A., Nayar, D. (2017). The hydrophobic effect and the role of cosolvents. J. Phys. Chem. B, 121, 9986–9998. Van Mersbergen, D., Wijnen, J.W., Engberts, J.B.F.N. (1998). 1,3-Dipolar cyclo-additions of benzonitrile oxide with various dipolarophiles in aqueous solutions. A Kinetic Study. J. Org. Chem., 63(24), 8801–8805.

Chemistry In and On Water

165

Wagner, P., Bollenbach, M., Doebelin, C., Bihel, F., Bourguignon, J.-J., Salomé, C., Schmitt, M. (2014). t-BuXPhos: A highly efficient ligand for Buchwald-Hartwig coupling in water. Green Chem., 16, 4170–4178. Wang, C., Salmon, L., Ciganda, R., Yate, L., Moya, S., Ruiz, J., Astruc, D. (2017). An efficient parts-per-million α-Fe2O3 nanocluster/graphene oxide catalyst for Suzuki-Miyaura coupling reactions and 4-nitrophenol reduction in aqueous solution. Chem. Commun., 53, 644–646. Wei, Y., Wu, X., Wang, C., Xiao, J. (2015). Transfer hydrogenation in aqueous media. Catalysis Today, 247, 104–106. Wiebus, E., Cornils, B. (2007). Water as a reaction solvent – an industry perspective. In Organic Reactions in Water, Principles, Strategies and Applications, Lindström, U.M. (ed.). Wiley-Blackwell, Oxford, 366–397. Woyciechowska, M., Forcher, G., Buda, S., Mlynarski, J. (2012). General switch in regioselectivity in the Mukaiyama aldol reaction of silyloxyfuran with aldehydes in aqueous solvents. Chem. Commun., 48, 11029–11031. Wu, P., Fokin, V.V. (2007). Catalytic azide-alkyne cycloaddition: Reactivity and applications. Aldrichim. Acta, 40, 7–17. Wu, X., Li, C., Zanotti-Gerosa, A., Pettman, A., Liu, J., Mills, A.J., Xiao, J. (2008). RhIII- and IrIII-catalyzed asymmetric transfer hydrogenation of ketones in water. Chem. Eur. J., 14, 2209–2222. Wu, X., Wang, C., Xiao, J. (2010). Asymmetric transfer hydrogenation in water with platinum group metal catalysts. Platinum Metals Rev., 54, 3– 19. Wurz, R.P., Charrette, A.B. (2002). Transition metal-catalyzed cyclopropanation of alkenes in water: Catalyst efficiency and in situ generation of the Diazo Reagent. Org. Lett., 4, 4531–4533. Xu, Y., Hua, Z., Zhang, J., Yang, J., Cao, Z., Zhang, D., He, L., Craig, V.S.J., Zhang, G., Liu, G. (2016). Mimicking enzymatic systems: Modulation of the performance of polymeric organocatalysts by ion-specific effects. Chem. Commun., 52, 3392. Yadav, J.S., Reddy, B.V.S., Sreenivas, M., Satheesh, S. (2007). Indium(III) chloride/water: A versatile catalytic system for the synthesis of C-furyl glycosides and trihydroxyalkyl furan derivatives. Synthesis, 1712–1716.

166

Biphasic Chemistry and The Solvent Case

Yan, Q., Fang, Y.C., Jiaa, Y.X., Duan, X.H. (2017). Chemoselective hydrogen peroxide oxidation of primary alcohols to aldehydes by a watersoluble and reusable iron(III) catalyst in pure water at room temperature. New J. Chem., 41, 2372–2377. Yang, F., Klumphu, P., Liang, Y.-M., Lipshutz, B.H. (2014). Coppercatalyzed trifluoromethylation of N-arylacrylamides “on water” at room temperature. Chem. Commun., 50, 936–938. Yang, Z., Zhu, Z., Luo, R., Qiu, X., Liu, J.-T., Yang, J.-K., Weiping Tang, W. (2017). Iridium-catalyzed highly efficient chemoselective reduction of aldehydes in water using formic acid as the hydrogen source. Green Chem., 19, 3296–3301. Yorimitsu, H., Oshima, K. (2002). Synthetic radical reactions in aqueous media. Synlett, 5, 674–686. Yorimitsu, H., Nakamura, T., Shinokubo, H., Oshima, K., Omoto, K., Fujimoto, H. (2000). Powerful solvent effect of water in radical reaction:  Triethylborane-induced atom-transfer radical cyclization in water. J. Am. Chem. Soc., 122, 11041–11047. Yorimitsu, H., Shinokubo, H., Matsubara, S., Oshima, K. (2001). Triethylborane-induced bromine atom-transfer radical addition in aqueous media: Study of the solvent effect on radical addition reactions. J. Org. Chem., 66, 7776–7785. Yoshida, K., Grieco, P.A. (1985). Synthesis and reactivity of (E)-4,6,7octatrienoic acid sodium salt in the aqueous Diels-Alder reaction. Chem. Lett., 14, 155–158. Yu, Y.Q., Wang, Z.L. (2012). A Simple, efficient and green procedure for Knoevenagel condensation in water or under solvent-free conditions. J. Chin. Chem. Soc., 60, 288–292. Yu, C., Liu, B., Hu, L. (2001). Efficient Baylis-Hillman reaction using stoichio-metric base catalyst and an aqueous medium. J. Org. Chem., 66, 5413–5418. Yu, J., Jin, Y., Lu, M. (2015). 3-Methyl-4-oxa-5-azahomoadamantane as an organo-catalyst for the aerobic oxidation of primary amines to oximes in water. Adv. Synth. Catal., 357, 1175–1180. Zheng, Z., Perkins, B.L., Ni, B. (2010). Diarylprolinol silyl ether salts as new, efficient, water-soluble, and recyclable organocatalysts for the asymmetric Michael addition on water. J. Am. Chem. Soc., 132, 50–51.

Chemistry In and On Water

167

Zhou, R., Wang, W., Jiang, Z.-J., Fu, H.Y., Zheng, X.-L., Zhang, C.-C., Chen, H., Li, R.-X. (2014). Pd/tetraphosphine catalytic system for Cu-free Sonogashira reaction “on water”. Catal. Sci. Technol., 4, 746–751. Zhou, C., Zhang, J., Liu, P., Xie, J., Dai, B. (2015). 2-PyrrolecarbaldiminatoCu(II) complex catalyzed three-component 1,3-dipolar cycloaddition for 1,4-disubstituted 1,2,3-triazoles synthesis in water at room temperature. RSC Adv., 5, 6661–6665. Zhuang, W., Marigo, M., Jørgensen, K.A. (2005). Organocatalytic asymmetric epoxidation reactions in water-alcohol solutions. Org. Biomol. Chem., 3, 3883–3885. Zuo, Y.-J., Qu, J. (2014). How does aqueous solubility of organic reactant affect a water-promoted reaction? J. Org. Chem., 79, 6832–6839.

4 Solvent-free Chemistry

4.1. Introduction The purpose of green chemistry is to develop chemical products and processes that reduce or eliminate the use and synthesis of hazardous and toxic substances (Anastas and Williamson 1999; Gérin 2002). By changing concepts and practices, this new approach will contribute to economically efficient and sustainable development. This includes the product synthesis steps that must be reconsidered in light of sustainable chemistry. One of the important factors in this activity is the reduction of by-products and waste, which are often toxic, as well as solvents, which are often used in large quantities. Many organic solvents are harmful from an ecological and public health point of view, and dangerous because they are often volatile and flammable. One of the approaches often adopted is to substitute these solvents with less dangerous and toxic compounds. Examples include water, ionic liquids or supercritical CO2. A more radical approach is simply to remove any solvent in synthesis. While this consideration offends the dogma of “no reaction in the absence of solvent”, once accepted, it leads to a new scientific and technological approach, which has demonstrated additional

Chapter written by Thomas-Xavier MÉTRO, Xavier BANTREIL, Jean MARTINEZ and Frédéric LAMATY.

Biphasic Chemistry and The Solvent Case,First Edition. Edited by Jean-Philippe Goddard, Max Malacria and Cyril Ollivier. © ISTE Ltd 2020. Published by ISTE Ltd and John Wiley & Sons, Inc.

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Biphasic Chemistry and The Solvent Case

benefits, such as an acceleration of reaction rates (and therefore synthesis times) and a specific preparation of certain compounds under these conditions. In addition, in a number of cases, a liquid reagent used in the reaction mixture can be used as a solvent (Welton 2006). 4.2. General information on solvent-free synthesis: why use a solvent? The main characteristic for the use of a solvent in synthesis is its ability to solubilize the reagents, which will allow them to come into contact, interact and react. It has been shown, however, that the choice of solvent can be crucial to the success of a transformation. Indeed, given its structure and the physicochemical consequences resulting from it (dielectric constant, dipole moment, tendency to establish hydrogen bonds, etc.) (Loupy and Haudrechy 1996), the solvent will be able to establish interactions with reactants and reaction intermediates, with a direct effect on the result and effectiveness of the reaction. Another important point, which mainly concerns chemical engineering and its applications for scaling up in industry, concerns the possibility of controlling heat exchanges more efficiently by the presence of a solvent. In order to promote a reaction, the solvent can transmit by convection the energy necessary for the transformation, produced by heating, while in the case of an exothermic reaction, it will contribute to the necessary elimination of excess thermal energy. 4.3. Working without solvents On the one hand, by avoiding the use of a solvent, several of the 12 principles of green chemistry can be satisfied, in terms of material savings, energy, safety and waste processing. On the other hand, the development of solvent-free reactions has proven to be an important driver of innovations that sometimes require a significant paradigm shift.

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It should also be noted that in some cases, one of the reagents used in the transformation is liquid. Strictly speaking, this process cannot be called a “solvent-free reaction” since the liquid reagent can be used as a solvent, but generally in much smaller quantities than in traditional reactions, hence contributing to the sustainable development of chemistry. Solid-solid or solid-gas reactions are different from this approach because no solubilization is possible. Special techniques such as grinding will bring the reagents into contact to react. When using a liquid as a reagent, conventional equipment can be used to perform a synthesis. In other cases, several activation methods may be used. Examples include microwaves (MWs) or photochemistry, where effects other than conventional thermal heating can be used in the reaction. In the more specific case of solid-solid reactions, it will be possible to use more specific milling techniques, with equipment such as mortar-pestle, ball-mill or extruder, which will induce significant mechanical forces. 4.4. Limitations of the technique The limits of the development of solvent-free synthesis concern solvent effects and heat and material transfers. As discussed above, solvent effects can be crucial for a transformation. It will therefore be difficult to completely remove the solvent from a synthesis, but it will be possible to reduce the quantities significantly. Another approach may be to revisit the synthesis method by including an approach in the absence of a solvent. The use of a solvent contributes to obtaining a homogeneous reaction medium, that can be mixed easily, with homogeneous distributions of reagents and heat. This is more difficult in the absence of a solvent, including for the acquisition of precise physical data such as temperature, mainly on a large scale. A practical aspect, made more difficult in the absence of a solvent, is the transport of material.

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Solubilized reagents can easily be brought into a reactor and the final product easily recovered for further processing. However, there are currently efficient solid transport techniques available that can overcome these problems. 4.5. In practice: methods and reactivity 4.5.1. Methods and equipment If one of the reagents is liquid, it can be used as a solvent. In this case, the conventional equipment used for solution synthesis is adapted. The principle involves mixing the reagents (liquid, solid or gas) and adjusting their temperature by heating or cooling. Many examples of solvent-free reactions between solids, solids and gases, or using inorganic carrier reagents – as catalysts – have been described (Kaupp 2005). In this type of reaction, the gas is in excess and is easily removed at the end of the reaction. 4.5.2. Examples The Biginelli reaction is a one-pot cyclocondensation between a βdicarbonyl compound, an aldehyde and urea or thiourea, resulting in differently substituted dihydropyrimidinones (Figure 4.1). Solventfree synthesis methods, using Yb(OTf)3 (Ma et al. 2000), acidic montmorillonite KSF (Bigi et al. 1999), or ionic liquids (Peng and Deng 2002) as catalysts, have been described. In these approaches, the catalyst is removed by simple filtration. When the reaction is carried out without solvents or catalysts, under mechanical agitation at 100– 105 °C for 1 hour, the dihydropyrimidinones were obtained with good yields (78–85%) after recrystallization in ethanol (Figure 4.1) (Ranu et al. 2002). No by-products were obtained and the results from this study were compared to those obtained under the same conditions using reflux in dichloromethane, THF or toluene, but never exceeding 20% yield.

Solvent-free Chemistry

O R1

O R2

R1 = Me, Et

+

R3-CHO +

H2N

R3= Alkyl, Aryl

O

100-105°C

X NH2

R3

R2

1h

NH R1

X = O,S

R2 = Me, OEt, OMe, Ph

173

N H

X

Yields 78-85 %

Figure 4.1. Biginelli reaction without a solvent or catalyst

The method, used at the laboratory level, for the preparation of 1 kg of dihydropyrimidinones, was found to be compatible with a wide variety of substrates and functional groups. Another example: heterocyclic structures have been prepared by filling a flask containing a solid such as o-aminophenol or different variously substituted benzoylhydrazides with gaseous BrCN. Placed under magnetic stirring and at room temperature overnight, the corresponding aminobenzoxazole or substituted oxadiazoles were obtained quantitatively (Figure 4.2) (Kaupp et al. 1998). NH2

BrCN

N

OH

Yield : 100%

O

O R NH2NH2

BrCN

Ar

Yield : 100%

NH2 HBr

O

NH2 HBr

N N

Figure 4.2. Quantitative gas–solid reaction

4.5.3. Scaling up: industrial applications Cyanotrimethylsilane (Me3SiCN, melting point 11 °C) was synthesized at a scale of 810 kg per batch in a solvent-free pilot study by hydrocyanic acid (HCN) silylating reaction in the presence of hexamethyldisilazane (HMDS) (Larson et al. 1997) (Figure 4.3).

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Biphasic Chemistry and The Solvent Case

3 HCN +

Me3SiNHSiMe3

+

Me3SiCl

5-20°C 30 min.

3 Me3SiCN +

NH4Cl

Figure 4.3. Synthesis of Me3SiCN

Pressure filtration, at a temperature below 25 °C, eliminates the only by-product, ammonium chloride, and recovers the highly pure Me3SiCN, with an efficiency of 97.5%. Methods involving solvents (polar) or phase transfer catalysts lead to lower yields (38–90%), the impossibility of carrying out the process on an industrial scale, and the production of solid waste with a high cyanide content, whose disposal is difficult and costly. Another remarkable solvent-free reaction application is the synthesis of polymers, such as polypropylene and polycarbonates. In an alternative process to Ziegler-Natta, polypropylene production is carried out using a new catalyst and without solvents (Hornke et al. 1990; Thayer 1995). The synthesis is carried out at a pressure of 40 bar, and the gaseous emissions are very low, and eliminated by incineration. During the process, the amount of aqueous effluent is significantly reduced because the amount of catalyst used is so small that no additional washing of the polymer is required. Note that 1,013 kg of polypropylene could be produced, and comparable results were obtained for the production of high-density polyethylene. Polycarbonate production is traditionally achieved by polycondensation reaction of bisphenol A, in the presence of phosgene, in a two-phase sodium hydroxide/dichloromethane system. In this process, NaCl is formed as a by-product. Its elimination requires numerous washes of the organic phase, containing polycarbonate, which results in the passage of 20 g·L−1 of dichloromethane in the aqueous phase. In addition, the resulting polymer is contaminated with impurities containing chlorine, thus negatively modifying its properties. In an alternative process developed by Ashai Chemical Industry Co. (Komiya et al. 1996), solvent-free and phosgene-free polycarbonate synthesis is achieved by prepolymerization of bisphenol A in the presence of

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175

diphenylcarbonate in the molten mixture (Figure 4.4). After crystallization, solid-state polymerization of the prepolymer results in high molecular weight polycarbonate. The quality of the polymer is higher than that produced by the process using phosgene and the production cost is comparable. O

O

CH3 HO

OH + CH3

CH3

* O

O

O C * O n

CH3 2

Bisphenol A

OH

Figure 4.4. Industrial synthesis of solvent-free polycarbonate

The preparation of alkyl glucopyranoside monoesters at position 6 was carried out by enzymatic esterification reaction of glucopyranosides, catalyzed by the thermally stable Candida antarctica lipase (Adelhorst et al. 1990) (Figure 4.5). HO O OH

RCO2H C. Antarctica OEt 70 °C, 24 h

OH OH

85% < yield < 90%

RCO2 O OH

OEt

OH OH

R = n-C7H15, n-C9H17, n-C13H21, n-C15H23, n-C17H25

Figure 4.5. Lipase-catalyzed synthesis of O-ethyl glucopyranoside fatty acid esters

The only by-product formed is 2,6-O-diacyl glucopyranoside. In this solvent-free process, 12.7 kg of O-ethylglucopyranosides are heated to 70 °C in the presence of a molten fatty acid and a lipase (400 g) immobilized on a support, under agitation, and at a pressure of 0.01 bar for 24 hours. Two distillations are necessary, one to remove the water formed during esterification, the other at the end of the reaction to separate the ester formed from the excess fatty acid. A filtration step then removes the enzyme. The latter can be recycled several times without loss of activity.

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Biphasic Chemistry and The Solvent Case

4.6. Mortar and pestle 4.6.1. Methods and equipment The use of a manually operated mortar and pestle (Figure 4.6) has resulted in a large number of laboratory scale reactions (Tanaka 2003). The mechanical action caused by shocks and friction between the pestle and the mortar has several roles: – reduce the size of the reagent particles and thus increase their reactive surface area; – thoroughly mix the reagents; – provide the energy necessary to advance the reaction. The final product can be recovered directly from the mortar without the use of solvents. Reactions can be carried out by continuous grinding of the reagents, but the reaction time is then limited to a few minutes. Grinding can also be carried out at regular intervals for up to several days. In both cases, the “effective” grinding time remains limited.

Figure 4.6. Example of a mortar and pestle

4.6.2. Examples Historically, mortar and pestle were the first tools that made it possible to perform synthesis starting from solid reagents in the

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absence of solvents. Even if mortar and pestle are now used only rarely, a very large number of reactions have been described using these tools: oxidation, reduction, creation of C-C, C-N, C-X bonds, multicomponent reactions, etc. All these reactions are not entirely compatible with the principles of green chemistry, since some use toxic reagents or catalysts, an excess of reagent, or require purification using organic solvents. We have chosen here to describe representative examples of existing work that is consistent with the principles of green chemistry. In 2006, Rong et al. (2006) described the one-pot condensation of an aldehyde and an aromatic ketone with malononitrile after 3–5 minutes of grinding (Figure 4.7). The expected products are isolated after simple filtration in water and then recrystallized in ethanol. R1 CHO +

+

R2 R1

R2

COCH3 2 NCCH 2CN

NaOH CN

R4 R3

R

4

R

3

NH 2 CN

Figure 4.7. Multicomponent reaction in a mortar

4.6.3. Scaling up: industrial applications As described above, the manual use of a mortar and pestle is limited: – by the effective grinding time, which rarely exceeds 10 minutes; – by the amount of reagent that can be ground (which does not exceed a few tens of grams); – by the reproducibility of the grinding process, which can vary from one manipulator to another. The emergence of mechanized mortars, such as the one shown in Figure 4.8, has solved these difficulties. This allows significantly

178

Biphasic Chemistry and The Solvent Case

longer grinding times and greater reliability and precision in the reproducibility of the mechanical action. a)

b)

Figure 4.8. RM 200 mortar from Retsch® (Source: images reproduced with the permission of Retsch, www.retsch.com)

Other types of mortars have also been developed, such as disc mortars or jaw ball-mills, but their applications in synthetic chemistry are still limited. 4.7. Ball-mills 4.7.1. Methods and equipment As shown in the previous section, the use of simple mortar and pestle allows a number of reactions to be carried out without solvents. However, the mortar and pestle have gradually been replaced by other more efficient mechanized instruments: ball-mills. Originally used for grinding inorganic materials, these devices are particularly suitable for organic and organometallic synthesis. Several types of mills are currently in use, but at the laboratory scale vibrating and planetary ball-mills (Figures 4.9 and 4.10) are the

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179

most common. Both operate on the same principle: the reagents are introduced into a bowl accompanied by one or more balls; when the bowl is set in motion, the shocks and friction between the balls, the reagents and the walls of the bowl will, as in the case of the mortar and pestle: – reduce the size of the reagent particles and thus increase their reactive surface area; – thoroughly mix the reagents; – provide the energy necessary to advance the reaction. In the case of the vibrating ball-mill, the bowl movements are horizontal, or vertical, and can increase up to a frequency of 60 Hz (Figure 4.9). Vibrating ball-mills can hold one or two bowls that are shaken in parallel, usually with volumes ranging from 1 to 50 ml, allowing a sample volume ranging from 0.3 to 20 ml. a)

b)

Figure 4.9. a) Retsch MM400 Vibrating Ball-Mill; b) scheme of ball motion in a vibrating reactor (Source: images reproduced with permission from Retsch, www.retsch.com) For a color version of this figure, see www.iste.co.uk/ malacria/biphasic.zip

In the case of the planetary mill, the bowl’s movements are similar to those of the Earth around the Sun: the bowl, which rotates on itself on a horizontal plane, is placed eccentrically on a disc also rotating on itself and on a horizontal plane (Figure 4.10). The bowl rotation frequency can be up to 1,100 rpm. The directions of rotation of the bowl and disc can be the same or opposite depending on the configuration of the ball-mill. A planetary mill usually allows one or two bowls to be shaken in parallel, but in some configurations, up to eight bowls can be shaken. Planetary mill bowls have larger volumes

18 80

Biphasic Chemistry C and The Solvent Cas se

thhan vibratingg mills, rangging from 10 0 to 500 ml,, allowing a sample voolume of 3–2200 ml to bee milled. Thee latest versioons of these devices allow in situ control c of thee temperaturee and pressuure developedd within thhe bowl. a)

b)

erisette 7 plan netary mill; (b) scheme of the e motion Fiigure 4.10. (a)) Fritsch Pulve of a pllanetary reactor. For a colorr version of thiis figure, see e.co.uk/malac cria/biphasic.ziip www.iste

These twoo types of ball-mills b allo ow reactions to be carrried out ussing solid reeagents, withhout having to dissolve them in an organic soolvent. It is also possiblle to carry out o reactionss with one oor more liqquid reagentts associated with solids.. In additionn, it has beenn shown thhat the addittion of veryy small amo ounts of a liiquid (non-rreactive) addditive can have h a signifiicant impact on the coursse of these “ssolventfreee” synthesees (section 4.7.2) 4 (Bowm maker 2013).. It should bbe noted thhat, in these specific casses, the quan ntities of liqquid used arre much loower than thee quantities of o solvent reequired durinng synthesess carried ouut “in solutioon”, during which w the reaagents are fullly solubilizeed. Both types of ball-mills are particu ularly suitablee for laboratory use. Iff scaling up is i consideredd, slightly diifferent instruuments will then be ussed (section 4.7.3). 4 4..7.2. Examp ples A very larrge number oof solvent-frree reactionss performed in ballmills are now m w described in i literature (James et al. a 2012; Doo 2017).

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181

We have chosen to present here the most significant reactions to show the diversity of applications of the ball-mills. The Knoevenagel condensation reaction has been extensively studied under solvent-free conditions and, in particular, on large quantities (section 4.7.3). Kaupp et al. have thus shown the applicability of this reaction to the vibrating mill with many substrates, using, in particular, aromatic aldehydes and various dicarbonyl compounds (Figure 4.11).

Figure 4.11. Knoevenagel condensation in a ball-mill

In this example, the only by-product formed is water that is simply removed by vacuum drying. It is important to note that in most examples of Knoevenagel reactions performed in a ball-mill, the yield obtained is quantitative, while starting reagents are used in stoichiometric quantities. No purification step is then necessary. In comparison, the same reaction in solution furnish the product in 86% yield after crystallization (Peet et al. 1995). The condensation of amines on carbonyl compounds are reactions that have been the subject of numerous syntheses by ball-milling. In solution, these reactions often require the presence of a strong acid, while in a ball-mill, no additional reagents are required. In a ball-mill, the product can be recovered directly from the grinding bowl and then obtained pure by simple drying to remove the water formed during the reaction. Kaupp et al. (2000b) have thus described the synthesis of many compounds resulting from such condensation with quantitative yields. A representative example of these reactions is shown in Figure 4.12.

182

Biphasic Chemistry and The Solvent Case

R3 N

CHO + R

R3NH2

+ H2O

1

R1

R2 1

2

R =H, R =NMe2 R1=H, R2=OH R1=H, R2=NO2 R1=OBn, R2=OMe R1=NO2, R2=H

R2 100%

3

R =Me, Et

Figure 4.12. Examples of amine-carbonyl condensation

One of the most commonly used reactions for the creation of carbon-carbon double bonds is the Wittig reaction. Pecharsky et al. (2002) have shown that it is possible to prepare stabilized phosphorus ylides by grinding solid phosphonium salts and K2CO3 (Figure 4.13). Remarkably, this Wittig reaction in the ball-mill is carried out in the presence of K2CO3, whereas Wittig reactions in solution traditionally require much stronger bases. O 1

Ph3P

R

K2CO3

R1 = C=O(Ph), C=O(OEt)

Ph3P CH2R1 X

K2CO3

Ph3P

R

1

R3

R3

-Ph3PO

2

R

2

R

H R1

R1 = H, Ph

Figure 4.13. One-pot preparation of phosphorus ylides and Wittig reaction

The addition of a stoichiometric quantity of solid carbonyl compounds allows the Wittig reaction to be carried out “one pot” with yields greater than 70% and quantitative for the most reactive compounds. In this example, Pecharsky uses a Spex 8000 planetary type ball-mill. Performing asymmetric synthesis is also possible in a ball-mill (Chauhan and Chimni 2012). Thus, Bolm et al. (2007) have shown the applicability of a reaction widely used in organic synthesis, the aldolization. The use of a chiral catalyst, (S)-proline, allows the

Solvent-free Chemistry

183

preparation of a wide variety of products with very good enantiomeric excesses (Figure 4.14). O

OHC R2

R2 = 4-NO2, 3-NO2, 2-NO2, 4-Cl, 2-MeO

OH R2

Ball-mill

R1 R1 = CH2, CHtBu, S

O

(S)-proline (10 mol%)

+

(+ Syn isomer)

R1 Anti isomer 65% < rdt < 99% 63% < ee < 99%

Figure 4.14. Asymmetric aldolization in a ball-mill

In this study, the results obtained with the ball-mill are systematically compared with those obtained under the same conditions using only magnetic stirring: the results obtained with the ball-mill are at least equivalent in terms of enantiomeric excess and yield. This example is particularly representative of “green” reactions since the principle of atom saving is respected: no by-products are formed. Ball-milling is also applicable to reaction cascades such as those described by Kaupp et al. (1999) (Figure 4.15) to prepare a functionalized indole or variety of pyrroles in a one-pot reaction. In this case, the transformation is done in four reaction steps to obtain the expected heterocycle. Ph O

O + N H

Ph

Ph

Ph

O

Ball-mill, 20-30 Hz

O Ph

25 °C, 3h

O

N Ph 100% Ph

OR2

O +

O Me

N H

R1

R1 = H, Me, Bn R2 = Me, Et

Ph

Ph O

Ball-mill, 20-30 Hz -20 to 25 °C, 3h

OR2 O Me

O Ph

N R1 100%

Figure 4.15. Synthesis of heterocycles via a reaction cascade

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Biphasic Chemistry and The Solvent Case

These compounds are all prepared with quantitative yields (compared to 46–81% in methanol) with the formation of water as the only by-product. The value of using a ball-mill is also found in the ability to modify the selectivities observed traditionally in solution (Hernández and Bolm 2017). Hanusa et al. (2014) were able to synthesize an unsolvated aluminum complex (Figure 4.16). Until then, all synthesis tests of this type of complex had only provided solvated complexes. The authors were also able to demonstrate the importance of obtaining an unsolvated complex by demonstrating that it was much more reactive to benzophenone than its solvated counterparts.

Figure 4.16. Synthesis of an unsolvated aluminum complex by ball-milling

Another advantage of using solvent-free conditions is the possibility to significantly increase reaction rates. Indeed, since the speed of a reaction is in most cases directly proportional to the concentration of the reagents, removing solvents significantly increases the concentration, and therefore the speed of a reaction. Under conventional stirring conditions, removing solvents very often leads to mass transfer limitations, especially in the presence of solids, which slows down the reaction. In contrast, ball-mills eliminate solvents while providing highly efficient agitation, thus eliminating the possibility of being limited by mass transfer. This phenomenon has been observed during peptide coupling reactions (Maurin et al. 2017). During the synthesis of the tetrapeptide Boc-VVIA-OBn, the speed of reaction of the three peptide couplings were considerably higher than the speed of the couplings performed in solution (Figure

Solvent-free e Chemistry

1 185

4.17). It I should bee noted here that very sm mall quantitties of a liquuid additive (here EtOA Ac) were useed during th he milling process, and thhat these quantities, q a although veery small compared c too conventionnal solutionn conditions, have a majoor role in thee efficiency of o the reactioon. Thee examples described in this t chapter are a only an overview o of tthe variety of reactionss described in literature and many reactions r couuld d heree. not be detailed By ball-milling: B O Oxyma (1.2 equiv) N 2PO 4 (4.0 equiv) NaH Boc--AA-OH + AH.H 2N peptide

EtOAc E E EDC (1.2 equiv)

or

In so olution: Oxym ma (1.2 equiv) DIPE EA (4.0 equiv) DMF F EDC (1.2 equiv)

Boc-VVIA-OB Bn

Figure e 4.17. Compa arison of the re eaction speed d of peptide co ouplings carrie ed o by ball-milliing (BM) and in out i solution

4.7.3. Scaling up p: industria al applicatio ons A laarge numberr of ball-millls are commeercially availlable in a wiide range oof sizes. Thhey are gennerally used for grindinng and mixiing materiaals with a wide vvariety of applicationns, from tthe homogenization of o small ssamples forr chemical analysis, to pyrotecchnics, cemeent, paints, ceeramics and the t food induustry. Althhough these ball-millingg techniques are widelly used on an industrial scale forr mining or construction n (Figure 4.18), very fe few chemiccal synthesis processes uusing ball-miills seem to be used on an industrial-scale todaay.

186

Biphasic Chemistry and The Solvent Case

a)

b)

Figure 4.18. a) Industrial ball-mill; b) workers inside a mill (Source: Genç 2016)

We have seen that at the laboratory level, up to several grams, vibrating and planetary mills are particularly suitable. However, this type of instrument does not allow substrates to be milled on a kilogram or larger scale. Indeed, the size and mass of the reactor and balls then required for such quantities make mechanical action difficult to create and energy consumption prohibitive for the targeted applications. However, instruments using slightly different grinding systems have been developed specifically for larger scale chemical synthesis applications. Thus, syntheses on several hundred grams, even kilograms, could be carried out. For example, Zoz has developed a new range of ball-mills called Simoloyer® (Figures 4.19 and 4.20).

cyclones

ball-mill Figure 4.19. Simoloyer® CM01-s1 ball-mill (Source: images reproduced with the permission of Zoz, www.zoz-group.de)

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187

Figure 4.20. Simoloyer® CM 100-s2 ball-mill (100 L reactor) (Source: image reproduced with the permission of Zoz, www.zoz-group.de)

These devices consist of a horizontal reactor in which the balls are placed. Unlike the devices described previously, where the movement of the bowl induced the movement of the balls, with the Simoloyer® ball-mills the balls are set in motion by rotating blades placed inside the milling chamber. The rotational speed of these blades can reach up to 1,800 rpm, allowing particularly efficient grinding of the substrate of interest. Figure 4.21 shows a section of a reactor where the blades are distinguished from the stationary balls and then the movements induced by the movement of the blades. The combined mechanical action of the balls and blades on the reagents will allow reactions to take place, as in the case of vibrating and planetary mills described earlier. a)

b)

Figure 4.21. Schematic section of the Simoloyer® CM 100-s2 reactor: a) stationary; b) running (Source: images reproduced with the permission of Zoz, www.zoz-group.de). For a color version of this figure, see www.iste.co. uk/malacria/biphasic.zip

188

Biphasic Chemistry and The Solvent Case

The milling chamber is also connected to a gas supply, allowing it to work under an inert atmosphere if necessary. This configuration also allows solid–gas reactions to be carried out by reacting a gas on the solid present in the grinding chamber. The introduction of a gas can also be used for the recovery of the product: a stream is created that leads the contents of the grinding chamber to a cyclone which separates, by gravity, the particles of ground products from the gases used. The volumes of the Simoloyer reactor chambers® range from 0.5 to 400 l; larger volumes are conceivable using this type of configuration. Using these devices, some chemical syntheses have been described, demonstrating the applicability of mechanochemical activation to large quantities. Thus, the reaction between 4-hydroxybenzaldehyde and 4aminobenzoic acid could be performed on a 200 g scale using the Simoloyer® CM01-s1 ball-mill. The corresponding imine was isolated as crystals with quantitative yield after only 15 minutes of grinding (Figure 4.22) (Kaupp et al. 2002). The water was removed by vacuum drying at 80 °C and no trace of products resulting from hydrolysis could be observed.

N

15 min

+ OH

CO 2H .H2 O

CO2 H

CHO

NH2

HO

100%

Figure 4.22. Synthesis of 200 g of an imine by ball-milling

Similarly, aminothiazolium-type heterocycles have been synthesized in a ball-mill in the absence of solvents (Kaupp et al. 2000a). The co-milling of thiourea and 2-bromoacetophenone in a 2 l Simoloyer reactor® resulted in the synthesis of 200 g of

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189

corresponding aminothiazolium with quantitative yield (Figure 4.23) (Kaupp et al. 2003a).

Figure 4.23. Solvent-free synthesis of aminothiazolium in a ball-mill

The creation of C-C bonds by Knoevenagel condensation was also performed on a 200 g scale using a Simoloyer reactor® (Kaupp et al. 2003b). Thus, the co-grinding of p-hydroxybenzaldehyde with barbituric and N,N'-dimethylbarbituric acids provided the corresponding barbituric acids in a quantitative manner (Figure 4.24). The products have been obtained pure after drying to remove residual water.

CHO

R N

O + R OH

N

O O

R N

O N

1h

R

O

-H 2 O O

R=H, Me OH

Figure 4.24. Knoevenagel condensation by ball-milling in the absence of solvent

Although the above examples show that it is possible to scale up the production of a solvent-free chemical synthesis using suitable ballmills, the quantity of product thus formed rarely exceeds 200 g. With the objective of producing larger quantities of Knoevenagel reaction products in the absence of solvent, James et al. (2017) recently described the use of an extruder.

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Biphasic Chemistry and The Solvent Case

4.8. Extruders 4.8.1. Methods and equipment In an extruder, the reagents are introduced in a barrel that contains one or more screws (Figure 4.25). The rotation of the screws allows the mixing and transport of the reagents throughout the barrel. The substrate to be extruded will undergo shear and compressive forces imposed by the rotation of the screw(s). a) b)

Figure 4.25. a) Twin-screw extruder with barrel open (Source: Thermo Scientific HAAKE MiniCTW); b) operating principle of an extruder. For a color version of this figure, see www.iste.co.uk/malacria/biphasic.zip

While examples of the use of ball-mills in a continuous mode are extremely rare, extruders are perfectly suited to the continuous introduction of reagents, and a fortiori, to the continuous extrusion of products. This makes it much easier to scale up production with an extruder. The barrel can also be heated and thermostatically controlled, whereas this is much more difficult to achieve with ballmills. The possibility of heating the barrel also allows the material to be extruded to reach a molten state, which is necessary to obtain an efficient extrusion. Indeed, the plastic deformation of substrates is essential to allow extrusion. Unlike ball-mills, extruders are totally ineffective in processing exclusively solid mixtures. While vibrating mills can grind very small quantities of samples ( 320 nm, at high and medium pressure), different types of lamps, with a variable power and a lifetime of 1,000–8,000 hours, are available today, both at the laboratory level and on an industrial scale. It should be noted that it is more and more common to use LEDs (light-emitting diodes), which are less energy consuming, especially when a photosensitive organic or organometallic catalyst is present in the reaction medium. During irradiation, heating phenomena due to the lamps will occur. It is therefore necessary to cool the reactor during irradiation. Commercial immersion tube reactors consist of a double-walled quartz (for lowpressure lamps) or Pyrex (for high-pressure lamps) sleeve for cooling the lamps. Several works describe the existing equipment, depending on the reactions to be carried out. Beyond the choice of lamp, an essential element for the proper functioning of a photochemical reaction is the elimination of oxygen, responsible for the deactivation of excited states, such as the triplet state which has a long life time. A rigorous degassing of the system, by flushing inert gas (nitrogen and argon), must therefore be carried out before irradiation. Conversely, in the case of photooxygenation reactions, oxygen is one of the reagents and a bubbling of the gas is carried out during the irradiation. Several books illustrate the technical conditions for setting up syntheses (Ninomiya and Naito 1989). There are microreactors, derived from chemical engineering research (Jähnisch et al. 2004) and used to carry out a large number of

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reactions, including photooxygenation. The reactions are carried out isothermally, which reduces the formation of secondary products, and the level of safety is improved. Figure 4.35 illustrates some examples of reactors used to perform gas–liquid, liquid–liquid or aerosol reactions. b)

a)

c)

Figure 4.35. Microreactors for photochemical reactions: a) gas–liquid; b) liquid–liquid (Source: Images (a) and (b) have been reproduced with the permission of the Institut für Microtechnik Mainz, www.imm-mainz.de); c) aerosol (Source: Image reproduced with the permission of Southern New England Ultraviolet Company, www.rayonet.org). For a color version of this figure, see www.iste.co.uk/malacria/biphasic.zip

4.10.2. Examples The field of asymmetric photochemical synthesis is stimulated by the need to obtain pure R or S enantiomers. Chiral phthalides were synthesized photochemically in the solid state (Sakamoto et al. 2000).

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The solid starting sample is located at the bottom of the reactor, cooled to 15 °C and irradiated with a mercury UV-visible lamp (high pressure) for 2 hours. Phthalides are obtained optically pure with very good yields (Figure 4.36).

Figure 4.36. Photochemical reaction in the solid state

More recently, α-oxoamide atropoisomers have been photochemically cyclized to synthesize to the two corresponding diastereoisomers, each diastereoisomer being optically pure (Figure 4.37) (Raghunathan et al. 2013). Note that the selectivity of the photochemical reaction is reversed when the reagent is in solution or in solid form.

Figure 4.37. Solid-state diastereoselective photochemical reaction. For a color version of this figure, see www.iste.co.uk/malacria/biphasic.zip

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Solid-phase photochemical synthesis is also widely used in [2+2] or [4+4] cycloaddition reactions. One of the difficulties encountered is the spatial arrangement of molecules to control the selectivity of the reaction. For example, in the photodimerization of 1-azaanthracene, the formation of the compound’s hydrochloride promotes the formation of the anti-HT dimer with nitrogen atoms as far apart as possible (Figure 4.38) (Yamada and Kawamura 2012). The protonation of nitrogen allows an arrangement of molecules in solution but also in solid form.

Figure 4.38. Controlled solid-state photodimerization

4.10.3. Scaling up: industrial applications As with other technologies, the transition from photochemical reaction from laboratory to industrial scale is not direct and may require significant modifications. An important parameter to consider this transfer is the quantum yield of a reaction, defined as the number of molecules produced for the absorption of a photon. To consider an industrial application, this quantum yield is often greater than 1 (Photochimie 94 1994). The most widely used solvent-free photochemical reactions are photopolymerization reactions based on multifunctional monomers or oligomers, known as UV curing or curing reactions (also known as UV curing, radiation curing, photocuring). Such photopolymerizations have applications in the field of varnishes, paints for the protection of various surfaces (paper, glass, metal, plastic, wood), microelectronics (inks), composite materials, dentistry (cavity treatments) and medicine (microencapsulation of drugs). They have many advantages: (1) the use of light energy (produced by an electrical source) instead of thermal energy; (2) lower production

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costs; (3) working at room temperature; and (4) the use of much smaller UV ovens than thermal drying tunnels. Thanks to the light energy, by working at temperature and without thermal activation, it is possible to transform a resin into a solid polymer. In general, monomers with at least one olefin (acrylates, maleates, maleimides, epoxides, oxetanes, vinyl and allyl ethers, liquid polybutadienes or modified silicones) are the preferred substrates for photopolymerization. Using the same light irradiation technique, photoreticulation generates a dense three-dimensional network and a material that has excellent resistance properties to organic solvents, chemicals and heat (Figure 4.39). Typically, the formulation (photopolymerizable) contains a photosensitive system (which absorbs light to generate reactive radicals), a monomer (whose role is to adjust viscosity), an oligomer or prepolymer (to give the material characteristic properties after the formation of the threedimensional polymer network), and formulation additives. Several nanocomposite materials have been industrially synthesized by Ciba SC, BASF, UCB Chemicals, Shell, Evans Chemicals, Dow Chemicals (Decker 2002). Reactions are carried out using a medium pressure mercury lamp (Salmi et al. 2006) or simply by exposure to sunlight (Keller et al. 2004) for a few seconds.

Figure 4.39. Cross-polymerization of polyurethane-diacrylate

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The use of solar energy, a renewable, free and inexhaustible energy, to induce or promote reactions is ideal in the context of green chemistry and sustainable development (Esser et al. 1994). The main disadvantage is that solar radiation is rarely constant and its intensity depends on day/night rhythms, climate, the geographical position of the reactors and their altitude. On an industrial scale, the photochemical pathway, using the sun as a source of photons, makes it possible to synthesize many high value-added products. Most of these large-scale photoinduced reactions are carried out in solution. Some examples of reactors, with reaction tubes placed at the focal point of mirrors for sunlight concentration, are shown in Figures 4.40 and 4.41. These devices, for which the light source is sunlight, present less risk than a high-pressure mercury lamp, in terms of explosion or ignition of organic substrates contained in reactors, the light source being much further away.

Figure 4.40. a) The PROPHIS reactor (3 m2 reflection area); b) its schematic diagram (Source: Images reproduced with permission from the Royal Society of Chemistry). For a color version of this figure, see www.iste.co.uk/ malacria/biphasic.zip

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a)

b)

Figure 4.41. Examples of reactors (3 m2 reflection surface): a) CPC; b) flatbed reactor (Source: Images reproduced with permission of the Royal Society of Chemistry)

4.11. Comparison of techniques The development of a solvent-free synthesis is not always generally suitable for all types of transformation. One activation method may be preferred over another depending on the synthesis to be performed. This is why it is difficult to find data comparing the effectiveness of different techniques for the same transformation. A rare example, presented below, concerns nitrone synthesis. Nitrones are important intermediates in organic synthesis. Among the different methods used for their preparation, the condensation reaction between an aldehyde and a substituted hydroxylamine on the nitrogen atom, in the presence of a base, is the most exploited. The condensation reaction can be carried out at different temperatures (cold, ambient or reflux) and the reaction times are variable (from a few hours to 2 days), depending on the substrates. In a traditional, very general approach, anhydrous conditions and an excess of aldehyde are necessary to achieve good yields (60–95%) including a chromatographic purification. These disadvantages are eliminated when nitrone synthesis is carried out without solvents, under mild conditions and in the presence of stoichiometric quantities of both substrates. The literature lists three activation methods for solvent-free nitrone synthesis: (1) grinding of substrates in a mortar (Bigdeli and Nikje 2001), (2) microwave heating or (3) use of a ball-mill (Colacino et al. 2008) (Figure 4.42). In all these cases, synthesis is carried out under ambient atmosphere.

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The synthesis of nitrones in a mortar is possible provided that 3Å molecular sieves, which act as a catalyst, are used as an additive: the yields are quantitative and the reactions are very rapid (15 minutes). In the case of the ball-mill, no additives were required during synthesis: the yields obtained are very good (71–100%), and in most cases better than in solvent-based syntheses. Reaction times are shorter (from 30 minutes to 2 hours instead of a few hours or days) and nitrones are obtained by simply filtering the reaction crude, with water, carbon dioxide and sodium chloride being the only by-products of the reaction (Figure 4.42). O R1

H

+

R2 NHOH.HCl

Ball-mill 30 Hz

-O + 2 R N

NaHCO3 0.5-2h

R1

+ NaCl + CO2 + 2 H2O

H

71-100%

Figure 4.42. Solvent-free nitrone synthesis (Colacino et al. 2008)

Solvent-free nitrone synthesis under microwave activation has proven to be the least effective: reaction times are long (more than 2 hours), temperature is high (120 °C) and substrate conversion is never complete, due to hydroxylamine degradation. Conversion is improved if excess hydroxylamine is used and the reaction is carried out in dichloromethane (Banerji et al. 2004). Table 4.1 compares the nitrone yields obtained with the three methods. R1

Ph

Ph

Ph

4-CN-C6H4

4-Me-C6H4

R2

Me

Bn

t-Bu

Me

Me

Microwave (Colacino et al. 2008) Rdt (%)

72

80

74

64

65

Ball-mill (Colacino et al. 2008) Rdt (%)

100

100

100

100

100

Mortar (Bigdeli and Nikje 2001) Rdt (%)

98

–

–

–

92

Table 4.1. Comparative study for the synthesis of nitrones

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4.12. Conclusion The reactions described in this chapter illustrate the wide range of applications of solvent-free reactions. Processes using a liquid reagent are generally conceptually accepted by chemists. On the other hand, the solid–gas and solid–solid reactions still encounter resistance. However, at present, the increasing number of publications reflects a renewed activity in this field with applications in all branches of chemistry. A new solvent-free continuous synthesis approach using solid reagents by extrusion technology is the subject of a growing number of promising studies. While some of these processes are used on a large scale, their effectiveness is not diminished when working on a laboratory scale and their development should be promoted in these environments, especially since the necessary equipment is often inexpensive. Further studies will be needed to broaden the scope of these reactions, particularly on an industrial scale. Reactions using a liquid reagent are often linked to another technology such as MWs, microreactors and photochemistry. Therefore, advances in these areas, which are also the subject of intense studies, will make it possible to advance solvent-free chemistry. As for solid–solid or solid–gas reactions, their scope will need to be broadened and studies on physicochemistry and thermodynamics will need to be further developed to allow effective applications on a large scale, while developing the practical side of these processes, especially for effective transfer of reagents and products. The most complete possible integration of solvent removal into chemical processes will be a key contribution to sustainable development. 4.13. References Books, journals Adelhorst, K., Björkling, F., Godtfredsen, S.E., Kirk, O. (1990). Enzyme catalyzed preparation of 6-O-acylglucopyranosides. Synthesis, 112–115.

Solvent-free Chemistry

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Adib, M., Mahdavi, M., Mahmoodi, N., Pirelahi, H., Bijanzadesh, H.R. (2006). A novel, one-pot, three component synthesis of 1,2,4-oxadiazoles under microwave irradiation and solvent free-conditions. Synlett, 1765– 1767. Anastas, P.T., Williamson, T.C. (eds) (1996). Green Chemistry, Designing Chemistry for the Environment. ACS Symposium Series, no. 626, 266. American Chemical Society, Washington DC. Anastas, P.T., Williamson, T.C. (eds) (1999). Green Chemistry: Frontiers in Benign Chemical Syntheses and Processes. Oxford University Press, New York. Anastas, P.T., Heine, L.G., Williamson, T.C. (eds) (2000). Green Chemical Syntheses and Processes. Oxford University Press, Oxford. Balema, V.P., Wiench, J.W., Pruski, M., Pecharsky, V.K. (2002). Mechanically induced solid-state generation of phosphorus ylides and the solvent-free Wittig reaction. J. Am. Chem. Soc., 124, 6244–6245. Banerji, A., Biswas, P.K., Sengupta, P., Dasgupta, S., Gupta, M. (2004). 1,3Dipolar cycloadditions: Part VIII: Microwave irradiation assisted synthesis of N-methyl-C-arylnitrones. Indian J. Chem. B: Org. Chem. Incl. Med. Chem., 43B(4), 880–881. Bernas, A., Kumar, N., Mäki-Arvela, P., Holmbom, B., Salmi, T., Murzin, D.Y. (2004). Heterogeneous catalytic production of conjugated linoleic acid. Org. Proc. Res. Dev., 8, 341–352. Bigdeli, M.A., Nikje, M.M.A. (2001). An efficient and rapid chemoselective synthesis of a-aryl-N-methylnitrones in dry media. Monat. Chemie, 132, 1547–1549. Bigi, F., Carloni, S., Frullanti, B., Maggi, R., Sartori, G. (1999). A revision of the Biginelli reaction under solid acid catalysis. Solvent-free synthesis of dihydropyrimidines over montmorillonite KSF. Tetrahedron Lett., 40, 3465–3468. Bowmaker, G.A. (2013). Solvent-assisted mechanochemistry. Chem. Commun., 49, 334–348. Braun, A., Maurette, M.T., Oliveros, E. (1991). Photochemical Technology. Wiley, Chichester.

208

Biphasic Chemistry and The Solvent Case

Chauhan, P., Chimni, S.S. (2012). Mechanochemistry assisted asymmetric organocatalysis: A sustainable approach. Beilstein J. Org. Chem., 8, 2132–2141. Colacino, E., Nun, P., Colacino, F.M., Martinez, J., Lamaty, F. (2008). Solvent-free synthesis of nitrones in a ball-mill. Tetrahedron, 64, 5569– 5576. Crawford, D.E., Miskimmin, C.K.G., Albadarin, A.B., Walker, G., James, S.L. (2017). Organic synthesis by twin screw extrusion (TSE): Continuous, scalable and solvent-free. Green Chem., 19, 1507–1518. Decker, C. (2002). Kinetic study and new applications of UV radiation curing. Macromol. Rapid Commun., 23, 1067–1093. Deshayes, S., Liagre, M., Loupy, A., Luche, J.-L., Petit, A. (1999). Microwave activation in phase transfert catalysis. Tetrahedron, 55, 10851–10870. Do, J.-L., Friščić, T. (2017). Mechanochemistry: A force of synthesis. ACS Central Science, 3, 13–19. Esser, P., Pohlmann, B., Scharf, H.-D. (1994). The photochemical synthesis of fine chemicals with sunlight. Angew. Chem. Int. Ed. Engl., 33, 2009– 2023. Esveld, E., Chemat, F., Van Haveren, J. (2000a). Pilot scale continuous microwave dry-media reactor. Part 1: Design and modeling, Chem. Eng. Technol., 23, 279–283. Esveld, E., Chemat, F., Van Haveren, J. (2000b). Pilot scale continuous microwave dry-media reactor. Part 2: Application to waxy esters production. Chem. Eng. Technol., 23, 429–435. Fouassier, J.P., Rabek, J.F. (eds) (1993). Radiation Curing in Polymer Science and Technology. Chapman and Hall, London. Garcìa, E., Ferrari, F., Garcìa, T., Martìnez, M., Aracil, M. (2001). Optimization of the enzymatic esterification of diglycerol and lauric acid. J. Surfactants and Detergents, 4, 257–262. Genç, Ö. (2016). Optimization of an industrial scale open circuit threecompartment cement grinding ball-mill with the aid of simulation. Int. J. Miner. Process., 154, 1–9.

Solvent-free Chemistry

209

Gérin, M. (ed) (2002). Solvants industriels, santé, sécurité, substitution. Masson, Paris. Gill, I., Valivety, R. (2002). Pilot-scale enzymatic synthesis of 1-O-β-Dgalactopy-ranosides in plasticized glass phases. Org. Proc. Res. Dev., 6, 692–699. Glasnov, T.N., Kappe, C.O. (2007). Microwave-assisted synthesis under continuous-flow conditions. Macromol. Rapid Commun., 28, 395–410. Guo, Z., Sun, Y. (2007). Solvent-free production of 1,3-diglyceride of CLA: Strategy consideration and protocol design. Food Chem., 100, 1076– 1084. Hernández, J.G., Bolm, C. (2017). Altering product selectivity by mechanochemistry. J. Org. Chem., 82, 4007–4019. Hornke, J., Lipphardt, R., Meldt, R. (1990). Herstellung von Polypropylen. Produktionsintegrierter umweltschultz in der chemischen industrie, Wiesner, J. (ed). Dechema, Frankfurt am Main. Jähnisch, K., Hessel, V., Löwe, H., Baerns, M. (2004). Chemistry in microstructured reactors. Angew. Chem. Int. Ed. Engl., 43, 406–446. James, S.L., Adams, C.J., Bolm, C., Braga, D., Collier, P., Friščić, T., Grepioni, F., Harris, K.D.M., Hyett, G., Jones, W., Krebs, A., Mack, J., Maini, L., Orpen, A.G., Parkin, I.P., Shearouse, W.C., Steed, J.W., Waddell, D.C. (2012). Mechanochemistry: Opportunities for new and cleaner synthesis. Chem. Soc. Rev., 41, 413–447. Kappe, C.O., Stadler, A. (2005). Microwaves in Organic and Medicinal Chemistry. Wiley-VCH, Weinheim. Kaupp, G. (2005). Organic solid-state reactions with 100% yield. Topics Curr. Chem., 254, 95–183. Kaupp, G., Schmeyers, J., Boy, J. (1998). Quantitative gas-solid reactions with ClCN and BrCN: Synthesis of cyanamides, cyanates, thiocyanates, and their derivatives. Chem. Eur. J., 4, 2467–2474. Kaupp, G., Schmeyers, J., Kuse, A., Atfeh, A. (1999). Cascade reactions in quantitative solid-state syntheses. Angew. Chem. Int. Ed. Engl., 38, 2896– 2899. Kaupp, G., Schmeyers, J., Boy, J. (2000a). Iminium salts in solid-state syntheses giving 100% yield. J. für praktische Chem., 342, 269–280.

210

Biphasic Chemistry and The Solvent Case

Kaupp, G., Schmeyers, J., Boy, J. (2000b). Quantitative solid-state reactions of amines with carbonyl compounds and isothiocyanates. Tetrahedron, 56, 6899–6911. Kaupp, G., Schmeyers, J., Naimi-Jamal, M.R., Zoz, H., Ren, H. (2002). Reactive milling with the Simoloyer®: Environmentally benign quantitative reactions without solvents and wastes. Chem. Eng. Sci., 57, 763–765. Kaupp, G., Naimi-Jamal, M.R., Ren, H., Zoz, H. (2003a). Reactive dry milling for environmental protection. [Online]. Available: http://gmbh. zoz.de/_AKTUELL/pdf_content/ publications/v40.pdf. Kaupp, G., Naimi-Jamal, M.R., Schmeyers, J. (2003b). Solvent-free Knoevenagel condensations and Michael additions in the solid state and in the melt with quantitative yield. Tetrahedron, 59, 3753–3760. Keith, L.H., Gron, L.U., Young, J.L. (2007). Green analytical methodologies. Chem. Rev., 107, 2695–2708. Keller, L., Decker, C., Zahouily, K., Benfarhi, S., Le Meins, J.M., MieheBrendle, J. (2004). Synthesis of polymer nanocomposites by UV-curing of organoclay-acrylic resins. Polymer, 45, 7437–7447. Komiya, K., Fukuoka, S., Aminaka, M., Hasegawa, K., Hachiya, H., Okamoto, H., Watanabe, T., Yoneda, H., Fukawa, J., Dozono, T. (1996). New Process for Producing Polycarbonate Without Phosgene and Methylene Chloride. In Green Chemistry, Designing Chemistry for the Environment, Anastas, P.T., Williamson, T.C. (eds). American Chemical Society, Washington, DC, 20–32. Kremsner, J.M., Stadler, A., Kappe, C.O. (2006). The scale-up of microwave-assisted organic synthesis. Topics Curr. Chem., 266, 233–278. Larson, G.L., Chawla, R.R., Subramaniam, C.S., John, T.V. (1997). A commercially viable synthesis of cyanotrimethylsilane. Org. Proc. Res. Dev., 1, 90–91. Leadbeater, N.E., Williams, V.A., Barnard, T.M., Collins Jr., M.J. (2006). Solvent-free, open-vessel microwave-promoted heck couplings: From the mmol to the mol scale. Synlett, 2953–2958. Li, J., Zhao, G., Gao, S., Lv, Y., Li, J., Xi, Z. (2006). Epoxidation of allyl chloride to epichlorohydrin by a reversible supported catalyst with H2O2 under solvent-free conditions. Org. Proc. Res. Dev., 10, 876–880.

Solvent-free Chemistry

211

Loupy, A. (1999). Solvent-free reactions in modern solvent in organic chemistry. Topic. Curr. Chem., 206, 155–207. Loupy, A. (2004). Synthèse organique sous micro-ondes en absence de solvant. Actu. Chimique, 272, 18–26. Loupy, A. (2006). Microwaves in Organic Synthesis. Wiley-VCH, Weinheim. Loupy, A., Haudrechy, A. (eds) (1996). Effets de milieu en synthèse organique. Elsevier-Masson, Paris. Loupy, A., Petit, A., Hamelin, J., Texier-Boullet, F., Jacquault, P., Mathé, D. (1998). New solvent-free organic synthesis using focused microwaves. Synthesis, 1213–1234. Ma, Y., Qian, C., Wang, L., Yang, M. (2000). Lanthanide triflate catalyzed Biginelli reaction. One-pot synthesis of dihydropyrimidinones under solvent-free conditions. J. Org. Chem., 65, 3864–3868. Mattay, J., Griesbeck, A. (eds) (1994). Photochemical Key Step in Organic Synthesis. Wiley-VCH, Weinheim. Maurin, O., Verdié, P., Subra, G., Lamaty, F., Martinez, J., Métro, T.-X. (2017). Peptide synthesis: Ball-milling, in solution, or on solid support, what is the best strategy? Beilstein J. Org. Chem., 13, 2087–2093. Medina, C., Daurio, D., Nagapudi, K., Alvarez-Núñez, F. (2010). Manufacture of pharmaceutical co-crystals using twin screw extrusion: A solvent-less and scalable process. J. Pharm. Sci., 99, 1693–1696. Metzger, J.O. (1998). Solvent-free organic syntheses. Angew. Chem. Int. Ed. Eng., 37, 2975–2977. Neas, E.D., Collins, M.J. (1988). Theoretical Concepts and Equipment Design. Introduction to Microwave Sample Preparation Theory and Practice, Kingston, H.M., Jessie, L.B. (eds). American Chemical Society, Washigton, DC, 7–32. Ninomiya, I., Naito, T. (1989). Photochemical Synthesis. Academic Press, London. Pappas, J.P. (ed.) (1992). Radiation Curing Science & Technology. Plenum Press, New York. Peet, N.P., Huber, E.W., Huffman, J.C. (1995). Reaction of ninhydrin with βdicarbonyl compounds. J. Heterocyclic Chem., 32, 33–41.

212

Biphasic Chemistry and The Solvent Case

Peng, J., Deng, Y. (2002). Ionic liquids catalyzed Biginelli reaction under solvent-free conditions. Tetrahedron Lett., 41, 5917–5919. Photochemistry (2007). Actualités Chimiques. Polshettiwar, V., Varma, R.S. (2008). Microwave-assisted organic synthesis and transformations using benign reaction media. Acc. Chem. Res., 41, 629–639. Raghunathan, R., Kumarasamy, E., Iyer, A., Ugrinov, A., Sivaguru, J. (2013). Intramolecular Paterno-Buechi reaction of atropisomeric αoxoamides in solution and in the solid-state. Chem. Commun., 49, 8713– 8715. Ranu, B.C., Hajra, A., Dey, S.S. (2002). A practical and green approach towards synthesis of dihydropyrimidinones without any solvent or catalyst. Org. Proc. Res. Dev., 6, 817–818. Rightmire, N.R., Hanusa, T.P., Rheingold, A.L. (2014). Mechanochemical synthesis of [1,3-(SiMe3)2C3H3]3(Al,Sc), a base-free tris(allyl)aluminum complex and its scandium analogue. Organometallics, 33, 5952–5955. Roberts, B.A., Strauss, C.R. (2005). Scale-up of microwave-assisted organic synthesis. Microwave-Assisted Organic Synthesis, Lindström, P., Tierney, J. (eds). Blackwell, Oxford, 237–266. Rodriguez, B., Bruckmann, A., Bolm, C. (2007). A highly efficient asymmetric organocatalytic aldol reaction in a ball-mill. Chem. Eur. J., 13, 4710–4722. Roffey, C.G. (1997). Photogeneration of Reactive Species for UV-Curing. Wiley, New York. Rong, L., Li, X., Wang, H., Shi, D., Tu, S. (2006). An efficient and facile synthesis of 2-amino-4,6-diarylbenzene-1,3-dicarbonitrile and 1,2dihydro-2-oxo-4,6-diarylpyridine-3-carbonitrile under solvent-free conditions. Chemistry Lett., 35, 1314–1315. Sakamoto, M., Sekine, N., Miyoshi, H., Mino, T., Fujita, T. (2000). Absolute asymmetric phthalide synthesis via the solid-state photoreaction of N,Ndisubstituted 2-benzoylbenzamides involving a radical pai intermediate. J. Am. Chem. Soc., 122, 10210–10211. Salmi, A., Benfarhi, S., Donnet, J.B., Decker, C. (2006). Synthesis of carbonpolyacrylate nanocomposite materials by crosslinking polymerization. Eur. Polymer J., 42, 1966–1974.

Solvent-free Chemistry

213

Shenoy, S.L., Cohen, D., Erkey, C., Weiss, R.A. (2002). A solvent-free process for preparing conductive elastomers by an in situ polymerization of pyrrole. Ind. Eng. Chem. Res., 41, 1484–1488. Strauss, C.R., Varma, R.S. (2006). Microwave in green and sustainable chemistry. Topics Curr. Chem., 266, 199–231. Tanaka, K. (2003). Solvent-Free Organic Synthesis. Wiley-VCH, Weinheim. Tanaka, K., Toda, F. (2000). Solvent-free organic synthesis. Chem. Rev., 100, 1025–1074. Thayer, A.N. (1995). Metallocene catalysts initiate new era in polymer synthesis. Chem. Eng. News, 73, 15–20. Tokumaru, T., Coyle, J.D. (1992). A collection of experiments for teaching photochemistry. Pure Appl. Chem., 64, 1343–1382. Varma, R.S. (1999). Solvent-free organic syntheses using supported reagents and microwave irradiation. Green Chem., 1, 43–55. Varma, R.S., Saini, R.K. (1997). Microwave-assisted reduction of carbonyl compounds in solid state using sodium borohydride supported on alumina. Tetrahedron Lett., 38, 4337–4338. Varma, R.S., Naicker, K.P., Kumar, D., Dahiya, R., Liesen, P.J. (1999). Solvent-free organic synthesis using supported reagents and microwave irradiation. J. Microwave Power Electromagn. Energy, 34, 113–123. Walsh, P.J., Li, H., Anaya de Parrodi, C. (2007). A green chemistry approach to asymmetric catalysis: Solvent-free and highly concentrated reactions. Chem. Rev., 107, 2503–2545. Webster, R. (1998). Radiation Curable Printing Inks and Coatings. Chemistry and Technology of UV and EB Formulation for Coatings, Inks and Paints, Oldring, P.T.K. (ed.). SITA Technology, London, 1–5. Welton, T. (2006). All solutions have a solvent. Green Chem., 8, 13. Yamada, S., Kawamura, C. (2012). [4 + 4] Photodimerization of azaanthracenes in both solution and solid phase controlled by cation-π interactions. Org. Lett., 14, 1572–1575.

Organizations Aceglass Incorporated, https://aceglass.com. German Aerospace Agency, www.dlr.de/.

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American Chemical Society Green Chemistry Institute®, www.acs.org/ content/acs/en/greenchemistry.html. Anton Paar, www.anton-paar.com. Biotage AB Headquarters, www.biotage.com. CEM μWave S.A.S., www.cem.com. Cientro de Invastigationes Energéticas, Medioambientales y Tecnológicas, plate-forme solaire d’Alméria (Espagne), www.psa.es. European Agency for Safety and Health at Work, https://osha.europa.eu/en. Fritsch GmbH, Milling and Sizing, www.fritsch-international.com. Institut für Mikrotechnik Mainz GmbH, www.imm.fraunhofer.de/. Institut national de recherche et de sécurité (INRS), www.inrs.fr. International Energy Agency, www.iea.org. International Occupational Hygiene Association (IOHA), ioha.net. Milestone srl, www.milestonesrl.com. National Renewable Energy Laboratory (NREL), www.nrel.gov. Occupational Safety and Health Administration (OSHA), www.osha.gov. Retsch Gmbh, www.retsch.com. Sairem, www.sairem.com. Southern New England Ultraviolet Company, https://rayonet.org. Spex CertiPrep, www.spexcsp.com. US environmental Protection Agency, www.epa.gov. Zoz Gmbh, www.zoz-group.de.

Websites https://lejournal.cnrs.fr/billets/une-chimie-sans-solvants-cest-possible. https://totallymicrowave.wordpress.com/. www.chemistryguide.org/environmental-chemistry.html/.

Solvent-free Chemistry

www.epa.gov/greenchemistry/. www.rsc.org/chemsoc/gcn/. www.sciencedirect.com/topics/chemistry/microwave-technology.

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List of Authors

Xavier BANTREIL Institut des biomolécules Max Mousseron University of Montpellier France Jean-Philippe GODDARD Laboratoire d’innovation moléculaire et applications University of Upper Alsace Mulhouse France Géraldine GOUHIER University of Rouen France Frédéric LAMATY Institut des biomolécules Max Mousseron University of Montpellier France

Max MALACRIA Institut parisien de chimie moléculaire Sorbonne University Paris France Jean MARTINEZ Institut des biomolécules Max Mousseron University of Montpellier France Thomas-Xavier MÉTRO Institut des biomolécules Max Mousseron University of Montpellier France Cyril OLLIVIER Institut parisien de chimie moléculaire Sorbonne University Paris France

Biphasic Chemistry and The Solvent Case,First Edition. Edited by Jean-Philippe Goddard, Max Malacria and Cyril Ollivier. © ISTE Ltd 2020. Published by ISTE Ltd and John Wiley & Sons, Inc.

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Biphasic Chemistry and The Solvent Case

Marie-Christine SCHERRMANN Institut de chimie moléculaire et des matériaux d’Orsay Paris-Sud University France

Jean-Marc VINCENT Institut des sciences moléculaires University of Bordeaux France

Index

A, C

P, R

activation methods, 171, 204 analytical methods and reaction monitoring, 20 catalysis, 29, 32, 33, 42, 57, 58, 61, 64, 65, 67, 70, 73, 74, 90, 109, 112, 122, 127, 145 chemistry supported, 1, 18, 29, 35 sustainable, 57, 169

perfluorocarbons, 57, 71 photochemistry, 171, 198, 201, 206 protecting groups, 77, 79 purification, 1, 4–6, 43, 45, 57, 59, 63, 70, 76, 79, 80, 82, 87, 88, 90, 92, 95, 98, 110, 113, 125, 142, 160, 177, 181, 204 rate cross-linking, 7, 8, 13, 14 functionalization, 9, 10, 12, 42 reagents, 2, 4–6, 10, 12, 23, 30, 34, 37, 38, 45, 57, 59, 62, 67, 69, 76, 77, 80, 81, 85, 99, 106–108, 115, 117, 126, 130, 145, 170–172, 176, 179–182, 184, 187, 190–192, 198, 202, 206 supported, 29, 45, 77

E, F effect diffusion, 13 proximity, 15 fluorophilicity, 58, 64 L, M ligands, 16, 47, 51, 55, 59, 65, 66, 91, 95, 96, 121, 128, 129, 132, 146, 162 linkers, 3, 18, 27, 29, 40, 45 microwave, 1, 40, 41, 77, 113, 171, 192, 193, 195, 196, 204–206, 211

S, T silica, 59, 62, 63, 73, 77, 78, 81, 82, 110, 121, 193 size of the beads, 12 solid-phase, 1–6, 16, 20, 23, 26, 27, 29–32, 34–36, 38, 40, 43–45, 76, 77, 201

Biphasic Chemistry and The Solvent Case,First Edition. Edited by Jean-Philippe Goddard, Max Malacria and Cyril Ollivier. © ISTE Ltd 2020. Published by ISTE Ltd and John Wiley & Sons, Inc.

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solvents, 1, 3, 5–7, 9–12, 16, 17, 19, 57, 59–61, 70–72, 74, 77, 87, 90, 100, 107, 113, 120, 121, 124, 135, 142, 169, 174, 180, 184, 188, 202, 206, 209, 214 spacer arms, 17 swelling properties, 10, 11, 13, 14, 19 synthesis, 1, 3–6, 9, 16, 18, 20, 23, 25–27, 29, 31, 32, 35–41, 43, 45, 57–59, 61, 72, 75–78, 81–90, 99, 100, 107, 108, 113, 117–119, 124, 125, 142–145, 169–176, 178, 182–186, 188, 189, 191, 193–197, 199, 201, 204–206, 211

mixture, 81–84 parallel, 37, 75, 79, 90 solid-phase, 3, 5, 20, 29, 43, 45, 76, 77 solvent-free, 170–172, 189, 197, 204 tags, 57–59, 62, 64, 77, 81, 82, 85, 87, 90 Teflon, 57, 58, 62, 63, 73, 74

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