Structure Elucidation by NMR in Organic Chemistry: A Practical Guide [3rd Revised Edition] 0470850078, 9780470850077

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Structure Elucidation By NMR In Organic Chemistry: A Practical Guide. Eberhard Breitmaier Copyright © 2002 John Wiley & Sons, Ltd. ISBNs: 0-470-85006-X (HB); 0-470-85007-8 (PB)

S:TR;U,CTUIRE ElU'CliDATI:ON

B:Y NMiR IN OIRGANilC CHIEM"ISTRY

S';TRUCTURE ｎｾｏｉｔａｄＡｃｕｬＮｅ B,V

NMR

I;N, O·RGANiIC CHEMilSTRV APractical Guide Third revised edition

EBERHARD BREITMAIER University ofBonn, Germany

JOHN WILEY &- SONS, LTD

Copyright © 2002

John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex P019 8SQ, England Telephone

(+44) 1243 779777

Email (for orders and customer service enquiries): [email protected] Visit our Home Page on www.wileyeurope.com or www.wiley.com All Rights Reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning or otherwise, except under the terms of the Copyright, Designs and Patents Act 1988 or under the terms of a licence issued by the Copyright Licensing Agency Ltd, 90 Tottenham Court Road, London WIT 4LP, UK, without the permission in writing of the Publisher. Requests to the Publisher should be addressed to the Permissions Department, John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex P019 8SQ, England, or emailed to [email protected], or faxed to (+44) 1243770571. This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. It is sold on the understanding that the Publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought. Other Wiley Editorial Offices John Wiley & Sons Inc., 111 River Street, Hoboken, NJ 07030, USA Jossey-Bass, 989 Market Street, San Francisco, CA 94103-1741, USA Wiley-VCH Verlag GmbH, Boschstr. 12, D-69469 Weinheim, Germany John Wiley & Sons Australia Ltd, 33 Park Road, Milton, Queensland 4064, Australia John Wiley & Sons (Asia) Pte Ltd, 2 Clementi Loop #02-01, Jin Xing Distripark, Singapore 129809 John Wiley & Sons Canada Ltd, 22 Worcester Road, Etobicoke, Ontario, Canada M9W ILl

British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library ISBN 047085006 X (Cloth) ISBN 0470850078 (paper) Produced from camera ready copy supplied by the author. Printed and bound in Great Britain by Antony Rowe Ltd, Chippenham, Wiltshire. This book is printed on acid-free paper responsibly manufactured from sustainable forestry in which at least two trees are planted for each one used for paper production.

The cover shows the 13C NMR spectrum of (1- and ｾＭｄｸｹｬｯｰｲ｡ｮｳ･ at mutarotational equilibrium (35% (1, 65% ｾＬ in deuterium oxide, 100 MHz, IHbroadband decoupling) with the CC INADEQUATE contour plot. An interpretation of the plot according to principles described in Section 2.2.7 gives the CC bonds of the two isomers and confirms the assignment of the signals in Table 2.12.

CONTENTS PREFACE

ix

PREFACE TO THE FIRST EDITION

x

SYMBOLS AND ABBREVIATIONS

xi

1

SHORT INTRODUCTION TO BASIC PRINCIPLES AND METHODS

1

1.1

1

1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9

Chemical shift Spin-spin coupling and coupling constants Signal mUltiplicity (multiplets) Spectra offirst and higher order Chemical and magnetic equivalence Fourier transform (FT) NMR spectra Spin decoupling Nuclear Overhauser effect Relaxation, relaxation times

10

2

RECOGNITION OF STRUCTURAL FRAGMENTS BY NMR

11

2.1 2.1.2 2.1.2 2.1.3 2.1.4 2.2 2.2.1 2.2.2 2.2.3 2.2.4 2.2.5 2.2.6 2.2.7 2.2.8 2.2.9 2.3 2.3.1 2.3.2 2.3.3 2.3.4 2.3.5

Functional groups 1H Chemical Shifts Deuterium exchange 13C Chemical shifts 15N Chemical shifts Skeletal structure (atom connectivities) HH Multiplicities CH Multiplicities HH Coupling constants CH Coupling constants NH Coupling constants HH COSY (geminal, vicina/, w-relationships of protons) CC INADEQUATE (CC bonds) Two-dimensional carbon-proton shift correlation via one-bond CH coupling Two-dimensional carbon-proton shift correlation via long-range CH coupling Relative configuration and conformation HH Coupling constants CH Coupling constants NH Coupling constants 13C Chemical shifts NOE Difference spectra

11 11 12 12

1 2

3 4 5 6 8

14

16 16 18 21

26 29

30 33

36 39 42 42 46

47 48 51

vi

CONTENTS

2.3.6 2.4 2.4.1 2.4.2 2.5 2.5.1 2.5.2 2.5.3 2.5.4 2.6 2.6.2 2.7

HH NOESY and ROESY Absolute configuration Diastereotopism Chiral shift reagents (ee determination) Intra- and intermolecular interactions Anisotropic effects Ring current ofaromatic compounds Intra- and intermolecular hydrogen bonding Protonation effects Molecular dynamics (fluxionality) 13C Spin-lattice relaxation times Summary

53 54 54 56 58 58 58 59 60 61 63 67

3

PROBLEMS

69

1-12 13-14 15-20 21-22 23-29 30-31 32-42 43-55

Application ofone-dimensionel tn NMR Temperature dependent 1H and 13C NMR spectra Application of one-dmensionelX NMR spectra CC INADEQUATE experiments Application ofone-dimensionel rn and 13C NMR spectra Application ofone-dlmenslona rrt 13C and 15N NMR spectra Combined application ofone and two-dimensional t't and 13C NMR experiments Identification and structural elucidation ofof natural products by one and two-dimensional 1H and 13C NMR

69 83 85 91 93 100 104

4

SOLUTIONS TO PROBLEMS

180

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

Dimethyl cis-cyclopropane-1 ,2-dicarboxylate Ethylacrylate cis-1-Methoxybut-1-en-3-yne frans-3-(N-Methylpyrrol-2-yl)propenal 1,9-Bis(pyrrol-2-yl)pyrromethene 3-Acetylpyridine Anthracene-1,8-dialdehyde frans-Stilbene-4-aldehyde 6,4'-Dimethoxyisoflavone Catechol (3,5,7,3',4'-pentahydroxyflavane) Methyloxirane and monordene 2-Methyl-6-(N,N-dimethylamino)-frans-4-nitro-frans-5-phenylcyclohexene (E)-3-(N,N-Dimethylamino)acrolein cis-1,2-Dimethylcyclohexane 5-Ethynyl-2-methylpyridine 5-Hydroxy-3-methyl-1 H-pyrazole o-Hydroxyacetophenone Potassium 1-acetonyl-2,4, 6-trinitrocyclohexa-2,5-dien ate frans-3-[4-(N,N-Dimethylamino)phenyl]-2-ethylpropenal

180 180 181 181 182 182 183 184 185 185 187 188 189 190 191 192 192 193 194

128

vii

CONTENTS

20 21 22 23 24 25 26 27

28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55

N-Butylsalicylaldimine Benzo[b]furan 3-Hydroxypropyl 2-ethylcyclohexa-1 ,3-diene-5-carboxylate Hex-3-yn-1-ol N,N-Diethylamino)ethyI4-aminobenzoate hydrochloride (procaine hydrochloride) 5,5'-Bis-(hydroxymethyl)-2,2'-bifuran N-Methyl-6,7-methylenedioxy-1-oxo-1 ,2,3,4-tetrahydroisoquinoline Ethoxycarbonyl-4-(3-hydroxypropyl)-1-methylpyrrole p-Tolylsulphonyl-5-propylpyridine 6-Methoxytetralin-1-one Triazolo[1,5-a]pyrimidine 6-n-Butyltetrazolo[1 ,5-a]pyrimidine and 2-azido-5-n-butylpyrimidine Hydroxyphthalide Dicyclopentadiene trans-1-Cyclopropyl-2-methylbuta-1,3-diene cis-6-Hydroxy-1-methyl-4-isopropylcyclohexene (carveol) trans-2-Methylcyclopentanol trans-2-(2-Pyridyl)methylcyclohexanol Nona-2-trans-6-cis-dienal 2,3-Diaza-7,8, 12,13,17,18-hexaethylporphyrin 2-Hydroxy-3,4,3',4'-tetramethoxydeoxybenzoin 3',4',7,8-Tetramethoxyisoflavone 3',4',6,7-Tetramethoxy-3-phenylcoumarin Aflatoxin B1 1,5-Dimethylcyclohexa-1 ,3-dien-5-ol-6-one, dimer Asperuloside Lacto-N-tetrose 9P-Hydroxycostic acid 14-(Umbelliferon-7-0-yl)driman-3,8-diol 3,4,5-Trimethyl-5,6-dihydronaphtho[2,3-b]furan Sendarwine Panaxatriol trans-N-Methyl-4-methoxyproline Cocaine hydrochloride Viridifloric acid 7-retronecine ester (heliospathulin) Actinomycin-D

194 195 195 196 197 198 199 200 202 203 205 205 207 207 208 210 210 211 212 213 214 216 217 218 220 222 225 226 229 232 234 237 240 242 244 246

REFERENCES

250

Formula index ofsolutions to problems

252

Subject index

255

PREFACE

Virtually, all students of chemistry, biochemistry, pharmacy and related subjects learn how to deduce molecular structures from nuclear magnetic resonance (NMR) spectra. Undergraduate examinations routinely set problems using NMR spectra, and masters' and doctoral theses describing novel synthetic or natural products provide many examples of how powerful NMR has become in structure elucidation. Existing texts on NMR spectroscopy generally deal with the physical background of the newer and older techniques as well as the relationships between NMR parameters and chemical structures. Very few, however, convey the know-how of structure determination using NMR, namely the strategy and methodology by which molecular structures are deduced from NMR spectra. This book, based on many lectures and seminars, attempts to provide advanced undergraduates and graduate students with a systematic, readable and inexpensive introduction to the methods of structure determination by NMR. Chapter 1 starts with a deliberately concise survey of the basic terms, parameters and techniques dealt with in detail in other books, which cover the basic principles of NMR, pulse sequences as well as theoretical aspects of chemical shifts and spin-spin coupling, and which this workbook is not intended to replace. An introduction to basic strategies and tactics of structure determination using one- and two-dimensional NMR methods then follows in Chapter 2. Here, the emphasis is always on how spectra and associated parameters can be used to identify structural fragments. This chapter presents those topics that are essential for the identification of compounds or for solving structures, including atom connectivities, relative configuration and conformation, intra- and intermolecular interactions and, in some cases, molecular dynamics. Following the principle of 'learning by doing', Chapter 3 presents a series of case studies, providing spectroscopic details of 55 compounds that illustrate typical applications of NMR techniques in the structural characterisation of both synthetic and natural products. The level of difficulty, the sophistication of the methodology required increases from question to question, so that all readers will be able to find material suited to their knowledge and ability. One can work independently, solve the problem from the spectra and check the result in the formula index, or follow the detailed solutions given in Chapter 4. The spectroscopic details are presented in a way that makes the maximum possible information available at a glance, requiring minimal page turning. Chemical shifts and coupling constants do not have to be read off from scales but are presented numerically, allowing the reader to concentrate directly on problem solving without the need for tedious routine work. Actual methods of two dimensional NMR such as some inverse techniques of heteronuclear shift correlation experiments (HMQC, HSQC, HMBC), proton shift correlations (TOCSY) and twodimensional detection of nuclear Overhauser effects (ROESY) are illustrated in Chapter 2 of this edition. New problems are added in Chapter 3 and 4 not only to replace some of the former ones but also in order to improve the quality and to demonstrate some applications of the actual methods shown in Chapter 2. All formulae have been redrawn using new software; all spectra have been scanned into the data file and the layout has been optimized. My thanks must go to Dr. Rudolf Hartmann for recording some of the two-dimensional NMR experiments, to Klaus Rotscheidt for scanning and his assistance in electronic editing, and especially to Julia Wade for having translated the original German text for the first English edition of this book. Eberhard Breitmaier

SYMBOLS AND ABBREVIATIONS

APT: Attached proton test, a modification of the J-modulated spin-echo experiment to determine CH multiplicities, a less sensitive alternative to DEPT CH COLOC: Correlation via long-range CH coupling, detects CH connectivities through two or three (more in a few cases) bonds in the CH COSY format, permits localisation of carbon nuclei two or three bonds apart from an individual proton

COSY: Correlated spectroscopy, two-dimensional shift correlations via spin-spin coupling, homonuclear (e.g. HH) or heteronuclear (e.g. CH) CH COSY: Correlation via one-bond CH coupling, also referred to as HETCOR (heteronuclear shift correlation), provides carbon-13- and proton shifts of nuclei in CH bonds as cross signals in a be versus DH diagram, assigns all CH bonds of the sample HH COSY: Correlation via HH coupling which has square symmetry because of equal shift scales in both dimensions (DH versus DH) provides all detectable HH connectivities of the sample

CW: Continuous wave or frequency sweep, the older, less sensitive, more time consuming basic technique ofNMR detection DEPT: Distortionless enhancement by polarisation transfer, differentiation between CH, CH2 and CH3 by positive (CH, CH3 ) or negative (CH2) signal amplitudes, using improved sensitivity of polarisation transfer FID: Free induction decay, decay of the induction (transverse magnetisation) back to equilibrium (transverse magnetisation zero) due to spin-spin relaxation, following excitation of a nuclear spin by a radio frequency pulse, in a way which is free from the influence of the radiofrequency field; this signal (time-domain) is Fourier-transformed to the FT NMR spectrum (frequency domain) FT NMR: Fourier transform NMR, the newer and more sensitive, less time consuming basic technique of NMR detection, almost exclusively used INADEQUATE: Incredible natural abundance double quantum transfer experiment, segregates AB or AX systems due to homonuclear one-bond couplings of less abundant nuclei, e.g. BC_ l3C; CC INADEQUATE detects CC bonds (carbon skeleton) present in the sample HMBC: Heteronuclear multiple bond correlation, inverse CH correlation via long-range CH coupling, same format and information as described for (BC detected) CH COLOC but much more sensitive (therefore less time-consuming) because of 1H detection HMQC: Heteronuclear multiple quantum coherence, e.g. inverse CH correlation via one-bond carbon proton-coupling, same format and information as described for (BC detected) CH COSY but much more sensitive (therefore less time-consuming) because of 1H detection

ｓｙｍｂｏｌｓａｎｄａｂ ｒｅｾａｮｏｎｓ

xii

HSQC: Heteronuclear single quantum coherence, e.g. inverse CH correlation via one-bond coupling providing the same result as HMQC but using an alternative pulse sequence NOE: Nuclear Overhauser effect, change of signal intensities (integrals) during decoupling experiments decreasing with spatial distance of nuclei NOESY: Nuclear Overhauser effect spectroscopy, detection of NOE in the HH COSY square format, traces out closely spaced protons in larger molecules ROESY: Rotating frame NOESY, detection of NOE in the HH COSY format with suppressed spin-diffusion, detects closely spaced protons also in smaller molecules TOCSY: Total correlation spectroscopy, in the homonuclear COSY format, e.g. HH TOCSY traces out all proton-proton connectivities of a partial structure in addition to the connectivities eJ, 3J, 4J, 51) as detected by HH COSY

J or 1J: nuclear spin-spin coupling constant (in Hz) through one bond (one-bond coupling) 2J, 3J, 4J, 5J: nuclear spin-spin coupling constant (in Hz) through two, three,four and five bonds (geminal, vicinal, longer-range couplings)

Multiplet abbreviations: S,s D,d T, t Q,q Qui, qui Sxt, sxt Sep, sep o b

Capital letters: Lower case letters:

8H , be,

ｾ

singlet doublet triplet quartet quintet sextet septet overlapping broad multiplets which are the result of coupling through one bond multiplets which are the result of coupling through more bonds than one Proton, carbon-13 and nitrogen-IS chemical shifts

Contrary to IUPAC conventions, chemical shifts b in this book are scaled in ppm in the spectra, thus enabling the reader to differentiate at all times between shift values (ppm) and coupling constants (Hz); ppm (parts per million) is in this case the ratio of two frequencies of different orders of magnitude, Hz / MHz = I : 106 without physical dimension Italicised data and multiplet abbreviations refer to I H in this book

Structure Elucidation By NMR In Organic Chemistry: A Practical Guide. Eberhard Breitmaier Copyright © 2002 John Wiley & Sons, Ltd. ISBNs: 0-470-85006-X (HB); 0-470-85007-8 (PB)

1 SHORT INTRODUCTION TO BASIC PRINCIPLES AND METHODS

1.1

Chemical shift

Chemical shift relates the Larmor frequency of a nuclear spin to its chemical environment 1-3. The Larmor frequency is the precession frequency Vo of a nuclear spin in a static magnetic field (Fig. 1.1). This frequency is proportional to the flux density B o of the magnetic field (volB o = const.) 1-3. It is convenient to reference the chemical shift to a standard such as tetramethylsilane [TMS, (CHJ)4Si] rather than to the proton F. Thus, a frequency difference (Hz) is measured for a proton or a carbon-13 nucleus of a sample from the I H or "c resonance of TMS. This value is divided by the absolute value of the Larmor frequency of the standard (e.g. 400 MHz for the protons and 100 MHz for the carbon-13 nuclei of TMS when using a 400 MHz spectrometer), which itself is proportional to the strength B o of the magnetic field. The chemical shift is therefore given in parts per million (ppm, 8 scale, OH for protons, 8c for carbon-l 3 nuclei), because a frequency difference in Hz is divided by a frequency in MHz, these values being in a proportion of 1:106 . z

Figure 1.1. Nuclear precession: nuclear charge and nuclear spin give rise to a magnetic moment of nuclei such as protons and carbon-13. The vector J.I of the magnetic moment precesses in a static magnetic field with the Larmor frequency Vo about the direction of the magnetic flux density vector Bo

Chemical shift is principally caused by the electrons in the molecule having a shielding effect on the nuclear spin. More precisely, the electrons cause a shielding field which opposes the external magnetic field: the precession frequency of the nuclear spin (and in turn the size of its chemical shift) is therefore reduced. An atomic nucleus (e.g. a proton) whose shift is reduced is said to be shielded (high shielding field); an atom whose shift is increased is said to be deshielded (low shielding field). This is illustrated in Fig. 1.2 which also shows that NMR spectra are presented with chemical shift and frequency decreasing from left to right.

1.2 Spin-spin coupling and coupling constants Indirect or scalar coupling 1-3 of nuclear spins through covalent bonds causes the splitting ofNMR signals into multiplets in high-resolution NMR spectroscopy in the solution state. The direct or

1

2

SHORT INTRODUCTION TO BASIC PRINCIPLES AND METHODS

dipolar coupling between nuclear spins through space is only observed for solid or liquid crystalline samples. In a normal solution such coupling is cancelled out by molecular motion. The coupling constant for first-order spectra (see Section 1.4) is the frequency difference 1 in Hz between two multiplet lines. Unlike chemical shift, the frequency value of a coupling constant does not depend on the strength of the magnetic field. In high-resolution NMR a distinction is made between coupling through one bond (1 or simply 1, one-bond couplings) and coupling geminal couplings), three bonds vicinal couplings) through several bonds, e.g. two bonds or four or five bonds (41 and 51, long-range couplings). For example, the CH2 and CH] protons of the ethyl group in ethyldichloroacetate (Fig. 1.2) are separated by three bonds; their tvicinal) coupling constant is ]1= 7 Hz.

el,

el,

5.93

IP

CI2CH-C,

Ethyl dichloroacetate

4.33

1.35

0-CH2 - CH3 Low(shielding) field deshielded protons

High (shielding) field shielded protons

CHCI3 ｾ

----,---------,-

ppm 7.26

5.93

I I

4.33

TMS

-

Ｍｾ I

1.35

0.0

Figure 1.2. 1H NMR spectrum of ethyl dichloroacetate (CDCb, 25 "C, 80 MHz). The proton of the CHCI2 group is less shielded (more strongly deshielded) in comparison with the protons of the CH2 and CH 3 residues

1.3 Signal multiplicity (multiplets) The signal multiplicity in first-order spectra (see Section 1.4) is the extent to which an NMR signal is split as a result of spin-spin coupling 1-3. Signals which show no splitting are denoted as singlets (s). Those with two, three, four, five, six or seven lines are known as doublets (d), triplets (t), quartets (q, Figs 1.2 and 1.3), quintets (qui), sextets (sxt) and septets (sep), respectively, but only where the lines of the multiplet signal are of equal distance apart, and the one coupling constant is therefore shared by them all. Where two or three different coupling constants produce a multiplet, this is referred to as a two- or three-fold multiplet, respectively, e.g. a doublet of doublets (dd, Fig. 1.3), or a doublet of doublets of doublets (ddd, Fig. 1.3). If both coupling constants of a doublet of doublets are sufficiently similar (if ｾ 12) , the middle signals overlap, thus generating a 'pseudotriplet' ('t', Fig. 1.3).

1.4

3

Spectra of first and higher order

The I H NMR spectrum of ethyl dichloroacetate (Fig. 1.2), as an example, displays a triplet for the CH3 group (nvo vicinal H), a quartet for the OCH2 group (three vicinal H) and a singlet for the CHClz fragment (no vicinal H for coupling).

/l

Ｈｾｊ

/("

J1> J2

"

.ｾ

J1 - J2

B }}lr IJ

rJ21 rJ21

2

J2

J, )

ｾＺ ｾｉ

1

onecoupling constant

twocoupling constants

twosimilar coupling constants

quartet

doublet of doublets

pseudotriplet

three coupling constants

threefold doublet

Figure 1.3. Quartet, doublet of doublets, pseudotriplet and threefold doublet (doublet of doublets of doublets)

1.4 Spectra of first and higher order First-order spectra (multiplets) are observed when the coupling constant is small compared with the frequency difference of chemical shifts between the coupling nuclei 2,3. This is referred to as an AI/Xn spin system, where nucleus A has the smaller and nucleus X has the considerably larger chemical shift. An AX system (Fig. 1.4) consists of an A doublet and an X doublet with the common coupling constant lAX. The chemical shifts are measured from the centres of each doublet to the reference resonance.

(vx- VA) » JAX AXsystem

Figure 1.4. Two-spin system of type AX with a chemical shift difference which is large compared with the coupling constants (schematic)

n=O 1 2 3 4

5 6

Singlet Doublet

2

Triplet Quartet Sextet Septet

3

3 4

Quintet

5 6

6

10 15

4

10 20

5 15

6

Figure 1.5. Relative intensities of first-order multiplets (Pascal triangle)

1

4

SHORT INTRODUCTION TO BASIC PRINCIPLES AND METHODS

Multiplicity rules apply for first-order spectra (A",xn systems): When coupled, nx nuclei of an element X with nuclear spin quantum number Ix = Yz produce a splitting of the A signal into nx + 1 lines; the relative intensities of the individual lines of a first-order multiplet are given by the coefficients of the Pascal triangle (Fig. 1,5), The protons of the ethyl group of ethyl dichloroacetate (Fig. 1.2) as examples give rise to an A.02 system with the coupling constant 3J AX = 7 Hz; the A protons (with smaller shift) are split into a triplet (two vicinal protons X; nx + 1 = 3); the X protons appear as a quartet because of three vicinal A protons (nA + 1 = 4). In general, for a given number, nx, of coupled nuclear spins of spin quantum number Ix, the A signal will be split into (2 n» Ix + 1) multiplet lines (e.g. Fig, 1.9). Spectra of greater complexity may occur for systems where the coupling constant is of similar magnitude to the chemical shift difference between the coupled nuclei. Such a case is referred to as an AmB n system, where nucleus A has the smaller and nucleus B the larger chemical shift. An AB system (Fig. 1.6) consists, for example, of an A doublet and a B doublet with the common coupling constant JAB, where the external signal of both doublets is attenuated and the internal signal is enhanced. This is referred to as an AB effect, a 'roofing' symmetric to the centre of the AB system 2; 'roofing' is frequently observed in proton NMR spectra, even in practically first order spectra (Fig. 1.2, ethyl quartet and triplet). The chemical shifts VA and VB are displaced from the centres of the two doublets, approaching the frequencies of the more intense inner signals.

Figure 1.6. Two-spin system of type AB with a small chemical shift difference compared to the coupling constant (schematic)

1.5 Chemical and magnetic equivalence Chemical equivalence: atomic nuclei in the same chemical environment are chemically equivalent and thus show the same chemical shift. The 2,2'- and 3,3'-protons of a 1,4-disubstituted benzene ring, for example, are chemically equivalent because of molecular symmetry. ortho

ooup'ng, 'JAX ｾ 7 - 8 H,

ｾａ

O'1'JV x'H

HA'

OCft

O':re 1'JVO para coupling: 5JAX' =0.5- 1 Hz

X'H

CH3

HA'

Magnetic equivalence: chemically equivalent nuclei are magnetically equivalent if they display the same coupling constants with all other nuclear spins of the molecule 2,3. For example, the 2,2'-

1.6

5

Fourier transform (FT) NMR spectra

(AA') and 3,3'-(X;X) protons of a 1,4-disubstituted benzene ring such as 4-nitroanisole are not magnetically equivalent, because the 2-proton A shows an ortho coupling with the 3-proton xCJ = 7-8 Hz), but displays a different para coupling with the 3'-proton X' (J= 0.5 -I Hz). This is therefore referred to as an AA AX' system (e.g. Fig. 2.6c) but not as an A2X2 or an (AXh system. The IH NMR spectrum in such a case can never be first-order, and the multiplicity rules do not apply. The methyl protons in ethyl dichloroacetate (Fig. 1.2), however, are chemically and magnetically equivalent because the 3J HH coupling constants depend on the geometric relations with the CH2 protons and these average to the same for all CH3 protons due to rotation about the CC single bond; they are the A 3 part of an A;X2 system characterising an ethoxy group (CH A 3-CHx 2-0-) in IHNMR.

1.6 Fourier transform (FT) NMR spectra There are two basic techniques for recording high-resolution NMR spectra 2-6. In the older CW technique, the frequency or field appropriate for the chemical shift range of the nucleus (usually IH) is swept by a continuously increasing (or decreasing) radio-frequency. The duration of the sweep is long, typically 2 Hz/s, or 500 s for a sweep of 1000 Hz, corresponding to ID ppm in 100 MHz proton NMR spectra. This monochromatic excitation therefore takes a long time to record. In the FT technique, the whole of the Larmor frequency range of the observed nucleus is excited by a radiofrequency pulse. This causes transverse magnetisation to build up in the sample. Once excitation stops, the transverse magnetisation decays exponentially with the time constant T2 of spin-spin relaxation provided the field is perfectly homogeneous. In the case of a one-spin system, the corresponding NMR signal is observed as an exponentially decaying alternating voltage (free induction decay, FID); multi-spin systems produce an interference of several exponentially decaying alternating voltages, the pulse interferogram (Fig. 1.7).The frequency of each alternating voltage is the difference between the individual Larmor frequency of one specific kind of nucleus and the frequency of the exciting pulse. The Fourier transformation (FT) of the pulse interferogram produces the Larmor frequency spectrum; this is the FT NMR spectrum of the type of nucleus being observed. Fourier transformation involving the calculation of all Larmor frequencies contributing to the interferogram is performed with the help of a computer within a time of less than 1 s. Pulse interferogram F(t)

FTNMR spectrum f (v)

Fourier transformation .

11

76.4

- 0.65 -- ..- - - .......

I

._...........•' \ "-..•'1, __ \

ｾ

ppm

_ . .. ._. --_ .. 1500 Hz··---

Figure 1.7. Pulse interferogram and FT 13C NMR spectrum of glycerol, (OOCH2hCHOO, [0 2 0 , 25

__ .

66.9

.. -c, 100 MHz]

1

6

SHORT INTRODUCTION TO BASIC PRINCIPLES AND METHODS

The main advantage of the FT technique is the short time required for the procedure (about 1 s per interferogram). Within a short time a large number of individual interferograms can be accumulated, thus averaging out electronic noise (FID accumulation), and making the FT method the preferred approach for less sensitive NMR probes involving isotopes of low natural abundance ( 13C, 15N). All of the spectra in this book with the exception of those in Figs. 1.8,2.19 and 2.25 are FT NMR spectra.

1.7 Spin decoupling Spin decoupling (double resonance) 2,3.5,6 is an NMR technique in which, to take the simplest example, an AX system, the splitting of the A signal due to J AX coupling is removed if the sample is irradiated strong enough by a second radiofrequency which resonates with the Larmor frequency of the X nucleus. The A signal then appears as a singlet; at the position of the X signal interference is observed between the X Larmor frequency and the decoupling frequency. If the A and X nuclei are the same isotope (e.g. protons), this is referred to as selective homonuclear decoupling. If A and X are different, e.g. carbon-13 and protons, then it is referred to as heteronuclear decoupling. Figure 1.8 illustrates homonuclear decoupling experiments with the CH protons of 3-aminoacrolein. These give rise to an AMX system (Fig. 1.8a). Decoupling of the aldehyde proton X (Fig. 1.8b) simplifies the NMR spectrum to an AM system AM = 12.5 Hz); decoupling of the M proton (Fig. 1.8c) simplifies to an AXsystem (JAX = 9 Hz). These experiments reveal the connectivities of the protons within the molecule.

eJ

HM AH, 3-Aminoacrolein ｏｾｎＯ

H

x

ｾ｣Ｌ

I

C I

,Hx

C 1I

'H

M

ｾＮＭＫ

A

__---,AL

c

12.5

ＭｴｾａＮ｟ｊｌ

b

a

ｾ

; . 12.5

()r) 9 Hz ＭｾａＮ

ＩｊｕｉＭ｟ｾ

i

85

I

ppm

73

I

525

Figure 1.8. Homonuclear decoupling of the CH protons of 3-aminoacrolein (CD30D, 25°C, 90 MHz). (a) 1H NMR spectrum; (b) decoupling at OH = 8.5; (c) decoupling at OH = 7.3. At the position of the decoupled signal in (b) and (c) interference beats are observed because of the superposition of the two very similar frequencies

1.7

Spin decoupling

7

In 13C NMR spectroscopy, three kinds of heteronuclear spin decoupling are used 5,6. In proton broadband decoupling of DC NMR spectra, decoupling is carried out unselectively across a frequency range which encompasses the whole range of the proton shifts. The spectrum then displays up to n singlet signals for the n non-equivalent C atoms of the molecule. Figures 1.9a and b demonstrate the effect of proton broadband decoupling in the 13C NMR spectrum of a mixture of ethanol and hexadeuterioethanol. The CH3 and CH2 signals of ethanol appear as intense singlets upon proton broadband decoupling while the CD 3 and CD z resonances of the deuteriated compound still display their septet and quintet fine structure; deuterium nuclei are not affected by JH decoupling because their Larmor frequencies are far removed from those of protons; further, the nuclear spin quantum number of deuterium is ID = 1; in keeping with the general multiplicity rule (2 nx Ix + I, Section lA), triplets, quintets and septets are observed for CD, CD z and CD 3 groups, respectively. The relative intensities in these multiplets do not follow Pascal's triangle (l: I: I triplet for CD; 1:3:4:3: 1 quintet for CD z; 1:3:6:7:6:3: I septet for CD 3 ) . 1252

140.5

21.2

22

19.2

45

b

Hz 100 50 I !l

18.41

f!

0

I" " !

58.02

CH3-CH2-0H 17.31

57.17

CD3-CD2-0D

a I

ppm

i

58.02 57.17

lL

j I

I

18.41 17.31

I

0

Figure 1.9. 13C NMR spectra of a mixture of ethanol and hexadeuterioethanol [27:75 v/v, 25 QC, 20 MHz]. (a) IH broadband decoupled; (b) without decoupling. The deuterium isotope effect 6cH - 6co on 13C chemical shifts is 1.1 and 0.85 ppm for methyl and methylene carbon nuclei, respectively

In selective proton decoupling of 13C NMR spectra, decoupling is performed at the precession frequency of a specific proton. As a result, a singlet only is observed for the attached C atom. Offresonance conditions apply to the other C atoms. For these the individual lines of the CH multiplets move closer together, and the relative intensities of the multiplet lines change from those given by the Pascal triangle; external signals are attenuated whereas internal signals are enhanced.

1

8

SHORT INTRODUCTION TO BASIC PRINCIPLES AND METHODS

Selective I H decoupling of DC NMR spectra was used for assignment of the CH connectivities (CH bonds) before the much more efficient two-dimensional CH shift correlation experiments (see Section 2.2.8) became routine. Off-resonance decoupling of the protons was helpful in determining CH multiplicities before better methods became available (see Section 2.2.2). In pulsed or gated decoupling of protons (broadband decoupling only between FIDs), coupled DC NMR spectra are obtained in which the CH multiplets are enhanced by the nuclear Overhauser effect (NOE, see Section 1.8). This method is used when CH coupling constants are required for structure analysis because it enhances the multiplets of carbon nuclei attached to protons; the signals of quaternary carbons two bonds apart from a proton are also significantly enhanced. Figure 1.10 demonstrates this for the carbon nuclei in the 4,6-positions of 2,4,6-trichloropyrimidine. 183.5 Hz

ｃｉｾｎ H

(' 211 ｾ N

2,4,6-Trichloropyrimidine

Cl

5

C-4,62

0.9Hz

..

",'1

"l ' .. '

120.35 ppm

a

b

Figure 1.10. 13C NMR spectra of 2,4,6-trichloropyrimidine [CsDs, 75% v/v 25 QC, 20 MHz]. (a) 13C NMR spectrum without proton decoupling; (b) NOE enhanced coupled 13 C NMR spectrum (gated decoupling)

1.8 Nuclear Overhauser effect The nuclear Overhauser effect 2,3 (NOE, also an abbreviation for nuclear Overhauser enhancement) causes the change in intensity (increase or decrease) during decoupling experiments. The maximum possible NOE in high-resolution NMR of solutions depends on the gyromagnetic ratio of the coupled nuclei. Thus, in the homonuclear case such as proton-proton coupling, the NOE is much less than 0.5, whereas in the most frequently used heteronuclear example, proton decoupling of DC NMR spectra, it may reach 1.988. Instead of the expected signal intensity of 1, the net result is to increase the signal intensity threefold (1 + 1.988). In proton broadband and gated decoupling of 13C NMR spectra, NOE enhancement of signals by a factor of as much as 2 is routine, as was shown in Figs 1.9 and 1.10.

1.8

Nuclear Overhauser effect

9

Quantitative analysis of mixtures is achieved by evaluating the integral steps of 1H NMR spectra. This is demonstrated in Fig. 1.11a for 2,4-pentanedione (acetylacetone) which occurs as an equilibrium mixture of 87 % enol and 13 % diketone.

2,4-Pentaned lone (acetyl acetone )

H

-

H3C, Ｏ ｃ ｾ C 11

o

87%

K

/CH 3

I

/0

13%C

87%

-lL

13%

_J

L ", -r··- -- ..- .... -.------------.-- .... --,--"

ppm

E 15.7

C

H Enol tautomer E

Keto (oxo) tautomer K

r ---

I

2.20

5.60

203

_.

r--- ---- ".----

,,- - - - _ . ..... J"

r--../- .. 86 1

"","Lt -_-.-'--- -------.---------_l_Jl1 2035---[----··

E

1926

Figure 1.11. NMR for 20 MHz for coupled 13 C NMR [result: keto: enol

'n.

_r-'-

_ _ _ _..J

r:- ; 81.%

ｾ

a

,

360

· ..··..· ----

pprn

r-

101.1

ＮｾＱＬＭ ""11

58'75

I

I

%

L------,-

ＵＸＮ ｌｾＰＳ

c

0

analysis of the keto-enol tautomerism of 2,4-pentanedione [CDCI 3, 50% v/v, 25°C, 60 MHz 13C]. (a) ' H NMR spectrum with integrals [result: keto: enol = 13 : 87]; (b) broadband dedecoupling with integrals spectrum; (c) 13C NMR spectrum obtained by inverse gated = 15: 85 (± 1)]

'n

'u

10

1

SHORT INTRODUCTION TO BASIC PRINCIPLES AND METHODS

A similar evaluation of the 13 C integrals in f H broadband decoupled 13C NMR spectra fails in most cases because signal intensities are influenced by nuclear Overhauser enhancements and relaxation times and these are usually specific for each individual carbon nucleus within a molecule. As a result, deviations are large (81 - 93 % enol) if the keto-enol equilibrium of 2,4-pentanedione is analysed by means of the integrals in the f H broadband decoupled 13C NMR spectrum (Fig. 1.11b). Inverse gated decoupling 2,3, involving proton broadband decoupling only during the FIDs, helps to solve the problem. This technique provides f H broadband decoupled 13C NMR spectra with suppressed nuclear Overhauser effect so that signal intensities can be compared and keto-enol tautomerism of 2,4-pentanedione, for example, is analysed more precisely as shown in Fig. 1.11c.

1.9 Relaxation, relaxation times Relaxation 2,3,6 refers to all processes which regenerate the Boltzmann distribution of nuclear spins on their precession states and the resulting equilibrium magnetisation along the static magnetic field. Relaxation also destroys the transverse magnetisation arising from phase coherence of nuclear spins built up upon NMR excitation. Spin-lattice relaxation is the steady (exponential) build-up or regeneration of the Boltzmann distribution (equilibrium magnetisation) of nuclear spins in the static magnetic field. The lattice is the molecular environment of the nuclear spin with which energy is exchanged. The spin-lattice relaxation time, T, , is the time constant for spin-lattice relaxation which is specific for every nuclear spin. In FT NMR spectroscopy the spin-lattice relaxation must 'keep pace' with the exciting pulses. If the sequence of pulses is too rapid, e.g. faster than 3 Tf max of the 'slowest' C atom of a molecule in carbon-13 resonance, a decrease in signal intensity is observed for the 'slow' C atom due to the spin-lattice relaxation getting 'out of step', For this reason, quaternary C atoms can be recognised in carbon-IS NMR spectra by their weak signals. Spin-spin relaxation is the steady decay of transverse magnetisation (phase coherence of nuclear spins) produced by the NMR excitation where there is perfect homogeneity of the magnetic field. It is evident in the shape of the FID (free induction decay), as the exponential decay to zero of the transverse magnetisation produced in the pulsed NMR experiment. The Fourier transformation of the FID signal (time domain) gives the FT NMR spectrum (frequency domain, Fig. 1.7). The spin-spin relaxation time, T2 , is the time constant for spin-spin relaxation which is also specific for every nuclear spin (approximately the time constant of FID). For small- to medium-sized molecules in solution T2 ｾ T, . The value of T2 of a nucleus determines the width of the appropriate NMR signal at half-height (fialf-width') according to the uncertainty relationship. The smaller is T2 , the broader is the signal. The more rapid is the molecular motion, the larger are the values of T, and T2 and the sharper are the signals ('motional narrowing} This rule applies to small- and medium-sized molecules of the type most common in organic chemistry. Chemical shifts and coupling constants reveal the static structure of a molecule; relaxation times reflect molecular dynamics.

Structure Elucidation By NMR In Organic Chemistry: A Practical Guide. Eberhard Breitmaier Copyright © 2002 John Wiley & Sons, Ltd. ISBNs: 0-470-85006-X (HB); 0-470-85007-8 (PB)

2. 1

11

Functional groups

2 RECOGNITION OF STRUCTURAL FRAGMENTS BY NMR

2.1 2.1.2

Functional groups 1HChemical Shifts

Many functional groups can be identified conclusively by their I H chemical shifts 1-3. Important examples are listed in Table 2.1, where the ranges for the proton shifts are shown in decreasing sequence: aldehydes (OH = 9.5 - 10.5), acetals (OH = 4.5 - 6), alkoxy (OH = 4 - 5.5) and methoxy functions (OH = 3.5 - 4), N-methyl groups (OH = 3 - 3.5) and methyl residues attached to double bonds such as C=C or C=X (X = N, 0, S) or to aromatic and heteroaromatic skeletons (OH = 1.82.5).

Table 2.1. 1H chemical shift ranges for organic compounds Enol-OH Carboxylic acid-OrPhenol-OH 020Alkanol-OH exchangeable protons Amide-NH Amine-NH Thiol-lThiophenol-SH J

Ir

-

•

I

Aldehyde-CH Heteroaromatics Aromatics Alkene-CH Alkyne-CH Acetal-CH R2CH-O-, RCHz-OCH30CH3N< CH3SCH3 at C=C or C=X Cyclopropane-CH CH3 bonded to metal

I n-etectro

•

• ,"'j"T •• • •• •• ••• n-e! etro ricr

dei eien (-) M·SL bstit ted -)-M

(+) M-s bsti uted ｾＭＩＫ

OH 15 14 13 12 11 10

9

8

7

-sub titut d

-

R2 ｈｾｃ

-

i

I

;c-c-

RC

6

5

4

3

2

-• 1

0-1

Small shift values for CH or CH2 protons may indicate cyclopropane units. Proton shifts distinguish between alkyne CH (generally OH = 2.5 - 3.2), alkene CH (generally OH = 4.5 - 6) and aromaticlheteroaromatic CH (OH = 6 - 9.5), and also between IT-electron-rich (pyrrole, furan, thiophene, OH = 6 - 7) and IT-electron-deficient heteroaromatic compounds (pyridine, OH = 7.5 - 9.5).

2

12

2.1.2

RECOGNITION OF STRUCTURAL FRAGMENTS BY NMR

Deuterium exchange

Protons which arc bonded to heteroatoms (XH protons, X = 0, N, S) can be identified in the 1H NMR spectrum by using deuterium exchange (treatment of the sample with a small amount of D 20 or CD 30D). After the deuterium exchange: R-XH

+ 020

=

R-XO

+ HOO

the XH proton signals in the 1H NMR spectrum disappear. Instead, the HDO signal appears at approximately OH = 4.8. Those protons which can be identified by D 20 exchange are indicated as such in Table 2.1. As a result of D 20 exchange, XH protons are often not detected in the 1H NMR spectrum if this is obtained using a dcutcriatcd protic solvent (e.g. CD 30D).

2.1.3

13C

Chemical shifts

The 13C chemical shift ranges for organic compounds 4-6 in Table 2.2 show that many carboncontaining functional groups can be identified by the characteristic shift values in the 13C NMR spectra. For example, various carbonyl compounds have distinctive shifts. Ketonic carbonyl functions appear as singlets falling between 8c = 190 and 220, with cyc1opentanone showing the largest shift; although aldehyde signals between 8c = 185 and 205 overlap with the shift range of keto carbonyls, they appear in the coupled 13C NMR spectrum as doublet CH signals. Quinone carbonyls occurs between 8c = 180 and 190 while the carboxy C atoms of carboxylic acids and their derivatives are generally found between 8c = 160 and 180. However, the 13C signals of phenoxy carbon atoms, carbonates, ureas (carbonic acid derivatives), oximes and other imines also lie at about 8c = 160 so that additional information such as the empirical formula may be helpful for structure elucidation. Other functional groups that are easily differentiated are cyanide (8c = 110 - 120) from isocyanide (8c = 135 - 150), thiocyanate (8c = 110 - 120) from isothiocyanate (8c = 125 - 140), cyanate (8c = 105 - 120) from isocyanate (8c = 120 - 135) and aliphatic C atoms which are bonded to different heteroatoms or substituents (Table 2.2). Thus ether-methoxy generally appears between 8c = 55 and 62, ester-methoxy at 8c = 52; N-methy1 generally lies between 8c = 30 and 45 and S-methyl at about 8c = 25. However, methyl signals at 8c = 20 may also arise from methyl groups attached to C=X or C=C double bonds, e.g. as in acetyl, CH3-CO-. If an H atom in an alkane R-H is replaced by a substituent X, the DC chemical shift Bc in the aBc position increases proportionally to the electronegativity of X (-1 effect). In the ｾＭｰｯｳｩｴｮＬ generally also increases, whereas it decreases at the C atom y to the substituent (y-effect, see Section 2.3.4). More remote carbon atoms remain almost uninfluenced (L1B c ｾ 0).

,..."..-c·

".

R-H

ﾷＮ｡ｃｹｃＶｾ

..-C,,----Ii .

/lDC

. X .: . J3 ..-c'-....., \.

"

0

R-X

2.1

13

Funcilonalgroups

In contrast to 1H shifts, 13C shifts cannot in general be used to distinguish between aromatic and heteroaromatic compounds on the one hand and alkenes on the other (Table 2.2). Cyclopropane carbon atoms stand out, however, by showing particularly small shifts in both the I3 C and the 'u NMR spectra. By analogy with their proton resonances, the 13C chemical shifts of 1t electrondeficient heteroaromatics (pyridine type) are larger than those of 1t electron-rich heteroaromatic rings (pyrrole type). Table 2.2.

13C

chemical shift ranges for organic compounds

200 Carbenium-Ions Ketones Aldehydes

-｣ｯｮｩｵｧｾｴ･

150

100

50

o (TMS)

150

100

50

o (TMS)

I

Acetals, Ketals Quinones Carboxylic acids and derivs. Thioureas Ureas, Carbonates Oxirnes Imines Isocyanides Cyanides Isothiocyanates Thiocyanates Isocyanates Cyanates Carbodiimides Heteroaromatics ＷｲＭｾＯ･

tro d ticien;

Aromatics (Cyclo-) Alkenes (Cyclo-) Alkynes (Cyclo-) Alkanes R3C- OR3C-NR2 R3C- SR3C-Halogen R2CH- OR2CH-NR2 R2CH- SR2CH-Halogen H3C- OH3C- NR 2 H3C-SH3C-Halogen Alkyl bonded to metal I

200

2

14

RECOGNITION OF STRUCTURAL FRAGMENTS BY NMR

Substituent effects (substituent increments) tabulated in more detail in the literature 1-6 demonstrate that l3 C chemical shifts of individual carbon nuclei in alkenes and aromatic as well as heteroaromatic compounds can be predicted approximately by means of mesomeric effects (resonance effects). Thus, an electron donor substituent D [D = OCHJ , SCHJ , N(CH3)2] attached to a C=C double bond shields the ｾＭｃ atom and the ｾＭｰｲｯｴｮ (+M effect, smaller shift), whereas the a-position is deshielded (larger shift) as a result of substituent e1ectronegativity (-I effect).

\

\p, a/

\1)

lH

CID

Donor in

H Cl. shields

in J3 postion

\1)

/

c-c Ａｾ｜

c=c

u/

oc-c A

Acceptor in

H Cl. deshields

\\

re>

v

IA

in J3 postion

The reversed polarity of the double bond is induced by a 1t electron-accepting substituent A (A = C=O, C=N, NO z): the carbon and proton in the ｾＭｰｯｳｩｴｮ are deshielded (-M effect, larger shifts). These substituents have analogous effects on the C atoms of aromatic and heteroaromatic rings. An electron donor D (see above) attached to the benzene ring deshields the (substituted) o-C atom (-I effect). In contrast, in the ortho and para positions (or comparable positions in heteroaromatic rings) it causes a shielding (+M effect, smaller 1H and BC shifts), whereas the meta positions remain almost unaffected. De

De

ｾ

1I

ｦｾ

Or';

j

t,

.

_. Ｌｾ

I

ｾＯ

8

(+)-M-substituent (electron donor D) bonded to the benzene ring: OH < 7.26 ; lie < 128.5

An electron-accepting substituent A (see above) induces the reverse deshielding in ortho and para positions (-M effect, larger I Hand 13C shifts ), again with no significant effect on meta positions. A8

ｾｦ

11

,,/

e

(-)-M-substituent (electron acceptor) bonded to the benzene ring: OH >7.26 ; lie> 128.5

2.1.4

15N

Chemical shifts

Frequently the 15N chemical shifts 7-9 (Table 2.3) of molecular fragments and functional groups containing nitrogen complement their I Hand 13C shifts. The ammonia scale 7 of 15N shifts used in

2.1

15

Functional groups

Table 2.3 shows very obvious parallels with the TMS scale of l3C shifts. Thus, the 15N shifts (Table 2.3) decrease in size in the sequence nitroso, nitro, imino, amino, following the corresponding behaviour of the l3C shifts of carbonyl, carboxy, alkenyl and alkyl carbon atoms (Table 2.2). 0'3 I(i)

>

/_N·:

>

o

-

15N

900

BN

C-Nitroso-

I

>

>

Table 2.3.

>

Chemical shift ranges for organonitrogen compounds

- . -• - ---.--_.--._. -800

700

600

500

1-

N-NitrosoNitroAzides

400

300

200

100

I

1-

I II

>

/c""..:o

1

I 1

Azo compounds Diazo-, diazonium-

ｾ ｲ｡ｺｾｮ･ｳ

Pyridine-N Imino-N

I

ｯｾｴ･ｲ

.1 ner

pynmidlr es

I

I

Pyrrole-N Cyanides Isocyanides

I

Inn r

cuter

hy

oxines

raze nes

mine

Guanidines

Ami 0-

•

Sulfonamides Thioamides Amides Thioureas, ureas Enamines

• •

I

Anilines

} zirid nes

Amines

-

BN

900

800

700

600

500

400

300

200

•

100

The decrease in shifts found in l3C NMR spectra in the sequence balkenes, aromatics

>

balkynes

>

ba1kanes

>

bcyclopropanes

also applies to the analogous N-containing functional groups, ring systems and partial structures (Tables 2.2 and 2.3): bimines, pyridines

>

bnitriles

>

bamines

>

baziridines

16

2

RECOGNITION OF STRUCTURAL FRAGMENTS BY NMR

2.2 Skeletal structure (atom connectivities) 2.2.1

HH Multiplicities

The splitting (signal multiplicity) of 1H resonances often reveals the spatial proximity of the protons involved. Thus it is possible to identify structural units such as those which often occur in organic molecules simply from the appearance of multipiet systems and by using the (n + 1) rule. The simplest example is the AX or AB two-spin system for all substructures containing two protons two, three or four bonds apart from each other, according to geminal, vicinal or w coupling. Figure 2.1 shows the three typical examples: (a) the AX system, with a large shift difference (vx - VA) between the coupled protons HA and HX in relation to their coupling constant JAX; (b) the AB system, with a smaller shift difference (VB - VA) of the coupled nuclei (HA and F) relative to their coupling constant J4B , and (c) the AB system, with a very small shift difference [( VB - VA) ｾ JAB] verging on the A2 case, whereby the outer signals are very strongly suppressed by the roofing effect (AB effect). Figure 2.2 shows the 1H NMR partial spectra of a few more structural units which can easily be identified. Structure elucidation does not necessarily require the complete analysis of all multiplets in complicated spectra. If the coupling constants are known, the characteristic fine structure of the single multiplet almost always leads to identification of a molecular fragment and, in the case of alkenes and aromatic or heteroaromatic compounds, it may even lead to the elucidation of the complete substitution pattern.

chemically non-equivalent geminal protons (cyctoetkenes, alkenes)

HA

-«\

>==(

\

H

H

2.5

H

\N=( 16.5 H

---,.---"==--H - 3.0 I H

HJ::' H

1.0

Geminal HH coupling, 2JH1i, depends characteristically on the polarity and hybridisation of the C atom on the coupling path and also on the substituents and on the HCH bond angle. Thus 2JHH coupling can be used to differentiate between a cyclohexane (-12.5 Hz), a cyclopropane (-4.5 Hz) or an alkene (2.5 Hz), and to show whether electronegative heteroatoms are bonded to methylene groups (Table 2.4). In cyclohexane and norbornane derivatives the w-shaped arrangement of the bonds between protons attached to alternate C atoms leads to distinctive 4JHH coupling (w-couplings, Table 2.4). Vicinal HH coupling constants, 3JHH , are especially useful in determining the relative configuration (see Section 2.3.1). However, they also reflect a number of other distinguishing characteristics, e.g. the ring size for cycloalkenes (a low value for small rings) and the a.-position of electronegative heteroatoms in heterocycles which is reflected by remarkably small coupling constants 3JHH (Table 2.5).

The coupling constants of ortho eJHH = 7 Hz), meta (4JHH = 1.5 Hz) and para protons eJHH ｾ 1 Hz) in benzene and naphthalene ring systems are especially useful in structure elucidation (Table 2.5). With naphthalene and other condensed (hetero-) aromatics, a knowledge of 'zig zag' coupling CSJHH = 0.8 Hz) is helpful in deducing substitution patterns.

2

22

RECOGNITION OF STRUCTURAL FRAGMENTS BY NMR

Table 2.5. Typical HH coupling constants (Hz) of aromatic and heteroaromatic compounds

2,3

s.JHH

ｾＩ

7.5

H

H

lJ(H

lQ

1.5

0.7

H H

(ｾＯｙｏＮＷ /y\ H H

C)QO.8

0.7

H

｛ｾｈ 5.5

H

/X, 0 \ ( /H H 1.8 2.6 4.8

\\ /7

r--'\.

H

3,4 3.5 3.5

/

( \ rH H

0.9

0.4

1.9

H---(X

y

.\c _I

H

H 0.9 1.3 1.0

X=O X= NH x=s

1.5 2.1 2.8

The HH coupling constants of pyridine (Table 2.5) reflect the positions of the coupling protons relative to the nitrogen ring. There is a particularly clear difference here between the protons in the 2- and 3-positions JHH = 5.5 Hz) and those in the 3- and 4-positions JHH = 7.6 Hz). Similarly, HH coupling constants in five-membered heteroaromatic rings such as thiophene, pyrrole and furan can be distinguished because of the characteristic effects of the electronegative heteroatoms on their 3JHH couplings (Table 2.5); in particular the 3JHH coupling of the protons in the 2- and 3positions, allow the heteroatoms to be identified (the more electronegative the heteroatom, the smaller is the value of 3JHH)' In the case of alkenes and aromatic and heteroaromatic compounds, analysis of a single multiplet will often clarify the complete substitution pattern. A few examples will illustrate the procedure. If, for example, four signals are found in regions appropriate for benzene ring protons (OH = 6 - 9, four protons on the basis of the height of the integrals), then the sample may be a disubstituted benzene (Fig. 2.6). The most effective approach is to analyse a multiplet with a clear fine structure

e

e

2.2

23

Skeletal structure (atom connectivities)

and as many coupling constants as possible, e.g. consider the threefold doublet at 6H = 7.5 (Fig. 2.6 a); it shows two ortho couplings (8.0 and 7.0 Hz) and one meta coupling (2.5 Hz); hence relative to the H atom with a shift value of 6H = 7.5. there are two protons in ortho positions and one in a meta position; to conclude, the molecule is an ortho-disubstituted benzene (o-nitrophenol, 3).

xx·

AA'

c - 1----,--,-----,-------,---

-

-.

8.0

r - .- ---,-----,--,-----,-----,------,-I

7.0

2-H

6-H 7,5 2.5

4-H 7,5 3.0 2.5

3.0 2.5

ppm 5-H 7.5 Hz

H

'[

H

H 1\

4

____)U ppm

i

8.5 3-H 8.0 2.5

b

8.0 5-H

6-H

8.0 70

8.0 2.0

2.5

4-H 8,0 7,0 2.0 Hz

OH H

H H

a

3 ppm

8.0

r

7.0

Figure 2.6. lH NMR spectra of disubstituted benzene rings [GDCI3 , 25 °G,200 MHz]. (a) o-Nitrophenol (3); (b) m-nitrobenzaldehyde (4); (c) 4,4'-dimethoxybenzil (5)

24

2

RECOGNITION OF STRUCTURAL FRAGMENTS BY NMR

A meta disubstituted benzene (Fig. 2.6 b) shows only two ortho couplings ("JHH = 7.5 Hz) for one signal (c5H =7.8) whereas another signal (c5H =8.74) exhibits only two meta couplings (4JHH = 3.0 and 2.5 Hz). In both cases one observes either a triplet (c5H =7.8) or a doublet of doublets (c5H = 8.74) depending on whether the couplings ("J HH or 4J HH) are equal or different. The AA 'XX' systems (Section 1.5) 2,3 which are normally easily recognisable from their symmetry identify para-disubstituted benzenes such as 4,4'-dimethoxybenzil (5) or 4- substituted pyridines. This method of focusing on a 1H multiplet of clear fine structure and revealing as many HH coupling constants as possible affords the substitution pattern for an alkene or an aromatic or a heteroaromatic compound quickly and conclusively. One further principle normally indicates the geminal, vicinal and w relationships of the protons of a molecule, the so called HH connectivities, i.e. that coupled nuclei have identical coupling constants. Accordingly, once the coupling constants of a multiplet have all been established, the appearance of one of these couplings in another multiplet identifies (and assigns) the coupling partner. This procedure, which also leads to the solutions to problems 1-12, may be illustrated by means of two typical examples.

2.5

8.5

0.5

2.5

8.5 0.5 Hz

a

I

ｾ

6

I

ppm

7.0

x

M

A

3J AM

= 8.5 Hz

(ortho)

4JMX

= 2.5 Hz

(meta)

5JAX

= 0.5 Hz

(para)

b I

ppm

7.0

Figure 2.7. lH NMR spectrum of 3,4-dimethoxybenzaldehyde (6) [aromatic shift range, CDCb, 25°C, (a) 100 MHz, (b) 200 MHz]

In Fig. 2.7 the 1H signal with a typical aromatic proton shift of c5H =7.1 shows a doublet of doublets with J-values of 8.5 Hz (ortho coupling, 3J HH) and 2.5 Hz (meta coupling, 4JHH). The ring proton in question therefore has two protons as coupling partners, one in the ortho position (8.5

2.2

25

Skeletal structure (atom connectivities)

Hz) and another in the meta position (2.5 Hz), and moreover these are in such an arrangement as to make a second ortho coupling impossible. Thus the benzene ring is 1,2,4-trisubstituted (6). The ring protons form an AMX system, and, in order to compare the change of frequency dispersion

and 'roofing' effects with increasing magnetic field strength, this is shown first at 100 MHz and then also at 200 MHz. The para coupling 5JAX' which is less frequently visible, is also resolved. From the splitting of the signal at OH = 7.1 (J-tl) a 1,2,3-trisubstituted benzene ring (7) might have been considered. In this case, however, the ortho proton (HA) would have shown a second ortho coupling to the third proton (Hx ). The application of the principle that coupled nuclei will have the same coupling constant enables the 'n NMR spectrum to be assigned completely (Fig. 2.7). The ortho coupling, 3JAM = 8.5 Hz, is repeated at OH = 6.93 and allows the assignment of HA; the meta coupling, 4JMX = 2.5 Hz, which appears again at OH = 7.28, gives the assignment of HX . The four signals in the 1H NMR spectrum of a pyridine derivative (Fig. 2.8) show first that it is a 2- or 3-monosubstituted derivative; a 4-monosubstituted pyridine would display an AA 'XX' system. The signal with the smallest shift (OH = 7.16) splits into a threefold doublet with coupling constants 8.1,4.8 and 0.7 Hz . The two 3J HH couplings of 8.1 and 4.8 Hz unequivocally belong to a ｾ proton of the pyridine ring according to Table 2.5. Step by step assignment of all three couplings (Fig. 2.8) leads to a pyridine ring 8 substituted in the 3-position. Again, signals are assigned following the principle that coupled nuclei will have the same coupling constant; the coupling constants identified from Table 2.5 for the proton at OH = 7.16 are then sought in the other multiplets. OH =8.52 4.8 Hz

:x;c xx: /

/1

I

ｾ

::::-....

H 8.1 Hz OH =7.79

2.4

4.8

07

1.5

ｾ

OH =8.68 0.7Hz H

H

Br H

8 8.1 2.4

81

1.5

0.7 Hz

4.8

,I id

iii

I'

1I11 ｉｾ

dl

I.,i.!!. ',.nl . ·lLi.I. '. ［ｾｉ 'i'.

L'II

,'l.11.IIi l

:' I

1

ppm

8.68

I

8.52

--"r"

7n

.. -----.--.--- · · - · · - - - - · - · · - · · - - - r - -

7M

Figure 2.8. 1H NMR spectrum of 3-bromopyridine (8) [CDCI 3 ' 25 QC , 90 MHz]

2

26

2.2.4

RECOGNITION OF STRUCTURAL FRAGMENTS BY NMR

CH Coupling constants

One-bond CH coupling constants JCH eJcFd are proportional to the s character of the hybrid bonding orbitals of the coupling carbon atom, (Table 2.6, from left to right) 4-6,16, according to JCH = 500

s

(1)

where s = 0.25,0.33 and 0.5 for Sp3_, Sp2_ and sp-hybridised C atoms, respectively. With the help of these facts, it is possible to distinguish between alkyl-C (JCH ｾ 125 Hz), alkenyland aryl-C (JCH ｾ 165 Hz) and alkynyl-C (JCH ｾ 250 Hz), e.g. as in problem 15. It is also useful for structure elucidation that JCH increases with the electronegativity of the heteroatom or substituent bound to the coupled carbon atom (Table 2.6, from top to bottom).

Table 2.6. Structural features (carbon hybridisation, ･ｬ｣ｴｲｯｮｧ｡ｩｶｾＬ pling constants JCH (Hz)

ring size) and typical one-bond CH cou4-6, 6

Sp3

ｾｈ

C Hybridisation

EJectronegativity

Sp2

125

"'N/ ｾｈ

140

-H

N=


Co

121.21 118.7 112-9 1118 1H2

I 61.2 . 567

55.8 ppm

i

8.48

785

i

I

I

729 719712699

396 387 378

125

Problem 41

Problem 41, continued Conditions: (CD3)2S0, 25°C, 200 MHz eH), 50 MHz (l3C). (a) CH COSY diagram (shaded contours) and CH COLOC spectra (unshaded contours) in one diagram with an expansion of the 1H NMR spectrum; (b) parts of l3C NMR spectra to be assigned, with 1H broadband decoupled spectrum below and NOE enhanced coupled spectrum (gated decoupling) above.

41b 6.2 3.S

6.0 3.0

9.2

I

)J ..

,.,.{""J\.f..ｾＢｶ｜ＯＬＩＮｻﾷａ

- ' 1 - · · ..- -

136.3

175.1

" ----·-.·

····T

, ,

- -•

.............,-r---

124.5 123. 3 121.5 121.2

61.2

I

118.7

56.7 55.8

112.9

f---r

Ｍｾ｟ＭＭ

111.2 111.8

3

126

PROBLEMS

Problem 42 3',4',6,7-Tetramethoxyisoflavone (3) was the target of the cyc1isation reaction of 3,4-dimethoxyphenol (1) with forrnyl-(3,4-dimethoxyphenyl)acetic acid (2) in the presence of polyphosphoric acid. H H3C0 ) 0 ( 0 H H3CO

+

0

H>C,Oro OCH, ｾ

o

ｾ

I

PPA

H3CO

-C2HsOH -H2 O

H3CO

ＭｾＮ

OCH3

OCH3 OCH3

3

2

1

A pale yellow, crystalline product is obtained which fluoresces intense blue and gives the NMR results 42. Does the product have the desired structure? Conditions: CDCI 3, 25°C, 200 MHz eH), 50 MHz (13C). (a) CH COSY (shaded contours) and CH COLOC diagrams (unshaded contours) in one diagram with enlarged section (b), and with expanded methoxy quartets (c); (d) sections of l3C NMR spectra, each with 1H broadband decoupled spectrum below and NOE enhanced coupled spectrum (gated decoupling) above.

42d

i

pprn

I

152.3

160.9

ｾ ｌｪｾ

ｌ ｇｾ ｌﾥ

'f

163

I

127.6

i

124.3

I

148.9 149.2 148.5

I

120.8

r

146.2

ｩ｟ｾ Ｍｴ ｌｊｪ

158160

I

I

I

112.2 110.8

111.5

160

i

107.8

I

99.3

Problem 42

127

Problem 42, continued

42

28Hz

JL_ _J ＧＭｾ

,fu 160.9

a

0

152.3 149.2 11.8.9 148.5 146.2

0

138.7

•

127.6

0

9"

(2:,0 00

0

0

124.3

o·

120.8

112.2 1115 1108 107.8

ｾ

00

ｾ

-::'

0

D

•

0

•

99.3

ｬｾ

ＱＵＲＮＳｾ

b

i 149.2 148.5

I

ppm

,.

it I

7.22 7.16

6.83 6.72 6.81

7.62

ri

ＬＭ Ｂｾ ｣Ｚ ｦ

146.2

ｾ

pprn

386 3.84 3.82 385

I

56.21 55.8

Ｍ］｣ｾｲ ｾ

ｾｾ

I

I

I

C

I

- lH L I

I

IfII

3863.84 3.853.82

ｾ

I-lz

r:

C

128

3

PROBLEMS

Problem 43 An aflatoxin is isolated from Aspergillus flavus. Which of the three aflatoxins, B 1 , G 1 or M1 , is it given the set ofNMR experiments 437 o 0 0 0 0

OCH3 Aflatoxin B 1

OCH3 Aflatoxin M 1

Conditions: (CD 3)2S0, 25 QC, 200 MHz eH), 50 MHz (l3C). (a) Sections of l3C NMR spectra, in each case with 1H broadband decoupled spectrum below and NOE enhanced spectrum (gated decoupling) above; 60 30

43a

S.S

la

ｾｲ

J\ I ｜ＺｾＧ

I

1\

Ir)) ,

I

j I 'It ｲｾｖ

I I:

""'.\(-¥'''''

I

200.9

......"'!'t_v -

I

I

1774

165.1

161.4

154.3

3.5

I

152.1

145.8

14.0 5.0 4,5

2.5

I

116.4

1

113.5

146.5

107.2

r

I

I

103.5 102.5

914

149.0

J .......

ａ Ａｾﾷ｜

..ｾＭＮｊ

.....

ｊｾﾷ

I ｾｲ

-

34.9

. .y ...ｾｩ＾ＮＬＢＧﾥＭｬｪ

I 28.8

......ｾ

129

Problem 43

Problem 43, continued (b) CH COSY (shaded contours) and CH COLOC plots (unshadcd contours) in one diagram with expanded 1H multiplets. 7

2.5

7 2.5 ltz

43b

._ J

200.9

1771.

I

165.1

j

161t,

-I

-c-

""1 152.1 .

_.

1458

=,

I

!

1164 1 1135 '; 1072 Ｍｾ 1035 102.5

I

1

s-

I

91l, -,

-

I--

ｾ

I I

! I

_.

57.2

ｾＧＱｱ

lE

, I

349 28.8

ppm

Ｍｾ 6926.72

539

424

3.91

-J= r

322

246

3

130

PROBLEMS

Problem 44 The degradation of 2,6-xylenol (2,6-dimethylphenol) by bacteria produces a metabolite with elemental composition C8HlO0 2 as determined by high-resolution mass spectrometry 39. Which carbon skeleton and which relative configuration are deducible from the NMR experiments 44, all obtained from one 1.5 mg sample? Conditions: CDC13, 25 QC, 400 MHz eH), 100 MHz (l3C). (a) HH COSY plot with 'n NMR spectrum and HH coupling constants; the signal at OH = 2.17 belongs to acetone (impurity). 40 1.5

44a

80 1.5

8.0 70

70

15

1.5

80

8.0 15

40

15 Hz

I

I

: I I

)

. .J

i

:i I

11

1

I

ii

ｾＭＧ

,

\.-.,

,t

o

o

0

o

o

i

0

6J

0

Q

j

6286.22

o

I I

5.44

ppm

i

333 322285

I

I1 I

1.79128126 717

Problem 44

131

Problem 44, continued (b) CH COSY plot with DEPT subspectra for analysis of the CH multiplicities;

44b

2144

203.1

--------: i

1 1 •

,! I

139.•

I

13S6j

135.4 -i

133 1

I I

r! J

,\.-

73L 72.6 -

53.7

-i

--

44.5 : 434;: 42.7

317261 ｾ 163 _

15.7 ·····--rr

ppm

6286.22

r-· 333 322 285

--,-----------,.,-1 r-

544

AM -

-

-

-

I

I1 ,

1.79 1.28126117

3

132

Problem 44, continued (c) CH COLOC plot, section of methyl protons;

44c

-- -- - -

--

-----Ｂｾｍ

214_4:--

....................- _.._--- _.

--- ｾ

---

c--

I I

203.1 -

I ! ｾ

ｾ

I

I

I

1394

135 6-(

BSt.:

---==-==-

--==-

133-1 '

73.7 ｾ

ｾ ｾ

72.6 -

! ,

, ,--, ,

53-7 44.5 .

43.4 ':l 42-7 .

30 _

c==-

-="-=""

-, 125 MHz (l3C); acetyl carbonyl (be = 169-171.4) and acetyl methyl resonances (be = 20.6 - 23.8, OH = 2.1 - 2.2) are not shown. (a) HH COSY plot with lHNMR spectrum;

46a

｟ｾＭＧＢｬ

00

I

,

oe Q.

Cl

I

m

Q

ｾ

«l)BC!

.&9. ｾ

e

11

P

J1

m

fJ

P

s

e

Q

Q

III

11

lII'

•

'" '--- ,-- ·T-_.... -r- .._......- -..· - , - ""]?"ＭＧｔｾ

5

3

139

Problem 46

Problem 46, continued (b) HC HSQC plot with 1H NMR spectrum;

46b

(Se

59.0

-d

61.0 61.5 61 7

0 60

UtI ｾｏｃ

62.0 62.3

;i&-

ｾ dl 8i

0

61

ｾ .; -'

65 ｾ

;:..

ｾ

66.9 689 69J 69.4 69.6 69.8

ｾ

=: l.

ｾ

'"'!o

704 70.7 70.9

(t)

\01

0 ｾ

:... 70

!

e

a;

0

71.1

ｾ

7185 71.9 749 7605 76.3

L

ｾＱ｜

Q

-1' 1007-, 989

[1::

t •

1008

ppm

r

:

5

I 4

3

ie:

3

140

PROBLEMS

Problem 46, continued

46c

o

•

0

0

"

:t:

q

I.

,

CO

III

0

ell

.0"

la

,+ + • »I •

• g

ｾ &r/fl

•

114>

..

J j I

11

" " ｾ

....

41 I

ppm

I

I

1

5

11

(10

11

I

• K'i

It ｾ ｟ｾＬ I)"ｉｾ 0 -11,

"

11

11

Cl • 11

11

ｾ

rAJ

/.ll

e

m

i t)

H

w

$

GCI

0

0

t

t

ｩｾ

tQll

ｾ

H. I

«1lI

•

(J

I ,

)3

•__..

0

I

I

4

..,---,--.,-,-r-..,......--r- ｟ｾ ＮＬ Ｍ ｲＮ

3

II I

I

J

Problem 46

141

Problem 46, continued (c) HH TOCSY plot with 1H NMR spectrum and selective HH TOCSY with soft pulse irradiation at OH = 5.70 (top); (d) HH ROESY plot with lHNMR spectrum, same section and same scales as shown in (c).

46d

I,

I

"

I I1

I

ｾ

I

10 1,

III III

oragQ

e

It Ｌｾ

• 00

•m

IS 11

'11

.(;1

•

•

I ｯｾ

'I§'

8

III

III

J ｾｏ flS'

0

ｾ

j

i

I

3

i

3

142

PROBLEMS

Problem 47 A compound with the elemental composition C 1sH2203 was isolated from the methanol extract of the Chilean medicinal plant Centaurea chilensis (Compositae) 41. What is the structure of the natural product, given the NMR experiments 47? Conditions: CD 30D, 15 mg per 0.3 ml, 400 MHz eH), 100 MHz (BC). (a) HH COSY plot from 6H = 1.2 to 3.5;

47a

!

--

m0

ｾｑ

l}

@)

,...,,,

\:cS)

ｾ

0

ｾ

c')

ｾｎＧ

«-»«

'5'

ｾ

tl ｾ

CJ

(j) ｩｾＧ 1

r

ppm

u

ｾ

ｾ

oc@

IJ)

ｉｾ

ｾ

I

I

3

2

ｾ ｾ

oco

Problem 47

143

Problem 47, continued (b) expanded IHmultiplets from

6H=

1.23 to 3.42;

47b

ｾｊ

\1\ /I!

JvUVL l( l(

Y

4.5

12.5

ppm 3.42

f,

\9

4.0

4.0 12.5 125

2.60

1.97

ＰＳＱｾＮｬ ｲ

4.5

An lA ｾＮ M r\ v \

J

/V\ I

V \

L

V

ｬＩ

ｾ

J

4.5 13.0 13.0

2.05 1.53

h

ｾｷ

ｾＥｩ ＵＲＧ 4.0

12.5

ｾＯｮ｜

1

I

4.5 25 4.5 4.5

12.5

lj 1.68

W 1.55

i/:\

1\

4.0

J\ )ILJI UJI

4.0

12.5

111

1I

W

ｾ

130 130 130

72.5 ｊ Ｎ Ｍ ｲ Ｑ ｾ

\

I

.

j

ｾ

I

t:

j

,!,r:

i! i I1

I V,. ";\J!ilI j :

I

U

'--.!

v-:

Yｾ y Y

4

125

1. 33

---r

1.23

ｾ

5

130 130Hz

3

144

PROBLEMS

Problem 47, continued (c) CH COSY diagram from Cc = 6 to 130 with IHbroadband decoupled l3C NMR spectrum (d), DEPT CHsubspectrum (e) and DEPT subspectrum (f, CH and CH] positive, CH2 negative);

47

11.2

24.5

. ..

. ..

30.8

36.5 J,0

•

_

37.8

38.5 38.9 42.3 49.8

80.0

I 1

j

I

i

,ｾ 1

I

1

\

I

f

&

I

e

1d

106.9 ｾ

1 •

C

1

2

3

4

5

6

6

123.4 ppm

145

Problem 47

Problem 47, continued (g) CH COLOC plot.

47 9 , ,

_JJLJ 170.4

ｉ｜ｪＮｶＯｾｊＧｌＭ

-.Jl.

. _

.------_._--- ---

l

151.0 146.9

123.4

106.9

I

80.0 -

•

o

0

.. I

49.8 38.9 42.3 37.8 38.5 36.5 30. 8 24.5

" !

ｾ

o

11.2 ppm

6

5

4

3

2

1

3

146

PROBLEMS

Problem 48 The umbelliferone ether structure 1 was suggested for a natural product which was isolated from galbanum resin 42. Does this structure fit the NMR results 48? Is it possible to give a complete spectral assignment despite lack of resolution of the proton signals at 200 MHz? What statements can be made about the relative configuration?

1 HO

48a

JJjJ 161.8 161.3 155,7

C>

11.3.5

-

C>

128,7

CO> -

113.1 ｾ

112,9 112,5-

ｾ

•

1016

•

7S.5 -

--

66.6 I'

ppm

co

,)

759 730

ＮＢＧｬｔｦｩｮｬｾ ＺＮＬ Ｑ Ｇ

6.82 6,80

1'1

619

4374,13

-1 "I

ﾷｪｾｬﾷ

339

r-t

".1

,-rTlrrr

147

Problem 48

Problem 48, continued Conditions: CDCI3, 50 mg per 0.3 rnl, 25°C, 200 and 400 MHz eH), 50 and 100 MHz (BC). (a,b) CH COSY(shaded contours) and CH COLOC plots (unshaded contours) in one diagram with DEPT subspectra for identification of the CH multiplets; (a) BC shift range from Oc = 66.6 to 161.8; (b) BC shift range from Oc = 16.0 to 75.5;

I I

ｾ

o

o

1.19

r !

1.30

l

1.39 - 1.49 1.53 1.55

t

1.65

1.84 1.90

ｾＬＭ

ｾＭｾＬＭ Ｍ ＭｔＭ ﾷ

72. 5 66.6 75.5

pprn

----,---,-----nl1,---.--,---,,...,-.----,.--'

Ｍ ＭＬＭｾ

59.4

48.4 44.1

37.4 32.7 28.4 24.6 20.0 16.0 37.9 25.1 22.1

3

148

PROBLEMS

Problem 48, continued (c) sections of 13e NMR spectra (lOO MHz), 1H broadband decoupled spectrum below and NOE enhanced coupled spectrum (gated decoupling) above, with expanded multiplets in the aromatic range;

48c 3.7

5.2

5.2

10.0 58

I I

III

!Ilii\

.JL_.L" '"

ｕＮｾ

ｾｬｊＮｌｪ｟

__ｌ｟ｾ 162.0

163.1

!

I

163.6

163.1 173.1

I

1.. 1..

, .....

I

ＭｾＭｮＭ

I

161.8 161.3 155.7

ｾ146.2 ｗｊＮｩＡｉｾ /. it

I:

J._1_..--",---.

lLＡｩＬｉｾｷｊ｟Ｎｵ

11' 1

I

143.6

:1

124.7

111

I

,

11

ｾ III

122.0 125.0

I

101.6

113.1 112.9 112.5

128.7

143.5

ppm

1'1

uJI Jｗｾｬ ｉｾ ｉｾ .'

l 'Uｾ ｾ

.

ｊｬｾ

126.2 1257 125.0 124.7 123.1 Hz 125.7125.2

I I

II

_L l. Ｍ ＬＭ Ｍ Ｌｾ Ｍ

75.5 72.5

... '-1--

66.6

ｾＮ

1 ..... _ -

59.4

Ｎ ＮＬｾＮ Ｎ ＮＬＭ Ｍ Ｍ ｲ ｾＭﾷＧＭ Ｍ

48.4 44.1

l------n--,

I

I

37.9 37.432.7 28.425.1 24.622.1 20.0 16.0

149

Problem 48

Problem 48, continued (d) In NMR spectrum with expanded multiplcts, integral and NOE difference spectra (200 MHz, irradiated at 6H= 0.80,0.90,0.96,1.19,3.39 and 4.13 /4.37).

48d

____ｾ ｟ ｌ

ｾＭ

__

ｾＭｾ

....

｟ａｾ

ＭｊＮｾ

. . .ｩｾｉ Ｂ

ppm

Ｍｾｶ｟ｹｬ J

7

i

I

I

6

ｾ

_ I

5

ｾ

) DJ, 4

I

3

I

I

ｾｨｴＭ

ｾｉ

2

1

150

3

PROBLEMS

Problem 49 A natural product isolated from the plant Euryops arabicus, native to Saudi Arabia, has the elemental composition C 1sH/ 60 determined by mass spectrometry. What is its structure, given the NMR experiments 49? Conditions: CDCI 3, 20 mg per 0.3 ml, 25 DC, 400 MHz (H), 100 MHz (13C). (a) /H NMR spectrum with expanded multiplets;

49a 1.5

11\

'.'

7. 1

1

I' i I

9.5 3.1

\

1.5

I

Hｾ ｾｩ

1\

h II

11

, I

ppm

I I

1.5

!I

\

1

7. 1

)

-c.,

7

ｩ｜Ｉｕｾ

it

"I

ｉｾ rl ｾ｜ 'yl

'! I 1

1

.

\

\'.

'II1 I

I"

j

6

I'1

V

!q

n l t!h I'l I,\tl 0 \i "I'

1\

11\

1I11I Il'! \

1

Ii \

,-d , I

"

1

16.5

1

ｬｩｾ 1

)

9.5 6.5

l

ｾ III ｾ

I 1

rI "/ l/

\

3

1.5

11

Hz

Ip

!JUU 2

I

!

I\ I i \)

.)

\,

Problem 49

151

Problem 49, continued (b) sections of l3C NMR spectra, in eaeh ease with 1H broadband decoupled spectrum below and NOE enhanced coupled spectrum (gated decoupling) above;

4gb

7.9

r

-

154.4

ﾷＧﾷＭｔﾷＭ Ｍ Ｍ ｾＭ

ppm

ＭＢＢｾＭＭＭ

-- . ｾＭＮ

Ｍｾ

Ｍｾ

141.7

133.2

37

ｬｾ ｊｌ ｉ

｟ｌｾ Ｍ

i

130.0

I

116.5

r

107.5

152

3

PROBLEMS

Problem 49, continued (c) CH COSY and CH COLaC plots in one diagram with DEPT sub spectra to facilitate analysis of the CH multiplicities;

49c

I

ilk

tLl.. ' ＱＵＴｾＭＧ

.-

r

,

I

Ii

14Uj -

;ｾ

i

!

1

1332 -i 130,0 J

o

1282,,:

ｾＧＳ

0

127.9-' • 126.6125.3

0

o

0

0

i

0

o0 ｾ

,,j------

i

116.51

!

ｌｾＭＮ

I

['"

c

i

107.5-

r-

•

!

,,"""

31.1-

Cl

27.51

r\F--.

-I

19.6 -;

•

14.1 -; 114.,

ppm

'r------

(; I !

1

133

7.05

ＭｾＢＱＧ

ｾＮ

6.54

5-94

｟Ｍ Ｍ Ｍｾ ｾＭｾ

.. ｟Ｎｾ

-'1 ﾷＭＢＧｬｾｲｷＮＬ

3.36

--

2632.30 2.44

J ＢＭｾｬ

1.76

i

L_

ｾ

153

Problem 49

Problem 49, continued (d) enlarged section of (c).

J.

IL 0

ｾＮｉＬ ｻｓＱ

1417'1 !

f}

49d

ｾ

". 1",,_

I.

o

154

3

PROBLEMS

Problem 50 A compound with the elemental composition C21H2806 determined by mass spectrornetry, was isolated from the light petroleum extract of the leaves of Senecio darwinii (Compositae, Hooker and Amolt) 43, a plant which grows in Tierra del Fuego (Chile). What structure can be derived from the set ofNMR experiments 50? Conditions: CDCh, 25 mg per 0.3 ml, 25°C, 400 MHz (H), lOO MHz (13C). (a) HH COSY plot;

50a

o»tf. ｾ ｯ ,.ifF eo,: '.

o

e

ppm

I

I

I

7

6

5

d

ｊｴ

"

ｾ

.0

""

0

155

Problem 50

Problem 50, continued (b) HH COSY plot, section from OH = 0.92 to 2.62;

SOb

o

o 8

00

C>

-0

o tJ

.[5)

CfZJ Y-:3/

§

8

f1 V+

·--··T

O

-

ppm 2.62

--T ..........

2.41

_00•••••

I

J

I

---r---

2. 06 1. 95 1.83 1.66 1.49 2.02

I

I

1.21 1.08 0.92

156

3

PROBLEMS

Problem 50, continued (c) CH COSY plot with DEPT subspectra to facilitate analysis of the CH multiplets;

SOc

185.2 176.4 170,4

146.8 145.2

o

o

134.3 120,9

75,8

(;I

75.0

o

""

ppm

7.31

6.29

4-.88

.

202.2 Hz

157

Problem 50

Problem 50, continued (d) CH COSY plot, sections from 6H = 0.92 to 2.62 and Dc = 8.8 to 54.9;

SOd

----

_ - _ .._.

L

o

54.9

49.5 44.1

34.5

0>

-ss»

29.5

21.2 18.7 18.6 15.7· 14.6

CP

c-

9.8 8.8-

ppm

2.62 2.41

2.06 1.83 1.49 2.021.95 7.66

1.21 0.92 7.08

3

158

PROBLEMS

Problem 50, continued (e) CH COLOC plot;

50e

r--

185.21 J

-

•

176.4 170.4 Ｎｾ

ｾ

146.8 145.2 ｾ

•

134.3 120.9

75.8

....

I---

• ｾ

a

..

54.9 49.5 44.1

-

34.5

0

29.5

9.8 ppm

731

6.29

2.41

1.83 1.21 0.92 2.02

1.08

\--

Problem 50

159

Problem 50, continued (C) /H NMR spectrum with expanded multiplets and NOE difference spectra, irradiations at iSH = 1.49, 1.66, 2.41 and 6.29.

SOf

1

ppm

ｾ ｟ｊ

731

4.88

t

ｾ｟ ｟ ｾ ｉＧ［ｬｕ｟ｾ

._._,__ . . . __ .

tl)}dL..:

'v,---

3

160

PROBLEMS

Problem 51 Sapogenins of the dammaran type were isolated from the leaves and roots of the plant Panax notoginseng, native to China 44. One of these sapogenins has the elemental composition C3aHS204 and produces the set ofNMR results 51. What is the structure of the sapogenin? Conditions: 20 mg, CDC1 3, 20 mg per 0.3 ml, 25 DC, 200 and 400 MHz (H), 100 MHz (13C). (a) HH COSY plot (400 MHz) with expansion ofmultiplets;

51a 10.0 4.5

10.0

11.5 5.0 Hz

5.0

,00

«»

I

L.

I

4

3

ppm

2

Q

G

Problem 51

161

Problem 51, continued (b) /H NMR and NOE difference spectra (200 MHz), decoupling of the methyl protons shown;

51b

-

_. --i -

irradiated I

•. "i!V,fl

Ｌｾ｟Ｎ Ｍｾ

ｾＭ

,.... r.J'l'\L_.__..

Ｎｾ

ＧＢＭｾ

ＢＭ ｾ Ｍ ｾ Ｍ Ｂ

.""

""\""

Ik t\,,1 J,III\

.-.•

Ｌｾ

ｾ｟

•." "- •. ",,,,'.' -'"''

ＮＬ ｾ

'mrrr [ i

M l il I\! ;1

ＧｊｉｾＢａ｜Ａ

,,I

Il}

vv , ,

...

1\1 ,11,11

,,_.J'"v"v...｜ＩａＮ ｬＧｖｦＬ｜［ ｊｾ

11

'\>J\

J--

at 0.88

0.92

Ui 0.97

1.04

1 '\ 1 \

... -- . . . . . . - - - - - . - - , - - - . - -

"0.--", . . . . -- - - - - . . - . . . . .- . - - - .... ----

......-

_ . -••• - - . - - . ' . - .

j)v.!'·"""'A)V

｜ＯｌＭＮａ Ｂ ｲﾷｾｉ

t,(V/lr -I!

1.16

I

ILJ

1.30

4

2

3

162

Problem 51, continued (c) CH COSy plot with enlarged section (d);

51c

.... ---._---_.-

78.5 76.6

73.2 69.8 686

61.1

.u»

547 51.1

-j

,I

vo.

'0--

- -r----,.. ...........-.---------ppm

4.08

3.50

3.15

PROBLEMS

Problem 51

163

Problem 51, continued

51d

49.4 1,8.7 47.0

41.0 393

39.2 38.7

36.5 35.7 -

311

27.2 25.2

19.4

17.21 1719 17.1 16.3

15.5

, .-., --'--rI I I rrr 7.64 1.551.501451.40 1.34 7.22 U07B 1.$ 730 7.25 7.207.16

- -- 1 r-..,..-----,--T - 1- 1

ppm

190

178 1.77 7n

Ir r I I r 1.03 1.07 1.04 0 'l7 0.92 088

3

164

Problem 51, continued (e) relevant section of CH COLOC plot.

51e

I

11

!I

11 1

11

1

) l"... . J

ｾ

I1

i Ｂ｜ｾ

'v,;)

, 78.5 -

76.6 -'

--

732

61.1

1

!

51.1 49.4 46.7 47.0

41 0 " 393 39.2 'C

- --

38 7 I

36.5 357

- -

--

311

311 30.9

_

1!ir',g

CJZ>.

272

194 -1 17.2

17.1 15.5 ppm

,

c::ao F" -

-r--

1JO I.D 1.20 1.16

c;-=a

c:::a . r"---r'l'

ｲＭ Ｍ Ｍｾ

104

097 0.920.88

PROBLEMS

165

Problem 52

Problem 52 A compound with the molecular formula C7H13N03, determined by mass spectrometry, was isolated from the plant Petiveria alliacea (Phytolaccaceae). What is its structure given the set of NMR results 52? Conditions: CD 30D, 30 mg per 0.3 ml, 25 -c, 400 and 200 MHz CH), 100 MHz (13C). (a) HH COSY plot (400 MHz) with expanded I H multiplets; 10.5

12.5 6.0

7.5

15.0 10.5

12.5 4.0

52a

7.0

Cl

Hz

0 c ｾ

o

o

ｾ

6 ()

ｾ o

o 0

rJ

0 ＢｾＧＭｲ

ppm 4.58

I

4.32

4.02

0

Cl I I

8)

_.

I

3.45 3.40 3.15

2.66

2.34

166

3

PROBLEMS

Problem 52, continued (b) CH COSY and CH COLOC plots in one diagram with DEPT spectrum (CH] negative, CH and CH j positive) and coupled (gated decoupling) 13C NMR spectrum above;

52b

Hz

J

{

2.34 2.66

_ _ _ _ _ _ _ｾ Ｎ ｟ ｾ

I

o0

l

3.15

-===t ,-,

3,40 3.45

Ｎｾｦ［Ｍ

4.02

o

4.32

, I


"

)o, __ •____ ｾ

- _ .. ｾ

II

33.9· i

ppm

! i--

..-.::t>

ＮＺ［ｾ

I

I

Ｌｾ

ｾｮ

2.92 251 2.22 2.44224

_._"

Problem 54

171

Problem 54 Amongst products isolated from Heliotropium spathulatum (Boraginaceae) were 9 mg of a new alkaloid which gave a positive Ehrlich reaction with p-dimethylaminobenzaldehyde 45. The molecular formula determined by mass spectrometry is C15H25N05. What is the structure of the alkaloid given the set ofNMR results 54? Reference 31 is useful in providing the solution to this problem. Conditions: CDC13, 9 mg per 0.3 ml, 25 QC, 400 MHz (H), 100 MHz (13C). (a) HHCOSYplot;

54a

ｾ,ｊ II.

o

o . 'I

ppm

f

560 564

8

c..

ＧＬｶＯｬ｛ｾｪ

N