Modelling 1 H NMR Spectra of Organic Compounds

Transcription

1 Modelling 1 H NMR Spectra of Organic Compounds Theory, Applications and NMR Prediction Software RAYMOND J. ABRAHAM Chemistry Department, The University of Liverpool, UK MEHDI MOBLI IBM Institute for Molecular Biosciences, The University of Queensland, St Lucia, Australia A John Wiley and Sons, Ltd, Publication

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3 Modelling 1 H NMR Spectra of Organic Compounds

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5 Modelling 1 H NMR Spectra of Organic Compounds Theory, Applications and NMR Prediction Software RAYMOND J. ABRAHAM Chemistry Department, The University of Liverpool, UK MEHDI MOBLI IBM Institute for Molecular Biosciences, The University of Queensland, St Lucia, Australia A John Wiley and Sons, Ltd, Publication

6 This edition first published John Wiley & Sons Ltd Registered office John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, United Kingdom For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at The right of the author to be identified as the author of this work has been asserted in accordance with the Copyright, Designs and Patents Act 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 or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books. Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. 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. The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for every situation. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of experimental reagents, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each chemical, piece of equipment, reagent, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom. Library of Congress Cataloging-in-Publication Data Abraham, R. J. (Raymond John), 1933 Modelling 1 H NMR spectra of organic compounds: theory and applications / Raymond Abraham, Mehdi Mobli. p. cm. Includes bibliographical references and index. ISBN (cloth) 1. Proton magnetic resonance spectroscopy. 2. Organic compounds spectra. 3. Organic compounds Structure. I. Mobli, Mehdi. II. Title. QD96.P7A dc British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library ISBN Set in 10/12pt Times by Integra Software Services Pvt. Ltd, Pondicherry, India Printed and bound in Great Britain by Antony Rowe Ltd, Chippenham, Wiltshire.

7 Contents Preface xi 1 Introduction to 1 H NMR Chemical Shifts Historical Background Basic Theory of NMR The 1 H Chemical Shift Nuclear Shielding and Reference Compounds H Substituent Chemical Shift (SCS) Two-bond (H.C.X) Effects Three-bond (H.C.C.X) Effects H SCSs in Olefins and Aromatics Long-range Effects on 1 H Chemical Shifts Steric (van der Waals) Effects Electric Field Effects π-electron Effects Hydrogen Bonding Shifts Tables of 1 H Chemical Shifts of Common Unsaturated and Saturated Cyclic Systems 17 References 20 2 Interpretation of 1 H NMR Coupling Patterns Fine Structure due to HH Coupling The Analysis of NMR Spectra Nomenclature of the Spin System, Chemical and Magnetic Equivalence Two Interacting Nuclei, the AB Spectrum Three Interacting Nuclei, the ABX Spectrum Four Interacting Nuclei Iterative Computer Analysis Automatic Iteration of Complex Spectra The Mechanism of Spin Spin Coupling Geminal HH Couplings ( 2 J HH ) Vicinal HH Couplings ( 3 J HH ) Ab initio Calculated Couplings Long-range HH Couplings 55

8 vi Contents 2.4 HF Couplings Geminal HF Couplings ( 2 J HF ) Vicinal HF Couplings Long-range HF Couplings 61 References 63 3 Chemical Shift Calculations and Molecular Structure Introduction Quantum Mechanical Calculations of 1 H Chemical Shifts The Database Approach Semi-empirical Calculations Theory of the CHARGE Program Through Bond Effects H Chemical Shifts of Substituted Methanes and Ethanes Through Space Effects Hydrogen Bonding Shifts Aromatic Compounds 80 References 82 4 Modelling 1 H Chemical Shifts, Hydrocarbons Introduction Alkane Chemical Shifts H..H and C..H Steric Interactions The Methyl Effect C C Bond Anisotropy Observed versus Calculated Shifts Alkene Chemical Shifts Introduction C C Bond Anisotropy and Shielding Observed versus Calculated Shifts Alkyne Chemical Shifts Introduction C C Bond Anisotropy and Shielding Observed versus Calculated Shifts Acetylene SCSs Contributions to the Acetylene SCSs Naphthyl and Phenanthryl Acetylenes Summary 129 References Modelling 1 H Chemical Shifts, Aromatics Aromatic Hydrocarbons Introduction Ring Currents, π-electron Densities and Steric Effects Observed versus Calculated Shifts 139

9 Contents vii 5.2 Heteroaromatics Introduction Theory and Application to Heteroaromatics Observed versus Calculated Shifts Ring Currents and π-electron Shifts Summary 166 References Modelling 1 H Chemical Shifts, Monovalent Substituents Introduction Fluorine Substituent Chemical Shifts Electric Field Theory Fluoroalkanes Fluoroalkenes and Aromatics Steric, Anisotropic and Electric Field Effects in Cl, Br and I SCSs Introduction Aromatic Halides Alkyl Halides Contributions to the 1 H SCSs in Halocyclohexanes Steric Coefficients for Halogens Alcohols and Phenols Introduction Alcohols and Diols Phenols Amines Introduction Theory and Application to Amines Observed versus Calculated Shifts Conformational Analysis Cyanides Introduction Theory and Application to the Cyano Group Observed versus Calculated Shifts Cyano SCSs Nitro Compounds Introduction Theory and Application to Nitro Compounds Observed versus Calculated Shifts SCSs of the Nitro Group Conformational Analysis Summary 241 References Modelling 1 H Chemical Shifts, Divalent Substituents Introduction Aldehydes and Ketones 247

10 viii Contents Aliphatic Aldehydes and Ketones Aromatic Aldehydes and Ketones Conformational Analysis Esters Introduction Theory, Application to Esters Observed versus Calculated Shifts Amides Introduction Theory, Application to Amides Aliphatic and Cyclic Amides Aromatic Amides Steric and Electric Field Effects in Acyclic and Cyclic Ethers Introduction Theory, Application to Ethers Oxygen SCSs in Ethers Observed versus Calculated Shifts Sulfoxides and Sulfones Introduction Theory, Application to Sulfoxides and Sulfones Molecular Geometries Observed versus Calculated Shifts Summary 297 References H Chemical Shifts and Structural Chemistry Introduction Electronic Structure Calculations Basis Sets Molecular Mechanics Calculations Conformer Generation Molecular Geometries and 1 H Chemical Shift Calculations Methyl Anthracene-9-carboxylate N-Formyl Aniline (1) Benzosuberone (2) Rate Processes and NMR Spectra Theory Amide Rotation Proton Exchange Equilibria Rotation about Single Bonds, Ring Inversion Processes Solvent Effects Introduction Non-polar Compounds Polar Aprotic Compounds Protic Compounds 331

11 Contents ix Diols and Polyhydroxy Compounds Chemical Shift Contributions Summary 345 References A Practical Approach to 1 H NMR Calculation and Prediction Introduction A Step-by-Step Description of Calculating 1 H NMR Spectra Molecular Modelling and Conformational Searching PCModel Calculating 1 H Chemical Shifts and J-Coupling Constants HNMRSPEC Displaying the Calculated 1 H Spectrum 1HPLOT Advanced Use of HNMRSPEC_S Iteration of 2nd Order 1 H Spectra from Pre-specified s and Js LAOCOON Automated Spectral Prediction Using the NMRPredict Software Concluding Remarks 368 Index 369

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13 Preface This book serves as an introduction to the structure dependence of 1 H chemical shifts and couplings and to the methods used to predict and model 1 H NMR spectra. The prediction of 1 H NMR chemical shifts to the accuracy required by the structural chemist is still a challenge for the theoretician. We present here a collection of 1 H chemical shifts in molecules of known conformation which cover most of the structure types and functional groups in organic chemistry. This data set is used to refine a simple mechanistic theory of 1 H chemical shifts and this also provides a useful breakdown of the interactions responsible for 1 H chemical shifts. Chapter 1 introduces the basic concepts of NMR and of the interactions responsible for 1 H chemical shifts in organic compounds. Chapter 2 gives the interpretation of 1 H coupling patterns, the analysis of 1 H spectra and a review of HH and HF couplings with up-to-date theory. Chapter 3 details the methods used to predict 1 H chemical shifts, and Chapters 4 7 give the observed and calculated 1 H chemical shifts of a variety of organic compounds. Chapter 8 considers the effects of structure calculations, rate processes and solvent on 1 H spectra and Chapter 9 details the use and application of the computer programs in the accompanying CD. These programs allow the user (a) to draw a molecule on the screen and minimize the conformational energy, (b) to calculate from this file the 1 H couplings and chemical shifts and (c) to predict and display the resulting 1 H NMR spectrum. It is also an introduction to the CHARGE routine which calculates the 1 H chemical shifts and couplings of an organic compound from the molecular structure. To obtain the 1 H NMR spectrum from the chemical shifts and couplings the secular determinant has to be solved and the frequencies and intensities of the spectral transitions calculated. This is achieved by the CALAC routine, a development of the LAOCOON program (see Chapter 2). The CHARGE routine is included in two computer programs, HNMRSPEC and NMRPredict, both of which calculate the 1 H NMR spectrum for a given compound from the couplings and chemical shifts given by the CHARGE routine. In HNMRSPEC this is performed by the CALAC routine. The CHARGE routine requires an accurate 3-dimensional molecular structure as input and this is provided by the PCMODEL program. Using the PCMODEL and HNMRSPEC programs plus the plotting program HPLOT the user can display the 1 H NMR spectrum of any given organic compound. The NMRPredict package includes both 1 H and 13 C spectral predictions. A neural network approach is used to predict 13 C chemical shifts. It includes two 1 H spectral prediction packages. One is a data based incremental prediction. The other incorporates both PCMODEL and the CHARGE routine. There is also a plotting routine to give the 1 H spectrum from the chemical shifts and couplings. The PCMODEL program is used here to generate the conformational profile of the

14 xii Preface compound studied. The CHARGE routine then predicts the 1 H chemical shifts and couplings of the conformations of the compound and the weighted average of these values is used in the NMRPredict software to calculate and display the resulting 1 H NMR spectrum. The PCMODEL, HNMRSPEC, CALAC, HPLOT and NMRPredict programs are provided on the CD with this book, with detailed examples of molecular input and output for all of them. There are three appendices, all databases of observed and calculated 1 H chemical shifts. A1 consists of 394 molecules of various types, A2 of 113 substituted benzenes and A3 of 65 substituted pyridines. The appendices are all on the CD-ROM. A number of people have helped in the research described in this book. Drs Tony Thomas and Lee Griffiths have assisted in this research for many years, both as research students and later as research collaborators. It is a pleasure to acknowledge their contributions and also those of other members of RJA s research group in Liverpool over the last 30 years, Drs Julie Fisher, Brian Hudson, Alan Rowan, Paul Smith, Ian Haworth, Guy Grant, Mark Warne, Mark Edgar, Nick Ainger, Marcos Canton, Matthew Reid, Manuel Perez, Rodothea Koniotou and Jonathan Byrne. We acknowledge also the technical help of Dr Paul Leonard and Mrs Sandra Otti and RJA acknowledges the award of a Leverhulme Trust Emeritus Fellowship to assist in the writing of this book. We also acknowledge the encouragement, patience and fortitude of Barbara and Louise, without which this book would not have been written. Who should read this book? The book is aimed at graduate and industrial scientists and would be of use to any student or researcher who is using 1 H NMR spectroscopy as an aid in determining the structure and conformation of organic and bio-organic molecules. Raymond J. Abraham and Mehdi Mobli

15 1 Introduction to 1 H NMR Chemical Shifts 1.1 Historical Background 1 H NMR spectroscopy began in 1945 when two groups of physicists, Bloch, Hansen and Packard 1 at Stanford and Purcell, Torrey and Pound 2 at Harvard, first detected the radiofrequency signal from atomic nuclei when placed in a magnetic field. They shared the 1952 Nobel Prize in Physics for this work. This was 1 H NMR as they used the hydrogen nuclei in water and paraffin wax to obtain their signals. As the technology developed other nuclei were found to exhibit NMR signals, but the resonance frequency of these signals depended on the chemical environment of the nuclei. This was first observed by Knight 3 in metals and metal salts and later by Dickinson 4 for the 19 F nuclei in fluorocompounds. Also Proctor and Yu 5 observed two signals in the 14 N spectrum of ammonium nitrate. They attributed this unexpected result to some nasty chemical effect. Thus the phenomenon of nuclear chemical shifts was discovered. Further advances in magnet resolution allowed the historic experiment of Arnold, Dharmatti and Packard, 6 when they resolved the three types of hydrogen atoms in ethanol (Figure 1.1), the first example of 1 H chemical shifts and this illustrated the immense potential of 1 H NMR in structural organic chemistry. Since this original discovery 1 H NMR spectroscopy is now widely used in all scientific disciplines from physics to medicine and is now even part of the high school syllabus. It is also the most common and powerful analytical tool of the research scientist. The detection of the hydrogen atom 1 H resonances in a molecule was possible since this isotope has a spin of 1 / 2, is magnetically active, has a high natural abundance and is present in most organic compounds. The other nucleus of general interest for the organic chemist, the carbon 12 C isotope, has zero spin and therefore no magnetic moment. The 13 C nucleus has spin 1 / 2 but has a natural abundance of only ca. 1 %. For this reason it took another two decades for the first 13 C NMR spectrum with acceptable quality to be produced. Modelling 1 H NMR Spectra of Organic Compounds: Theory, Applications and NMR Prediction Software Raymond Abraham and Mehdi Mobli c 2008 John Wiley & Sons, Ltd