Chemistry for Pharmacy Students General, Organic and Natural Product Chemistry Satyajit D. Sarker University of Ulster, Coleraine, Northern Ireland, UK Lutfun Nahar University of Ulster, Coleraine, Northern Ireland, UK Chemistry for Pharmacy Students Chemistry for Pharmacy Students General, Organic and Natural Product Chemistry Satyajit D. Sarker University of Ulster, Coleraine, Northern Ireland, UK Lutfun Nahar University of Ulster, Coleraine, Northern Ireland, UK Copyright #2007 John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex PO19 8SQ, England Telephone (þ44) 1243 779777 Email (for orders and customer service enquiries): [email protected] Visit our Home Page on www.wiley.com All Rights Reserved. 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Anniversary Logo Design: Richard J. Pacifico Library of Congress Cataloging-in-Publication Data Sarker, Satyajit D. Chemistry for pharmacy students: general, organic, and natural product chemistry / Satyajit D. Sarker, Lutfun Nahar. p.; cm. Includes bibliographical references. ISBN 978-0-470-01780-7 (cloth : alk. paper) 1. Chemistry–Textbooks. I. Nahar, Lutfun, Ph. D. II. Title. [DNLM: 1. Chemistry, Pharmaceutical. 2. Chemistry. QV 744 S517c 2007] QD31.3.S377 2007 540–dc22 2007017895 British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library ISBN 978-0-470-01780-7 (HB) 978-0-470-01781-4 (PB) Typeset in 11/14pt Times by Thomson Digital Printed and bound in Great Britain by Antony Rowe Ltd., Chippenham, Wilts 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. This book is dedicated to pharmacy students from all over the world Contents Preface ix 1 Introduction 1 1.1 Role of chemistry in modern life 1 1.2 Physical properties of drug molecules 3 2 Atomic structure and bonding 17 2.1 Atoms, elements and compounds 17 2.2 Atomic structure: orbitals and electronic configurations 18 2.3 Chemical bonding theories: formation of chemical bonds 21 2.4 Electronegativity and chemical bonding 27 2.5 Bond polarity and intermolecular forces 28 2.6 Significance of chemical bonding in drug–receptor interactions 31 3 Stereochemistry 35 3.1 Stereochemistry: definition 36 3.2 Isomerism 36 3.3 Significance of stereoisomerism in determining drug action and toxicity 53 3.4 Synthesis of chiral molecules 55 3.5 Separation of stereoisomers: resolution of racemic mixtures 56 3.6 Compounds with stereocentres other than carbon 57 3.7 Chiral compounds that do not have a tetrahedral atom with four different groups 57 4 Organic functional groups 59 4.1 Organic functional groups: definition and structural features 60 4.2 Hydrocarbons 61 4.3 Alkanes, cycloalkanes and their derivatives 61 4.4 Alkenes and their derivatives 103 4.5 Alkynes and their derivatives 108 4.6 Aromatic compounds and their derivatives 112 4.7 Heterocyclic compounds and their derivatives 143 4.8 Nucleic acids 170 4.9 Amino acids and peptides 179 4.10 Importance of functional groups in determining drug actions and toxicity 184 4.11 Importance of functional groups in determining stability of drugs 188 5 Organic reactions 191 5.1 Types of organic reaction 191 5.2 Radical reactions: free radical chain reactions 192 5.3 Addition reactions 197 5.4 Elimination reactions: 1,2-elimination or b-elimination 223 viii CONTENTS 5.5 Substitution reactions 232 5.6 Hydrolysis 260 5.7 Oxidation–reduction reactions 264 5.8 Pericyclic reactions 278 6 Natural product chemistry 283 6.1 Introduction to natural product drug discovery process 283 6.2 Alkaloids 288 6.3 Carbohydrates 303 6.4 Glycosides 319 6.5 Terpenoids 331 6.6 Steroids 352 6.7 Phenolics 359 Index 371 Preface The pharmacy profession and the role of pharmacists in the modern healthcare systems have evolved quite rapidly over the last couple of decades. The services that pharmacists provide are expanding with the introduction of supplementary prescribing, provision of health checks, patient counselling and many others. The main ethos of pharmacy profes- sion is now as much about keeping people healthy as treating them when they are not well. The modern pharmacy profession is shifting away from a product focus and towards a patient focus. To cope with these changes, and to meet the demand of the modern pharmacy profession, the pharmacy curriculum, especially in the developed world, has evolved significantly. In the western countries, almost all registered pharmacists are employed by the community and hospital pharmacies. As a consequence, the practice, law, management, care, prescribing science and clinical aspects of pharmacy have become the main components of pharmacy curriculum. In order to incorporate all these changes, naturally, the fundamental science compo- nents, e.g. chemistry, statistics, pharmaceutical biology, microbiology, pharmacognosy and a few other topics, have been reduced remarkably. The impact of these recent changes is more innocuous in the area of pharmaceutical chemistry. As all drugs are chemicals, and pharmacy is mainly about the study of various aspects of drugs, including manufacture, storage, actions and toxicities, metabolisms and managements, chemistry still plays a vital role in pharmacy education. However, the extent at which chemistry used to be taught a couple of decades ago has certainly changed significantly. It has been recognized that while pharmacy students need a solid foundation in chemistry knowledge the extent cannot be the same as chemistry students may need. There are several books on general, organic and natural product chemistry available today, but all of them are written in such a manner that the level is only suitable for undergraduate Chemistry students, not for Pharmacy undergraduates. Moreover, in most modern pharmacy curricula, general, organic and natural product chemistry is taught at the first and second year undergraduate levels only. There are also a limited number of Pharmaceu- tical Chemistry books available to the students, but none of them can meet the demand of the recent changes in pharmacy courses in the developed x PREFACE countries. Therefore, there has been a pressing need for a chemistry text covering the fundamentals of general, organic and natural product chemistry written at a correct level for the Pharmacy undergraduates. Physical (Preformulation) and Analytical Chemistry (Pharmaceutical Analysis) are generally taught separately at year 2 and year 3 levels of any modern MPharm course, and there are a number of excellent and up-to-date texts available in these areas. During our teaching careers, we have always struggled to find an appropriate book that can offer general, organic and natural product chemistry at the right level for Pharmacy undergraduate students, and address the current changes in pharmacy curricula all over the world, at least in the UK. We have always ended up recommending several books, and also writing notes for the students. Therefore, we have decided to address this issue by compiling a chemistry book for Pharmacy students, which will cover general, organic and natural product chemistry in relation to drug molecules. Thus, the aims of our book are to provide the funda- mental knowledge and overview of all core topics related to general, organic and natural product chemistry currently taught in Pharmacy undergraduate courses in the UK, USA and various other developed countries, relate these topics to the better understanding of drug molecules and their development and meet the demand of the recent changes in pharmacy curricula. This book attempts to condense the essentials of general, organic and natural product chemistry into a manageable, affordable and student-friendly text, by concentrating purely on the basics of various topics without going into exhaustive detail or repetitive examples. In Pharmacy undergraduate courses, especially in the UK, we get students of heterogeneous educational backgrounds; while some of them have very good chemistry background, the others have bare minimum or not at all. From our experience in teaching Pharmacy undergraduate students, we have been able to identify the appropriate level that is required for all these students to learn properly.