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CHEMISTRY
FOR PHARMACY
STUDENTS
­C HEMISTRY
FOR PHARMACY
STUDENTS
General, Organic and
Natural Product Chemistry

Second Edition

LUTFUN NAHAR
Liverpool John Moores University
UK

SATYAJIT SARKER
Liverpool John Moores University
UK
This edition first published 2019
© 2019 John Wiley & Sons Ltd

Edition History
1e published 2007, ISBN 9780470017807

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 law. Advice
on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions.

The right of Lutfun Nahar and Satyajit Sarker to be identified as the authors of this work has been asserted in accor-
dance with law.

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Library of Congress Cataloging-in-Publication Data

Names: Nahar, Lutfun, author. | Sarker, Satyajit, author.

Title: Chemistry for pharmacy students : general, organic and natural
product chemistry / Lutfun Nahar (Liverpool John Moores University, UK),
Satyajit Sarker (Liverpool John Moores University, UK).
Description: Second edition. | Hoboken, NJ : Wiley, 2019. | Includes index. |
Identifiers: LCCN 2019009751 (print) | LCCN 2019016343 (ebook) | ISBN
9781119394464 (Adobe PDF) | ISBN 9781119394488 (ePub) | ISBN 9781119394433
(pbk.)
Subjects: LCSH: Chemistry–Textbooks. | Pharmaceutical chemistry–Textbooks.
Classification: LCC QD31.3 (ebook) | LCC QD31.3 .S377 2020 (print) | DDC
540–dc23
LC record available at https://lccn.loc.gov/2019009751

Cover Design: Wiley

Cover Images: © fotohunter /iStock/Getty Images Plus, © Elena Elisseeva/Getty Images, © Thomas Northcut/Getty
Images, © REB Images/Getty Images

Set in 9/13pts Ubuntu by SPi Global, Chennai, India

10 9 8 7 6 5 4 3 2 1
Dedicated to pharmacy students, from home
and abroad
Contents
Preface to the second edition xv
Preface to the first edition xvii
Chapter 1: Introduction 1
1.1 ­ ole of Chemistry in Modern Life
R 1
1.2 ­Solutions and Concentrations 4
1.3 ­Suspension, Colloid and Emulsion 6
1.4 ­Electrolytes, Nonelectrolytes and Zwitterions 7
1.5 ­Osmosis and Tonicity 8
1.6 ­Physical Properties of Drug Molecules 10
1.6.1 Physical State 10
1.6.2 Melting Point and Boiling Point 10
1.6.3 Polarity and Solubility 11
1.7 ­Acid–Base Properties and pH 13
1.7.1 Acid–Base Definitions 14
1.7.2 Electronegativity and Acidity 18
1.7.3 Acid–Base Properties of Organic Functional Groups 19
1.7.4 pH, pOH and pKa Values 22
1.7.5 Acid–Base Titration: Neutralization 30
1.8 ­Buffer and its Use 32
1.8.1 Common Ion Effects and Buffer Capacity 34

Chapter 2: Atomic Structure and Bonding 37

2.1 A­ toms, Elements and Compounds 37
2.2 ­Atomic Structure: Orbitals and Electronic Configurations 39
2.3 ­Chemical Bonding Theories: Formation of Chemical Bonds 43
2.3.1 Lewis Structures 43
2.3.2 Resonance and Resonance Structures 47
2.3.3 Electronegativity and Chemical Bonding 48
2.3.4 Various Types of Chemical Bonding 49
2.4 ­Bond Polarity and Intermolecular Forces 54
2.4.1 Dipole–Dipole Interactions 54
2.4.2 van der Waals Forces 55
2.4.3 Hydrogen Bonding 56
2.5 ­Hydrophilicity and Lipophilicity 57
2.6 ­Significance of Chemical Bonding in Drug–Receptor Interactions 60

vii
 2.7 S­ ignificance of Chemical Bonding in Protein–Protein Interactions 63
2.8 ­Significance of Chemical Bonding in Protein–DNA Interactions 63

Chapter 3: Stereochemistry 65
3.1 S­ tereochemistry: Definition 66
3.2 ­Isomerism 66
3.2.1 Constitutional Isomers 66
3.2.2 Stereoisomers 67
3.3 ­Stereoisomerism of Molecules with More than One Stereocentre 82
3.3.1 Diastereomers and Meso Structures 82
3.3.2 Cyclic Compounds 84
3.3.3 Geometrical Isomers of Alkenes and Cyclic Compounds 85
3.4 ­Significance of Stereoisomerism in Determining Drug Action and Toxicity 88
3.5 ­Synthesis of Chiral Molecules 91
3.5.1 Racemic Forms 91
3.5.2 Enantioselective Synthesis 92
3.6 ­Separation of Stereoisomers: Resolution of Racemic Mixtures 93
3.7 ­Compounds with Stereocentres Other than Carbon 94
3.8 ­Chiral Compounds that Do Not Have Four Different Groups 94

Chapter 4: Organic Functional Groups 97

4.1 O­ rganic Functional Groups: Definition and Structural Features 97
4.2 ­Hydrocarbons 100
4.3 ­Alkanes, Cycloalkanes and Their Derivatives 100
4.3.1 Alkanes 100
4.3.2 Cycloalkanes 108
4.3.3 Alkyl Halides 111
4.3.4 Alcohols 119
4.3.5 Ethers 125
4.3.6 Thiols 129
4.3.7 Thioethers 131
4.3.8 Amines 134
4.4 ­Carbonyl Compounds 140
4.4.1 Aldehydes and Ketones 140
4.4.2 Carboxylic acids 148
4.4.3 Acid Chlorides 154
4.4.4 Acid Anhydrides 155
4.4.5 Esters 157
4.4.6 Amides 160
4.4.7 Nitriles 163
4.5 ­Alkenes and their Derivatives 164
4.5.1 Nomenclature of Alkenes 165
4.5.2 Physical Properties of Alkenes 166

viii Contents
 4.5.3 Structure of Alkenes 167
4.5.4 Industrial uses of Alkenes 167
4.5.5 Preparations of Alkenes 168
4.5.6 Reactivity and Stability of Alkenes 168
4.5.7 Reactions of Alkenes 169
4.6 ­Alkynes and their Derivatives 169
4.6.1 Nomenclature of Alkynes 170
4.6.2 Structure of Alkynes 170
4.6.3 Acidity of Terminal Alkynes 171
4.6.4 Heavy Metal Acetylides: Test for Terminal Alkynes 171
4.6.5 Industrial Uses of Alkynes 172
4.6.6 Preparations of Alkynes 172
4.6.7 Reactions of Alkynes 172
4.6.8 Reactions of Metal Alkynides 174
4.7 Aromatic Compounds and their Derivatives 174
4.7.1 History 175
4.7.2 Definition: Hückel’s Rule 175
4.7.3 General Properties of Aromatic Compounds 175
4.7.4 Classification of Aromatic Compounds 176
4.7.5 Pharmaceutical importance of Aromatic
Compounds: Some Examples 177
4.7.6 Structure of Benzene: Kekulé Structure of Benzene 179
4.7.7 Nomenclature of Benzene Derivatives 183
4.7.8 Electrophilic Substitution of Benzene 184
4.7.9 Alkylbenzene: Toluene 190
4.7.10 Phenols 192
4.7.11 Aromatic Amines: Aniline 199
4.7.12 Polycyclic Benzenoids 207
4.8 Importance of Functional Groups in Determining Drug
Actions and Toxicity 209
4.8.1 Structure-Activity Relationships of Sulpha Drugs 210
4.8.2 Structure-Activity Relationships of Penicillins 211
4.8.3 Paracetamol Toxicity 213
4.9 ­Importance of Functional Groups in Determining
Stability of Drugs 213

Chapter 5: Organic Reactions 215

5.1 T­ ypes of Organic Reactions Occur with Functional Groups 215
5.2 ­Reaction Mechanisms and Types of Arrow in Chemical Reactions 216
5.3 ­Free Radical Reactions: Chain Reactions 217
5.3.1 Free Radical Chain Reaction of Alkanes 217
5.3.2 Relative Stabilities of Carbocations, Carbanions, Radicals
and Carbenes 219

Contents ix
 5.3.3 Allylic Bromination 221
5.3.4 Radical Inhibitors 222
5.4 ­Addition Reactions 223
5.4.1 Electrophilic Additions to Alkenes and Alkynes 223
5.4.2 Symmetrical and Unsymmetrical Addition to Alkenes and Alkynes 226
5.4.3 Nucleophilic Addition to Aldehydes and Ketones 240
5.5 ­Elimination Reactions: 1,2-Elimination or β-Elimination 254
5.5.1 E1 Reaction or First Order Elimination 255
5.5.2 E2 Reaction or Second Order Elimination 256
5.5.3 Dehydration of Alcohols 257
5.5.4 Dehydration of Diols: Pinacol Rearrangement 259
5.5.5 Base-Catalysed Dehydrohalogenation of Alkyl Halides 260
5.6 ­Substitution Reactions 265
5.6.1 Nucleophilic Substitutions 266
5.6.2 Nucleophilic Substitutions of Alkyl Halides 273
5.6.3 Nucleophilic Substitutions of Alcohols 276
5.6.4 Nucleophilic Substitutions of Ethers and Epoxides 282
5.6.5 Nucleophilic Acyl Substitutions of Carboxylic Acid Derivatives 286
5.6.6 Substitution Versus Elimination 293
5.7 ­Electrophilic Substitutions 294
5.7.1 Electrophilic Substitution of Benzene 294
5.8 ­Hydrolysis 300
5.8.1 Hydrolysis of Carboxylic Acid Derivatives 300
5.9 Oxidation–Reduction Reactions 305
5.9.1 Oxidizing and Reducing Agents 305
5.9.2 Oxidation of Alkenes 305
5.9.3 Oxidation of Alkynes 307
5.9.4 Hydroxylation of Alkenes 307
5.9.5 Oxidative Cleavage of syn-Diols 308
5.9.6 Ozonolysis of Alkenes 308
5.9.7 Ozonolysis of Alkynes 309
5.9.8 Oxidation of Alcohols 309
5.9.9 Oxidation of Aldehydes and Ketones 311
5.9.10 Baeyer–Villiger Oxidation of Aldehydes or Ketones 312
5.9.11 Reduction of Alkyl Halides 312
5.9.12 Reduction of Organometallics 312
5.9.13 Reduction of Alcohols via Tosylates 313
5.9.14 Reduction of Aldehydes and Ketones 313
5.9.15 Clemmensen Reduction 315
5.9.16 Wolff–Kishner Reduction 316
5.9.17 Reduction of Acid Chlorides 316
5.9.18 Reduction of Esters 317

x Contents
 5.9.19 Hydride Reduction of Carboxylic Acids 318
5.9.20 Reduction of Oximes or Imine Derivatives 318
5.9.21 Reduction of Amides, Azides and Nitriles 319
5.9.22 Reductive Amination of Aldehydes and Ketones 320
5.10 ­Pericyclic Reactions 320
5.10.1 Diels–Alder Reaction 320
5.10.2 Essential Structural Features for Dienes and Dienophiles 321
5.10.3 Stereochemistry of the Diels–Alder Reaction 322
5.10.4 Sigmatropic Rearrangements 323
5.10.5 Hydrogen Shift 323
5.10.6 Alkyl Shift: Cope Rearrangement 324
5.10.7 Claisen Rearrangement 324

Chapter 6: Heterocyclic Compounds 327

6.1 H­ eterocyclic Compounds and their Derivatives 327
6.1.1 Medicinal Importance of Heterocyclic Compounds 328
6.1.2 Nomenclature of Heterocyclic Compounds 329
6.1.3 Physical Properties of Heterocyclic Compounds 331
6.2 ­P yrrole, Furan and Thiophene: Unsaturated Heterocycles 332
6.2.1 Physical Properties of Pyrrole, Furan and Thiophene 333
6.2.2 Preparations of Pyrrole, Furan and Thiophene 333
6.2.3 Reactions of Pyrrole, Furan and Thiophene 335
6.3 ­P yridine 339
6.3.1 Physical Properties of Pyridine 339
6.3.2 Preparations of Pyridine 340
6.3.3 Reactions of Pyridine 340
6.4 ­Oxazole, Imidazole and Thiazole 342
6.4.1 Physical Properties of Oxazole, Imidazole and Thiazole 343
6.4.2 Preparations of Oxazole, Imidazole and Thiazole 344
6.4.3 Reactions of Oxazole, Imidazole and Thiazole 345
6.5 ­Isoxazole, Pyrazole and Isothiazole 346
6.5.1 Physical Properties of Isoxazole, Pyrazole and Isothiazole 348
6.5.2 Preparations of Isoxazole, Pyrazole and Isothiazole 348
6.5.3 Reactions of Isoxazole, Pyrazole and Isothiazole 348
6.6 ­P yrimidine 349
6.6.1 Physical Properties of Pyrimidine 350
6.6.2 Preparations of Pyrimidine 350
6.6.3 Reactions of Pyrimidine 351
6.7 ­Purine 352
6.7.1 Physical Properties of Purine 353
6.7.2 Preparations of Purine 353
6.7.3 Reactions of Purine 353

Contents xi
 6.8 Q­ uinoline and Isoquinoline 354
6.8.1 Physical Properties of Quinoline and Isoquinoline 354
6.8.2 Preparations of Quinoline and Isoquinoline 355
6.8.3 Reactions of Quinoline and Isoquinoline 357
6.9 ­Indole 358
6.9.1 Physical Properties of Indole 359
6.9.2 Preparations of Indole 359
6.9.3 Reactions of Indole 360
6.9.4 Test for Indole 361

Chapter 7: Nucleic Acids 363

7.1 N­ ucleic Acids 363
7.1.1 Synthesis of Nucleosides and Nucleotides 365
7.1.2 Structure of Nucleic Acids 366
7.1.3 Nucleic Acids and Heredity 370
7.1.4 DNA Fingerprinting 373
7.2 ­Amino Acids and Peptides 373
7.2.1 Fundamental Structural Features of an Amino acid 376
7.2.2 Essential Amino Acids 376
7.2.3 Glucogenic and Ketogenic Amino Acids 377
7.2.4 Amino Acids in Human Body 377
7.2.5 Acid–Base Properties of Amino Acids 378
7.2.6 Isoelectric Points of Amino Acids and Peptides 378

Chapter 8: Natural Product Chemistry 381

8.1 I­ ntroduction to Natural Products 381
8.1.1 Natural Products 381
8.1.2 Natural Products in Medicine 382
8.1.3 Drug Discovery and Natural Products 385
8.2 ­Alkaloids 390
8.2.1 Properties of Alkaloids 391
8.2.2 Classification of Alkaloids 391
8.2.3 Tests for Alkaloids 410
8.3 ­Carbohydrates 410
8.3.1 Classification of Carbohydrates 411
8.3.2 Stereochemistry of Sugars 414
8.3.3 Cyclic Structures of Monosaccharides 415
8.3.4 Acetal and Ketal Formation in Sugars 416
8.3.5 Oxidation, Reduction, Esterification and Etherification
of Monosaccharides 417
8.3.6 Pharmaceutical Uses of Monosaccharides 420
8.3.7 Disaccharides 420
8.3.8 Polysaccharides 423

xii Contents
 8.3.9 Miscellaneous Carbohydrates 426
8.3.10 Cell Surface Carbohydrates and Blood Groupings 428
8.4 ­Glycosides 429
8.4.1 Biosynthesis of Glycosides 430
8.4.2 Classification 430
8.4.3 Test for Hydrocyanic Acid (HCN) 432
8.4.4 Pharmaceutical Uses and Toxicity 432
8.4.5 Anthracene/Anthraquinone Glycosides 433
8.4.6 Isoprenoid Glycosides 436
8.4.7 Iridoid and Secoiridoid Glycosides 440
8.5 ­Terpenoids 442
8.5.1 Classification 442
8.5.2 Biosynthesis of Terpenoids 443
8.5.3 Monoterpenes 445
8.5.4 Sesquiterpenes 446
8.5.5 Diterpenes 455
8.5.6 Triterpenes 461
8.5.7 Tetraterpenes 465
8.6 ­Steroids 466
8.6.1 Structures of Steroids 467
8.6.2 Stereochemistry of Steroids 468
8.6.3 Physical Properties of Steroids 468
8.6.4 Types of Steroid 469
8.6.5 Biosynthesis of Steroids 471
8.6.6 Synthetic Steroids 472
8.6.7 Functions of Steroids 473
8.7 ­Phenolics 476
8.7.1 Phenylpropanoids 477
8.7.2 Coumarins 478
8.7.3 Flavonoids and Isoflavonoids 481
8.7.4 Lignans 486
8.7.5 Tannins 489

Index 493

Contents xiii
Preface
to the second
edition
The first edition of Chemistry for Pharmacy Students: General, Organic and Natural
Product Chemistry was written to address the need for the right level and appro-
priate coverage of chemistry in any modern Pharmacy curricula. The first edition
reflected on the changing face of Pharmacy profession and the evolving role of
pharmacists in the modern healthcare systems, and was aimed at placing chem-
istry more in the context of medicines and patients. Since the publication in 2007,
in subsequent years, the first edition has been translated into the Greek, Japanese
and Portuguese languages, and has acclaimed huge acceptance and popularity
among Pharmacy students, as well as among academics who teach chemistry in
Pharmacy curricula all over the world.
It has been over a decade since the publication of the first edition. We feel
that it has now become necessary to compile a second edition, which should be a
thoroughly revised and enhanced version of the first. The second edition will also
cater for the chemistry requirements in any ‘Integrated Pharmacy Curricula’, where
science in general is meant to be taught ‘not in isolation’, but together with, and
as a part of, other practice and clinical elements of Pharmacy curricula. Whatever
may be the structure and content of any Pharmacy curriculum, there will always be
two fundamental aspects in it – medicines (drugs) and patients.
Pharmacy began its journey as a medicine (drug)-focused science subject but,
over the years, it has evolved as a more patient-focused subject. Irrespective of
the focus, the need for chemistry knowledge and understanding in any Pharmacy
curricula cannot be over-emphasized. We know that all drugs are chemicals. The
ways any drug exerts its pharmacological actions and also toxicity in a patient are
governed by a series of biochemical reactions. Therefore, chemistry knowledge
and understanding are fundamental to any Pharmacy programme, which is essen-
tially the study of various aspects of drugs, their applications in patients, patient
care and overall treatment outcome.
Like the first edition, this revised, reorganized and significantly enhanced sec-
ond edition covers all core topics related to general, organic and natural product
chemistry currently taught in Pharmacy undergraduate curricula in the UK, USA

xv
 and various other developed countries, and relates these topics to drug molecules,
their development and their fate once given to patients. While the second edition
still provides a concise coverage of the essentials of general, organic and natural
product chemistry into a manageable, affordable and student-friendly text, by con-
centrating purely on the basics of various topics without going into exhaustive
detail or repetitive examples, the first chapter, which deals with various properties
of drug molecules, has been significantly ‘beefed up’ in this second edition. Gen-
erally, the contents of the second edition are organized and dealt with in a similar
way, to the first to ensure that the contents are suitable for year 1 (level 4) and
year 2 (level 5) levels of most of the Pharmacy curricula. Theoretical aspects have
been covered in the context of applications of these theories in relation to drug
molecules, their discovery and developments.
Chapter 1 presents an account of general aspects of chemistry and their contri-
butions to modern life, with particular emphasis on modern medicine and discus-
sions on various important properties of drug molecules, for example, pH, polarity
and solubility; it also covers some related fundamental concepts like electrolytes,
zwitterion, osmosis, tonicity and so on. Chapter 2 incorporates the fundamentals
of atomic structure and bonding and discusses the relevance of chemical bonding
in drug molecules and drug–receptor interactions, while Chapter 3 covers key
aspects of stereochemistry with particular focus given on the significance of ste-
reoisomerism in determining drug action and toxicity. Chapter 4 deals with organic
functional groups, their preparations, reactions and applications. All major types
of organic reactions and their importance in drug discovery, development, delivery
and metabolism in patient’s body are outlined in Chapter 5. Chapter 6 is about het-
erocyclic compounds; their preparations, reactions and applications. While nucleic
acids are covered in Chapter 7, various aspects of natural products including the
origins, chemistry, biosynthesis and pharmaceutical importance of alkaloids, car-
bohydrates, glycosides, iridoids and secoiridoids, phenolics, steroids and terpe-
noids are presented in Chapter 8.
Although the primary readership of the second edition still remains to be the
Pharmacy undergraduate students (BPharm/MPharm), especially in their first and
second years of study, further readership can come from the students of various
other subject areas within Biomedical Science and the Food Sciences, Life Sciences
and Health Sciences, where the basic chemistry knowledge is essential for their
programmes.
Dr Lutfun Nahar
Professor Satyajit Sarker

xvi Preface to the second edition

­Preface
to the first
edition
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 profession is now as much about keeping people healthy
as treating them when they are not well. Modern pharmacy profession is shift-
ing 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, pharmacy
curriculum, especially in the developed world, has evolved significantly. In the west-
ern 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 compo-
nents of pharmacy curriculum. In order to incorporate all these changes, naturally,
the fundamental science components, 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, metabo-
lisms 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 remarkably. It has been recognised that, while pharmacy
students need a solid foundation in chemistry knowledge, the extent cannot be
the same as the chemistry students may need.
There are several books on general, organic and natural product chemistry
available today, but all of them are written in a manner that the level is only suit-
able for undergraduate Chemistry students, not for Pharmacy undergraduates.
Moreover, in most modern pharmacy curricula, general, organic and natural prod-
ucts chemistry is taught at the first and second year undergraduate levels only.
There are also a limited number of Pharmaceutical Chemistry books available to

xvii
 the students, but none of them can meet the demand of the recent changes in
Pharmacy courses in the developed countries. Therefore, there has been a press-
ing need for a chemistry text covering the fundamentals of general, organic and
natural products chemistry written at a correct level for the Pharmacy undergrad-
uates. Physical (Preformulation) and Analytical Chemistry (Pharmaceutical Anal-
ysis) 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 products 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 rela-
tion to drug molecules. Thus, the aims of our book are to provide the fundamental
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 var-
ious 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 the 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. While we recognise that learning styles and levels vary from student
to student, we can still try to strike the balance in terms of the level and stan-
dard at a point, which is not too difficult or not too easy for any students, but
will certainly be student-friendly. Bearing this in mind, the contents of this book
are organised and dealt with in a way that they are suitable for year 1 and year 2
levels of pharmacy curriculum. While the theoretical aspects of various topics are
covered adequately, much focus has been given to the applications of these the-
ories in relation to drug molecules, their discovery and developments. Chapter 1
provides an overview of some general aspects of chemistry and their importance
in modern life, with particular emphasis on medicinal applications, and brief dis-
cussions on various physical characteristics of drug molecules, e.g. pH, polarity,
and solubility. While Chapter 2 deals with the fundamentals of atomic structure
and bonding, Chapter 3 covers various aspects of stereochemistry. Chapter 4
incorporates organic functional groups, and various aspects of aliphatic, aromatic

xviii ­Preface to the first editio

and heterocyclic chemistry, amino acids, nucleic acids and their pharmaceutical
importance. Major organic reactions are covered adequately in Chapter 5, and
various types of pharmaceutically important natural products are discussed in
Chapter 6.
While the primary readership of this book is the pharmacy undergraduate stu-
dents (BPharm/MPharm), especially in their first and second year of study, the
readership could also extend to the students of various other subject areas within
Food Sciences, Life Sciences and Health Sciences who are not becoming chemists,
yet they need to know the fundamentals of chemistry for their courses.
Dr Satyajit Sarker
Dr Lutfun Nahar

­Preface to the first editio xix

Chapter 1
Introduction
Learning Objectives
After completing this chapter, students should be able to
•• describe the role of chemistry in modern life;
•• define some of the physical properties of drugs, for example, melting point,
boiling point, polarity, solubility and acid-base properties;
•• explain the terms pH, pKa, buffer and neutralization.

1.1 ­R OLE OF CHEMISTRY IN MODERN LIFE

Chemistry is the science of the composition, structure, properties and reactions of
matters, especially of atomic and molecular systems.
Life itself is full of chemistry, that is, life is the reflection of a series of contin-
uous biochemical processes. Right from the composition of the cell to the whole
organism, the presence of chemistry is conspicuous. Human beings are physically
constructed of chemicals, live in a plethora of chemicals and are dependent on
chemicals for their quality of modern life. All living organisms are composed of
numerous organic substances. Evolution of life begins from one single organic
compound called a nucleotide. Nucleotides join together to form the building
blocks of life. Our identities, heredities and continuation of generations, all are
governed by chemistry.
In our everyday life, whatever we see, use or consume have been the gifts of
research in chemistry for thousands of years. In fact, chemistry is applied every-
where in modern life. From the colour of our clothes to the shapes of our PCs,

Chemistry for Pharmacy Students: General, Organic and Natural Product Chemistry,
Second Edition. Lutfun Nahar and Satyajit Sarker.
© 2019 John Wiley & Sons Ltd. Published 2019 by John Wiley & Sons Ltd.
 all are possible due to chemistry. It has played a major role in pharmaceutical
advances, forensic science and modern agriculture. Diseases and their remedies
have also been a part of human lives. Chemistry plays an important role in under-
standing diseases and their remedies; that is, drugs.
Medicines or drugs that we take for the treatment of various ailments are chem-
icals, either organic or inorganic molecules. However, most drugs are organic mole-
cules. These molecules are either obtained from natural sources or synthesized in
chemistry laboratories. Some important drug molecules are discussed here.
Aspirin, an organic molecule, is chemically known as acetyl salicylic acid and
is an analgesic (relieves pain), antipyretic (reduces fever) and anti-inflammatory
(reduces swelling) drug. Studies suggest that aspirin can also reduce the risk
of heart attack. It is probably the most popular and widely used analgesic drug
because of its structural simplicity and low cost. Salicin is the precursor of aspirin.
It is found in the willow tree bark, whose medicinal properties have been known
since 1763. Aspirin was developed and synthesized in order to avoid the irritation
in the stomach caused by salicylic acid, which is also a powerful analgesic, derived
from salicin. In fact, salicin is hydrolysed in the gastrointestinal tract to produce
D-glucose and salicyl alcohol (see Section 8.4). Salicyl alcohol, on absorption, is
oxidized to salicylic acid and other salicylates. However, aspirin can easily be syn-
thesized from phenol using the Kolbe reaction (see Section 4.7.10.6).

OH OH O OH O OH

O-Glucosyl OH OH O
O

Salicin Salicyl alcohol Salicylic acid Aspirin

(A precursor of aspirin) Acetyl salicylic acid

Paracetamol (acetaminophen), an N-acylated aromatic amine having an acyl

group (R─CO─) substituted on nitrogen, is an important over-the-counter head-
ache remedy. It is a mild analgesic and antipyretic medicine. The synthesis of
paracetamol involves the reaction of p-aminophenol and acetic anhydride (see
Section 4.7.10.6).

O
H
OH N

NH2 OH
4-Aminophenol Paracetamol
Acetaminophen

L-Dopa (L-3,4-dihydroxyphenylalanine), an amino acid, is a precursor of the

neurotransmitters dopamine, norepinephrine (noradrenaline) and epinephrine

2 Chemistry for Pharmacy Students

(adrenaline), collectively known as catecholamines, and found in humans as well
as in some animals and plants. It has long been used as a treatment for Parkinson’s
disease and other neurological disorders. L-Dopa was first isolated from the seed-
lings of Vicia faba (broad bean) by Marcus Guggenheim in 1913, and later it was
synthesized in the lab for pharmaceutical uses.

COOH
HO
CH2 C
H
NH2
O
OH N
H
OH HO H CH3
(L)-Dopa Morphine
(The precursor of dopamine)

Morphine is a naturally occurring opiate analgesic found in opium and is a strong

pain reliever, classified as a narcotic analgesic (habit-forming) (see Section 8.2.2.5).
Opium is the dried latex obtained from the immature poppy (Papaver somniferum)
seeds. Morphine is widely used in clinical pain management, especially for pain
associated with terminal cancers and post-surgery pain.
Penicillin V (phenoxymethylpenicillin), an analogue of the naturally occurring
penicillin G (see Section 7.3.2), is a semisynthetic narrow-spectrum antibiotic use-
ful for the treatment of bacterial infections. Penicillin V is quite stable even in high
humidity and strong acidic medium (e.g. gastric juice). However, it is not active
against beta-lactamase-producing bacteria. As we progress through various chap-
ters of this book, we will come across a series of other examples of drug molecules
and their properties.

H H
H H H H
N N S
S O
N O N
O O
O
COOH H
COOH
Penicillin G Penicillin V
(The first penicillin of the penicillin Phenoxymethylpenicillin
group of antibiotics)

In order to have proper understanding and knowledge about these drugs

and their behaviour, there is no other alternative but to learn chemistry.
Everywhere, from discovery to development, from production and storage to
administration, and from desired actions to adverse effects of drugs, chemistry
is directly involved.
In the drug discovery stage, suitable sources of potential drug molecules are
explored. Sources of drug molecules can be natural, such as a narcotic ­analgesic,
morphine, from P. somniferum (poppy plant), synthetic, such as a popular

Chapter 1: Introduction 3
 ­ nalgesic and antipyretic, paracetamol, and semisynthetic, such as penicillin
a
V. Whatever the source is, chemistry is involved in all processes in the discovery
phase. For example, if a drug molecule has to be purified from a natural source,
for example, plant, the processes like extraction, isolation and identification are
used, and all these processes involve chemistry (see Section 8.1.3.1).
Similarly, in the drug development steps, especially in pre-formulation and for-
mulation studies, the structures and the physical properties (e.g. solubility and
pH), of the drug molecules are exploited. Chemistry, particularly physical prop-
erties of drugs, is also important to determine storage conditions. Drugs having
an ester functionality, for example, aspirin, could be quite unstable in the presence
of moisture and should be kept in a dry and cool place. The chemistry of drug mol-
ecules dictates the choice of the appropriate route of administration. Efficient
delivery of drug molecules to the target sites requires manipulation of various
chemical properties and processes; for example, microencapsulation, nanopar-
ticle-aided delivery and so on. When administered, the action of a drug inside
our body depends on its binding to the appropriate receptor and its subsequent
metabolic processes, all of which involve complex enzyme-driven biochemical
reactions.
All drugs are chemicals, and pharmacy is a subject that deals with the study of
various aspects of drugs. Therefore, it is needless to say that to become a good
pharmacist the knowledge of the chemistry of drugs is essential. Before moving on
to the other chapters, let us try to understand some of the fundamental chemical
concepts in relation to the physical properties of drug molecules (see Section 1.6).

1.2 ­S OLUTIONS AND CONCENTRATIONS

A solution is a mixture where a solute is uniformly distributed within a solvent.
A solute is the substance that is present in smaller quantities and a solvent usually
the component that is present in greater quantity. Simply, a solution is a special
type of homogenous mixture composed of two or more substances. For example,
sugar (solute) is added to water (solvent) to prepare sugar solution. Similarly,
saline (solution) is a mixture of sodium chloride (NaCl) (solute) and water (solvent).
Solutions are extremely important in life as most chemical reactions, either in lab-
oratories or in living organisms, take place in solutions.
Ideally, solutions are transparent and light can pass through the solutions. If
the solute absorbs visible light, the solution will have a colour. We are familiar with
liquid solutions, but a solution can also be in any state, such as solid, liquid or gas.
For example, air is a solution of oxygen, nitrogen and a variety of other gases all
in the gas state; steel is also a solid-state solution of carbon and iron. Solutes may
be crystalline solids, such as sugars and salts that dissolve readily into solutions,
or colloids, such as large protein molecules, which do not readily dissolve into solu-
tions (see Section 1.3).

4 Chemistry for Pharmacy Students

 In Chemistry, especially in relation to drug molecules, their dosing,
therapeutic efficacy, adverse reactions and toxicity, we often come across with
the term concentration, which can simply be defined as the amount of solute
per unit of solvent. Concentration is always the ratio of solute to solvent and
it can be expressed in many ways. The most common method of expressing the
concentration is based on the amount of solute in a fixed amount of solution
where the quantities can be expressed in weight (w/w), in volume (v/v) or both
(w/v). For example, a solution containing 10 g of NaCl and 90 g of water is a 10%
(w/w) aqueous solution of NaCl.
Weight measure (w/w) is often used to express concentration and is commonly
known as percent concentration (parts per 100), as shown in the previous example
of 10% NaCl aqueous solution. It is the ratio of one part of solute to one hundred
parts of solution. To calculate percent concentration, simply divide the mass of
the solute by the total mass of the solution, and then multiply by 100. Percent
concentration also can be displayed, albeit not so common, as parts per thousand
(ppt) for expressing concentrations in grams of solute per kilogram of solution. For
more diluted solutions, parts per million (ppm), which is the ratio of parts of solute
to one million parts of solution, is often used. To calculate ppm, divide the mass
of the solute by the total mass of the solution, and then multiply by 106. Grams per
litre is the mass of solute divided by the volume of solution in litres. The ppt and
ppm can be either w/w or w/v.
Molality of a solution is the number of moles of a solute per kilogram of solvent,
while molarity of a solution is the number of moles of solute per litre of solution.
Molarity (M) is the most widely used unit for concentration. The unit of molarity is
mol/l or M. One mole is equal to the molecular weight (MW) of the solute in grams.
For example, the MW of glucose is 180. To prepare a 1 M solution of glucose, one
should add 180 g of glucose in a 1.0 l volumetric flask and then fill the flask with
distilled water to a total volume of 1.0 l. Note that molarity is defined in terms of
the volume of the solution, not the volume of the solvent. Sometimes, the term
normality (N), which can be defined as the number of mole equivalents per litre
of solution, is also used, especially for various acids and bases, to express the
concentration of a solution. Like molarity, normality relates the amount of solute
to the total volume of solution. The mole equivalents of an acid or base are calcu-
lated by determining the number of H+ or HO − ions per molecule: N = n × M (where n
is an integer). For an acid solution, n is the number of H+ ions provided by a formula
unit of acid. For example, a 3 M H2SO4 solution is the same as a 6 N H2SO4 solution.
For a basic solution, n is the number of HO − ions provided by a formula unit of base.
For example, a 1 M Ca(OH)2 solution is the same as a 2 N Ca(OH)2 solution. Note that
the normality (N) of a solution is never less than its molarity.
A concentrated solution has a lot of solute per solvent, a diluted solution has a
lot of solvent, a saturated solution has maximum amount of solute, and a super-
saturated solution has more solute than it can hold. Supersaturated solutions are
relatively unstable, and solute tends to precipitate out of the mixture to form

Chapter 1: Introduction 5
 crystals, resulting in a saturated solution. The equilibrium of a solution depends
on the temperature.
A stock solution is prepared with a known concentration, from which a diluted
solution can be made. The process of adding more solvent to a solution or removing
some of the solute is called dilution. In other words, dilution is the process of
reducing the concentration of a solute in solution, usually simply by mixing with
more solvent. Any unit can be used for both volume and concentration as long as
they are the same on both sides of the equation. The concentration of the diluted
solution can easily be calculated from the following equation:

C1V1 C2V2

Where, C1 and C2 are the initial and final concentrations and V1 and V 2 are the initial
and final volumes of the solution.
A serial dilution, often used in various in vitro assays, is simply a series of simple
dilutions. Serial dilutions are made in increments of 1000 (103), 100 (102), 10 (10-
fold) or 2 (twofold), but 10-fold and twofold serial dilutions are commonly used.
Serial dilutions are an accurate method of making solutions of low molar concen-
trations. The first step in making a 10-fold serial dilution is to take stock solution
(1 ml) in a tube and then to add distilled water (9 ml) or other suitable solvents. For
making a twofold serial dilution one should take stock solution (1 ml) in a tube and
then add distilled water (1 ml) or other suitable solvents.

1.3 ­S USPENSION, COLLOID AND EMULSION

A suspension is a heterogeneous mixture between two substances one of which is
finely dispersed into the other. Note that in a suspension, the solute particles do
not dissolve, but are suspended throughout the bulk of the solvent. Most common
suspensions include sand in water, dust in air and droplets of oil in air. The size of
the particles is large enough (more than 1 μm) to be visible to the naked eye. In
suspension, particles are so large that they settle out of the solvent if not con-
stantly stirred. Therefore, it is possible to separate particles in any suspension
through filtration. A suspension of liquid droplets or fine solid particles in a gas
is called an aerosol. In relation to the atmosphere, the suspended particles, for
example, fine dust and soot particles, sea salt, biogenic and volcanogenic sul-
phates, nitrates and cloud droplets, are called particulates.
A colloid is a mixture, where microscopically dispersed insoluble particles
(10–1000 nm) of one substance are evenly suspended throughout another sub-
stance indefinitely. Note that to quality as a colloid, the mixture must not settle.
Like a suspension, a colloid consists of two separate phases, a dispersed phase
(solute) and a dispersing medium (continuous phase or solvent). Colloidal particles
consist of small particles of one substance dispersed in a continuous phase of a
different composition, known as colloidal dispersions. The properties of colloids

6 Chemistry for Pharmacy Students

and ­solutions are different due to their particle size. A colloidal dispersion, for
example, milk, is not a true solution but it is not a suspension either, because it
does not settle out on standing over time like a suspension.
Colloidal particles can be studied by various methods, for example, diffusion,
electrophoresis and scattering of visible light and X-rays. There are several types
of colloids, and the most popular one is called colloidal solution, where the solid
forms the dispersed phase and the liquid forms the dispersion medium. The par-
ticles of the dispersed phase in a colloidal solution are known as colloidal particles
or micelles. A gas may be dispersed in a liquid to form a foam (e.g. shaving lather)
or in a solid to form a solid foam (e.g. marshmallow); a liquid may be dispersed in
a gas to form an aerosol (e.g. aerosol spray), in another liquid to form an emulsion
(e.g. mayonnaise) or in a solid to form a gel (e.g. cheese); a solid may be dispersed
in a gas to form a solid aerosol (e.g. smoke in air), in a liquid to form a sol (e.g. ink)
or in a solid to form a solid sol (e.g. certain alloys). Colloids are often purified by
dialysis, which is a slow process.
Colloids are important in drug delivery, as colloidal carriers (e.g. nanoparticles)
are used in controlled or sustained release and site-specific delivery of drugs.
Nanoparticles are solid, colloidal particles consisting of macromolecular substances
that vary in size from 10–1000 nm; they are natural or synthetic polymers. Depend-
ing on the interactions between the dispersed phase and the dispersing medium,
colloidal solutions are classified as lyophilic (solvent loving) and lyophobic (solvent
hating). The colloidal particles are strongly solvated in the dispersing medium of
a lyophilic colloidal solution, for example, emulsion. When water is the dispersing
medium, it is known as hydrophilic. The colloidal particles are not solvated in the
dispersing medium of a lyophobic colloidal solution, such as a suspension. When
water is the dispersing medium, it is called hydrophobic.
An emulsion is an integrated mixture of two immiscible liquids such as oil and
water, stabilized by an emulsifying agent (emulsifier or surfactant). Simply, an
emulsion is a fine dispersion of minute droplets of one liquid in another in which
it is not soluble or miscible. For example, a type of paint used for walls, consisting
of pigment bound in a synthetic resin, which forms an emulsion with water. An
emulsifying agent (emulsifier) is a substance that keeps the parts of an emulsion
mixed together. Water soluble emulsifiers form oil in water (o/w) emulsion, while
oil soluble emulsifiers usually give water in oil (w/o) emulsion. Emulsions are usu-
ally prepared by vigorously shaking the two components together, often with the
addition of an emulsifying agent, in order to stabilize the product formed.

1.4 ­E LECTROLYTES, NONELECTROLYTES

AND ZWITTERIONS
Electrolytes are species that form ions, when dissolved in water and commonly
exist as solutions of acids, bases or salts. They are essential minerals in the body,

Chapter 1: Introduction 7
Another random document with
no related content on Scribd:
JESUS, Discovery of a fragment of the Logia or Sayings of.

See (in this volume)

ARCHÆOLOGICAL RESEARCH: EGYPT: DISCOVERY OF A
FRAGMENT.

----------JEWS: Start--------

JEWS:
Discovery of the sole mention of the people of Israel in
Egyptian inscriptions.

See (in this volume)

ARCHÆOLOGICAL RESEARCH: EGYPT: RESULTS.

JEWS:
General results of recent archæological research as affecting
our knowledge of the ancient Hebrews.

See (in this volume)

ARCHÆOLOGICAL RESEARCH: IN BIBLE LANDS.

JEWS: A. D. 1897:
Freedom of residence in Russia given
to the university educated.

See (in this volume)

RUSSIA: A. D. 1897.

JEWS: A. D. 1897-1901.
The Zionist movement.

"The three closing days of August [1897] saw a congress at

Basle concerning the significance of which friends and foes
alike seem already pretty well agreed. It was the Congress of
Zionists. Zionists! Until then that word was almost unknown to
the public at large. Zionism virtually made its bow to the
Gentile world at Basle, and disclosed for the first time what
its aims and its needs were. … It was in my work, 'The Jewish
State,' which appeared a year and a half ago, that I first
formulated what the Congress at Basle virtually adopted as an
axiom. In the terms of that definition: 'Zionism has for its
object the creation of a home, secured by public rights, for
those Jews who either cannot or will not be assimilated in the
country of their adoption.'

"Nothing was more instructive at the Basle Congress than the

vigour—I might almost say violence—with which the
representatives of the great Jewish strata of population
resisted any attempt to limit the guarantees for a State based
on public rights. The executive appointed to draw up a
programme had proposed 'a legally secured home.' The
delegates, however, were not satisfied, and clamoured for an
alteration to 'secured on the basis of international rights.'
It was only by adopting the intermediary expression 'public
rights' that an agreement was arrived at. The significance of
this logomachy is, that what the Jews desire is not to acquire
more tracts of land, but a country for the Jewish people, and
to emphasise that desire in terms as plain as possible without
wounding certain legitimate and sovereign susceptibilities. We
can acquire land any day in our private right everywhere. But
that is not the point with Zionists. In our case we have
nothing to do with private rights. That will come later—as
well as the land speculators—once our movement has achieved
success. What the Zionists are alone directing their attention
to is the 'public rights' idea. In that they hope to find a
remedy for the old evil. Were I to express myself
paradoxically, I should say that a country belonging to the
Jews on the basis of public rights, even though down to the
very last parcel it was the legally secured property of
non-Jews, would mean the final solution of the Jewish
question. … We have held a gathering at Basle before the whole
world, and there we saw the national consciousness and the
popular will break forth, at times like a convulsive upheaval.
To Basle came Jews of all countries, of all tongues, of all
parties, and of all forms of religious confession. There were
more than 200 representatives of the Jewish people—most of
them delegates for hundreds and thousands. Men from Roumania
alone brought over 50,000 signatures of those who had sent
them there. There surely was never such a motley assembly of
opinions in such a narrow space before. On the other hand,
there would certainly have been more conflict of opinion in
any other deliberative assembly than there was in this. …

"It would … appear to be to the interest of Turkey to come to

an arrangement with the Jews. But, what are the interests
which other Governments would have in assisting the
realisation of a legally guaranteed Jewish home? The interest
would vary with each country, but it is present in some form
or other everywhere. It would mean the drawing off of an
unhappy and detested element of population which is reduced
more and more to a condition of despair, and which, scattered
over the face of the earth, and in a state of unrest, must
perforce identify itself with the most extreme parties
everywhere. Governments and all friends of the existing order
of things cannot bring themselves to believe that, by helping
us in the solution we propose, they could give peace to an
element which has been driven to revolution and rendered
dangerous through its dispersion. That a highly conservative
people, like the Jews, have always been driven into the ranks
of revolutionists is the most lamentable feature in the
tragedy of our race. Zionism would mean an end to all that. We
should see results accrue for the general condition of
mankind, the full benefits of which we cannot even guess.
There are, of course, a great number of existing political
difficulties to be overcome, but these, given the necessary
good will, might be surmounted."

Theodor Herzl,
The Zionist Congress
(Contemporary Review, October, 1897).
{284}

"The programme of the Philo-Zionists as defined in their

printed constitution is as follows:

(a) To foster the national idea in Israel.

(b) To promote the colonization of Palestine and neighbouring

territories by Jews, by establishing new colonies and
assisting those already established.

(c) To diffuse the knowledge of Hebrew as a living language.

(d) To further the moral, intellectual, and material status of

Israel.

The English Association, known as the Chovevi Zion, is

presided over by Colonel Albert Edward Goldsmid, Assistant
Adjutant-General of Her Majesty's Forces; it has 35
established 'Tents' spread through the length and breadth of
the United Kingdom. … Similar associations have been
established in America, Germany, France, Russia, Austria,
Denmark, Switzerland, and other countries; and there is a
central committee meeting at Paris, where the organisation of
new colonies and development of existing ones in the Holy Land
is systematically carried out. Even before these associations
had been called into existence Baron Edmond de Rothschild of
Paris, encouraged by the success of the agricultural schools
at Jaffa, founded by the late Charles Netter, had devoted his
vast influence and his open purse to the work; and there is a
separate administration in Palestine charged with the control
and management of what are known as 'the Baron's colonies.'

"To-day we have in Palestine between twenty and thirty

distinct colonies or communities spreading along the coast
from Askalon in the south to Carmel in the north, and along
the Jordan from the Waters of Meron to the Sea of Galilee in
the east. The population of these colonies varies from 100 to
700 souls, and they may safely be estimated to number 10,000
souls in all, independently of the large number of Jewish day
labourers from neighbouring towns and villages, to whom they
give occasional employment. There are 50,000 more Jews—mostly
refugees—in the various Holy Cities, and the immediate problem
is to get these—or the better part of them—also on the land.
The current language of the colonists is the Hebrew of the
Bible, although many of them have acquired the native Arabic,
and also French, which is taught in their schools. They have
their places of worship, their houses of study, their modest
institutes, their public baths, and in fact the counterpart in
small of all the features of the model European village: and
they have, thanks to the Baron and the Philo-Zionists'
Associations, the most modern appliances and complete
installations for the prosecution of their agricultural
works."

Herbert Bentwich,
Philo-Zionists and Anti-Semites
(Nineteenth Century, October, 1897).

"At the beginning of March, 1898, an important Conference was

held in London, attended by delegates from nearly 50
societies, representing 10,000 English Zionists, and
resolutions were passed adopting the International programme,
and making provisions for a federation of all the English
Zionist bodies. Similar conferences were held in New York, in
Berlin, in Galatz (Roumania), and other great centres; and
local federations were everywhere formed to give greater
strength and solidity to the general organization. At the
second International Congress, which was held at Basle in
August, 1898, and was attended by an imposing body of more
than 500 delegates, the Executive Committee were able to
report that the 'Basle programme' had received the support of
913 Zionist organizations (out of which over 700 had sprung up
since the first Congress), it being calculated that these
represented at least a quarter of a million of active members.
The Congress had become the authorised representative and
exponent of the people's wishes, and the Zionists had become a
power to be reckoned with in any settlement of the Jewish
question. Prominent among the attendants at this world
gathering were the Rabbis—crown officials from orthodox Russia
and Poland, as well as the elect of reform congregations from
America—who took an active interest in the settlement of the
programme of work for the ensuing year, which was the main
business of the meeting."

H. Bentwich,
The Progress of Zionism
(Fortnightly Review, December, 1898).

At the International Zionist Congress which assembled in

London on the 13th of August, 1900, the report of the
executive committee on the progress which the movement has
made showed as follows: "In Russia there are at least 100,000
members of Zionist societies; in England the movement is
supported by 38 societies, as against 16 last year, and all
these societies have increased membership. Thanks to the work
of the English Zionist Federation Zionism has made great
headway in England. In the United States there are 135
societies, as against 102 last year. Notwithstanding the war
in South Africa, the contributions towards the expenses of the
movement have been well maintained. Having regard to the
returns received by the executive committee the reporter felt
no hesitation in saying that to-day the vast majority of the
Jewish nation were in favour of Zionism."

London Times,
August 15, 1900.

Late in December, 1900, it was announced at Vienna that the

Sultan had issued or renewed a decree, according to which the
 Jews are forbidden to remain in Palestine for longer than
three months. This measure, which applies both to traders and
pilgrims, further prohibits the acquisition by Jews of landed
property. It was suggested that the wholesale exodus of Jews
from Russia and their recent emigration from Rumania gave rise
to the apprehension that they might overcrowd Palestine. This
apprehension is said to have been strengthened by the
increasing activity of the Zionists, who are suspected in
certain circles in Constantinople of pursuing distinct
political ends. According to another suggestion, Russia had
grown jealous of the Jewish colonization of Palestine, fearing
it to be in the interest of German policy, and had used
influence to check it.

"Viewed merely on its prosaic side, Zionism is by no means a

visionary scheme. The aggregation of Jews in Palestine is only
a matter of time, and it is better that they should be
aggregated there under their own laws and religion, and the
mild suzerainty of the Sultan, than under the semi-barbarous
restrictions of Russia or Roumania, and exposed to recurrent
popular outbreaks. True, Palestine is a ruined country, and
the Jews are a broken people, but neither is beyond
recuperation. Palestine needs a people, Israel needs a
country. If, in regenerating the Holy Land, Israel could
regenerate itself, how should the world be other than the
gainer? In the solution of the problem of Asia, which has just
succeeded the problem of Africa, Israel might play no
insignificant part. Already the colony of Rishon le Zion has
obtained a gold medal for its wines from the Paris Exposition,
which is not prejudiced in the Jew's favor.
{285}
We may be sure the spiritual wine of Judæa would again pour
forth likewise that precious vintage which the world has drunk
for so many centuries. And as the unscientific activities of
the colonization societies would have paved the way for the
pastoral and commercial future of Israel in its own country,
so would the rabbinical sing-song in musty rooms prove to have
 been but the unconscious preparation of the ages for the
Jerusalem University.

"But Palestine belongs to the Sultan, and the Sultan refuses

to grant the coveted Judæan Charter, even for dangled
millions. Is not this fatal? No, it matters as little as that
the Zionists could not pay the millions, if suddenly called
upon. They have barely collected a quarter of a million (in
English pounds). But there are millionaires enough to come to
the rescue, once the charter was dangled before the Zionists.
It is not likely that the Rothschilds would see themselves
ousted from their familiar headship in authority and
well-doing, nor would the millions left by Baron Hirsch be
altogether withheld. And the Sultan's present refusal is
equally unimportant, because a national policy is independent
of transient moods and transient rulers. The only aspect that
really matters is whether Israel's face be, or be not, set
steadily Zionwards,—for decades and even for centuries. Much
less turns on the Sultan's mind than on Dr. Herzl's. Will he
lose patience? for leaders like Herzl are not born in every
century."

I. Zangwill,
The Wandering Jew and the New Century
(Sunday School Times, January 12, 1901).

JEWS: A. D. 1899.
In Palestine.

"In view of the impetus given the Zionist movement by the

second Zionist congress, held at Basel in September, and also
by the Palestine journey of Emperor Wilhelm II, the present
status of Jews in Palestine becomes a matter of general
interest. Out of a total population in Palestine of some
200,000 souls, about 40,000 are Jews, as against 14,000 twenty
years ago. In Jerusalem, there are 22,000 Jews, half of whom
have immigrated from Europe and America and are called
Asehkenazim to distinguish them from the oriental Israelites,
the Sephardists. Nine hundred and sixty families, numbering
about 5,000 souls, inhabit the twenty-two Jewish colonies in
Palestine which have been founded and subsidized by Europeans
—ten by Baron Edmond de Rothschild, representing the Alliance
Israélite Universelle; the rest by the Jewish Colonization
Association and by the Odessa Company.

"The idea of gathering in Palestine homeless Jews scattered

all over the globe was championed in the forties by Moses
Montefiore, but with indifferent success. In the eighties,
however, the immigration of Jews to Palestine assumed
significant proportions. Of the twenty-two present colonies,
the 'Jacob Memorial' is the largest, supporting more than
1,000 souls. It boasts a graded school (five teachers), a
synagogue, etc., and 4,000 acres of land under cultivation, on
which are raised fruit (chiefly grapes), honey, and mulberry
leaves, the rearing of silkworms being a leading industry. The
'First to Zion' is another quite important colony, owning
2,000 acres of land. Some forty two-storied stone dwelling
houses greet the eye of the approaching stranger; also a
school house with a Hebrew library, a synagogue, and a
hospital. One million five hundred thousand vines and 25,000
olive, almond, orange, and mulberry trees belong to this
colony, which also possesses famous wine cellars. The 'Hope of
Israel,' a mile beyond Yafa, in the plains of Sharon, is
perhaps best known for its agricultural school, in which one
hundred or more pupils are taught gardening. Recently, a high
school for Jewish girls was established in Yafa. The 'Head
Corner Stone,' amid the hills beyond Tiberias, with
snow-capped Hermon in the background, is another quite
prosperous Jewish colony in Palestine. Being near the source
of the Jordan, water is plentiful; and its situation, high up
above the level of Lake Gennesareth, insures fair climatic
conditions. In the 'Door of Hope,' dairy farming is profitably
followed and experiments made in tea planting. This colony is
said to have 1,000,000 vines.
"Entirely irrespective of whether or not the Zionists will
succeed in awakening in the Jewish people a national spirit
and forming a Judean monarchy or republic, with its parliament
in Jerusalem and its representation in foreign capitals, the
present agitation makes for the development of a country which
is but a shadow of its former self, and which will generously
respond to modern influences. The Sultan seems quite disposed
to grant railway, harbor, and other franchises, and it is
possible that the new Jewish Colonial Bank, the organization
of which was decided upon in Basel, will be permitted, under
certain guaranties, to play an important part in the
industrial advancement and growth of Palestine. The movement
is furthermore bringing out new qualities in the Jews residing
in Palestine. They are no longer content with studying the
Talmud and living on charity, but are waking to the fact, as
the Hebrew would put it, that to till the ground is worship of
God.

"It should not be inferred from statements here made that

peace and prosperity have suddenly become the lot of the Jews
in Palestine. Only a few days ago, Rev. William King Eddy, of
Sidon, returned from beyond the Jordan, and he informs me that
a Jewish colony situated not far from El Mzerib (on the
caravan route from Damascus to Mekka) was recently attacked by
predatory Bedouin tribes. The settlers were all driven away,
their gardens and crops destroyed. Even a road built by the
Jews to connect their frontier colony with older ones in
Galilee, west of the river, was at least partially
obliterated. Taxes are more oppressive than ever, officials
are corrupt, and prohibitive measures regarding immigration
are still in force, although inadequate. I think, however, I
am justified in saying that the prospects are brighter than
ever for the Jews in Palestine and for Palestine itself.
European influence has obtained a foothold in the country, and
the tide of modern ideas can not be long debarred. Only four
or five weeks ago, an English company announced its
 determination to build a broad-gauge railway from the sea at
Haifa through the very heart of Samaria and Galilee to
Damascus and on to Bagdad, and active operations have already
commenced."

G. B. Ravndal,
United States Consul at Beirut
(United States Consular Reports, April, 1899, page 691).

{286}

JEWS: A. D. 1901.
Turkish order regulating visits to Palestine.

A Press telegram from Washington, February 16, 1901, states

that "Consul Merrill, at Jerusalem, has reported to the State
Department that the Turkish Minister of the Interior at
Constantinople has issued an order relative to Jews who visit
Palestine, which went into effect on January 29. The order
applies to an Jews who come to Palestine from other countries
as pilgrims or visitors. The conditions of the order are as
follows: On arriving at Joppa the visitor must deliver his
passport to the Turkish authorities and receive therefor a
Turkish document. The visitor is allowed to stay in the
country three months, when he must leave, surrendering the
Turkish permit and receiving his own. Foreign consuls are to
compel the Jews who overstay the three months' period to leave
Turkey."

----------JEWS: End--------

JOAN OF ARC, The Beatification of.

The beatification of Joan of Are, recommended by the

Congregation of Rites, at Rome, was pronounced by the Pope,
January 28, 1894.
JOHANNESBURG: Origin.

See (in this volume)

SOUTH AFRICA (THE TRANSVAAL): A. D. 1885-1890.

JOHANNESBURG: A. D. 1895-1896.
Revolutionary conspiracy of Uitlanders.

See (in this volume)

SOUTH AFRICA (THE TRANSVAAL): A. D. 1895-1896.

JOHANNESBURG: A. D. 1900.
Taken by the British forces.

See (in this volume))

SOUTH AFRICA (THE FIELD OF WAR): A. D. 1900 MAY-JUNE).

JOINT HIGH COMMISSION, Anglo-American.

See (in this volume)

CANADA: A. D. 1898-1899.

JOLO, The Sultan of.

See (in this volume)

PHILIPPINE ISLANDS: A. D. 1899 (MAY-AUGUST).

JONES, Samuel M., Mayor of Toledo.

See (in this volume)

TOLEDO, OHIO: A. D. 1899-1901.

JOUBERT, General Pietrus Jacobus:

In the South African War.

See (in this volume)

SOUTH AFRICA (THE FIELD OF WAR):
 A. D. 1899 (OCTOBER-DECEMBER).

JOUBERT, General Pietrus Jacobus:

Death.

See (in this volume)

SOUTH AFRICA (THE FIELD OF WAR): A. D. 1900 (MARCH).

JUBILEE, The Diamond, of Queen Victoria.

See (in this volume)

ENGLAND: A. D. 1897 (JUNE).

JUBILEE OF THE HOLY YEAR 1900, Proclamation of the Universal.

See (in this volume)

PAPACY: A. D. 1900-1901.

JU JU SACRIFICE.

See (in this volume)

NIGERIA: A. D. 1807.

K.

KAFIRISTAN: Its conquest by the Afghans.

See (in this volume)

AFGHANISTAN: A. D. 1896.

KAGAYAN, or CAGAYAN, The American acquisition of.

See (in this volume)

UNITED STATES OF AMERICA: A. D. 1898 (JULY-DECEMBER).

KAIRWAN: Opened to tourists.

 See (in this volume)
TUNIS: A. D. 1881-1898.

KAISER WILHELM II.

See (in this volume)

GERMANY.

KAISER WILHELM SHIP CANAL, The.

See (in this volume)

GERMANY: A. D. 1895 (JUNE).

KAMERUNS, The: Cost of maintenance.

See (in this volume)

GERMANY: A. D. 1809 (JUNE).

KANG YEU-WEI, Chinese reformer.

See (in this volume)

CHINA: A. D. 1898 (JUNE-SEPTEMBER), and after.

KAPILAVASTU, Discovery of the ruins of.

See (in this volume)

BUDDHA.

KARNAK, Fall of eleven columns of the temple of.

See (in this volume)

ARCHÆOLOGICAL RESEARCH: EGYPT: FALL OF KARNAK
COLUMNS.

KASSALA, Italian evacuation of.

See (in this volume)

 ITALY: A. D. 1897.

KATIPUNAN, The.

See (in this volume)

PHILIPPINE ISLANDS: A. D. 1896-1898.

KEARSARGE, Loss of the.

The United States cruiser Kearsarge, destroyer of the

Alabama, was totally wrecked, February 2. 1894, on
Roncadore Reef, off the Mosquito coast, her crew being
saved.

KENGI.

See (in this volume)

ARCHÆOLOGICAL RESEARCH: BABYLONIA: AMERICAN
EXPLORATION.

KENTUCKY: A. D. 1895-1900.
Political conflicts.
Assassination of Governor Goebel.

In 1895 a Republican Governor, William O. Bradley, was elected

in Kentucky by a majority of nearly 9,000 votes. In 1896 the
conflict of political parties became fierce and dangerous, on
the occasion of the election of au United States Senator to
succeed the Democratic incumbent, J. C. S. Blackburn, whose
term would expire March 3d, 1897. On joint ballot in the
Legislature the Republicans and Democrats had 68 votes each,
and the Populists had 2,—the latter thus bolding a balance of
power: But the two Populist members were divided, and the
Democrats could not act together, owing to the division in
their party on the money question. The "sound-money" Democrats
refused support to Senator Blackburn, who obtained the caucus
nomination of his party for re-election, and their votes were
 scattered. The Republicans were united on a candidate, and
secured one of the Populist votes, but needed one more to give
them a majority. They attempted to win the needed vote by
unseating a Democrat in the Lower House whose seat was
contested; but the Democrats promptly neutralized their move
by unseating two Republicans in the Upper House. The passions
excited by the factious contest had by this time become so
violent and threatening that in March, 1897, the Governor of
the State deemed it necessary to call out several companies of
militia to preserve peace at Frankfort. In the end, the
Legislature adjourned without electing an United States
Senator; but a special session was called and the election
accomplished, on the 28th of April, William J. Deboe,
Republican, winning the senatorial seat.

{287}

In the following year (1898) the Democrats secured strong

majorities in both branches of the Legislature, and, under the
lead of Senator William Goebel, passed an election bill which was
bitterly denounced as a contrivance for fraud. It created a
State election board, appointed by the existing Legislature
for four years, which board should name three commissioners in
each county, by whom all election and registration officers
should be chosen. Notwithstanding this provision of partisan
returning officers, the Democrats were so divided on the
silver question in the gubernatorial election of 1899, and
further weakened by personal hostilities which Goebel, who
became their candidate for governor, had stirred up, that the
official returns of the election gave William S. Taylor, the
Republican candidate, a plurality of more than 2,000 votes
over Goebel. There had been fear of riot in Louisville on
election day, and the Governor had called out State troops to
preserve order. The defeated party claimed that military
interference in that city had made the election illegal, and
demanded that the returns from Louisville should be thrown
out. On both sides there were accusations of fraud, and a
dangerous state of political excitement ensued again. But two
of the three members (all Democrats) of the State Board of
Election Commissioners decided that Taylor, the Republican
candidate, had been lawfully elected, and he was inaugurated
Governor on the 12th of December. Goebel and his partisans,
refusing to accept the decision, determined to unseat Governor
Taylor, by authority of the Legislature, in which they
controlled a considerable majority of votes.

The Legislature met and organized on the 1st of January, 1900.

The Governor prepared to defend his possession of the office
by summoning troops of the State Guard from the strong
Republican districts of the mountain region, and 1,000 or more
armed men arrived in Frankfort on the 25th. There had been
fighting between the two parties already, and the situation
now became desperately strained. Some kind of a bloody outcome
seemed inevitable, but no one could anticipate the barbarous
tragedy which ensued. As Senator Goebel was walking to the
state house, on the 30th of January, he was shot from one of
its windows, by a hidden assassin, receiving a wound from
which he died February 3d. The Legislature at once closed its
investigation of the election, and voted to recognize the
dying William E. Goebel as Governor, with J. C. W. Beckham as
his Lieutenant and the successor to the office in the event of
his death. Governor Taylor issued an address to the people of
the State, denouncing the murder and enjoining the
preservation of order. At the same time he proclaimed an
adjournment of the Legislature, closed the State House against
it, and summoned its members to reassemble on the 6th of
February, not at Frankfort, but at the distant small mountain
town of London. Goebel, on his death-bed, took the oath of
office, and issued orders dismissing Governor Taylor's
Adjutant-General, appointing another in his place, and
commanding the force at Frankfort to return to their homes.

The President of the United States was applied to by Governor

Taylor for recognition and support, but decided that he had no
authority to interfere. The supporters of Goebel applied with
more effect to the Circuit Court of Kentucky, which issued a
writ enjoining Governor Taylor from the use of armed force to
prevent the Legislature from meeting. A clerk who succeeded in
serving the writ by tacking it on the door of the Governor's
office was seized and held prisoner by the military, and a
writ of habeas corpus requiring his deliverance was disobeyed
for several days. All authority was breaking down, and a state
of political chaos being produced. To save the State from
actual anarchy and civil war, a conference of leaders in both
parties was held at Louisville, February 5, and an agreement
reached to withdraw troops from the capital, allow the
Legislature to meet there, and abide by its action, with
promise to repeal the obnoxious election law. Governor Taylor
refused acceptance of the agreement. He dismissed the troops,
however, on the 12th, and called the Legislature to meet at
the capital. The Democratic members of that body were holding
meetings at Louisville, the Republican members at London. The
latter obeyed the call to Frankfort, while the former
continued at Louisville, both fragments claiming to be the
Legislature of the State. A petition to the United States
Circuit Court, for injunctions against the Democratic
claimants for certain of the minor State offices, was denied
by Judge Taft on the 14th.

On the 21st, Republican and Democratic leaders came to another

agreement, that the gubernatorial question should be settled
in the courts,—first in those of the State, and then carried
by appeal to the Supreme Court of the United States. This
agreement prevailed, and the case, as between Governor Taylor
and Governor Beckham (declared to be Governor by a majority of
the members of the Legislature after Governor Goebel's death)
was peacefully adjudicated in favor of the latter. The Circuit
Court of the State recognized the Legislature's decision of
the election as final; the Court of Appeals, with only one of
three Republican judges dissenting, did the same, April 6. On
April 30 the case was argued, on appeal, before the Supreme
 Court of the United States, and on the 21st of May that
tribunal decided that it had no jurisdiction. This ended
attempts to dispute the authority of Governor Beckham.

Strenuous efforts were being made to implicate his competitor,

Mr. Taylor, as accessory to the murder of Goebel. Several
persons had been arrested and put on trial for that crime,
including Caleb Powers, the Secretary of State in Governor
Taylor's fallen government, from the window of whose office it
was claimed that the cowardly shot had been fired. The trials
were scandalized by confessions of perjury and charges and
counter-charges of subornation on the part of witnesses. In
August, Powers was found guilty and sentenced to imprisonment
for life. Subsequently, Henry E. Youtsey received the same
sentence, while James Howard was condemned to death. Appeals
were taken in each case. Mr. Taylor, under indictment as an
accomplice, had left the State, and a requisition for his
rendition was refused by the Governor of Indiana, where he
sojourned. He indignantly denied all knowledge of the alleged
conspiracy to kill his competitor, but claimed that a fair
trial could not be secured to him if he was placed in the
power of his political enemies.

{288}

In October, a new election law was passed by the Legislature

and signed by the Governor. It provides that, of the three
State Election Commissioners, one is to be taken from each of
the dominant parties, upon the recommendation of the State
Central Committee, and the Clerk of the Court of Appeals, an
elective officer, is to act as umpire. The Commissioners are
to be appointed by the Governor. They are to appoint the
county boards, one from each party, with the Sheriff as
umpire. All the boards are to have only ministerial powers,
and the law gives the right of appeal in all cases of contests
to the courts except in the case of Governor and
Lieutenant-Governor, which must be tried by the Legislature,
 as the constitution prescribes. The Goebel law made the boards
supreme. The new law also provides for an equitable division
of election officers.

KHAIBAR:
Inclusion in a new British Indian province.

See (in this volume)

INDIA: A. D. 1901 (FEBRUARY).

KHALIFA, The.

See (in this volume)

EGYPT: A. D. 1885-1896; 1897-1898; and 1899-1900.

KHARTUM, Destruction of.

See (in this volume)

EGYPT: A. D. 1885-1896.

KHARTUM, Gordon Memorial College.

See (in this volume)

EGYPT: A. D. 1898-1899.

KIANG-HUNG: Cession to France.

See (in this volume)

CHINA: A. D. 1894-1895 (MARCH-JULY).

KIAO-CHAU: A. D. 1897.
Seizure by Germany.

See (in this volume)

CHINA: A. D. 1897 (NOVEMBER).

KIAO-CHAU: A. D. 1899.