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Stereochemistry

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Stereochemistry
Stereochemistry

Ranjit S. Dhillon
Inder Pal Singh
Chinnappan Baskar

Narosa Publishing House

New Delhi Chennai Mumbai Kolkata
Stereochemistry
540 pgs. | 540 figs. | 13 tbls.

Ranjit S. Dhillon (Retd.)

Department of Chemistry
Punjab Agricultural University
Ludhiana
Inder Pal Singh
Department of Natural Products
National Institute of Pharmaceutical Education and Research
Mohali
Chinnappan Baskar
THDC Institute of Hydropower Engineering and Technology (Tehri)
Uttarakhand Technical University, Dehradun

Copyright © 2014, Narosa Publishing House Pvt. Ltd.

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Unauthorised export is a violation of terms of sale and is subject to legal action.

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ISBN 978-81-8487-241-5

Published by N.K. Mehra for Narosa Publishing House Pvt Ltd.,

22, Delhi Medical Association Road, Daryaganj, New Delhi 110 002

Printed in India
 This book is dedicated to my beloved wife
Late Mrs. Sukhjinder
for her unwavering support and encouragement.
Prof R. S. Dhillon
 Preface

Stereochemistry has expanded many folds in recent years to include stereochemical

principles, stereochemical concepts, nomenclature, stereochemical course
of reactions, and molecular rearrangements etc. The interest in the subject
upsurged because of the demand for pure enantiomers in pharmaceuticals,
flavors, agrochemicals and related industries and availability of variety of
reagents that give mainly one of the stereoisomers and expansion of new
techniques such as 13C NMR, 2-D and solid-state NMR, X-ray diffraction.
That the optical rotation of enantiomers of tartaric acid is opposite because
of their hemihedric crystals was first noted by Louis Pasteur (1848). The
dissymmetry in carbon compounds resulting from tetrahedral model was
proposed independently by two young chemists Jacobus H. van’t Hoff (recipient
of first Nobel Prize in Chemistry in 1901) and J. A. Le Bel in 1874. The subject
then continued to get impetus and recognition by way of Nobel prizes to D.H.R.
Barton and O. Hassel in 1969 and John Cornforth and Vladimir Prelog in 1975.
Stereochemical concepts can now be explained in more precise terminologies
as there is considerable progress in stereoselective synthesis, stereodynamics,
topicity, prostereoisomerism, cyclostereoismerism etc. There are a few text
books that incorporate the need of both the students and the research workers
but their approach is clearly meant for initiated.
The present text is an effort with an aim to make the subject clear at
fundamental level so that it can be adopted at any stage of college and university
teaching – who are yet to initiate. The efforts have been made to understand
the stereostructures in different ways of their projections. Special attention is
given to serve the need of the students so that they can enhance their skill and
knowledge in the field of stereochemistry. The authors have taught this subject
for several years to college and university students and their suggestions and
difficulties have been taken into consideration in the present text.
The book covers all important aspects of stereochemistry starting right from
the history of stereochemistry and discussing molecular geometry in terms of
bond distances and dihedral angles important for understanding stereochemistry.
The book generates interest by discussing the biological importance of chirality
and its effect on taste, odor, agrochemicals and pharmaceuticals. The thalidomide
tragedy underlines the importance of using ‘Chirally Pure’ molecules as drugs.
viii Preface

This is followed by chapters discussing the basic principles, conformations

and configurations in an easy-to-understand language, the methods for writing
structures in two dimensional and three dimensional projections and their
interconversions. The molecular symmetry and chirality and stereochemical
nomenclature is beautifully explained. A chapter covers prostereoisomerism
and stereoselective synthesis. Another chapter discusses in details chirality in
molecules devoid of any stereogenic atoms. A complete chapter is devoted to
practical methods for determining stereochemistry of organic compounds using
NMR and HPLC based methods. The final chapter discusses methods for
determination of enantiomeric composition. Each chapter on the book includes
summary and some problems at the end and some additional problems are
given at the end of the book.
This book is intended to serve as a valuable textbook for students at the
undergraduate and the postgraduate level. This book should be equally useful
for researchers in various organic chemistry laboratories. It will also serve as
an invaluable reference book for college and university libraries.
The authors thank Dr. (Mrs.) Shikha Baskar, Mrs. Urvashi, Mr. Yadvinder,
Mr. Sandeep, Dr. Divya of Punjab Agricultural University, Ludhiana, Prof. S. S.
Chimni of Guru Nanak Dev University, Amritsar and Dr. Harbinder S. Dhillon,
Associate Professor (Molecular Biology), Delaware State University, USA;
Dr. (Mrs.) Saurabh K. Patel, Department of Chemistry, Veer Narmad South
Gujarat University, Surat and Mrs Anu Singh, SLIET, Longowal.
Dr. Baskar would like to thank Prof D. S. Chauhan, Vice Chancellor
(GLA University Mathura) and Secretary General (Association of Indian
Universities), Dr. Arun Kumar Shah, Director, THDC Institute of Hydropower
Engineering and Technology Tehri and Er. A. L. Shah, OSD, THDC-IHET for
their motivation and support.
We would like to thank Narosa Publishing House Pvt. Ltd, particularly
Mr. N. K. Mehra and Mr. Shashikant for their patience, help and
suggestions.
As authors we bear responsibility for all interpretations, opinions and errors
in this work. We welcome valuable comments and suggestions from our readers
for the improvement of future edition of this book, which may be addressed to
baskarc@gmail.com.

Ranjit S. Dhillon
Inder Pal Singh
Chinnappan Baskar
 Contents

Preface vii
1. History of Stereochemistry 1.1
1.1 Louis Pasteur, Father of Organic Stereochemistry 1.2
2. Molecular Geometry 2.1
2.1 Introduction 2.1
2.2 Bond Distances and Bond Angles 2.1
2.3 Bond Angles and Shapes of the Molecules 2.4
2.4 Torsion Angle or Dihedral Angle 2.6
2.5 Klyne-Prelog Terminology for Torsion Angles 2.7
2.6 Hydrogen Bond 2.10
2.7 Isomers 2.12
2.8 Problems 2.17
3. The Biological Importance of Chirality 3.1
3.1 Introduction 3.1
3.2 In Taste 3.1
3.3 In Odor 3.1
3.4 Chiral Foodstuffs 3.3
3.5 Agrochemicals 3.3
3.6 Pharmaceuticals 3.4
3.7 Stereochemical Specificity 3.6
3.8 Problems 3.7
4. Stereoisomerism 4.1
4.1 Introduction 4.1
4.2 Classification 4.1
4.3 Stereogenic Center or Atom or Unit and Chirality 4.3
4.4 Enantiomers – Optical Isomerism 4.8
4.5 Diastereomers 4.18
4.6 Conformation and Configuration 4.22
x Contents

4.7 Constitutionally Symmetrical Chiral Molecules:

Degenerate Cases 4.28
4.8 Barrier between Stereoisomerism: Residual Stereoisomers 4.34
4.9 Summary 4.37
4.10 Problems 4.37
5. Optical Activity, Chirality, Enantiomeric and
Diastereomeric Excess 5.1
5.1 Introduction 5.1
5.2 Plane Polarized Light 5.1
5.3 The Cause of Optical Activity 5.2
5.4 The Polarimeter 5.6
5.5 Specific Rotation 5.7
5.6 Optical Activity 5.9
5.7 Tetrahedral Carbon and Isomer Number 5.10
5.8 The Phenomenon of Chirality 5.13
5.9 Absolute Configuration and Optical Rotation 5.16
5.10 Enantiomeric Excess and Enantiomeric Ratio 5.18
5.11 Diastereomeric Excess and Diastereomeric Ratio 5.21
5.12 Natural Products and Enantiomeric Purity 5.22
5.13 Summary 5.23
5.14 Problems 5.24
6. Molecular Projections 6.1
6.1 Introduction 6.1
6.2 Three-Dimensional Representation and its Conversion
to Fischer’s Projection – A 2D Representation 6.1
6.3 Fischer Projections – Characteristics and Limitations 6.4
6.4 Sawhorse Projections 6.7
6.5 Newman Projections 6.9
6.6 Flying-Wedge Projections 6.10
6.7 Zig-Zag Projections 6.11
6.8 Homomers 6.13
6.9 Interconversions of Fischer-Sawhorse-Newman Projections 6.15
6.10 Conversion of Fischer Projections into a Flying-Wedge
and Zig-Zag Representations 6.16
6.11 Problems 6.19
 Contents xi

7. Molecular Symmetry and Chirality 7.1

7.1 Introduction 7.1
7.2 Symmetry Operations or Elements 7.1
7.3 What Symmetry Criterion Leads to Optical Activity? 7.9
7.4 Summary 7.10
7.5 Problems 7.11
8. Nomenclature 8.1
8.1 Introduction 8.1
8.2 Fischer’s D and L Nomenclature 8.1
8.3 R and S Nomenclature 8.6
8.4 Absolute Configuration and Relative Configuration 8.18
8.5 D, L and R, S Nomenclature – A Comparison 8.19
8.6 Configurational Notation/Descriptor and Optical Activity:
No Relation 8.19
8.7 Symbols for Stereoheterotopic Faces 8.20
8.8 Pro-R and pro-S-Nomenclature – Prochiral Centers 8.22
8.9 r- and s-Nomenclature 8.23
8.10 Erythro and Threo Nomenclature 8.24
8.11 Meso Nomenclature 8.25
8.12 Epimers 8.27
8.13 Anomers 8.28
8.14 Invertomers 8.29
8.15 s-cis and s-trans Isomers 8.29
8.16 a- and b-Stereochemical Nomenclature 8.31
8.17 Exo and Endo-Nomenclature 8.32
8.18 Syn and Anti Nomenclature 8.34
8.19 Like (l) and Unlike (u) Nomenclature 8.35
8.20 in, out Nomenclature of Bridgeheads 8.36
8.21 cis and trans Nomenclature for Alkenes and Cumulenes 8.37
8.22 E, Z Nomenclature for Alkenes, Oximes, Cumulenes 8.37
8.23 cis, trans-Nomenclature for Cyclanes 8.39
8.24 Summary 8.41
8.25 Problems 8.43
9. Stereoisomerism in Unsaturated Compounds 9.1
9.1 Introduction 9.1
9.2 Stereochemistry of Alkenes 9.1
xii Contents

9.3 Nomenclature of Oximes 9.10

9.4 Nomenclature of Alkylidenecycloalkanes 9.11
9.5 cis, trans-Isomerism and Acidity 9.11
9.6 Stereochemistry of Conjugated Unsaturated Molecules 9.12
9.7 Stereoisomerism of Cumulenes 9.16
9.8 Summary 9.17
9.9 Problems 9.18
10. Conformation of Acylic and Cyclic Compounds 10.1
10.1 Introduction 10.1
10.2 Acyclic Compounds 10.1
10.3 Auwers-Skita Rule or Conformational Rule 10.12
10.4 Cycloalkanes 10.13
10.5 Cyclohexene 10.37
10.6 Cyclohexene Oxide 10.38
10.7 Nomenclature of Substituted Cyclanes:
Cyclopropanes, Cyclobutanes and Cyclohexanes 10.40
10.8 Disubstituted Derivatives of Cyclohexane 10.45
10.9 Medium Rings: Conformations 10.48
10.10 Ring Strain 10.56
10.11 Perhydrophenanthrenes 10.58
10.12 Perhydroanthracenes 10.61
10.13 Anomers and Anomeric Effect 10.63
10.14 Decalins 10.70
10.15 Bicyclo [2.2.2] Octane 10.76
10.16 Stereochemistry of Bridgehead Positions 10.79
10.17 Summary 10.80
10.18 Problems 10.82
11. Prostereoisomerism and Asymmetric Synthesis 11.1
11.1 Introduction 11.1
11.2 Prochiral Axis and Prochiral Planes 11.4
11.3 Homotopic Ligands and Faces 11.5
11.4 Heterotopic Ligands and Faces 11.12
11.5 Asymmetric Synthesis or Stereoselective Synthesis 11.24
11.6 Summary 11.78
11.7 Problems 11.79
 Contents xiii

12. Chirality in Molecules Devoid of Stereogenic Atom 12.1

12.1 Introduction 12.1
12.2 Axially Chiral Molecules 12.1
12.3 Molecules with Planar Chirality 12.16
12.4 Chirality due to Helical Shape 12.23
12.5 Optical Active Catenanes: Axial Chirality 12.24
12.6 Retro-Enantio Isomers 12.25
12.7 Conformational Cycloenantiomerism or Cyclic
Directionality (of Conformational Origin) 12.26
12.8 Conversion of Planar Chirality to Axial Chirality 12.27
12.9 Summary 12.27
12.10 Problems 12.29
13. Racemization and Resolution of Enantiomers 13.1
13.1 Racemization 13.1
13.2 Resolution 13.11
13.3 Summary 13.28
13.4 Problems 13.29
14. Dynamic Stereochemistry 14.1
14.1 Introduction 14.1
14.2 Dynamic Stereochemistry: Conformation and Reactivity 14.1
14.3 Stereoelectronic Effects 14.11
14.4 Conformationally Rigid Diastereomers of Monocyclic
Compounds – Reaction Rates 14.21
14.5 Stereoselective Synthesis of Enolates 14.21
14.6 Summary 14.25
14.7 Problems 14.25
15. Methods for Determination of Stereochemistry 15.1
15.1 Stereochemical Assignments using 1H NMR 15.1
15.2 NMR Methods for Determination of Absolute
Configuration 15.7
15.3 Determination of Anomeric Configuration of Sugars
and Glycosides 15.18
15.4 HPLC Methods for Absolute Configuration 15.22
15.5 Circular Dichroism 15.26
15.6 Summary 15.29
15.7 Problems 15.30
15.8 List of References 15.30
xiv Contents

16. The Influence of Strains, Interactions on Molecular

Structure 16.1
16.1 Introduction 16.1
16.2 Factors Effecting Molecular Structure 16.2
16.3 Effect of Short Bonds: Six-Membred Ring
Containing Two Heteroatoms 16.14
16.4 A1,2 and A1,3 Strains 16.15
16.5 Problems 16.20
17. Methods for Determination of Enantiomeric 17.1
Composition
17.1 Introduction 17.1
17.2 Polarimetric Methods 17.1
17.3 Gas Chromatographic Methods 17.2
17.4 Liquid Chromatographic Methods 17.5
17.5 High-Performance Liquid Chromatography with
Chiral Solvents 17.6
17.6 NMR Spectroscopy 17.8
17.7 Problems 17.23
Index I.1
 About the Authors

Dr. Ranjit S. Dhillon

Dr. Ranjit S. Dhillon is a retired Professor of Organic
Chemistry at the Punjab Agricultural University (PAU),
Ludhiana, Punjab, India. He received his PhD from PAU
under the direction of Prof. P. S. Kalsi. He spent two
years as a Post-doctoral Fellow with Nobel Laureate Prof.
Akira Suzuki at Hokkaido University, Sapporo, Japan. Dr.
Dhillon has supervised 12 PhD students and 20 M. Sc.
students in the areas of development of new eco-friendly
synthetic methodologies and chemistry of natural products. His research work
mainly “Versatile boranes and borohydrides” carried out at PAU was cited by
Nobel Laureate Late Prof. Herbert C. Brown in his research articles, many other
eminent scientists, and in text books of Organic Chemistry. Prof Dhillon has
published over 60 peer-reviewed papers and one book chapter.
He is the author of Hydroboration and Organic Synthesis (Springer-Verlag,
2007); Co-editor of Biomass Conversion: The Interface of Biotechnology,
Chemistry and Materials Science (Springer-Verlag, 2012) and co-author of
Engineering Chemistry text book (Wiley India, 2012). He is the recipient
of meritorious teacher award from PAU. He is currently teaching Organic
Chemistry to the students of various universities in California, USA.
Dr. Inder Pal Singh
Dr. Inder Pal Singh is an Associate Professor in the
Department of Natural Products at National Institute
of Pharmaceutical Education and Research (NIPER),
SAS Nagar, India. He received his PhD from Shizuoka
University Japan. He received fellowships from Monbusho
Japan, Oregon State University, Corvallis, USA and
JSPS, Japan. His research interests include isolation and
characterization of bioactive natural products, synthesis
of bioactive natural products and their analogs for
various therapeutic areas such as HIV and leishmaniasis, and analysis and
standardization of medicinal plants and herbal products.
 A.2 About the Authors

He has published about 70 research articles and 10 reviews. He is on

several national and international grant reviewing committees and is a referee
for several leading journals.
Dr. Chinnappan Baskar
Dr. Chinnappan Baskar is an Associate Professor of
Chemistry and Academic In-charge, THDC Institute of
Hydropower Engineering and Technology, Uttarakhand
Technical University, Dehradun, India. He has received his
M. Sc. Chemistry from the Indian Institute of Technology
Madras and PhD in Organic and Materials Chemistry
from the Department of Chemistry, National University
of Singapore (NUS), Singapore. He has joined the faculty
in the Department of Chemistry, Lovely Professional
University (LPU) as a Reader then promoted to Head of the Department. He
moved to the Department of Environmental Engineering and Biotechnology,
Myongji University, South Korea in September 2009 as a Brain Korean 21
(BK21) Research Professor and co-researcher in Energy and Environmental
Fusion Technology Center, Myongji University.
He has worked as Director (Academic Affairs), Dev Bhoomi Group
of Institutions, Dehradun, Uttarakhand. Dr. Baskar research interests
include synthetic organic chemistry, conducting polymers, green chemical
transformations, and ionic liquids. He has published several research papers in
reputed international journals and conference proceedings. He has received the
“Teaching Excellence Award” from THDC-IHET. He is the Editor of Biomass
Conversion: The Interface of Biotechnology, Chemistry and Materials Science
(Springer-Verlag, 2012; this book is rated as one of the timely-demanded
reference book and it was one of the top 25% most downloaded ebooks in
the relevant Springer book collection in 2012) and the author of Engineering
Chemistry text book (Wiley India, 2012).

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