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Dynamic Stereochemistry of Chiral Compounds
Principles and Applications
Dynamic Stereochemistry of Chiral
Compounds
Principles and Applications

Christian Wolf
Department of Chemistry, Georgetown University, Washington, DC, USA
ISBN: 978-0-85404-246-3

A catalogue record for this book is available from the British Library

r The Royal Society of Chemistry 2008

All rights reserved

Apart from fair dealing for the purposes of research for non-commercial purposes or for private study, criticism or
review, as permitted under the Copyright, Designs and Patents Act 1988 and the Copyright and Related Rights
Regulations 2003, this publication may not be reproduced, stored or transmitted, in any form or by any means,
without the prior permission in writing of The Royal Society of Chemistry or the copyright owner, or in the case of
reproduction in accordance with the terms of licences issued by the Copyright Licensing Agency in the UK, or in
accordance with the terms of the licences issued by the appropriate Reproduction Rights Organization outside the
UK. Enquiries concerning reproduction outside the terms stated here should be sent to The Royal Society of
Chemistry at the address printed on this page.

Published by The Royal Society of Chemistry,

Thomas Graham House, Science Park, Milton Road,
Cambridge CB4 0WF, UK

Registered Charity Number 207890

For further information see our web site at www.rsc.org

Preface

Since the pioneering work of Pasteur, Le Bel and van’t Hoff stereochemistry has evolved to a multi-
faceted and interdisciplinary field that continues to grow at an exponential rate. Today, dynamic
stereochemistry plays a fundamental role across the chemical sciences, ranging from asymmetric
synthesis to drug discovery and nanomaterials. The immense interest and activity in these areas
have led to the development of new methodologies and research directions in recent years. Chirality
plays a pivotal role in efforts to control molecular motion and has paved the way for microscopic
propellers, gears, switches, motors and other technomimetic devices. The concepts of Euclidian
chirality have been extended to topological chirality of fascinating mechanically interlocked
assemblies including rotaxanes, catenanes, and even molecular knots or pretzelanes. The impressive
advance of asymmetric synthesis has been accompanied by significant progress in stereochemical
analysis. Mechanistic insights into isomerization reactions and information about the conforma-
tional and configurational stability of chiral compounds are indispensable for today’s chemist, and
new techniques such as dynamic chromatography and stopped-flow procedures that complement
chiroptical and NMR spectroscopic methods have been established. A profound understanding of
the stability of chiral target compounds, intermediates and starting materials to racemization and
diastereomerization is indispensable for planning an efficient synthetic route. In many cases,
interconversion of stereoisomers compromises the efficacy of asymmetric synthesis and ultimately
results in the loss of stereochemical purity, but it can also be advantageous. While the usefulness
and scope of asymmetric transformations of the first and second kind have been known for a long
time, dynamic kinetic resolution, dynamic kinetic asymmetric transformation and dynamic ther-
modynamic resolution have become powerful synthetic alternatives. Many strategies that afford
excellent control of stereolabile substrates and reaction intermediates have been developed and are
nowadays routinely employed in the synthesis of a wide range of chiral compounds including
natural products. Asymmetric synthesis of complex target compounds generally entails incorpo-
ration of several chiral elements in addition to strategic carbon-carbon bond formation. Once
molecular chirality has been established it is often necessary to further manipulate it. Numerous
methods for selective translocation of a chiral element along an existing carbon framework or
interconversion of elements of chirality without loss of stereochemical purity have been introduced
and provide invaluable synthetic prospects. Both, the progress and the diversity of stereodynamic
chemistry, in particular asymmetric synthesis, are unrivaled and constantly fueled by an enormous
amount of new scientific contributions.
Over the last twenty years, several excellent books about asymmetric synthesis have appeared.
Traditionally, asymmetric synthesis is discussed based on (1) reaction types, for example aldol

v
vi Preface

reactions, hydroboration, epoxidation, dihydroxylation, hydrogenation, and so on, or (2) emerging

concepts such as organocatalysis, biomimetic methods and phase-transfer catalysis. In addition,
many reviews on broadly applicable asymmetric catalysts and methods can be found in the
literature. While there is no need to duplicate these books and articles, I have felt that a
conceptually different textbook that embraces asymmetric synthesis, interconversion of chiral
compounds, analytical methods suitable for the study of racemization and diastereomerization
reactions, as well as a discussion of topologically chiral assemblies and molecular propellers,
switches and motors in the context of dynamic stereochemistry would be very helpful for both
teaching and research. Stereoselective synthesis, analysis and stereodynamic properties and appli-
cations of chiral compounds are now combined in one text. The book is aimed at graduate students
and is intended to serve as a guide for researchers with an interest in synthetic, analytical and
mechanistic aspects of dynamic stereochemistry of chiral compounds.
This book is organized into three parts that contain nine chapters and a glossary of important
stereochemical terms and definitions. The first chapter provides an introduction to the significance
and interdisciplinary character of dynamic stereochemistry. Chapter 2 covers principles, termino-
logy and nomenclature of stereochemistry with an emphasis on Euclidian and topological chirality.
The reader is familiarized with stereodynamic properties of chiral compounds and the relative
contributions of interconverting configurational and conformational isomers to selectivity, reac-
tivity and chiral recognition. Racemization, enantiomerization and diastereomerization including
mutarotation and epimerization are discussed in Chapter 3. Mathematical treatments of reversible
and irreversible isomerization kinetics are presented and the wealth of racemization and dia-
stereomerization mechanisms is reviewed separately for each class of compounds to provide a
systematic overview. Numerous examples of compounds with individual energy barriers to enan-
tioconversion are given to highlight steric and electronic effects. The principles and scope of
analytical techniques that are commonly used to determine the conformational and configurational
stability of chiral compounds are discussed in Chapter 4. Special emphasis is given to chiroptical
methods, variable-temperature NMR spectroscopy, dynamic chromatography, and stopped-flow
analysis.
The second part of this book focuses on asymmetric synthesis. Chapter 5 introduces the reader to
the principles of asymmetric synthesis and outlines basic concepts of stereodifferentiation and
reaction control. Chapter 6 covers asymmetric synthesis with chiral organolithium compounds and
atroposelective synthesis of biaryls and nonbiaryls. This discussion leads to other strategies that are
aimed at manipulation of chirality without concomitant racemization or diastereomerization, for
example chirality transfer and interconversion of chiral elements during pericyclic rearrangements,
SN2 0 and SE2 0 displacements, and self-regeneration of stereogenicity with temporary or transient
chiral intermediates. Synthetic methods that utilize relays and stereodynamic catalysts for ampli-
fication of chirality and asymmetric induction link the above topics to the following chapter.
Strategies that incorporate stereolabile chiral compounds and intermediates into asymmetric
synthesis under thermodynamic (asymmetric transformations of the first and second kind, dynamic
thermodynamic resolution) or kinetic reaction control (dynamic kinetic resolution and dynamic
kinetic asymmetric transformation) are presented in Chapter 7. Because of the considerable overlap
and relevance to some of the above methodologies, kinetic resolutions are also covered in detail.
The scope and application spectrum of asymmetric reactions and concepts presented in Chapters 5
to 7 are highlighted with many examples and the stereochemical outcome is explained with a
mechanistic rationale including transition state structures whenever possible.
The third part of this book comprises stereodynamic devices, manipulation of molecular motion,
and the chemistry of topologically chiral assemblies. Chapter 8 examines the central role that
chirality plays in the design of molecular propellers, bevel gears, brakes, switches, sensors, and
motors. The synthesis, chirality and stereodynamics of catenanes, rotaxanes and other mechani-
cally interlocked compounds are presented in Chapter 9.
Preface vii

A single monograph can not comprehensively cover the enormous scope and the many facets of
dynamic stereochemistry. Topics such as switching and amplification of chirality in polymers, gels
and liquid crystals had to be excluded due to limitations of space and time. In writing this book
during the last two and a half years, I have tried to adhere to well-defined and established
stereochemical terminology and emphasized important limitations and conflicting definitions in the
text. To assist the reader, a detailed glossary of stereochemical definitions and terms is included at
the end of the book, and a list of abbreviations and acronyms is provided at the beginning. All
topics are extensively referenced and the principal researcher is frequently named in the text to
encourage further reading and to facilitate additional literature search.
I would like to thank my colleagues, in particular Professors William H. Pirkle and the late
Wilfried A. König, and my students for continuing inspiration and helpful discussions. I wish to
thank Thomas J. Nguyen for the technical drawings illustrating the conceptual linkage between
macroscopic mechanical devices and their molecular analogs. And I am particularly grateful to my
wife Julia for her patience, encouragement and understanding during the endless hours involved in
writing this book.

Christian Wolf
Washington, DC
This book is dedicated to
my wife Julia
Contents

Chapter 1 Introduction 1

References 4

Chapter 2 Principles of Chirality and Dynamic Stereochemistry 6

2.1 Stereochemistry of Chiral Compounds 6

2.2 Dynamic Stereochemistry of Cyclic and Acyclic Chiral Compounds 15
References 27

Chapter 3 Racemization, Enantiomerization and Diastereomerization 29

3.1 Classification of Isomerization Reactions of Chiral Compounds 30

3.1.1 Racemization 31
3.1.2 Enantiomerization 34
3.1.3 Diastereomerization 36
3.1.4 Epimerization and Mutarotation 40
3.2 Stereomutations of Chiral Compounds: Mechanisms and Energy Barriers 44
3.2.1 Alkanes 44
3.2.2 Alkenes and Annulenes 46
3.2.3 Allenes and Cumulenes 52
3.2.4 Helicenes and Phenanthrenes 53
3.2.5 Alkyl Halides, Nitriles and Nitro Compounds 54
3.2.6 Amines 56
3.2.7 Aldehydes, Ketones and Imines 58
3.2.8 Alcohols, Ethers, Acetals, and Ketals 60
3.2.9 Carboxylic Acids and Derivatives 65
3.2.10 Amino Acids 68
3.2.11 Silicon, Phosphorus and Sulfur Compounds 71
3.2.12 Organometallic Compounds 74
3.2.13 Supramolecular Structures 80

ix
x Contents

3.3 Atropisomerization 84
3.3.1 Biaryls, Triaryls and Diarylacetylenes 85
3.3.2 Nonbiaryl Atropisomers 94
3.3.3 Cyclophanes 104
3.3.4 Atropisomeric Xenobiotics 107
3.4 Pharmacological and Pharmacokinetic Significance of Racemization 109
References 112

Chapter 4 Analytical Methods 136

4.1 Chiroptical Methods 140

4.2 NMR Spectroscopy 143
4.3 Dynamic Chromatography 153
4.3.1 Dynamic High Performance Liquid Chromatography 159
4.3.2 Dynamic Gas Chromatography 164
4.3.3 Dynamic Supercritical Fluid Chromatography and Electrokinetic
Chromatography 167
4.4 Chromatographic and Electrophoretic Stopped-flow Analysis 168
4.5 Comparison of Analytical Methods 172
References 172

Chapter 5 Principles of Asymmetric Synthesis 180

5.1 Classification of Asymmetric Reactions 180

5.2 Kinetic and Thermodynamic Control 183
5.3 Asymmetric Induction 186
5.3.1 Control of Molecular Orientation and Conformation 189
5.3.2 Single and Double Stereodifferentiation 194
References 198

Chapter 6 Asymmetric Synthesis with Stereodynamic Compounds: Introduction, Conversion

and Transfer of Chirality 204

6.1 Asymmetric Synthesis with Chiral Organolithium Reagents 205

6.1.1 a-Alkoxy- and a-Amino-substituted Organolithium
Compounds 207
6.1.2 Sulfur-, Phosphorus- and Halogen-stabilized Organolithium
Compounds 212
6.2 Atroposelective Synthesis of Axially Chiral Biaryls 215
6.2.1 Intramolecular Atroposelective Biaryl Synthesis 217
6.2.2 Intermolecular Atroposelective Biaryl Synthesis 220
6.2.3 Atroposelective Ring Construction 224
6.2.4 Desymmetrization of Conformationally Stable Prochiral
Biaryls 225
6.2.5 Asymmetric Transformation of Stereodynamic Biaryls 226
6.3 Nonbiaryl Atropisomers 231
6.4 Chirality Transfer and Interconversion of Chiral Elements 233
Contents xi

6.4.1Chirality Transfer in SN2 0 and SE2 0 Reactions 234

6.4.2Rearrangements 240
6.4.2.1 1,2-Chirality Transfer 241
6.4.2.2 1,3-Chirality Transfer 242
6.4.2.3 1,4-Chirality Transfer 250
6.4.2.4 1,5-Chirality Transfer 252
6.4.3 Intermolecular Chirality Transfer 254
6.4.4 Transfer of Stereogenicity Between Carbon and Heteroatoms 255
6.4.5 Conversion of Central Chirality to Other Chiral Elements 257
6.4.6 Conversion of Axial Chirality to Other Chiral Elements 261
6.4.7 Conversion of Planar Chirality to Other Chiral Elements 270
6.5 Self-regeneration of Stereogenicity and Chiral Relays 271
6.5.1 Stereocontrolled Substitution at a Chiral Center 271
6.5.2 Self-regeneration of Stereocenters 276
6.5.3 Self-regeneration of Chiral Elements with Stereolabile Intermediates 282
6.5.4 Chiral Relays 289
6.6 Asymmetric Catalysis with Stereolabile Ligands 292
6.6.1 Stereodynamic Achiral Ligands 294
6.6.2 Stereolabile Axially Chiral Ligands 296
6.7 Stereoselective Synthesis in the Solid State 302
References 304

Chapter 7 Asymmetric Resolution and Transformation of Chiral Compounds under

Thermodynamic and Kinetic Control 331

7.1 Scope and Principles of Asymmetric Resolution and Transformation 334

7.2 Asymmetric Transformation of the First Kind 334
7.3 Asymmetric Transformation of the Second Kind 337
7.3.1 Crystallization-induced Asymmetric Transformation 337
7.3.2 Asymmetric Transformation based on Chromatographic
Separation 344
7.4 Kinetic Resolution and Dynamic Kinetic Resolution 346
7.4.1 Kinetic Resolution 346
7.4.1.1 Enzyme-catalyzed Kinetic Resolution 347
7.4.1.2 Nonenzymatic Kinetic Resolution 351
7.4.1.3 Parallel Kinetic Resolution 355
7.4.2 Dynamic Kinetic Resolution 359
7.4.2.1 Enzyme-catalyzed Dynamic Kinetic Resolution 360
7.4.2.2 Nonenzymatic Dynamic Kinetic Resolution 365
7.5 Dynamic Kinetic Asymmetric Transformation 372
7.6 Dynamic Thermodynamic Resolution 378
References 382

Chapter 8 From Chiral Propellers to Unidirectional Motors 399

8.1 Stability and Reactivity of Stereodynamic Gears 399

8.2 Structure and Ring Flipping of Molecular Propellers 403
8.3 Dynamic Gearing in Biaryl-, Triaryl- and Tetraaryl Propellers 405
xii Contents

8.4 Molecular Bevel Gears 411

8.5 Vinyl Propellers 414
8.6 Propeller-like Coordination Complexes with Helicity Control 418
8.7 Static Gearing and Cyclostereoisomerism 419
8.8 Molecular Brakes, Turnstiles and Scissors 421
8.9 Chiral Molecular Switches 423
8.10 Stereodynamic Sensors 432
8.11 Chiral Molecular Motors 435
References 437

Chapter 9 Topological Isomerism and Chirality 444

9.1 Synthesis of Catenanes and Rotaxanes 445

9.1.1 Statistical Methods 445
9.1.2 Template-assisted Assembly 447
9.1.3 Topological Isomerization 450
9.2 Chiral Catenanes 451
9.3 Chiral Rotaxanes 458
9.4 Knots and Borromean Rings 465
9.5 Topological Isomerism of Shuttles, Switches, Sensors, and Rotors 467
References 473

Glossary Stereochemical Definitions and Terms 480

Subject Index 503

Abbreviations and Acronyms

a axial
a0 pseudoaxial
AAA asymmetric allylic alkylation
Ab antibody
Ac acetyl
ac anticlinal
acac acetylacetonate
ACN acetonitrile
AD asymmetric dihydroxylation
Ad adamantyl
AE asymmetric epoxidation
AIBN azobisisobutyronitrile
Ala alanine
ap antiperiplanar
aq aqueous
Ar aryl
Asp aspartic acid
atm atmospheric pressure
ATP adenosine triphosphate
b0.5 peak width at half height
Bc butyryl
BHT 2,6-di-tert-butyl-4-methylphenol
Bn benzyl
Boc t-butoxycarbonyl, t-BuOC(O)-
BPDM benzphetamin N-demethylase
Bu n-butyl
Bz benzoyl
1C degree Celsius
c concentration; conversion
CAL Candida antarctica lipase
CAN cerium ammonium nitrate
Cat catalyst
Cb N,N-diisopropylcarbamoyl, (i-Pr)2NC(O)-
Cby 2,2,4,4-tetramethyloxazolidine-3-carbonyl
xiii
xiv Abbreviations and Acronyms

Cbz carbobenzyloxy, BnOC(O)-

CD circular dichroism
CDA chiral derivatizing agent
CEC capillary electrochromatography
CIDR crystallization-induced dynamic resolution
CIP Cahn–Ingold–Prelog
CLA chiral Lewis acid; complete line shape analysis
cod 1,5-cyclooctadiene
Cp cyclopentadienyl
CPE circular polarization of emission
CPL circularly polarized light
CP-MAS cross polarization magic angle spinning
18-crown-6 1,4,7,10,13,16-hexaoxacyclooctadecane
CSA chiral solvating agent
CSP chiral stationary phase
CSR chiral shift reagent
Cy, c-C6H11 cyclohexyl
CZE capillary zone electrophoresis
D sodium D-line (589 nm); absolute configuration (Fischer–Rosanoff convention)
d day(s)
DABCO 1,4-diazabicyclo[2.2.2]octane
dba dibenzylidene acetone
DBB 4,4 0 -di-tert-butylbiphenyl
DBN 1,5-diazabicyclo[4.3.0]non-5-ene
DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
DCC dicyclohexyl carbodiimide
DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
de diastereomeric excess
DEAD diethyl azodicarboxylate
DGC dynamic chromatography
DHPLC dynamic high performance liquid chromatography
DIAD diisopropyl azodicarboxylate
DIEA N,N-diisopropylethylamine
DKR dynamic kinetic resolution
dm decimeter
DMAD dimethyl azodicarboxylate
DMAP 4-dimethylaminopyridine
DME 1,2-dimethoxyethane
DMEKC dynamic micellar electrokinetic chromatography
DMF N,N-dimethyl formamide
DMSO dimethyl sulfoxide
DNA deoxyribonucleic acid
DNB 3,5-dinitrobenzoyl
DNMR dynamic nuclear magnetic resonance
DOPA 3,4-dihydroxyphenylalanine
dppf 1,1 0 -bis(diphenylphosphino)ferrocene
dr diastereomeric ratio
DSFC dynamic supercritical fluid chromatography
DSubFC dynamic subcritical fluid chromatography
DTR dynamic thermodynamic resolution
Abbreviations and Acronyms xv

DYKAT dynamic kinetic asymmetric transformation

E electrophile
E enzymatic enantioselectivity factor
(E) entgegen, relative configuration
e equatorial
e0 pseudoequatorial
ECCD exciton-coupled circular dichroism
ee enantiomeric excess
eepss enantiomeric excess at photostationary state
e.g. exempli gratia, for example
en ethylenediamine
enant enantiomerization
epi epimer; epimerization
equiv equivalent
er enantiomeric ratio
EROD ethoxyresorufin-O-deethylase
ESR electron spin resonance
Et ethyl
et al. et alii, and others
EXSY NMR exchange spectroscopy
FID flame ionization detection
Fmoc fluorenyl-9-methoxycarbonyl
G Gibbs free energy
Ga Gibbs activation energy
g gram
g anisotropy factor
GC gas chromatography
Gly glycine
H enthalpy
Ha activation enthalpy
h hour(s); Planck’s constant
HCH hexachlorocyclohexane
hfc heptafluorobutyrylcamphorato
HKR hydrolytic kinetic resolution
hn irradiation of light
HOMO highest occupied molecular orbital
HPLC high performance liquid chromatography
HSA human serum albumin
i-Bu isobutyl
i.e. id est, that is
i-Pr isopropyl
IR infrared
J joule
J coupling constant
K Kelvin
K equilibration constant
k kilo
k rate constant
kB Boltzmann’s constant
KHMDS potassium hexamethyldisilazide
xvi Abbreviations and Acronyms

KR kinetic resolution
L liter; ligand; absolute configuration (Fischer-Rosanoff convention)
l length
LASER light amplification by stimulated emission of radiation
LDA lithium diisopropylamide
Leu leucine
LHMDS lithium hexamethyldisilazide
ln natural logarithm
LTMP lithium tetramethylpiperidide
LUMO lowest unoccupied molecular orbital
Lys lysine
M molar
(M) denotes left-handed helicity (CIP convention)
m milli
m meta
MC 3-methylcholanthrene
m-CPBA 3-chloroperbenzoic acid
Me methyl
MEKC micellar electrokinetic chromatography
Mes mesityl
Met methionine
min minute(s)
MOM methoxymethyl
MP mobile phase
MS mass spectrometry
Ms methylsulfonyl, CH3SO2-
MTBE methyl tert-butyl ether
N 0,1,2,3 . . .
n nano
n 1,2,3 . . .
nA population of state A
NADH nicotinamide adenine dinucleotide
NADPH nicotinamide adenine dinucleotide phosphate
NBS N-bromosuccinimide
Nf nonaflate, C4F9SO2-
NLE nonlinear effect
nm nanometer
NMO N-methylmorpholine N-oxide
NMR nuclear magnetic resonance
NOESY nuclear Overhauser effect spectroscopy
NSAID nonsteroidal anti-inflammatory drug
Nu nucleophile
o ortho
obs observed
ORD optical rotary dispersion
Ox oxidation
(P) denotes right-handed helicity (CIP convention)
p para
PB phenobarbital
PCB polychlorinated biphenyl
Abbreviations and Acronyms xvii

PCL Pseudomonas cepacia lipase

Ph phenyl
pH
log10 [H3O1]
Phe phenylalanine
Phg phenylglycine
PhMe toluene
Piv trimethylacetyl
PKR parallel kinetic resolution
PLP pyridoxal-5 0 -phosphate
PM3 parametric method 3 (semi-empirical molecular modeling software)
PMB para-methoxybenzyl
PPAR peroxisome proliferator-activated receptor
ppm parts per million
Pr n-propyl
PS lipase from Pseudomonas stutzeri
py pyridine
R alkyl; universal gas constant
(R) rectus, denotes absolute configuration (CIP convention)
rac racemic; racemization
Red reduction
RNA ribonucleic acid
S entropy
(S) sinister, denotes absolute configuration (CIP convention)
Sa activation entropy
s second(s)
s enantioselectivity factor
s-Bu sec-butyl
sc synclinal
SE electrophilic substitution
SFC supercritical fluid chromatography
sia 3-methyl-2-butyl
SMB simulated moving bed chromatography
SN nucleophilic substitution
SNi intramolecular nucleophilic substitution
SP stationary phase
sp synperiplanar
SRS self-regeneration of stereocenters
SubFC subcritical fluid chromatography
T temperature
Tc coalescence temperature
t time
TBAF tetrabutylammonium fluoride
TBDMS tert-butyldimethylsilyl
TBDPS tert-butyldiphenylsilyl
TBHP tert-butyl hydroperoxide
t-Boc t-butoxycarbonyl, t-BuOC(O)-
TBS tributylsilyl
t-Bu tert-butyl
TCDD 2,3,7,8-tetrachlorodibenzo-p-dioxin
Tf triflate, CF3SO2-
xviii Abbreviations and Acronyms

TFA trifluoroacetic acid; trifluoroacetyl

TFAA trifluoroacetic anhydride
tfc trifluoroacetylcamphorato
THF tetrahydrofuran
THP tetrahydropyran
TIPS triisopropylsilyl
tipyl 2,4,6-triisopropylphenyl
TLC thin layer chromatography
TMEDA N,N,N 0 ,N 0 -tetramethylethylenediamine
TMS trimethylsilyl
Tol tolyl
Tr trityl, Ph3C-
TR-CPL time-resolved circularly polarized luminescence
TS transition state
Ts tosyl, 4-CH3C6H4SO2-
TTF tetrathiafulvalene
Tyr tyrosine
URO uroporphyrinogen
UV ultraviolet
UV-vis ultraviolet-visible
V volt
VCD vibrational circular dichroism
VE valence electron
(Z) zusammen, relative configuration
a denotes anomer; C-2
a rotation angle; chromatographic enantioselectivity factor
a,o denotes chain termini
b denotes anomer; C-3
g C-4
D heat; difference; right-handed complex
d C-5
e ellipticity
y molar ellipticity
k transmission coefficient
L left-handed complex
l wavelength
m micro
n frequency
t1/2 half-life time
F quantum yield for photoracemization
w mole fraction
(þ) dextrorotatory
(–) levorotatory
Structures and Acronyms of Chiral Ligands

Ph
PPh2 OH PPh2 O O Ph
P Ph
PPh2 OH PPh2 N N N O
Ph P
B
R R
BINAP BINOL BIPHEB BIPHOS BOX CBS oxazaborolidine

CO2Et CO2i-Pr
NH2
H OH H OH O
NH2 NMe2 PPh2
HO H HO H
OH O PPh2
CO2Et CO2i-Pr
DABN DAIB DET DIPT DIOP

Et
Et Et
Et
R N N N N
N N N N O O
P O O H H
R H H
Ph NH2 MeO O O OMe
R MeO OMe
P
Ph NH2 R N N
N N
DPEN DUPHOS (DHQD)2-PHAL (DHQD)2-AQN

F3C OMe OH PPh2 N N

NMe2
O CO2H NH2
O Fe H Me R OH HO R

C3F7 R R
hfc MTPA NOBIN PPFA salen

O O
R R
O PPh2 O PPh2 O OH Ph NHTs
O PPh2 O PPh2 O
N N O OH O
O R R Ph NHTs
O CF3
SEGPHOS sparteine SYNPHOS TADDOL tfc TSDPEN

xix
CHAPTER 1

Introduction

In 1848, Louis Pasteur, one of the pioneering stereochemists, recognized the omnipresence and
significance of chirality, which prompted his famous statement that the universe is chiral (l’univers
est dissymme´trique).1 Today, we know that chirality can indeed be encountered at all levels in
nature – in the form of the elementary particle known as the helical neutrino, inherently chiral
proteins, carbohydrates and DNA, or helical bacteria, plants and sea shells. Pasteur realized that
chiral objects exist as a pair of enantiomorphous mirror images that are nonsuperimposable and
related to each other like a right-handed and left-handed glove. At the molecular level, chirality
gives rise to enantiomers that can exhibit strikingly different chemical and physical properties in a
chiral environment. Many biologically active compounds, for example pharmaceuticals, agro-
chemicals, flavors, fragrances, and nutrients, are chiral, and more than 50% of today’s top-selling
drugs including Lipitor (cholesterol reducer, global sales in 2004: $12.0 billion), Zocor (cholesterol
reducer, $5.9 billion), Plavix (antithrombic, $5.0 billion) and Nexium (antiulcerant, $4.8 billion) are
sold as single enantiomers, Figure 1.1.
The increasing demand for enantiopure chemicals has been accompanied by significant progress
in asymmetric synthesis2–8 and catalysis,9–14 and by the development of analytical techniques for
the determination of the stereochemical purity of chiral compounds. Stereoselective analysis
usually entails chiroptical measurements,15 NMR and mass spectroscopic methods,16–18 electro-
phoresis,19 chiral chromatography20 or UV and fluorescence sensing assays,21–27 and it can provide
invaluable information about the stability of chiral compounds to racemization and dia-
stereomerization. A renowned example of a chiral drug that undergoes fast enantioconversion
under physiological conditions is thalidomide (Thalidomid, Contergan) which was prescribed to
pregnant women in the 1960s to alleviate morning sickness. One of the enantiomeric forms of
thalidomide does indeed have sedative and antinausea effects, but the other enantiomer is a potent
teratogen.i The racemic drug was approved in Europe for the treatment of pregnant women
suffering from nausea and its use caused severe birth defects. Even formulation of the pure
nontoxic (R)-enantiomer of thalidomide would have been unsafe because racemization takes place
in vivo and the teratogenic (S)-enantiomer is rapidly generated in the human body, Scheme 1.1.ii
Since the thalidomide tragedy, the significance of the stereochemical integrity of biologically
active compounds has received increasing attention and the investigation of the stereodynamic

i
Teratogenic agents interfere with embryonic development and cause congenital malformations (birth defects) in babies.
ii
Despite its inherent toxicity and stereochemical instability, thalidomide has recently been approved by the US Food and
Drug Administration under a specially restricted distribution program for cancer therapy and for the treatment of the
painful disfiguring skin sores associated with leprosy.
1
2 Chapter 1

OMe

O
H HO2C N O
N S N H
.. HO2C OH
N
OMe F
(S)-omeprazole (S)-ibuprofen (S)-flurbiprofen (S)-propranolol
(proton pump inhibitor used for (anti-inflammatory drug) (anti-inflammatory drug) (β-adrenergic blocker)
treatment of esophagitis, ulcer)
OH
HO2C NH2 CO2Et
O S
OH N N
N Cl MeO P S CO2Et
MeO
N
OH
(S)-DOPA (S)-bupivacaine (2R,3R)-paclobutrazol (S)-malathion
(neurotransmitter precursor used (local anaesthetic) (fungicidal agent) (insecticidal agent)
for treatment of Parkinson's disease)

Figure 1.1 Structures of chiral pharmaceuticals and agrochemicals.

O O O

N O N O N O
NH NH NH
O O O HO O O
(S)-(-)-thalidomide (R)-(+)-thalidomide
(teratogen) (sedative and antinausea agent)

Scheme 1.1 Interconversion of the enantiomers of thalidomide.

properties of chiral molecules has become an integral part of modern drug development. For
example, a variety of 2-arylpropionic acids including ibuprofen (Advil), naproxen (Aleve), keto-
profen (Oruvail), and flurbiprofen (Ansaid) has found widespread use as pain relievers and
nonsteroidal anti-inflammatory drugs (NSAIDs). The anti-inflammatory activity of these profens
resides primarily with the (S)-enantiomer.iii The enantiomers of flurbiprofen possess different
pharmacokinetic properties and show substantial racemization under physiological conditions.
Although (S)-naproxen is the only profen that was originally marketed in enantiopure form, in vivo
interconversion of the enantiomers of NSAIDs is an important issue in preclinical pharmacological
and toxicological studies.28 Another noteworthy example that underscores the significance of
racemization of chiral drugs is the potent gastric acid secretion inhibitor omeprazole (Prilosec)
which has been used in its racemic form for the treatment of esophagitis and ulcer.29 The active
form of this prodrug is an achiral sulfenamide derivative, and one could conclude that the presence
of a chiral center in omeprazole does not affect its pharmacological activity. Nevertheless, the
enantiomers of omeprazole have strikingly different pharmacokinetic profiles. The (S)-enantiomer
of omeprazole affords higher bioavailability in humans because the (R)-form is more readily
metabolized in the liver. To enhance the potency of this blockbuster drug, the pharmaceutical
industry has launched esomeprazole (Nexium), the pure (S)-enantiomer of omeprazole.
The unique structure and mode of action of the antibiotic glycopeptide vancomycin (Vancocin)
has fascinated synthetic and medicinal chemists alike. The antibacterial activity of vancomycin, i.e.,

iii
Some (S)-profens have distinct ulcerogenic properties that are increased in the presence of the (R)-enantiomer.
Introduction 3

its ability to inhibit cell wall biosynthesis, stems from its rigid macrocyclic structure which is crucial
for effective recognition and binding to the terminal D-alanine-D-alanine sequence of bacterial
peptides. The cup-shaped structure of vancomycin is a consequence of the chirality of the amino
acids in conjunction with the chiral axis of the actinoidinic acid moiety consisting of aryl rings A
and B and the planar chirality of aryl ethers C and E, Scheme 1.2. The stereodynamics of these
chiral elements have played a pivotal role in the total synthesis of the vancomycin aglycon (the part
of the glycopeptide lacking carbohydrate units).30–33 An intriguing example is Evans’ synthesis of
vancomycin from a bicyclic precursor bearing an unnatural (M)-actinoidinic acid moiety. Evans
and coworkers recognized that the axial chirality of the atropisomeric actinoidinic acid unit is
controlled by the global aglycon architecture, rather than by individual proximate stereogenic
elements. They also realized that rotation about the central C–C bond between aryl rings A and B
proceeds at ambient temperature and favors formation of the (P)-conformer with high selectivity.
In fact, thermal equilibration at 55 1C results in atropisomerselective interconversion of the two
diastereomeric tetrapeptides and establishes the desired axial chirality with 90% diastereomeric
excess. This thermodynamically controlled transformation significantly enhances the overall effi-
ciency of the total synthesis of vancomycin, Scheme 1.2. Similarly, Boger and others exploited
thermally controlled atropisomerization reactions which have been strategically incorporated into
several synthetic routes towards vancomycin and other complex antibiotics including teicoplanin.

HO
HO OH OPiv
HO OPiv
H 2N O OMs OMs
O O O
O C D C D
O HO Cl HO Cl
Cl H O O
H 55°C H H
O O N N N
NHTFA N
C D E O O NHTFA
HO Cl OH O
H O O O NH O NH O
H H B
N N N (P) B
N NH (M )
O MeHN MeHN
H A OH 95 : 5
O O NHMe OH A HO
NH O O
B HO HO OH
HO2C
NH2
A OH
OH
HO

Scheme 1.2 Structure of vancomycin (left), and stereoisomer interconversion favoring the formation of the
natural (P)-diastereoisomer of a tetrapeptide precursor (right).

The unique stereodynamics of chiral compounds have paved the way to artificial machines and
other molecular devices that lie at the interface of chemistry, engineering, physics, and molecular
biology. The design of gears, rotors, switches, scissors, brakes, shuttles, turnstiles, and even motors
showing unidirectional motion has certainly been inspired by the coordinated movement in
biological systems such as muscle fibers, flagella and cilia.34–36 Feringa and coworkers developed
light-driven molecular motors derived from sterically overcrowded chiral alkenes exhibiting ther-
mal bistability and nondestructive read-out.37,38 The subtle interplay between the chiral center and
the inherently helical conformation of this type of molecular motor provides control of the rotation
about the carbon–carbon double bond in a series of thermally and photochemically initiated
isomerization steps. In other words, both chirality and conformational flexibility are essential for
unidirectional motion of the rotor around the stator, Scheme 1.3. The first isomerization step
requires irradiation of UV light to a solution of the stable (3 0 S)-(P)-trans-form of the chiral alkene.
This generates a photostationary state favoring 69.4% of the unstable (3 0 S)-(M)-cis-form that
thermally relaxes to 94% of the stable (3 0 S)-(P)-cis-isomer in the second step. The same concept is
exploited for photoisomerization of the (3 0 S)-(P)-cis-alkene to 48.9% of the (3 0 S)-(M)-trans-isomer
4 Chapter 1

S S

Step 1

S photoinduced
OMe OMe
rotor isomerization
> 280 nm
S 30.6% : 69.4% S
3 stable (3′S)-(P)-trans-form unstable (3′S)-(M)-cis-form

4 2
thermal helix inversion at 55˚C thermal helix inversion at 55˚C
Step 4 Step 2
1 83.4% : 16.6% 6.0% : 94.0%
OMe
stator S S
S
Step 3

OMe photoinduced OMe

isomerization
> 280 nm
S S
48.9% : 51.1%
unstable (3′S)-(M)-trans-form stable (3′S)-(P)-cis-form

Scheme 1.3 Four isomerization steps of a unidirectional motor.

in the third step which is followed by thermal helix inversion to regenerate 83.4% of the (3 0 S)-(P)-
trans-isomer in the final step. Since the interconverting isomers exist as mixtures obeying
Boltzmann distributions and reversible reaction kinetics, this molecular motor is not rotating in
an exclusively monodirectional sense. However, the discrete and synergetic photochemical and
thermal isomerization reactions of the diastereomeric mixtures result in an overall clockwise
motion observed from the stator.
Since the discovery of the ubiquity of chirality by Pasteur, stereochemistry has undoubtedly
emerged as one of the most important and fascinating areas within the chemical sciences.
Stereochemistry embraces a broad variety of closely intertwined static and dynamic aspects that
are all related to the three-dimensional structure of molecules. While static stereochemistry deals
with the spatial arrangement of atoms in molecules and the corresponding chemical and physical
properties, dynamic stereochemistry emphasizes structural change and comprises asymmetric
reactions as well as interconversion of configurational and conformational isomers. The few
examples outlined above highlight both the significance of chirality and the fundamental role that
dynamic stereochemistry plays in modern chemistry, spanning multiple disciplines from asymmet-
ric synthesis and drug discovery to material sciences. The principles and applications of
stereodynamic chemistry of chiral compounds are discussed in the chapters following.

REFERENCES
1. Pasteur, L. Ann. Chim. Physique 1848, 24, 442-459.
2. Helmchen, G.; Hoffmann, R. W.; Mulzer, J.; Schaumann, E. Stereoselective Synthesis in
Methods of Organic Chemistry, Houben-Weyl, Vol. 21a-21f, 4th ed., Thieme, Stuttgart, 1995.
3. Gawley, R. E.; Aubé, J. Principles of Asymmetric Synthesis, Tetrahedron Organic Chemistry
Series, Elsevier, New York, 1996.
4. Ho, T.-L. Stereoselectivity in Synthesis, Wiley-VCH, New York, 1999.
5. Lin, G.-Q.; Li, Y.-M.; Chan, A. S. C. Principles and Applications of Asymmetric Synthesis,
Wiley-VCH, New York, 2001.
6. Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2024-2032.
Introduction 5

7. Song, C. E.; Lee, S.-G. Chem. Rev. 2002, 102, 3495-3524.

8. Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991-8035.
9. Jonathan, M. J. W. Catalysis in Asymmetric Synthesis, Sheffield Academic Press, Sheffield,
1999.
10. Ojima, I. Catalytic Asymmetric Synthesis, 2nd ed., Wiley-VCH, New York, 2000.
11. Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008-2022.
12. Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187-2209.
13. Inanaga, J.; Furuno, H.; Hayano, T. Chem. Rev. 2002, 102, 2211-2225.
14. Mikami, K.; Terada, M.; Matsuzawa, H. Angew. Chem., Int. Ed. 2002, 41, 3554-3571.
15. Ding, K.; Shii, A.; Mikami, K. Angew. Chem., Int. Ed. 1999, 38, 497-501.
16. Guo, J.; Wu, J.; Siuzdak, G.; Finn, M. G. Angew. Chem., Int. Ed. 1999, 38, 1755-1758.
17. Evans, M. A.; Morken, J. P. J. Am. Chem. Soc. 2002, 124, 9020-9021.
18. Markert, C.; Pfaltz, A. Angew. Chem., Int. Ed. 2004, 43, 2498-2500.
19. Reetz, M. T.; Kuhling, K. M.; Deege, A.; Hinrichs, H.; Belder, D. Angew. Chem., Int. Ed. 2000,
39, 3891-3893.
20. Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds, John Wiley & Sons, New
York, 1994, pp. 214-274.
21. Pu, L. Chem. Rev. 2004, 104, 1687-1716.
22. Mei, X.; Wolf, C. Chem. Commun. 2004, 2078-2079.
23. Zhao, J.; Fyles, T. M.; James, T. D. Angew. Chem., Int. Ed. 2004, 43, 3461-3464.
24. Eelkema, R.; van Delden, R. A.; Feringa, B. L. Angew. Chem., Int. Ed. 2004, 43, 5013-5016.
25. Mei, X.; Wolf, C. J. Am. Chem. Soc. 2004, 126, 14736-14737.
26. Tumambac, G. E.; Wolf, C. Org. Lett. 2005, 7, 4045-4048.
27. Folmer-Andersen, J. F.; Lynch, V. M.; Anslyn, E. V. J. Am. Chem. Soc. 2005, 127, 7986-7987.
28. Leipold, D. D.; Kantoci, D.; Murray Jr., E. D.; Quiggle, D. D.; Wechter, W. J. Chirality 2004,
16, 379-387.
29. Lindberg, P.; Braendstroem, A.; Wallmark, B.; Mattsson, H.; Rikner, L.; Hoffman, K.-J. Med.
Res. Rev. 1990, 10, 1-54.
30. Evans, D. A.; Wood, M. R.; Trotter, B. W.; Richardson, T. I.; Barrow, J. C.; Katz, J. L.
Angew. Chem., Int. Ed. 1998, 37, 2700-2704.
31. Evans, D. A.; Dinsmore, C. J.; Watson, P. S.; Wood, M. R.; Richardson, T. I.; Trotter, B. W.;
Katz, J. L. Angew. Chem., Int. Ed. 1998, 37, 2704-3708.
32. Boger, D. L.; Miyazaki, S.; Kim, S. H.; Wu, J. H.; Loiseleur, O.; Castle, S. L. J. Am. Chem.
Soc. 1999, 121, 3226-3227.
33. Boger, D. L.; Miyazaki, S.; Kim, S. H.; Wu, J. H.; Castle, S. L.; Loiseleur, O.; Jin, Q. J. Am.
Chem. Soc. 1999, 121, 10004-10011.
34. Kelly, T. R.; DeSilva, H.; Silva, R. A. Nature 1999, 401, 150-152.
35. Koumura, N.; Zijlstra, R. W. J.; van Delden, R. A.; Harada, N.; Feringa, B. L. Nature 1999,
401, 152-155.
36. Leigh, D. A.; Wong, J. K. Y.; Dehez, F.; Zerbetto, F. Nature 2003, 424, 174-179.
37. Koumura, N.; Geertsema, E. M.; Meetsma, A.; Feringa, B. L. J. Am. Chem. Soc. 2000, 122,
12005-12006.
38. Van Delden, R. A.; ter Wiel, M. K. J.; de Jong, H.; Meetsma, A.; Feringa, B. L. Org. Biomol.
Chem. 2004, 2, 1531-1541.
CHAPTER 2

Principles of Chirality and Dynamic

Stereochemistry

Stereochemistry has evolved into a multi-faceted discipline, and numerous concepts and descriptors
have been introduced since the discovery and analysis of chiral organic compounds by van’t Hoff,
Le Bel and Pasteur in the nineteenth century. Unfortunately, the stereochemical terminology used
in the literature is not always well defined, and in some cases it can be ambiguous. The principles of
stereoisomerism and chirality and the relationship between reactivity and stereodynamics of chiral
compounds are discussed in this chapter and complemented with brief definitions in the glossary.

2.1 STEREOCHEMISTRY OF CHIRAL COMPOUNDS

Stereoisomeric compounds exhibit the same constitution, i.e., molecular formula and connectivity
of atoms, but have a different spatial arrangement. Stereoisomers are classified into enantiomers
and diastereoisomers. Chiral molecules that have the relationship of mirror images are called
enantiomers. All other stereoisomers are diastereoisomers, Figure 2.1. Enantiomers have the same
chemical and physical properties when present in an achiral environment. But they show different
chiroptical behavior and cause a clockwise (dextrorotatory (þ)-form) or counterclockwise (levo-
rotatory (–)-form) rotation of the plane of linearly polarized light by equal amounts.i Enantiomers
may have distinguishable properties in a chiral environment if they experience diastereomeric
interactions. For example, the enantiomers of chiral drugs such as omeprazole, ibuprofen and
DOPA exhibit different pharmacological and pharmacokinetic activities because they interact with
enzymes and receptors consisting of amino acids and other chiral biomolecules. By contrast,
diastereoisomers usually have different chemical and physical properties in both achiral and chiral
environments. Many chiral compounds possess a tetrahedral carbon atom bearing four different
substituents, Figure 2.2. The presence of one chiral carbon center in a molecule gives rise to a pair
of two enantiomers. Other important stereogenic centers consist of a nitrogen, phosphorus, boron,
silicon or sulfur atom carrying nonidentical substituents, Figure 2.3.
Enantiomers and diastereoisomers can be chiral due to the presence of an asymmetric center, but
this is not always the case. A compound is chiral if it is not superimposable on its mirror image.
This unequivocal definition provides a necessary and sufficient condition for chirality. Chiral
i
The absolute configuration of a chiral compound, and the assignment of its three-dimensional structure based on CIP rules
(descriptors R,S) must not be confused with its ability to rotate the plane of monochromatic linearly polarized light in a
clockwise or counterclockwise direction (descriptors þ,
).
6
Principles of Chirality and Dynamic Stereochemistry 7

Cl Cl H2N Cl
Pt Pt CO2H HO2C
H2N NH2 Cl NH2 HO OH
cis-diamminedichloroplatinum trans-diamminedichloroplatinum
OH HO

diastereoisomers
diastereoisomers
(2R,3S)-2,3-dihydroxybutyric acid (2S,3R)-2,3-dihydroxybutyric acid
CO2H HO2C
HO OH enantiomers
HO2C CO2H
(R)-lactic acid (S)-lactic acid
OH HO
HO OH
enantiomers

(2S,3S)-2,3-dihydroxybutyric acid (2R,3R)-2,3-dihydroxybutyric acid

(E)-2-butene (Z)-2-butene
enantiomers
diastereoisomers

Figure 2.1 Examples of enantiomers and diastereoisomers.

OH O
Cl O
Br Et
O
NH2 OH
(R)-2-bromobutane (S)-1-phenylpropanol (R)-1-aminoindan (R)-2-chlorobutyric acid (S)-styrene oxide (1S,4R)-camphor
CO2H
OH
O CHO Me Ph H2N
OH HO
HO
O CH2OH H2N OH
(1R,2S,5R)-menthol (R)-2-methylsuccinic acid (R)-glyceraldehyde (1R,2S)-norephedrine (S)-leucine

Figure 2.2 Chiral compounds with asymmetric carbon atoms.

O O O OR′′′

N N P P P P B
R R′′ R R′′ R R′′ R R′′ R OR′′ R OH RO OR′′
R′ R′ R′ R′ R′ R′ R′O
amines amine oxides phosphines phosphine oxides phosphinic esters phosphinous acids borates
R′′′ OH R′′′ R′′′
Si Si S S N P S
R R′′ R R′′ R O R O R R′′ R R′′ R R′′
R′ R′ R′ RO R′ R′ R′
silanes silanols sulfoxides sulfinic esters ammonium ions phosphonium ions sulfonium ions

Figure 2.3 Chiral compounds with stereogenic centers others than carbon atoms.

molecules may possess a rotation axis, but no symmetry plane, rotation-reflection axis and
inversion center. This criterion may be fulfilled by the presence of an asymmetric center or other
elements of chirality. Many organic compounds lack asymmetric atoms but possess axial, planar or
helical chirality. For example, substituted allenes, biphenyls, spiranes, and alkylidenecycloalkanes
have a chiral axis and exist in the form of two enantiomers. Certain ansa compounds,
8 Chapter 2

Cl H CO2H
H3C H3C CH3
•
Cl H H H
H
(S)-2,2'-dimethylbiphenyl (S)-1,3-dichloroallene (R)-4-methylcyclohexylideneacetic acid (S)-2,6-dimethylspiro[3.3]heptane (S)-spirobiindan

CO2H CO2H

O O
COCH3
Fe
(CH2)9
(S)-(E)-cyclooctene (R)-[2.2]paracyclophane- (R)-1,11-dioxa[11]cyclophane- (R)-1-acetyl-2-methyl-
carboxylic acid carboxylic acid ferrocene (P)-hexahelicene

Figure 2.4 Molecules with a chiral axis, plane or helix.

CO2H HO2C
HO CO2H HO2C OH
HO OH
symmetry plane
OH HO
HO CO2H HO2C OH
HO2C CO2H
(R,R)-(+)-form (S,S)-(-)-form (R,S)-form (S,R)-form

enantiomers meso form

diastereoisomers

N N N N N N N N
(R,R)-form (S,S)-form (R,S)-form (S,R)-form

enantiomers meso form

diastereoisomers

Figure 2.5 The stereoisomers of tartaric acid (top) and 1,8-bis(2 0 -methyl-4 0 -quinolyl)naphthalene (bottom).

paracyclophanes, trans-cycloalkenes with a twisted double bond, and metallocene complexes

display a chiral plane, and helicenes afford a chiral helical structure, Figure 2.4.
Chiral compounds may have one or more than one stereogenic center, axis, plane or helix. In
most cases, each element of chirality gives rise to two distinct stereoisomers, and one can expect 2n
stereoisomers for n chiral elements. However, the existence of a symmetry plane, rotation-reflection
axis or inversion center results in degeneracies. A compound that possesses at least one of these
symmetry elements is achiral because it is superimposable on its mirror image. Tartaric acid has
two chiral centers and should exhibit two diastereoisomeric pairs of enantiomers. In fact, it exists
only in the form of two enantiomeric (R,R)- and (S,S)-isomers and a third diastereoisomeric form
that has a symmetry plane and is achiral because its mirror images are superimposable and
therefore identical, Figure 2.5. Similarly, 1,8-bis(2 0 -methyl-4 0 -quinolyl)naphthalene has two chiral
axes but affords three stereoisomers: two enantiomers and one meso form. These examples clearly
demonstrate that the presence of a stereogenic element in a molecule such as a tetrahedral carbon
Principles of Chirality and Dynamic Stereochemistry 9

atom bearing four different substituents or a chiral axis does not necessarily render the molecule
chiral.
A discussion of the stereochemistry of chiral compounds requires a clear understanding of the
relevant nomenclature. The Cahn–Ingold–Prelog (CIP) rules are used to give an unambiguous
description of the absolute configuration of enantiomers and diastereoisomers.1,2 Because of its
importance, the CIP convention and the descriptors R, S, M, and P are explained below in some
detail, whereas definitions of other stereochemical terms can be found in the glossary. The
descriptors R, S, M, and P are applicable to all kinds of chiral elements. First, the priority of
the atoms attached to the chiral element is assigned based on the following sequence rules:

1. Atoms with a higher atomic number have a higher rank than atoms with a lower atomic
number. Note that the substituent with the lowest priority at a tetrahedral carbon atom may
be a hydrogen atom or a lone electron pair at a three-coordinate chiral heteroatom such as
nitrogen, phosphorus or sulfur. Isotopes with higher atomic mass number precede isotopes
with lower mass number, e.g., D 4 H and 13C 4 12C.
2. When two or more substituents are the same element, one has to compare atoms in the next
sphere until the priority of all groups has been established. It is important that all
substituents in a given sphere must be evaluated before one proceeds further away from
the core of the chiral element to the next array of atoms. Comparison of a dimethyl acetal
moiety with an ethoxy group shows that the former has a higher priority because it carries
two oxygens, in contrast to the ether moiety which bears only one oxygen atom. In other
words, all atoms in one sphere must be fully analyzed before one continues to the next
sphere. In the case of equal priority of a given sphere, one always proceeds by following the
branch of the highest priority until a rank can finally be assigned, Figure 2.6.
3. The rank of substituents carrying multiple bonds is established based on the principle of
ligand complementation. Multiple bonds are complemented by phantom atoms through
multiple representation of atoms that are doubly or triply bonded. An organometallic p-
complex is treated the same way. A metal carrying an alkene or alkine ligand is hypothet-
ically replaced by one (two) metal(s) attached to each end of the ligand, e.g., a palladium
p-complex bearing an olefinic group –CH¼CHR is represented by –C(Pd)H–C(Pd)HR. The
rule of ligand complementation is also applicable to polydentate and cyclic ligands. A cyclic
structure is disconnected and complemented with a phantom atom at the bonds where it
reduplicates itself. For example, the priority of the substituted pyrrolidine shown in Figure
2.7 is assigned by cutting the ring into two hypothetical branches with peripheral phantom
atoms in addition to the real branches. Disconnection at A gives –CH2NHCH2CH2(C)
having the highest priority because –CH2NHCH2CH3, the group that is assigned second
priority, carries a peripheral hydrogen which has a lower priority than a phantom carbon.
Disconnection at B results in the formation of –CH2CH2NHCH2(C), which has the lowest
rank. This case thus also illustrates that, for a given element, a real atom has precedence
over a phantom atom: –CH2CH2NHCH2CH3 4 –CH2CH2NHCH2(C).

determines branch of the highest priority

(3)
(4 ) OMe (1) (3)
(2) OEt determines rank (2)
(Br > Cl) Br (1) OH (4) OH Cl
(R) OMe
(S)

Figure 2.6 Comparison of CIP spheres and determination of the branch of the highest priority.
10 Chapter 2

HN
HN
HN (3)
A ligand (S)
(4) (C) N
complementation (2)
B N H
H
N NH
(C) = phantom carbon
H (1) (C)

Figure 2.7 Ligand complementation in cyclic compounds.

(3) (3)
(1) (4)
(1) OMe (4) OMe (2)

(R) (S) (S) (S) (2)

(Z) (E)

Figure 2.8 CIP rules for stereoisomeric substituents.

4. If ligands possess a different stereochemical environment and can not be distinguished based
on the above, the following rule applies: cis-configuration precedes trans-configuration,
Z 4 E, R 4 S, M 4 P, Figure 2.8.

The CIP rules described above give the following priority of common functional groups:

–I 4 –Br 4 –Cl 4 –SO3H 4 –SO2R 4 –SR 4 –SH 4 –P(O)R2 4 –PR2 4 –F 4 –OR 4

–NO2 4 –NR2 4 –NH2 4 –CO2R 4 –CO2H 4 –C(O)R 4 –CHO 4 –CH(OR)2 4 –CH(OH)2
4 –CH2OR 4 –CH2OH 4 –CN 4 –CH2NH2 4 o-tolyl 4 m-tolyl 4 p-tolyl 4 –C6H5 4
–CRCH 4 t-Bu 4 –CH(C6H13)2 4 cyclohexyl 4 vinyl 4 i-Pr 4 benzyl 4 allyl 4 n-alkyl 4 –H.

Once the priority of the substituents or groups around the chiral center is established, the
molecule is viewed in such a way that the moiety with the lowest priority is placed behind the
central atom. The three remaining substituents or groups are thus oriented towards the viewer and
afford a tripodal arrangement. If the sense of direction following the established priority of these
three substituents describes a clockwise rotation, (R)-configuration (for Latin rectus, right) is
assigned. If the rotation is counterclockwise, the chiral center has (S)-configuration (for Latin
sinister, left), Figure 2.9.
This nomenclature can also be applied to compounds possessing a chiral axis or plane. In both
cases the priority of substituents must be assigned with the help of an additional CIP rule, which
specifies that the groups on an arbitrarily chosen side of a chiral axis or plane always precede
substituents on the other side of the stereogenic element. It is helpful to view the chiral axis of
biphenyls, allenes and spiro compounds as a stretched tetrahedron. Because of the inherently lower
symmetry of a stretched tetrahedron compared to a regular tetrahedron, it does not require the
presence of four different substituents to constitute a chiral axis. For example, 2,2 0 -dimethyl-
biphenyl is chiral. The symmetric substitution pattern gives rise to a C2-symmetric structure, but
incorporation of the same substituents to a tetrahedral carbon generates an achiral compound with
a symmetry plane. To assign the CIP descriptor to an axially chiral compound, one can choose
either side of the chiral axis to determine the first two priorities. This side always has precedence
over the opposite side. Then the remaining ranks are assigned on the side of lower priority, and the
clockwise (Ra) or counterclockwise (Sa) sense of rotation is established. Some classes of com-
pounds, including (E )-cycloalkenes, cyclophanes and metallocenes, display a planar aryl or alkene
group that may have one or several substituents residing outside that plane. A substitution pattern
that destroys a perpendicular symmetry plane or an inversion center establishes planar chirality.
Principles of Chirality and Dynamic Stereochemistry 11

(3) (2)
H (4) (4) (4)
(3) HO2C H (2)
C P S •
(3) Cl I (1) (3) Me (3) Me
Ph (1) O (1) (4) H CO2H (1)
(2) Br (2) Et (2) t-Bu (4) (1)
(S )-bromochloroiodomethane (S)-ethylmethylphenylphosphine (S)-tert-butylmethylsulfoxide (P)- or (S)-glutinic acid (P)- or (S)-2,2'-dimethylbiphenyl

(3) NO2 (2) OH

pilot atom
(3) (1)
CO2H (1) (3) (1)
(3) D
(2)
(4) O N (1) (4) H (2)
2 H (2) (4)
(P)- or (S )-2,2'-dinitro-5-hydroxybiphenyl (M )- or (R)-4-deuteriocyclohexylidene- (M )- or (R)-spiro[3.3]heptane-1,5-diene (P)- or (R)-(E)-cyclooctene
(the hydroxyl group is too remote acetic acid
from the chiral axis to matter)

CO2H
(3)
(M)
(2) atom of highest
(1) Fe Fe (1)
precedence (P)
pilot atom (2)

(3) (4)
(P)- or (R)-[2.2]paracyclophane- (S )-2-ethyl-1,4-dimethylferrocene
carboxylic acid (M )-hexahelicene meso decahelicene

Figure 2.9 Description of axial, planar and helical chirality based on CIP rules. Chiral axes of symmetrically
substituted biaryls, allenes and spiro compounds are arbitrarily viewed from the right-hand side
to assign CIP priorities.

To assign CIP descriptors for molecules with a chiral plane, one views the plane from the so-called
pilot atom which is the out-of-plane atom closest to the stereogenic element. The arrangement of
the next three subsequent atoms located in the chiral plane determined according to the CIP rules
will either describe a clockwise (Rp) or a counterclockwise (Sp) rotation.ii Although metallocenes
exhibit planar chirality, they are conventionally treated as molecules with a chiral center. First,
bonds between the p-donor and the metal atom are complemented as described above and the atom
of the highest priority is determined. The asymmetric environment of this tetrahedral atom is then
analyzed using the CIP rules to assign the absolute configuration, Figure 2.9.
As mentioned above, molecules with a helical shape may also be chiral. The sense of helicity is
described as right-handed (P) if it resembles a screw that rotates clockwise away from the viewer,
and left-handed (M ) if the rotation is counterclockwise. While hexahelicene exists in the form of
two enantiomers, decahelicene has two stereogenic elements, i.e., two helical turns, which gives rise
to a pair of (P,P)- and (M,M )-enantiomers and a meso (M,P)-isomer having an inversion center,
Figure 2.9. The sense of chirality in molecules with a stereogenic axis or plane may also be
characterized using descriptors M and P. For axially chiral compounds, only the substituents of the
highest CIP rank on each side of the stereogenic axis (denoted 1 and 3 in Figure 2.9) are considered.
After determination of these two substituents, one views the molecule along the chiral axis from an
arbitrarily chosen side. The helical descriptors are then assigned through rotation of the front
substituent in direction to the substituent located at the rear of the axis. The descriptor P denotes a
clockwise rotation, whereas M is assigned in the case of a counterclockwise rotation. In order to
assign helical descriptors to a chiral plane, one looks from the pilot atom at the subsequent atoms
using the CIP convention. Again, the descriptor P refers to a clockwise rotation and M to a
counterclockwise movement. Application of the two conventions to axially chiral compounds
reveals that descriptors Ra and M, as well as Sa and P, correspond to each other. In the case of
planar chirality, the descriptors Rp and P, and Sp and M, respectively, are synonymous.

ii
The use of suffixes a and p to indicate axial and planar chirality is optional.
12 Chapter 2

(a) (b)

+ +

achiral achiral achiral achiral achiral chiral

Figure 2.10 Achiral (a) and chiral (b) catenanes devoid of classical elements of chirality.

In addition to classical or Euclidian elements of chirality, introduction of directionality to

mechanically interlocked molecules can generate so-called topological chirality. Examples of
nonclassical chirality can be encountered in catenanes and rotaxanes. Catenanes contain two or
more interlocked rings, and rotaxanes consist of a molecule that is threaded through at least one
cyclic molecule which is trapped on the rod by bulky terminal groups. Intertwining of two achiral
rings often affords an achiral catenane, but a chiral assembly existing in the form of two mirror
images is obtained if the two achiral rings possess directionality, Figure 2.10.3,4 Similarly, incor-
poration of directionality into both axle and wheel of a rotaxane generates topological chirality. In
this case, the wheel attains either a clockwise or a counterclockwise orientation with respect to the
axle, resulting in cycloenantiomerism, vide infra.5 Topologically chiral compounds may lack
classical elements of chirality but still exist as a pair of enantiomers.
The assignment of the absolute configuration of topologically chiral molecules has been under
debate for some time, and different procedures utilizing CIP rules have been proposed.6,7 The
chirality of catenanes and rotaxanes composed of oriented ring and thread components can be
described through a combination of axial and polar vectors generating a right-handed or a left-
handed screw. The directionality of the interlocked units is assigned based on CIP priority rules. In
both ring and thread of a rotaxane, the direction from the atom of the highest priority to the atom
of the second highest priority following the shortest distance is determined to define (a) an axial
vector depicting the orientation of the thread and (b) a polar vector describing the orientation of
the ring. If the vector combination represents the motion of a right-handed screw, (R)-configur-
ation is assigned, whereas the (S )-enantiomer resembles a left-handed screw, Figure 2.11. [2]Ro-
taxanes consisting of only one oriented component are of course achiral. However, the presence of
at least one directional ring on a [3]rotaxane exhibiting a nondirectional thread gives rise to
topological chirality, Figure 2.12. The concept used for the assignment of the absolute configur-
ation outlined for chiral [2]rotaxanes can also be applied to cyclostereoisomeric [3]rotaxanes that
are chiral only by virtue of directionality of at least one ring component. In this case, one views the
oriented wheel which absolute configuration is under consideration from the direction of the other
wheel. The part of the thread bearing the second wheel has a higher priority than the part carrying
the wheel under consideration. For the determination of the configuration at ring B of the
[3]rotaxane shown in Figure 2.12, the side of the nondirectional axle bearing ring A receives a
higher priority to artificially assign an axial vector. Combination of this axial vector and the polar
vector of ring B then establishes (R)-configuration. Applying the same method to determine the
chirality at ring A confirms that the [3]rotaxane possesses (R,R)-configuration.
To apply the same concept to catenanes, one describes the orientation of one ring with a polar
vector while the other is viewed as a local thread and assigned an axial vector. The ring used to
determine the direction of the axial and polar vector, respectively, can be chosen arbitrarily. For
example, assignment of the axial vector based on the local directionality of ring A and the polar
vector based on the orientation of ring B affords (R)-configuration for the [2]catenane shown in
Figure 2.13.
The concept of cyclostereoisomerism resulting from ring directionality and the distribution
pattern of chiral but otherwise identical building blocks in a cyclic molecule, for example (R)- and
(S )-enantiomers of alanine in cyclohexaalanine, was first introduced by Prelog and Gerlach.8,9 The
Principles of Chirality and Dynamic Stereochemistry 13

achiral ring unit

achiral thread H H
N N
atom with second
highest CIP priority O O

O
O2
S
N N
H H O2 O
S
atom with highest atom with second N N
CIP priority highest CIP priority H H

axle directionality ring directionality based based on

atom with highest shortest distance from S to N
CIP priority

(S)-[2]rotaxane (R)-[2]rotaxane

H H H H
O N N N N O
O2 O2
O O S S O O
N N N N
H H H H

O2 O O O2
S S
N N N N
H H H H

axial vector shows axle directionality (S)-configuration (R)-configuration axial vector shows axle directionality

polar vector shows wheel directionality polar vector shows wheel directionality

Figure 2.11 Assignment of the absolute configuration of the enantiomers of a [2]rotaxane.

ring A ring B

H H H H
N N N N
O O O O
O O
H H
N O O N
O
O O

O2 O O O2
S S
N N N N
H H H H
axle (no directionality)

ring A ring B (R)-configuration (R)-configuration

Figure 2.12 Structure of an (R,R)-[3]rotaxane.

amino acid sequence and connectivity of stereogenic centers exhibiting both (R)- and (S)-configur-
ation in cyclopeptides give rise to cycloenantiomers and cyclodiastereoisomers, Figure 2.14. The
presence of ring directionality in cyclopeptides consisting of both enantiomers of one amino acid
does not change the overall number of possible stereoisomers, i.e., a cyclic peptide exists in as many
stereoisomers as the open chain form. Mislow therefore suggested that the term cyclostereoiso-
merism should be restricted to cases in which ring directionality generates additional stereoisomers,
and demonstrated that this can be achieved with hexaisopropylbenzene derivatives. For instance,
14 Chapter 2

(R)-[2]catenane

achiral ring unit axial vector of A

HN NH O polar vector
N NH
O O
H O of B
HN NH
O MeO MeO
(R)-configuration
O
O H O2S
MeO O2S N NH
atom with highest HN NH O polar vector
O
O2S CIP priority of A
HN NH
atom with second highest
CIP priority axial vector of B
ring B (R)-configuration
ring A

cyclic directionality based on CIP rules

Figure 2.13 Assignment of the absolute configuration of a [2]catenane based on CIP rules.

Me H H Me
H H H H
Cl Cl
N N Br H Br
H Br
HN (R) Me Me (S) NH Br
(S) (R) H (R) (R) H
Me Me Cl Cl (S)
O O (S)
Me H H Me
O O NH HN O O
H (S) (R) H Me Me
O (S) (R) Me
HN O H H O O NH Me
O O H Me Me H
Me Me
(S) (R) Me H H Me
Me (R) NH HN (S) Me
N N Me Me
H H H Me Me Me
Me H
H H
H Me Me H
cyclohexaalanine 1,2-bis(bromochloromethyl)-3,4,5,6-tetraisopropylbenzene

Figure 2.14 Structures of cycloenantiomeric cyclohexaalanine (left) and 1,2-bis(bromochloromethyl)-

3,4,5,6-tetraisopropylbenzene (right). Note that the two molecules of cyclohexaalanine differ
on account of the directional sense of the peptide bonds, i.e., R-S-S-R-S-S versus
S’R’R’S’R’R.

the directionality of 1,2-bis(bromochloromethyl)-3,4,5,6-tetraisopropylbenzene is due to static

gearing between the aryl substituents, which effectively increases the number of possible stereo-
isomers, see Chapter 8.7.10–12 The same situation arises with cyclostereoisomeric rotaxanes.
Removal of directionality in either the axle or the wheel in the chiral rotaxane shown in Figure
2.11 would eliminate topological chirality and thus reduce the number of stereoisomers; as a result,
one would observe only a single achiral [2]rotaxane instead of two enantiomers.
By analogy with topologically chiral rotaxanes and catenanes consisting of interlocked achiral
components, metal complexes containing two or more chelating ligands can display helical
chirality, even if all the individual components are achiral. For example, tris(ethylenediamine)co-
balt(III), [Co(en)3]31, is a chiral octahedral complex that exists in the form of two enantiomers. The
assignment of the absolute configuration of octahedral tris-chelate complexes is determined by the
sense of the helical coordination sphere generated by the ligands. The view along one of the three-
fold rotation axes of the octahedral complex reveals a sense of clockwise rotation similar to a right-
handed screw in a D-complex, whereas the enantiomeric L-complex resembles a left-handed screw
with a counterclockwise helical sense, Figure 2.15.
Principles of Chirality and Dynamic Stereochemistry 15

N N
N N N
N N N N N N N N
= ethylenediamine (en)
Co Co
N N N N
N
N N N N N
N = threefold rotation axis
N ∆-[Co(en)3]3+ Λ-[Co(en)3]3+ N
right-handed screw left-handed screw

Figure 2.15 Assignment of the absolute configuration of chiral metal complexes.

2.2 DYNAMIC STEREOCHEMISTRY OF CYCLIC AND ACYCLIC CHIRAL

COMPOUNDS
Dynamic stereochemistry deals with reversible and irreversible changes of the three-dimensional
structure of molecules, for example during thermal interconversion of conformational isomers,
photochemical isomerization, and acid- or base-catalyzed racemization. Stereodynamic properties
of chiral compounds are critical to the success of asymmetric synthesis including dynamic kinetic
resolution and chirality transfer processes, and they have been exploited in a wide range of
applications involving chiral amplification with relays and switches or correlated motion in
propellers, gears and motors. The diversity and complexity of dynamic stereochemistry becomes
evident through a discussion of conformational and configurational isomerism.
Stereoisomers can be classified into configurational and conformational isomers, which are
sometimes distinguished based on their stereochemical stability. Interconversion of configurational
isomers often requires bond breaking, whereas conformational isomers usually (but not exclusively)
isomerize without bond breaking. Accordingly, a relatively high energy barrier to racemization or
diastereomerization is commonly associated with configurational isomerism. The thermodynamic
stability and bond breaking criteria stress the physical organic properties of stereoisomers: the
isolable enantiomers of bromochlorofluoroiodomethane, Tröger’s base, and butylmethyl-
phenylphosphine are considered to be configurational isomers because they are stable to race-
mization at room temperature. By contrast, the enantiomers of methylethylpropylamine are often
viewed as conformational isomers because they rapidly interconvert through nitrogen inversion,
Figure 2.16. Similarly, the enantiomers of axially chiral biphenyls can either be classified as
configurational or conformational isomers. For instance, 2,2 0 -di-tert-butylbiphenyl has a high
energy barrier to racemization which is observed only at temperatures above 150 1C but the
enantiomers of 3,3 0 -di-tert-butylbiphenyl can not be isolated at room temperature due to rapid
rotation about the chiral axis. Although the isolation and stability criteria are practical, these
examples demonstrate that the categorization of structurally related molecules belonging to the
same class of compounds into conformational and configurational isomers is somewhat arbitrary.
The ambivalence of this definition is even more evident in the case of 2,2 0 -diiodobiphenyl, which
has a rotational energy barrier of 97 kJ/mol.13 Chromatographic isolation of the enantiomers,
which slowly racemize at room temperature, is possible if the process is not too time-consuming.iii
However, a clear definition of the isolation conditions, such as temperature and time scale, that
should be applied to distinguish configurational from conformational isomers does not exist.
Biaryls may or may not be stable to racemization at room temperature, and enantioconversion can
proceed via rotation about the chiral axis or bond breaking. For example, the enantiomers of

iii
The enantiomers of 2,2 0 -diiodobiphenyl show on-column racemization during HPLC separation on triacetyl cellulose at
ambient temperatures. Pure enantiomers of 2,2 0 -diiodobiphenyl can be isolated if the chromatographic process is rapid, but
racemization occurs upon standing or during HPLC if the separation process is slow.
16 Chapter 2

t-Bu t-Bu
F N

C P
Cl I Me
Ph
Br Bu N t-Bu t-Bu
(S)-bromochlorofluoro- (S)-butylmethylphenyl- (S,S)-Tröger's base (S)-2,2'-di-tert-butylbiphenyl rotation about the axis of
iodomethane phosphine 3,3'-di-tert-butylbiphenyl

O O
Et N N • O N
Pr N
Me N N
N N
Me
Pr
Et
N-inversion of ethylmethylpropylamine electrocyclic ring opening and isomerization of 1-(2'-methylphenyl)-4,6-dimethylpyrimidin-2-one

Figure 2.16 Chiral compounds exhibiting conformational or configurational isomerism and racemization
mechanisms.

1-arylpyrimidine-2-thiones and their oxygen analogs can be conveniently isolated by chiral chro-
matography but undergo racemization during [3,3]-electrocyclic rearrangement involving ring
opening and bond breaking at elevated temperature.14,15 Clearly, the stability and bond-breaking
criteria are vague and sometimes incompatible.
Alternatively, configurational isomers have been defined as stereoisomers possessing different
bond angles while conformers differ in torsion angles. It should be noted that bond and torsion
angles can vary in amplitude and sign. For example, the enantiomers of butyl-
methylphenylphosphine display bond angles of the same value, albeit with opposite sign. As the
relative stability becomes irrelevant, the enantiomers of compounds with a chiral center, including
Tröger’s base and ethylmethylpropylamine, are considered configurational isomers. All axially
chiral biaryls mentioned above afford conformational enantiomers, irrespective of their rotational
energy barrier or isomerization mechanism. One shortcoming of this classification is that (E)- and
(Z)-alkenes, or the enantiomers of allenes and (E)-cycloalkenes, having a chiral axis or plane may
thus be regarded as conformational isomers. This seems somewhat counterintuitive to many
chemists. Both definitions are commonly used in the literature to classify stereoisomers. Since the
stability criterion and the corresponding isolation conditions are not clearly defined, and are
problematic in some cases, the distinction between configurational and conformational isomerism
in the present book is based on differences in bond and torsion angles, respectively.
Organic compounds often exist as a mixture of constantly interconverting conformational
isomers. In many cases, achiral compounds populate both achiral and racemic chiral conforma-
tions at equilibrium. As has been discussed above for tartaric acid, 2,3-diaminobutane has two
chiral centers and forms three configurational isomers, i.e., a meso (2R,3S)-isomer and a pair of
enantiomers with (2R,3R)- and (2S,3S)-configuration. A comparison of the chemical and physical
properties of acyclic configurational stereoisomers requires analysis of the corresponding mixtures
of fluxional conformers. A closer look at the three-dimensional structure of meso 2,3-diamino-
butane reveals that it adopts three conformational isomers, with torsion angles varying in either
magnitude or sign. The meso isomer can populate an achiral antiperiplanar and two enantiomeric
synclinal conformers that rapidly rotate about the central carbon–carbon bond at room tempera-
ture, while (2R,3R)-2,3-diaminobutane and its enantiomer are inherently chiral and exist as a
mixture of three interconverting diastereomeric rotamers, Figure 2.17. The ratio of the achiral to
the two equienergetic chiral conformations of meso 2,3-diaminobutane can be expected to change
with temperature and to vary in the gas, liquid and solid state, but the mixture is always racemic in
the absence of a chiral bias. It is important to realize that facile rotation about the carbon–carbon
bond in compounds such as meso 2,3-diaminobutane generates enantiomeric conformational
isomers that become diastereomeric in a chiral environment; in other words, the presence of a
Principles of Chirality and Dynamic Stereochemistry 17

meso (2R,3S)-2,3-diaminobutane (2R,3R)-2,3-diaminobutane

NH2 NH2 NH2 NH2 NH2 NH2
H3C H H2N CH3 H NH2 H CH3 H3C NH2 H2N H
H CH3 H CH3 H CH3 H CH3 H CH3 H CH3
NH2 H CH3 NH2 H CH3
achiral enantiomers

diastereoisomers
diastereoisomers

Figure 2.17 Newman projection of the conformational isomers of (2R,3S)- and (2R,3R)-2,3-diaminobutane.

R R

E R

(M)-biphenyl (P)-biphenyl

R R R R
R R R R
anti-form syn-form syn-form anti-form

-180o -90o 0o 90o 180o

Figure 2.18 Energy profile of 2,2 0 -disubstituted biphenyls.

nonracemic chiral additive can disturb the equilibrium between the enantiomers. Chelating inter-
actions of meso (2R,3S)-2,3-diaminobutane with an achiral compound, for example maleic acid,
selectively stabilizes and thus favors synclinal conformations over the antiperiplanar rotamer, but it
does not change the racemic equilibrium. By contrast, hydrogen bond interactions or salt formation
with a chiral acid such as (2R,3R)-tartaric acid render the enantiomeric conformers of meso
2,3-diaminobutane diastereomeric and selectively favor one over the other.
Axially chiral biphenyls undergo racemization via rotation about the pivotal aryl–aryl bond, see
Chapter 3.3. In the ground state conformation, the aryl planes are neither coplanar nor orthogonal
due to a compromise between resonance stabilization and steric interactions. While coplanarity of
the aromatic rings would maximize resonance stabilization, it would also cause severe repulsion
between ortho-substituents. The steric interactions between ortho-substituents are minimized in an
orthogonal geometry, but at the expense of p-electron overlap which decreases with the cosine
of the torsion angle. As a result, the enantiomers of 2,2 0 -disubstituted biaryls populate two
diastereomeric syn- and anti-conformations, with torsion angles in solution usually ranging from
30 to 80 1, and 100 to 150 1, respectively. In most cases, the anti-form is thermodynamically more
stable but 2,2 0 -dihalobiphenyls have been reported to prefer the syn-conformation.16,17 A typical
energy profile of 2,2 0 -disubstituted biphenyls is shown in Figure 2.18.iv
It is therefore not surprising that conformational equilibria of acyclic and cyclic compounds
affect the stereochemical outcome of asymmetric transformations, see Chapters 6.5 and 6.6. A well

iv
Incorporation of sterically demanding substituents into the ortho-positions of biphenyl significantly increases the energy
barrier to rotation and favors a near-orthogonal ground state geometry.
18 Chapter 2

Cram's rule Br
X
Mg
Ph
R′ M BrMgO Ph O
O O O OMgBr H CH3
(S) Si-face
S M (S) H CH3 PhMgBr H CH3
(R) attack
Ph Me Ph
Ph Ph Me
L Ph Me Ph
R 80% de favored transition state

Cram's chelation rule Me Me

R′ X Mg
M O OMe Si-face
OMgMe attack
Me OMgMe O OMe
(S) OMe Me2Mg (S) OMe
O OR Ph
H Me Ph (R)
H Me
Ph
S L 99% de Ph
favored transition state
R

Scheme 2.1 Rationalization of the stereoselectivity of 1,2-nucleophilic additions to chiral ketones, based on
Cram’s rule.

known example is the asymmetric 1,2-addition of organometallic reagents and hydrides to carbonyl
compounds possessing an adjacent chiral center. The diastereofacial selectivity of a nucleophilic
addition to a chiral ketone depends on the conformational dynamics of the substrate, and a variety
of models that attempt to predict the selectivity of such 1,2-asymmetric inductions has been
developed. A powerful rationale was introduced by Cram.18 Assuming a noncatalytic, kinetically
controlled reaction, and disregarding electronic effects and the Curtin–Hammett principle, Cram
reasoned that the stereoselectivity of nucleophilic attacks on acyclic ketones and aldehydes could be
rationalized by considering a single substrate conformation. He postulated that the substrate
resides throughout the reaction in a preferred conformation having the largest substituent L
attached to the chiral center antiperiplanar to the adjacent carbonyl function. The organometallic
reagent then approaches the carbonyl group from the less sterically hindered side with the smallest
substituent S because the medium-sized substituent M affords greater steric hindrance, Scheme 2.1.
The diastereoselectivity of the Grignard reaction between phenylmagnesium bromide and (S)-
3-phenylbutan-2-one can be rationalized by looking at the Newman projection of the favored
transition state. Since the proton provides less steric hindrance than the methyl substituent,
phenylation occurs preferentially from the Si-face, producing (2R,3S)-2,3-diphenylbutan-2-ol in
80% diastereomeric excess. This simple but powerful rationale was later extended to the so-called
Cram chelation model to accurately predict the selectivity of a nucleophilic attack on chiral
substrates that possess a stereocenter bearing a heteroatom in a- or b-position to the carbonyl
function.19 Cram and others showed that a-alkoxy ketones and Grignard reagents form a cyclic
structure having the alkoxy group synperiplanar to the carbonyl function, Scheme 2.1. The
restricted conformational freedom leads to a highly diastereoselective transition state in which
the nucleophile is delivered from the less sterically hindered face exhibiting the smaller ligand S. In
contrast, attack from the opposite side is impeded by the presence of the larger ligand L. For
example, formation of an intermediate dimethylmagnesium complex of (S)-2-methoxy-1-phenyl-
propanone effectively locks the substrate into a single conformer and thus restricts the number of
possible transition states, which increases stereoselectivity. Comparison of the diastereotopic faces
of the five-membered chelate explains why the nucleophilic attack on the carbonyl moiety
preferentially occurs from the Si-face, yielding (2R,3S)-3-methoxy-2-phenylbutan-2-ol in excellent
diastereomeric excess.20
The preceding discussion, and additional examples given in Chapters 5, 6 and 7, emphasize the
importance of careful stereodynamic analysis of chiral substrates, reagents and catalysts for
Principles of Chirality and Dynamic Stereochemistry 19

prediction or interpretation of asymmetric induction. The mechanism of Grignard reactions of

a- and b-alkoxy carbonyls is further complicated by Schlenk equilibria, competition between
acyclic and cyclic reaction pathways and solvation effects. Cram’s model correctly predicts the
stereochemical outcome of many diastereoface-differentiating additions, except for reactions
involving a-halogenated ketones and a-substituted cyclohexanones. To overcome these limitations,
the simple rationale introduced by Cram has been further refined by Karabatsos,21 Felkin,22,23
Anh,24 and Heathcock,25,26 accounting for the Bürgi–Dunitz trajectory,27 as well as for complicated
conformational equilibria, Hammond’s postulate,28 Curtin–Hammett kinetics,29 and competing
steric and electronic effects. Nevertheless, Cram’s model is still commonly used to predict 1,2-
asymmetric induction in nucleophilic additions to aldehydes, ketones, imines, and their derivatives.
The stereodynamics of chiral compounds can afford sophisticated relays and molecular devices,
including propellers and motors mimicking nature, see Chapters 6.5.4, 8.1 and 8.11. Allosteric
regulation and homotrophic or heterotrophic cooperativity of enzymes is controlled by reversible
binding of molecular activators and inhibitors. The binding of a so-called effector induces a change
in the three-dimensional enzyme structure, which ultimately affects a distant active site, i.e.,
conformational communication in proteins is the basis for remote reaction control. The idea of
stereoselective communication and remote chiral induction is fascinating to synthetic chemists and
stereochemists alike. An impressive example of stereodynamic control resulting in highly selective
chiral induction transmitted through 22 bonds of a conformationally responsive relay has been
accomplished by Clayden and coworkers.30 Conformational analysis of an array of three rigid
amide-substituted xanthenes confirmed that the tertiary amide groups prefer anti-conformation to
minimize the overall dipole moment and steric repulsion, Scheme 2.2. Introduction of an ephedrine-
derived (S)-oxazolidine residue at one terminus of a tris(arenedicarboxamide) framework consist-
ing of three xanthene rings induces a right-handed twist (P-helicity) on the first two amide groups
attached to the neighboring arenedicarboxamide. This local conformational induction then propa-
gates by a domino effect through the contiguous xanthenedicarboxamide moieties showing either
(M)- or (P)-helicity. As each of the six amide groups adopts an anti-conformational orientation
relative to the previous one, the central chirality of the oxazolidine ring triggers formation of a

N N N N
O O O O
(S) (P) (P) (P) (P)
O O CHO
N O
O (M) (M)
Ph O O
N N

PhMgBr, -78 oC

N N N N
O O O O OH
(S) (P) (P) (P) (P) 77%, 95% de
O O
N O (S) Ph
O (M) (M)
Ph O O
N N

25 Å

Scheme 2.2 Remote stereocontrol and asymmetric induction via conformational communication along a
tris(xanthenedicarboxamide) relay.
20 Chapter 2

1,2-isomers 1,3-isomers 1,4-isomers

cis trans cis trans cis trans

∆G = 7.83 kJ/mol
o
∆G = 8.20 kJ/mol
o
∆G = 7.95 kJ/mol
o

trans-1,2-isomer cis-1,3-isomer trans-1,4-isomer

ee aa ee aa ee aa

∆G = 11.5 kJ/mol
o
∆G = 15.5 kJ/mol
o
∆G = 11.5 kJ/mol
o

Figure 2.19 Relative stability of configurational (top) and conformational isomers (bottom) of dimethyl-
cyclohexanes. The more stable isomer is underlined.

robust atropisomeric array and controls the outcome of diastereoselective reactions at the remote
aldehyde group located at the other terminus. Grignard reaction with phenylmagnesium bromide at
–78 1C gives the corresponding secondary (S)-alcohol in 77% yield and 95% de as a consequence of
[1,23]-asymmetric induction over a distance of 2.5 nm.
The high degree of rotational freedom inherent to acyclic molecules allows effective minimization
of steric and torsional strain. Cyclic molecules experience less conformational flexibility to balance
both factors. The stereodynamic behavior of cyclic molecules is more restricted than that of acyclic
compounds, and is controlled by torsion (Pitzer) and angle (Baeyer) strain, and other stabilizing or
destabilizing forces such as hydrogen bonding, dipole–dipole interactions and 1,3-syndiaxial or
1,4-transannular repulsion. Three-membered and a few four-membered rings are flat while the ring
geometry of all other cycloalkanes is nonplanar and usually quite fluxional. Puckering of four-
membered rings is common and reduces torsion strain, albeit at the expense of some angle strain.
Five- and six-membered rings form envelope and chair conformations to balance torsion and angle
strain. As a consequence, substituents can occupy equatorial or axial positions, and this generates a
variety of stereoisomers.
Monosubstitued cyclohexanes are achiral but exist as a mixture of two diastereomeric chair
conformations that rapidly interconvert at room temperature via ring inversion. Isomerization of
one chair to the other proceeds via transient boat and twist conformations, converting axial into
equatorial positions and vice versa.31 In general, the chair bearing the substituent in equato-
rial position is thermodynamically favored. Disubstituted cyclohexanes can have cis- or trans-
configuration. In the case of cis-1,2-, trans-1,3-, and cis-1,4-cyclohexanes, one substituent occupies
an axial and the other an equatorial position. By contrast, the corresponding trans-1,2-, cis-1,3-,
and trans-1,4-disubstitued isomers interconvert between diaxial and diequatorial chair conforma-
tions, the latter being thermodynamically favored, with the exception of some diaxial cis-1,3-
disubstituted cyclohexanes that are stabilized by intramolecular interactions such as hydrogen
bonding and trans-1,2-dihalocyclohexanes which preferentially populate the diaxial conformation,
Figure 2.19. In particular, intramolecular hydrogen bonding can have a dramatic effect on the
relative stability of conformational isomers. Spectroscopic analysis of the stereodynamics of
methyl-b-D-2,4-di-O-pyrenecarbonylxylopyranoside by Yuasa and coworkers revealed that the
4
C1-conformer of this carbohydrate exhibiting all four substituents in equatorial positions is
favored over the 1C4-conformation in DMSO and methanol, Scheme 2.3.32 However, intra-
molecular hydrogen bonding between the free hydroxyl and the methoxy group stabilizes the
1
C4-conformation and excimer formation in chloroform and other aprotic solvents. The ring flip is
therefore controlled by intramolecular hydrogen bonding and the presence or absence of solvents
that interfere with this interaction.
Principles of Chirality and Dynamic Stereochemistry 21

4 1
C1-conformer C4-conformer H OMe
O O
O
O
O
HO OMe
O O O O O
CHCl3
O DMSO

Scheme 2.3 Ring inversion of methyl-b-D-2,4-di-O-pyrenecarbonylxylopyranoside.

All trans-1,2- and trans-1,3-disubstituted cyclohexanes are chiral, even when the two substituents
are identical. In these cases, ring flipping does not result in racemization and the enantiomers are
isolable at room temperature. For example, ring inversion of the diequatorial isomer of trans-1,2-
diaminocyclohexane generates the corresponding diaxial conformer but it does not produce a
mirror image, Figure 2.20. The situation is different in cis-1,2- and cis-1,3-disubstituted cyclohex-
anes. Although cis-1,2-diaminocyclohexane is inherently chiral, the enantiomeric conformers can
not be isolated at room temperature due to rapid interconversion via chair inversion. The diaxial
and diequatorial isomers of cis-1,3-diaminocyclohexane possess a symmetry plane and are achiral.v
Introduction of different substituents into 1,2- and 1,3-disubstituted cyclohexanes provides a
mixture of separable stereoisomers, e.g., cis- and trans-1-amino-2-methylcyclohexane exist as two
pairs of noninterconverting enantiomers. The conformations of cis- and trans-1,4-disubstituted
cyclohexanes have a plane of symmetry and are generally achiral.
Nucleophilic additions to 4-substituted cyclohexanones often proceed with low selectivity
because of the conformational flexibility of the six-membered ring and weak stereoselective
induction from the remote substituent. However, the sterically demanding tert-butyl group prefers
to reside in the equatorial position and effectively locks 4-tert-butylcyclohexanone into one
conformation, which in most cases improves diastereoselectivity. Since the contribution from the
less stable cyclohexanone conformer having the tert-butyl group in the axial position is negligible,
the prediction of diastereoselective reactions of 4-tert-butylcyclohexanone is simplified and requires
stereochemical analysis of only a single conformer. Most nucleophiles including Grignard and
organolithium reagents approach the carbonyl group at an angle close to 109 1 (Bürgi–Dunitz
trajectory) from the site opposite to the bulky tert-butyl group. Reetz and Stanchev obtained the
axial carbinol via organiron(II)-mediated diastereofacial addition of butylmagnesium chloride in
76% de. This is generally attributed to a less shielded equatorial attack on the carbonyl of the
predominant conformation of 4-tert-butylcyclohexanone, Scheme 2.4.33 By contrast, very small
nucleophiles such as hydrides or acetylides experience less steric interaction with the remote 4-tert-
butyl group and favor the axial approach to avoid local interactions with the axial hydrogens at C-2
and C-6. Reduction of 4-tert-butylcyclohexanone with lithium aluminum hydride proceeds pref-
erentially via axial attack and produces the equatorial alcohol as the major product.
Incorporation of small groups into the a-position of cyclohexanone does not change the
preference of lithium aluminum hydride for an axial attack. Computation of the two conformations
of (R)-2-methylcyclohexanone shows that the methyl group does not strongly interfere with an axial
approach. The predominant formation of (1R,2R)-trans-2-methylcyclohexan-1-ol can be attributed
to a relatively rapid hydride addition to the major conformer of (R)-2-methylcyclohexanone having

v
The same considerations apply to cyclopentanes, i.e., trans-1,2- and trans-1,3-disubstituted cyclopentanes are chiral,
irrespective of the structure of the substituents. Similarly, trans-1,2-cyclobutanes and trans-1,2-cyclopropanes are inherently
chiral, whereas both cis- and trans-1,3-cyclobutanes exhibiting identical substituents are achiral.
22 Chapter 2

trans-diaminocyclohexanes cis-diaminocyclohexanes
NH2 NH2 NH2
NH2 NH2
NH2 H2N NH2 NH2 H2N
NH2 H2N ea-conformation ae-conformation
NH2 NH2
ee-conformation aa-conformation aa-conformation ee-conformation
rapidly interconverting enantiomers
noninterconverting enantiomers

NH2 NH2 H2N NH2

NH2 NH2
* *
NH2 H2N interconverting achiral conformations
H2N NH2
NH2 NH2
ea ae ae ea

noninterconverting enantiomers
*ring flipping produces identical structures

trans-1-amino-2-methylcyclohexanes cis-1-amino-2-methylcyclohexanes

ee NH2 H2N ee ea NH2 H2N ea

NH2 NH2 NH2 NH2

aa aa ae ae

noninterconverting enantiomers noninterconverting enantiomers

Figure 2.20 Conformations and chirality of disubstituted cyclohexanes.

Diastereoselective Gignard addition

axial attack OH
BuMgCl major isomer
109o
Bu
O BuMgCl axial carbinol
O Fe(acac)2 Bu
109o
interconverting chair minor isomer
conformations equatorial attack OH
(favored) equatorial carbinol

Diastereoselective reduction
axial attack OH
(favored)
109o minor isomer
H H
O LiAlH4 axial carbinol
o H
109
H major isomer
H OH
H equatorial carbinol
equatorial attack

Scheme 2.4 Stereoselective Grignard reaction and reduction of 4-tert-butylcyclohexanone with LiAlH4.

the methyl group in the equatorial position, Scheme 2.5. An increase in the steric bulk of the
a-substituent further locks the ketone into the equatorial conformation and results in enhanced
steric hindrance to an axial attack. In the case of 2-tert-butylcyclohexanone, these interactions
exceed the repulsion between the approaching hydride and the axial hydrogens at C-2 and C-6, and
Principles of Chirality and Dynamic Stereochemistry 23

axial attack
(favored) 109o
H OH H
Me Me Me
O LiAlH4
H + OH
109o cis-(1S,2R)-2-methyl- trans-(1R,2R)-2-methyl-
H
H cyclohexan-1-ol cyclohexan-1-ol
H 24% 76%
equatorial attack
axial attack
(favored)

equatorial attack

axial attack
equatorial attack
(favored)
axial attack
H OH H
t-Bu t-Bu t-Bu
O LiAlH4
H + OH
H cis-(1S,2R)-2-methyl- trans-(1R,2R)-2-methyl-
H cyclohexan-1-ol cyclohexan-1-ol
H 58% 42%
equatorial attack
(favored)

Scheme 2.5 Diastereoselective reduction of (R)-2-alkylcyclohexanones.

reduction with LiAlH4 affords 2-tert-butylcyclohexanol as a 58:42 diastereomeric mixture in favor

of the cis-isomer.34
An interesting example that underscores the significance of the relative population and inter-
conversion of configurational isomers is the diastereoselective N-oxidation of N-methyl-4-tert-
butylpiperidine, Scheme 2.6.35,36 As a result of facile N-inversion, this compound exists as a mixture
of two rapidly interconverting isomers having either an equatorial or an axial methyl group. The
piperidine conformer that bears the methyl group in the equatorial position is approximately 60
times more thermodynamically stable than the axial conformer due to 1,3-syndiaxial repulsion
between the axial methyl group and two axial hydrogens. Reaction with hydrogen peroxide
proceeds more quickly with the minor diastereoisomer because it provides a more accessible
equatorial position for oxidation. Although N-inversion is a rapid process, the relative population
of the conformational piperidine isomers has a major effect on the stereochemical outcome of the
oxidation. The reported oxidation product ratio of 19:1 in favor of the axial N-oxide can be
attributed to competing nitrogen inversion and diffusion-controlled diastereoselective oxidation.vi
Cyclohexenes exist in two half-chair conformations that rapidly isomerize at room temperature.
Because the double bond and the two adjacent saturated carbon atoms C-3 and C-6 are in one
plane, allylic substituents reside in pseudoequatorial and pseudoaxial positions while carbons C-4
and C-5 generate truly axial and equatorial positions. Similar to cyclohexanes, substituents
preferentially occupy equatorial positions, although the energetic difference between equatorial
and axial conformers is less pronounced in cyclohexenes as a consequence of the reduced steric
repulsion experienced by axial substituents. In cyclohexene rings, axial groups participate in only
one 1,3-synpseudoaxial interaction, whereas two 1,3-syndiaxial interactions with truly axial
hydrogens destabilize the axial conformation in cyclohexanes, Figure 2.21. For the same reason,
the general preference of allylic substituents for a pseudoequatorial orientation is less pronounced
than the difference in the relative stability of axial and equatorial positions in saturated rings.
Electronegative substituents such as halides or amino, amido and alkoxy groups favor the
pseudoaxial position.37 In accordance to the anomeric effect observed with carbohydrates, the
vi
Because both N-inversion and oxidation are rapid processes with similar reaction rates, the Curtin–Hammett principle does
not apply.
24 Chapter 2

1,3-syndiaxial
repulsion
H
H H H O
H k1
H2O2 N H2O2
N N N
O k4 k3
k2
equatorial N-oxide axial N-methylpiperidine equatorial N-methylpiperidine axial N-oxide
5% (minor isomer) (major isomer) 95%
k1/k2 ~ 60 k3 < k4

Scheme 2.6 Oxidation of N-methyl-4-tert-butylpiperidine.

isopropylcyclohexane 4-isopropylcyclohexene
H H
H
H H
H H i-Pr
H H
H i-Pr
H H H H
H i-Pr H H
equatorial conformer
1,3-syndiaxial i-Pr H
repulsion 1,3-synpseudoaxial equatorial conformer
axial conformer repulsion
axial conformer

X
X = Cl, Br, NHR, OH, OR
π σ*

resonance stabilization in unsaturated rings

with pseudoaxial electronegative substituents

Figure 2.21 Substituent effects on the relative stability of cyclohexane and cyclohexene conformations.

preference for the pseudoaxial position has been explained with resonance stabilization due to
overlap of the p-system of the double bond and an antibonding orbital of the allylic s-bond.
The relative stability of the half-chair conformation of disubstituted cyclohexenes or tetralin
(1,2,3,4-tetrahydronaphthalene) derivatives depends on a variety of intramolecular interactions in
addition to torsion and angle strain. Most important are resonance between the double bond and
the pseudoaxial allylic s-bond, synpseudoaxial repulsion, dipole–dipole interactions, and hydrogen
bonding. For example, incorporation of a methyl group into the saturated moiety of 4-(3 0 ,5 0 -
dinitrobenzamido)-1,2,3,4-tetrahydrophenanthrene at carbons C-1, C-2 and C-3 alters the relative
stability of the conformer having the benzylic amido group in pseudoaxial position. Wolf and
Pirkle studied the conformational preference and rigidity of disubstituted 4-(3 0 ,5 0 -dinitrobenz-
amido)-1,2,3,4-tetrahydrophenanthrene derivatives which are structural analogs of the so-called
Whelk-O selector.38 Initially developed to separate the enantiomers of naproxen and other profens,
this selector forms a chiral cleft which appears to be crucial for enantioselective recognition.vii It is
assumed that only one enantiomer of a given racemate can diffuse into the cleft to undergo
simultaneous hydrogen bonding to the amide function and face-to-face and face-to-edge inter-
actions with the aromatic moieties while maintaining a heavily populated low energy conformation,
Figure 2.22.39–44
The propensity of the DNB group to occupy the pseudoaxial position in 4-(3 0 ,5 0 -dinitrobenz-
amido)-1,2,3,4-tetrahydrophenanthrenes was evaluated based on chromatographic structure-activity
relationships. Chiral HPLC separation of the racemic Whelk-O analogs shown in Table 2.1 on an

vii
The Whelk-O selector has been used extensively for chromatographic enantioseparation of compounds exhibiting a
stereogenic center, axis or plane in close proximity to a hydrogen bond acceptor (usually a carbonyl group).
Principles of Chirality and Dynamic Stereochemistry 25

(3R,4R)-Whelk-O selector
O
O
pseudoaxial (S)-naproxen diamide
DNB group
Me2N

(S)-naproxen dimethylamide
3)
NO2

O
NO2

2) NH
1)

equatorial methyl

1) hydrogen bonding cis-(3R, 4R)-4-(3',5'-dinitrobenzamido)-3-

methyl-1,2,3,4-tetrahydrophenanthrene
2) face-to-edge interaction
3) face-to-face interaction

Figure 2.22 Chiral cleft and favored conformation of the Whelk-O selector participating in simultaneous
hydrogen bonding, face-to-face and face-to-edge interactions with (S)-naproxen dimethyl-
amide. Hydrogens bonded to carbon atoms are not shown. [Reproduced with permission from
Tetrahedron 2002, 58, 3597–3603.]

(S)-naproxen amide-derived chiral stationary phase allowed determination of the difference in the
Gibbs free energy, DDG1, of transient diastereomeric complexes according to Equation 2.1.

DDG ¼
RT ln a ð2:1Þ

where a is the chromatographic separation factor, and DG1 is the Gibbs free energy of the formation
of transient diastereomeric complexes.

These energetic differences can be correlated to the influence of the methyl group on the relative
stability of the Whelk-O conformers. Stabilization of a cleft-like structure bearing a pseudoaxial
DNB group results in high enantioselectivity because (S)-naproxen fits perfectly into the chiral
pocket of one of the chromatographed Whelk-O enantiomers, as depicted in Figure 2.22. In
contrast, enantioselective recognition is diminished when the Whelk-O enantiomers are likely to
adopt a structure with a pseudoequatorial DNB group. In this case, the difference in the Gibbs free
energy, DDG1, of the transient diastereomeric complexes formed between the CSP and the
enantiomeric solutes is reduced as none of them can accommodate simultaneous hydrogen
bonding, face-to-face and face-to-edge interactions. Introduction of a methyl group into positions
C-1, C-2 and C-3 of the 4-amidotetrahydrophenanthrene ring yields three pairs of diastereoisomers
having either cis- or trans-configuration, Table 2.1. In order to understand the chiral recognition
mechanism, one has to remember that the tetrahydrophenanthrene ring of these Whelk-O analogs
resembles a cyclohexene or tetralin structure and that the benzylic electron-withdrawing benzamido
group generally prefers the pseudoaxial position.
The difference in the Gibbs free energy between the transient diastereomeric complexes formed
by the enantiomers of 4-(3 0 ,5 0 -dinitrobenzamido)-1,2,3,4-tetrahydrophenanthrene and the (S)-
naproxen-derived chiral stationary phase was determined as 3.87 kJ/mol. The high selectivity has
been attributed to extensive population of the conformer that has the benzamido substituent in
26 Chapter 2

Table 2.1 Energetic differences of transient diastereomeric

complexes of Whelk-O analogs and immobi-
lized (S)-naproxen diamide.
Whelk-O derivative Relative configuration DDG1 [kJ/mol]

/ 3.87
DNBHN

cis-3,4- 4.05
DNBHN

trans-3,4- 3.77
DNBHN

cis-2,4- 1.52
DNBHN

trans-2,4- 3.02
DNBHN

cis-1,4- 3.56
DNBHN

trans-1,4- 1.92
DNBHN

Only one enantiomer of the racemic Whelk-O analogs is shown.

DNB ¼ 3,5-dinitrobenzoyl group.

pseudoaxial position, thus forming a chiral cleft exhibiting the 3,5-DNB group perpendicular to the
tetrahydrophenanthrene plane, which is a prerequisite for effective chiral recognition. Incorpora-
tion of a methyl group into the adjacent position provides cis- and trans-4-(3 0 ,5 0 -dinitrobenz-
amido)-3-methyl-1,2,3,4-tetrahydrophenanthrene. The cis-configuration preferentially populates
the conformation with a pseudoaxial DNB group and an equatorial methyl group over the
conformer having the DNB group in pseudoequatorial and the methyl substituent in axial position.
The cis-3,4-disubstituted Whelk-O analog therefore strongly favors the cleft-like conformation and
undergoes highly enantioselective interactions with (S)-naproxen exceeding 4.0 kJ/mol. By con-
trast, the cleft-like conformation is less heavily populated in the trans-3,4-disubstituted Whelk-O
derivative because it bears an axial methyl group. The stereoselectivity observed with the trans-
isomer is therefore reduced to 3.77 kJ/mol. The enantiomers of trans-4-(3 0 ,5 0 -dinitrobenzamido)-
2-methyl-1,2,3,4-tetrahydrophenanthrene can afford a conformation having the two substituents in
Principles of Chirality and Dynamic Stereochemistry 27

the preferred pseudoaxial and equatorial orientations, whereas the cis-2,4-isomer must place the
methyl group in axial position in order to form the cleft with a pseudoaxial DNB group. The cleft-
like conformer is therefore more heavily populated by the trans-2,4-isomer than by the cis-
derivative. Accordingly, (S)-naproxen effectively differentiates between the enantiomers of the
trans-isomer (DDG1 ¼ 3.02 kJ/mol) but enantioselective separation and recognition of the cis-
diastereomer is diminished (1.52 kJ/mol). Finally, cis-4-(3 0 ,5 0 -dinitrobenzamido)-1-methyl-1,2,3,4-
tetrahydrophenanthrene shows superior enantioselectivity (DDG1 ¼ 3.56 kJ/mol) over the
trans-disubstituted analog (1.92 kJ/mol) because the cleft-like conformer is destabilized in the latter
due to synpseudoaxial interactions experienced by the methyl group. Clearly, the relative stability
and stereoselectivity of the cleft-like Whelk-O conformers originate from an energetic compromise
between the tendency of the DNB group to occupy a pseudoaxial position and the preference of the
methyl group for an equatorial or pseudoequatorial orientation.

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CHAPTER 3

Racemization, Enantiomerization and

Diastereomerization

The development of mechanistic insights into isomerization reactions, and information about the
conformational and configurational stability of chiral compounds under various conditions, are
indispensable for today’s chemist. Racemization, enantiomerization and diastereomerization of
chiral compounds play a key role across the chemical sciences and provide multiple opportunities
for asymmetric synthesis, the design of microscopic motors and machines, drug discovery and
medical diagnosis. A basic understanding of the properties and reactions of chiral compounds
requires in-depth analysis of the stereodynamics of coexisting isomers. Compounds that exist as a
mixture of rapidly interconverting stereoisomers are often conveniently, albeit inaccurately, viewed
as one averaged structure. A closer look reveals that organic compounds are generally fluxional and
adopt more than one conformation or configuration. For example, amines that have three different
substituents at the stereogenic nitrogen atom exist as a pair of configurationally unstable
enantiomers, and monosubstituted cyclohexanes populate two diastereomeric chair conformations
(and negligible twist conformations) having the substituent in either equatorial or axial position.
Because of the inherently low energy barrier to interconversion, it is often difficult to distinguish
between the individual isomers of stereolabile compounds. The energy barrier to pyramidal
inversion of ethylmethylisopropylamine is 31.4 kJ/mol, and the activation energy required for ring
flipping of the isomers of chlorocyclohexane is about 44 kJ/mol, Scheme 3.1. Both processes,
racemization of ethylmethylisopropylamine and diastereomerization of chlorocyclohexane, are fast
and only one averaged species is observed by NMR spectroscopy at room temperature. One can
distinguish between diastereotopic proton signals of the individual isomers of monosubstituted
cyclohexanes or chiral amines in the presence of a chiral shift reagent under cryogenic conditions
when the rates of interconversion are relatively slow with respect to the NMR time scale.
Alternatively, faster methods such as time-resolved microwave and IR spectroscopy generate an
instantaneous rather than a time-averaged spectrum and can be used to study the structures and
properties of stereolabile isomers even at room temperature.

.. Et
Me i-Pr
N N Cl
Me
i-Pr ≠
Et ≠
.. ∆G ≈ 44 kJ/mol
Cl
∆G = 31.4 kJ/mol

Scheme 3.1 Interconversion of the stereoisomers of ethylmethylisopropylamine and chlorocyclohexane.

29
30 Chapter 3

3.1 CLASSIFICATION OF ISOMERIZATION REACTIONS OF CHIRAL

COMPOUNDS
Stereomutations of conformationally and configurationally unstable chiral molecules can be
treated as a macroscopic process, in which an enantiopure or diastereomerically pure compound
is transformed by thermal equilibration either to a racemate or to a diastereoisomeric mixture.
Alternatively, isomerization reactions can be viewed at the molecular level. The macroscopic
change is by definition irreversible, whereas the microscopic view takes into account the individual
rate constants of reversible reactions, Figure 3.1.1 Racemization is an irreversible process that is
completed when 50% of an enantiopure compound has been converted to the other enantiomer.
The corresponding half-life time is the time during which the enantiomeric excess of a chiral
mixture has been reduced to half its initial value, for example from 100% ee to 50% ee. At the
microscopic level, the same process is perceived as a reversible enantiomerization reaction with a
different rate constant kenant ¼ 0.5 krac. This process is completed when all molecules have been
converted to the other enantiomer. The half-life time of enantiomerization is the time required for
50% interconversion, i.e., a change from 100% ee to 0% ee. Enantiomerization is usually reversible
and leads to the formation of a racemate but many unidirectional processes resulting in complete
enantioconversion are known. For example, (R)-profens are enantioselectively and irreversibly
transformed to the (S)-enantiomer by coenzyme A conjugate.2,3 Such unidirectionality can also be
achieved if enantioconversion is coupled with stereoselective removal of one enantiomer from the
equilibrium, for instance by dynamic kinetic resolution or asymmetric transformation of the second
kind. Monitoring of the macroscopic change of a nonracemic mixture of stereolabile enantiomers
using polarimetry or circular dichroism spectroscopy provides the rate of racemization, while other
methods such as dynamic chromatography or proton–deuterium substitution analysis by 1H NMR
spectroscopy afford enantiomerization rates. Since enantiomerization and racemization kinetics
are frequently employed to describe the same process, it is important to distinguish between the
different mathematical treatment and the corresponding rate constants, kenant and krac, respectively.
Kinetic analysis of diastereomerization is more complex than the study of racemization or
enantiomerization because the rate constant for the transformation of one diastereomer to another
is different from the rate constant of the reverse reaction. Diastereomers possess different thermo-
dynamic stabilities and an equimolar ratio is not usually obtained at equilibrium. Epimerization is
a special case of diastereomerization, as it refers solely to the interconversion of epimers.i The
macroscopic analogy to epimerization is mutarotation which describes the irreversible change in
the optical rotation of an epimeric mixture until equilibrium is reached.

Racemization
(R) krac (R) (S)
(R) (S) krac (S)
(R) (R) (S)
(R) (S) (S)
(R) (R) (R) (S) (S) (S)

Enantiomerization
kenant
(R) (S ) krac = 2 kenant
kenant
Diastereomerization
k1
(R,R) (R,S) k1 ≠ k-1
k-1

Figure 3.1 Classification of isomerization reactions of chiral compounds.

i
Epimers are defined as diastereoisomers that differ in only one configuration of two or more elements of chirality.
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Title: Physics

Author: Willis E. Tower

Thomas D. Cope
Charles H. Smith
Charles M. Turton

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 PHYSICS
TOWER, SMITH, TURTON,
AND
COPE

(See p.441)
Three-color Printing
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 PHYSICS
BY

WILLIS E. TOWER, M. SCI. (Univ. of

Illinois)
HEAD OF THE DEPARTMENT OF PHYSICS, ENGLEWOOD
HIGH SCHOOL, CHICAGO

CHARLES H. SMITH, M. E. (Cornell)

HEAD OF THE DEPARTMENT OF PHYSICS AND ASSISTANT
PRINCIPAL, HYDE PARK SCHOOL, CHICAGO

CHARLES M. TURTON, A. M. (Syracuse)

HEAD OF THE DEPARTMENT OF PHYSICS, BOWEN
HIGH SCHOOL, CHICAGO
IN COLLABORATION WITH

THOMAS D. COPE, Ph.D. (Pennsylvania)

ASSISTANT PROFESSOR OF PHYSICS, UNIVERSITY
OF PENNSYLVANIA
BASED UPON
PRINCIPLES OF PHYSICS
BY
TOWER, SMITH and TURTON
WITH 7 PLATES AND 448 OTHER ILLUSTRATIONS
PHILADELPHIA
P. BLAKISTON'S SON & CO.
1012 WALNUT STREET
Copyright, 1920, by P. Blakiston's Son & Co.
 PREFACE
In the preparation of this text, the pupil, his experience, needs, and
interests have been constantly kept in mind. The order of topics,
illustrations, and problems have been selected with the purpose of
leading the pupil into a clear understanding of the physical
phenomena continually taking place about him.
The recommendations and conclusions reached by the "New
Movement in the Teaching of Physics" have been incorporated into
the book as a whole. These conclusions indicate that the most
efficient teaching in physics involves a departure from the
quantitative, mathematical methods of presentation that were in
general use a dozen or more years ago, toward a method better
adapted to the capabilities, interests, and requirements of the young
people in our physics classes.
The older methods are effective with a portion of the student body
which has the greater mathematical ability and training, but they
discourage a large majority of the pupils who are not gifted or
prepared for severe mathematical analysis. For this reason, many of
the more difficult mathematical demonstrations often given in
physics texts are omitted. Most of the problems involve only the
units employed in practical every-day measurements.
The portions of Mechanics that are ordinarily so difficult for the
average pupil are not taken up until he has covered considerable
ground with which he is more or less familiar and not until he has
become somewhat accustomed to the methods of study and the
technical terms of the subject.
The pupil comes to the study of physics with a great number of
experiences and impressions of physical phenomena continually
occurring about him. In recognition of this fact, it has been thought
best to consider first the explanation of common things well known
to all pupils, such as the diffusion of gases, evaporation of liquids,
expansion of bodies when heated, and capillary action. Since the
molecular theory of matter is now supported by so many conclusive
evidences, we have not hesitated to make free use of it in the early
chapters. The applications of this theory are extremely helpful in
explaining every-day phenomena. Our experience shows that
beginners in physics understand and apply this theory without
difficulty.
The illustrations and drawings have been selected from a
pedagogical rather than a spectacular point of view. Practically all of
them are new. The problems and exercises have been selected for
the distinct purpose of illustrating the principles taught in the text
and for their practical applications.
Many direct applications to common every-day experiences are given
in order to connect the subject matter with the home environment
and daily observation of physical phenomena. Some phenomena are
mentioned without detailed explanation as it is felt that the
presentation of these subjects in this manner is better for this grade
of student than a complete analysis.
Some of the special features of the text may be briefly summarized
as follows:
(A) Simplicity of presentation is emphasized. The methods of attack,
the illustrations and examples employed in developing the subjects
are particularly adapted to beginners in physics.
(B) The text is divided into some seventy-seven sections, each
containing material enough for one recitation.
(C) Each of these sections is summarized by a list of important topics
which point out to the pupil the principles and subject matter
requiring most careful attention. The lists of important topics are
also of assistance to the teacher in assigning recitations.
(D) The problems and practical exercises emphasize physical
principles as distinguished from mathematical training. A list of
exercises is placed at the end of the several sections. They are in
sufficient number to permit testing at many points and of a choice of
problems by teachers.
The authors wish to express their appreciation for suggestions and
helpful criticisms to many who have read the text in manuscript or
proof. Especially to Professor A. P. Carman of the University of Illinois
and his associate, Professor F. R. Watson, who have gone carefully
over the whole text; and to Mr. Chas. M. Brunson, Scott High School,
Toledo, Ohio, Mr. Frank E. Goodell, North High School, Des Moines,
Iowa, and to Mr. Walter R. Ahrens, Englewood High School, Chicago,
for assistance in reading the proofs. Also to Mr. W. H. Collins, Jr.,
Bowen High School, Chicago, who supervised the preparation of
drawings for the diagrams and figures; and to many firms and
individuals that have courteously furnished material for illustrations.
Willis E. Tower.
Charles H. Smith.
Charles M. Turton.
 ON THE STUDY OF PHYSICS
When a pupil begins the study of Physics he has in his possession
many bits of knowledge which are fundamental in the science. He
has learned to throw a ball and can tell how a thrown ball moves. He
has drawn out nails with a claw hammer. He has seen wood float
and iron sink. He has sucked liquids up through straws. In his
mother's kitchen, he sees water as ice, liquid, and steam. On a
wintry day he reads the temperature on a thermometer. He sees
sparks fly from car wheels when the brakes are applied. He has
played with a horseshoe magnet, and has found the north by means
of a compass. The telephone, the electric light and the motor he
sees, and perhaps uses, many times a day. He dresses before a
mirror, focuses his camera, watches the images at a moving picture
show, and admires the colors of the rainbow. He has cast stones into
water to watch the ripples spread, has shouted to hear the echo,
and perhaps plays some musical instrument. These, and a thousand
other things, are known to the intelligent and normal boy or girl who
has reached the age at which the study of Physics is properly begun.
To a great extent even the terms used in the science are familiar to
the beginner. He speaks of the horse-power of an engine, reads
kilowatt-hours from the meter in the cellar, and may know that
illuminating gas costs one dollar per thousand "cubic feet." "Ampere"
and "volt" are words he frequently hears and sees.
When he takes up the study of Physics, the attitude of the student
toward these familiar things and words must undergo a change.
Casual information about them must be changed to sound
knowledge, purposely acquired. Hazy notions about the meanings of
words must be replaced by exact definitions. Bits of knowledge must
be built into a structure in which each fact finds its proper place in
relation to the others.
The only agent which can accomplish these changes is the student
himself. He must consciously and purposely seek the truth and must
reflect upon it until he sees it in its relation to other truth. Upon him,
and upon him alone, rests the final responsibility for the success or
failure of his study.
But the student is not without assistance. In his teacher he finds a
guide to stimulate, to direct, and to aid his efforts, and a critic to
point out wherein his efforts have failed and wherein they have
succeeded. Weights, measures, and other apparatus are furnished to
enable him to answer for himself questions which have arisen in his
studies.
In addition to these the student has his text book, his teacher for his
hours of private study. A good text book is an inspiring teacher in
print. It directs attention to things familiar to the student through
long experience, and inspires him to make a closer scrutiny of them.
It invites him to observe, to analyze, to compare, to discover
likenesses and differences in behavior. It questions him at every
turn. Its ever repeated challenge reads, "Weigh and consider." It
furnishes him needed information that he cannot otherwise acquire.
It satisfies his desire to know, "By whom, where, when, and how
was this first discovered?"
The student of Physics must never forget that he is studying not
pages of text but the behavior and properties of iron, water, mica,
moving balls, pumps, boiling liquids, compressed air, mirrors, steam
engines, magnets, dynamos, violins, flutes, and a host of other
things. His studies should, whenever possible, be made first hand
upon the things themselves. The text is an aid to study, never a
substitute for the thing studied.
It is an excellent plan for each student to select some one thing for
special study, the telephone for example. By observation,
experiment, and reading, he may acquire a large amount of valuable
information about such a subject while pursuing his course in
Physics. Every part of the science will be found to bear some relation
to it.
The student who takes up the study of Physics in the way suggested
will find himself at the end of a year of study in possession of much
new and valuable knowledge about the physical world in which he
lives. By virtue of this knowledge he will be better able to enjoy the
world, to control it, and to use it.
Thomas D. Cope.
Philadelphia.
 CONTENTS
Chapter I. Introduction And Measurement. Page

(1) Introduction 1
(2) States of Matter 4
(3) The Metric System 8

Chapter II. Molecular Forces And Motions.

(1) Molecular Motions in Gases 13

(2) Molecular Motions in Liquids 18
(3) Molecular Forces in Liquids 21
(4) Molecular Forces in Liquids and Solids 27
(5) Molecular Forces in Solids 31

Chapter III. Mechanics or Liquids.

(1) Liquid Pressure 36

(2) Transmission of Liquid Pressure 41
(3) Archimedes' Principle 47
(4) Density and Specific Gravity 52

Chapter IV. Mechanics Of Gases.

(1) Weight and Pressure of the Air 55

(2) Compressibility and Expansibility of the Air 62
(3) Pneumatic Appliances 66

Chapter V. Force And Motion.

(1) Force, how Measured and Represented 79

(2) Motion. Newton's Laws 85
(3) Resolution of Forces 96
 (4) Moment of Force and Parallel Forces 99
(5) Gravitation and Gravity 103
(6) Falling Bodies 109
(7) The Pendulum 115

Chapter VI. Work And Energy.

(1) Work and Energy 119

(2) Power and Energy 123
(3) The Lever and Simple Machines 129
(4) Wheel and Axle and Pulley 136
(5) Efficiency and the Inclined Plane 142
(6) Friction and its Uses 147
(7) Water Power 152

Chapter VII. Heat, Its Production And Transmission.

(1) Sources and Effects of Heat 159

(2) Temperature and Expansion 162
(3) Expansion of Gases, Liquids and Solids 167
(4) Modes of Transmitting Heat 173
(5) Convection, Heating and Ventilation 179
(6) The Moisture in the Air, Hygrometry 191
(7) Evaporation 196

Chapter VIII. Heat And Work.

(1) Heat Measurement and Specific Heat 200

(2) Heat and Changes of State 205
(3) Heat and Work 212
(4) Heat Engines 222

Chapter IX. Magnetism.

(1) General Properties of Magnets 228

(2) Theory of Magnetism, Magnetic Fields 232
(3) The Earth's Magnetism 238
Chapter XI. Static Electricity.

(1) Electrification and Electrical Charges 243

(2) Electric Fields and Electrostatic Induction 247
(3) Electric Theories, Distribution and Electric Charges
252
(4) Potential, Capacity, and the Electric Condenser 257
(5) Electrostatic Generators 262

Chapter XI. Electric Currents Produced By Voltaic Cells.

(1) Electrical Currents and Circuits 267

(2) The Simple Voltaic Cell and its Action 270
(3) Practical Voltaic Cells 274

Chapter XII. Magnetic Effects Of Electric Currents, And Electrical

Measurements.

(1) The Magnetic Effect of Electric Currents 279

(2) Electrical Measurements 289
(3) Ohm's Law and Electrical Circuits 298
(4) Grouping of Cells and Measuring Resistance 302

Chapter XIII. Chemical And Heat Effects Of Electric Currents.

(1) The Chemical Effect of Electric Currents 307

(2) The Storage Battery and Electric Power 312
(3) The Heat Effect of Electric Currents 318

Chapter XIV. Induced Currents.

(1) Electromagnetic Induction 326

(2) The Dynamo and the Motor 335
(3) The Induction Coil and the Transformer 343
(4) The Telephone 349

Chapter XV. Sound.

 (1) Sound, Source, Speed, Media 354
(2) Waves and Wave Motion 357
(3) Intensity and Pitch of Sound 363
(4) Musical Scales and Resonance 368
(5) Interference, Beats, Vibration of Strings 374
(6) Tone Quality, Vibrating Plates and Air Columns 384

Chapter XVI. Light.

(1) Rectilinear Propagation of Light 388

(2) Photometry and Law of Reflection 393
(3) Mirrors and Formation of Images 400
(4) Refraction of Light 410
(5) The Formation of Images by Lenses 416
(6) Optical Instruments 423
(7) Color and Spectra 430
(8) Nature of Light 442

Chapter XVII. Invisible Radiations.

(1) Electric waves and Radioactivity 448

Chapter XVIII. Wireless Telephony And Alternating Currents.

(1) Wireless Telephony 460

(2) Alternating Currents 466
Index 487

PHYSICS
 CHAPTER I
INTRODUCTION AND MEASUREMENT

(1) Introduction
1. Physics, an Explanation of Common Things.—Many students
take up the study of physics expecting to see wonderful experiments
with the "X" rays, wireless telegraphy, dynamos, and other
interesting devices. Others are dreading to begin a study that to
them seems strange and difficult, because they fear it deals with
ideas and principles that are beyond their experience and hard to
comprehend.
Each of these classes is surprised to learn that physics is mainly an
explanation of common things. It is a study that systematizes our
knowledge of the forces and changes about us; such as the pull of
the earth, the formation of dew, rain and frost, water pressure and
pumps, echoes and music, thermometers and engines, and many
other things about us with which people are more or less familiar.
Physics is like other school subjects, such as mathematics and
language, in having its own peculiar vocabulary and methods of
study; these will be acquired as progress is made in the course.
The most useful habit that the student of physics can form is that of
connecting or relating each new idea or fact that is presented to him
to some observation or experience that will illustrate the new idea.
This relating or connecting of the new ideas to one's own personal
experience is not only one of the best known means of cultivating
the memory and power of association, but it is of especial help in a
subject such as physics, which deals with the systematic study and
explanation of the facts of our every-day experience.
2. Knowledge—Common and Scientific.—This leads to the
distinction between common knowledge and scientific knowledge.
We all possess common knowledge of the things about us, gained
from the impressions received by our senses, from reading, and from
the remarks of others. Scientific knowledge is attained when the bits
of common knowledge are connected and explained by other
information gained through study or experience. That is, common
knowledge becomes scientific, when it is organized. This leads to the
definition: Science is organized knowledge.
Common knowledge of the forces and objects about us becomes
scientific only as we are able to make accurate measurements of
these. That is, science is concerned not only in how things work, but
even more in how much is involved or results from a given activity.
For example, a scientific farmer must be able to compute his costs
and results in order to determine accurately his net profits. The
business man who is conducting his business with efficiency knows
accurately his costs of production and distribution.
This book is written in the hope that it will make more scientific the
student's common knowledge of the forces and changes in the world
about him and will give him many ideas and principles that will help
him to acquire the habit of looking from effects to their natural
causes and thus tend to develop what is called the scientific habit of
thought.
3. Hypothesis, Theory, and Law.—Three words that are
frequently used in science may be mentioned here: hypothesis,
theory, and law. An hypothesis is a supposition advanced to explain
some effect, change, or condition that has been observed. For
example, the Nebular Hypothesis of which many high-school
students have heard, is an attempt to explain the origin of the sun,
the earth, the planets, and other solar systems.
A theory is an hypothesis which has been tested in a variety of ways
and which seems to fit the conditions and results so that it is
generally accepted as giving a satisfactory explanation of the matter
in question. The Molecular Theory of Matter which states that matter
of all kinds is composed of very small particles called molecules (see
Art. 6), is a familiar example of a theory.
A theory becomes a law when it may be definitely proved. Many
laws are expressed in mathematical language, e.g., the law of
gravitation. (See Art. 88.) Many of the laws of physics are illustrated
by laboratory experiments, which show in a simple way just what
the law means.

Exercises

Explain what is meant by the following terms and expressions:

1. Common knowledge.
2. Scientific knowledge.
3. Science.
4. Topics in physics.
5. Scientific habit of thought.
6. Value of relating new ideas to former experiences.
7. Hypothesis.
8. Theory.
9. Law.

(2) The States of Matter

4. Physics Defined.—In the study of any science or field of
knowledge, it is helpful to have a basis for grouping or classifying
the facts studied. In physics we are to study the objects, forces, and
changes about us, to understand them and their relations to one
another. Accordingly, physics, dealing with the material world about
us, is often defined as the science of matter and energy, matter
being anything that occupies space and energy the capacity for
doing work. This definition of physics while not strictly accurate is
sufficiently comprehensive for our present purpose.
5. The Three States of Matter.—Our bodies are matter since they
occupy space. Further, they possess energy since they are able to do
work. In beginning the study of physics it will simplify our work if we
study one of these topics before the other. We will therefore begin
with matter and consider first its three states.
Some bodies are solid; as ice, iron, wax. Others are liquid; as water,
mercury, oil. Still others are in the state of gas; as steam, air, and
illuminating gas. Further we notice that the same substance may be
found in any one of the three states. For example water may be
either ice, water or steam; that is, either a solid, a liquid, or a gas.
Most persons have heard of liquid air and possibly some know of ice
air, i.e., air cooled until it not only liquefies, but is solidified. On the
other hand, iron may be melted and, if heated hot enough, may be
turned into iron vapor. In fact most substances by heating or cooling
sufficiently may be changed into any one of the three states.
Before defining the three states, let us consider the structure of
matter. This may help us to answer the question: How is it possible
to change a hard solid, such as ice, into a liquid, water, and then into
an invisible gas like steam? This is explained by the molecular theory
of matter.
6. The Molecular Theory of Matter.—It is believed that all bodies
are made up of very small particles called molecules, and that these
instead of being packed tightly together like square packages in a
box, are, strange as it may seem, very loosely packed even in solids
and do not permanently touch their neighbors. The size of these
molecules is so minute that it has been estimated that if a drop of
water could be magnified to the size of the earth, the molecules
magnified in the same proportion would be in size between a
baseball and a football. The air and all other gases are believed to
be made up of molecules in rapid motion, striking and rebounding
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