Stereochemistry and Organic Reactions

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Dipak Kumar Mandal
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Stereochemistry and Organic Reactions
Conformation, Configuration, Stereoelectronic Effects and
Asymmetric Synthesis
Stereochemistry and
Organic Reactions
Conformation, Configuration, Stereoelectronic
Effects and Asymmetric Synthesis

Dipak K. Mandal
Formerly of Presidency College/University
Kolkata, India
Academic Press is an imprint of Elsevier
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Preface

Organic stereochemistry is a vast and important subject. It is an intrinsic part of

all organic chemistry. Planning and executing stereoselective synthesis to pre-
pare single enantiomers as well as single diastereomers is an exhilarating
science that has registered enormous progress over the years, and still is in fast
development. Understanding of the factors that determine the high levels of
three-dimensional control in organic synthesis is an essential and fundamental
topic for all students of organic chemistry. It is not surprising therefore that
stereochemistry is covered in every undergraduate, advanced undergraduate
and graduate course in organic chemistry. It is my involvement in teaching this
subject to undergraduate and graduate students for more than 30 years that has
inspired me to write this book. The purpose of this endeavour is entirely
pedagogic, keeping in view that our students desperately crave understanding,
not factual knowledge alone. Understanding requires a ‘feel’ for the set of
principles that influence the stereochemistry of organic molecules and their
reactions, which is in the heart of this book; the historical development has been
generally given short shrift.
The book is primarily structured in three parts (Part I–III), and each part is
factored into several chapters. An appendix is included in Part IV. Part I deals
with the stereochemistry—conformation and configuration—of acyclic
molecules (Chapters 1 and 2) and cyclic molecules (Chapter 3). The stereo-
chemistry of organic reactions follows thereafter. Part II provides an introduc-
tion to perturbation molecular orbital theory for the origin of stereoelectronic
effects (Chapter 4) and an introduction to the principles of stereoselectivity
and hierarchical levels or generations of asymmetric synthesis (Chapter 5) as
a background aid to follow the reaction stereochemistry covered in Part III.
I hope this unique style would help enhance the pedagogy of this text. The ste-
reochemistry of reactions with particular emphasis on diastereoselectivity and
asymmetric synthesis are presented in seven chapters along the lines of mech-
anistic classes. Two elaborate chapters (Chapters 6 and 7) are devoted to ionic
reactions, the most abundant class, two for pericyclic reactions (Chapters 8 and
9), and one each for transition metal-catalysed reactions (Chapter 10), radical
reactions (Chapter 11) and photochemical reactions (Chapter 12).
The book is distinct from other contemporary textbooks in that it brings a
holistic approach by providing, within the limits of space and time, separate
chapters on the stereochemistry of reactions of all mechanistic types ranging

xvii
xviii Preface

from ionic, pericyclic, transition metal-catalysed to radical and photochemical.

This would undoubtedly help reveal the unifying principles for stereochemical
understanding and prediction. Another important difference between this book
and others is the emphasis on the working of stereochemistry, specifically how
to delineate the stereochemistry of products. Learning stereochemistry is hard
work. I have found that students are often not quite comfortable to work
stereochemistry for themselves. They need some more help. To address their
concerns, I have always been looking for innovative approaches to stereochem-
ical issues. My efforts have produced some simple and general stereochemical
rules/guidelines, some of which have been published in three papers in the
Journal of Chemical Education. These published (also some unpublished)
rules/mnemonics have been used extensively in the relevant chapters as an
aid to draw quickly and correctly the product stereochemistry in organic
reactions.
As an element of learning and pedagogy, I have provided over 150 problems
within the chapters, reinforcing the main themes in the text. I hope that students
could test their learning immediately while reading through the chapters. These
problem sets should be considered an integral part of the course. The detailed
answers to the problems with references, wherever necessary, are given in
Appendix in Part IV. I have provided a total of about 1,400 references to pri-
mary and review literature, with each chapter containing a reference list at
its end. These references will enable the readers to go further into the subject.
The approach presented in this book is distinct and class tested. I have tried
to find a level to suit everyone in his/her own way from the undergraduate to the
research level. I hope this book will be of value and interest to the students,
teachers and researchers of organic, biological and medicinal chemistry, and
also to a wider circle of readers including biologists, pharmacologists, polymer
chemists and chemists working in industry who might wish to have an overview
of this highly fascinating field of chemistry.
I would like to thank the anonymous reviewers for helpful suggestions. I am
grateful to the editorial members Emily M. McCloskey and Allison Hill,
production manager Paul P. Chandramohan, and their colleagues at Elsevier
for excellent support and cooperation. Finally, I thank my wife Tapasi and
my daughter Sudipta for their continuous support and my son Tirtha for his
active help in artwork and referencing. I could not finish without thanking
my little granddaughter Adrita who has provided me the necessary fillip during
the preparation of this book.

Dipak K. Mandal
Kolkata, India
Abbreviations

Ac acetyl (MeCO)
acac acetylacetonato (MeCOCHCOMe
)
AIBN azobisisobutyronitrile [Me2C(CN)N]N(CN)CMe2]
Alpine-Borane B-isopinocamphenyl-9-borabicyclo[3.3.1]nonane
AQN anthraquinone
9-BBN 9-borabicyclo[3.3.1]nonane
BINAL-H binaphthyllithium aluminium hydride
BINAP 2,20 -bis(diphenylphosphino)-1,10 -binaphthalene
BINOL 1,10 -bi-2-naphthol
Bn benzyl (PhCH2)
Boc tertiary-butoxycarbonyl (Me3COC]O)
box bis-oxazoline
bpy 2,20 -bipyridine
Bs brosyl or p-bromobenzenesulphonyl (4-BrC6H4SO2)
Bu butyl [Me(CH2)3]
i-Bu isobutyl (Me2CHCH2)
s-Bu secondary-butyl [MeCH2C(Me)H]
t-Bu tertiary-butyl (Me3C)
Bz benzoyl (PhCO)
CAN cerium(IV) ammonium nitrate [Ce(NH4)2(NO3)6]
Cbz benzyloxycarbonyl (PhCH2OC]O)
CD circular dichroism
CE Cotton effect
CIR chiral inducing reagent
cod 1,5-cyclooctadiene
mCPBA meta-chloroperbenzoic acid (3-ClC6H4CO3H)
CSP chiral stationary phase
Cy cyclohexyl (C6H11)
DAIB 3-exo-(dimethylamino)isoborneol
dba trans,trans-dibenzylideneacetone [(PhCH]CH)2CO]
de diastereomeric excess
DET diethyl tartrate
DHQ dihydroquinine
DHQD dihydroquinidine
DIBAL-H diisobutylaluminium hydride (i-Bu2AlH)
DIP-Cl diisopinocamphenylboron chloride (Ipc2BCl)

xix
xx Abbreviations

DIPT diisopropyl tartrate

DMAD dimethyl acetylenedicarboxylate (MeO2CC^CCO2Me)
DME 1,2-dimethoxyethane (MeOCH2CH2OMe)
DMF N,N-dimethylformamide (Me2NCH¼O)
DMSO dimethylsulphoxide (Me2S]O)
dr diastereomer ratio
DTBP 2,6-di-t-butylpyridine
e2 electron
ee enantiomeric excess
ESR electron spin resonance
Et ethyl (MeCH2)
FMO frontier molecular orbital
fod 2,2-dimethyl-6,6,7,7,8,8,8-heptafluoro-3,5-octanedionate
1G/2G/3G/4G first/second/third/fourth generation
gb gauche-butane
GC gas chromatography
HOMO highest occupied molecular orbital
HMPA hexamethylphosphoramide [(Me2N)3P]O]
HPLC high performance liquid chromatography
IND N-carboxy-indoline
IR infrared
ISC intersystem crossing
Ipc2BH diisopinocamphenylborane
Ipc2BOTf diisopinocamphenylboron triflate
KHMDS potassium hexamethyldisilazide [(Me3Si)2NK]
LCAO linear combination of atomic orbitals
Lcp left circularly polarized
LDA lithium diisopropylamide (i-Pr2NLi)
L-DOPA (S)-30 ,40 -dihydroxyphenylalanine
LiHMDS lithium hexamethyldisilazide [(Me3Si)2NLi]
LiTMP lithium tetramethylpiperidide
L-Selectride lithium tri(sec-butyl)borohydride [Li(s-Bu)3BH]
LUMO lowest unoccupied molecular orbital
2,6-Lutidine 2,6-dimethylpyridine
Me methyl (CH3)
Meerwein’s trimethyloxonium tetrafluoroborate (Me3 O + BF4
)
salt
Ms mesyl or methanesulphonyl (MeSO2)
NAD+ nicotinamide adenine dinucleotide
NADH nicotinamide adenine dinucleotide hydride (reduced form of
NAD+)
NaHMDS sodium hexamethyldisilazide [(Me3Si)2NNa]
NBS N-bromosuccinimide
NGP neighbouring-group participation
 Abbreviations xxi

NMO N-methylmorpholine-N-oxide
NMR nuclear magnetic resonance
op optical purity
ORD optical rotatory dispersion
Oxone potassium peroxymonosulphate (2KHSO5KHSO4K2SO4)
Ph phenyl (C6H5)
PHAL phthalazine
PHOX phosphinooxazoline
PMP 1,2,2,6,6-pentamethylpiperidine
PPTS pyridinium p-toluenesulphonate
Pr propyl [Me(CH2)2]
i-Pr isopropyl (Me2CH)
2-Py 2-pyridinyl
QP quinine hypophosphite
QDP quinidine hypophosphite
RAMP (R)-1-amino-2-(methoxymethyl)pyrrolidine
Red-Al sodium bis(2-methoxyethoxy)aluminium hydride
[NaAlH2(OCH2CH2OMe)2]
Rcp right circularly polarized
r.t. room temperature
SAEP (S)-1-amino-2-(1-ethyl-1-methoxypropyl)pyrrolidine
SAMP (S)-1-amino-2-(methoxymethyl)pyrrolidine
SET single electron transfer
SOMO singly occupied molecular orbital
TADDOLs α,α,α0 ,α0 -tetraaryl-1,3-dioxolane-4,5-dimethanols
TAPA α-(2,4,5,7-tetranitro-9-fluorenylideneaminooxy)
propionic acid
TEMPO 2,2,6,6-tetramethylpiperidine-1-oxyl
TBDMS tertiary-butyldimethylsilyl (t-BuMe2Si)
TBDPS tertiary-butyldiphenylsilyl (t-BuPh2Si)
Tf triflyl or trifluoromethanesulphonyl (CF3SO2)
TFA trifluoroacetic acid (CF3CO2H)
TFAE 2,2,2-trifluoro-1-(9-anthryl)-ethanol
TfO2 triflate (CF3 SO3
)
THF tetrahydrofuran
TIPS triisopropylsilyl (i-Pr3Si)
TLC thin layer chromatography
TMEDA N,N,N0 ,N0 -tetramethylethylenediamine [Me2N(CH2)2NMe2]
TMS trimethylsilyl (Me3Si)
TOT tri-o-thymotide
Ts tosyl or p-toluenesulphonyl (4-MeC6H4SO2)
TS transition structure
UV ultraviolet
Part I

Stereochemistry of organic
molecules
A molecule is a microscopic grouping of atoms linked together by bonds, and its
structure is a concept at the molecular level, whereas a physical property refers
to an assembly of molecules or compound at the macroscopic level. Part I com-
prises three chapters (Chapters 1–3) which deal with the concepts of symmetry,
chirality, conformation, configuration and topicity in organic molecules, and
methods based on physical properties to achieve resolution of racemates and
to determine conformation, configuration and enantiomeric composition.
Chapter 1

Acyclic molecules 1:
Conformation and symmetry

Organic stereochemistry1–4 is the chemistry of organic molecules in three-

dimensional, and is an intrinsic part of all organic chemistry. Organic stereo-
chemistry is usually factorized into stereochemistry of molecules (static
aspects) and stereochemistry of reactions (dynamic aspects). Stereochemistry
of molecules broadly refers to conformation and configuration. In this chapter,
we will describe the conformation and symmetry of acyclic molecules.

1.1 Stereoisomerism in molecules

The constitution of a molecule is defined by the sequence of atoms and bonds
building up the molecule. Molecules with the same molecular formula but with
a difference in constitution (bonding connectivity) are called constitutional iso-
mers. For example, 1-butene and 2-butene are two constitutional isomers of
C4H8. The differences between the constitutional isomers are topological.
Again, molecules with identical constitution can differ in their stereochemical
structure, i.e. arrangement of atoms or groups in three-dimensional space. Such
molecules with the same constitution but different stereochemical arrangements
are called stereoisomers. Stereoisomers, in turn, may differ in conformation
(conformational isomers or conformers) or configuration (configurational iso-
mers). A configurational isomer may exist in several conformational isomers.
The stereoisomers (conformational or configurational) are further classified
into enantiomers and diastereomers. Enantiomers are the stereoisomers that are
mirror images of each other. Notably, the enantiomeric relationship can exist
only between two stereoisomers. Since the two enantiomers do not differ in
the distances between the constitutionally equivalent atoms but differ when
one is reflected in a mirror plane, their difference is topographical. On the other
hand, stereoisomers that are not mirror images of each other are called diaste-
reomers. Thus, the stereoisomers that are not enantiomers are diastereomers.
Evidently, the diastereomeric relationship is possible between two or more ste-
reoisomers. As the distances between the constitutionally equivalent atoms of

Stereochemistry and Organic Reactions. https://doi.org/10.1016/B978-0-12-824092-2.00001-0

Copyright © 2021 Elsevier Inc. All rights reserved. 3
4 PART I Stereochemistry of organic molecules

the diastereomers are different, their difference is geometric. For the classifica-
tion of isomerism, see also Fig. 2.1 (Chapter 2).

1.2 Representation of tetrahedral molecules: Perspective

(flying wedge, zigzag) and projection (Fischer, sawhorse,
Newman) formulas
A tetrahedral sp3 carbon is bonded to four ligands (atoms or groups). Of the four
bonds, a maximum of two bonds can lie on a plane (say, the plane of the paper)
when one bond (third) is above the plane and the other (fourth) is below the
plane, as shown for CHFClBr 1.1 (Fig. 1.1). To draw the tetrahedral structure,
the following convention is adopted in this text: a bold bond in wedged form
indicates a front (up) ligand; a hashed bond in untapered form indicates a rear
(down) ligand.
The representation 1.1 is called a flying wedge formula. A rotation around
the CdH bond lying on the plane can place other three ligands (F, Cl, Br) out of
the plane 1.2 (use a molecular model). In this representation, only one bond
(CdH) is lying on the plane. Now, if the CdH bond is tilted backwards, a rep-
resentation 1.3 is obtained when no bond is lying on the plane. This type of rep-
resentation in which two horizontal bonds lie above the plane and two vertical
bonds are below the plane can be transformed into a projection formula called
the Fischer projection. The representations 1.1–1.3 indicate perspective formu-
las. The projections of the bonds in the perspective formula 1.3 on the plane of
the paper give a Fischer projection 1.4. Remember that horizontal and vertical
bonds in a Fischer projection correspond to above the plane and below the plane
bonds respectively. All four representations (1.1–1.4) are equivalent.
A given perspective or projection formula can be transformed into equiva-
lent formula(s) by rotating in groups of three, or by making two (or even num-
ber) interchanges. Fig. 1.2A shows that a flying wedge formula of CHFClBr is
converted into an equivalent formula by clockwise rotation of three ligands (F,
Br, Cl) through 120 degrees around CdH bond or by making two interchanges
as indicated. Similar procedures also apply to a Fischer projection, as shown in
Fig. 1.2B. Note that keeping any ligand (say, H) fixed, the other three ligands (F,
Cl, Br) are rotated. This procedure can be repeated to draw other equivalent
Fischer projections. As shown in Fig. 1.2B, a Fischer projection can also be

FIG. 1.1 Representations of a tetrahedral molecule CHFClBr in perspective formulas and Fischer
projection.
 Acyclic molecules 1: Conformation and symmetry Chapter 1 5

FIG. 1.2 Methods for drawing (A) equivalent flying wedge formulas and (B) equivalent Fischer
projections for a tetrahedral molecule CHFClBr.

rotated 180 degrees in the plane to obtain an equivalent Fischer projection.

Fig. 1.2B also shows that two interchanges give an equivalent Fischer projec-
tion. Remember that any two ligands can be chosen for an act of exchange.
The representations of a CdC bond with the spatial disposition of associ-
ated ligands are needed in stereochemical descriptions. The simplest molecule
with a CdC bond is ethane. For molecules with a number of CdC bonds, a
stereochemical representation often needs to be drawn with respect to a
particular CdC bond. As for example, consider 2-bromo-3-chlorobutane
(MeCHBrCHClMe) in a staggered conformation and in an eclipsed conforma-
tion (see Section 1.3).
Fig. 1.3A shows perspective formulas (flying wedge and zigzag) and projec-
tion formulas (sawhorse and Newman) of a staggered conformation of 2-bromo-
3-chlorobutane. The flying wedge formula is drawn viewing the C2dC3 bond
sideways (use a molecular model) when the four-carbon chain lies in the plane
of the paper. Note that, for each tetrahedral carbon C2 or C3, two bonds are on
the plane, one bond is above the plane and the other is below the plane. If the
C2dC3 bond is viewed in oblique fashion, one obtains a sawhorse projection
formula, in which Br and Cl are on the same side of the CdC bond as in the
equivalent flying wedge formula. A Newman projection formula is obtained
when the C2dC3 bond is viewed end-on. The main carbon chain of the flying
wedge formula can also be drawn as a horizontal zigzag chain with ligands
6 PART I Stereochemistry of organic molecules

FIG. 1.3 Representations of a CdC bond and associated ligands of 2-bromo-3-chlorobutane:

(A) a staggered conformation in flying wedge, sawhorse, Newman and zigzag formulas, and
(B) an eclipsed conformation in flying wedge, sawhorse, Newman and Fischer formulas.

(other than H) pointing up or down. This perspective zigzag formula (devised by

Masamune) always denotes a staggered conformation. A zigzag formula does
not represent an eclipsed conformation.
Fig. 1.3B shows a perspective formula (flying wedge) and projection formu-
las (sawhorse, Newman and Fischer) for an eclipsed conformation. The flying
wedge, sawhorse and Newman formulas are drawn in a similar manner as
described above. Note that, in the Newman projection, the ligands on the back
carbon (C3) are artificially rotated a little so that they are not obscured
completely. In the Fischer projection, horizontal and vertical ligands at the
C2dC3 bond indicate above the plane and below the plane ligands respec-
tively. In contrast to a zigzag formula, a Fischer projection always denotes
an eclipsed conformation, and does not represent a staggered conformation.

1.3 Conformation
Conformation has been defined5 as “the spatial arrangement of the atoms
affording distinction between stereoisomers which can be interconverted by
rotations about formally single bonds.” The term has been extended to include
inversion at trigonal pyramidal centres (see later Section 2.5.2). Conformational
analysis refers to the study of the relative stability of conformations and relating
conformation to the properties and reactivity of molecules. Since a CdC σ
bond is cylindrically symmetrical, internal rotation at the CdC bond is not
likely to affect the bond orbital. However, the rotation about the CdC bond
is not absolutely free and there occurs an energy barrier to rotation. Conforma-
tions also arise as a result of rotation about CdN and CdO bonds.
 Acyclic molecules 1: Conformation and symmetry Chapter 1 7

FIG. 1.4 A positive torsion angle (ϕ).

1.3.1 Torsion angles and torsional strain

In a nonlinear chain of four atoms AdC1dC2dB, the torsion angle (ϕ) for the
two bonds AdC1 and C2dB is defined as the angle between the projections of
AdC1 and C2dB on a plane perpendicular to C1dC2 (Fig. 1.4). The torsion
angle has both magnitude and a sign. Looking along the CdC bond in either
direction (C1 ! C2 or C2 ! C1), if the turn from the front atom to the rear atom
is clockwise, ϕ is positive and if the turn is anticlockwise ϕ is negative.
Internal rotation changes the torsion angle. Conformation may be described
in terms of exact magnitude and sign of ϕ. However, when exact values of ϕ are
not known or relevant, conformation may be described using a range of torsion
angles (30 degrees), known as Klyne–Prelog classification6 (Table 1.1).
The dihedral angle is a term similar to the torsion angle but unlike a tors-
ion angle, the dihedral angle is an unsigned angle. Torsion angles of 120
and 60 degrees (see Table 1.1) correspond to dihedral angles of 240 and
300 degrees, respectively. The term dihedral angle will not generally be used
in this text.
The torsional strain (or Pitzer strain) refers to the interaction that leads to the
variation of potential energy as a function of torsion angle. The torsion angle

TABLE 1.1 Klyne–Prelog specification of torsion angles.

Torsion angle (ϕ) (degrees) Designation

0  30 (30 to +30) synperiplanar (sp)
+60  30 (+30 to +90) +synclinal (+ sc)
+120  30 (+90 to +150) +anticlinal (+ac)
180  30 (+150 to 150) antiperiplanar (ap)
120  30 (150 to 90) anticlinal (ac)
60  30 (90 to 30) synclinal (sc)

Synclinal (ϕ  60 degrees) is often called gauche (g+  + 60 degrees, g   60 degrees).

Antiperiplanar (ϕ  180 degrees) is frequently called anti.
8 PART I Stereochemistry of organic molecules

function is naturally a Fourier series. However, for a simple C(sp3)dC(sp3)

single bond, the torsional potential (Vϕ) appears to follow a simple cosine
function as
1
Vϕ ¼ V0 ð1 + cos 3ϕÞ (1.1)
2
where V0 is a constant. For a CdCdCdC chain, V0 is 3.1 kcal mol1.7 When
ϕ ¼ 0 degrees for the eclipsed (synperiplanar) conformation, the Eq. (1.1) gives
Vϕ ¼ V0, i.e. the torsional potential is at a maximum. The torsional potential is at
a minimum (Vϕ ¼ 0) when ϕ ¼ 60 degrees for the staggered (synclinal)
conformation.

1.3.2 Nonbonded van der Waals interactions

At infinite distance, the energy of interaction of two nonbonded atoms is zero.
As the two atoms approach each other, an attractive force (London or dispersion
force) operates which is taken as  ar6 (a is a constant and r is the internuclear
distance). This leads to a lowering of the energy. At a still closer distance, a
repulsive force due to closed-shell repulsion takes place which is expressed
as br12 (b is a constant). The overall nonbonded potential (Vnb) is then
expressed by Eq. (1.2), called a Lennard-Jones potential.
Vnb ¼ ar6 + br12 (1.2)
Fig. 1.5 shows a plot of Vnb against r.
van der Waals radius refers to the distance between two nonbonded atoms at
which there is no net attraction or repulsion. At this point, the distance (r0 )
between the two atoms is the sum of their van der Waals radii. Nonbonded inter-
actions may be attractive or repulsive depending on the internuclear distance.
When the distance between two specified atoms is less than the sum of their
van der Waals radii, they repel each other. Such repulsion due to crowding is
referred to as van der Waals strain or steric strain.

FIG. 1.5 Nonbonded van der Waals interactions between two atoms.
 Acyclic molecules 1: Conformation and symmetry Chapter 1 9

The approximate values of van der Waals radii (in Å) of a few atoms or
groups are given below.

H F Cl Br I CH3
1.25 1.35 1.8 1.95 2.15 2.0

1.3.3 Molecular mechanics

Only a very brief introduction to molecular mechanics is presented here. An
overview and a general account of the methods of molecular mechanics can
be found elsewhere.8,9
Strain in a molecule arises from a nonideal molecular geometry and several
strain factors contribute to the total strain energy of the molecule. These include
bond length strain, bond angle strain, torsional strain and nonbonded interac-
tions. The total strain energy (Vstrain) is given by
X X X X
Vstrain ¼ Vr + Vθ + Vϕ + Vnb (1.3)
where Vr is bond length strain due to bond stretching or compression, Vθ is bond
angle deformation strain, Vϕ is torsional strain (Eq. 1.1) and Vnb is nonbonded
interactions (Eq. 1.2).
The bond length strain (Vr) is assumed to follow a Hooke’s law expression as
1
V r ¼ k r ðr  r 0 Þ2 (1.4)
2
where r is the bond length at any given instant, r0 is the mean or equilibrium
bond length and kr is a constant for a type of bond. It is assumed that such con-
stants can be transferred between molecules in molecular mechanics calcula-
tion. Typically, Vr is 3.2 kcal mol1 if r  r0 is only 10 pm (0.1 Å) for a CdC
single bond. Thus a change of bond length is energetically very costly.
The bond angle bending is also, to a first approximation, a quadratic
function as
1
Vθ ¼ k θ ð θ  θ 0 Þ 2 (1.5)
2
where θ  θ0 is the change in bond angle from the equilibrium bond angle taken
as 109°280 , and kθ is the appropriate force constant. Typically, kθ is
0.025 kcal mol1 degrees2 for CCC angle. Thus Vθ is only 0.3 kcal mol1 for
a 5 degrees deformation in bond angle. The bond angle change may arise from
the rehybridization of the pivotal atom through variations of s and p character of
the orbitals involved in bonding.
It is of note that the list of terms in Eq. (1.3) can be enlarged to include intra-
molecular electrostatic (coulombic) interactions (VE) for polar groups if
10 PART I Stereochemistry of organic molecules

present, solvation ( VS) and cross terms with two parameters to improve Vstrain.
A molecular mechanics calculation begins with the calculation of strain energy
of a trial structure obtained from a molecular model or from a similar molecule
in the X-ray structural database. Computationally, the structure of a molecule
with n atoms is a vector of 3n Cartesian coordinates. By changing the coordi-
nates and recomputing the energies, the energies of all geometries slightly devi-
ated from the original trial structure can be explored. The energy as a function of
the coordinates is minimized using a suitable computer algorithm and the explo-
ration is repeated until a structure is found at an energy minimum so that any
further deformation leads to a higher energy. The structure at the energy min-
imum is taken to be the predicted structure of the molecule. The method permits
the calculation of both structure and energy.
The mathematical functions (force fields) that accurately model the various
strain interactions for a wide variety of molecules have been developed. The
term force field signifies that the array of atoms is in a field of interatomic
forces. The method allows the strain energy of any particular conformation
to be estimated. By calculating different energies of various conformations,
it is possible to predict the lowest energy conformation.

1.3.4 Conformation of ethane

The simplest molecule with a single CdC bond is ethane. The internal rotation
of one methyl group relative to the other changes the torsion angle and gives rise
to conformations. In principle, infinite number of conformations is possible.
The potential energy curve for rotation about the CdC bond in ethane shows
that there are three degenerate minima and three degenerate maxima (Fig. 1.6).

FIG. 1.6 Potential energy as a function of torsion angle for ethane.

 Acyclic molecules 1: Conformation and symmetry Chapter 1 11

The three minima correspond to torsion angles ϕ ¼  60degrees, 180 degrees

and represent staggered conformations while the three maxima correspond to
eclipsed conformations (ϕ ¼ 0 degrees, 120 degrees). The conformations that
are located at the energy minima are called conformational isomers or con-
formers. Therefore ethane has three indistinguishable staggered conformers.
The energy difference between the eclipsed and the staggered conformation is
2.9 kcal mol1 which gives the energy barrier to internal rotation in ethane.10
Thus, at any instant, any individual molecule is likely to be in the staggered
conformation. The eclipsed conformation is regarded as a transition structure
(TS) conformation for the interconversion between staggered conformations.
The energy barrier is not so high; at room temperature a rapid interconversion
of staggered conformers takes place through an eclipsed conformation.

1.3.4.1 Torsional barrier and kinetics

An idea of the rate of rotation can be obtained from an estimate of approximate
rate constant using transition state theory. The rate constant (k) for a process
derived from transition state theory is given by
kB T ΔG6¼ =RT
k¼ e (1.6)
h
where kB is Boltzmann constant and ΔG6¼ is the free energy barrier. Assuming
entropy term to be insignificant for a conformational process, ΔG6¼ is taken to
be the conformational energy barrier (2.9 kcal mol1). Substituting this value in
Eq. (1.6), the value of k at 25°C (298 K) is obtained as
 
1:38  1023 ð298Þ ð29004:18Þ=ð8:31Þð298Þ 1
k¼   e s ¼ 4:6  1010 s1
6:62  1034
The rate of rotation at 25°C is thus extremely fast with an average time
between crossings is to the order of 1010 s.
The relative instability of the eclipsed conformation is attributed to torsional
strain or Pitzer strain. Any deviation from the lowest energy staggered confor-
mation is accompanied by torsional strain which reaches a maximum at the
eclipsed conformation.

1.3.4.2 Origin of the torsional strain

The origin of the rotational barrier (torsional barrier) has been much
debated.11,12 The steric repulsion in the eclipsed conformation is at most a
minor factor since the H atoms of the two methyl groups are barely within
the van der Waals distance. In orbital terms, the steric repulsion, if any, would
arise from the filled orbital/filled orbital repulsion of the CdH bonds in
eclipsed ethane. The main factor responsible for the torsional barrier is σ–σ*
hyperconjugation (in frontier orbital terms, HOMOσ/LUMOσ∗ interaction),
12 PART I Stereochemistry of organic molecules

FIG. 1.7 Origin of torsional barrier in ethane attributed to σ–σ* hyperconjugation.

which stabilizes the staggered conformation much more than the eclipsed con-
formation, and hence favours the former (Fig. 1.7).
Calculations13 indicate that if the hyperconjugation effects are switched off,
eclipsed conformation is preferred. Thus hyperconjugation, not the filled/filled
repulsion, is the origin of the torsional barrier in ethane.11,13 It should be noted
that there are three anti H/H pairs in staggered ethane so that each σ–σ* hyper-
conjugation stabilizes it roughly by 1 kcal mol1. In other words, each H/H
eclipsing raises the energy by 1 kcal mol1.

1.3.4.3 Conformation of propane and butane for rotation about

C1-C2 bond
In molecules of the type H3CdCH2R, the conformational situation is very similar
to that of ethane. Thus propane (R¼ Me) and butane (R¼ Et) has three degene-
rate staggered conformers due to rotation about C1dC2 bond. There are also
three degenerate eclipsed conformations. Fig. 1.8 shows one staggered and
one eclipsed conformation of propane and butane. Due to R/H (R ¼ Me, Et)
eclipsing, the torsional barrier in propane or butane is higher than in ethane.
The torsional barrier in propane is estimated to be 3.4 kcal mol1.14,15 Thus a

FIG. 1.8 Staggered and eclipsed conformations of propane and butane due to rotation about
C1dC2 bond.
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