Module 8 Stereochemistry

Lecture 23 Stereochemistry IV
So far, all the stereogenic centres discussed involve a carbon atom with 4 different
substituents attached to it (asymmetric centre). However, in case of trivalent central
atoms having a lone pair of electrons, the lone pair of electrons may be considered as a
fourth substituent. Usually, in such cases, the enantiomers will undergo Walden inversion
from one form to other. The Walden inversion may however be prevented by locking
using bulky substituents. Here, while the trisubstituted aliphatic amines easily undergo
inversion, the same is not possible for aziridines as it would require twisting of the 3-
membered ring. Similarly, in Troger’s base, the trivalent nitrogen is present on bridge
head and cannot undergo inversion (Figure 1).

Walden Inversion No Walden Inversion

CH3
CH3 H3C CH3 N
H3C CH3 N
N N N N
H3C CH3
CH3 H H
H3C
Troger's base
Aziridines exist as enantiomers
Figure 1

It is also to be remembered that for a compound to have enantiomers, it must be non-

superimposable on its mirror image. This condition can also be satisfied by certain other
compounds which do not have asymmetric centre. As an example, cis-octahedral
complexes may exhibit enantiomers even though they lack an asymmetric centre (Figure
2).

3+ 3+

O O

O O O O
O O
Fe Fe
O O O
O O O O O

O O O
O

Figure 2
Some compounds which do not have asymmetrically substituted carbon atoms (no
stereogenic centre) may still be chiral if they feature two perpendicular planes which are
not symmetry planes. If these disymmetric (chiral) planes cannot freely rotate against
each other, the corresponding compounds are chiral. Compounds of this type are said to
be axially chiral. Some examples of this type involve unsymmetrically substituted
allenes, biphenyl derivatives and spiro compounds (Figure 3).

H3C H3C H3C CH3

H H H H
H CH3 H CH3 H3C
H3C H3C H
achiral achiral

H3C CH3
NO2 O2N
H3C CH3 H3C CH3
H H H H CH3 H3C
O2N NO2
chiral chiral
Figure 3
In case of biphenyl derivatives, if both aromatic ring systems are asymmetrically
substituted, the compounds are chiral. As the chirality of these structures originates not
from an asymmetrically substituted atom center, but from an asymmetric axis around
which rotation is hindered, these enantiomers are also called atropisomers. In the
biphenyls, the ortho-substitutents must be large enough to prevent rotation around the
central single bond. Since only the hindered rotation about the central C-C single bond
leads to the stereoisomerism of these compounds. Therefore, biphenyl- and binaphtyl-
derivatives are conformational stereoisomers (not configurational stereoisomers).
Planar chirality may arise if an appropriately substituted planar group of atoms or ring
system is bridged by a linker-chain extending into the space above or below of this plane.
Some common examples are the planar chirality of cyclophanes or alkenes as shown
below (Figure 4).

CH3 H3C O O

Fe CH3 H3C Fe
H3C CH3

[2,2]-paracyclophane 1-acetylf errocene

Figure 4

Helices are also chiral as they can exist in enantiomeric left- or right-handed forms.
Typical examples for helical strutures are provided by the helicenes (benzologues of
phenanthrene). With four or more rings, steric hinderance at both ends of these molecule
prevents the formation of planar conformations, and helicenes rather adopt non-planar,
but helical and enantiomeric structures with C2 symmetry (Figure 5).

H3C H3C CH3 CH3

CH3 H3C

H3COOC COOCH3
H3COOC H3C CH3 COOCH3

[8]-helicene enantiomers
dimethyl 5,6,8,10-tetramethylheptalene-1,2-dicarboxylate
Figure 5
The stereochemistry of a substrate may have profound effect on the rate of a reaction or
the composition of the products of a particular reaction. With respect to the composition
of products obtained by a reaction two terms are important.
Stereoselective reactions are those reactions which give one predominant product of
the two or more products possible because the reaction pathway has a choice. Either
the pathway of lower activation energy is preferred (kinetic control) or the more
stable product (thermodynamic control). Thus, E1 dehydration of 1-phenylpropan-1-
ol provides (E)-prop-1-enylbenzene as the major product (Scheme 1).
Ph H3O+/H2SO4 Ph
CH3 CH3 Ph +
CH3 Ph CH3
OH E1
1-phenylpropan-1-ol (E)-prop-1-en-1-ylbenzene (Z)-prop-1-en-1-ylbenzene
racemate major minor
Scheme 1

On the other hand, stereospecific reactions lead to the production of a single isomer
as a direct result of the mechanism of the reaction and the stereochemistry of the
starting material. There is no choice. The reaction gives a different diastereoisomer of
the product from each stereoisomer of the starting material. In case of E2 elimination
of ((1S,2R)-1-bromopropane-1,2-diyl)dibenzene, only the E-alkene is formed as the
product (Scheme 2).

H3C Ph H3C Ph
CH3
NaOCH3 Ph H
Ph H H Br
Ph Br -HBr
CH3OH B -
Br Ph H H3C Ph
Ph H
((1S,2R)-1-bromopropane-1,2-diyl)dibenzene (E)-prop-1-ene-1,2-diyldibenzene
Scheme 2

These two classes of reactions may further be subdivided into enantioselective or

diastereoselective reactions and enantiospecific or enantiospecific reactions based on the
product formed.
In some reactions, an achiral centre may be converted to a chiral centre. Similarly, a
double bond may be converted into chiral centres. To understand the relationship
between an achirl substate and chiral product, two new terms need to be introduced.

Prochirality is the geometric property of an achiral object (or spatial arrangement of

points or atoms) which is capable of becoming chiral in a single desymmetrization step
(Figure . An achiral molecular entity, or a part of it considered on its own, is thus called
prochiral if it can be made chiral by the replacement of an existing atom (or achiral
group) by a different one. An achiral object which is capable of becoming chiral in two
desymmetrization steps is sometimes described as proprochiral (Scheme 3).

H H H D T D
H COOH H COOH H COOH
proprochiral centre prochiral centre chiral centre

Scheme 3

In the case of addition reactions, multiple bonds may be reduced to single bonds giving
rise to chiral centres (Scheme 4). In these cases, there are no prochiral centres but rather
prochiral faces. Thus, the term prochirality also applies to an achiral molecule or entity
which contains a trigonal system and which can be made chiral by the addition to the
trigonal system of a new atom or achiral group. The addition of hydrogen to one of the
faces of the prochiral ketone methyl ethyl ketone gives one of the enantiomers of the
chiral alcohol. Since the addition of hydrogen generates an enantiomer and not a
diastereomeric alcohol, so the faces in this case are referred to as enantiotopic faces.
However, the same faces may regarded as diastereotopic if the addition of a nucleophile
generates a diastereomic species. Thus, addition of cyanide anion to one of the
diastereotopic faces of the chiral aldehyde shown below converts it into one of the
diastereoisomers of the cyanohydrin. The two faces of the trigonal system may be
described as Re and Si. The allotment of the descriptor follows a rule similar to the
allotment of R and descriptors. First, the substituents are assigned priority according to
the CIP rules. Next, consider the molecule in the plane of paper. Then, looking from the
top, an arrow from the first-priority group, through the second, to the third. If the arrow
points clockwise, the face is called (Re). If the arrow points counter-clockwise, the face is
called (Si).

H H H H H H CN H H
H3C H- H3C CN- H3C H + H3C CN
H3C
Ph O Ph OH Ph O Ph OH Ph OH
enantiotopic diastereotopic
f aces f aces

1 view f rom view f rom 1

O this side O this side O
2 3 3 2
Ph H Ph H H Ph
Si f ace Re f ace

Scheme 4

In the next few pages, some of the reactions discussed in various chapters will be
discussed from a perspective of stereochemistry (Scheme 5). SN2 reactions of
cyclohexane derivatives present a nice case. If the conformation of the molecule is fixed
by a locking group, the inversion mechanism of the SN2 reaction, means that, if the
leaving group is axial, then the incoming nucleophile will end up equatorial and vice
versa.

-
X X H H
H Nu- - Nu
t Bu t Bu t Bu
Nu

leaving group is axial Nucleophile occupies

equitorial position

-
H Nu H Nu
X Nu- - H
t Bu t Bu t Bu
X

leaving group is equitorial

Nucleophile occupies
axial position

Scheme 5
It is, however, found that the substitution of an axial substituent proceeds faster than the
substitution of an equatorial substituent. This is because, in the formation of the transition
-molecular orbital of the carbon-leaving group (C-X)
bond. In the case of an axial attack, this line of attack is hindered by the axial groups at 3
and 5 positions. For an equatorial attack the direction of attack is parallel with the axial
groups antiperiplanar to the leaving group and hence much less hindered (Figure 6).

Nucleophile's path is hindered

by the hydrogen atoms X
Nu-
H H
H t Bu H
t Bu X HH
Nu-
Nucleophile is parallel
to the hydrogen atoms

Figure 6

Similarly, the ring closing to form epoxides occurs only in the trans isomer. The cis
isomer adopts a conformation where one of the groups is axial (less bulky one), while the
other is equatorial. In this conformation the two groups are not antiperiplanar as required
for a SN2 reaction. The trans isomer, on the other hand adopts a conformation where both
the groups are equatorial to each other. Though, it still seems not suited for a SN2 attack
but the attack can take place in the diaxial conformation which may be generated from
the diequitorial conformation by ring flipping. Though the former is less stable than the
latter, a small amount of the molecule in diaxial conformation may drive the reaction
forward (Le Chatelier’s principle) (Scheme 6).

OH OH RO- O-
Cl
Cl Cl O-
Cl
both conf ormations donot
have proper geometry f or SN2

OH O-
OH RO- O- O
Cl Cl
Cl Cl

Scheme 6
As with substitution, the elimination reaction in cyclohexane derivatives is also
dependent on the conformation. Since E2 reactions can occur only through an
antiperiplanar transition state so they must be stereospecific in nature. Thus, in the
elimination of trans-1-chloro-2-methyl cyclohexane, the elimination takes place from the
diaxial isomer (Scheme 7).

CH3 CH3 CH3

H
CH3
Cl CH3
Cl Cl

Scheme 7

One of the most profilic stereoselective reactions is the nucleophillic attack on carbonyl
compounds. These compounds have two stereogenic faces and, thus, it is a question on
which face will the attack preferentially take place. In this respect two empirical rules
have been developed which predict the same result.

Cram’s rule: According to this rule, if the molecule is observed along the axis,
(represented as shown below), where S, M and L stand for small, medium and
large, respectively. The oxygen of the carbonyl orients itself between the small
and the medium sized groups. The rule is that the incoming group preferentially
attacks on the side of the plane containing the small group (Scheme 8).
Y-
O Y
M M S
S
HO R
LR L
major product
Y
X
O L O Y
M XY S L
S M
R OH
LR Y- S R M
L is capable of chelation major product

Scheme 8
But, when chelation may occur between the carbonyl oxygen and the
counteraction of the incoming nucleophile, then the result of Cram’s rule may be
reversed. In this case the large group chelates counter cation of attacking
nucleophile and carbonyl oxygen.
Felkin Ahn model: The statement of the rule is same as that of Cram’s rule but
the objective is achieved by reasoning from a different angle. Assuming that
there isn’t an unusually electronegative atom on the carbon next to the carbonyl,
the largest group (L) prefers a conformation where it is perpendicular to the
carbonyl C=O. This gives two relatively competitive lowest energy
conformations, with the medium (M) and smallest (S) groups differing in their
proximity to the carbonyl oxygen.
O O
S S
L L

MR R M

It is further determined that the nucleophile prefers to attack away from the large
group at an angle of 107°. Thus, it attacks nearer to the small (S) group giving
rise to only one diastereomer.

M O OH
Y- M L
Y- L
Y R
S R S

If, howev - to the

carbonyl, there is a slight change. This ‘slight change’ is that this electronegative
group(X) becomes the equivalent of the ‘large’ group in the Felkin-Ahn model.
The reason for this that the energy of the C-

LUMO (lowest unoccupied molecular orbital). This really means is that this
conformational arrangement is more reactive than any other.
A few examples will clarify the case of application of these rules. The major product for
reduction of (R)-2-phenylpropanal can be predicted according to the Cram’s rule
(Scheme 9).

H AlH3
(M) (S) O H
H3C H H3C H3C H CH3
LiAlH4
H H
Ph HO H HO Ph
(L) O Ph
PhH
(R)-2-phenylpropanal (S)-2-phenylpropan-1-ol

Scheme 9

However, to determine the configuration of the product of the reaction between (R)-2-
methoxypropanal and dimethyl zinc, the Cram’s chelate rule needs to be applied. In this
case a chelate is formed between methoxy group’s oxygen and carbonyl group with zinc
(Scheme 10).

Zn2+ HO OCH3
O H3C O H3CO O H3C CH3
CH3 H3C CH3 H H
H OCH3 CH3 H3CO OH
OCH3 HH CH3- H H
HH
R
( )-2-methox ypropanal (2R,3S)-3-methoxybutan-2-ol
Scheme 10

Similarly Felkin Anh model is applied for the following example. Here, the large,
medium and small groups are phenyl, ethyl and methyl groups, respectively. The attack
of hydride (R)-2-phenylpentan-3-one takes from the side of the smallest group (Scheme
11).

H3C O H3C OH
CH3 H C2H5 CH3
LiAlH4
C2H5 Ph H Ph Ph H
Ph Ph CH3
H3C OH
O H C2H5 H C2H5 OH
H3Al H
(R)-2-phenylpentan-3-one (2R,3R)-2-phenylpentan-3-ol

Scheme 11
In this case, there is an electronegative atom containing a lone pair of electrons. Here,
also classification of the groups into large, medium and small group. As a result of the
overlap between C-
shown below even more important. This results in great increase in the degree of
diastereoselectivity (Scheme 12).

NBn2
H
H3C
CH3 O
=

H3C O O CH
3 HO CH3
-
NBn2 Bn2N O
Bn2N
OCH3 COOCH3
H H H
H3C CH3 CH3 CH3 CH3
H3C

=
NBn2 H3C CH3
OH
H3C COOCH3 = H3C COOCH3
CH3 OH Bn2N H
Scheme 12
In case of cyclohexanone derivatives, a cyclic system, the addition of a nucleophile
generates either a conformation with the nucleophile at an equatorial or an axial position.
However, unless the molecule is locked in a particular conformation, it does not matter
whether the nucleophile is attacking a line to the equatorial or axial position since a ring
inversion can put the molecule in a favourable conformation. However, in 4-
t
butylcyclohexanone, the t-butyl group always occupies equatorial conformation. Now,
with the increase in steric bulk of the attacking nucleophile, there will be tendency to
attack at the equatorial position as compared to the axial position. Thus, the reduction of
4-tbutylcyclohexanone with LiAlH4 results in mostly in trans alcohol while Grignard
addition of C2H5MgBr results in mostly cis-alcohol (Scheme 13).

H OH
CH3 O CH3 CH3
H3C LiAlH4 H3C + H3C
OH H
H3C H3C H3C
90% 10%

C2H5 OH
CH3 CH3
CH3 O H3C
EtMgBr H3C C2H5
H3C OH H3C
H3C
H3C
29% 79%
Scheme 13

Steric hindrance often slows down a reaction. Similarly, sometimes steric assistance
increases the rate of a reaction. The phenomena can be seen in the ester hydrolysis of
conformationally locked cyclohexane deivatives. In the ester hydrolysis the rate
limimting slow step is the formation of sp3 hybrid intermediate by the nucleophilic
addition on the trigonal carbonyl group. This imparts some steric bulk to the intermediate
as well as decreases its degree of solvation as the species is now negatively charged.
Thus, on going from the ester to the intermediate, the steric requirement of the ester
group increases as it passes through the transition state. As a result, the difference in free
energies of the axial and equatorial isomers is enhanced in the transition state than in the
ground states and the axial isomer reacts at a slower rate. This is an example of steric
hindrance. However, in the chromic acid oxidation of cyclohexyl alcohols a different
scenario. This reaction is supposed to consist of two steps, the rapid formation of a
chromate ester followed by its rate determining decomposition into a ketone. In this case
the axial alcohols are oxidized faster than their equatorial isomers. This occurs because
the difference in free energies between the axial and the equatorial chromate esters in the
ground state exceeds that between the respective transition states due to more ketone like
structure of the latter.