*Stereochemistry:

• 2.1 Molecular chirality and elements of symmetry: Mirror plane symmetry, inversion centre, rotation-
reflection (alternating) axis. Chirality of compounds without a stereogenic centre: cummulenes, spirans and
biphenyls.
• 2.2 Conformations of cyclohexane, mono, disubstituted cyclohexanes and their relative stabilities.
Molecular Chirality:
a) Molecule having chiral centre: Tartaric acid have two chiral carbons, number of optical isomers= 22=4. Out of
these, two isomers are optical active (i.e. dextro and laevo rotatory) and other is meso-tartaric acid which is
optically inactive as its structure even presence of two chiral centres.
b) Molecule do not have chiral centre: even absence of a chiral centre in some substituted biphenyls and allenes
which molecules are chiral or optically active. Examples:
Thus, presence or absence of chiral centre is not a sufficient condition for optical activity. The necessary condition for
a molecule to be optically active is that it must have a totally dissymmetric structure (chiral structure of the entire
molecule).
Molecular dissymmetry means the original molecule (i.e. object) is nonsuperimposable on its mirror image molecule.
For complex molecules, it is not possible to check the superimposability of its mirror image. The method is to inspect
the molecule with respect to the following three elements of symmetry.
Elements of symmetry is a geometrical entity example: plane, line and point.
i) Mirror plane of symmetry (σ) :
A molecule possesses a plane of symmetry if
(a) all the atoms of the molecule are in the same plane.
Example: cis-1,2-dichloroethene possesses a plane of symmetry. The designation sigma (σ) for planes of symmetry
comes from the German word Spiegel (meaning mirror).
(b) The planes of symmetry which are perpendicular to the principal axis are termed σh (h for horizontal) whereas
those containing the principal axis are marked σv (v for vertical).
(c) A plane (mirror- plane) can be passed through the molecule, so that it divides the molecule into two symmetrical
halves, one half reflecting the other.
A plane of symmetry is a plane which divides the molecule (or object) into two halves which are mirror images of
each other and two halves may not be superposable. A molecule having such a plane is optically inactive or achiral.
Examples:
1. cis 1,2-cyclopropanediol have one vertical plane (σv)which is passing methylene carbon and mid point of
opposite bond.
2. cis 1,3 –dimethylcyclobutane has two vertical planes (one is passing methyl bearing carbon and other passing
through opposite methylene carbons).
3. cis 2,4 –dimethyloxetane has one vertical plane which is passing methylene carbon and oxygen.
4. meso-tartaric acid has one vertical plane which is passing middle of molecule.
5. cis 1,3-dichlorocyclopentane have one vertical plane which is passing methylene carbon and mid point of
opposite bond.
6. cis- 1,2-dichlorocyclohexane is achiral due to plane of symmetry. trans- 1,2-dichlorocyclohexane is chiral.
7. cis- 1,4-dichlorocyclohexane is achiral due to plane of symmetry. trans- 1,4-dichlorocyclohexane is achiral
due to centre of symmetry.
8. cis- 3,6-dimethyl-1,3-dioxane is achiral due to plane of symmetry. trans- 3,6-dimethyl-1,3-dioxane is achiral
due to centre of symmetry. No plane of symmetry but have centre of symmetry.
9. Cis 2,5-dimethylcyclopentanone is achiral.1,4-dioxane has plane of symmetry.
 ii) Inversion centre (i) or centre of symmetry: It is a point or atom in a molecule from which when lines are
drawn on one side to any atom and produced to the equal distance on the opposite side, meet the same kind of
atom in the molecule.
Example: trans 2,4-dimethyl-trans-1,3-cyclobutane dicarboxylic acid has the centre of symmetric, hence it is
optically inactive.
trans 3,6-dimethyl-2,5- diketopiperazine
trans 1,3-dimethylcyclobutane
COOH
HO
H
COOH COOH C
C
H
C C OH
COOH
H H OH
OH

Staggered or anti conformation Eclipsed conformation

Cl H
trans-1,2-dichloroethylene
C C

H Cl

iii) Rotation-reflection axis of symmetry (Sn): A molecule(I) is said to possess an n-fold alternating axis of
symmetry if
(i) on rotating through an angle of 3600/n about this axis, molecule (II) and then
(ii) followed by reflection of the molecule (II), thus formed, in a plane perpendicular to the axis, the mirror
image(III) is exactly identical to the original molecule(I).
Example: 2,4-dimethylcyclobutane-1,3-dicarboxylic acid contains two- fold alternating axis of symmetry.
S2 A
A COOH A COOH
H
CH3 H
H3C
H
CH3 H
H H . CH3
COOH . H
COOH . H H 900
900 .
.
H COOH H
CH3 .
H CH3 B
B
B COOH
900
A
H CH3 H
CH3

H COOH
H COOH . H
COOH
H COOH
.

H CH3
CH3 H B
 Thus, this molecule has (360/180=2) two-fold alternating axis of symmetry (S2). There is no naturally
occurring molecule which has been found to have an alternating axis of symmetry. The first synthetic
molecule was prepared by Proskow and MeCasland in 1956. It is a spiro molecule, trans 3, 3/, 4, 4/-
tetramethylspiro-(1,1/)-dipyrrolidium-p-toluene sulphonate. It contains four fold alternating axis of symmetry
(S4).
Chirality of the molecules without chiral centre
Stereochemistry of cumulenes:
Cumulenes are hydrocarbons having two or more cumulative (consecutive or adjacent) double bonds.

Cumulenes

H
H
H3C H
H H
C C
H H
CH3 H
H
H

Cl
H
C
Cl
H
The terminal carbon atoms should have unsymmetrical substitutions (different groups or atoms) for chiral molecule.
Unsymmetrical substituted allene will not have element of symmetry and also, a molecule has not superimposable its
mirror image, then this molecule possesses molecular chirality.
Example:
Natural occurring antibiotic mycomycin has chirality (presence of allene)
HC≡C-C≡C-CH=C=CH-CH=CH-CH=CH-CH2COOH
Natural occurring (-) glutinic acid has chirality.

H
COOH

HOOC H
First chiral allene was prepared by Maitland (1935) after van’t Hoff’s (1875) prediction (substituted allene exist in
enantiomeric form).
1,3-diphenyl-1,3-di-α-naphthyl-2-propen-1-ol (I) is dehydrated with (+)-or (-)- camphor-10-sulphonic acid, to get
substituted allene (II)
Substituted allenic acid (III) (3-(1-naphthyl-1,3-diphenylallene-1-carboxylic acid into glycollic ester) is resolved
through brucine salt.
Wotiz (1951) have resolved simpler allenic acid by strychnine.
Nakagawa (1961): 1,5-di-t-butyl-1,5-di- 4- chlorophenylpentatetraene in optically active form.
Jacob (1957): 1,3-diphenylpropyne is absorb by alumina containing brucine which give (-) allene
Stereochemistry of Biphenyls:
H H
2 2/
1 1/

6 6/
H H

Biphenyl is represented by two phenyl groups which are joined by a single bond (sp 2-sp2) which is called the pivotal
bond. Distance between ortho hydrogen’s in adjacent phenyl rings is 0.29 nm which is greater than twice the van der
Waals radius of hydrogen (2x 0.12=0.24 nm) i.e. free rotation around pivotal bond without any steric repulsion. Planar
unsubstituted biphenyl does have a vertical plane of symmetry.
2,2/,6,6/-tetrasubstituted biphenyls are classified according to the nature of the substituent.
i) Non-resolvable: The very small size (or volume) of atoms or groups like hydrogen, methoxy or fluorine are not
restricting the rotation of pivotal bond.
Example: 2,2/-difluoro-6,6/-dimethoxybiphenyl is non-resolvable. (achiral)
ii) Resolvable but easily racemized: Biphenyl contain at least two amino or two carboxyl groups or one amino and
one carboxyl group; remaining groups are fluoro or methoxy (but other than hydrogen). 6,6/- difluorodiphenic
acid is resolvable and is readily racemized.
iii) iii) Resolvable and non- racemized:
Example: 2,2/-difluoro-6,6/-dinitrobiphenyl is resolvable. (chiral)
The rotation about the pivotal bond does not occur due to steric repulsion between the bulky ortho
substituents. Both phenyl rings lie in different planes which are approximate 90O i.e to make impossible for
symmetry operation. Due to higher energy barrier (more than 80 kJ/mol) of bulky ortho substituents are
separating the enantiomers. Isolable stereoisomers resulting from restricted rotation around a single bond is
known as atropisomerism and the isomers are called atropisomers.
Effective radii of atoms and groups (nm):
 H F OH/OCH3 COOH NH2 Cl CH3 NO2 Br I
0.094 0.139 0.145 0.156 0.156 0.169 0.173 0.192 0.2 0.22
CH 3 COHN O H
CH3 H2N COOH N
i) Ac2O H2SO4

ii) (O)

NH2 H3C HOOC N

NHCOCH 3 (B) H
(A) (C) O

Compounds (A) and (B) are resolvable, but Compound (C) is non-resolvable due to the ortho positions are
joined by planar rings.
Biphenyl atropisomers with only two bulky ortho substituents are 2,2/-di-t-butylbiphenyl which is prepared
from optically active 6,6/-di-t-butylbiphenyl-2,2/-dicarboxylic acid by decarboxylation gives highly stable
enantiomers.

H3C
CH3 CH3
NO 2 O NO 2 O NO 2 O NO 2

COOH H COOH H NO 2 COOH H

A bulky group adjacent to an ortho substituent exerts a buttressing effect (to support). Thus, the rate of racemization of
the 3 / -nitro derivative is much lower than that of the 5 / -nitro derivative. The nitro group in position 3 / has a greater
stabilizing effect than in position 5 /. The nitro group in the position 3/ would tend to force the methyl group away.
Biphenyl-2,2/-disulphonic acid with only two ortho substituents is resolvable because of much higher bulk of SO 3H.
Even a single bulky group like 3/-bromobiphenyl-2-trimethylarsonium iodide can give rise to atropisomerism.
4,4/,5,5/,6,6/- hexahydroxydiphenic acid is naturally occurring optically active biphenyl.
Stereochemistry of Spiranes:
In spiranes, both the double bonds in allene are replaced by rings (usually cycloalkane or cycloheteroalkane). The two
terminal methylene planes are perpendicular to each other as in allenes and if pairs of geminal substituents (a,b) are non-
equivalent, the compounds would exhibit enantiomerism. The rings are assumed to have rigid planar structure and
diametrically opposite methylene planes are perpendicular to each other so that axial chirality would develop similar to
that in allenes with proper substitution.
Example:
Spiro[3,3]heptane-2,6-dicarboxylic acid
 H
H
COOH
HOOC
4-carbethoxy-4/-phenyl-1,1/-spiro-bispiperidinium bromide.

H H
+
N
Ph COOC2H5
spiro[4,4]nonane-1,6-dione 5,5/-spiro-bis hyantoin

O O H
N O
NH

N NH
O
O H O
Conformations of cyclohexane
According Sachse(1890) and Mohr(1918) theory, there are two extreme conformations of cyclohexane; the lowest
energy chair form and the highest energy boat conformation.
The chair conformation was confirmed by Hassel(1947) with electron diffraction method, also by Barton (1950).
C3 is three- fold axis of symmetry.
The chair form has four carbon atoms in one plane, remaining two carbons have above and below this plane. There are
two type of C-H bonds in a methylene (-CH2-). Each carbon atom has one C-H bond parallel to the three-fold axis,
which called axial bond (i.e. Ha). There are six axial bonds, in which three axial bonds are placed above the plane and
remaining three are below the plane and arrange alternately.
The remaining six C-H bonds are inclined at an angle of 109028/ to the three- fold axis, which called equatorial bond
(i.e. He). Similar to axial bond, three equatorial bonds are β-H and other three equatorial bonds are α-H and arrange
alternately.
The boat form has four carbon atoms (shows in above figure, C2, C3, C5 and C6) lies on one plane and other two carbon
atoms re placed either above the plane or below this plane.
The four carbon atoms (i.e. C2, C3, C5 and C6) have an axial and an equatorial C-H bond each. Other two C-H bonds (i.e
C1 and C4) are across the ring and out of four hydrogen, one from each of the hydrogen are close to each other which
are named as flag pole (Hf) bonds and remaining two C-H bonds are far apart are called bowspirit (Hb) bonds.
Why chair form is more stable than boat?
In chair form, all C-C-C bond angle are 109.50 and all the bonds are staggered i.e. free from bond eclipsing strain and
angle strain.

H H H H H
H H H
5 H 1 C1
1
H H H H 2 2
H 3 H 6 H
6
4 H 4 H C4 H
H H H H H
H H H
2
Staggered bonds in chair form Gauche
H

In chair form, all the C-H bonds an adjacent carbon atom are in Gauche conformation (or position).
Gauche Strain = 6* 0.8 = 4.8 kcal/mole
There is van der Waal’s stain due to crowding between flag-pole hydrogens which are lie 1.83 A0 apart i.e. closer than
the sum of their van der Waal’s radii (2.4 A0).
In boat form, the four C-C bonds are gauche position and the others two C-C bonds are fully eclipsed.
Strain = (4*0.8) + (2*3.8) = 10.8 kcal/mole.
The boat conformation of cyclohexane is about 6 kcal/mole higher in energy than the chair form.
Thus, the chair form being very stable, constitute over 99.9% of cyclohexane at equilibrium (250C).
In addition to the chair and boat conformations, there are two more conformations of cyclohexane during the
interconversion of chair to boat form.
The boat form is easily twisted so that the flag-pole hydrogens move apart to either side of the molecule and carbon
atoms C2, C3, C5 and C6 become non-planer and thereby the hydrogen become Gauche w. r. t. each other. This is called
twist-boat conformation which has less torsional strain compared to the boat form about 1.5 kcal/mole.
The maximum energy conformation at transition state is called half-chair form is about 10 kcal/mole energy than chair
form.
Monosubstituted cyclohexane: 21= 2 forms
Van der Waal’s strains, 0.85 * 2 = 1.7 kcal/mole
1,3-diaxial (or non-bonded) interaction (1.7 kcal/mole) 95% equatorial form and 5% axial form at 250C.
Monosubstituted cyclohexanes exist in two non-equivalent diastereomeric chair conformations, Conformer(A) has
substituent methyl group in the axial position. Conformer(B) has substituent methyl group in the equatorial position.
The axial conformer (A) has two additional gauche interactions involving CH3-C1-C2-C3 and CH3-C1-C6-C5. The
equatorial conformer (B) does not have any additional gauche interaction. The overall steric interactions; 1,3-diaxial
interaction are shown in conformer (A)i.e. methyl group at axial position (van der Waal distance=1.83 nm between
methyl group and two 3H)
Van der Waal’s strains, 0.85 * 2 = 1.7 kcal/mole
1,3-diaxial (or non-bonded) interaction (1.7 kcal/mole) 95% equatorial form and 5% axial form of methylcyclohexane
at 250C.
Due to high 1,3-diaxial interaction between tertiary hydrogens and 3H in tertiary-butyl at axial position (-ΔG= 4.8
kcal/mole), tertiary butyl group is 99.9 % remains at equatorial position.
Others atom/ group at axial position, increasing in enthalpies:
F<CN<Cl<OH(in aprotic solvent)< OCH3<NH2<CH3<C2H5<CH(CH3)2<<C(CH3)3.

Disubstituted cyclohexanes: 22 = 4 forms

C H3 C H3
Plane of symmetry
C H3 C H3
cis-1,2-dimethylcyclohexane

C H3 C H3

C H3 CH3

trans-1,2-dimethylcyclohexane

Cis-isomers (a,e) and (e,a):

(a,e)

H
H CH3
H H
H 1 2

H H
3 CH3 H3C
2 1

(I) H H (IV)

C H3
CH3 1
C H3 H 3C
2
H 2 H
1
H
H
(II) (III)

(e,a):

H H
1 2

3
C H3 H3 C
H H H
2 1
H C H3
CH3

The structure(I) has no element of symmetry, it cannot be superimposed on its mirror image (IV). Thus, it should show
optical activity. But the compound (I) flips to the compound (II) which is equivalent to compound (IV). Both the
enantiomers have same stability, thus there are equally populated. Therefore, cis-isomer are optically inactive due to
external compensation.
Trans isomers: (a,a) and (e,e)

(a,a):

H
H3C H

H 1 2

H H3C
3 H H H3C
2 1
H H
(A) C H3 (D)

CH3
H 1
C H3 H
2
C H3 2 H
1
C H3 (C)
(B) H

(e,e):

H CH3
1 2

3
CH3 H
CH3 H
2 1
(m) H C H3 (p)

H
CH3 1
H H 3C
2 2 H3C
H 1
H (o)
C H3
(n)

In the trans form structures (m) in (e,e) and (A) in (a,a) have no element of symmetry and but, they cannot be convert
into their mirror images by flipping,

Therefore, trans-1,2- dimethylcyclohexane (e,e) as well as (a,a) conformers exist as pairs of enantiomers.

There are indeed four stereoisomers, but isolate only three. (a,e) = (e,a) in equal in

Enthalpy for cis-1,2- dimethylcyclohexane (a,e)= 2.5 kcal/mole due to two 1,3-diaxial non-bonded interactions (0.85
* 2 = 1.7) and one gauche interaction(0.8).

Enthalpy for trans-1,2- dimethylcyclohexane (a,a)= 3.4 kcal/mole due to four diaxial non-bonded interactions (0.85 *
4 = 3.4).

Enthalpy for trans-1,2 dimethylcyclohexane (e,e)= 0.8 kcal/mole due to one gauche interaction.
Stability order: most stable in this is trans-1,2 dimethylcyclohexane (e,e) then

cis-1,2- dimethylcyclohexane (a,e) and least stable is trans-1,2- dimethylcyclohexane (a,a).

1,3-Disubstituted cyclohexane: 22 = 4 forms

 C H3 C H3
Plane of symmetry Plane of symmetry

C H3 C H3
cis-1,3-dimethylcyclohexane

C H3
C H3

C H3 CH3

trans-1,3-dimethylcyclohexane

H H H
H
H
CH3 H
H H CH3
H3C (S)
(P)
H CH3

H
H H
H H 3C
H H H
H 3C
CH3 CH3 H
(Q) (R)

In the cis form structures (P) in (e,e) and (I) in (a,a) have mirror plane of element of symmetry i.e. meso compound.
1,3-cis isomer are achiral in the planar structure as well as the two chair conformers (a,a) and (e,e).

In the trans form structures (A) in (a,e) have no element of symmetry and also, they cannot be convert into their mirror
images by flipping. However, the ring flip in trans-1,3-dimethylcyclohexane does not racemize but regenerates the
same enantiomer, only converts (+) into (+) and (-) into (-) enantiomers.

Therefore, trans-1,3- dimethylcyclohexane (a,e) as well as (e ,a) conformers trans-1,3 isomer is chiral and exist as pairs
of enantiomers.

There are indeed four stereoisomers, but isolate only three.

Enthalpy for cis-1,3- dimethylcyclohexane (a,a)= 5.5 kcal/mole (23 kJ/mol)due to 1,3-diaxial has two (one for each
axial methyl group) corresponding to an enthalpy of ~1.7 kcal (or 7.5 kJ/mol) and 1,3-diaxial methyl-methyl interaction
corresponding to an enthalpy of ~3.8 kcal (or 15.5 kJ/mol).
Enthalpy for cis-1,3- dimethylcyclohexane (e,e)= zero kcal/mole. No gauche interaction.
Enthalpy for trans-1,3- dimethylcyclohexane (a,e)= 1.7 kcal/mole due to two diaxial non-bonded interactions (0.85 *
2 = 1.7).

Stability order: most stable in this is cis-1,3- dimethylcyclohexane (e,e) then trans-1,3- dimethylcyclohexane (a,e) and
least stable is cis-1,3- dimethylcyclohexane (a,a).

The difference between cis and trans isomers is ΔH= -7.5 kJ/mol, (experimental=-8.2), ΔScal= -5.8 JK-1mol-1 and ΔG=-
5.64 kJ/mol.

Stability in diaxial cis-1,3-cyclohexanediol is due to intramolecular hydrogen bonding. Also, in diaxial cis- 1,3-
cyclohexanedicarboxylic acid as anhydride.

When the two substituents are different, both the cis and trans isomers are resolvable, diequatorial conformation is
most stable and in equatorial-axial conformation, bulky group predominantly in the equatorial position.

1,4-dimethylcyclohexane:

The cis-isomer exists in two identical (e,a) and (a,e) conformations and

Trans in two non-equivalent (e,e) and (a,a) conformations of which diequatorial form is more stable by four gauche
interactions (15 kJ/mol)

The vertical plane passing through C-1 and C-4 is a σ plane (ie mirror plane of symmetry).

Thus, all the conformers are achiral even the two substituents are different.

Dimethylcyclohexane Enthalpy stability

cis-1,2- (a,e) 2.5

trans-1,2- (a,a) 3.4

(e,e) 0.8 most

cis-1,3- (a,a) 5.5

(e,e) 0 most

trans-1,3- (a,e) 1.7

cis-1,4- (a,e) 1.7

trans-1,4- (a,a) 3.4

(e,e) 0 most