Conformational Analysis

Conformational analysis
• The different arrangements of the atoms in space that result from rotations of
groups about single bonds are called conformations of the molecule.
•An analysis of the energy changes that a molecule undergoes as groups rotate
about single bonds is called conformational analysis.

Me H Me CO2H
H CO2H HO2C Me H CO2H H Me

H H H H
CO2H CO2H CO2H CO2H
Me Me Me Me
Me
OH
Me
Me Me
HO HO
Et

OH Et
Et Et

Different Different
conformations configurations
 Conformations of ethane

Staggered conformation Eclipsed conformation

H H
H H 0
60
H C C
Wedge-and-dash C C H
H
structures H
H H
H
H
H
H H

600 H H
H H
Sawhorse H
projections
H H
H H

H HH
H H 600
Newman H
projections H H H H
H
H
 Torsion or Dihedral angle

The single parameter differentiating such conformers is an angle between two

planes that contain atoms ABC and BCD in themselves. This dihedral angle is
called a "torsion" angle and is most frequently used for specification of the type
of conformations.
 Types of Strain
• Steric - Destabilization due to the repulsion
between the electron clouds of atoms or groups.
Groups try to occupy some common space.
• Torsional - Destabilization due to the repulsion
between pairs of bonds caused by the
electrostatic repulsion of the electrons in the
bonds. Groups are eclipsed.
• Angle - Destabilisation due to distortion of a
bond angle from it's optimum value caused by
the electrostatic repulsion of the electrons in the
bonds. e.g. cyclopropane
 Potential energy of ethane as function of torsion angles

•staggered conformation has potential energy minimum

•eclipsed conformation has potential energy maximum
• staggered conformation is lower in energy than the eclipsed by
2.9 kcal/mole (12 kJ/mole)
 Why is the eclipsed conformation higher in energy
than the staggered conformation?

•The H-atoms are too small to get in each other’s

way-steric factors make up < 10% of the rotational
barrier in ethane
 Torsional strain
Caused by repulsion of the bonding electrons of one substituent with the bonding
electrons of a nearby substituent

filled orbitals repel

 Stabilizing interaction between filled

C-H  bond and empty C-H  *
antibonding bonding orbital

The real picture is probably a mixture of all 3 effects

• The rotational barrier is (12 kJ/mol) small enough to allow the conformational isomers
to interconvert million of times per second
 Conformations of butane

B D

Potential energy of butane as a function of torsion angle

A  “synclinal” or “gauche”
B  “anticlinal”
C  “anti-periplanar” or “anti”
D  “syn-periplanar” or “fully eclipsed
 C  “anti-periplanar” or “anti”
No torsional strain as the groups are staggered and CH 3 groups
are par apart

A  “synclinal” or “gauche”
van der Waals forces between two CH3 groups are repulsive: the
electron clouds repel each other which accounts for 0.9
Kcal/mole more energy compared to anti conformer

B  “anticlinal”
• Calculations reveal that at room temperature ~72% of the molecules of
butane torsional
are in thestrain andconformation,
“anti” large van der waals repulsive
28% are forces
in “gauche”
between the H and CH3 groups
conformation

D  “syn-periplanar” or “fully eclipsed

Highest energy due to torsional strain and large van der

waals repulsive force between the CH3 groups
n-Butane Torsional Energy Profile

H H
H
H
E2 C
E1
H Me
H MeMe
H
C
H
MeH H H
Me C

e
n
e
rg
y
H H +5.1
H Me
C
H H +3.6 Me G
Me A
+0.88
Ref = 0

H H
H Me Me H
staggered C C gauche
conformation Me H Me H conformation
H H

 E = +0.88 kcal/mol

H H
H CH3
H H H H
H H
H H
CH3 H
H H
staggered gauche
conformation conformation
 Butane in “Chair” Form
H H
H CH3
H H H H
H H
H H
CH3 H
H H
staggered gauche
conformation conformation

H H
H
1,3-diaxial
CH3 CH3 H
CH3
H H CH3
H H
H H
H H
H H
H
H H
H
gauche A 1,3-diaxial interaction is the same as a gauche
conformation conformation!!

H H H
H H H

H H H H
H H H
H
CH3 CH3 CH3 CH3
H H H
An equatorial substituent is more stable because it is in the staggered conformation.
staggered
conformation
 Conformations and Conformers
Butane can exit in an infinite number of conformations (6 most important have
been considered), but has only 3 conformers (potential energy minima)-the two
“gauche”conformations and the “anti” conformations

• The preference for a staggered conformation causes carbon chains to

orient themselves in a zig zag fashion, see structure of decane
 n-Pentane

Me Me Me

H Me

Anti-Anti

Gauche-Anti

Me Me
Me Me
H H
H H

Gauche-Gauche
double gauche pentane or "syn-pentane"
The Syn-Pentane Conformation
CH3 CH3

CH3 CH3

CH3
CH3
 G = –5.5 kcal/mol
H3C

H3 C
2 gauche and 1 syn-pentane fully staggered

syn-pentane = G– 2 gauche = 5.5 –2(0.88) = + 3.7 kca/ mol

CH3 H CH3 H CH3 H

CH3 CH3 CH3

gauche gauche syn-pentane

 The syn-Pentane Interaction - Consequences

OH O
Me Bourgeanic acid
OH
Me Me Me

Using our knowledge of acyclic conformational analysis, we can predict the

conformation found in the crystal state of a bourgeanic acid derivative.
 The syn-Pentane Interaction - Consequences

OH O
Me Bourgeanic acid
OH
Me Me Me

avoid syn-pentane!

Using our knowledge of acyclic conformational analysis, we can predict the

conformation found in the crystal state of a bourgeanic acid derivative.
 Conformations of 2,3-dimethylbutane

Me
Me
Me
Me

H H H

Me H H Me Me Me

Me Me Me Me Me Me

Me Me H

P-Gauche M-Gauche anti (achiral)

# One achiral anti form

# Two enantiomeric Gauche forms
# Equally populated, Gauche = 2 x anti
 Conformations of mono/poly halogenoalkanes

Cl
Me
n-Propyl chloride
Cl Cl Cl

H Me Me H H H

H H H H H H

H H Me

P-Gauche M-Gauche anti (achiral)

Gache forms are favoured due to London forces (van der Waals force of attraction)

Cl
Et
n-Butyl chloride
Cl Cl Cl

H Et Et H H H

H H H H H H

H H Et

P-Gauche M-Gauche anti (achiral)

Gache forms are slightly favoured due to London forces (van der Waals force of attraction)
 Conformations of mono/poly halogenoalkanes

X
X
1,2-dihalogenoethanes

X X X

H X X H H H

H H H H H H

H H X

P-Gauche M-Gauche anti (achiral)

# In the gaseous state anti is predominant (steric and electronic)

# In the Liquid state (in polar solvent of high dielectric constant) gauche forms
have significant population
 Conformations of vicinal-dihalogeno compounds

Br
Br

Br Br
Br
Me H
Me H
Me Br H Me Br
H Me
eclipsed (meso)
Br H
Br H Me H Me H
Me H
Me
Me H
Br
meso
Gauche 1 Gauche 2
anti (80%)

Br
H
eff = close to zero Equal in energy and 20% populated

Me Br
Me H

eclipsed (d/l)
Br Br
Br

Me Br Me H Br
Me H
H Br
Br H
Me Me Me H
Me H H
d/l form H Me
Br
eff = not zero
36% 42% 22%

eff (d/l) >eff (meso)

 Conformations and H-bonding
X (X = OH, NH2, F, Cl, Br, OMe, NHMe, NMe2 etc)
HO
1,2-disubstituted ethanes

H H
O O OH

H X X H H H

H H H H H H

H H X

P-Gauche M-Gauche anti (achiral)

# Intramolecular H-bonding (vicinal groups); stability (8-20 kJ/mol)

# For effective H-bonding, donor and acceptor must be close enough (either eclipsed
or Gauche)
# In eclipsed, however atoms come within contact distance, so VDW repulsive forces
make them unstable
# In gauche (torsion angle of 60-70 o) ideally suited for intra-H bonding, predominant
conformer
 Conformations and H-bonding
Me
OH OH
OH HO butane-2,3-diols
Me

Me H H
Me H
H O O

eclipsed (meso) O
Me O Me
Me H H
HO H
HO H
Me H H Me
Me
meso H H

P-Gauche M-Gauche
The intramolecular H-bond is always Enantiomeric and equally populated
stronger in the d/l (and racemic) forms,
they are more stable than the meso
H
isomers O
H
O
OH
H Me H O O Me
H H
H OH
HO H
Me OH
Me Me H Me H
Me H
d/l form Me H
eclipsed (d/l) More populated

The intramolecular H-bonding in d/l form is stronger than in the meso form
Saturated Cyclic Compounds
 Cyclopropane
Angle and Torsional Strain
 Cyclic compounds twist and bend to minimize the 3 different kinds of strain
1. Angle strain 2. Torsional strain 3. Steric strain

Cyclopropane
• banana bonds
poor orbital overlap
HCH 115°

Electron density diverts away

from the ring by 21°
•Torsional strain

For sp3: 25% s & 75% p charector

Here the four hybrid orbitals of C are far from Good overlap
equivalent Strong bond

External orbitals: 33% S & 67% p  sp2

Internal orbitals: 17% S & 83% p  sp5
Poor overlap
Weak bond
 Cyclobutane

H
H
H
H H
H
H H
to reduce torsional angle
Cyclobutane
Interplanar angle 35°
 Cyclobutane
ax ax  Eclipsing torsional strain overrides
eq increased bond angle strain by puckering.
eq eq
eq
ax  Ring barrier to inversion is 1.45 kcal/mol.
ax

n G = 1 kcal/mol favoring R = Me equatorial

n 1,3 Disubstitution prefers cis diequatorial to trans

by only 0.58 kcal/mol for di-bromo compound.

n 1,2 Disubstitution prefers trans diequatorial to cis

by 1.3 kcal/mol for diacid (roughly equivalent to the
cyclohexyl analogue.)
 Cyclopentane
H H H H
H H
H H H
H
H H H
H
H
H H H H H
Envelope Half chair

The energy difference is little

• one carbon atom is bent upwards
• The molecule is flexible and shifts conformation constantly
• Hence each of the carbons assume the pivotal position in rapid
succession .
• The additional bond angle strain in this structure is more than
compensated by the reduction in eclipsed hydrogens.
• With little torsional strain and angle strain, cyclopentane is as stable
as cyclohexane.
 Cyclopentane
H
H
H H
H H H H H H
H H H
H H
H
H H H H
Envelope Half-Chair

 Two lowest energy conformations of cyclopentane (10 envelope and 10 half chair conformations)
differ by only 0.5 kcal/mol. They are in rapid conformational flux (pseudorotation) which causes the
molecule to appear to have a single out-of-plane atom "bulge" which rotates about the ring.

Since there is no "natural" conformation of cyclopentane, the ring conforms to minimize

interactions of any substituents
H present. H

H H
H H H
H O
H
H
H H H
H H H
H

A single substituent strongly prefers the A carbonyl or methylene prefers the planar
equatorial position of the flap of the envelope position of the half-chair (barrier 1.15
(barrier ca. 3.4 kcal/mol, R = CH3). kcal/mol for cyclopentanone).

Me

Me
H H
1,2 Disubstitution prefers
trans for steric/torsional
reasons (alkyl groups) and 1,3 Disubstitution: Cis-1,3-dimethyl cyclopentane
dipole reasons (polar groups). only 0.5 kcal/mol more stable than trans.
 Cyclohexane
HA

ring-flip
HA

HB
Chair conformation HB
flagpole hydrogens
1.8 A0

H H Sum of the van der Waals radii = 2.4 A0

H
HH H

Boat conformation
H H
H H
Newman projection of the
boat conformation
How to Draw a
Chair Conformation

all opposite bonds

are parallel
 Ha Ha He He

Ha He Ha He

He He He Ha Ha Ha
He Ha

Ha He Ha
He Ring flipping or
Ha Ha He He
inversion
 Interconversions of Cyclohexane

Chair Half boat Twist boat boat

Erel=0.0 kcal/mol Erel=10 Erel=5.5 Erel=6.5

Twist boat Half boat Opposite sense Chair

Opposite sense

Planar Erel= very large >20 kcal/mol

Rings can Flip from one Chair Conformation to Another
Rings can Flip from one Chair Conformation to Another
 Cyclohexane energy profile for cyclohexane ring reversal

Half chair Half chair

H
1-1.15
boat
(4.2-6.3)

Twist boat

chair chair
• The energy difference between the chair, boat, and twist conformation of
cyclohexane are low enough to make their separation impossible at r.t. At room
temperature approx. 1 million introversions occur each other second.
• More than 99% of the molecules are estimated to be in chair conformation at
any given time
 Flipping Chair Conformations
• All axial bonds become equatorial
• All equatorial bonds become axial
• All “up” bonds stay up
• All “down” bonds stay down
axial up

eq. up
Axial-up becomes Equatorial-up
 Monosubstituted cyclohexane
X

This conformation is lower in energy

Why?
H X When X=CH3, conformer with Me in axial is higher in
H energy by 7.3 kJ/mol than the corresponding equatorial
conformer.
Result: 20:1 ratio of equatorial:axial conformer at 200 C
1,3-diaxial interaction
H H
X The black bonds are anti-
H
X periplanar
H H (only one pair shown)
H H

X H X
H H
H H
H H
The black bonds are synclinal
(gauche)
(only one pair shown)
 X

Conc. of equatorial conformer

K= Conc. of axial conformer

X Equilibrium Energy diff. between % with

constant axial and equatorial substitutent
conformers equatorial
kJ/mol
H 1 0 50
Me 19 7.3 95
Et 20 7.5 95
i-Pr 42 9.3 98
t-Bu >3000 >20 >99
OMe 2.7 2.5 73
Ph 110 11.7 99
 1,2-symmetrically disubstituted cyclohexane
CH3 CH3

CH3
CH3
CH3 CH3
1 gauche-butane interaction 4 gauche-butane interaction
0.9 kcal/mol 4 x 0.9 kcal/mol = 3.6 kcal/mol
Difference in stability between 3.6 - 0.9 = 2.7 kcal/mol
the conformational isomers
Diastereomeric, chiral and therefore resolvable

CH3 CH3
CH3 CH3

CH3
CH3 H3C
CH3
This has 3 gauche-butane
interactions

Enontiomeric, chiral and not resolvable

It exists as a dl-pair, but since barrier to rotation is low to allow separation.

Therefore the ()- pair is inseparable and hence the compound is optically inactive.
 A closer look of 1,2-symmetrically di-substituted cyclohexane

"e" becomes "a"

"a" becomes "e"
(1R,2S)-1,2-dimethylcyclohexane

Planar structure
shows cis is meso (3) (1)
and achiral (2)
H
CW (LP is B); R CCW (LP is B); S
H
(1) (2) (3)
H H

Flipping

R S
(3) CCW (LP is B); S CW (LP is B); R
(2) (1)
(3)
(2)
(1)

They are non-superposable

mirror images and constitutes a
(1S,2R)-1,2-dimethylcyclohexane pair of rapidly interconvertible
enantiomers
 1,3-symmetrically disubstituted cyclohexane

CH3 Diastereomers, achiral

CH3

H3C
CH3 CH3
CH3 2GB + 1 syn-pentane interaction

Very bad steric

situation ~ 5.5 kcal/mol (2 x 0.9 = 1.8 kcal/mol
+ Methyl-Methyl interaction)

CH3 Identical, chiral CH

3
CH3
H3C

CH3
CH3
It is a resolavable molecule
2-gauche-butane interaction = 1.8 kcal/mol

cis-isomer is stable than trans isomer

 Topoisomerisation process (ring flipping leads to identical compounds)

CCW (LP is B) CW (LP is F)

(2) (2)
(3) H H
(1) (1)
H H
(3)
(1S,3S)-1,3-dimethylcyclohexane

Flipping

(3) CCW (LP is B) CW (LP is F)

(1) H (2)
H (2)
H H

(1)
(3)

(1S,3S)-1,3-dimethylcyclohexane

# Trans 1,3-di-symmetrically substituted cyclohexane exists in a resolvable pair

# Ring inversion (flipping) converts (+) into (+) and (-) into (-) enantiomers. This is
called topoisomerisation process
 1,4-symmetrically disubstituted cyclohexane

CH3
Identical, achiral
H3C CH3

CH3 CH3
CH3

2-gauche-butane interaction, 2 x 0.9 = 1.8 kcal/mol

CH3
CH3 Diastereomers, achiral

CH3
H3C

CH3
CH3 Both have plane of symmetry, achiral

Trans is stable than cis

 Relative population of 1,2-dihalo cyclohexanes

Br

X Br
Br
X
Br
X
X Liquid 65 35
cis (a,e); eff = positive
Gaseous 95 5
in CCl4 84 16
X = Cl, Br, I in benzene 52 48

X
X
XX
X X
(a,a); eff = zero (e,e); eff = positive
X = Cl, Br, I
dipole-dipole repulsion dipole-dipole repulsion
is minimum (= 180o) is high (= 60o)

# The population of diaxial conformer increases across Cl<Br<I (as size increases)
# The population of di-equatorial conformer is high in solvent of high dielectric
constant (such as benzene, dioxane)
 Concept of locking group in conformational analysis

H B
B
H
B
Major
B = iPr, tBu etc

Bulky group always locked itself in the "e" position unstable

tBu Me tBu Me
tBu Me
tBu Me

cis cis

tBu
tBu Me
tBu Me
Me
trans Not preferred
 Preferred Conformations
OH
OH

OH

Disfavoured
OH

H
t-butyl group H
a locking group

Twist boat
Write preferred conformation for
Me OH

i-Pr

Me

OH Me

OH
favoured
Conformational preferences of 1,2 or 1,3-ditertbutyl cyclohexanes (presence of 2 locking groups)

tBu tBu
tBu tBu

cis
tBu tBu H
tBu tBu
tBu
tBu
cis H
Major
tBu H
tBu
tBu tBu
tBu tBu
H
trans Major

tBu
tBu tBu
H tBu
tBu tBu
H
Major
 Conformational preferences of intramolecular H-bonding and dipole-dipole repulsion

H H
O O
HO OH
HO OH

cis Substantially populated

OH
OH OH
HO
OH H OO H
O H
tr ans stable, but electronic repulsion
cis is also dominating

OH OH
X
XO H

trans X
(e,e)
Intra-H; but strong (a,a); no intra-H; butdipole-dipole
X = Br, Cl, I
dipole-diple repulsion repulsion is minimum

Equally populated
 Cycloheptane

Chair (+2.16 kcal/mol) Twist-Chair (0 kcal/mol)

Boat (+3.02 kcal/mol) Twist-Boat (+2.49 kcal/mol)

The easiest way to imagine cycloheptane is in chair-form:

Hendrickson, J. B. JACS 1961, 83, 4537.

 Cyclooctane
5
Chair-Boat
Lowest-energy conformation 5

7
7

1 3
Transannular strain 1 3
between C3 & C7

Ring strain originates in eclipsing interactions and transannular

van der Waals interactions

1 7

3 3

Underside view of boat-chair C3 & C7 eclipsing interactions

 Cyclooctane

Methyl position 1 2 3 4 5
7
(pseudoeqatorial)
G 1.8 2.8 >4.5 -0.3 6.1
(pseudoaxial) (kcal/mol)
1 3

Chair-Boat (BC)
Lowest-energy conformation

O
Carbonyl is positioned at C3 or C7 Olefin is positioned at C3-C4 or C6-C7

Still, W. C.; Galynker, I. Tetrahedron 1981, 37, 1981.

O

O
Me
N

OH O

Rigid molecules from cyclohexane conformers

 H
H H H
Me H H Me
H Me H H
Most stable
P1

P2

Conformational equilibrium in 1-phenyl-1-methyl cyclohexane

 Conformational preferences can be modulated under forced reaction condition

O O
OH OH CO2H O O
HO CO2H
heat
CO2H

O O O O O O
HO2C CO2H CO2H CO2H CO2H
heat
CO2H

OH
OH O
heat O
HO2C
-H2O
CO2H
Twist boat lactone
Cis-4hydroxycyclohexanecarboxylic acid
 Conformational Analysis of Bicyclic Systems

Me

Me H 11
1 13
17
H H
10
O
14
7
4

The steroid nucleus provided the stimulation for the development of

conformational analysis, particularly of polycyclic ring systems. D. H. R. Barton
was awarded a Nobel prize in 1969 for his contributions in this area.

Decalin Ring System (6/6)

H H
H

H H
rigid mobile

G°þ = 0 kcal/mol G° = +2.4 kcal/mol

 Bicyclic Systems

H
3
Gauche-butane interactions
H C1 C2
4 2 C1 C3
C4 C3
1
G°(est) = 3(0.88) = 2.64 kcal/mol

Can you estimate the energy difference between the two methyl-decalins shown below?

Me Me

H H
 Me
Me

H
H

4 GB (2 each from the axial Me)

3GB in cis decalin +
2 GB by axial Me = 5 GB
Identify the chair or boat-six membered rings in the following structures

O O
Me Me

OH OH
HO Br

OH O
O

H
But But
OH HO
Br
OH

OH O O

H
How many GB interactions are there in the following molecules?

Me Me

Me Me
 Me1
Me1

Me2
Me2

8 GB (4 each from the both axial Me) 3GB in cis decalin +

2 GB by axial Me1+
2GB by axial Me2+
1GB between Me1 & Me2
= 8 GB