Conformational Analysis

Carey & Sundberg: Part A; Chapter 3

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

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.
Conformation and hydrogen bonding
Conformation of butane-2,3-diols
 Cycloalkanes
Ring strain
No of atoms in Internal angle in 109.50-internal
ring planar ring angle*

3 600 49.50
4 900 19.50
5 1080 1.50
6 1200 -10.50
7 128.50 -190
8 1350 -25.50
* a measure of strain per C-atom

All internal angles 109.5 0C

 109.50-internal angle

3 49.50
4 19.50
5 1.50
6 -10.50
7 -190
8 -25.50

•Ring strain largest for 3-membered rings, then decreases

through a 4-membered ring and reaches a minimum for 5-
memberd ring.
•Prediction: planar 5-membered ring should have the minimum
level of ring strain.
•The ring strain keeps on increasing as the rings get larger after
the minimum at 5
H
• the difference between any two in series
is very nearly constant at around –660 kJ/mole

• assuming there is no strain in the straight-chain

alkanes, each extra –CH2 group contributes an
extra 658.7 kJ/mole to the heat of combution

• if cycloalkane is strain free, its heat of combustion

should be n X 658.7 kJ/mole. If there is some strain
,more energy is given out on combustion

Look at the graph which shows, for each ring size:

(a) angle strain per CH2 group
(b) heat of combustion per CH2 group
• The greatest strain is in the 3-membered ring.
• The strain decreases with ring size and reaches a minimum for 6-membered ring.
• The strain then increases, but not as quickly as the angle calculation suggested: it
reaches a maximum at 9 and then decreases.
• The strain remains constant at ~14, not increases steadily as the angle-strain suggested.

Q • Why 6-membered ring is more strain free?

• Why there is still some strain in 5-membered ring?
 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.)
 H H
H H
H
H
H Cyclopentane
H H
H H
H H H
H H
H H H
H
H H H
Envelope H Half chair
H
H H H H
H

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 present.
H
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 H
H H

Boat conformation
HH H
H

Newman projection of the

boat conformation
 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 Chair Twist boat boat

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

Twist boat Half Chair Opposite sense Chair

Opposite sense

Planar Erel= very large >20 kcal/mol

 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
 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
 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
 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.
 CH3 Diastereomers, achiral
CH3

H3C
CH3 CH3
CH3

Very bad steric

situation ~ 5.5 kcal/mol (4 x 0.9 = 3.6 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

 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

 Problem: Which of the following compounds are resolvable,
and which are non resolvable?Which are truly meso?
a) cis-1,2-cyclohexane diol; b) trans-1,2-cyclohexane diol;
c) cis-1,3-cyclohexane diol; d) trans-1,3-cyclohexane diol;
e) cis-1,4-cyclohexane diol; f) trans-1,4-cyclohexane diol.
Hint:
OH
OH
OH
OH OH
OH
OH
OH trans (resolvable)
Non resolvable (easily interconvertible by flipping)
OH
OH OH
HO
OH OH
cis (meso) trans (resolvable)
OH
OH
HO OH
HO
OH
achiral (absence of chirality center)
 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.

Rigid molecules from cyclohexane conformers
Conformational equilibrium in 1-phenyl-1-methyl cyclohaxane
 OH CO2H O
O
HO
CO2H

Lactonization of 3-hydroxy cyclohexane carboxylic acid

CO2H CO H O O O
2
HO2C
CO2H

Cyclic anhydride formation from 1,3-cyclohexanedicarboxylic acid

OH H H
OH O O
HO
OH

Intramolecular H-bonding in 1,3cyclohexanediol

 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
E2 eliminations have anti-periplanar transition states

Two conformations with H and X coplanar

In E2 eliminations, the new  bond is formed by

overlap of the C-H  bond with the C-X *
antibonding orbital
E2 eliminations have anti-periplanar transition states

Me groups gauche Me groups anti-

(syn-clinal) periplanar
more hindered Less hindered

Reaction is stereoselective
 Br H3C C6H5
Only one proton for removal OH
C6H5
C6H5
(faster)
CH3 C6H5 H
H Ph Br
Br Br Ph
Ph CH3
CH3
H
Ph H H Ph
CH3
Ph H H

Br H3C C6H5
C6H5 OH
C6H5
(slower)
CH3 H C6H5
Br
H Ph Br Me
Br Me Ph
Ph
H
Me H Ph
Ph
Ph H
H H
 Br C6H5 CO2H
C6H5 CO2H
C6H5 CO2H
C5H5N
H COC6H5 H
H COC6H5 COC6H5

Whereas Br
C6H5 H
HO2C C6H5
C5H5N

H COC6H5 H COC6H5

Br
H C6H5 H
C6 H5 C5H5N

H COC6H5
H COC6H5

CO2H
 Problem: On treatment with the aromatic base pyridine, racemic 1,2-dibromo-1,2-diphenyl ethane
loses HBr to yield trans-1-bromo-1,2-diphenyl ethane; In contrast the meso dibromide loses Br 2 to
yield trans-1,2-diphenyl ethene. Suggets a mechanism?

Hnit: Ph Br
Ph
Br
Ph H
Br H H H Ph Br2 loss is not favored
Ph
H Br H Br
Br
Ph
Racemic

H
Ph -HBr Ph
H Br
Ph
Br Ph
Ph Ph Br Br
PhH Ph
H Br Ph
Br H H -Br2
H Br Ph Ph
H Br
Ph Br
meso