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 conformations Different 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 to differentiate 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 others

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

D
B

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 CH3 groups
are far away from each other

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 B anticlinal
reveal that at room temperature ~72% of the molecules of
butane are in the anti conformation, 28% are in gauche
torsional strain and large van der waals repulsive forces
conformation
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
 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
gaucheconformations 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
 Cycloalkanes

Is the energy per CH2 is same in this series?

Is the energy per CH2 is same in the straight chain alkanes?

CH3-(CH2)n-CH3

Does the value of n has an effect on combustion energy per CH2?

 Heats of combustion for straight chain alkanes of formula
CH3(CH2)nCH3

Straight chain n -Hcombustion Difference

alkanes kJ mol-1 kJ mol-1
ethane 0 1560 -------
propane 1 2220 660 the difference between
butane 2 2877 657 any two in series very
nearly constant at around
pentane 3 3536 659 660 kJ/mole (energy per
hexane 4 4194 658 CH2)
heptane 5 4853 659
octane 6 5511 658
nonane 7 6171 660
decane 8 6829 658
undecane 9 7487 658
dodecane 10 8148 661
Therefore in cycloalkanes
heat of combustion should
be n X 658.7 kJ/mole.

If there is some strain,

more energy should
given out on combustion
 Cycloalkanes:
Ring strain

ce per CH2 697 686 664 659 662.4 663.8 kJ mol-1

Ideal angles 60 90 108 120 128.5 135

Deviation* 49.5 19.5 1.5 -10.5 -19 -25.5
from 109.5
* a measure of strain per C-atom

All internal angles 109.5 0C

 Why 6-membered ring is more strain free?
Why there is still some strain in 5-membered ring?

strain and ce are more in the 3-membered ring.

strain decreases with ring size and reaches a minimum for 5-membered ring.
ce decreases with ring size and reaches minimum for 6-membered ring
The ce increases, but not as quickly as the angle calculation suggested: it
reaches a maximum at 9 and then decreases.
ce remain constant from ~14, not increases steadily as the angle-strain suggests.
 Hydrogenation
at high pressure

pyrolysis Br2 water

Br Br

more strenuous
conditions required
H H

pyrolysis Br2 water

No reaction
H H
 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
 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.
 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
 Ha Ha
He He
Ha He
Ha He
He He He
He Ha Ha Ha
Ha

He Ha He Ha
Ha Ha Ring flipping or
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 in each 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 The black bonds are synclinal
(gauche)
H H (only one pair shown)
H H
 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 H
t-butyl group
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 of rotation is low to allow separation.

Therefore the ()- pair is inseparable and hence the compound is optically inactive.
 CH 3 Diastereomers, achiral

CH 3

H3C
CH 3 CH 3
CH 3

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

Why is the eclipsed conformation higher in energy than the staggered conformation?

As two nonpolar groups approach

each other, the van der Waals
attractive force increases to a
maximum,then decreases and
becomes repulsive

van der Waals radii, A0 The van der Waals radius one-
half the distance between two
H N O F
equivalent atoms at the point of the
1.2 1.5 1.4 1.35 energy minimum
CH2 P S Cl
2.0 1.9 1.85 1.8

CH3 Br
1.95
2.0
I
2.15
 Q. Compound A reacts faster by the SN2 mechanism than the compound B
H3C CH3 H3C CH3

Br Br
A B

Nu CH3 Nu
H H
H
H3C H
Br Br
H3C H3C
less hindered
approach Q. Compound A reacts faster by the SN1 mechanism than compound B
Br Br

A B
 Reactive differences between axial and equatorial conformers

X H
X- H

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

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

Nu- = -SPh
X- = -OTs TS
Reaction 1 found to be 31 times faster than 2
Nu X

H H
H hindered by t-Bu H

X
axial hydrogens
t-Bu H
H Nu
 Epoxide formation

OH OH

X X

X
O
O O

X X

O
O
No epoxide

Only diaxial conformation forms epoxide

X
 Epoxides

O O

X +
+
O
X

TS
This TS is same for ring opening or formation of epoxide

Since the opening is possible only in diaxial substituted cylohexanes,

the ring opening products also has to be diaxial
 Epoxides

H O H

H
Y OH
Y
O
H H
Y
H H
H Y O OH

H Y H Y
(Product formed)
 But But
Q. 1. Ph3P, X2
CH2Cl2

2. H2O
~95% OH
O X

Whereas
But But
1. Ph3P, X2
CH2Cl2

2. H2O
~95% X
O HO

X = Cl, Br, I
 O But O

But
X X

OH Twist boat, too high

O
in energy to form.

Barrier to reaction
Bu t But that matters not the
X final product
X

X
But X
Ring opening of
cyclohexene oxides
But always leads directly to
O O diaxial products
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
H
C6H5 C6H5
HO2C C5H5N

H COC6H5 H COC6H5

Br
H C6H5 H
C6H5 C5H5N

H COC6H5
H COC6H5

CO2H
Predict the product of following reaction

OMe

HO2C H
HNO2

HO

NH2
 CH3 CH3
CH3
Q.
NaOEt
+
(faster
Cl reaction)

1:3
OEt
H H
Me

Me

Cl Cl

CH3 CH3
Cl Me

NaOEt Me
Cl
(250 times H
Cl slower) Slow
OEt
Q. Br
Br
I

(faster)

Br
Br
I

(slower)

Br
Br
fast fast
Br

Br

I I
Br
Br Br fast
Br
I
I
slow
I
SN2
 Reactions of 2-bromo-4-phenylcyclohexanols with base and silver oxide
C6H5 Br O

O
OH
C6H5 C6H5
Ag2O H
or OH- Ag2O Ag2O
or OH- Or OH-
OH
OH H
Stable not
C6H5 suitable for -HBr
OH
C6H5 Br C6H5
Br
Br
Ag2O
C6H5 Br OH
CHO
Ag2O induces Br-
C6H5
C6H5
Br
OH- O

C6H5
OH
Predict the product
OH

H+
Me
Me

OH

OH2 Me

Me
Me
Me
O
OH
 CHO

:OH
..
OH NaNO2, HCl NaNO2, HCl N2
N2

OH
OH
NH2 NH2

OH

OH
H
:OH
.. NH2 NH2
OH NaNO2, HCl NaNO2, HCl
N2
N2

O
O
Q. Br
Br
I

(faster)

Br
Br
I

(slower)

Br
Br
fast fast
Br

Br

I I
Br
Br Br fast
Br
I
I
slow
I
It is more difficult to form an acetal of compound A than of B.
Why?
O

O
HO OH O

H+

A
A
O

O
HO OH O

H+

B
B
Which compound should saponify faster (A or B)?
CO2Et CO2Et

A B

O Ans: B
EtO OH OH
O
OEt
vs