Chemistry 531

Organic Synthesis
Topic Number 01

Structure of Organic Compounds

Acyclic Conformational Analysis

Cyclic Conformational Analysis
Allylic Strain

F. Michael

Monday,
January 3, 2005

Chem 531

Acyclic Conformational Analysis-1

D. A. Evans, F. Michael

The following discussion is intended to provide a general

overview of acyclic conformational analysis
Carey & Sundberg, Advanced Organic Chemistry, Part A. Chapter 3
Conformational, Steric and Stereoelectronic Effects
R. W. Hoffmann, Chem. Rev. 1989, 89, 1841-1860
Allylic 1-3-Strain as a Controlling Element in Stereoselective Transformations
Eliel & Wilen, Stereochemistry of Organic Compounds, Wiley, 1994

Ethane & Propane

Ethane Rotational Barrier: The FMO View

One can see from space-filling models that the van der Waals radii of the
hydrogens do not overlap in the eclipsed ethane conformation. This makes the
steric argument for the barrier untenable.
An alternative explanation for the rotational barrier in ethane is that better
hyperconjugative overlap is possible in the staggered conformation than in the
eclipsed conformation as shown below.
In the staggered conformation there are 3 anti-periplanar CH Bonds

H
H

RH

R
H
C

H
H

eclipsed
conformation

staggered
conformation

E = +3.0 kcal mol-1 (R = H)

E = +3.4 kcal mol-1 (R = Me)

C
CH
HOMO

For purposes of analysis, each eclipsed conformer may be broken up into its
component destabilizing interactions.

CH

* CH
LUMO

CH

In the eclipsed conformation there are 3 syn-periplanar CH Bonds

Incremental contributions to the barrier:

Structure

Eclipsed atoms E (kcal/mol)

ethane

3 (HH)

3 x 1.0

3.0

propane

2 (HH)
1 (HMe)

2 x 1.0
1 x 1.4

3.4

CH

H
CH
HOMO

* CH
LUMO
CH

Following this argument one might conclude that:

Conventional Explanation: Steric interaction between eclipsed groups.

The staggered conformer has a better orbital match between bonding and
antibonding states.
Big debate: See:
Pophristic, V. Nature, 2001, 411, 565. (It's not sterics)
Bickelhaupt, F. M. Angew. Chem., Int. Ed. 2003, 42, 4183. (Yes, it is)
Weinhold, F. Angew. Chem., Int. Ed. 2003, 42, 4188. (No, it's not)

The staggered conformer can form more delocalized molecular orbitals.

Me
Me
Me

Calculate the the rotational barrier about the C1-C2

bond in isobutane

D. A. Evans, F. Michael

Chem 531

Acyclic Conformational Analysis: Butane

The 1,2-Dihaloethanes
X
H

H
H

C
H

H
C

X = Cl; H = + 0.91.3 kcal/mol

X = Br; H = + 1.41.8 kcal/mol
X = F; H = 0.6-0.9 kcal/mol

Eliel. page 609

Observation: While the anti conformers are favored for X = Cl, Br, the gauche
conformation is prefered for 1,2-difluroethane. Explain.

Butane
Using the eclipsing interactions extracted from propane & ethane we should be
able to estimate all but one of the eclipsed butane conformations

staggered
conformation

G = RT Ln K
or

G = 2.3RTlog10K

At 298 K:

2.3RT = 1.4 (G in kcal/mol)

eclipsed
conformation

H
Me

Relationship between G and Keq and pKa

Me
H

H
H

H
C

Discuss with class the origin of the gauche stabiliation of the difluoro anaolg.

Recall that:

Me

Me

E=?

Eclipsed atoms

E (kcal/mol)

1 (HH)

+1.0 kcal/mol

2 (HMe)

+2.8 kcal/mol

E est = 3.8 kcal/mol

The estimated value of +3.8 agrees quite well with the value of +3.6 reported
by Allinger (J. Comp. Chem. 1980, 1, 181-184)

G298 = 1.4 log10Keq

n-Butane Torsional Energy Profile

pK = log [H+]

Since

G298 = 1.4 x pKeq

which is = 1.4 x pKa
Keq

pKeq

1.0

10

-1

1.4

100

-2

2.8 kcal/mol

E1
H
H

energy

Hence, pK is proportional to the free energy change

E2

Ref = 0

H
H
C

Me A

MeMe

Me
H

C
H

H
C

C
H
Me

Me

H
H

+3.6

Me
Me

+0.88

+5.1

Chem 531

Acyclic Conformational Analysis: Butane

D. A. Evans, F. Michael
Butane continued

From the torsional energy profile established by Allinger, we should be able to

extract the contribution of the MeMe eclipsing interaction to the barrier:

staggered
conformation

RR

C
H
H

Me
Me

H
H

Me

Me

General nomenclature for diastereomers resulting from rotation about a

single bond
(Klyne, Prelog, Experientia 1960, 16, 521.)

+5.1 kcal/mol

eclipsed
conformation

H
H
R

2 (HH)

+2.0
+3.1

1 (MeMe)

R
C

sp

-60

Incremental contributions to the energy.

E (kcal/mol)

From the energy profiles of ethane, propane, and n-butane, one may extract
the useful eclipsing interactions summarized below:

sc

ac

ac

-120

E (kcal/mol)

+1.0

Me

+1.4

Me

Me

+3.1

Nomenclature for
staggered conformers:

H
H

Me
H

H
Me

70%

Me

H
H

gauche(+)
or g+
15%

C
R

180

Torsion angle

Me

Me
H
C

trans or t
or (anti)
Conformer population
at 298 K:

Me

+120

ap

X
Y

+60

sc

Hierarchy of Eclipsing Interactions

X

Let's extract out the magnitude of the MeMe interaction:

Eclipsed atoms

H
H

gauche(-)
or g15%

Designation

Symbol

n-Butane
Conformer
E2

Energy Maxima

0 30

syn periplanar

sp

Energy Minima

+60 30

+ syn-clinal

+ sc (g+)

+120 30

+ anti-clinal

+ ac

E1

180 30

antiperiplanar

ap (anti or t)

-120 30

- anti-clinal

- ac

E1

-60 30

- syn-clinal

- sc (g-)

Acyclic Conformational Analysis: Pentane

D. A. Evans, F. Michael

Chem 531

n-Pentane
Rotation about both the C2-C3 and C3-C4 bonds in either direction (+ or -):
Me
Me

H
Me

g+t

Me

Me

g+g-

Me

Me

Me

Me

t,t

H
Me

Me

Me

H
Me

tg-

H
g+g+

The new high-energy conformation: (g+g)

Me

The double-gauche pentane

conformation

Me

H
H

tg+

Me
H

Me

g-g-

Me

Estimate of 1,3-Dimethyl Eclipsing Interaction

Me

H
g+g-

G = +5.5 kcal/mol
G = X + 2Y where:

g-t

X = 1,3(MeMe)
Y = 1,3(MeH) = gauche butane

1
1

Me
t,t

Me

g-g+

Me

1,3(MeH) = gauche butane = 0.9 kcal/mol

1,3(MeMe) = G 2Y = 5.5 1.8 = +3.7 kcal/mol
+

1 (t,t)
Anti(2,3)-Anti(3,4)

2 (g t)
Gauche(2,3)-Anti(3,4)

1,3(MeMe) = + 3.7 kcal mol -1

1
1

Estimates of In-Plane 1,2 &1,3-Dimethyl Eclipsing Interactions

3
+

4 (g g )
Gauche(2,3)-Gauche'(3,4)
double gauche pentane
syn-pentane

+g+)

Me

Me

Me

Me

Me

Me

Me

Me

3 (g

Gauche(2,3)-Gauche(3,4)

From prior discussion, you should be able to estimate energies of 2 & 3 (relative to 1).
On the other hand, the least stable conformer 4 requires additional data before is
relative energy can be evaluated.

~ 3.1

~ 3.7

~3.9

~ 7.6

It may be concluded that in-plane 1,3(MeMe) interactions are Ca +4

kcal/mol while 1,2(MeMe) interactions are destabliizing by Ca 3.1 kcal/mol.

Evans, Kim, Breit, Michael

Conformational Analysis: Cyclic Systems-1

Introductory Concepts

Chem 531

Cyclopropane

Three Types of Strain:

Necessarily planar.
Substituents are therefore eclipsed.
Disubstitution prefers to be trans.

Prelog Strain: van der Waals interactions

Baeyer Strain: bond angle distortion away from the ideal
H

Pitzer Strain: torsional rotation about a bond

= 120
Almost sp2, not sp3

Baeyer Strain for selected ring sizes

size of ring Heat of Combustion
(kcal/mol)
3
4
5
6
7
8
9
10
11
12
13
14
15

499.8
656.1
793.5
944.8
1108.3
1269.2
1429.6
1586.8
1743.1
1893.4
2051.9
2206.1
2363.5

Total Strain Strain per CH2

(kcal/mol)
(kcal/mol)
27.5
26.3
6.2
0.1
6.2
9.7
12.6
12.4
11.3
4.1
5.2
1.9
1.9

9.17
6.58
1.24
0.02
0.89
1.21
1.40
1.24
1.02
0.34
0.40
0.14
0.13

= 3080 cm-1

"angle strain"
deviation from 10928'

Walsh Model for Strained Rings:

2444'
944'
044'
-516'

Rather than and * c-c bonds, cyclopropane has sp2 and p-type
orbitals instead.

(antibonding)

(antibonding)

Eliel, E. L., Wilen, S. H. Stereochemistry of Organic Compounds Chapter 11, John Wiley & Sons, 1994.

(antibonding)

Baeyer "angle strain" is calculated from the deviation of the

planar bond angles from the ideal tetrahedral bond angle.

Nonbonding

H
side view

Discrepancies between calculated strain/CH2 and the "angle

strain" results from puckering to minimize van der Waals or
eclipsing torsional strain between vicinal hydrogens.
Why is there an increase in strain for medium sized rings even
though they also can access puckered conformations free of
angle strain? The answer is transannular strain- van der Waals
interactions between hydrogens across the ring.

(bonding)

(bonding)

1 (bonding)

Evans, Kim, Breit, Michael

ax

ax
eq
eq

= 28

eq

eq
ax
ax

Cyclopentane

Cyclobutane

145-155

Chem 531

Conformational Analysis: Cyclic Systems-2

Eclipsing torsional strain overrides

increased bond angle strain by puckering.
Ring barrier to inversion is 1.45 kcal/mol.

Cs Envelope

C2 Half-Chair

Cs Envelope

Two lowest energy conformations (10 envelope and 10 half chair conformations
Cs favored by only 0.5 kcal/mol) 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.
G = 1 kcal/mol favoring R = Me equatorial

Cs Envelope
1,3 Disubstitution prefers cis diequatorial to
trans by 0.58 kcal/mol for di-bromo cmpd.

1,2 Disubstitution prefers trans diequatorial to

cis by 1.3 kcal/mol for diacid (roughly equivalent to
the cyclohexyl analogue.)

A single substituent prefers the equatorial position of the flap of the envelope
(barrier ca. 3.4 kcal/mol, R = CH3).
1,2 Disubstitution prefers
trans for steric/torsional
reasons (alkyl groups) and
dipole reasons (polar groups).

Me
Me

1,3 Disubstitution: Cis-1,3-dimethyl cyclopentane

0.5 kcal/mol more stable than trans.

A carbonyl or methylene prefers the planar position of

the half-chair (barrier 1.15 kcal/mol for cyclopentanone).
X

Conformational Analysis: Cyclic Systems-3

Evans, Kim, Breit, Michael

Methylenecyclopentane and Cyclopentene

Cyclohexane Energy Profile (kcal/mol)

Strain trends:

Half-Chair

>

Chem 531

Decrease in eclipsing strain

more than compensates for the
increase in angle strain.

>

Boat
11.0

Relative to cyclohexane derivatives, those of cyclopentane prefer an sp2

center in the ring to minimize eclipsing interactions.
"Reactions will proceed in such a manner as to favor the formation or retention
of an exo double bond in the 5-ring and to avoid the formation or retention of
the exo double bond in the 6-ring systems." Brown, H. C., Brewster, J. H.;
Shechter, H. J. Am. Chem. Soc. 1954, 76, 467.

Examples:

H
O

5.3

Chair

Chair Cyclohexane

OH

k5

Hax

k6
= 23
k5

NaBH4

Hax

Heq

Heq
Heq
Hax

O
OEt

95.5:4.5 keto:enol

Heq

Heq

Heq
Hax

Hax

Hax

Boat Cyclohexane

flagpole interaction = 2.9 kcal/mol

Conan, J-Y.; Natat, A.; Priolet, D. Bull. Soc. Chim., Fr. 1976, 1935.
O

Hax

Hax

Heq

perfectly staggered, no torsional strain

nearly perfect bond angles, no angle strain

Hflag

OH

Hax
Heq

OH

hydrolyzes
13 times faster than

Hax
Heq

Heq

Brown, H. C.; Ichikawa, K. Tetrahedron 1957, 1, 221.

Inverted Chair

Twist Boat

NaBH4

k6

1.6

Heq

Heq

Heq
Heq

Heq
OEt

76:24 enol:keto

Brown, H. C., Brewster, J. H.; Shechter, H. JACS 1954, 76, 467.

Heq H

HH
eq

Heq
Hax

Hax
Hax

4 eclipsing = 4 kcal/mol

Hflag

Hax

HH
ax

Total E = 4.0+2.9 = 6.9 kcal/mol higher in energy

H
Hax

Conformational Analysis: Cyclic Systems-4

Evans, Breit, Michael

Monosubstituted Cyclohexanes: A Values

R

The "relative size" of a substituent and the associated A-value may not correlate.
For example, consider the CMe3 and SiMe3 substituents. While the SiMe3
substituent has a larger covalent radius, is has a smaller A-value:

H
H

Keq

G = RTlnKeq
Me

CH3 - axial has 2 gauche butane interactions more than a CH3-equatorial.

Expected destabilization: 2 0.9 kcal/mol = 1.8 kcal/mol;
Observed: 1.8 kcal/mol
Me

Me
C

Me

Me
C Me

Me

Si

Me
Me
H

AValue

Me

>4.5

2.5

1.1

The impact of double bonds on A-values:

The AValue, or -G, is the preference of the substituent for the

equatorial position.

Lambert, Acc. Chem. Res. 1987, 20, 454

A value (kcal/mol)

A value (kcal/mol)

F
Cl
Br
I
OH
OMe
OAc
NH2
NR2
CO2H
CO2Na
CO2Et
SO2Ph

0.3
0.5
0.5-0.6
0.5
0.7
0.8
0.7
1.8
2.1
1.2
2.3
1.1
2.5

CN
CCH
NO2
CH=CH2
Me
Et
n-Pr
n-Bu
i-Pr
t-Bu
Ph

0.2
0.4
1.1
1.7
1.8
1.9
2.1
2.1
2.1
>4.5
3.1

H
H

substituent

R = Me
R = OMe
R = OAc

0.8
0.8
0.6

A-value
(cyclohexane)
1.8
0.8
0.7

The Me substituent appears to respond strictly to the decrease in nonbonding interactions

in axial conformer. With the more polar substituents, electrostatic effects due to the
trigonal ring carbon offset the decreased steric environment.

Cyclohexene prefers the half-chair conformation.

A Values depend on the relative size of the particular substituent.

reduced 1,3-diaxial
eliminated 1,3-diaxial

AValue

1.8

Me
H

Me
Me

Me

1.9

Me
Sn Me

Can you explain these observations?

Chem 531

2.1

Me
Me
H

>4.5

Eact for interconversion = 5.3 kcal/mol

Conformational Analysis: Cyclic Systems-5

Evans, Breit, Michael

Let's now consider vicinal substitution

Polysubstituted Cyclohexane A Values

As long as the substituents on the ring do not interact in either
conformation, their A-values are roughly additive

Me
H

Case 1:

1,4 Disubstitution: A Values are roughly additive.

Me

The prediction:

G = 0 kcal/mol

Me

Me

1,3 Disubstitution: A Values are only additive in the trans diastereomer

Case 2:

H
Me

Me

H
OH

Me

The new interaction!

EtO

+ 0.9

H
Me

Me
Me

Problem:
Can you rationalize the stereochemical outcome of this reaction?

For X = Me
H

The conformer which places the isopropyl group equatorial is much more
strongly preferred than would be suggested by A- Values. This is due to
a syn pentane OH/Me interaction.

Me

Me

H
X

OH

G = A(Me) A(X)

Me
Me

H
H

G = 1 gauche butane 2A(Me)

If the added gauche butane destabilization in the di-equatorial

conformer had not been added, the estimate would have been off.

Me H

G = +2.74 kcal/mol

Observed:
G = 2(1.8) = 3.6 kcal/mol

Me

Me

G = +0.88 2(1.74) = +2.6 kcal/mol

Me
Me

Me

Me

Me

Chem 531

H
Me

Me

G = 2(0.9) + 1(+3.7)= 5.5 kcal/mol

+ 3.7

+ 0.9

n-C4H9

LiNR2
MeI
H

Me

EtO
n-C4H9

diastereoselection 89:11
D. Kim & Co-workers, Tetrahedron Lett. 1986, 27, 943.

Conformational Analysis: Cyclic Systems-6

Evans, Breit, Michael

Geminal (1,1) substitution

Me

(4)

(1)
Me

(2)

Me

G = 1.9 kcal/mol

The Reference:
N

G = 0.36 kcal/mol

Me

G = 3.0 kcal/mol

Hydrogen is "bigger" than the Nlone Pair.

Me

G = 2.9 kcal/mol

Me

G = 1.4 kcal/mol

The A-value of Nsubstituents is slightly larger than the corresponding

cyclohexane value. Rationalize.

Me
O

(3)

Me

H
H

G = 1.8 kcal/mol

Me
Me

Me

G = 1.6 kcal/mol

A-Values for N-Substituents in Piperidine

Heteroatom-Substituted 6-Membered Rings

Me

Reference:

G = 2.5 kcal/mol

(6) H N

Allinger, Tet. Lett. 1971, 3259

When the two substituents are mutually interacting you can predict neither the magnitude or the
direction of the equilibrium. Analyze this case.

Me

Me

G = 0.32 kcal/mol

Me

G = +2.8 1.7 = +1.1 kcal/mol

Observed:

(5)

G = A(Ph) A(Me)

The prediction:

Me

Me
Ph

Me
Ph

Chem 531

H
H

Me

H
O

Me

G = 4.0 kcal/mol

G = 2.0 kcal/mol

A-values at the 2-position in both the O & N heterocycles are larger than
expected. This is due to the shorter CO (1.43 ), and CN (1.47 ) bond
lengths relative to carbon (CC; 1.53 ). The combination of bond length and
bond angle change increases the indicated 1,3-diaxial interaction (see eq 1, 4).
See Eliel, page 740754

Me

O
H

G = -0.8 kcal/mol

Me

The axial Me group in the top equation is ~0.2A closer to the axial
hydrogens than it is in cyclohexane.

Conformational Analysis: Bicyclic Ring Systems

Evans, Breit, Michael

Heteroatom-Substituted 6-Membered Rings

Me

Chem 531

Estimate the energy difference between the two methyl-decalins

shown below.

Me

Me

Me

H
H

Hydrindane Ring System (6/5)

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.

rigid

mobile

Decalin Ring System (6/6)

H

mobile

Relative G
rigid

0.5 kcal/mol

The turnover to favor the cis fusion results from the entropic preference for the
less ordered cis isomer.

The 5-5 Ring System

favored

2.4 kcal/mol

Relative G

Relative G 6.4 kca/mol

0
All smaller fused ring systems prefer(require) cis fusion.

Let's identify the destabilizing gauche butane interactions in the cis isomer
H

3
H

4
1

Me

Gauche-butane interactions
C1 C2
C1 C3
C4 C3

H
C

A/B Trans

Me

A/B Cis

G(est) = 3(0.9) = 2.7 kcal/mol

Predict the conformational flexibility of a A/B Trans vs. A/B Cis Steroid!

Conformational Analysis: Axial vs Equatorial Reactivity

Evans, Breit, Michael

Different reactivity for axial and equatorial substituents

SN2 Reactions (Displacement with PhS)

Axial substituents are more hindered, thus less reactive in many

transformations

Me3C

krel

0.13
H

Me3C

krel

OH

OTs

krel
OH

OH

Me3C

krel

Me
CO2H

krel

Me3C

Me3C

Me
OH

OH

Me

H
Me

3.36

Steric Hindrance and Steric Assistance

CO2H
CO2H

The rate-determining step is breakdown of the chromate ester. This is an

apparent case of strain acceleration

0.04
H

3.2

Me

krel

Me3C

Acid-catalyzed esterification

OH
OH

Me

krel

31

0.27

CO2H

Alcohol Oxidation with CrO3

Me3C

The axial diastereomer is not always slower reacting:

OH

Me3C

OTs

Acetylation with Ac2O/pyridine

H

Chem 531

TS

TS
G > G

0.05

TS

G < G

Ester Saponification
CO2Et

H
Me3C

krel

CO2Et

Me3C

G A

G B

G ref

0.05
GS
GS

GA > G ref

GS
Reference Case

GB < G ref

Conformational Preferences About sp3sp2 Bonds

D. A. Evans, F. Michael

Chem 531

Relevant Orbital Interactions:

Torsional Strain: the resistance to rotation about a bond

Torsional energy: the energy required to obtain rotation about a bond

H
H

Torsional Angle: also known as dihedral angle

H
C

Torsional steering: Stereoselectivity originating from transition state torsional

energy considerations

H
H

H
H

H
H

H H

-1

G = +3 kcal mol

H
H
H
H

Propene

H
H

C
H

H
H

H
H

The eclipsed conformation (conformation A) is preferred.

Polarization of the carbonyl decreases the 4 electron destabilizing
Rotational barrier: 1.14 kcal/mol
Houk, JACS 1983, 105, 5980-5988.

Confomation A is more stable than B and represents the most stable

conformation of propene

Conformational Preferences
1-Butene (X = CH2); Propanal (X = O)
H

Wiberg K. B.; Martin, E. J. Amer. Chem. Soc. 1985, 107, 5035-5041.

How does one account for this observation?

H
H
O

Eliel, pg 615+

H
H
C

CH's properly aligned for overlap

hence better delocalization

Conformational Preferences: Acetaldehyde

eclipsed
Torsional Strain (Pitzer Strain): Ethane

CH & electrons are

destabilizing

Dorigo, A. E.; Pratt, D. W.; Houk, K. N. JACS 1987, 109, 6591-6600.

staggered

Me
X

H
H

Me
H

Conformation A is preferred. There is little steric repulsion between the

methyl and the X-group in conformation A.

Evans, Duffy, Ripin, Michael

Conformational Barriers to Rotation: Olefin A1,2 Interactions

2-propen-1-ol

1-butene

Me

H
C
H Me

= 180
H
H

Me
H

Me

+1.32 kcal
H

+0.49 kcal

C
H

C
H

=0

Conforms to ab initio (3-21G) values:

Wiberg, K. B.; Martin, E. J. Am. Chem. Soc. 1985, 107, 5035.

1,2 Eclipsing is worse than 1,3 eclipsing because the

hydrogens are closer in 1,3 eclipsing (2.4 vs. 2.5 A)

= 180

H
H

= 120

=0
C
H HO

= 120

OH
H

HO
H

= 180

= 60

+1.33
kcal

H
H

E (kcal/mol)

H
C

OH

The Torsional Energy Profile

=0

(Deg)

Me
C

Me

= 50
C

The Torsional Energy Profile

OH

(Deg)

Chem 531

=0

OH

H
H

+1.18 kcal

C
H

+2.00
kcal

H
H

+0.37 kcal
= 180

Evans, Duffy, Ripin, Michael

Conformational Barriers to Rotation: Olefin A1,2 Interactions-2

2-methyl-1-butene
H

Me

H
Me

2-methyl-2-propen-1-ol
H

Me

Me

OH

= 180 H
H

= 60

Me
H

C
H Me

H
C

= 110
Me

+1.39 kcal
Me
H

+0.06 kcal

H
H

C
H

+2.68
kcal

Me

1,2 Me-Me eclipsing is strongly disfavored (2.7 kcal/mol)

H
H

H
H

= 180

=0

Me
H

OH
Me

= 120
+1.16 kcal

Me
H
OH

=0

H
C
H

H
C
H HO

=0

E (kcal/mol)

E (kcal/mol)
H

= 180
HO

=0

Me

OH

Me
Me

Me
H

The Torsional Energy Profile

= 50
C

(Deg)

The Torsional Energy Profile

Me

(Deg)

Chem 531

H
H

C
H

Me

+2.01
kcal

+0.21 kcal
= 180

Evans, Duffy, Ripin, Michael

Conformational Barriers to Rotation: Olefin A1,3 Interactions

(Z)-2-pentene

(Z)-2-buten-1-ol

Me

Me

Me

H
C

Me

C
H Me

Me

Me

Me

H
C

OH

(Deg)
The Torsional Energy Profile

The Torsional Energy Profile

H

OH

(Deg)
H

Chem 531

=0

=0

Me

C
H HO

H
C

= 180

H
Me

= 180

+3.88 kcal

Me
H
=0

= 90

Me

Me

C
H

H
H

H
C

Me
H

Values calculated using MM2 (molecular mechanics) force fields

via the Macromodel multiconformation search.
Now, 1,3 Me-Me eclipsing interaction is most disfavored (3.9 kcal/mol)

OH
H

= 120
OH
Me

= 180

C
H

+1.44 kcal

+0.52
kcal

C
H

+0.86
kcal

H
=0

= 180

Review: Hoffman, R. W. Chem. Rev. 1989, 89, 1841.

Evans, Duffy, Ripin, Michael Conformational Barriers to Rotation: Olefin A1,3 Interactions-2
(Z)-2-hydroxy-3-pentene

Summary of A1,2 and A1,3 strain

Rotate clockwise

Neither

Me
HO
Me

Chem 531

Me

OH

H
R

Me

RL

RS

RL

H
C

H RL
C
R

RS
C

RS

no real preference

A1,2 strain

(Deg)

The Torsional Energy Profile

=0
Me

C
H HO

Me

RS

= -80
HO
Me
H

put largest group here

to avoid both
eclipsing interactions

H
H

= 80 Me
Me
H

Me

+0.34

Me

C
H

Me
H

C
H

H
OH

H
OH

+0.40 kcal

put H here to have

smallest eclipsing
interaction

= 110

Me

+0.66H

RL
R

H
C

RL
C

=0

Best conformations place the smallest substituent (H) next to the (Z)methyl group to minimize eclipsing interactions

Me
H

HO

RS

A1,2 strain and A1,3 strain

= 180

put H here to have

smallest eclipsing
interaction

R
H

RL
R

RS

RS

= 150
H
C

Me

RL

A1,3 strain

+4.68

H
C

H
H

= -140

+2.72

OH
C
H Me

H
Me

RL
H

RS

H
C

RL
C

H
RS

A1,3 strain is more important than A1,2 strain

(4.0 vs. 2.7 kcal/mol)