1

Acyclic Conformational Analysis

Rotamer Barriers in Saturated Compounds

We have seen that staggered conformers of small hydrocarbons (e.g. ethane & butane) are more
stable than eclipsed conformers and generally predominate at equilibrium. This structural preference is
usually attributed to steric effects, and has been termed torsional strain (or Pitzer strain). In the case of
ethane, rotation towards an eclipsed structure brings the electrons in C–H bonds on the different C
atoms closer to each other, thereby increasing repulsion. The distance between closest hydrogen atoms
in ethane is roughly 2.5 Å in the staggered form, compared with 2.3 Å in the eclipsed rotamer. This
latter distance is comparable to known instances of steric hindrance, such as the hydrogens in axial-
methylcyclohexane and ortho hydrogens in biphenyl. However, since the bond vectors in ethane are
diverging by nearly 40º, this comparison may not be compelling.

Since the eclipsed conformer of ethane has three eclipsed C–H bonds, it is tempting to attribute 1.0
kcal/mole of strain to each, resulting in a total of 3 kcal/mole torsion strain. Indeed, it has been noted
that the rotational energy barriers in methyl amine and methanol are lower by 1 kcal/mole for each
eclipsed C–H bond that is missing, as shown in group A of the following diagram. Although the non-
bonding electron pair(s) in these compounds are shown in spatially directed sp 3 orbitals, the exact
location is a subject of debate and they do not appear to offer any significant steric hindrance. It might
be argued that the C–X bond length is shortened and the C–X–H bond angle narrowed in the alcohol and
amine, but molecular structure calculations indicate the eclipsed H---H distance remains the same.

The second group of structures (B) shows the influence of one or more methyl substituents on one of
the ethane carbons.
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Each methyl increases the rotational barrier by about 0.5 kcal/mole, although
the effect of the third substituent (neopentane) is somewhat greater. Because a methyl
group is substantially larger than a hydrogen, one might have expected a greater barrier
to rotation; however, the C–C bond is more than 40% longer than the C–H bond,
reducing the overall steric crowding. The diagram on the right illustrates this feature,
which is amplified by the divergent vectors of the C–H and C–Y bonds. Consequently, the relative
distance r2 is greater than r1. Since it takes less energy to bend a covalent bond than to stretch or
shorten it, some of the crowding strain in propane and isobutane might be relieved by opening the C-C-
C bond angle. However, this would not be effective in neopentane (the last structure in B), hence this
barrier is slightly higher than expected.

The influence of bond length on steric hindrance is dramatically demonstrated by the group of
compounds labeled D. The covalent radii of substituent atoms increases in the order H < F < Cl < Br < I,
with F being less than twice as large as H, Cl being three times as large, and Br and I being roughly 3.5
and 4 times the size of hydrogen. The C–X bond lengths also increase in the same order, with C–F being
25% longer than C–H, C–Cl being 62% longer, and the Br and I bonds longer still. The consequences of
these opposing factors is apparent in the barriers. Additional chlorine substituents increase the
rotational barrier, with the 1,1,1-trichloro compound having a greater than expected effect, similar to
the neopentane case.

Stretching the C–C bond would also reduce the steric hindrance to rotation. Although this not
normally possible, an approximation is found in the two C–Si compounds listed in group F. Because the
C–Si bond is 21% longer than C–C and Si–H is over 35% longer than C–H the barrier in CH3–SiH3 is
nearly half of that in ethane. Remarkably, the barrier in tetramethylsilane is even lower. Measurements
on eclipsed conformers of these compounds indicate the H:Y distance (noted in the above diagram) is
2.74 Å when Y=H and 2.94 when Y=CH3.

The barriers in dimethyl ether and trimethyl amine are unexpectedly high, as shown in group
C. Each methyl group seems to add 1.2 to 1.6 kcal/mole to the barrier. For example, the barrier in
dimethyl amine is 3.6 kcal/mole, which agrees well with the methyl component in dimethyl ether (1.6
in both cases). However the second methyl in trimethyl amine then adds only 0.8 kcal/mole. The
shorter bond lengths and smaller bond angles in these compounds may contribute to these variations,
which are poorly understood.
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Finally the presence of a polar

substituent on each ethane carbon often results
in a relatively high barrier, as shown by the
compounds in group E. It is instructive to
compare 1,2-dichloroethane with butane. From
the previous discussion, one might anticipate a
lower barrier for the former, as a consequence of
the longer C–Cl bond. However, the full barrier
for the dichloro compound is roughly twice as
high, and may be attributed to dipole repulsion
between the polar C–Cl bonds as they approach
each other. The energy difference between the
anti and gauche staggered conformers of 1,2-
dichloroethane is about 45% higher than the
difference in butane, and the lower barrier
between these conformers is 25% higher. The
diagram on the right, which may be toggled from
one compound to the other by clicking, shows
these features. Unexpectedly, hexachloroethane
has a barrier only about 20% higher than 1,2-dichlorooethane. This may be due in part to a 0.03 Å
increase in the C–C bond length (about 2%), caused by the extensive dipole repulsion.
The rotational energy diagram on the right reflects enthalpy measurements made in the gas phase. In
solution or as the pure liquid the magnitude of the barriers often decreases, and the energy difference
between anti and gauche conformers changes in favor of the latter. For butane, the anti-gauche
difference drops from 0.85 to 0.55 kcal/mol in the liquid. In the case of 1,2-dichloroethane solutions,
polar solvents lower the energy of the gauche conformer to such a degree that it becomes favored at
equilibrium.

Recent studies of rotational barriers in substituted ethanes suggest that a significant

contribution comes from sigma bond-antibond interactions which stabilize an anti configuration of W
and Z groups in W–C–C–Z constitutions, relative to their gauche orientation. This stereoelectronic
factor, which is similar to hyperconjugation, becomes larger as the electronegativity difference between
W and Z increases. The conformational preferences of 1,2-difluoroethane and 1-fluoropropane provide
instructive examples, as shown on the right.

Although 1,2-difluoroethane should suffer dipole repulsion as the fluorine atoms approach each
other, the gauche form is more stable than the anti conformer (ΔHº = 0.6 kcal/mol).
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This
surprising
fact may
be
explained
by the
two
hyperconj
ugative
bond
interactio
ns in the
gauche
form,
shown by
the resonance formulas in the gray-shaded box. These act to stabilize the gauche rotamer, and do not
exist in the anti conformer. The overall barrier to rotation in this compound is about 6 kcal/mol,
significantly lower than the dichloro analog discussed above.

A comparison of 1,2-difluoroethane and 1,2-dichloroethane is informative. The bond dipoles of

C–F and C–Cl are similar, with the latter being slightly larger because of its longer bond. The
hyperconjugative interactions that stabilize the gauche rotamer are stronger for fluorine than for
chlorine, due to the former's greater electronegativity relative to hydrogen. Taken together, these
differences shift the conformational equilibria of 1,2-dihaloethanes from preferentially anti in the
chloro, bromo and iodo compounds to gauche for the difluoride.

The case of 1-fluoropropane demonstrates another factor. The C2–C3 rotational barrier is
about 1 kcal/mol less than that of butane, and the gauche conformer is slightly favored (ΔHº = 0.09
kcal/mol). A similar behavior is observed for 1-chloropropane. Hyperconjugative stabilization is
possible for all staggered conformations, and is probably not a determining factor. When the strong C–F
bond dipole rotates to approach the CH3–CH2 bond it induces an opposite dipole in that bond. As drawn
on the right above, this may actually result in an attractive interaction between the methyl and fluorine
substituents (as well as methyl and chlorine in 1-chloropropane).

The concepts described above have been used to explain and predict many other cases of
conformational isomerism. Three such examples are shown below, all measured in the gas phase. The
rotational barriers of the two 2,3-dichlorobutane diastereomers are significantly different, the meso
isomer being ΔHº = 12.5 kcal/mol, and the racemic compound being ΔHº = 9.5 kcal/mol.
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Rotamer Barriers in Unsaturated Compounds

Alkenes

The rotation of a methyl group (or any alkyl group) relative to a double bond is an important
conformational event. Propene provides a simple example, as shown below. In the course of the methyl
rotation a C–H bond eclipses either an sp2C–H bond or the C=CH2 bond, but not simultaneously. The
energy of this rotation follows a simple sine-curve similar to the rotational barrier of ethane, with a
smaller amplitude (ca. 2 kcal/mol). The conformer in which the C=CH2 bond is eclipsed is the lower
energy rotamer, possibly reflecting a stabilizing interaction between σ-C–H bonds of methyl and the π*-
antibonding orbital. This conformer will be termed eclipsed, and the higher energy alternative
bisected.

Adding a methyl group to propene, as in 1-butene, doubles the number of eclipsed and
bisected conformers. Interestingly, the overall rotational barrier is reduced, and the energy difference
between the two eclipsed rotamers is over twenty times greater than the difference between the two
bisected forms. This is illustrated in the following diagram. The eclipsing shown by magenta colored
arrows in conformer B2 is referred to as allylic 1,2-strain (A 1,2-strain). If the vinyl hydrogen is replaced
by a larger methyl group, as in 2-methyl-1-butene, this strain adds about 1.3 kcal/mol to the rotational
barrier.
A larger substituent, such as tert-butyl in 3,3-dimethyl-1-butene, does not change significantly the
stability order of eclipsed relative to bisected rotamers.
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Rotamers of 1-Butene

Double bond stereoisomers, such as (E) and (Z)-2-pentene have very different rotational energy
barriers. The E-isomer, shown below, has a rotational profile very similar to that of 1-butene (above).
Since the C-1 methyl is directed away from the ethyl group, this is not surprising.

Rotamers of (E)-2-Pentene

For the Z-isomer, the C-1 methyl is cis to the ethyl group, leading to severe steric crowding in the E1
and B1 conformers, shown again by colored arrows. This destabilizing hindrance is called allylic 1,3-
strain (A 1,3-strain). Unexpectedly, A 1,3-strain renders eclipsed conformer E2 slightly higher in energy
than bisected conformer B2. The perpendicular conformation, P, is lower in energy than either E2 or B2.
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Rotamers of (Z)-2-Pentene

To examine an energy plot of these rotamers click the following button:

Aldehydes and Ketones

The conformations and rotational energy profile of acetaldehyde, shown below, are very similar
to propene. The activation energy for rotation is half that of propene, reflecting the absence of a
hydrogen on the oxygen atom. This is the same kind of change noted earlier for ethane compared with
methanol.

By comparison, the conformational energy profile of propanal differs significantly from that of
1-butene. As shown below, conformer E1 is more stable than E2 by roughly 0.8 kcal/mol, reflecting the
relatively small size of oxygen. Even the larger substituent in 3-methylbutanal prefers this
conformation. Furthermore, the activation energy for interconversion of the chiral eclipsed E 2
conformers is very small, and it is not possible to relate experimental behavior to a preferred
conformer. Ketones, of course, will exhibit A-1,2-strain in conformer B2.
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Rotamers of Propanal

Although the conformational differences shown here are not large, addition reactions to
aldehydes and ketones are sensitive to the configuration of substituents on the α-carbon atom. Because
of the importance of such asymmetric induction in the stereoselective formation of new stereogenic
centers, it has been extensively studied. A full discussion of this topic is available in the stereoelectronic
effects section of this text.

Esters and Amides

Esters and amides generally have higher rotational barriers and greater conformational
preference than do aldehydes and ketones, with the trans or Z form being more stable, as illustrated in
the following diagram. For example, the CH3O–CHO barrier in methyl formate is 12 to 13 kcal/mol
(trans is more stable than cis by 4.75 kcal/mol), and the enthalpic preference for trans increases to ca. 8
kcal/mol in methyl acetate (R1 = R2 = CH3).

These planar conformations are favored by a stabilizing n-π conjugation, as shown by the
resonance formulas on the right. This requires the delocalizing n-electron pair on the ether oxygen to
occupy a p-orbital-like orientation ortho to the plane of the carbonyl group. The remaining n-electron
pair must then occupy a sp2-orbital, designated by the cyan colored oval. In the trans-conformer this
electron pair overlaps with the anti-bonding C–O σ- bond of the carbonyl group, as described
elsewhere. Dipole repulsion also contributes to a destabilization of the cis form.
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The contribution of n-π conjugation to the structure of amides is even greater than observed in
esters, as indicated by their lower C=O stretching frequency. Thus, the barrier to rotation about the
NH2–CHO bond in formamide is over 18 kcal/mol, and the CH3NH–CHO bond in N-methylformamide is
more than a kcal/mol greater. Such barriers permit the observation of conformational isomers of
amides by room temperature nmr. For simple amides like N-methylacetamide and the formamides
noted above, the trans conformer is more stable than cis by more than 1.5 to 2.5 kcal/mol.

Six-Membered Rings

Cyclohexane Derivatives

Conformations of cyclohexane and its simple substituted derivatives have been described
elsewhere in this text. The chair conformation is the favored configuration, and bulky substituents
prefer to occupy an equatorial location. The left hand structures and table in the following diagram
summarize the free energy differences between equatorial and axial orientations of some simple
groups. These energies are commonly reported as A values. An axial methyl group is hindered by two
gauche butane interactions, each accounting for ca. 0.9 kcal/mol. Since an axial ethyl group may rotate
so that it appears no larger than a methyl to the remaining axial hydrogens on the same side of the ring,
its A value is the same as methyl. Larger alkyl groups have increased A values, commensurate with
increased crowding with the axial hydrogens. The trimethylsilyl group has a value half that of a tert-
butyl group, reflecting the longer bond length of C–Si. Click the button for a table of common A values.

The heterocyclic compounds on the right side of the diagram illustrate the decreased axial
hinderance that results from the absence of nearby axial hydrogens. From the smaller but significant
energy differences shown, it may be concluded that the steric hindrance of non-bonding electron pairs
on oxygen cannot be ignored. Other factors in these cases are the shorter bond length and tighter C-O-C
angle, which may act to increase hindrance, as shown by the lower right example.
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Cyclohexene Derivatives

Inserting a double bond into a cyclohexane ring (exo or endo) introduces distortion that
influences structural and chemical behavior. In the case of an exocyclic double bond, an axial hydrogen
is removed from one side of the ring, and the increased bond angle at the sp2-carbon expands some of
the remaining axial:axial distances. The conformational preference for an equatorial methyl substituent
in 3-methylcyclohexanone is thereby reduced, as shown on the left of the following diagram. However,
the change in bond angle perturbs the strain free cyclohexane configuration to such a degree that
double bond addition reactions are exceptionally favored. Thus, the heat of hydrogenation of
methylenecyclohexane is roughly 1 kcal/mol greater than that of methylenecyclopentane or
methylenecycloheptane. Furthermore, the rate and equilibria constants for addition reactions of
cyclohexanone are greater than those for comparable reactions of similar ketones.

The endocyclic double bond in cyclohexene produces an even greater change in structure, as
illustrated on the right side of the above diagram. The planar configuration of the double bond favors a
pair of half-chair conformations, having a 5.3 kcal/mol equilibrium barrier. A model of a twist chair is
displayed on the right. Twisting of the allylic carbons skews the orientation of their axial and equatorial
bonds into pseudo axial or equatorial directions. These locations may be identified in the model by
clicking the last button.

Allylic strain exists when an equatorial allylic substituent is hindered by a substituent on the
double bond. A good example of how this strain may influence the course of a reaction is found in
enamine formation from α-substituted cyclohexanones. The following equations are typical. Most
significantly, the enamine double bond is generally formed away from the α-substitution, especially
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with pyrrolidine. The A 1,3-strain shown in the bracketed formulas is undoubtedly responsible for this
regioselectivity. Second, when a reference point exists, the α-substituent is found to be axial in the final
product, reflecting A 1,2-strain.