leads to a different mutual relation of atom A
and D and results in population of a set of different rotational isomers
or "conformations".
Conformation is a spatial arrangement of a molecule of a given constitution and configuration.
In the case of a four atom molecule linked in a chain
manner, rotation of atom A or D about the inner B-C bond by an angle leads to a different mutual relation of atom A
and D and results in population of a set of different rotational isomers
or "conformations".
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.
The conformation of a molecule containing two tetrahedral atoms linked together can be represented as a "sawhorse" or as a Newman projections. In the Newman projection the molecule is viewed along the axis of a rotatable bond.
Interconversion of conformers proceed by an infinite number of intermediate conformers, however, only a few of them have energy minima.
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The number of such conformations (conformers) depends on the number of energy minima on the energy profile. In the case of ethane molecule three energy minima are encountered during 360o rotation. These minima correspond to "staggered" conformers. Unless it is specifically justified by certain constraints, most conformations of acyclic compounds are staggered. The maxima on the energy potential correspond to "eclipsed" conformations. When all substituents on one tetrahedral center (carbon) are identical all energy minima are the same. In the case of symmetrically disubstituted ethane one conformer has the lowest energy. This conformer corresponds to anti-peri-planar orientation (conformation) of two largest substituents in the system. Unless influenced by factors other then steric size the antiperiplanar conformers are the most stable.
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Movie of Butane: Note that half way rotation about the C-C bond (180¡) gives the antiperiplanar (ap) conformation.
QuickTime Movie(165K)
Since the conformational changes will take simultaneously about two bonds multiple energy
minime are possible. The energy profile can be represented as a three dimensional contour
plot with 1 and 2 torsional angles as axes.
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In the case when more than two bonds are simultaneously involved in conformational changes, the potential energy can be expressed as a function of multiple torsional angles in multidimensional space. This potential dependence is often referred to as "conformational space".
The ratio of conformers depends on their relative free energy,
.
where:
K, equilibrium constant
R, gas constant (1.98 cal/mol*K)
T, standard temperature (298 K)
In the case of butane the difference between the synclinal (sometime also termed "gauche") and antiperiplanar (sometimes also termed "anti") conformer is 0.9 kcal/mol. (see the energy profile shown shown previously). This gives the equilibrium constant K = 4.53.
In this case equilibrium involves two energetically identical synclinal conformers (+sc and -sc) and an ap conformer. The equilibrium constant can thus be defined as:
K = [ap]/2[sc]
In addition, since [sc] = [-sc] (both synclinal conformers have the same energy, and hence also the same population, or molar fraction), and the sum of molar fractions of all conformers:
[sc] + [-sc] + [ap] = 1, and
2[sc] + [ap] = 1.
Hence,
[ap] = 4.53*2[sc]
[sc] = [-sc] = 0.09, and [ap] = 0.82.
With sp3 carbon linked to sp2 site two conformers are possible: eclipsed and bisecting. Surprisingly, the eclipsed conformation is oflower energy for propene and acetaldehyde. The origin of the stabilization of the eclipsed conformer is not clear.
Ester bonds:
The Z isomer is much more stable than the E conformer (only a few percent
of E isomer is present in the equilibrium). The reason for this stabilization
is a significant overlap of the p-orbitals of oxygen with the C=O bond
(p-
). This causes the ester group to be
essentially planar and slows down conformational changes, increasing the
unfavorable interactions between the R group and ester R' group.
Attraction between the slightly positively charged
-carbon and the negatively charged oxygen
further stabilize the Z conformation. Additional stabilization is due to
overlap of the in-plane n-orbital at the oxygen atom with the antibonding
orbital of the C-O bond (*).
Amide bonds:
In the amide group the C-N bond is much shorter than a single bond. The C-N-C angle is almost 120o suggesting the double bond character of the C-N bond, and an almost sp2 hybridization of nitrogen. The barier for rotation is very high (ca. 20-22 kcal/mol). The rate of conformational changes can be further lowered by involvement of the NH group in hydrogen bonding with neighbouring molecules (formation of dimers, etc.) or fragment of the same molecules, giving rise to rigid conformers (alpha-helix, beta-sheet of protein).
Effect of hydrogen bonding
Hydrogen bonds have a locking effect on the conformation about the C-C bonds. For example, the most stable conformer of both meso- and dl-butane-2,3-diol is sc, since it enables formation of the hydrogen bond between the hydroxyl group. In meso-compound this hydrogen bonding overrides two unfavorable synclinal-interactions: one between methyl groups and one between oxygen atoms.
Anomeric effect:
In the case when two heteroatoms (usually oxygen, sulfur and hologenides) are bonded to the same carbon atom the preferred conformation is different that the one predicted on the steric effect grounds. This conformational bias is called anomeric effect (based on analogy to sugar carbon atom C-1). In this case the determining factor is the interaction of the nonbonding electron pair of the heteroatom with the electron deficient orbital of C-heteroatom bond. The effect is that the synclinal conformer is more stable than the antiperiplanar conformer. The typical illustration of such effect is greater stability of alpha-anomers of sugars than beta-anomers.
Conformation of saturated six-membered rings is important in view of the fact that they are key building block of most carbohydrates and are also featured in such compounds as inositol phosphates and cyclic 3',5'-nucleoside phosphates. Five-membered rings are a component of nucleosides, and their conformation has to do with conformation of DNA.
In general, all rings other than three-membered and aromatic ones are nonplanar. The origin of nonplanarity is due to the balance between valence bond angle strain (Baeyer strain) and torsional strain. The distortion of the bond angles costs much more energy than the torsion strain. Ring strain (read additional energy accumulated in the ring) is reflected in the stability of cyclic molecules. Strained molecules tend to undergo chemical reactions which relieve strain, such as hydrolytic ring opening. Strain could be also relieved by adopting least-strained non-planar conformations.
Six-Membered Rings. Six-membered saturated rings adopt most frequently two chair conformations which exist in the state of rapid equilibration. The chair-chair transition interchanges the axial ligands (marked as a) with equatorial ones (marked as e). This transition in most cyclohexanes occurrs very rapidly, and for most practical reasons the distinction between e and a hydrogens then disappears, (all ligands in uniformly substituted cyclohexane become equivalent).
The transition from one chair to another is not a single step process. It occurs through several energy minima representing half chair, boat and twisted conformations. The boat and twist conformations have high energy, therefore are only observed as predominant form very infrequently when the six-membered ring is fashioned with large substituent or when it is included in a fused bicyclic structures.
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The rate and equilibria of chair-chair transition depends on:
Monosubstituted cyclohexanes exist as a mixture of the two chair conformations, whereby the substituent occupies the equatorial or axial position. The equilibrium between these forms depends on the substituents propensity to occupy the given position. This can be expressed most conveniently as a difference of free energies of each conformer. This difference between the conformers is termed conformational energy (C.E.) and is given below for most common substituents.
It could be used to calculate conformational equilibria (somewhat inaccurately) for various substituted ring compounds. Conformational energy is a combination of several factors mentioned above.
Size is the single most important factor in some ligands. This is caused by the steric repulsions of the axially placed ligands with two axial protons at the beta-positions. Therefore t-Bu substituent is almost exclusively found in the equatorial position, and NMe3 + in unmeasurably high. Such conformationally "biased" systems are called anancomeric.
Due to their hydrogen bonded properties and protonation equilibria conformational energies of hydroxyl and amino groups are strongly dependent on solvent conditions. This is caused by the formation of hydrogen-bonded oligomers, especially at low temperatures where most measurements are performed. The small difference of C.E. between OH and OR is largely due to a possibility of rotation of R-group about any of the C-O bonds which can place the R in the unhindered place.
The large differences between NH2/NH3+ and COOH/COO- have to do with the increase of the effective size of the group due to extensive solvation of the NH3+ or COO-.
| Group | C.E. -(kcal/mol) |
|---|---|
| F | 0.25 |
| Cl,Br, I | 0.25--067 |
| OH | 0.6--1.0 |
| NH2 | 1.27 |
| NH3+ | 1.7--2.0 |
| COOH, COOR | 1.25--1.4 |
| COO | 2.0 |
| Me | 1.7 |
| Ph | 2.8 |
| t-Bu | 4.7 |
Conformational energies are not additive in principle, i.e. the presence of one methyl group will influence the effect of the second group on the conformational equilibrium. The magnitude of this non-additivity depends on the type of the group (two hydroxyl group can form hydrogen bond to each other to lock the system in a particular conformation) and relative position (the nonadditivity of energies for 1,2- substituents could be greater than in the 1,4-relation).
Cyclohexene adopts a half-chair conformation with inversion barrier at 5.3 kcal/mol (ca. 11 kcal/mol for cyclohexane). Carbon atoms 1,2,3 and 6 lie in one plane; one carbon is above, one below the plane. In the 4-substituted compounds equatorial conformer is a more stable one, however, the conformational energy is usually smaller (by ca. 50%) than that for cyclohexanes. For 3-substituted compounds (allylic derivatives) the existing mesomeric structures may be responsible for propensity of electronegative substituents to occupy a pseudoaxial position.
Cyclohexanones exist in the chair conformations, but the interconversion barrier is only 4.0 kcal/mol. The difference between the chair and the twist forms is also very small (2.7 kcal/mol). Because of the ring strain cyclohexanones undergo addition reactions faster then their corresponding acyclic counterparts. For 2-substituted ketones the axial-equatorial epimerization occurs through the enol form.
The conformational equilibria in cyclopentyl system are much different from cyclohexane. First, in a flat conformation the planar bond angle would be 108o, therefore there is almost no Bayer strain. The only strain results from eclipsed orientation of ligands on the adjacent carbon atoms. Due to this fact cyclopentyl system is extremely sensitive to the nature of substitution. The most stable conformers of cyclopentane are envelope and half chair. In the envelope only one atom is out-of-plane formed by four other atoms.
In the half-chair form two atoms are out-of-plane form by three other atoms; one is above, one is below the plane. The barriers for interconversion between the envelopes or half-chairs are exteremely slow. Therefore, these molecules are in the state of "conformational flux". The distortion made by the out-of-plane atom (atoms) appears to be in a motion around the ring giving rise to the term "ring pseudorotation".
During such full cycle of pseudorotation there are a total of 10 different envelopes and 10 different half-chairs. Substituents in the cyclopentyl system shift conformational equilibrium of the ring into one or a few of half-chairs or envelopes. The cyclopentyl system has therefore a great flexibilty and adaptability to accomodate a structural need of higher organization.
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Simple considerations of conformational energies for hydroxycyclohexane
predict that the equatorial conformer is more stable and predominates in
the equilibrium mixture. An analogous equlibration experiment performed
on oxacyclohexane derivatives (such as glucose) indicates to the contrary.
The content of the -anomer in the
equilibrium mixture following "mutarotation" is greater than
could be explained by the conformational energy of the OH group.
In the corresponding methyl glucoside -anomer predominates by a factor
2:1! (alpha-anomer has an axial OH group while beta-anomer has an
equatorial hydroxyl group at C-1 of the hexose). This tendency
of the axial anomer to predominate was termed "the anomeric
effect".
As explained earlier, stabilization of the "gauche" conformer is due to
a donation of the electron pair on the oxygen into electron deficient
bonding orbital of C-X 
bond (exocyclic C-O
bond in the case of glycosides). This donation can be only achieved in
the antiperiplanar orientation of the bond and electron pair, i.e. in the
-anomer.
Another effect "exoanomeric effect" results from interaction of the electron pairs on the exocyclic oxygen with the endocyclic C-O bond. This interaction is favorable only in the gauche conformer about the exocyclic C-O bond, therefore the anomeric effect has not only the influence on the axial/equatorial isomerism in acetals (saccharides), but also a strong effect on the conformation of oligosaccharides.
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