Cyclohexane equatorial—axial conformation equilibrium

Valuable information on conformational equilibrium can be obtained particularly by N.M.R. technique. When a molecule can exist in several conformations which rapidly interchange, then any proton which assumes all possible positions in a very short time, the n.m.r. spectrum would show only one peak. This happens in most open chain compounds and even in cyclohexanes where the interconversion is very rapid. But if the interconversion is slowed or prevented, either by cooling or due to the inherent structure in the molecule, the hydrogens of each conformer appear separately and so more than one peak would appear. For example by cooling cyclohexane to -110°C, two peaks appear, one due to equatorial and the other to the axial hydrogens. 

Taft steric values. A, values from the axial-equatorial conformational equilibrium in cyclohexane v, Charton steric parameters. ... 

The equilibrium constants derived from the 31P NMR spectra at temperatures below coalescence show that there is a considerable predominance of the axial conformer of 2-diphenylphosphinoyltetrahydrothiopyran (Table 26) which contrasts with the equatorial preference in the corresponding cyclohexane derivative. This result indicates a strong anomeric effect, estimated at 2.40 kcal mol-1. The corresponding data for the anancomeric cis and trans 4-/-butyl derivative at chemical equilibration are presented in Table 26. The large difference in AG° at 173 and 323 K is compatible with a significant entropy effect, calculated AS° = +4.8 0.7 cal K.mol-1, with... 

The equilibrium free energy difference between XX and XXI is assumed to be quite small because the energy difference values between the equatorial and axial conformers for the methyl (AG = 6.3-7.9 kJ/mol) and the two methoxy (AG = 2.1-2.9 kJ/mol) substituents of the cyclohexane ring are almost equal645. 

As we learned in Chapter 4, monosubstituted cyclohexanes exist as an equilibrium mixture of two conformations having either an axial or equatorial substituent. 

For a monosubstituted oxane, the excess free enthalpy of the conformation with an axial substituent over the conformation with an equatorial substituent is, as we know by definition, the conformational free energy (CFE) of the substituent in oxane at this position. These values, possibly measured indirectly by utilizing intennediate compounds, are shown in Table 2.2. Equatorial conformations correspond to anti conformations in butane and methoxyethane, and the axial conformations (not represented) to gauche conformations. We can observe that the environment of derivative 2.20 is closest to that of the cyclohexane and that the CFE is of the same order. On the other hand, the presence of the cyclic oxygen lowers notably the CFE of derivative 2.19. The important point is the noteworthy increase in the CFE of compound 2.18, where the methyl group is close to the cyclic oxygen and possesses, on one side, an environment similar to that of methoxyethane. Let us look at the equilibrium (2.4) of the dimethylated derivative 2.21. 

Substitution on a cyclohexane ring does not greatly affect the rate of conformational inversion, but does change the equilibrium distribution between alternative chair forms. All substituents that are axial in one chair conformation become equatorial on ring inversion, and vice versa. For methylcyclohexane, AG for the equilibrium is -1.8kcal/mol, corresponding to a composition with 95% of the equatorial methyl conformation. 

The A value, the free-energy difference between the two chair conformations with axial and equatorial alkyl groups, is widely used as a measure of steric size . For all alkyl groups there is less than 7% of the axial conformation present at ambient temperature and direct quantitative observation of the equilibrium is not possible. Historically, indirect examination of conformational equilibria in disubstituted cyclohexanes has been used to predict equilibria in monoalkyl compounds (assuming additivity of substituent effects), and reviews of early work in this field and of the pitfalls encountered have been given... 

We saw in Chapter 2 that glucose can cyclize to form either the a ox hemiacetal. All of the substituents on the tetrahydropyran ring of glucose are equatorial except for the hemiacetal hydroxyl group, which may be either axial (for the a anomer) or equatorial (for the 6 anomer). If the conformational preferences of the tetrahydropyran ring are similar to those of cyclohexane, then an A value for OH of 0.87 in a protic solvent would predict that the axial anomer should comprise no more than 10% of the mixture. Experimentally, it has been determined that the a anomer is present to the extent of 34% of the equilibrium population of conformers. In the case of o-marmose, the a anomer (10) is the major isomer, and the )3 anomer (11) comprises only 32% of the equilibrium mixture. This preference for axial conformer in carbohydrates has been termed the anomeric effect. This term is also used for any system R-Y-C-X, where X is an electronegative atom and Y is an atom with at least one lone pair. 

Gunther and Aydin (1981) have investigated the conformational equilibrium (59) in di-cyclohexane. The two conformational isomers [65a] and [65b] with deuterium in the axial and in the equatorial position can be frozen out in the 100 MHz C spectrum below — 80 C. The deuteriated carbons in the two isomers have different intrinsic isotope shifts which are upheld compared to the nondeuteriated carbons. The triplet with the smaller coupling constant was assigned to the carbon with axial deuterium and was shifted 0.0482 ppm to higher held than the triplet caused by the carbon with equatorial deuterium. 

When cyclohexane is substituted by an ethynyl group, —C=CH, the energy difference between axial and equatorial conformations is only 1.7 kj (0.41 kcal)/mol. Compare the conformational equilibrium for methylcyclohexane with that for ethynylcyclohexane and... 

CyclohexanethioL In substituted cyclohexanes the number of possible conformations increases considerably, since the equatorial-axial equilibrium has to be considered in addition to that of the chair-skew-boat equilibrium. For thermodynamic calculations the contributions of these two equilibria have to be treated separately. ... 

Conformational Analysis. - Freitas et al studied the conformational equilibrium of tra 5-l,2-difluoro-, tra s -l,2-dichloro-, and trani-l,2-dibromo-cyclohexanes, in which the halogen atoms have the two possible conformations of the axial-axial (aa) conformer and the equatorial-equatorial (ee) conformer. The observed /(H, H) coupling constant, is obtained as the weighted average of the aa conformer s coupling and the ee conformer s coupling Jee as follows ... 

The energy differences between the axial and the equatorial forms of many monosubsti-tnted cyclohexanes have been measured several are given in Table 4-3. In many cases (but not all), particnlarly for alkyl substituents, the energy difference between the two forms increases with the size of the snbstituent, a direct consequence of increasing unfavorable 1,3-diaxial interactions. This effect is particularly pronounced in (l,l-dimethylethyl)cyclohexane (tert-butylcyclohexane). The energy difference here is so large (about 5 kcal moF ) that very little (about 0.01%) of the axial conformer is present at equilibrium. 

Introducing one or more sp carbon atoms into the six-membered ring introduces more strain, since these atoms require 120 ° angles. Any addition reaction that converts the system to a saturated cyclohexane will tend to be more favorable than for a comparable acyclic system. Thus, cyclohexanone is a little more susceptible to addition reactions than acetone. However, in cyclohexanone, two 1,3-diaxial interactions are removed (7.31, 7.32), This means that for substituted cyclohexanones, the axial conformation is less unfavorable than for a related cyclohexane. As noted earlier, the difference in energy between axial and equatorial conformations for methyl cyclohexane is 7.5 kj mol", and there is only about 5 % of the axial conformer at equilibrium. For 3-methylcyclohexanone, the energy difference is only 2.9 kJ mol", and at equilibrium, there is 25 % of the axial isomer (7.33). 

For the equilibrium between the axial and equatorial conformations of a monosubstituted cyclohexane. 

The Aae criterion was applied to the problem of the piperidine equilibrium (10 11) by examining the H-NMR spectrum of the deutero derivatives 12, 13, and 14 at — 85°C when ring inversion is slow on the NMR time scale.37 The Aae values are recorded in Table I. The preferred conformation for the N-substituted piperidines 13 and 14 was assigned as lone-pair axial because for these compounds Aae values were similar to those in quinolizidine. However, in piperidine (12), where the Aae value is similar to that in cyclohexane, the lone pair was assumed to occupy the equatorial position in the preferred conformation. In support of this contention, protonation of... 

Booth and Little40 observed a chemical shift difference (Aae) of about 0.4 ppm for the C-2 and C-6 methylene protons in 4-methylpiperidine, which was assumed to exist as an equilibrium containing 95% of the C-methyl equatorial conformation. N-Methylation of 4-methylpiperidine caused an upfield shift of 0.22 ppm for the C-2 equatorial proton and of 0.68 ppm for the C-2 axial proton. Comparison of these values with those observed for the proton adjacent to methyl groups in cyclohexane led these authors to the... 

Another example is the ring inversion of cyclohexanes. These are usually nonresolvable equilibrium mixtures of rapidly interconverting conformers at room temperature, the configuration of substituents changing frori) axial to equatorial. 

A substituent on a cyclohexane ring (in the chair conformation) can occupy either an axial or an equatorial position. In many cases, the reactivity of the substituent depends on whether its position is axial or equatorial. The two possible chair conformations for methylcyclohexane are shown in Figure 3-23. These conformations are in equilibrium because they interconvert at room temperature. The boat (actually the twist boat) serves... 

In a nionosubstituted cyclohexane, there can exist two different chair con formers one with the substituent axial, the other with it equatorial. The two chair conformers will be in rapid equilibrium (by the process we have just described) but they will not have the same energy. In almost all cases, he conformer with the substituent axial is higher in energy, which means there will be less of this form present at equilibrium. 

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