Cyclohexanes conformation isomerisms

We now focus our attention on conformational isomerism in 1,2-disubstituted cyclohexanes. Our model system will be 1,2-difluorocyclohexane and we first examine the relative stabilities of the two trans 1,2-difluorocyclohexanes, i.e. axial-axial (aa) and equatorial-equatorial (ee). These two molecules are shown below along with a listing of the dominant stabilizing a—a interactions. 

This boat-chair difference is not immediately obtainable from experiment, e.g. the high-temperature conformational isomerization—and then quenching—of cyclohexane does not result in a chair — boat interconversion, but rather chair — twist-boat M. Squillacote, R. S. Sheridan, O. L. Chapman and F. A. L. Anet, 7. Am. Chem. Soc., 97, 3244 (1975). 

Conformational isomerism in cyclohexane Cyclohexane (C6H12) is a six-carbon cyclic alkane that occurs extensively in nature. Many pharmaceutically important compounds possess cyclohexane rings, e.g. steroidal molecules. If we consider cyclohexane as a planar and regular hexagon, the angles are 120° (cf. 109.5° for sp hybrids). 

The cis-trans isomerism of cyclohexane derivatives (Section 5-1 A) is complicated by conformational isomerism. For example, 4-tert-butylcyclohexyl chloride theoretically could exist in four stereoisomeric chair forms, 1, 2, 3, and 4. 

The chair conformer can undergo conformational isomerism to a second chair conformer which is degenerate in energy with the first. Cyclohexane is thus a dynamic molecule which exists largely in one of two chair isomers. These are the lowest energy conformations. Other higher energy conformations of cyclohexane include the boat form, which is 10.1 kcal/mol (42.3 kJ/mol) above the chair form, and the twist boat form, which lies 3.8 kcal/mol (15.9 kJ/mol) above the chair form. 

Hasha DL, Eguchi T, lonas I. Dynamical effects on conformational isomerization of cyclohexane. I Chem Phys 1981 75 1571-1573. 

Summary Rules for Naming Alkanes 94 3-4 Physical Properties of Alkanes 95 3-5 Uses and Sources of Alkanes 97 3-6 Reactions of Alkanes 99 3-7 Structure and Conformations of Alkanes 100 3-8 Conformations of Butane 104 3-9 Conformations of Higher Alkanes 106 3-10 Cycloalkanes 107 3-11 Cis-trans Isomerism in Cycloalkanes 109 3-12 Stabilities of Cycloalkanes Ring Strain 109 3-13 Cyclohexane Conformations 113... 

A. Allerhand, F.-M. Chen and H. S. Gutowsky, Spin-echo NMR studies of chemical exchange. HI. Conformational isomerization of cyclohexane and dn-cyclohexane. J. Chem. Phys., 1965, 42(9),... 

Conformational isomerism in cycloalkyl and cycloheteroalkyl structures is characterized by several different conformational extremes. For example, cyclohexane systems can exist in three distinct conformations boat, twist boat, and chair. Of these, the chair form is the most stable conformation because steric... 

To illustrate the role of quantum energy flow on rates of conformational isomerization, we calculate the rate of ring inversion of cyclohexane. Measurements of rates of ring inversion by NMR in the vapor phase and in nonpolar liquids reveal an interesting pattern in the variation of the rate over a broad range of collision frequency with solvent. In the vapor phase, the rate increases with... 

Conformational Isomerism in Substituted Cyclohexanes Section 2.8 (a) bromocyclohexane... 

Conformational Isomerism in Cyclohexane Section 2.8B The structures show a one-carbon bridge between the first and fourth carbons of the ring. In the boat form, the first and fourth carbons are directed toward one another and are easily tied together by the single bonds to the —CH2— bridge. 

Very high pressures (e.g., in excess of 2000 atm) can be achieved by means of high pressure probes, but these are relatively demanding to construct (58) and tend to require a full-time commitment. The rewards that can be achieved by such efforts are exemplified by the elegant studies of the dynamic structure of liquids (59) or the conformational isomerization of cyclohexane (60), andby the estimation of volumes of activation for a number of chemical processes (58,61). 

An example of pressure effects on the dynamic properties of liquids is given in the study by Hasha et al. of conformational isomerization in liquid cyclohexane. In contrast to classical transition-state theory, stochastic models predict that for such reactions the transmission coefficient, k, should depend on the collision frequency between the solvent and the solute molecules, which is a measure of the coupling of the reaction coordinate with the... 

Fig- 4.28 (a) The reduced transmission coefficient, k, as a function of pressure and (b) the relationship between the transmission coefficient, k, and the viscosity, ti, for conformational isomerization of cyclohexane at 225 K in (1) acetone-de, (2) carbon disulphide, and (3) methylcyclohexane-dn. (Reprinted with permission from The American Chemical Society.)... 

Hasha D L, Eguchi T and Jonas J 1981 Dynamical effects on conformational isomerization of cyclohexane J. Chem. Phys. 75 1571-3... 

Figure 4.24. Representations of conformational isomerism for (Z)-l,3-dimethyl-cyclohexane (a and b) and ( )-l,3-dimethylcyclohexane (c and d). The hydrogens attached to Q and C4-C6, inclusive, have been omitted for clarity.

A further common example of conformational isomerism is the chair and boat forms of cyclohexane (Figure 20.58). The two forms are able to flip between each other but the boat form is under more strain. The bond angles are close to tetrahedral, so there is little angle strain, but the boat form of cyclohexane does have eclipsed bonds on four of its carbon atoms. This eclipsing produces a significant amount of torsional strain. More importantly, the close contact of the flagpole hydrogens at either end of the molecule destabilizes the boat conformation. 

Because chair cyclohexane has two kinds of positions, axial and equatorial, we might expect to find two isomeric forms of a monosubstituted cyclohexane. In fact, we don t. There is only one methylcyclohexane, one bromocydohexane, one cycJohexanol (hydroxycyclohexane), and so on, because cyclohexane rings are confbnnationally mobile at room temperature. Different chair conformations readily interconvert, exchanging axial and equatorial positions. This interconversion, usually called a ring-flip, is shown in Figure 4.11. 

In general, things are simpler than that, much to our advantage. Within the limits set by the precision of the present estimates, structural features like the chair, boat, or twist-boat conformations of cyclohexane rings, as well as the butane-gawc/ze effects or the cis-tmns isomerism of ethylenic compounds leave no recognizable distinctive trace in zero-point plus heat content energies. Indeed, whatever residual, presently... 

These considerations apply to all cycloalkane derivatives, including steroids. However, the chair form of a ring is inherently more stable than the boat form. Moreover, the fnsed-ring natnre of the system lends it a very considerable rigidity, and cis-trans isomerization wonld necessitate the breaking and formation of covalent bonds. Therefore, steroid snbstitnents maintain their conformation at room temperature, whereas cyclohexane substituents usually do not. Steroids are classified according to their substituents in addition to their occurrence. 

On each carbon, one bond is directed up or down and the other more or less in the plane of the ring. The up or down bonds are called axial and the others equatorial. The axial bonds point alternately up and down. If a molecule were frozen into a chair form, there would be isomerism in monosubstituted cyclohexanes. For example, there would be an equatorial methylcyclohexane and an axial isomer. However, it has never been possible to isolate isomers of this type at room temperature.219 This proves the transient existence of the boat or twist form, since in order for the two types of methylcyclohexane to be non-separable, there must be rapid interconversion of one chair form to another (in which all axial bonds become equatorial and vice versa) and this is possible only through a boat or twist conformation. Conversion of one chair form to another requires an activation energy of about 10 kcal/mol (42 kJ/mol)220 and is very rapid at room temperature.221 However, by... 

Cycloalkanes can be oxygenated when irradiated in the presence of nitrobenzene.196 A 50% yield of cyclohexanol and cyclohexanone is achieved from cyclohexane. Since the product ratio is independent of reaction time, the alcohol is not an intermediate in ketone formation. Isomeric 1,2-dimethylcyclohexanes give an identical mixture of the isomeric tertiary alcohols, indicative of conformational equilibration and the presence of a radical intermediate. 

---