Conformational Inversion in Cyclohexane

We have seen that alkanes are not locked into a single conformation. Rotation around the central carbon-carbon bond in butane occurs rapidly, interconverting anti and gauche conformations. Cyclohexane, too, is conformationally mobile. Through a process known as ring inversion, or chair-chair interconversion, one chair conformation is converted to another chair. 

Energy diagram for ring inversion in cyclohexane. The energy of activation is the difference in energy between the chair and half-chair conformations. The skew boat conformations are intermediates. The boat and half-chair conformations are transition states. 

The most important result of ring inversion is that any substituent that is axial in the original chair conformation becomes equatorial in the ring-inverted form and 

The consequences of this point are developed for a number of monosubstituted cyclohexane derivatives in the following section, beginning with methylcyclohexane. 

Ring inversion in methylcyclohexane differs from that of cyclohexane in that the two chair conformations are not equivalent. In one chair the methyl group is axial in the other it is equatorial. At room temperature approximately 95% of the molecules of methylcyclohexane are in the chair conformation that has an equatorial methyl group, whereas only 5% of the molecules have an axial methyl group. 

Place equatorial bond at C-1 so that it is parallel to the bonds between C-2 and C-3 and between C-5 and C-6. 

Following this pattern gives the complete set of equatorial bonds. 

A guide to representing the orientations of the bonds in the chair conformation of cyclohexane. 

Chapter 3 Alkanes and Cycloalkanes Conformations and cis-trans Stereoisomers 

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This chapter assesses the ability of molecular mechanics and quantum chemical models to properly assign preferred conformation, and to account quantitatively for differences in conformer energy as well as for barriers to rotation and inversion. The chapter ends with a discussion of ring inversion in cyclohexane. 

Special cases of these involving transition states for rotation about single bonds, inversion of pyramidal nitrogen and phosphorus centers and ring inversion in cyclohexane, have been discussed in the previous chapter. The only difference is that these conformational processes are typically well described in terms of a simple motion, e.g., rotation about a single bond, whereas the motion involved in a chemical reaction is likely to be more complex. 

A potential energy diagram for ring inversion in cyclohexane is shown in Figure 3.18. In the first step the chair conformation is converted to a skew boat, which then proceeds to the inverted chair in the second step. The skew boat conformation is an intermediate in the process of ring inversion. Unlike a transition state, an intermediate is not a potential energy maximum but is a local minimum on the potential energy profile. 

The effect of introducing /j -hybridized atoms into acyclic molecules was discussed in Section 2.2.1, and it was noted that torsional barriers in 1-alkenes and aldehydes are somewhat smaller than in alkanes. Similar effects are seen when sp centers are incorporated into six-membered rings. Whereas the energy barrier for ring inversion in cyclohexane is 10.3 kcal/mol, it is reduced to 7.7 kcal/mol in methylenecy-clohexane ° and to 4.9 kcal/mol in cyclohexanone. The conformation of cyclohexene is described as a half-chair. Structural parameters determined on the basis of electron diffraction and microwave spectroscopy reveal that the double bond can be accommodated into the ring without serious distortion. The C(l)—C(2) bond length is 1.335 A, and the C(l)-C(2)-C(3) bond angle is 123°. The substituents at C(3) and C(6) are tilted from the usual axial and equatorial directions and are referred to as pseudoaxial and pseudoequatorial. 

The inversion of the cyclohexyl radical can occur by a conformational process. This is expected to have a higher barrier than the radical inversion, since it involves bond rotations very similar to the ring inversion in cyclohexane. An of 5.6kcal/mol has been measured for the cyclohexyl radical. " A measurement of the rate of inversion of a tetrahydropyranyl radical k = 5.7 x 10 at 22°C) has been reported. ... 

The study of the pressure effects on the conformational inversion of cyclohexane in different solvents represents the second illustrative example of the application of high resolution, high pressure FT NMR. 

There were two main motivations for our study. First, we wanted to follow the effects of pressure on the conformational inversion of cyclohexane in different solvents acetone-dg, carbon disulfide and perdeuterated methylcyclohexane. Secondly, in view of recent theoretical research in the area of stochastic models for isomerization reactions as proposed by Montgomery, Chandler and Berne ( 8) and by Skinner and Wolynes ( 9) we attempted to provide the first experimental proof of the theoretical prediction of large pressure effects on the transmission coefficient, or otherwise stated, a large colllslonal contribution to the activation volume for an isomerization reaction. Our results show that we were successful in both aspects. 

Conformational inversion (ring flipping) is rapid in cyclohexane and causes all axial bonds to become equatorial and vice versa As a result a monosubstituted derivative of cyclohexane adopts the chair conforma tion in which the substituent is equatorial (see next section) No bonds are made or broken in this process... 

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... 

Energy differences between conformations of substituted cyclohexanes can be measured by several physical methods, as can the kinetics of the ring inversion processes. NMR spectroscopy has been especially valuable for both thermodynamic and kinetic studies. In NMR terminology, the transformation of an equatorial substituent to axial and vice versa is called a site exchange process. Depending on the rate of the process, the difference between the chemical shifts of the nucleus at the two sites, and the field strength... 

Cyclobutane adopts a puckered conformation in which substituents then occupy axial-like or equatorial-like positions. 1,3-Disubstituted cyclobutanes show small energy preferences for the cis isomer since this places both substituents in equatorial-like positions. The energy differences and the barrier to inversion are both smaller than in cyclohexane. 

Five- and six-membered rings formed by coordination of diamines with a metal ion have the stereochemical characteristics of cyclopentane and cyclohexane. The ethylenediamine complexes have puckered rings and the trimethylenediamine complexes have chair conformations. The methylene protons are nonequivalent in these nonplanar conformations, taking on the character of equatorial and axial substituents. They are made equivalent as the result of rapid conformational inversion at room temperature, just as in the alicyclic compounds (Fig. 7.1). This has been observed in nmr studies of planar and octahedral complexes of ethylenediamine-type ligands with a number of metals. 

Indeed, in all diastereoisomers of type 72 we established an inverse shift of the ring protons at C—3, C—5, and the protons of the P—O—R group (Table 9). The assignment Z or E is justified only when the Vz conformations in 72 Z and 72 E are the favoured ones. On the other hand, axial CO-CH3 groups in cyclohexane series come at lower field than equatorial H of CO-CH3 which fits to the lowfield absorption of the E-ester CH3 group. 

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... 

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