Substituted cyclohexanes

In a monosubstituted cyclohexane, there can exist two different chair conformers 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, the conformer with the substituent axial is higher in energy, which means there will be less of this form present at equilibrium. 

For example, in methylcyclohexane (X=CH3), the conformer with the methyl group axial is 7.3 kJ mol i higher in energy than the conformer with the methyl group equatorial. This energy difference corresponds to a 20 1 ratio of equatoriahaxial conformers at 25 °C. 

The table shows the preference of a number of substituted cyclohexanes for the equatorially substituted conformer over the axially substituted conformer at 25 °C. 

X Equilibrium constant, K Energy difference between axial and equatorial conformers, kJ mol Percentage with substituent equatorial 

Note the following points (also referred to in Chapter 12). 

Combustion of hydrocarbons (Sections 3-11 and 4-2) typically starts with the abstraction of an H atom by O2- Methylcyclohexane bums particularly well, because of the presence of the relatively weak tertiary C-H bond (Section 3-1), and is therefore used as an additive to jet fuel. 

We can now apply our knowledge of conformational analysis to substituted cyclohexanes. Let us look at the simplest alkylcyclohexane, methylcyclohexane. 

The two forms of chair methylcyclohexane are in equilibrium. The equatorial conformer is more stable by 1.7 kcal moF (7.1 kJ moF ) and is favored by a ratio of 95 5 at 25°C (Section 2-1). The activation energy for chair-chair interconversion is similar to that in cyclohexane itself [about 11 kcal moF (46 kJ moF )], and equilibrium between the two conformers is established rapidly at room temperature. 

Calculate K for equatorial versus axial methylcyclohexane from the AG° value of 1.7 kcal moF Use the expression AG° (in kcal moF ) = —1.36 log K. (Hint If log = x, then K = 10. ) How weU does your result agree with the 95 5 conformer ratio stated in the text  

Change in Free Energy on Flipping from the Cyclohexane Conformer with the Indicated Substituent Equatorial to the Conformer with the Substituent Axial 

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Nesselrodt D R, Potts A R and Baer T 1995 Stereochemical analysis of methyl-substituted cyclohexanes using 2+1 resonance enhanced multiphoton ionization Anal. Chem. 67 4322-9... 

Structural keys describe the chemical composition and structural motifs of molecules represented as a Boolean array. If a certain structural feature is present in a molecule or a substructure, a particular bit is set to 1 (true), otherwise to 0 (false). A bit in this array may encode a particular functional group (such as a carboxylic acid or an amidelinkage), a structural element (e.g., a substituted cyclohexane), or at least n occurrences of a particular element (e.g., a carbon atom). Alternatively, the structural key can be defined as an array of integers where the elements of this array contain the frequency of a specific feature in the molecule. 

The physical, chemical cind biological properties of a molecule often depend critically upo the three-dimensional structures, or conformations, that it can adopt. Conformational analysi is the study of the conformations of a molecule and their influence on its properties. Th development of modem conformational analysis is often attributed to D H R Bcirton, wh showed in 1950 that the reactivity of substituted cyclohexanes wcis influenced by th equatoricil or axial nature of the substituents [Beirton 1950]. An equcilly important reaso for the development of conformatiorml analysis at that time Wcis the introduction c analytic il techniques such as infreired spectroscopy, NMR and X-ray crystaillograph] which actucilly enabled the conformation to be determined. 

Several substituted cyclohexane derivatives may also be obtained by the reduction of a benzenoid precursor. Partial reduction of resorcinol, for example, and subsequent methyla-tion yields 2-methylcyclohexane-I,3-dione, which is frequently used in steroid synthesis (M.S. Newman, 1960 see also p. 71f.), From lithium-ammonia reduction of alkoxybenzenes l-alkoxy-l,4-cyclohexadienes are obtained (E.J. Corey, 1968 D). 

The overall picture of the many results which have been obtained with hetero-substituted cyclohexane rings is a very consistent one. Cyclohexane itself in its lowest energy conformation adopts the so-called chair conformation, as depicted in Figure 3 by the two outer formulae (a, b). These are contained in energy wells ca. 42 kJ moP deep. Another conformation, of low abundance in cyclohexane at normal temperatures, but which is important in some substituted derivatives, is the twist form (c, d). This is ca. 22 kJ moP less stable than the chair forms, and it lies on the lowest-energy pathway between them. 

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... 

For substituted cyclohexanes, the slow-exchange condition is met at temperatures below about —50 C. Table 3.5 presents data for the half-life for conformational equilibration of cyclohexyl chloride as a function of temperature. From these data, it can be seen that conformationally pure solutions of equatorial cyclohexyl chloride could be maintained at low temperature. This has been accomplished experimentally. Crystallization of cyclohexyl chloride at low temperature affords crystals containing only the... 

The free-energy difference between conformers is referred to as the conformational free energy. For substituted cyclohexanes, it is conventional to specify the value of — AC ° for the equilibrium... 

Other substituted cyclohexanes are similar- to methylcyclohexane. Two chair confonnations exist in rapid equilibrium, and the one in which the substituent is equatorial is more stable. The relative fflnounts of the two confor-rnations depend on the effective size of the substituent. The size of a substituent, in the context of cyclohexane confor-rnations, is related to the degree of branching at the atom connected to the ring. A single... 

Recendy, Darzens reaction was investigated for its synthetic applicability to the condensation of substituted cyclohexanes and optically active a-chloroesters (derived from (-)-phenylmenthol). In this report, it was found that reaction between chloroester 44 and cyclohexanone 43 provided an 84% yield with 78 22 selectivity for the axial glycidic ester 45 over equatorial glycidic ester 46 both having the R configuration at the epoxide stereocenter. 

Saturated cyclic hydrocarbons, normally known as naphthenes, are also part of the hydrocarbon constituents of crude oils. Their ratio, however, depends on the crude type. The lower members of naphthenes are cyclopentane, cyclohexane, and their mono-substituted compounds. They are normally present in the light and the heavy naphtha fractions. Cyclohexanes, substituted cyclopentanes, and substituted cyclohexanes are important precursors for aromatic hydrocarbons. 

Substituted cyclohexanes are the most common cycloalkanes and occur widely in nature. A large number of compounds, including steroids and many pharmaceutical agents, have cyclohexane rings. The flavoring agent menthol, for instance, has three substituents on a six-membered ring. 

The chair conformation of cyclohexane has many consequences. We ll see in Section 1.1.9, for instance, that the chemical behavior of many substituted cyclohexanes is influenced by their conformation. In addition, we ll see in Section 2S.5 that simple carbohydrates such as glucose adopt a conformation based on the cyclohexane chair and that their chemistry is directly affected as a result. 

Interactive to learn to draw and assess the stability of substituted cyclohexanes. 

The same kind of conformational analysis just carried out for cis- and fraus-l,2-dimethylcydohexane can be done for any substituted cyclohexane, such as as-l-tert-butyl-4-chlorocydohexane (see Worked Example 4.3). As you might imagine, though, the situation becomes more complex as the number of... 

Drawing the Most Stable Conformation of a Substituted Cyclohexane... 

Anti periplanar geometry for E2 reactions is particularly important in cyclohexane rings, where chair geometry forces a rigid relationship between the substituents on neighboring carbon atoms (Section 4.8). As pointed out by Derek Barton in a landmark 1950 paper, much of the chemical reactivity of substituted cyclohexanes is controlled by their conformation. Let s look at the E2 dehydro-halogenation of chlorocyclohexanes to see an example. 

Figure 11.19 The geometric requirement for E2 reaction in a substituted cyclohexane. The leaving group and the hydrogen must both be axial for anti peri-planar elimination to occur.

Steric strain (Sections 3.7) The strain imposed on a molecule when two groups are too close together and try to occupy the same space. Steric strain is responsible both for the greater stability of trans versus cis alkenes and for the greater stability of equatorially substituted versus axially substituted cyclohexanes. 

For example, chemists are required to interpret diagrams of a molecule of cyclohexane, or of substituted cyclohexanes, when it is represented as a flat-looking hexagonal projection, or as a side-on view to show the chair form, or as a Newman projection (Fig. 1.8). 

EXERCISE 6.30 Below you will see one chair conformation of a substituted cyclohexane. Draw the other chair (i.e., do a ring flip) ... 

It should be noted that equatorial or diequatorial conformers of substituted cyclohexanes could be accommodated in the thiourea canals by the stacking of guests at an oblique angle or parallel to the canal axis. X-ray structural data is so far unavailable... 

A popular measure of steric requirements is A, the free energy difference involved in the axial-equatorial equilibrium of substituted cyclohexane. Recommended d-values for i-C3H9 and tert-C4H9 are 2.1 and >4.4, respectively. Eliel, E. L. Chem. Educ. 37,126(1960) Angew. Chem. Int. Ed. Engl. 4, 761 (1965)... 

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