Monosubstituted cyclohexanes

The most stable form of a monosubstituted cyclohexane is, like cyclohexane itself, a chair conformation. There are, however, two valid chair conformations and again, like cyclohexane, these are interconvertible by ring inversion. In the particular case of methylcyclohexane, they are shown by 22 and 23. 

It can be seen that in 22 there are two destabilizing cis 1,3-diaxial interactions between Me and H. The molecule responds to these interactions by undergoing ring inversion to produce 23 in which the methyl group is now in the relatively open equatorial position. At 25 °C the equilibrium ratio of 23 to 22 is ca. 18 1, and this corresponds to a free energy difference of AG°, = -7.1 kJ mol1. 

The equilibrium constant, K, is related to the standard free energy, AG°, by equation (1). In Table 1.3, values of AG° for a number of values of K are presented it will be useful to become familiar with the range of values of AG° involved. For example, if K is 9, the derived value of AG°, ca. -5.5 kJ mol-1, is quite modest. 

Conformational inversion of monosubstituted cyclohexanes results in equilibration of the substituent between axial and equatorial positions. The bulkier a substituent, the more it prefers the equatorial position. The 1.1-dimethylethyl group occupies the equatorial position exclusively, 

In 1-methylethylcyclohexane (isopropylcyclohexane) the conformer with the equatorial substituent (shown in 24) is now favoured over its axial counterpart by a factor of ca. 35 because of the larger size of the alkyl substituent, and this ratio corresponds to AG° = -8.8 kJ mol-1. 

We have seen that when a cyclohexane ring flips, all equatorial bonds become axial and all axial bonds become equatorial. Now lets consider the consequences of flipping a substituted cyclohexane ring. The chair—chair interconversion of monosubstituted cyclohexanes occurs very rapidly. However, the two conformations of monosubstituted cyclohexanes, unlike those of cyclohexane, are not equally stable. 

Methylcyclohexane rapidly interconverts between two conformations of unequal energy. At room temperature, 95% of the conformations have an equatorial methyl group and 5% have an axial methyl group. The axial conformation has unfavorable interactions with axial hydrogens at C-3 and C-3.  

Look along the C-1 to C-6 bond to see the eclipsed, gauche butane interaction. 

WORKED PROBLEM 5.8 Draw a Newman projection looking down the side H2C—CH2 bond of the full-boat cyclohexane. 

ANSWER This task is relatively easy. Once again, set your eye slightly to one side so as to see the carbon-hydrogen bonds on the rear carbon. 

One chair cyclohexane will equilibrate with another as long as the environment supplies the requisite 10.8 kcal/mol to traverse the energy barrier. Under normal conditions this process is easy but at very low temperature, we can freeze out one chair form by lowering the temperature to the point at which there isn t enough energy available to cross the energy barrier to the other chair. 

How much of the relatively high-energy twist form is there at 25 °C We will see many such calculations in Chapter 8, but the chair-twist equilibrium can be treated like any equilibrium process. A calculation shows that a relatively small energy difference of AG = 5.5 kcal/mol results in an enormous preference for the more stable isomer of the pair, about 10 .The take-home lessori here is that small energy differences between two molecules in equilibrium result in a very large excess of the more stable isomer. 

The danger of relying too strongly on two-dimensional representations of molecules is shown nicely by methylcyclohexane. Two-dimensional structures give no hint of the richness of the complicated, three-dimensional structure of this molecule they even hide the presence of two conformational isomers of methylcyclohexane (Fig. 5.26). 

Draw 1,1-dimethylcyclohexane in a chair conformation, indicating which methyl group in your drawing is axial and which is equatorial. 

Draw two different chair conformations of cyclohexanol (hydroxycyclohexane), showing all hydrogen atoms. Identify each position as axial or equatorial. 

Identify each of the colored positions—red, blue, and green—as axial or equatorial. Then carry out a ring-flip, and show the new positions occupied by each color. 

Even though cyclohexane rings flip rapidly between chair conformations at room temperature, the two conformations of a monosuhstituted cycfohexane aren t equally stable. In methylcyclohexane, for instance, the equatoriaf conformation is more stabfe than the axial conformation by 7.6 kj/mol (1.8 kcal/ mol). The same is tme of other monosubstituted cyclohexanes a substituent is almost always more stable in an equatorial position than in an axial position. 

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A monosubstituted cyclohexane, e.g. methylcyclohexane, exists theoretically in two isomeric forms with a chair-form ring, and the methyl substituent either axial or equatorial. Since these rapidly interconverl through a CH3... 

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

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

A substituent is less crowded and more stable when it is equatorial than when it is axial on a cyclohexane ring. Ring flipping of a monosubstituted cyclohexane allows the substituent to become equatorial. 

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. 

Monosubstituted cyclohexanes are more stable with their substituent in an equatorial position, but the situation in disubstituted cyclohexanes is more complex because the steric effects of both substituents must be taken into account. All steric interactions in both possible chair conformations must be analyzed before deciding which conformation is favored. 

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 (a) and the others equatorial (e). 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... 

Since in chair form, the bonds are axial or equatorial, therefore monosubstituted cyclohexane exists in two isomeric forms-the axial or equatorial. So while considering a reaction with a monosubstituted cyclohexane, one must consider the reaction of both the species, just as while writing... 

Such interconversions with monosubstituted cyclohexanes and also with disubstituted ones do not involve any rearrangement i.e., no chemical bonds are broken nor reformed, only their conformation changes and this has been confirmed by NMR studies e.g., methyl cyclohexane at -110°C gives separate signals for equatorially or axially oriented methyl groups. 

In a completely different interpretation Zefirov (242) proposed a new concept of frontier-orbital mixing (243) to explain how conformational and electronic effects in monosubstituted cyclohexanes are transmitted to remote 8-carbon atoms (Scheme 36). The orbitals at C(l) and C(4) in 112 are considered to be equatorial (242). A perturbation at C(l) (H is replaced by X) produces an electron-density shift from H(4) toward C(4) (242), which is associated with an upheld shift of the latter s signal. Although this approach appears to be quite crude and does not account for axial substituents, it deserves fiirther attention. 

Although analysis of the consequences of ring flip in a monosubstituted cyclohexane is pretty straightforward, the presence of two or more substituents requires careful consideration to decide which conformer, if any, is the more favoured. Let us illustrate the approach using 1,4-dimethylcyclohexane. Now, two configurational isomers of this structure can exist, namely trans and... 

In the trans isomer, one methyl is written down (dotted bond) whilst the other is written up (wedged bond). If we transform this to a chair conformation, as shown in the left-hand structure, the down methyl will be equatorial and the up methyl will also be equatorial. With ring flip, both of these substituents then become axial as in the right-hand conformer. From what we have learned about monosubstituted cyclohexanes, it is now easily predicted that the diequatorial conformer will be very much favoured over the diaxial conformer. 

Hence A (fra .s) = 4117.24kcal/mol for fra .s-l,4-di- -butylcyclohexane and A /(m) = 4113.72kcal/mol for the cis form. These two results are indicative of ring conformation since cA-l,4-di-t-butylcyclohexane is undoubtedly in a twist-boat form while the other is in chair conformation. The spectra of t-butylcyclohexane (in chair conformation) and of rrani-l,4-di- -butylcyclohexane are indeed very similar, except, of course, for carbon 4, which is the same as carbon 1 in the disubstituted molecule, whereas it is similar to the unsubstimted carbons in the monosubstituted cyclohexane. 

Ring-flip in chair conformation of monosubstituted cyclohexane... 

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... 

The six axial bonds are directed upward or downward from the plane of the ring, while the other six equatorial bonds are more within the plane. Conversion of one chair form into another converts all axial bonds into equatorial bonds and vice versa. In monosubstituted cyclohexanes, for electronic reasons, the more stable form is usually the one with the substituent in the equatorial position. If there is more than one substituent, the situation is more complicated since we have to consider more combinations of substituents which may interact. Often the more stable form is the one with more substituents in the equatorial positions. For example, in ct-1,2,3,4,5,6-hexachlorocyclohexane (see above) four chlorines are equatorial (aaeeee), and in the /Tisomer all substituents are equatorial. The structural arrangement of the /3-isomer also greatly inhibits degradation reactions [the steric arrangement of the chlorine atoms is unfavorable for dehydrochlorination (see Chapter 13) or reductive dechlorination see Bachmann et al. 1988]. 

Viewed another way, if the axial-equatorial energy difference is mainly a function of steric bulk, then it might be used to assess the relative size of various groups. That is, if the energy difference between the two chair conformational isomers of a monosubstituted cyclohexane were measured, it might serve as a... 

Table 6.1 A Values Free-Energy Differences between Axial and Equatorial Conformations of Monosubstituted Cyclohexanes (kcal/mol)...

Identify the more stable conformation of a monosubstituted cyclohexane also, identify substituents as axial or equatorial when the structure is flipped from one chair conformation to another. 

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