Cyclohexane trans substituents

It is believed that equatorial substituents such as chlorine or bromine would increase the guest diameter beyond the allowed values (assuming that the guest molecules stack roughly parallel to the canal68)). Support for this comes from the study of fluorocyclohexane where the population of the axial conformer is not enhanced to any major extent70. Nitro-71) and cyano-cyclohexane, trans-l,2-dichloro-, trans-1,2-dibromo-, tram-1,4-dichloro-, trans-1,4-dibromo-, and trans-l-bromo-4-chloro-cyclohexane all pack most efficiently in the thiourea canals as the axial or diaxial conformer 68,72. Tram-2,3-dichloro-1,4-dioxane behaves similarly73. In contrast isocyanato-, tram-1,4-diiodo-, trans-1 -bromo-4-iodo-, and tram-1 -chloro-4-iodo-cyclohexane are present as mixtures of the axial/equatorial or diaxial/diequatorial conformations as appropriate 68,72). The reason for this anomalous behaviour of the iodosubstituted cyclohexanes is not clear. 

In disubstituted compounds, the rule for alkyl groups is that the conformation is such that as many groups as possible adopt the equatorial position. How far it is possible depends on the configuration. In a c -l,2-disubstituted cyclohexane, one substituent must be axial and the other equatorial. In a tram-1,2 compound both may be equatorial or both axial. This is also true for 1,4-disubstituted cyclohexanes, but the reverse holds for 1,3 compounds the trans isomer must have the ae conformation and the cis isomer may be aa or ee. For alkyl groups, the ee conformation predominates over the aa but for other groups this is not necessarily so. For example, both fram-l,4-dibromocyclohexane and the corresponding di-chloro compound have the ee and aa conformations about equally populated228 and most irons-1,2-dihalocyclohexanes exist predominantly in the aa conformation.229 Note that in the... 

When additional substituents ate bonded to other ahcycHc carbons, geometric isomers result. Table 2 fists primary (1°), secondary (2°), and tertiary (3°) amine derivatives of cyclohexane and includes CAS Registry Numbers for cis and trans isomers of the 2-, 3-, and 4-methylcyclohexylamines in addition to identification of the isomer mixtures usually sold commercially. For the 1,2- and 1,3-isomers, the racemic mixture of optical isomers is specified ultimate identification by CAS Registry Number is fisted for the (+) and (—) enantiomers of /n t-2-methylcyclohexylamine. The 1,4-isomer has a plane of symmetry and hence no chiral centers and no stereoisomers. The methylcyclohexylamine geometric isomers have different physical properties and are interconvertible by dehydrogenation—hydrogenation through the imine. 

The CH fragment which is linked to the OH group (Sh = 5.45 ) can easily be located in the H and NMR spectra. The chemical shift values Sc =74.2 for C and Sh = 3.16 for //are read from the CH COSY plot. The H signal at S,i = 3.16 splits into a triplet (11.0 Hz) of doublets (4.0 Hz). The fact that an antiperiplanar coupling of 11 Hz appears twice indicates the diequatorial configuration (trans) of the two substituents on the cyclohexane ring 5. If the substituents were positioned equatorial-axial as in 4 or 5, then a synclinal coupling of ca 4 Hz would be observed two or three times. 

When two or more substituents are present on a cyclohexane ring, the interactions between the substituents must be included in the analysis. The dimethylcyclohexanes provide an example in which a straightforward interpretation is in complete agreement with the experimental data. For 1,2-, 1,3-, and 1,4-dimethylcyclohexane, the free-energy change of the equilibrium for the cis trans isomerization is given below. ... 

Reactions such as catalytic hydrogenation that take place at the less hindered side of a reactant are common in organic chemistr-y and are examples of steric effects on reactivity. Previously we saw steric effects on structure and stability in the case of cis and trans stereoisomers and in the preference for equatorial substituents on cyclohexane rings. 

A summary of the various axial and equatorial relationships among substituent groups in the different possible cis and trans substitution patterns for disubstituted cyclohexanes is given in Table 4.2. 

This is also true for 1,4 disubstituted cyclohexanes, but for 1,3 compounds, the reverse is true, the trans must have a e and cis either aa or ee conformation. But if the substituents are alkyl groups, the diequatorial predominates the diaxial. The trans 1, 2-e e conformations are thermodynamically more stable than cis 1, 2 isomers which therefore occurs as a e form. 

Whereas in benzene and in its derivatives the six substituents lie in the same plane, namely, that of the ring, they are distributed in cyclohexane in two planes parallel to that of the ring. Hence there results a special type of spatial isomerism when two hydrogen atoms united to different carbon atoms are replaced. The isomerism is caused by the position of the two substituents, for they may lie in the same plane (m-form), or one in each plane (iraws-form). The phenomenon is closely related to the cis-trans isomerism of the ethylenes, of which the best-known example is that of maleic and fumaric acids. 

The presence of a nitro substituent can enhance the intramolecular charge transfer in the excited state dramatically, so that the normal trans-to-cis isomerization of l-[2(4-nitrophenyl)ethenyl]pyrene in cyclohexane is completely suppressed74 in polar solvents such as acetonitrile (equation 66). 

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. 

The ring-chain tautomerism of tetrahydro-l,3-oxazines is very sensitive to the stability differences, the substituents and the ring-fusion effect (Section IV,A). It also reveals a considerable stability difference in favor of the cis isomers. In the reactions of the cis- and trans-2-amino-l-cyclohexanols, as compared with the hydrindane analog systems, where the heteroatoms form an oxazolidine ring cis- or tra 5-fused with cyclohexane, the corresponding stability differences were again found to be in favor of the cis isomer (93JOC1967). 

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. 

Molander has developed effective protocols for the cyclization/hydrosilylation of 1,6-enynes catalyzed by lanthanide metallocene complexes/ For example, reaction of cyclohexyl-substituted 1,6-enyne 15a with phenylsilane catalyzed by Cp 2YMe(THF) in cyclohexane at room temperature for 2h gave silylated alkylidene cyclopentane 16a as a 6.5 1 mixture of trans. cis isomers (Table 5, entry 1). The diastereoselectivity of the reaction depended strongly on the nature of the allylic substituent. For example, yttrium-catalyzed cyclization/ hydrosilylation of the ethyl-substituted enyne 15b gave silylated cyclopentane 16b in 88% yield as a single diastereomer (Table 5, entry 2). 

A number of cyclohexane derivatives with tertiary amino substituents, especially dimethylamine, have proven to be opioid analgesics. Tilidine, which was synthesized at the beginning of the 1960s, is one of these compounds. Its trans NMe2/C02Et configuration is important for activity since the corresponding cis-isomer is less potent. 

SAMPLE SOLUTION (a) The most stable conformation is the one that has the larger substituent, the fe/t-butyl group, equatorial. Draw a chair conformation of cyclohexane, and place an equatorial tert-butyl group at one of its carbons. Add a methyl group at C-3 so that it is trans to the tert-butyl group. 

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