Disubstituted derivatives of cyclohexane

Disubstituted cyclopropanes exemplify one of the simplest cases involving stabil ity differences between stereoisomers A three membered ring has no conformational mobility so the ring cannot therefore reduce the van der Waals strain between cis sub stituents on adjacent carbons without introducing other strain The situation is different m disubstituted derivatives of cyclohexane... 

Use your answers from Problem 3.44 to complete the following table, showing correlations between cis, trans isomers and axial, equatorial positions for disubstituted derivatives of cyclohexane ... 

Terephthalic acid has been obtained from a great many /)-disubstituted derivatives of benzene or cyclohexane by oxidation with permanganate, chromic acid, or nitric acid. The following routes appear to have preparative value from />-toluic acid, />-methylacetophenone,2 or dihydro-/)-tolualdehyde by oxidation with permanganate from f>-cymene by oxidation with sodium dichromate and sulfuric acid from />-dibromobenzene or from /i-chloro- or -bromobenzoic acid by heating at 250° with potassium and cuprous cyanides and from />-dibromo-benzene, butyllithium, and carbon dioxide. ... 

C. Reduced nickel (20% on diatomite) served as the catalyst. Hydrogenation was carried out in a reactor made of copper (20 x 0.6 cm) at 70°C. In the hydrogenation of disubstituted derivatives of benzene and cyclohexane, cis- and fra s-isomers are formed, their ratio depending on the structure of the compounds being hydrogenated and on the hydrogenation conditions. 

Turova-Polyak and co-workers have carried out extensive studies of naphthene isomerization with AICI3, particularly of the substituted cyclopentanes. The conversion of mono- and disubstituted cyclopentanes to cyclohexanes was reported as an analytical technique for the determination of cyclopentanes in mixture with paraffins (411). Ethyl-cyclopentane at room temperature gave an 18-20% yield of cyclohexane derivatives (412). At 140-145°, an 85% yield of 1,3,5-trimethyl-cyclohexane was obtained. This work was also extended to 1,1-dimethyl-cyclopentane (410), up to 95% of which was converted to methyl-cyclohexane at 115°. Similar conversions of alkylated cyclopentanes were also reported by Shulkin and Plate (375). These researches parallel similar work done in the United States. 

Disubstituted cyclohexane derivatives present a more complex system because there are two chair conformations as well as other conformations. For all comparisons of enantiomers and diastereomers of cyclohexane derivatives, assume that the chair conformation is the only one of interest (see Chapter 8, Section 8.5.4). Even with this simplifying assumption, both chair conformations must be examined for each diastereomer. An example is 1,2-dimethyl-cyclohexane, which has a cis-diastereomer (G3) and a trans-diastereomer (G4A-G4E). It appears that G3 has a plane of symmetry by simply looking at the planar structure, and this is correct. In other words, G3 is a meso compound. However, G4A is labeled as having no symmetry, which indicates it should be a mixture of enantiomers. Is this correct One enantiomer of trans-diastereomer G4A [(li ,2 S)-dimethyIcycIohexane] has two chair conformations G4B and G4C. There is one axial and one equatorial methyl group in each chair conformation, and in the flat representation (G4A) a line is drawn between the methyl groups that suggests that the structure should be examined for the presence of a plane of symmetry. 

The chemoenzymatic synthesis of the analgesic U-(—)-50,488 [41] and new C2-symmetric bisaminoamide ligands derived from N,N-disubstituted trans-cyclohexane, ,2-diamine [41] has been possible by a CALB-catalyzed resolution using ethyl acetate as solvent and acyl donor [42]. 

Table 4.8 The Physical Constants of Cis- and Ttwmx-Disubstituted Cyclohexane Derivatives...

In the ring closures of the 1,2-disubstituted 1,3-difunctional cyclohexane, cycloheptane, and cyclooctane derivatives discussed in Sections II,A,B, and C, no appreciable differences were found in the reactivities of the cis and trans isomers. In contrast, very significant differences were observed in the cyclization reactivities of the cis and trans 1,2-disubstituted 1,3-difunctional cyclopentane derivatives, such as 1,3-amino alcohols, 2-hydroxy-l-carboxamides or /S-amino acids. Whereas the cis isomers reacted readily, their trans counterparts did not undergo ring closure in most cases. This difference was manifested in the formation of both d - and e -fused derivatives. 

Muthusamy et al. (82) prepared a number of oxacyclic ether compounds from the tandem ylide formation-dipolar cycloaddition methodology. Their approach provides a synthetic tactic to compounds such as ambrosic acid, smitopsin, and linearol. Starting with either cyclopentane or cyclohexane templates, they prepared ylide sizes of five or six, which are trapped in an intermolecular cycloaddition reaction by the addition of DMAD. The products are isolated in good overall yield. In a second system, 2,5-disubstituted cyclohexenyl derivatives are utilized to generate the pendent ylide, then, A-phenylmaleimide is added in an intermolecular reaction, accessing highly substituted oxatricyclic derivatives such as 182 (Scheme 4.43). 

Mono- and 1,1-disubstituted cyclohexanes. There are several electron diffraction investigations of mono-substituted cyclohexanes. Cyclohexylfluoride301 exists as 57% e and 43% a which means that the equatorial position is favored by about 710 J/mol. A microwave study302 yielded 1.6+ 1.2 kJ/mol for this energy difference. Cyclohexylchloride303 is very similar to the fluorine derivative in that the gas phase... 

Configurational isomerism is encountered in bi- and polysubstituted cyclic molecules, as well as in fused ring systems. In the simple case of bisubstituted monocyclic systems, cis-trans-isomehsm exists provided that the two substituents are not gemi-nal. Thus, 1,2-, 1,3- and 1,4-disubstituted cyclohexane derivatives (LII) show this... 

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