Cyclohexanone derivatives conformation

The principles involved in the conformational analysis of six-membered rings containing one or two trigonal atoms, for example, cyclohexanone and cyclohexene are similar. The barrier to interconversion in cyclohexane has been calculated to be 8.4-12.1 kcal mol . Cyclohexanone derivatives also assume a chair conformation. Substituents at C2 can assume an axial or equatorial position depending on steric and electronic influences. The proportion of the conformation with an axial X group is shown in Table 4.4 for a variety of substituents (X) in 2-substituted cyclohexanones. 

Octant rule A rule that attempts to predict the conformation of a carbonyl carbon by cutting it into octants using three perpendicular planes each of which bisects the carbonyl carbon, and then looking at the orientation of the substituents within each octant. Used mainly on cyclohexanone derivatives. 

The photochemical fragmentation of 7-methyl-2,2,5-triphenyl-l-oxa-5,6-diaza-spiro-[2,4]-hept-6-en-4-one has been studied." Interest in solid state photochemistry continues to burgeon. The present paper" discusses the problems associated with the proximity of the components of radical pairs or biradicals within the constrictions of the crystalline environment. This problem has been addressed by examining the photochemical reactivity of a series of cyclohexanone derivatives (119) whose solution-phase photochemistry is well known. The irradiations, using X = 350 nm, were carried out on microcrystals dispersed in potassium bromide. The influence of the conformations within the crystals and substitution were studied. The relative yields of the product, the corresponding cyclopentane, are shown beside the appropriate structure." ... 

In one of the first reported stereoselective alkylation reactions [18], Yamada described the use of a methyl prolinate as chiral auxiliary in the methylation of a cyclohexanone-derived enamine (Fig. 3 reaction D).The low stereoselectivity of the reaction clearly depends on the possibility for the alkylation to occur on a different conformation of the enamine, namely the one in which the C-C double bond is transoid to the stereocenter, that thus cannot exert any useful stereocontrol. 

The conformational problems of cyclohexene derivatives are somewhat different than those observed with cyclohexanone or cyclohexane derivatives. The presence of the alkene moiety effectively flattens four carbons of the ring, which changes the different steric effects for substituents with an incoming reagent, relative to cyclohexanone derivatives. The most abundant conformations of cyclohexenone derivatives are 310 and 311. The first problem that arises in conjugated derivatives is the competition of 1,2- with 1,4-addition for... 

Enolates derived from cyclic compounds such as cyclohexane carboxylic acid or cyclohexane carboxalde-hyde generate enolates that are unique. These enolates have an exocyclic double bond that can exist as ( ) and (Z) isomers. The facial and orientational bias in alkylation and condensation reactions of such enolates is influenced by the conformation of the ring it is attached to. Alkylidene cyclohexane enolates show a preference for equatorial attack, just as cyclohexanone derivatives do (sec. 4.7.C,D). 

This and previous results are in accord with the finding of Lukacs et al. [55, 56] that an apparent relationship between the stereochemistry at the C5 carbon of the cyclohexanone derivatives produced in the Ferrier reaction and the conformation of... 

The enamines derived from cyclohexanones are of particular interest. The pyrrolidine enamine is most frequently used for synthetic applications. The enamine mixture formed from pyrrolidine and 2-methylcyclohexanone is predominantly isomer 17.106 A steric effect is responsible for this preference. Conjugation between the nitrogen atom and the tt orbitals of the double bond favors coplanarity of the bonds that are darkened in the structures. In isomer 17 the methyl group adopts a quasi-axial conformation to avoid steric interaction with the amine substituents.107 A serious nonbonded repulsion (A1,3 strain) in 18 destabilizes this isomer. 

Steric control elements are also important for the diastereoselectivity in alkylations of mono-cyclic cyclohexanone enolates. However, electronic control becomes more evident in these systems compared to monocyclic cyclopentanone enolates The flexibility of the six-membered ring system, and the large number of possible ring conformations, makes predictions of the diastereoselectivity difficult. In general, one may conclude that the diastereoselectivity in alkylations of enolates derived from monocyclic cyclohexanones is not as high as in alkylations of cyclopentanone enolates. The syntheses of compounds 21-27 demonstrate the effect of substitution in each position of the six-membered ring49,61 -7°. 

The oxidation of imines derived from substituted cyclohexanones occurs predominantly from the equatorial direction. However, the product oxaziridines can undergo subsequent equilibration to favor a more stable conformation which places the bulkier nitrogen substituent in an equatorial conformation (equation 44)219. 

On the other hand, lithium enolates derived from substituted endocyclic ketones have largely been exploited in the synthesis of steroids since the regioselectivity of their deprotonation can be controlled and high levels of 1,2- and 1,3-stereoselection occur9,418. The control is steric rather than electronic, with the attack directed to the less substituted ji-face of the enolate for conformationally rigid cyclopentanones, whereas stereoelectronic control becomes significant for the more flexible cyclohexanones. Finally, an asymmetric variant of the formation of a-branched ketones by hydration of camphor-derived alkynes followed by sequential alkylation with reactive alkyl halides of the resulting ketones was recently reported (Scheme 87)419. 

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