Conformations of cyclohexanone

There is another aspect to the question of the reactivity of the carbonyl group in r ck)hexanone. This has to do with the preference for approach of reactants from the axial ir equatorial direction. The chair conformation of cyclohexanone places the carbonyl coup in an unsynunetrical environment. It is observed that small nucleophiles prefer to roach the carbonyl group of cyclohexanone from the axial direction even though this is 1 more sterically restricted approach than from the equatorial side." How do the ctfcnaices in the C—C bonds (on the axial side) as opposed to the C—H bonds (on the equatorial side) influence the reactivity of cyclohexanone ... 

Figure 1.2.7 The major conformers of cyclohexanone. Twist boat and boat forms become stable conformers.

The Robinson annelation was introduced in Chapter 26, p. 638. The flattened chair conformation of cyclohexanones shown here is described in detail in Chapter 32, p. 830. 

A chemist can evaluate two molecules and make estimates of their relative diffusion constants. The linear 1-hexanone, for example, will diffuse relatively quickly, whereas the relatively rigid chair conformation of cyclohexanone makes it notoriously slow to diffuse out of the many polymers for which it is a good solvent. Similarly, 1-butanol will diffuse... 

The conformational energy of an alkyl group at C—3 of cyclohexanone is substantially less than that of an alkyl group in cyclohexane because of reduced... 

Bicyclic keto ester (22) was needed for conformational studies. The common atoms are marked ( ) and the obvious disconnections of this symmetrical molecule require double alkylation of cyclohexanone with a reagent such as (23), Double 1,5-diCO disconnection of (22) is impossible as you will discover if you attempt it. 

For simple, conformationally biased cyclohexanone enolates such as that from 4-t-butylcyclohexanone, there is little steric differentiation. The alkylation product is a nearly 1 1 mixture of the cis and trans isomers. 

Crystalline samples of syndiotactic poly(methyl methacrylate) (st-PMMA) may be obtained from chloroacetone 178). This guest could be completely replaced by a variety of other guest molecules such as acetone, 1,3-dichloroacetone, bromoacetone, pinacolone, cyclohexanone, acetophenone and benzene. The X-ray diffraction patterns for these inclusion compounds were similar. These data indicate that the st-PMMA chains adopt a helical conformation of radius about 8 A and pitch 8.85 A. The guest molecules are located both inside the helical canals and in interhelix interstitial sites. 

In some very early work the conformation of a-methyl groups in cyclohexanone oximes (76) was assigned from solvent shifts. Results are summarized in Table 17. In solutes bearing a lone pair of electrons on nitrogen, the benzene-solute collision complex is likely to occur at a site as far as possible from the nitrogen. Shifts have been summarized for aziridines, oximes and imines, and for the latter a complex of type 77 was proposed. 

The development of conditions for stoichiometric formation of both kinetically and thermodynamically controlled enolates has permitted the extensive use of enolate alkylation reactions in multistep synthesis of complex molecules. One aspect of the reaction which is crucial in many cases is the stereoselectivity. The alkylation step has a stereoelectronic preference for approach of the electrophile perpendicular to the plane of the enolate, since the electrons which are involved in bond formation are the n electrons. A major factor in determining the stereoselectivity of ketone enolate alkylations is the difference in steric hindrance on the two faces of the enolate. The electrophile will approach from the less hindered of the two faces, and the degree of stereoselectivity depends upon the steric differentiation. For simple, conformationally based cyclohexanone enolates such as that from 4 - /- b u ty I eye I o h cx an o ne, there is little steric differentiation. The alkylation product is a nearly 1 1 mixture of the cis and trans isomers. 

The simplest case of substrate-controlled diastereoselection is the incorporation of the controlling stereocenter and the prostereogenic center into a cyclohexane or cyclopentane ring. In the classical example of nucleophilic attack on a conformationally anchored cyclohexanone, axial and equatorial attack are possible, leading to diastereomers 1 and 2, respectively. 

The Sn reactions of cyclohexanone acetals substituted at C(2) with sulfur, iodine, or chlorine are thought to occur when the nucleophile attacks the oxocarbenium ion intermediate with the substituent on C(2) in an axial conformation.104 The most stereospecific reactions (i.e. >92% trans), were when the substituent at C(2) was sulfur. This mechanism (Scheme 26) is supported by HF/6-31G calculations that show the oxocarbenium ion (66) with the sulfur at C(2) in the axial position to be the most stable, and by the high yield of the trans-isomer (67) in the products. 

Since the adamantane ring system is composed of three interlocking cyclohexane rings, all in the perfect chair conformation, /3-sub stituted adamanta-nones are also ideal models for establishing quantitative substituent contributions to the optical rotatory dispersion of cyclohexanones in the undisturbed chair form. A variety of optically active /3-equatorial and /3-axial substituted adamantanones have been synthesized 18°-184) and their circular dichroism determined 184-185) jji generai) axial polar substituents (C02R, Cl,... 

Side Note 10.1. Electronic Effects in the Reduction of Conformationally Fixed Cyclohexanones... 

Equatorial, and Axial Addition of Classic Grignard Reagents and Reetz-Grignard Reagents to a Conformationally Fixed Cyclohexanone... 

Alkylations of enolates, enamines, and silyl enol ethers of cyclohexanone usually show substantial preference for axial attack. The enamine of 4-f-butylcyclohexanone, which has a fixed conformation because of the i-butyl group, gives 90% axial alkylation and only 10% equatorial alkylation with n-Prl. 

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