Cyclohexanone facial selectivity

Fukui [51] predicted the deformation of the LUMO of cyclohexanone by the orbital mixing rule [1,2] and explained the origin of the % facial selectivity of the reduction of cyclohexanone. Tomoda and Senju [52] calculated the LUMO densities on the... 

When a nucleophilic reagent, Nu X+ (or Nu—X), is reacted with a ketone, com-plexation of oxygen by X+ may precede attack at carbon. Geometric changes associated with such complexation have been calculated for a series of 4-substituted cyclohexanones. The results allow the facial selectivity of the subsequent nucleophilic attack to be predicted, and without the need to calculate the transition-state geometry. 

Shi and Boyd suggest that the difference between the selectivity of 4-equatorially-substituted cyclohexanones and 4-axially-substituted cyclohexanones arises from the change in the direction of the dipole orthogonal to the carbonyl plane. This is consistent with Kamernitzky and Akhrem s proposal that the facial selectivity is determined by a difference in the electrostatic fields on the upper and lower sides of the carbonyl double bond 87. 

Wipf has shown that 4,4-disubstituted cyclohexanones undergo nucleophilic attack where the facial selectivity is determined by dipolar control. Thus, compounds of the type 23 underwent nucleophilic attack anti to the electronegative substituent at C(4), whereas the fluorinated analogue, 24, underwent attack syn to the oxygen, in accordance with the inversion of the dipole moment. They found that the logarithm of the experimentally observed facial selectivity for nucleophilic attack was correlated linearly (R = 0.998) with the calculated dipole moments. The facial selectivities were also shown to depend upon the nature of the nucleophile, hydride ions and alkynyl carbanions being essentially unselective. 

Table 1 Facial Selectivities for the Addition of Organometallics to Substituted Cyclohexanones in the...

Any explanation of facial selectivity must account for the diastereoselection observed in reactions of acyclic aldehydes and ketones and high stereochemical preference for axial attack in the reduction of sterically unhindered cyclohexanones along with observed substituent effects. A consideration of each will follow. Many theories have been proposed [8, 9] to account for experimental observations, but only a few have survived detailed scrutiny. In recent years the application of computational methods has increased our understanding of selectivity and can often allow reasonable predictions to be made even in complex systems. Experimental studies of anionic nucleophilic addition to carbonyl groups in the gas phase [10], however, show that this proceeds without an activation barrier. In fact Dewar [11] suggested that all reactions of anions with neutral species will proceed without activation in the gas phase. The transition states for reactions such as hydride addition to carbonyl compounds cannot therefore be modelled by gas phase procedures. In solution, desolvation of the anion is considered to account for the experimentally observed barrier to reaction. 

The Felkin-Anh model has also been used to explain the preference for axial attack by nucleophiles on cyclohexanones and the effect of proximate substituents on facial selection. The anti periplanar geometry that Anh regarded as important in nucleophilic attack of carbonyl compounds is compromised by torsional strain in the reactions of cyclohexanones from the equatorial face. Felkin slated Whereas both torsional strain and steric strain can be simultaneously minimised in a reactant-like transition state when the substrate is acyclic... this is not possible in the cyclohexanone case.. ..These reactions all proceed via reactant-like transition states. In the absence of polar effects, their steric outcome is determined by the relative magnitude of torsional strain and steric strain [in the axial and equatorial transition states] [16]. 

The effect of a gradual increase in the bulk of a given type of nucleophile on the facial selectivity of a given cyclohexanone could also be gleaned from a measurement of the relative axial approach. The axial selectivity decreases in the order 45 % >31% >18% 0 % on changing the nucleopohilic reagent from... 

The Exterior Frontier Orbital Extension (EFOE) model has been applied to predict r-facial selectivity in nucleophilic additions to imines and iminium ions of the cyclohexanone, tropinone, and adamantan-2-one systems." A review of the EFOE model," and other references to its use, are described later under Regio-, Enantio-, and Diastereo-selective Aldol Reactions. 

Delivery of an electrophile to the less hindered face of an enolate also occurs in intramolecular alkylation reactions. When 500 was treated with potassium fert-butoxide, a mixture of (E) and (Z) enolates (501 and 502. respectively) was obtained. Intramolecular displacement of bromide generated a single isomer (503). In this case, the electrophile can approach the enolate from only one face (the bottom or a face). Because of this conformational constraint, both (E) and (Z) enolates lead to the same product. In cyclopentanone and cyclohexanone enolates. an increase in the size of a facial blocking group increases selectivity. When that group was small, the selectivity decreased. 

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