Cieplak nucleophilic attack

Consideration of the stabilizing interaction between the low-lying CT "-orbital associated with the bond forming between the incoming hydride and the carbonyl carbon, and remote electron-donor o-orbitals led Cieplak to an explanation for many kinetic and stereochemical effects in cyclohexanones that were previously unexplained. The normal preference for axial attack in simple cyclohexanones was attributed to the improved electron-donor ability of carbon-hydrogen bonds over carbon-carbon bonds that would be antiperiplanar to the incoming nucleophile in the transition state. 

This theory is simple to apply and accounts for many experimental observations, with the proviso that there are likely to be situations where steric effects predominate. The Cieplak hypothesis is also supported by le Noble s work on 5-substituted adamantan-2-one attack of nucleophiles occurs at the syn face if the 5-substituent is an electron-withdrawing group [33] and at the anti face if it is a donor (see later section) [34]. A serious problem with the Cieplak analysis, which is relevant to all systems where this hypothesis has been applied, concerns the large energy difference between the adjacent CT-orbital(s) and the a orbital of the transition state, which will result in a minimum of orbital mixing and stabilisa-tion/destabilisation, and this is discussed in more detail later [35-38]. 

The reduction of 4-ferf-butylcyclohexanone by LiAlH4 in THF at 0 °C affords a mixture of the tram- and ris-alcohols in 88.5 11.5 ratio (Table 1) [9]. The predominant attack takes place obviously from the axial direction as predicted above by the Cieplak model. This selectivity is expected to diminish when the ring carries an equatorial methyl group on C3 because it will (a) not introduce an element of steric interaction during the course of the nucleophilic addition, and (b) raise... 

Like the N- m e t h y I - 2 - ad a m a n ta n o ne species above, 5-aza-2-adamantanone N-oxide exhibits axial selectivity by a margin of 96 4 on reduction with NaBH4 in isopropanol. Cieplak model predicts axial selectivity for the overall electron-attracting character of the N+-0 bond. The Anh-Felkin model fails as it is opposite of the Cieplak model in concept and allows attack of a nucleophile anti to the more electron-deficient bond on the a carbon. The computed 3D structures of 5-aza-2-adamantanone N-oxide and its protonated derivative are shown in Fig. 12. 

A useful orbital approach by Cieplak has suggested that the nucleophile will attack the carbonyl anti to the best donor ligand. 

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