Facial Selectivity in Reaction of Carbonyls A Computational Approach

6 TT-Facial Selectivity in Reaction of Carbonyls A Computational Approach 

The calculation of transition states and activation energies is now possible for even complex systems. High-level computational methods [2], facilitated by fast computers, and improvements in algorithms now give activation barriers which approximate to experimental values for reactions where the mechanism is known. However, when multiple conformations are possible the problem becomes expensive and time consuming. Inclusion of solvent in calculations is costly and complex and has only been possible in recent years [3]. 

An understanding of facial selection in aldehyde and ketone chemistry, the topic of this chapter, requires a knowledge of the reacting species and the mechanism for reaction. Addition to carbonyls can occur by a formally non-allowed [ j2-i- 2] pathway or by an electrophile- or nucleophile-driven mechanism (Fig. 6-1) [4]. 

The energy difference of the HOMO of the nucleophile and the LUMO of the carbonyl compared to the LUMO of the electrophile and the HOMO n-orbital of the carbonyl will be a factor in establishing whether the reaction is electrophile or nucleophile driven. In the case of a reaction catalysed by acid the reaction is considered to be electrophile driven and attack of the nucleophile occurs to the protonated carbonyl. A carbonyl, coordinated with a Lewis acid or cation (e.g. H, Li , Na , AIH3 [5-7]) or uncoordinated, can be attacked by a neutral or anionic nucleophile. In the former case the nucleophile must bear an acidic hydrogen to allow for the formation of a neutral product [4]. Since reduction of aldehydes and ketones is exothermic the Hammond postulate dictates that the transition state is closer in energy and structure to the reactants than to the products. 

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. 

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J. M. Coxon, R. T. Luibrand, 71-Facial Selectivity in Reactions of Carbonyls A Computational Approach, in Modern Carbonyl Chemistry (J. Otera, Ed.), Wiley-VCH, Weinheim, 2000, 155-184. 

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