Computational studies cyclohexanone reactions

A DFT study found a corresponding TS to be the lowest energy.167 This study also points to the importance of the solvent, DMSO, in stabilizing the charge buildup that occurs. A further computational study analyzed the stereoselectivity of the proline-catalyzed aldol addition reactions of cyclohexanone with acetaldehyde, isobu-tyraldehyde, and benzaldehyde on the basis of a similar TS.168 Another study, which explored the role of proline in intramolecular aldol reactions, is discussed in the next section.169... 

Computational study of the formation of a spiro-epoxy intermediate in the reaction of cyclohexanone with bromoform, in alkaline medium, has confirmed the reliability of... 

After these studies were published. Professors Barbas and List independently contacted Houk, and the List collaboration developed. Houk remembers that List suggested Why don t you try the reaction of cyclohexanone plus ben-zaldehyde. We ll do the experiments but I won t tell you the results—so you can make a real prediction. And that s the way it developed. That took quite some time—3 to 4 months to do all the computations—since we had to predict something. That s a more arduous task than explaining something. We were concerned about missing a TS, so we went about a systematic search. And then we told List our results and there was really spectacular agreement. ... 

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. 

Houk and coworker have examined the stereoselectivily in a series of amino acids in an intramolecular aldol reaction using the DFT(B3LYP) computational tool [51]. They attributed increased conformational flexibility in the stereoselective bond forming transition state as the origin of the lower enantiomeric excess noted with acyclic primary amino acids. Himo, Cordova, and coworkers have used density functional theory computations to examine the stereocontroUing transition states for the (S)-alanine catalyzed intermolecular aldol reaction between cyclohexanone and para-nitrobenzaldehyde [52]. In a very recent study, Houk, Mahrwald, and coworkers compared the transition states of an asymmetric aldol reaction... 

---