Catalysis of the Aldol Reaction in Water

The catalyzed aldol reaction in pure water offers a cautionary tale on overinterpretation of computationally derived mechanisms. The term catalysis may seem to be inappropriately applied to the role of water in the aldol reaction. The aldol reaction is in fact usually much slower in water than in organic solvents. Rather, as will be demonstrated, the catalytic role of water is to create an alternate pathway with a lower barrier than that for the noncatalytic, but aqueous, reaction. 

In an effort to understand the role of nomicotine in catalyzing aqueous aldol reactions, Noodleman and Janda examined the aldol reaction of acetaldehyde and acetone in an organic solvent (THF, tetrahydrofuran) and water. The calculations were performed at B3LYP/6-311-l-G(2d,2p)//B3LYP/6-311(d,p) and were corrected for ZPVE at HF/3-21G and the effects of solvent using the COSMO model at B3LYP/6-311(d,p). 

30 is quite large, they downplayed it by suggesting that the computational method might have an error of 2-3 kcal mol for each critical point and that perhaps an alternative mechanism exists. They did note that the barrier for Reaction 6.30 in water is greater than that for Reaction 6.29 in THE, consistent with experiment. 

In the following year, Houk provided three alternate mechanisms for the aldol reaction in water, computing the critical points at B3LYP/6-311++G(3d,3p) //B3LYP/6-31G(d) with the CPCM solvation model. Honk noted that the proposed mechanism. Reaction 6.30, begins not with acetone but with its enol, produced 

Houk s first alternative mechanism. Reaction 6.31, posits the direct proton transfer from acetone to acetaldehyde to form an ion pair. This process requires a great deal of energy, 59 kcal mol and even though the subsequent formation of the C-C bond and the ultimate aldol product occur without fur er barrier, this mechanism requires too much energy to be competitive. 

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