This paper is not going to make a lot of computational chemists very happy at all. It’s from Dan Singleton and Erik Plata at Texas A&M, and it’s on the Morita-Bayliss-Hillman reaction. More specifically, though, it’s on the many computational attempts to decide on the mechanism of the MBH reaction, and taken together, they’re not a pretty sight. The authors do some good old physical organic chemistry to help establish the real mechanism (which had already been proposed some years ago), and let’s just say that things don’t always match up very well.
Computational methods are simply scientific models. Any model makes some inaccurate predictions but models can retain utility despite significant propensities for inaccuracy. Inaccurate predictions aid the choice of models for future predictions. Because of this, the central scientific problem in the computational study of the MBH mechanism is not the inaccuracy of the predictions. Rather, it is the absence of any particular prediction at all. Fully-defined computational methods (including the choice of basis set, entropy calculation, and solvent model) of course make quite specific predictions. However, there is neither a consensus best-choice method nor a common view on the right way to choose a method. When evaluable, the most accurate choice varies with the system at hand. In the MBH reaction, defensible and expectantly publishable choices of computational approaches lead to predictions of the facility of the proton-shuttle process that vary by 35 orders of magnitude in the stability of 19, while also diverging in the geometry and preferred stereochemistry of transition state 13. This variance is in practical terms indistinguishable from making no prediction. In addition, studies of the MBH mechanism have not been considered falsified by extreme inaccuracies in predictions. In the terminology of Pauli, computational mechanistic chemistry is “not even wrong” about the MBH mechanism.
Here’s a C&E News article if you don’t have access to JACS. It’s true that predicting reaction mechanisms is a challenge for computational methods, because you are, out of necessity, looking at high-energy molecular states and trying to distinguish between them. It’s especially tough with a polar reaction mechanism, because solvation effects (which we still don’t have as good a handle on as we need) become very important in stabilizing transition states, assisting proton transfers, and so on. But at the same time, this sort of problem is just the sort of thing that many such groups work on: the MBH mechanism has been the subject of 11 separate computational papers.
The authors here try to figure out what has gone wrong. The errors mostly seem to be in the enthalpy term, which would suggest trouble with those polar interactions. A good number of the earlier studies predicted a proton-shuttle mechanism, which turns out not to be operating at all. The problem is that current programs have a much easier time handling proton-shuttle mechanisms, while full-scale proton transfer to and from a solvent molecule is much harder to model. So there’s a constant danger of arriving at a mechanism because it’s computationally tractable, not because it’s real. Digging into the individual equilibria, it appears that some approaches did very well on particular reaction steps, but blew up completely on others: 14, 20, or 35 orders of magnitude off for the equilibrium constants, I would say, is enough to warrant that description. And it’s very hard to see what factors led to the failures or successes – in fact, it’s quite possible that some of the best individual predictions were themselves fortuitous. Overall, though, no computational approach got things anywhere near correct.
The problems in the computational study of mechanisms encountered in the MBH reaction certainly cannot be used to paint all computational mechanistic studies. Many, either by simplicity or carefully designed use of the computations, would not be susceptible to the difficulties encountered here. At least, however, it would seem that studies of complex multimolecular polar reactions in solution should be undertaken and interpreted only with extreme care.
That’s for sure. And while this is a harder problem, in many ways, than docking a ligand into a protein, we should keep in mind that polar interactions and the treatment of solvation are very important parts of those calculations, too, and looking under this particular hood tells us that we have a long way to go on those.