The Dangers of Blind DFT Predictions

Figuring out the mechanism of an organic reaction is hard work. There are so many possible experiments (kinetics, binding, Hammett, crossover, etc.). Each experiment is finicky in its own way and often there just isn’t time to figure it all out. So, many groups understandably turn to DFT studies. Just punch in a possible mechanism, make predictions, and if the barriers are reasonable, proceed as if the mechanism is correct.

How safe is that? After all, DFT has made great strides and must surely be accurate for “vanilla” reactions, right? In this study, I teamed up with my friends to look at just such a reaction: carbonyl-olefin metathesis (COM). Corinna and her group have pioneered this fascinating methodology and have been trying to determine whether the reaction is stepwise or concerted for years.

I was drawn to this problem because DFT predicts a “forbidden” concerted [2+2] mechanism. The electronic barrier is 13 kcal/mol using B3LYP-D3(BJ)/jul-cc-pVDZ/PCM(1,2-DCE). I chose this DFT by following “best practices”: I did a coupled cluster benchmark (DLPNO-CCSD(T)/aug-cc-pVTZ) in the gas phase and checked that this method gives <1 kcal/mol errors. The original COM report used a different DFT, but the conclusion of a concerted [2+2] seems reasonable, right? You can’t even really compute a stepwise pathway…all the structures just collapse!

Unfortunately, the mechanism is wrong! Hannah measured the ¹H/²H and ¹²C/¹³C kinetic isotope effects (KIEs) and they clearly indicate a stepwise mechanism. We checked further with a Hammett study and we see a large and negative rho value, indicating the intermediacy of a betaine. It makes sense, too, if you look at the substrate scope: prenyl and styrenyl olefins work, but not primary olefins. If it were really a supra-/antara-facial [2+2], you would think that electronics would be less important and unhindered olefins would be best!

But if the DFT itself is accurate, how can the prediction be wrong? Solvation. The PCM solvent model (everyone uses this or something like it) treats solvent like a continuous field and works reasonably well for neutral-ish species, but breaks down for charge-separated species like betaines because they can’t account for specific solute-solvent interactions. If you have a mechanism where the ground state is neutral-ish (olefin+carbonyl) and the transition state is highly polarized (betaine), then you’ll get poor cancellation of solvation errors. In this case, it’s a catastrophe! The whole mechanism is wrong!

Corin and I modeled the reaction again with explicit solvent (immersing the solute in a bath of 1,2-DCE molecules). The result is a stepwise mechanism with a betaine intermediate. This doesn’t get done very often because these sorts of computations are really expensive and tricky to run, but that has to change! Typical computational models with implicit solvation can and do fail (sometimes spectacularly) for vanilla polar reactions!