I just came back from KOST-2015, an international congress on heterocyclic chemistry in Moscow, Russia. The conference was superbly put together by my friends, Profs. Nenajdenko and Vatsadze in memory of Prof. Kost (http://www.kost2015.ru). Of all the scientific vignettes I was exposed to, one particularly thought-provoking insight comes to mind. It deals with the inner workings of Prof. Togni’s electrophilic trifluoromethylation reagents (http://pubs.acs.org/doi/pdf/10.1021/cr500223h). In his talk, Togni described the genesis of this research program and commented on a variety of nucleophilic partners that can be trifluoromethylated with the help of his hypervalent iodine-containing molecules. I am showing one of them below without any intent to dwell on the specific reactions. Two forms exist: the parent and the protonated one, with the latter being the desired electrophilic trifluoromethylating species. In order to maintain high selectivity of CF3 transfer, one needs to avoid decomposition by way of premature cleavage of the Cphenyl-I bond. If one maintains the oxygen atom in its protonated form, this detrimental pathway is avoided. The question is: why? This is where frontier orbitals come to rescue. I am not going to show their symmetry as it would be rather tedious. In the aforementioned Chem. Rev. article, you can see all those red and blue blobs. The key is that protonation changes the area where LUMO is localized, offering a compelling rationale for why the non-protonated form is labile at the Cphenyl-I bond. I thought this is a great example of using frontier molecular orbitals to explain the reactivity preferences and I hope students take this lesson to heart. There is no way there is anything terribly complex in some of these computations.
If you wonder where those hypervalent iodine species come from, they are derived from TMSCF3, whose chemistry I had a pleasure of working on in Professor Prakash’s lab a while back (http://pubs.acs.org/doi/abs/10.1021/cr9408991). It is curious that, among many different areas of use, the nucleophilic trifluoromethylating reagent (TMSCF3) has found application in efforts to generate electrophilic trifluoromethylating reagents.