Electrostatic vs orbital control

Electrostatic vs orbital control has always been challenging to teach, at least for me. Indeed, the boundaries are sometimes blurred. We all know what each of these concepts mean. Electrostatic interactions are due to the presence of ionized chemical entities and to the electronegative and electropositive properties of atoms. On the other hand, orbital interactions are between frontier molecular orbitals that belong to the reaction partners and need not be polarized (e.g. a Diels-Alder reaction between butadiene and ethylene). Earlier today, I had to revisit some classic papers by Professor Tanner of Denmark. This work describes his lab’s efforts towards the total synthesis of balanol, which is a neat natural product that has activity (not amazing by today’s standards) against protein kinase C. While reading this work, I got reminded about a really nice example of electrostatic vs orbital control. In the Tanner case, it is electrostatics that rule. Shown below are two cases – an aziridine and epoxide opening. Each example leads to ring-opening with very high regioselectivity. You will note that C4 position is being hit preferentially in both cases, despite the obvious similarity between C3 and C4 surroundings. There may be some steric effects that govern this selectivity, but the authors ascribe their findings to electrostatic control. According to Tanner’s calculations, there is very little LUMO component on each of the methines in the three-membered rings. However, there is a notable difference between partial charges and they correlate with regioselectivity. If it were orbital control – how can one possibly imagine that fluoride and azide would give the same major regioisomer (they also did cyanide and cuprate – all go C4!)? In my view, this is a good example of electrostatic control. I would add, though, that contemporary computational approaches may provide additional clarification of this phenomenon.

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http://www.sciencedirect.com/science/article/pii/S0040402097001671

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