The field of physical organic chemistry has seen its ups and downs. Who can forget the foundational experiments done by Jack Roberts some 60+ years ago? These studies clarified the benzyne mechanism of nucleophilic aromatic substitution, which is one of our textbook favourites. This was certainly among the highlights in the illustrious history of this area of inquiry as researchers pushed the envelope in everything ranging from clever experimental design to the development of new spectroscopic tools. There were also a number of downs, one of the most notable ones going back to the 1970’s, when there were literally whole volumes of JOC dedicated to the non-classical ion problem. I do not mean any disrespect to this tremendously important area, but the funding agencies stopped funneling money into physical organic chemistry once they realized that the community went a bit too far in its overzealous focus on one set of problems.

What I like are the papers in which foundational concepts rooted in physical organic chemistry of the type we teach in our chemistry courses are put to good use in chemical biology. There are many reasons why this is so and, honestly, the primary one is educational in nature: it is easy to tell students that, if they understand conjugate addition (for example), they would be able to rationally design bioactive molecules. On this note, here is a great paper in Nature Chemical Biology by Jack Taunton of UCSF. Take a look at the two acrylates shown above. As Jack points out in his paper, it is somewhat of a paradox that the nitrile functionality increases the reactivity of the electrophile, yet eliminates the formation of irreversible adducts with cysteine. On the basis of this nitrile-driven reactivity difference it was possible to design slowly dissociating covalent inhibitors of RSK2 kinase (pdb 4D9U
, below). This is the physical organic chemistry that I like…

http://www.nature.com/nchembio/journal/v8/n5/full/nchembio.925.html