On copper, click chemistry, and our craft

I am still in Pyatigorsk. Valery Fokin, one of the founders of click chemistry gave a talk earlier today. In it, Valery shared the results of a mechanistic investigation aimed at understanding the inner workings of the copper-catalyzed [3+2] cycloaddition between azides and alkynes, one of the workhorses of bioorthogonal chemistry. The Cliff notes summary of his study is shown below. We need to think about two distinctly different roles of copper here. One is to make the terminal copper acetylide, whereas the other one – to recruit the azide. Together, the two conspire to fuse the 5-membered ring.


Valery’s recent Science paper is the account you may want to look at:


The methodology used to collect some very complex kinetic data is what interested me the most. Microcalorimetry was used, which is a method that enables one to follow step-wise changes in enthalpy as the reaction progresses. Donna Blackmond has done some nice foundational work in this area.

At the end of the day we retreated to the hotel and had some wine and whiskey with Valery. It was great to see my dad join the conversation. He is a physicist by training and some of the comments he made were thought-provoking. For instance, he noted that it is just astounding how many different, substrate-dependent reaction conditions we deal with. For him seeing all our tricks involving some random combinations of additives is mind-boggling. He thinks that the fact that no one has systematized and created a fractal-based approach to handling complexity in chemistry is just insane. Indeed, chemistry is odd in that regard and appears to be so much more empirical than pretty much any other branch of science. This is why comparing it to what happened to quantum mechanics during the last century (when Einstein just saw it all and went after his unifying theories) is a stretch. But who knows. Maybe there will be someone like Mendeleev in the future who will make sense of it all and will create some multi-dimensional system for reactions. I doubt it, though. I think chemistry will remain more of a witch’s brew…

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