Synthetic chemists have developed some nifty tricks to design catalysts that promote chemical transformations. Many of the corresponding reactions used to be close to impossible even a few years ago. But let’s just think about it one more time and address a question of whether or not we are better in catalysis than our biological colleagues. This is where it gets a little slippery. When we teach the foundations of catalysis to our first year students, we tell them that a catalyst lowers the transition state barrier of a reaction. It follows that, in order to design a catalyst for pretty much anything, one needs to think about ways to lower the transition state barrier. But let me ask you: how many times do you actually think about exactly what I just said? If you are a chemist who has been active in the area of catalysis, can you, in good faith, look at yourself in the mirror and say that you have designed a catalyst “ab initio” (I do not mean computation, I simply mean “from first principles”, as this latin term implies)? We draw intermediates, starting materials, and products. However, it is not easy to think and imagine what ironically appears to be the most important component in catalysis – the transition state. I seriously cannot think of one decent example. We think about substrate binding, we think about sterics, and we indirectly imply that we are “poking” at a transition state, but we never explicitly worry about that highest point on the energy landscape when we design catalysts. In this regard, enzyme chemists are way ahead of us. Think about the so-called transition state analog for a second. There is no such thing in small molecule catalysis, is there?

Earlier today, my good friend Professor Vy Dong was in town, to attend the PhD defense of her student Kevin Kou (sorry – Dr. Kou). Vy is now at the University of California, Irvine. Kevin gave a great talk, where he showed his mastery of catalyst design. I was particularly intrigued by some of the mechanistic details that suggested that the so-called trans effect was at play in his system. Below you can see the rationale for the observed catalytic efficiency: there is a nice electronic differentiation of the two phosphorus centers in the ligand, which is translated into the observed modulation of activity at the two sites where the action is taking place (I refer to the nucleophilically activated hydride and the electrophilically activated oxygen atom). Examples such as this offer a glimpse into the modern tools accessible to catalyst designers. I still note, though, that the techniques we have in our disposal do not (yet) allow us to design catalysts based on the definition we give in our first year chemistry classes. I am going to chuckle next time I tell my students “….a catalyst is a molecule that lowers the transition state barrier of a reaction...”.

Great job, Kevin!

http://pubs.acs.org/doi/pdf/10.1021/ja504296x