The demons of entropy in cross-coupling reactions

I have been absent for some time. Last Friday I gave a talk at Xerox in Mississauga and, ever since Sunday night, I have been at the University of Rochester as their Chambers Memorial Lecturer for 2015. This visit has given me an opportunity to learn about a ton of new chemistry and, thus far, my visit has been tremendously satisfying. Because I was asked to give three different lectures, I anticipated that this experience would be more intimidating than my typical visit to a school. At the end, I think I was able to find my groove and prepared three different talks.

I have followed the work of Daniel Weix for some time and was keen to learn about his lab’s recent advance published in Nature. This paper is interesting for several reasons. First of all, it describes a solution to the problem of making unsymmetrical biaryls from two different electrophiles, which runs counter to the conventional way of joining a nucleophilic species (e.g. a boronate) and an electrophilic one (e.g. an aryl halide). The solution offered by the Weix lab has come in the form of a multimetallic system comprising nickel and palladium. While the idea might seem transparent on paper, the devil is in the details and the realization of unsymmetrical coupling has been elusive and took years to develop. Apart from some really interesting scope study (just look at compound 19), there are notable mechanistic lessons in this paper. In my view, the most important of them relates to confronting entropic factors (in other words, reducing the possible amount of products you might imagine here). It turns out that the palladium intermediate formed does not react with itself, is stable, and accumulates in solution. On the other hand, the nickel intermediate is “hot” and transient. It has capacity to react with itself or with the aforementioned palladium complex. Understanding the relative concentrations of these species in solution holds the key to attaining high selectivity of this reaction. When Daniel described this system to me, I was also left with the impression that potassium fluoride played a very important accelerating role in this imaginative catalytic process.

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http://www.nature.com/nature/journal/v524/n7566/full/nature14676.html

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