Look Ma’, No Leaving Group!

Anxionnat, B.; Pardo†, D. G.; Ricci, G.; Cossy, J. Monoalkylation of Acetonitrile by Primary Alcohols Catalyzed by Iridium Complexes Org. Lett. ASAP July 6, 2011

So after a long hiatus from blogging, I finally got time to catch up on the lit. Let me tell you, summer is the best time for a (chemistry) graduate student. Not only can you get a lot of work done due to being free from classes and teaching, but you can do all sorts of other fun non-chemistry things like softball. The UConn chemistry department team is really doing well this year and I’m proud to be a part of the team. As far as research goes, we’ve made some really great breakthroughs recently and I have begun preparing the SI (UGH!) and manuscript for our work with Dr. Tilley. I also have an article of my own coming out shortly in Tetrahedron Letters which I’ll be sure to post a link to. I’m also really proud of the undergrads that are working with me. One of them came in with minimal organic training in June and now I can just tell her to run a column and she does so without help. Our other undergrad is tackling an entire methodology project by herself and doing a bang up job of it. So life in lab is pretty good (for now…)

One of most beautiful aspects of organic chemistry (at least to me) is the skill set required to succeed. Not only do you have to be good at your standard laboratory practices (calculations, safety, etc) but you also need to be a master of a plethora of spectroscopic tools. Moreover, you are always learning whether it be new reactions or new lab skills. For example, until this past week, I had never performed a “prep plate” (preparative TLC). I had seen it done both in my time at Columbia and at UConn but I had never had a need to do one before this week. I loved it. It was even easier than a column and just as selective. One of my fifth year friends taught me how to do one and it worked well! So the question for the week is what do you love most about organic chemistry or chemistry in general?
So this week’s article comes from, surprise surprise, Organic Letters. When I spotted this article, I didn’t even scan the author names, I went right to the article. Later I realized that the author was none other than an excellent organic chemist from France, Janine Cossy. This isn’t the first time that a Cossy article is appearing on my blog. She puts out some excellent work and this article is no exception.
The article begins by describing a particular problem with acetonitrile when alkylation is attempted. Namely, acetonitrile always seems to undergo multiple alkylations instead of simple monoalkylation in your standard basic deprotonation and alkyl halide addition. Alternatively, a copper-mediated coupling using cyanomethylcopper (CuMeCN) could achieve monoalkylation of allyl bromide to acetonitrile. But the article points out that all these methods rely on “toxic” alkyl halides (which is a stretch in my opinion, they aren’t that bad if you are careful). Recently alkylation of nitriles(albeit activated ones in which the group coming off nitrile at the alpha position is anion-stabilizing), using alcohols has been accomplished via transition metal catalysis. This is touted as a substantially more environmentally-friendly means of alkylation due to the only by-product being water. Additionally, the starting materials are orders of magnitude less toxic. Seeking to eliminate limitation that only activated nitriles can be used, Cossy and coworkers looked into the possibility of using acetonitrile as a model nonactivated nitrile and alcohol to perform monoalkylation.
Initially they chose a very cheap alcohol, benzyl alcohol, to screen conditions. The iridium catalyst was the first stepping stone, ultimately finding [IrcodCl]2 was the best catalyst for their reaction. However, the reaction was unacceptably slow (roughly 3 days). Hence they sped it up by heating it via microwave irradiation. They found that, if one loading of iridium was used, acceptable conversion could be obtained after nine hours. However, Cossy did something interesting here. Instead of loading all of the iridium, it was loaded in two portion. Not only did this up the conversion, it cut the reaction to 1 hour! This dramatic improvement likely relates to catalyst lifetime in the reaction conditions.

With the conditions for alkylation established, they sought to see how well this reaction performed when other (more complicated) alcohols were used. They didn’t just limit themselves to various benzyl alcohols (i.e. just changing the substitution pattern on the phenyl ring) they looked at various heterocycles and even alkyl alcohols such as heptanol. Interestingly, alkyl alcohols required much longer reaction times (12 hrs) but yield were reasonable. In general yield were good usually in the mid 70 percent range. But wait, there’s more!

Due to the number of groups studying these sorts of reactions, several mechanisms have been tossed around. Cossy decided to modify one of the more popular ones to reflect her reaction:

It’s somewhat complex but nonetheless amazing. First, you have your standard acid-base reaction creating a cesium alkoxide. That alkoxide then coordinates to the iridium and undergoes an oxidation, creating a metal hydride species and an aldehyde. The aldehyde then reacts with the acetonitrile in a condensation reaction to yield a vinyl nitrile. This olefinic species is quickly reduced by the iridium hydride to yield the product and regenerate the catalyst. Overall, this was an excellent piece of work by Cossy and coworkers. I look forward to follow up work on this reaction!


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