Rearranging your face

It’s hard to go wrong with rearrangement chemistry. It’s really the most atom-economical chemistry that one can do, converting one molecule into another without the influence of anything aside from heat, light, and/or solvent. Sam Danishefsky delivers a nice two-for-one in his latest Organic Letters contribution on the reaction of isonitriles with carboxylic acids to generate what one might call “amide anhydrides” (see diagram). S.D. calls them, perhaps more clearly than I, “N-formyl amides.”
Using computational chemistry, Danishefsky rules out polar and radical intermediates for the reaction, demonstrating that two concerted (but not necessarily synchronous) processes must take place. In the first, the electron-rich carboxylic acid group approaches the electrophilic, carbene-esque carbon of the isonitrile. Simultaneously, the isonitrile carbon receives electron density from the carbonyl O and donates it to the acidic proton, which ultimately generates a mixed hydride intermediate…an “imine anhydride,” if you will. Not a rearrangement per se, but 100% atom economical nonetheless.

The second process is a bona fide rearrangement, as the COPh group migrates from oxygen to nitrogen and a second carbonyl (formyl) group forms. Calculations showed both concerted processes to be exothermic in the gas phase and in chloroform, while polar and radical mechanisms proved to have intermediate steps that were ridiculously endothermic. Organic chemistry takes a few torturous steps up the slippery slope that is computational chemistry!



  1. Good post, good coverage. Though, I have to throw the BS card on S.D.

    It’s been said (which is code for “in my personal opinion”) that relying on computational chemistry for mechanistic details is akin to relying on Mapquest directions to predict the traffic patterns in a road trip between Boston and Phoenix.

    I’m not sure S.D. can run a computational analysis and immediately declare, “BAM! It’s not a radical mechanism,” which I admit is a very interesting visual. Of course, this’ll spark the old utility of computational chemistry debate. I’d suggest running Hammett plots or drop in a radical clock. I guess what I’m arguing is that computational chemistry may not be the best, most tangible analytical route because it’s fundamentally a guess based on the hypothetical energetics of a reaction pathway.

    Think of it this way. I once saw an organic chemist and a computational chemist get into a heated debate about pentazole. The CC was convinced that the OC could make pentazole and it would be stable enough for handling/analysis/scale up because his numbers said so. The fight ended when the OC handed the CC his keys to the lab.

    How’s grad school going so far?

    P.S. are you on facebook?


  2. I start classes tomorrow. Go figure, my first “class” is the lecture I’m TA’ing for at 9am. But yeah, things are going great so far. I am on Facebook (entirely too much, I might add)…search for Michael Evans at UofI.

    Good Mapquest analogy there. I agree with you that computational chemistry can be sketchy from an absolute point of view, but relative to a lot of the other organic-computational stuff out there, I thought this was a relatively thorough study. There’s no substitute for good old-fashioned experimental work.


  3. I don’t know if this is necessarily a bad thing in regards to the computational work. I think that this is where the computational guys help makes things run a little more smoothly.

    However, where their bread-and-butter shouldn’t be is designing molecules for drugs. If you can’t even figure out how the kinase inhibitor is docking into the ATP pocket, you have very little business trying to come up with an idea as to what else should go in there.

    Once, one of the molecules that was put forth as a possible kinase inhibitor as generated by one of our computational guys was water. Another was hydrogen sulfide. And he didn’t seem to think anything of it.


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