Sorry for the lack of clues this week. I was overcome by the joy of an extended weekend, and by the time A Retrosynthetic Life floated through my mind it was a little late for clues. If you were desperate though, my colleague introduced me to a new way of cheating the Mega Chemist Challenge – it turns out you can past images into Google searches – I had no idea. Seems like a little too much work to me though…..
This weeks Mega Chemist was Professor Daniel J. Weix from the University of Rochestester, NY. Weix obviously knew he would feature on the Mega Chemist Challenge and as a consequence set out to make my life as difficult as possible by not having a personal profile on his website. As a result, the following has been cobbled together from numerous sources and therefore may be a little prone to errors.
Weix completed his PhD under the supervision of Prof. Johnathan Ellman (of Ellman’s auxillary fame) at the University of California, Berkeley, in 2005. Wiex’s first paper was actually working on an improved and scalable synthesis of Ellman’s auxiliary (DOI: 10.1021/ol034254b). Weix then scored a couple of more JACS papers with Ellman before moving to the Hartwig group at Yale, working on Iridum catalysed allylations. Weix followed Hartwig to Illinois to complete his post-doctoral work before taking a faculty position at Rochester in 2010.
This weeks papers are Weix’s recent JACS Article (DOI 10.1021/ja301769r) on the nickel catalysed reductive cross coupling of aryl halides and alkyl halides, the follow-up to his first independent research paper (JACS DOI 10.1021/ja9093956) paper published in 2010.
In contrast to traditional cross-coupling methods (Negishi, Suzuki, Stille, Kumada etc.) that couple a nucleophilic carbon (C delta +) and electrophilic carbon (C delta -), Weix couples two electrophilic carbon atoms directly, avoiding the formation stoichiometric organometallic species.
Avoiding the formation stoichiometric organometallic intermediates has allowed Weix to identify reaction conditions that require no effort to exclude air or water – reactions are performed in ‘wet’ flasks under an atmosphere of air – which should float the boat of the industrial chemists amongst you. The mild conditions and avoidance of often very basic organometallic intermediates means a very high functional group tolerance and allows for substrates prone to elimination or with acidic protons.
In Weix’s initial communication he identifies coupling conditions that work well for Ar-I with Alkyl-I, though less successfully with bromides.
I found the 10.7 mol% of catalyst very amusing – what happens if you deviate from this I am not sure, but rounding to the nearest mg shouldn’t do that much damage! The functional group tolerance is is great and far exceeds that of traditional coupling methods – lots of electrophilic centres, acidic protons, and even a Boronic ester come through unscathed – making subsequent derivatisation very facile indeed.
The follow-up paper goes about setting to rest the substrate limitations of the initial publication. New reaction conditions gave increased yields for aryl- and alkylbromides substrates, introduced the reductive coupling of vinyl-bromides and demonstrated the reaction of the much more widely available arylchlorides. Weix also beautifully demonstrated the complimentary nature of his reductive couplings to conventional cross couplings carrying silanols, boronic esters, stannanes and pseudohalides (OTs, OTf) through the reaction conditions with synthetically useful yield.
There are more added bonuses to be found if you delve into this paper yourself – mechanistic studies, Hammet plots, a look at ligand affects, inspection of the role of each reagent etc. are all there for the taking. Studies on electron rich chlorides, and the coupling heterocycles and the like are ongoing.
These two papers provide a very useful alternative to traditional coupling techniques. No special handling techniques required, fairly cheap to run, and with a wide functional group tolerance – what more could you want?
……….well, I would trade in DMPU for a whole host of solvents – but then I just want it all!
Professor Weix is definitely one to keep an eye out for.
This weeks diagrams have been unceremoniously lifted from Weix’s papers – (DOI 10.1021/ja301769r) (DOI 10.1021/ja9093956) – and copyright is most definitely his.
A Retrosynthetic Life 