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Analytical Chemistry

Organometallic Oddities

Synthetic organic chemists spend a lot of time using organometallic coupling reactions, because they can be such great ways to make carbon-carbon (and carbon-heteroatom) bonds. And that’s the currency of the realm: do you want to build up larger molecules from smaller precursors in a controlled fashion? You’re going to have to make bonds when and where you want them to form.

But those organometallic reagents are tricky beasts, whether catalytic or stoichiometric. Just understanding what the actual structures of some of them are has occupied people for years on end, because a given system can adopt a whole range of structures – and thus form completely different reagents – depending on solvent, temperature, counterions, concentration, added salts, stoichiometry, order of addition, and so on. To make matters more interesting, some of the actual reactive species are formed only in small, transient amounts, which makes proving their existence even more fraught.

Here’s a recent example. One of the many things you can do with Grignard reagents, a classic organometallic species if ever there was, is to couple them onto vinyl bromides and haloalkenes in general, with iron catalysis. It turns out, though, that the yields for this are far better when the reaction is run in N-methylpyrrolidone (NMP) than in any other solvent (an effect discovered in 1998, over twenty years since the reaction was first reported). That one’s not exactly the first choice for this sort of thing, so it’s interesting to know that it works so well. But why?

It had already been figured out that if you take methylmagnesium bromide and an iron(III) salt in THF, that a new species forms: magnesium(penta-THF) chloride cation and a penta-iron-octa-methyl cluster anion. That was thought to be the active methyl-coupling reagent, but the yields are never that great in THF (which is probably what led to the solvent screening work that uncovered the NMP effect). Now we finally know what that works. In that new solvent, a completely different complex salt forms: magnesium hexa-NMP cation (+2 charge), with two trimethyliron anions.

Those irons are exceptionally reactive; you really don’t see alkyliron species without other stabilizing ligands on them very often, but for some reason you get them here. NMP is a pretty highly coordinating solvent, so in the absence of experimental evidence you’d figure that the solvent is in there on both the iron and magnesium centers. But it turns out that it’s just the latter (as suggested by magnetic circular dichroism spectra in solution, and Mössbauer spectroscopy along with X-ray diffraction on isolated crystals of the complex. Mössbauer is not the first technique you reach for (since you need an appropriate gamma-ray source) but it’s extremely sensitive to several different kinds of changes that affect the energy levels of sensitive nuclei, which are mostly metals.

So now we know, and another piece of knowledge gets added to the organometallic pile, and another idea for future reagents and reactions gets queued up. Eventually we’ll understand this stuff.

11 comments on “Organometallic Oddities”

  1. Mad Chemist says:

    I wonder how the reaction would work if one were to start with an iron (II) salt, instead of an iron (III). Given that the iron gets reduced in the course of the reaction, it’s likely that the Grignard is reducing it. So I would guess that one might be able to run the reaction with a lower excess of the Grignard if an iron (II) salt were used. Still, knowing how strange synthesis can be, that idea might not work at all.

    1. A Nonny Mouse says:

      There is an extensive review from 2014 in Organic Reactions vol 83

  2. Chester says:

    If chelation of the magnesium cation is driving the formation of the active species, I wonder if crown ethers or cryptands could be used in place of a large excess of NMP.

  3. CMCguy says:

    Do you really think we can ever advance to a stage to completely understand organometallics? Although perhaps may be considered less complex than biologic systems even with increases in elaborate characterizations and tools along with solid principles of the physical chemical actions our comprehension may only take us so far. It brings to mind anecdotes of reactions that work or do not work based minute traces of contaminants that perturb the system either in positive or negative, often explained but not understood. Probably like many things in chemistry we do not really know everything but can seek utility in a controlled and systematic manner to exploit in useful way.

  4. milkshake says:

    When trying a cross-coupling of this kind, my first go would be with CuCN, then Pd, saving Fe, Co, Ni for the last. Working up NMP+Grignard combo is no fun especially on process scale (even though NMP can be washed out from MTBE layer completely with LiCl aqueous solution).

    What I dislike about Fe, Co, Ni catalyzed cross-couplings is the ease of entering free radical manifold as demonstrated recently for example by the Baran group

    1. MB says:

      Milkshake please write a book full of practical advice for people.

    2. DRP says:

      Unless you want to couple an sp3 carbon, in which case radical manifolds are the reason it works so much better than Pd

  5. CMCguy says:

    BTW do you have the 1998 citation for NMP benefit in Grignard reactions? I recall learning and using NMP, albeit as a minor additive not alternate solvent, in processes during the early to mid 90’s. I can not recall whom provided that advise but may have been Henry Rapoport who was a excellent consultant for such gems, often buried in obscure citations that I trust the search tools now-a-days would be able to locate

    1. Derek Lowe says:

      That’s G. Cahiez, H. Avedissian, Synthesis 1998, 1199 – 1205

  6. David Edwards says:

    While TIWWW is still dormant, this is what I come here for. Another of Derek’s surprise looks at what we thought we knew, but didn’t.

    It probably says rather a lot about me, that I spent no less than four hours chasing links on Grignard reagents and Mössbauer spectroscopy after reading this, just so that I understood in something resembling proper detail, what’s going on here. Learning about Mössbauer spectroscopy on its own was a fun roller coaster ride for the grey cells, and another of those pieces of ingenuity that I wish I’d learned more about a long time ago.

    1. Anonymous says:

      Rudolf Mossbauer discovered the M Effect while still a student doing his PhD research. It was he who observed and explained the phenomenon, designed and executed experiments and published the work as sole author (Z. fur Physik A, 1958) before defending his thesis. He won the Nobel Prize in 1961 (only 3 years later, short for a Nobel). His research supervisor did not try to take (read as “steal”) the credit; he did not try to discredit or suppress M’s work. As if that could happen today.

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