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A Catalytic Dess-Martin?

I have not tried this new reaction out, but it could be a real convenience, in several ways, for synthetic organic chemists. The authors, from Texas A&M, had previously reported an air-driven catalytic route to iodine (III) oxidants, and now they extend that work all the way up to iodine (V). The key is generation of an iodine (III) species that then disproportionates, sending some of it back down and some of it up to the +5 oxidation state, with the whole process driven by stirring in air. That may not make your pulse run any faster if you’re not an organic chemist, but many bench chemists will read that and say “Hey, does this mean that they have a catalytic Dess-Martin reagent?”

Well, they might. A whole range of oxidations are reported, and the reactions are characteristic of what you’d get with the actual Dess-Martin. Unfortunately, I don’t see the transformation I always used to break out that reagent for – trifluoromethyl secondary alcohol to trifluoromethyl ketone. You can tell that I worked on protease inhibitors for a while – that group is a classic serine protease inhibitor warhead, since the electrophilic ketone would rather be a ketal or hemiketal, all things considered, and if you stick it down into an active site it’ll tie up the serine residue for quite a while. At any rate, Dess-Martin is in many cases the sovereign remedy for that oxidation, and it would be good to see if this system can do it as well.

Why does one care? Well, the Dess-Martin reagent is quite useful (it’ll do oxidations on sensitive frameworks that other reagents will tear up), but it’s a problematic beast. It has gone in and out of commercial availability over the years, because an intermediate in its preparation is most definitely explosive if mishandled. I’ve made the stuff myself (back when I was making those trifluoromethyl ketones), and I did not enjoy the process. Particularly since (at that stage in the development of the synthetic route to the reagent) the last step tended to just up and fail on you, which meant that you had passed through the Valley of the Explosive Intermediate only to have all your effort for naught. I went through that, too. Improved routes have been developed, but no one does even those cheerfully.

And I have seen an explosion during the preparation, some years ago in a nearby lab, and it’s a very fortunate thing that no one was injured. There was plenty of shattered Pyrex and plenty of smoke hanging in the air, for sure. The problem is that when people make the stuff, they generally make a good-sized batch so they never have to do it again, so the bang is correspondingly bigger when things go wrong. Mind you, I had a 100g commercial bottle of the stuff right next door in my freezer, so these guys didn’t even have to be making the reagent in the first place: always check the compound inventory system, folks.

That happens less often these days. The new routes really are better, which has allowed the reagent to become an article of commerce again (I see that Sigma-Aldrich lists up to 250g bottles, albeit for nearly $2000) but the fact remains that the final reagent itself is also a rather energetic material. It would definitely be nicer if it appeared only catalytically, a statement that probably applies to all these high-oxidation-state iodine reagents. And if you can run that catalytic cycle off ambient oxygen, so much the better. I hope that this paper does the trick!

 

19 comments on “A Catalytic Dess-Martin?”

  1. Sam B says:

    Buy from AK Sci! Much cheaper

    1. David Gooden says:

      EVERYTHING from AKSCi is cheaper!! they are my go to vendor

  2. Cato says:

    To me this is a pretty exciting advance for other applications of hypervalent iodines–namely organocatalytic chiral hypervalent iodine promoted reactions. The problem has been that typically rather strong oxidants have been required to generate the I+3 or I+5 (e.g., Cl2, peroxides), with probably some of the mildest conditions I have seen as mCPBA/HFIP/RT used in chemistry by several Japanese groups (Kita and others). Of course this excludes a lot of catalytic processes if you want to go through the chiral catalyst and not through some background non-specific oxidation. The low temperature and use of aprotic solvent is pretty nice for this type of application–if this is general I expect to see some new organocatalytic chemistry coming out soon!

      1. Cato says:

        Oxone at 70 oC is not a mild system for chiral organocatalysis….

  3. A Nonny Mouse says:

    Can similarly use N-hydroxyphthalimide/Co(AcAc) systems or with iodobenzene/mCPBA.

    Always intended to try, but never go round to it.

  4. Aleksei Besogonov says:

    That’s… a lot of oxygen.

  5. Okemist says:

    Derek, I would argue that the chemist near the explosion was injured with burns; and his labmate with the pacemaker was close to cardiac arrest. But it could certainly have been worse.

    1. Derek Lowe says:

      True. I was thinking more in terms of tourniquets, etc.

  6. milkshake says:

    this method is not very practical, and it is ugly from the safety point of view. 1. Many of their iodinanes work at +70C in nitromethane. Thank you very much. As for use of O2 to oxidize iodobenzene in the presence of acetaldehyde or propionaldehyde (catalyzed with Co(II)) – they are just generating percetic acid in situ. That too I will give pass, on large scale. Obviously the catalytic method using 15mol% of iodobenzene (+ Co + aldehyde) cannot be used on sensitive substrates with C=C

    You are much better off making your own periodnane by preparing IBX intermediate with Oxone, and Acetylating it with Ac2O to periodnane in the presence of TsOH as described in the Ireland procedure. Addition of TsOh greatly improves reliability of preparation of Dess-Martin, and lowers the reaction temperature.

    1. Longbin Liu says:

      Glad you likes the TsOH prep.

    2. Tourettes of Chemistry says:

      For all the reasons stated in the initial post this remains very interesting.

      Suggested priority for further development if the ‘fall-off-the-cliff’ thermodynamics can be repeatedly captured in a catalytic cycle (???):

      http://orgsyn.org/demo.aspx?prep=v88p0168

      Not exactly Dess-Martin but it certainly has much precedent from that known work. Of course, some other options for the same chemistry overall are out there yet have their own quirks.

  7. Pi tips, take us out says:

    Hey Derry, you and your activist ilk also involved in taking down verma? Or was he spared because he is a PI? Just postdocs loose their jobs, huh, for allegations or whatnot?

    1. anon says:

      Who is Derry, what is verma, and WTF is Pi talking about?

  8. Pi, in for it says:

    U activists types need to apply the same scrutiny to that desire to weed out “fringe” pseudoscience as you do to hurting your fellow scientists ( calling lawyers, whatnot) dairy, you know what im talking bout.

  9. Ru barf says:

    We questioned whether visible light could be tolerated… 🔦

  10. David Edwards says:

    I’ve read that Dess-Martin Periodinane is itself somewhat problematic in the explosions department, though not as tricky as IBX. DMP was determined here to lack the impact sensitivity of IBX, but to retain the tendency to decompose explosively on heating, so it’s just as well that the oxone/TsOH preparation route works a good way below decomposition temp, and that DMP performs its oxidation tricks under mild conditions. So any synthesis route that achieves the same results as DMP will definitely be welcome if it doesn’t involve large quantities of unstable oxidising agents in the reaction vessel.

    Though the thought occurs to me, that DMP is one of those reagents that should be looked at in a flow chemistry situation – namely, find a way of generating it reliably in a flow chemistry setup, then consuming it in the desired oxidation reaction as fast as it’s made. The explosive decomposition problem will be minimised if there’s only 1 or 2 millimoles of actual DMP in existence at any one time in the setup. Perhaps there’s someone already working on this?

    When I finally sat down and engaged the grey cells, I did think that having all those oxygen atoms in close proximity to a hypervalent iodine was a recipe for, shall we say, interesting things to happen in the wrong circumstances … possibly involving Derek’s patented “side order of kaboom”.

  11. Jay says:

    Is IBX actually more explosive than DMP? My impression was that was largely a myth, that in pure form both should be handled carefully, though especially in the older preps IBX was more likely to be contaminated with crap that made it less stable.

    The one time I had to use it, I just used the IBX in a THF/water suspension, rather than making the DMP. I suppose if I’d wanted to store the oxidant, I probably would have made it into the supposedly more stable DMP (and of course it’s low solubility is the real reason to turn it into DMP, though in my case my molecule was polar enough to work ok in the water/THF).

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