musings on music and life

October 12, 2016

Classics in Organic Chemistry, Part VII

Filed under: Classics in Organic Chemistry — sankirnam @ 6:04 pm

Ok, let’s keep the train rolling here…

This next topic is related to an ill-defined project I worked on early in my PhD, where I was investigating synthetic reactions related to isocyanide synthesis using TMSCN. One of the first places my advisor told me to look was at an intriguing 1982 JACS communication by Prof. Paul Gassman. To preface, it is well-established that the cyanide ion is ambident and can react from either the or the C position; the conditions employed can influence whether a nitrile or isonitrile will be obtained as the product. Gassman’s paper revisited this topic using epoxides as the electrophile, and he demonstrated that by intelligently choosing the right Lewis Acid (ZnI2 in this case), one can obtain β-isocyano alcohols as the product upon ring-opening with TMSCN (followed by desilylation with KF).


Now that I reflect about the background for this paper, it is actually not as serendipitous as I had used to think as a first/second year grad student. Gassman had previously published a few papers, including an Organic Syntheses procedure, for converting ketones to cyanohydrins; the conditions employed in the above reaction are pretty much identical, save for switching out the ketone for an epoxide.

The utility of this reaction lies in the fact that isocyanides are extremely valuable synthons – there are a family of extremely useful multicomponent reactions based on isocyanides, including the Ugi Reaction and the Passerini Reaction. These reactions succeed because the isocyanide is a rare example of a (1,1)-amphoteric molecule; the same atom (the R-carbon) establishes a connection with both the nucleophile (carboxylic acid) and electrophile (aldehyde or imine). The Ugi reaction was developed by Prof. Ivar Ugi (no surprise), and I discovered a cool fact about him when I happened to check out his book Isonitrile Chemistry from the library, and I saw that it said “Prof. Ivar Ugi, University of Southern California”. Apparently he was a faculty member at USC for a short time (around a year or two) in the early 70’s, before Prof. Olah came to USC.

In any case, the next question is, how does this isocyanation work? In my mind, the mechanism is pretty straightforward; it’s simply a variant of the Ritter reaction with TMSCN, avoiding the use of aqueous acids to prevent hydration of the intermediate nitrilium ion or isocyanide to an amide. This reaction has seen a slow stream of contributions – you can see the references for a list of papers that describe the conversion of various types of compounds to isocyanides or amides. Recently, Ryan Shenvi (Scripps) revisited this chemistry and somehow got a paper in Nature; I don’t understand why this was selected for publication, because as you can see here, there’s nothing truly original about it, and the conditions are not really practical:

A solution of trifluoroacetate 13 (32.0mg, 0.1 mmol) in TMSCN(0.1ml) was cooled to 0 ℃ and treated with a solution of anhydrous Sc(OTf)3 (1.5 mg, 0.003 mmol) in TMSCN (0.1 ml). […]”

The reaction is carried out neatusing TMSCN as the solvent! Not really scalable, and only for the truly desperate.

If you ask me, the cyanation reactions are more intriguing, because the mechanism is more unclear. Prof. Weber (who used to be at USC) demonstrated a complementary reaction to Gassman’s reaction above; when Et2AlCl is used as the Lewis acid instead of ZnI2nitriles are obtained instead. The mechanism invoked by Prof. Weber involves a little more hand-waving, however:


The first step involves the interconversion of TMSCN with its isocyano isomer. It’s not far-fetched on paper, and you can certainly defend this using the Curtin-Hammett principle. However, the literature support for this is rather weak; detailed spectroscopic studies of triorganosilyl cyanides gave no evidence for the presence of the isocyano form. However, another Japanese group studied this set of reactions with more Lewis Acids, and what seems apparent to me is that soft Lewis acids seem to promote formation of the isocyanide, whereas hard Lewis acids promote formation of the cyanide. Thus, two different mechanisms are at play depending on the Lewis acid involved. With reactions involving cyanide, the nitrogen preferentially attacks hard electrophiles (i.e. carbocations, giving the Ritter reactions, as well as other electron-deficient species). My proposal is that the first step would be a nitrilium ion formed from TMSCN attacking the aluminum atom; this species would be the active cyanating agent. If anyone is up for it, it may be possible to characterize this species; Melanie Sanford recently wrote about rapid-injection (RI)-NMR being used to characterize transient Cu(III) intermediates, and the same technique could possibly be used here. In contrast, other Lewis acids (ZnI2, Pd salts, etc.) activate the epoxide for nucleophilic ring-opening by attack of the nitrogen in TMSCN, which is drawn to the nascent carbocation by Coulombic forces.

do have some ideas for new synthetic reactions based on this chemistry, but that will have to be explored once I can get back in a lab.


  1. Gassman, P. G.; Guggenheim, T. L. J. Am. Chem. Soc. 1982104, 5849 
  2. Spessard, G. O.; Ritter, A. R.; Johnson, D. M.; Montgomery, A. M. Tetrahedron Lett. 198324, 655 (This paper was published independently and at the same time as Gassman’s paper above, and describes the same results)
  3. Gassman, P. G.; Talley, J. J. Org. Synth. 198160, 14  (Gassman’s 1981 prep for converting aldehydes/ketones to cyanohydrins with TMSCN)
  4. Okada, I.; Kitano, Y. Synthesis 201124, 3997 (Refs. 3-9 cover converting various functional groups to isocyanides)
  5. Kitano, Y; Chiba, K.; Tada, M. Tetrahedron Lett. 199839, 1911
  6. Kitano, Y.; Chiba, K. Tada, M. Synthesis20013, 437
  7. Kitano, Y.; Chiba, K. Tada, M. Synlett19993, 288
  8. Kitano, Y.; Manoda, T.; Miura, T.; Chiba, K.; Tada, M. Synthesis 20063, 405
  9. Pronin, S. V.; Reiher, C. A.; Shenvi, R. A. Nature 2013501, 195
  10. Mullis, J. C.; Weber, W. P. J. Org. Chem. 1982 47, 2873 (Weber’s conditions for the ring-opening of epoxides and oxetanes with TMSCN + Et2AlCl)
  11. Seckar, J. A.; Thayer, J. S. Inorg. Chem. 1976 15, 501 (Detailed spectroscopic study on the interconversion of the iso- and normal forms of triorganosilyl cyanides)
  12. Hickman, A. J.; Sanford, M. S. Nature2012484, 177 (Review in which various methods for characterizing transient high-valent metal intermediates are discussed, including RI-NMR)

This is by no means an exhaustive list; I have many more papers with me on this topic. If you want them, let me know.

Finally, I have to include this link to Prof. Andrei Yudin’s blog, which got this whole discussion started in my mind.



  1. The alcohol (ester) inversion paper was submitted to Nature because contact ion pair inversion of unstabilized carbenium ions with high stereoselectivity is challenging and has some, but relatively little, precedent. The paper appeared in Nature because the referees and editor agreed that it was significant. In particular, the influence of leaving group halogenation on stereoselectivity was interesting since it might imply an alteration in rate of diffusion away from the cation. Because the reaction is intermolecular (both the leaving group and the nucleophile), balancing the rate of anion diffusion versus nucleophile attack is very hard – that’s why most SN1 reactions are racemizing. In contrast, epoxide openings, for example, can be concerted not stepwise (e.g. JACS 1998 3526). Since the reaction simplifies the synthesis of the marine isonitrile class, it has also found some utility.
    While it would have made a nice JACS paper, I thought it might be of interest to a broader audience.
    Hope this helps answer your questions. If you have more questions, I would be happy to answer them by email.

    Comment by Ryan Shenvi — October 14, 2016 @ 9:41 am

    • Thank you Prof. Shenvi for the comment! I do agree with your first statement, and this then leads into what would be some very nice studies in pure physical organic chemistry in order to determine the effect of the medium on the reaction and hopefully move away from having to use TMSCN as the solvent. While antiquated, studying this reaction using Winstein-Grunwald kinetics can elucidate the ionizing ability of the medium (TMSCN) and hopefully substitute another solvent with similar properties.
      Of course, the kicker is that you might still need a large excess of TMSCN since you’re operating in that regime in between the SN1 and SN2 reactions – there’s substantial carbocation character in the transition state, and you’re making a contact ion pair, which needs to be broken.

      Comment by sankirnam — October 14, 2016 @ 10:21 am

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