In London, one has the pleasures of attending occasional one day meetings at the Burlington House, home of the Royal Society of Chemistry. On November 5th this year, there was an excellent meeting on the topic of Challenges in Catalysis, and you can see the speakers and (some of) their slides here. One talk on the topic of Direct amide formation – the issues, the art, the industrial application by Dave Jackson caught my interest. He asked whether an amide could be formed directly from a carboxylic acid and an amine without the intervention of an explicit catalyst. The answer involved noting that the carboxylic acid was itself a catalyst in the process, and a full mechanistic exploration of this aspect can be found in an article published in collaboration with Andy Whiting’s group at Durham.[1] My after-thoughts in the pub centered around the recollection that I had written some blog posts about the reaction between hydroxylamine and propanone. Might there be any similarity between the two mechanisms?
That mechanism can be represented as above, which (as per the hydroxylamine mechanism) comprises three transition states and two intermediates. The original study[1] reported just the one TS1. Editing out the starting coordinates from the PDF-based supporting information (the process is not always easy) enabled an IRC (intrinsic reaction coordinate) for TS1 to be easily computed.[2]
This reveals that TS1 is not the complete story, there is still much of the reaction left to complete. The energy profile is charted (using the ωB97XD/6-311G(d,p/SCRF=p-xylene method) according to the scheme above as reactants ⇒ TS1 ⇒ Intermediate 1 ⇒ TS2 ⇒ Tetrahedral intermediate ⇒ TS3 ⇒ products. Computed properties for this more detailed pathway are transcluded here from the digital repository[3] and appear at the end of this post.
- TS1 yields what might be called a zwitterionic intermediate. However, this has a relatively small dipole moment (5.7D). Thus, against accepted wisdom, such apparently ionic intermediates CAN be involved in reactions occurring in non-polar solvents!
- TS2 is rather unexpected, involving synchronous proton transfer coupled to anomerically related C-OH bond rotation. This rotation changes the anomeric interactions with the adjacent substituents; in my experience I have never before seen a reaction mode quite like this one!
- TS3 collapses the tetrahedral intermediate by synchronous proton transfer and C-O bond cleavage, and is (in this model) the rate determining step. The free energy barrier corresponds to a half-life at 298K of about half an hour.
- The product is calculated as exoenergic with respect to reactants,; the reaction does drive to form an amide (and any catalysis of course will not influence that final outcome, only its kinetics).
If you read the original article[1] you will realise the above only scratches the surface of the many fascinating properties of this apparently very simple reaction. Thus, not addressed above is why amides are only formed in certain solvents (xylene for example) but not others. The solvent may have a specific role to play which is not modelled simply by its continuum dielectric or its boiling point. There is much else that could be said.
References
- H. Charville, D.A. Jackson, G. Hodges, A. Whiting, and M.R. Wilson, "The Uncatalyzed Direct Amide Formation Reaction – Mechanism Studies and the Key Role of Carboxylic Acid H‐Bonding", European Journal of Organic Chemistry, vol. 2011, pp. 5981-5990, 2011. https://doi.org/10.1002/ejoc.201100714
- H.S. Rzepa, "C21H21NO4", 2014. https://doi.org/10.14469/ch/74636
- H.S. Rzepa, "A computed mechanistic pathway for the formation of an amide from an acid and an amine in non-polar solution.", 2014. https://doi.org/10.6084/m9.figshare.1235300
