{"id":13047,"date":"2014-11-12T08:42:27","date_gmt":"2014-11-12T08:42:27","guid":{"rendered":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/?p=13047"},"modified":"2014-11-12T08:42:27","modified_gmt":"2014-11-12T08:42:27","slug":"a-computed-mechanistic-pathway-for-the-formation-of-an-amide-from-an-acid-and-an-amine-in-non-polar-solution","status":"publish","type":"post","link":"https:\/\/www.rzepa.net\/blog\/?p=13047","title":{"rendered":"A computed mechanistic pathway for the formation of an amide from an acid and an amine in non-polar solution."},"content":{"rendered":"
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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\u00a0meeting on the topic of Challenges in Catalysis<\/em>,\u00a0<\/em>and you can see the speakers and (some of) their slides here<\/a>. One talk on the topic of\u00a0Direct amide formation – the issues, the art, the industrial application<\/b><\/a> 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\u00a0that 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]<\/a><\/span> My after-thoughts in the pub centered around the recollection that I had written some blog posts about\u00a0the reaction between hydroxylamine and propanone<\/a>. Might there be any\u00a0similarity between the two mechanisms?<\/p>\n

\"amide\"<\/a><\/p>\n

That mechanism can be represented as above, which (as per the hydroxylamine mechanism) comprises three transition states and two intermediates. The original study[1]<\/a><\/span> reported just the one\u00a0TS1<\/strong>. Editing out the\u00a0starting coordinates from the PDF-based supporting information (the process is not always easy<\/a>) enabled an\u00a0IRC (intrinsic reaction coordinate) for TS1<\/strong> to be easily computed.[2]<\/a><\/span><\/p>\n

\"origa\"<\/a><\/p>\n

\"origa\"<\/a>
\nThis reveals that TS1<\/strong> is not the complete story, there is still much of the reaction left to complete. The energy profile is charted (using the \u03c9B97XD\/6-311G(d,p\/SCRF=p-xylene method) according to the scheme above as reactants<\/strong> \u21d2 TS1<\/strong> \u21d2 Intermediate 1<\/strong> \u21d2 TS2<\/strong> \u21d2 Tetrahedral intermediate<\/strong> \u21d2 TS3<\/strong> \u21d2 products<\/strong>. Computed properties for this\u00a0more detailed pathway are transcluded here<\/a>\u00a0from the digital repository[3]<\/a><\/span> and appear at the end of this post.<\/p>\n

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  1. TS1<\/strong> 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<\/em> be involved in reactions occurring in non-polar solvents!<\/li>\n
  2. TS2<\/strong> 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\u00a0I have never before seen a reaction mode quite like this one!<\/li>\n
  3. TS3<\/strong> collapses the tetrahedral intermediate by synchronous proton transfer and C-O bond cleavage, and is (in this model) the rate determining step. \u00a0The free energy barrier corresponds to a half-life at 298K of about half an hour.<\/li>\n
  4. The product is calculated as exoenergic<\/strong> 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).<\/li>\n<\/ol>\n

    If you read the original article[1]<\/a><\/span> you will realise the above only scratches the surface of\u00a0the 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\u00a0not 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.<\/p>\n

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