ChaosEngine
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Unconventional Cyanohydrin Synthesis
Cyanohydrins are useful precusors to alpha-hydroxy acids and amines via their oxidation and reduction respectively. Alpha-hydroxy acids can be further
oxidized to aldehydes, such as in the synthesis of Vanillin from Vanillyl mandelic acid. In short, Cyanohydrins are really useful functional groups.
Typically this functional group is synthesized via the nucleophilic addition of potassium cyanide with an aldehyde (i.e. the Cyanohydrin reaction).
What I am interested in, and hopefully you can point me in the right direction to finding, is a direct route from a nitrile starting material.
Unfortunately my Google searches and March's Advanced Chem. 6th ed. came up empty.
I figure this reaction must exist because similar reactions can be easily found; for instance, the alkylation of nitriles (such as in the synthesis of
Ritalin from phenylacetonitrile and its organobromide nucleophile). This supposedly occurs because nitriles are so electron withdrawing that the alpha
carbon behind the nitrile loses a hydrogen atom rather easily.
So if a halogen or halocarbon can attack this spot, why not a hydroxide nucleophile? Any ideas? I would really appreciate a link to somewhere I could
learn more.
Be gentle, it's my first post.
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Nicodem
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Thread Moved
24-9-2014 at 08:05 |
bbartlog
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I think you are confused about which carbon is getting attacked, or else you have your nitriles and cyanohydrins mixed up. Nucleophilic attack by OH-
on the carbon next to the nitrogen in something like phenylacetonitrile leads rapidly to hydrolysis and the formation of the carboxylic acid, see http://www.wikipremed.com/03_organicmechanisms.php?mch_code=... for some decent visuals.
In order to get a cyanohydrin, we would need to see a nucleophilic attack on the *next* carbon down the line (so that the CN moiety, the "cyano" in
"cyanohydrin", remained undisturbed). And so far as I can see, there's no reason a nucleophile would prefer that atom.
The less you bet, the more you lose when you win.
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ChaosEngine
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The Reaction Mechanism
Thanks bbartlog for trying to help, but I wasn't referring to nitrile hydrolysis but rather to the generation of a Nitrile anion, allowing attack one
carbon down from the nitrile as you accurately surmised I was trying to say. Wikipedia has a discussion of this sort of reaction here
Organic Reaction Volume XI by Rodger Adams calls this downstream carbon "an active methylene" group, with nitriles being somewhere in activity between
ketones and esters. Apparently a strong base will form a ketene-like arrangement which then allows the carbon downstream to be ionized and attacked by electrophiles:
N≡C-CH2-R + Base<sup>-</sup> ↔ <sup>-</sup>N=C=CH-R + Conjugate acid ↔ N≡C-C<sup>-</sup>H-R
This final "ionic resonance hydrid" is then liable to electrophilies... which is where I made my dumb mistake, hydroxide is a nucleophile not an
electrophile. Got so into what I hoped was true that I was blinded to see that.
Thanks again for trying to help though.
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ChaosEngine
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Error in my last post.
Organic Reactions Volume IX by Rodger Adams was the right source, not Volume 11.
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bbartlog
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Interesting. I hadn't heard of that. Looks sort of limited in scope though.
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