Sciencemadness Discussion Board

Nicotinamide dehydration

Pumukli - 6-1-2019 at 11:45

I tried to prepare nicotinonitrile (3-cyano-pyridine) recently but failed.

At first I tried simply distilling nicotinamide at ordinary pressure in the hope that at the high temperature of the distillation it would dehydrate and yield nicotinonitrile. No, it did not work. Something happened, I could smell that a small ammount of ammonia got released but not too much. And ammonia is a sign of hydrolysis rather than dehydration, so it is not a good sign anyway.

Then I tried mixing equimolar quantities of the amide and ZnCl2 and "distill" the mixture. Guess what!
No apparent reaction. The temperature of the sand bath went up to 425 Celsius (measured just under the bottom of the flask) but no reaction. At least not what I expected: I thought at least a few drops of the nitrile would distill off slowly, based on its b.p. being around 200 Celsius. (Work up is not finished, but I don't have high hopes.)

I tried this distillation method because it worked wonderfully on another aromatic amide and provided a nice ammount of the corresponding nitrile - and I could not go more OTC than this. :-) (Yes, I plan to do a write-up in the prepublication section on that successful reaction.)

I tried ZnCl2 because it works sometimes. And is also fairly OTC.
I'd rather not use the big gun phosphorpentoxide though. All I want is the nitrile, preferably starting from the amide, because the amide is OTC. :-)

Do anyone have a bright idea (besides the obvious P2O5) on this particular reaction? And please, not the other obvious amide - amine - Sandmeyer rxn with CuCN route! Too much steps and wasteful for such a simple target. I would like something more elegant, one-pot method! :-)

AvBaeyer - 6-1-2019 at 19:25

Beyond P2O5 you are pretty much out of options. Larock's "Comprehensive Organic Transformations" [amides to nitriles section] shows reagents such as thionyl chloride, tosyl chloride, various activated phosphorus compounds, and some acid chlorides such as phosgene and oxalyl chloride. An older review is referenced [Chem. Rev. v42, 189 (1948)] which may provide some insight into older chemistry.

Good luck.


clearly_not_atara - 6-1-2019 at 19:45

There are some cases where amide -> nitrile happens with excess MeCN and a transition metal catalyst, usually palladium. Basically Pd catalyses both hydration and dehydration of nitriles and MeCN acts as a water acceptor.

MeCN itself can be prepared by refluxing acetamide over alumina; it usually escapes the reflux due to its much lower boiling point.

[Edited on 7-1-2019 by clearly_not_atara]

UC235 - 6-1-2019 at 21:21

Try which is a paper using ammonium sulfamate. They don't discuss nicotamides, whose chemistry is not necessarily that of benzamides, but the conversion works very well on benzamides. Possibly it will be trapped in the reaction mixture as a salt, though.

Dr.Bob - 7-1-2019 at 10:17

A simple google search brought up a few ways:

T3P can also dehydrate amides to nitriles in some cases,

Pumukli - 7-1-2019 at 11:58

Thank you for the tips!

As I started this thread I would like to append another reference here too. I found this ref today so here it goes:

Kekule (yes, the benzene guy) mentions in a Berichte article (Deut. Chem. Ges. Ber. VI, 110-114) that Letts (the nitrile synthesis guy) found in an experiment that "when benzamide distilled with potassium-benzoate yields benzonitrile." Using ammonium-benzoate instead of the potassium salt is ineffective.

The Letts-synthesis is also interesting: two moles of benzoic acid distilled with one mole of KSCN "scarcely anything but benzonitrile is formed".

These methods seem to be also amateur-friendly.

Boffis - 15-6-2021 at 01:28

Hi Pumukli, did you ever try this again with any of the alternative suggestions?

Pumukli - 11-8-2021 at 05:32

Hi. I tried the ammonium-sulfamate method. It gave some nitrile, yes.