Nitrile Chemistry

The Importance of Nitriles in Chemistry

Research supported by an EU Marie Curie International Incoming Fellowship

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A nitrile is a compound that contains a –CN (cyano) functional group with a carbon–nitrogen triple bond. The simplest organic nitrile is CH3–CN and is called acetonitrile, which is a good solvent for organic reactions. Nitriles are very useful in daily life. For example, methyl cyanoacrylate is used in super glue. The cyanoacrylate monomer (liquid form) is sensitive to humidity (found in air and on the surface of the bonding substrates) and forms polymer within seconds at room temperature. Another prevalent nitrile polymer is nitrile rubber, which is a copolymer of acrylonitrile and butadiene. Nitrile rubber is resistant to oils, so it is used widely in latex-free gloves, hoses that transport oils, seals and various moulded goods.


Superglue Nitrile glove


Structurally diverse nitrile-containing compounds are present in many medicinal drugs. At present more than 30 nitrile-containing pharmaceuticals are prescribed for a diverse array of medicinal indications. Nitrile-containing compounds such as saxaglipitin (trade name onglyza) have been developed for treating diabetes. Another very important drug called cimetidine (trade name tagamet), is widely used for heartburn and peptic ulcers. Blockbuster drug anastrazole (trade name arimidex), is used for the treatment of breast cancer after surgery. Recently, anastrazole has entered the WHO list of most essential drugs. Other drugs (such as clopidogrel, trade name plavix, which is used to inhibit blood clots in coronary artery disease) can be prepared from nitrile compounds.


Nitrile drugs


The nitrile (–CN) group is a useful functional group in organic compounds. Not only are these compounds important in their own right, but also they are valuable as a way to prepare many different classes of organic molecules and bioactive compounds. Nitriles can be converted easily to carboxylic acids, amides, amines, aldehydes, ketones, tetrazoles, and other groups. They have therefore found widespread use in organic synthesis.


Nitrile rxns

Another benefit of nitrile compounds arises from the ease of their deprotonation and electrophilic quench adjacent to the nitrile group. It is possible to remove the proton next to the nitrile with a base and then form a new bond at this position by adding an electrophile. This chemistry gives access to different substituted nitriles. The nitrile functional group is small and the anion formed after deprotonation is reactive, so even quaternary substituted products can be formed readily.

A drawback of this chemistry is that the deprotonation typically gives a metallated nitrile that loses any pre-set configuration next to the nitrile. In our research, we are studying the possibility to maintain the configuration and therefore prepare single mirror image products from metallated nitriles. This would be useful for the preparation of chiral nitrile compounds. This research is funded by a grant from the Marie Curie International Incoming Fellowships Scheme (FP7-PEOPLE-2013-IIF) with postdoctoral researcher Dr Arghya Sadhukhan.


Nitrile metallations

Breaking News

We have recently discovered that a piperidine with a nitrile in the 2-position can undergo highly selective deprotonation then quench with an electrophile.
This work has just been published in Chemical Science

A. Sadhukhan, M. C. Hobbs, A. J. H. M. Meijer, I. Coldham, Chem. Sci. 2017, 8, 1436–1441.
'Highly enantioselective metallation–substitution alpha to a chiral nitrile'
DOI: 10.1039/C6SC03712G

For example:

Piperidine metallation


For some other related references, see, for example:

F. F. Fleming, L. Yao, P. C. Ravikumar, L. Funk, B. C. Shook, J. Med. Chem. 2010, 53, 7902.
'Nitrile-Containing Pharmaceuticals: Efficacious Roles of the Nitrile Pharmacophore'
DOI: 10.1021/jm100762r

G. Barker, M. R. Alshawish, M. C. Skilbeck, I. Coldham, Angew. Chem. Int. Ed. 2013, 52, 7700.
'Remarkable Configurational Stability of Magnesiated Nitriles'
DOI: 10.1002/anie.201303442

M. Sasaki, T. Takegawa, K. Sakamoto, Y. Kotomori, Y. Otani, T. Ohwada, M. Kawahata, K. Yamaguchi, K. Takeda, Angew. Chem., Int. Ed. 2013, 52, 12956.
'Enantiodivergent Deprotonation/Acylation of alpha-Amino Nitriles'
DOI: 10.1002/anie.201306443

D. Nath, M. C. Skilbeck, I. Coldham, F. F. Fleming, Org. Lett. 2014, 16, 62.
'Arylthio-Metal Exchange of alpha-Arylthioalkanenitriles'
DOI: 10.1021/ol403020s

B. W. H. Turnbull, P. A. Evans, J. Am. Chem. Soc. 2015, 137, 6156.
'Enantioselective Rhodium-Catalyzed Allylic Substitution with a Nitrile Anion: Construction of Acyclic Quaternary Carbon Stereogenic Centers'
DOI: 10.1021/jacs.5b02810

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