Cyanoethylation

Cyanoethylation is a process for the attachment of CH₂CH₂CN group to another organic substrate. The method is used in the synthesis of organic compounds.[1]

Cyanoethylation entails addition of protic nucleophiles to acrylonitrile. Typical protic nucleophiles are alcohols, thiols, and amines. Two new bonds form: C-H and C-X (X = carbon, nitrogen, sulfur, phosphorus, etc):

${\displaystyle \mathrm {YH+H_{2}C{=}CH{-}CN\longrightarrow Y{-}CH_{2}{-}CH_{2}{-}CN} }$

The β-carbon atom that is furthest from the nitrile group is positively polarized and therefore binds the heteroatom on the nucleophile. Acrylonitrile is a Michael acceptor.[2] The reaction is normally catalyzed by a base.[3]

Tris(cyanoethyl)phosphine is produced by the cyanoethylation of phosphine.[4]

Cyanethylation is used to prepared numerous commercial chemicals. Detailed laboratory procedures are available for several variants of this reaction.

• Cyanoethylation of amines.[5][6]
• Cyanoethylation of phosphines.[7]
• Cyanoethylation of carbon nucleophiles.[8] In one commercial example, acetone is cyanoethylated to give the keto hexanenitrile, a precursor to 2-methylpyridine.[9]

An alternative method for cyanoethylation entails alkylation of the substrate with 3-chloropropionitrile.

De-cyanoethylation

Cyanoethyl is a protecting group. It is removed by treatment with base:

RNuCH₂CH₂CN + OH^− → RNu^− + CH₂=CHCN + H₂O

This methodology is popular in the synthesis of oligonucleotides.[10]

References

1. Eller, Karsten; Henkes, Erhard; Rossbacher, Roland; Höke, Hartmut (2000). "Amines, Aliphatic". Ullmann's Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. doi:10.1002/14356007.a02_001. ISBN 3527306730.
2. Smith, Michael B.; March, Jerry (2007), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (6th ed.), New York: Wiley-Interscience, ISBN 978-0-471-72091-1
3. Hajime Kabashima, Hideshi Hattori (1998). "Cyanoethylation of Alcohols Over Solid Base Catalysts". Catalysis Today. 44 (1–4): 277–283. doi:10.1016/S0920-5861(98)00200-4..
4. Trofimov, Boris A.; Arbuzova, Svetlana N.; Gusarova, Nina K. (1999). "Phosphine in the synthesis of organophosphorus compounds". Russian Chemical Reviews. 68 (3): 215–227. doi:10.1070/RC1999v068n03ABEH000464. S2CID 250775640.
5. J. Cymerman-Craig, M. Moyle (1956). "N-2-Cyanoethylaniline". Organic Syntheses. 36: 6. doi:10.15227/orgsyn.036.0006.
6. S. A. Heininger (1958). "3-(o-Chloroanilino)propionitrile". Organic Syntheses. 38: 14. doi:10.15227/orgsyn.038.0014.
7. Theodore E. Snider, Don L. Morris, K. C. Srivastava, K. D. Berlin (1973). "1-Phenyl-4-Phosphorinanone". Organic Syntheses. 53: 98. doi:10.15227/orgsyn.053.0098.
8. E. C. Horning A. F. Finelli (1950). "α-Phenyl-α-Carboethoxyglutaronitrile". Organic Syntheses. 30: 80. doi:10.15227/orgsyn.030.0080.
9. Shimizu, S.; Watanabe, N.; Kataoka, T.; Shoji, T.; Abe, N.; Morishita, S.; Ichimura, H. "Pyridine and Pyridine Derivatives". Ullmann's Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. doi:10.1002/14356007.a22_399. ISBN 978-3527306732.
10. Liu, Qiang; Van Der Marel, Gijsbert A.; Filippov, Dmitri V. (2019). "Chemical ADP-ribosylation: Mono-ADPr-peptides and oligo-ADP-ribose". Organic & Biomolecular Chemistry. 17 (22): 5460–5474. doi:10.1039/c9ob00501c. hdl:1887/85621. PMID 31112180. S2CID 160014127.