[75-05-8]  · C2H3N  · Acetonitrile  · (MW 41.05)

(solvent for inorganic and organometallic reagents; undergoes addition reactions to nitrile group; anion is nucleophilic reagent; Ritter reaction reagent; oxidizing agent in combination with H2O2)

Alternate Names: methyl cyanide; ethanenitrile; cyanomethane.

Physical Data: mp -45 °C; bp 81.6 °C; d 0.787 g cm-3 (20 °C).

Solubility: miscible with water and most organic solvents (but not petroleum); forms constant boiling mixture containing 16% water, bp 76 °C.

Form Supplied in: colorless liquid; widely available. Drying: fractional distillation from CaH2 or P2O5.

Analysis of Reagent Purity: GLC; HPLC grade (99.9+% purity) commercially available.

Handling, Storage, and Precautions: flammable volatile liquid; keep dry; toxic vapor; mild lachrymator; possible skin irritant; evolves toxic fumes if heated to decomposition; incompatible with fuming HNO3, N2O4/In, 2-cyano-2-propylnitrate, ClF/F2, Cl3HSi/diphenyl sulfoxide, metal perchlorates, HClO4, fuming H2SO4, heat/conc. H2SO4, and N-fluoro compounds.2

Solvent Properties.

Acetonitrile is neutral, aprotic, polar (3.9 D) with a dielectric constant of 38 at 20 °C; it promotes ionic processes in solution. It is suitable for a wide range of physical organic techniques including HPLC, UV (l > 190 nm), and electrochemistry.3 However, its outstanding ability is to facilitate reaction between organic substrates and inorganic materials (eq 1).4 These reagents include: Group 1 and 2 salts; AgI, CeIV, CuI, CuII, FeIII, HgII, MnIV, MnVII, PdII, RhIII, RuIV, SnII, TeIV, and TlIII salts; R4N+, ArN2+, MeCO+, NO2+, and Ph3RP+ salts. In some cases, such as CuCl2.(MeCN)2 and PdCl2.(MeCN)2, the complexes involved are isolable.5

Reactions at Methyl.6

Deprotonation of acetonitrile using strong base affords the nitrile-stabilized anion,7a which can add to other nitrile molecules producing diacetonitrile7b or the trimer 4-amino-2,6-dimethylpyrimidine (eq 2).7c The dimerization process is the forerunner of the Thorpe-Ziegler synthesis of large ring systems.8 Mixed b-enaminonitriles9a or diacetonitrile itself9b undergo condensation with carbonyl compounds, producing pyridine derivatives.

The anion performs conventional substitution reactions with alkyl halides and epoxides,6 but Cyanomethylcopper is especially effective for cyanoalkylation of allylic halide reagents (eq 3).10 Esters react with the monoanion yielding b-ketonitriles, which are readily converted by Boron Trifluoride or Polyphosphoric Acid into the corresponding b-ketoamides (eq 4).11

Aldol-type condensations with aldehydes and ketones produce the cyanomethyl alcohols12a or unsaturated nitriles (eq 5),12b depending on the chosen conditions. Acetonitrile anion results in exclusively 1,2-addition to conjugated enones in THF at -78 °C, in contrast to the behavior of other nitriles.12c

Addition Reactions.13

Acetonitrile yields acetophenone derivatives (eq 6) when reacted with phenols (or phenolic ethers) and Lewis acids (Hoesch reaction).14 It reacts with alcohols in the presence of dry HCl to yield imidates (Pinner reaction)15a which can react with further alcohol to produce orthoacetate esters,15b or with amines to yield acetamidines (eq 7).15c,d

The Blaise reaction16 of bromo esters with acetonitrile produces b-keto esters (eq 8) in a process analogous to the Reformatsky reaction. Acetonitrile reacts with ammonia and hydrogen sulfide to yield thioacetamide. Higher thioamides can be produced by reacting this with nitriles and distilling the lower boiling MeCN from the resulting equilibrium mixture.17

Acetonitrile also reacts with thiols to yield thioimidates,15a with amines to give acetamidines,18 and with 1,2-amino alcohols to produce 2-oxazolines (eq 9).19

Ritter-Type Reactions.20

The acetonitrile nitrogen atom is an extremely weak nucleophile, but attacks carbenium ions to yield a nitrilium ion, which proceeds to an imidate and then undergoes hydrolysis to the amide (eq 10).21 Since carbenium ions may be generated from a very wide range of functional groups under strongly acidic conditions, the Ritter reaction provides a facile one-flask route to N-alkylacetamides. As expected, the carbenium ions may participate in rearrangement or transannular reactions before undergoing substitution (eq 11).22 Alternatively, the nitrilium ion may be generated via other electrophilic reagents23 (eq 12),24 and it can also undergo intramolecular closure to yield heterocyclic products (eq 13).25

Reactions with Hydrogen Peroxide and Base.

The Radziszewski reaction26 describes the formation of amide products and dioxygen when nitriles are treated with Hydrogen Peroxide solution under basic conditions. Yields of aliphatic amides27a are 50-70%, while those of aromatic amides27b are typically 80-95%. This reaction proceeds via the intermediacy of the peroxyimidic acid (eq 14).28 If an alkene functionality is present, then it is epoxidized with concomitant reduction of the peroxyimidic acid to the amide (the Payne oxidation)29 in a simple one-flask process. A convenient procedure is to react the alkene and nitrile with H2O2 in methanol using potassium hydrogen carbonate as the base (pH ca. 8).30a

The Payne oxidation has the advantage that the oxidant is generated in situ, while the mildly basic conditions ensure that labile epoxides do not undergo acid-catalyzed degradation (eq 15)30b and competing Baeyer-Villiger oxidations may be suppressed (eq 16).29c In some cases the peroxycarboxylic acid and Payne processes may give differing outcomes,31a stereochemistry,31b or regioselectivity.31c While both benzonitrile and acetonitrile are commonly employed, the latter reagent has operational advantages. Its oxidation products are water soluble and easily removed during reaction workup, whereas the benzamide coproduct requires a more complex separation.

1. (a) The Chemistry of the Cyano Group; Rappoport, Z., Ed.; Interscience: New York, 1970. (b) Smith, P. A. S. The Chemistry of Open-Chain Nitrogen Compounds; Benjamin: New York, 1965; Vol. 1.
2. Bretherick, L. Handbook of Reactive Chemical Hazards, 3rd ed.; Butterworths: London, 1985.
3. Coetzee, J. F. Progr. Phys. Org. Chem. 1967, 4, 45.
4. Uemura, S.; Okazaki, H.; Onoe, A.; Okano, M. JCS(P1) 1977, 676.
5. Endres, H. Comp. Coord. Chem. 1987, 2, 261.
6. Arseniyadis, S.; Kyler, K. S.; Watt, D. S. OR 1984, 31, 1.
7. (a) Gornowicz, G. A.; West, R. JACS 1971, 93, 1714. (b) Krüger, C. JOM 1967, 9, 125. (c) Ronzio, A. R.; Cook, W. B. OSC 1955, 3, 71.
8. (a) Schaefer, J. P.; Bloomfield, J. J. OR 1967, 15, 1. (b) Davis, B. R.; Garratt, P. J. COS 1991, 2, 848.
9. (a) Meyer, E. von JPR 1908, [ii] 78, 497. (b) Shibata, K.; Urano, K.; Matsui, M. BCJ 1988, 61, 2199.
10. Corey, E. J.; Kuwajima, I. TL 1972, 487.
11. (a) Eby, C. J.; Hauser, C. R. JACS 1957, 79, 723. (b) Hauser, C. R.; Eby, C. J. JACS 1957, 79, 725.
12. (a) Crouse, D. N.; Seebach, D. CB 1968, 101, 3113. (b) DiBiase, S. A.; Lipisko, B. A.; Haag, A.; Wolak, R. A.; Gokel, G. W. JOC 1979, 44, 4640. (c) Sauvetre, R.; Roux-Schmitt, M.-C.; Seyden-Penne, J. T 1978, 34, 2135.
13. Zil'berman, E. N. RCR 1962, 31, 615.
14. (a) Spoerri, P. E.; DuBois, A. S. OR 1949, 5, 387. (b) Gulati, K. C.; Seth, S. R.; Venkataraman, K. OSC 1943, 2, 522.
15. (a) Roger, R.; Neilson, D. G. CRV 1961, 61, 179. (b) McElvain, S. M.; Nelson, J. W. JACS 1942, 64, 1825. (c) Dox, A. W. OSC 1941, 1, 5. (d) Shriner, R. L.; Neumann, F. W. CRV 1944, 35, 351.
16. (a) Kagan, H. B.; Suen, Y.-H. BSF 1966, 1819. (b) Hannick, S. M.; Kishi, Y. JOC 1983, 48, 3833.
17. (a) Hurd, R. N.; DeLaMater, G. CRV 1961, 61, 45. (b) Taylor, E. C.; Zoltewicz, J. A. JACS 1960, 82, 2656.
18. Oxley, P.; Partridge, M. W.; Short, W. F. JCS 1947, 1110.
19. Witte, H.; Seeliger, W. AG(E) 1972, 11, 287.
20. (a) Krimen, L. I.; Cota, D. J. OR 1969, 17, 213. (b) Bishop, R. COS 1991, 6, 261. (c) Johnson, F.; Madroñero, R. Adv. Heterocycl. Chem. 1966, 6, 95.
21. Parris, C. L.; Christenson, R. M. JOC 1960, 25, 331.
22. Stetter, H.; Gärtner, J.; Tacke, P. CB 1965, 98, 3888.
23. Meerwein, H.; Laasch, P.; Mersch, R.; Spille, J. CB 1956, 89, 209.
24. Scheinbaum, M. L.; Dines, M. JOC 1971, 36, 3641.
25. Lora-Tamayo, M.; Madroñero, R.; Muñoz, G. G.; Leipprand, H. CB 1964, 97, 2234.
26. (a) Radziszewski, Br. CB 1855, 18, 355. (b) McMaster, L.; Langreck, F. B. JACS 1917, 39, 103.
27. (a) McMaster, L.; Noller, C. R. JIC 1935, 12, 652. (b) Noller, C. R. OSC 1943, 2, 586.
28. (a) Wiberg, K. B. JACS 1955, 77, 2519. (b) McIsaac, J. E.; Ball, R. E.; Behrman, E. J. JOC 1971, 36, 3048.
29. (a) Payne, G. B.; Williams, P. H. JOC 1961, 26, 651. (b) Payne, G. B.; Deming, P. H.; Williams, P. H. JOC 1961, 26, 659. (c) Payne, G. B. T 1962, 18, 763.
30. (a) Bach, R. D.; Knight, J. W. OSC 1990, 7, 126. (b) Pich, K. C.; Bishop, R.; Craig, D. C.; Dance, I. G.; Rae, A. D.; Scudder, M. L. Struct. Chem. 1993, 4, 41.
31. (a) Chaudhuri, N. K.; Ball, T. J. JOC 1982, 47, 5196. (b) Carlson, R. G.; Behn, N. S. JOC 1967, 32, 1363. (c) Carlson, R. G.; Behn, N. S.; Cowles, C. JOC 1971, 36, 3832.

Roger Bishop

The University of New South Wales, Kensington, NSW, Australia

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