Acetone Cyanohydrin

[75-86-5]  · C4H7NO  · Acetone Cyanohydrin  · (MW 85.11)

(hydrogen cyanide source easier to handle and less toxic than HCN; transhydrocyanation; epoxide cleavage; formylation of arenes)

Physical Data: mp -19 °C; bp 82 °C/23 mmHg; bp 95 °C/760 mmHg; d 0.932 g cm-3; n20D = 1.3992; fp 63 °C.

Solubility: freely sol water, usual organic solvents; insol petroleum ether, carbon disulfide.

Form Supplied in: light yellow liquid; widely available.

Analysis of Reagent Purity: IR: 3480 (s, OH); 2420 (w, CN); 1H NMR: 1.65 (s, 6H); 3.68 (br, 1H).

Handling, Storage, and Precautions: use in a fume hood. Highly toxic and harmful liquid. May be fatal if inhaled, swallowed, or absorbed through skin (toxicity data: oral (rat) LD50 0.17 g kg-1; skin (rabbit) LD50 17 mg kg-1). Causes severe irritation, while high concentrations are extremely destructive to tissues of mucous membranes and upper respiratory tract, eyes, and skin. Symptoms of exposure may include burning sensation, coughing, wheezing, laryngitis, shortness of breath, headache, or even cyanosis. Keep tightly closed and away from heat and open flame. Store in cool and dry place; combustible. Incompatible with strong acids, strong bases, strong oxidizing agents, and strong reducing agents. Thermal decomposition may produce hydrogen cyanide, carbon monoxide, and carbon dioxide.

Transhydrocyanation (Cyanohydrin Formation).

Acetone cyanohydrin has long been known to interchange HCN with aldehydes or ketones to form their corresponding cyanohydrins.1 The reaction is catalyzed by bases and the cyanohydrin product is subject to rapid racemization due to the reversible nature of the reaction.2 However, subsequent acetylation of the cyanohydrin product with Isopropenyl Acetate acetate using a lipase from Pseudomonas cepacia (Amano) as catalyst furnishes preferentially the (S)-isomer (eq 1),3 while the unreacted (R)-isomer is continuously racemized through reversible transhydrocyanation.

(R)-Cyanohydrins are obtained in high enantiomeric purity by a one-step biocatalyzed reaction of aromatic or aliphatic aldehydes with acetone cyanohydrin. In this case the use of powered almond meal provides an inexpensive catalyst which eliminates the need to purify and immobilize the enzyme, leading to products with high enantiomeric purity (eq 2).4 Similar products are obtained using the flavoprotein D-oxynitrilase (EC as catalyst.5

Cyanohydrins of steroid ketones are prepared by HCN exchange with acetone cyanohydrin without the presence of a catalyst, since the product precipitates from solution. Thus the 17-monocyanohydrins of steroidal 3,17-diones are prepared in practically quantitative yield (eq 3).6 Similarly, a-silyloxynitriles are prepared from O-trimethylsilylated acetone cyanohydrin by transcyanosilylation7 in the presence of Potassium Cyanide and 18-Crown-6.

Hydrogen Cyanide Addition.

Acetone cyanohydrin is used as a Hydrogen Cyanide source which is easier to handle and less toxic than HCN.1,8 Thus the Michael addition of HCN to a,b-unsaturated ketones is achieved by an exchange with acetone cyanohydrin in 10% aq Na2CO3. This reaction is found to proceed in excellent yield with chalcones9 or steroid ketones.10 Similar addition with high stereoselectivity using acetone cyanohydrin in conjunction with naked cyanide ions (KCN in nonpolar aprotic solvent containing 18-crown-6) has also been reported (eq 4).11 On the other hand, addition of HCN to aldimines using acetone cyanohydrin furnishes a-aminonitriles (eq 5).12

Ring Opening.

Acetone cyanohydrin with stoichiometric Triethylamine opens 1,2-epoxides regiospecifically to give b-hydroxynitriles. The addition of cyanide occurs at the least substituted carbon (eq 6).13 The same conditions are applied for the cyclopropane ring opening of methyl 2-oxobicyclo[3.1.0]hexane-1-carboxylate in almost quantitative yields.14

Aromatic Formylation.

Acetone cyanohydrin has been proposed as an easy-to-handle formylation reagent for arenes, thus replacing the hazardous hydrogen cyanide in the Gatterman reaction (eq 7).15

Acetone Cyanohydrin Nitrate.

Caution: moderately explosive, bp 65-66 °C/10 mmHg. Prepared by nitration of acetone cyanohydrin with fuming Nitric Acid and Acetic Anhydride (eq 8),16 this reagent is unique for the conversion of amines to nitramines under alkaline conditions. Thus primary nitramines are obtained in 50-60% yield, while aliphatic and alicyclic secondary nitramines are produced in yields varying from 55-80% (eq 8).17 The reagent is also useful for the nitration of a variety of active methylene compounds (in the form of their sodio derivatives), providing a general route for the synthesis of a-nitro esters (eq 9).18

Related Reagents.

t-Butyldimethylsilyl Cyanide; Cyanotrimethylsilane; Diethylaluminum Cyanide; Hydrogen Cyanide; Potassium Cyanide; Sodium Cyanide; Tetraethylammonium Cyanide; Zinc Cyanide.

1. (a) Nazarov, I. N.; Akhrem, A. A.; Kamernitskii, A. V. ZOB 1955, 25, 1345. (b) Kobayashi, Y.; Hayashi, H.; Miyaji, K.; Inoue, S. CL 1986, 931; (c) Mori, A.; Kinoshita, K.; Osaka, M.; Inoue, S. CL 1990, 1171.
2. (a) Ogata, Y.; Kawasaki, A. In The Chemistry of The Functional Groups; Patai, S., Ed; Interscience: New York, 1970; Vol 2, Chapter 1, pp 21-32. (b) Morrison, J. D.; Mosher, H. S. Asymmetric Organic Reactions; Prentice-Hall: Englwood Cliffs, NJ, 1971; Chapter 4, pp 133-141.
3. (a) Inagaki, M; Hiratake, J.; Nishioka, T.; Oda, J. JACS 1991, 113, 9360. (b) Inagaki, M; Hiratake, J.; Nishioka, T.; Oda, J. JOC 1992, 57, 5643.
4. Huuhtanen, T. T.; Kanerva, L. TA 1992, 3, 1223.
5. Ognyanov, V. I.; Datcheva, V. K.; Kyler, K. S. JACS 1991, 113, 6992.
6. Ercoli, A.; De Ruggieri, P. JACS 1953, 75, 650.
7. Evans, D. A.; Truesdale, L. K. TL 1973, 14, 4929.
8. (a) Mori, A.; Inoue, S. CL 1991, 145; (b) Danda, H; Chino, K.; Wake, S. CL 1991, 731.
9. Betts, B. E.; Davey, W. JCS 1958, 4193.
10. Julia, S.; Linares, H.; Simon, P. BSF 1963, 2471.
11. Liotta, C. L.; Dabdoub, A. M.; Zalkow, L. H. TL 1977, 1117.
12. De Kimpe, N.; Sulmon, P.; Stevens, C. T 1991, 47, 4723.
13. (a) Mitchell, D.; Koenig, T. M. TL 1992, 33, 3281. (b) Kasai, N.; Sakaguchi, K. TL 1992, 33, 1211.
14. Kondo, K.; Takahatake, Y.; Sugimoto, K.; Tunemoto, D. TL 1978, 907.
15. Rahm, A.; Guilhemat, R.; Pereyre, M. SC 1982, 12, 485.
16. Freeman, J. P.; Shepard, I. G. OS 1963, 43, 83; Freeman, J. P.; Shepard, I. G. OSC 1973, 5, 839.
17. Emmons, W. D.; Freeman, J. P. JACS 1955, 77, 4387.
18. Emmons, W. D.; Freeman, J. P. JACS 1955, 77, 4391.

Serkos A. Haroutounian

Agricultural University of Athens, Greece

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