Chemistry:4-Chlorophenylacetonitrile

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4-Chlorophenylacetonitrile (sometimes referred to as 4-chlorobenzyl cyanide) is an organic compound that serves as a useful synthetic intermediate in medicinal chemistry. It is a chlorinated derivative of benzyl cyanide. The compound has a wide range of applications in the pharmaceutical industry and is also used in the synthesis of pesticides. It is toxic if ingested or absorbed through the skin,[1] and it acts as a chemical pollutant in the environment.[2]

Applications

Pharmaceuticals

4-Chlorophenylacetonitrile has beed used in the synthesis of:

Pesticides

4-Chlorophenylacetonitrile is sometimes used in the synthesis of 2-(4-chlorophenyl)-3-methyl butyric acid (aka fenvaleric acid [2012-74-0]).[10] This has use in the synthesis of fenvalerate.

Synthesis

196 g (4 mol) of sodium cyanide, 12.5 g (40 mmol) of tributylbenzylammonium chloride and 660 mL of water are initially introduced into a 2 l multineck apparatus with reflux condenser, internal thermometer and dropping funnel, and the mixture is heated to 90 °C. At the same temperature, 644 g (4 mol) of molten 4-chlorobenzyl chloride are added dropwise in 1 hr, and the mixture is then stirred for 2 hr. After having been cooled to about 35 °C., the organic phase is separated off, washed with water and fractionated over a short column. 552 g of 4-chlorobenzyl cyanide (91% of theory) are obtained.[11][12]

For alternative synthesis see:[13][14]

Reactions

  • Hydrolysis of 4-chlorophenylacetonitrile gives 4-chlorophenylacetic acid [1878-66-6]. This has application in the synthesis of arhalofenate, clorindione, and metaglidasen
  • Reduction of 4-chlorophenylacetonitrile gives 4-chlorophenethylamine [156-41-2]. This has application in the synthesis of lorcaserin.

Toxicity

4-Chlorophenylacetonitrile exhibits significant acute toxicity across multiple exposure routes. Oral administration in rats shows an LD50 of 50 mg/kg,[15][1] while intraperitoneal exposure in mice yields a lower LD50 of 27 mg/kg.[15] Skin exposure in rabbits demonstrates toxicity at 200 mg/kg (lowest lethal dose).[15] The compound is classified as Acute Toxicity Category 2-3 under GHS hazard statements, indicating fatal or toxic effects if swallowed, inhaled, or absorbed through skin.[2][16][1] It causes severe eye irritation (H319) and skin irritation (H315),[16][2] with additional respiratory risks from inhalation exposure (H335).[16] Regulatory data emphasize its Toxic designation for all primary exposure pathways, requiring strict handling precautions.[16][2][1]

References

  1. ↑ 1.0 1.1 1.2 1.3 "4-Chlorobenzyl cyanide". Safey Data Sheet. Thermo Fisher Scientific. https://www.fishersci.com/store/msds?partNumber=AC108810050&countryCode=US&language=en. 
  2. ↑ 2.0 2.1 2.2 2.3 "4-Chloro Benzyl Cyanide". Material Safety Data Sheet. CDH Fine Chemicals. 
  3. ↑ "Halofenate". Drugs of the Future 2 (7): 452. 1977. doi:10.1358/dof.1977.002.07.1002549. 
  4. ↑ Luskey K, Luo J, "Use of (-) (3-trihalomethylphenoxy) (4-halophenyl) acetic acid derivatives for treatment of insulin resistance, type 2 diabetes, hyperlipidemia and hyperuricemia", US patent 8481597, issued 9 July 2013
  5. ↑ Hoffmann K, Hunger A, Kebrle J, Rossi A, "Benzimidazoles", US patent 2935514, issued 3 May 1960
  6. ↑ The Organic Chemistry of Drug Synthesis. John Wiley & Sons. 13 May 1980. pp. 257. ISBN 978-0-471-04392-8. https://books.google.com/books?id=r-eqWrMoO18C&pg=PA257. 
  7. ↑ Walter LA, "New cyclic amidines, their therapeutic use and process for their preparation", DE patent 1905353, issued 1969
  8. ↑ Bolhofer WA, "Phenoxy substituted phenylacetic acids", US patent 3517051, issued 23 June 1970
  9. ↑ "Synthesis of sibutramine, a novel cyclobutylalkylamine useful in the treatment of obesity, and its major human metabolites". Journal of the Chemical Society, Perkin Transactions 1 (21): 2583. 1996. doi:10.1039/p19960002583. 
  10. ↑ Weber J, Lappe P, Springer H, "Process for the preparation of 2-(4-chlorophenyl)-3-methylbutyric acid", US patent 5072037, issued 10 December 1991
  11. ↑ "Synthesis of 4-chlorobenzyl cyanide". PrepChem. https://prepchem.com/4-chlorobenzyl-cyanide/. "Literature source: US04650910" 
  12. ↑ Henneke KW, Wedemeyer K, "Process for the preparation of substituted styrenes", US patent 4650910, issued 1987
  13. ↑ Verbrugge PA, Uurbanus EW, "Preparation of benzyl cyanides", US patent 4056509, issued 1 November 1977
  14. ↑ "A Facile Synthesis of Nitriles from 1-Nitro-1-alkenes by Electroreduction". Synthesis 1987 (7): 631–633. 1987. doi:10.1055/s-1987-28028. 
  15. ↑ 15.0 15.1 15.2 "4-Chlorophenylacetonitrile". Safety Data Sheet. TCI Chemicals. https://www.tcichemicals.com/BE/en/sds/C0585_EU_6N.pdf. 
  16. ↑ 16.0 16.1 16.2 16.3 "4-Chlorophenylacetonitrile". PubChem. U.S. National Library of Medicine. https://pubchem.ncbi.nlm.nih.gov/compound/4-Chlorobenzyl-cyanide. 



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