Ethyl cyanoacetate

Ethyl cyanoacetate is an organic compound that contains a carboxylate ester and a nitrile. It is a colourless[1] liquid with a pleasant odor. This material is useful as a starting material for synthesis due to its variety of functional groups and chemical reactivity.

Ethyl cyanoacetate
Identifiers
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.003.009
EC Number
  • 203-309-0
UNII
UN number 3276 2666
Properties
C5H7NO2
Molar mass 113.116 g·mol−1
-67.3·10−6 cm3/mol
Hazards
GHS pictograms
GHS Signal word Warning
H302, H312, H319, H332
P261, P264, P270, P271, P280, P301+312, P302+352, P304+312, P304+340, P305+351+338, P312, P322, P330, P337+313, P363, P501
NFPA 704 (fire diamond)
Flammability code 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g. canola oilHealth code 1: Exposure would cause irritation but only minor residual injury. E.g. turpentineReactivity code 1: Normally stable, but can become unstable at elevated temperatures and pressures. E.g. calciumSpecial hazards (white): no code
1
1
1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

Production

Ethyl cyanoacetate may be prepared in various ways:

Properties

Physical properties
Vapour pressure of ethyl cyanoacetate

Ethyl cyanoacetate is a colorless liquid, it boils at atmospheric pressure at 209 °C.[5] The vapor pressure follows the Antoine equation log10(P) = A−(B/(T+C)) (P in bar, T in K) with A = 7.46724, B = 3693.663 and C = 16.138 in the temperature range from 341 to 479 K[6] In solid phase, two polymorphic forms can occur.[7] Below -111 °C, the crystal form II is dominant.[7] Above this temperature, the crystal form I is formed which melts at -22 °C.[5] The heat capacity at 25 °C is 220.22 J K−1 mol−1.[7]

Chemical properties

With its three different reactive centers—nitrile, ester, acidic methylene site—ethyl cyanoacetate is a versatile synthetic building block for a variety of functional and pharmacologically active substances. It contains an acidic methylene group, flanked by both the nitrile and carbonyl, and so can be used in condensation reactions like the Knoevenagel condensation or the Michael addition. This reactivity is similar to that of esters of malonic acid. As an example of reactivity at the nitrile, diethyl malonate is obtained from cyanoacetic acid ethyl ester by reaction with ethanol in the presence of strong acids.[2] Heating in the presence of sodium ethoxide forms the dimeric 3-amino-2-cyano-2-pentendiaciddiethylester.[8]

Use

Due to its functionality cyanoacetate reacts:

  • At the nitrile group in various ways:
    • Hydrogenation leads to the β-amino acid β-alanine
    • Nucleophilic attack at the carbon, as a step in the synthesis of many heterocycles (see below) and other products
    • As a safe cyanide-donor reagent[9]
  • Nucleophilic attack at the ester group, as part of acyl substitution: reaction with ammonia leads to cyanoacetamide, which can be converted by dehydration with PCl5 or POCl3 to malononitrile.[10]
  • Via the acidic methylene group as a nucleophile

Ethyl cyanoacetate is a building block for the synthesis of heterocycles which are used for example as drugs:

Also many other functional heterocycles are in good yields accessible from ethyl cyanoacetate, such as 3-substituted coumarin derivatives.[13]

Non-cyclic products from this starting material include:

Ethyl cyanoacetate is also used to prepare 3,3-diphenylpropan-1-amine, which is the precursor used in the synthesis of Prenylamine & Droprenilamine.

Safety

Ethylcyanoacetate has an LD50 of 2820 mg/kg (oral, rat).[14]

References
  1. Entry on Cyanessigsäureester. at: Römpp Online. Georg Thieme Verlag, retrieved 2016-06-15.
  2. J. K. H. Inglis. "Ethyl Cyanoacetate". Organic Syntheses. doi:10.15227/orgsyn.008.0074.
  3. EP application 1028105, Hanselmann, Paul & Hildebrand, Stefan, "Process for the preparation of cyanoacetic esters", published 2000-08-16, assigned to Lonza AG
  4. EP patent 1208081, Hanselmann, Paul & Hildebrand, Stefan, "Method for producing cyanoacetic acid esters", issued 2004-04-14, assigned to Lonza AG
  5. Record of CAS RN 105-56-6 in the GESTIS Substance Database of the Institute for Occupational Safety and Health, accessed on 3. März 2011.
  6. Stull, D.R. (1947). "Vapor Pressure of Pure Substances Organic Compounds". Ind. Eng. Chem. 39 (4): 517–540. doi:10.1021/ie50448a022.
  7. Khodzhaeva, M.G.; Bugakov, Yu.V.; Ismailov, T.S.: Heat capacity and thermodynamic functions of ethyl cyanoacetate in Khim.-Farm. Zhur. 21 (1987) 760-762, DOI:10.1007/BF00872889.
  8. Dorokhov, V. A.; Baranin, S. V.; Dib, A.; Bogdanov, V. S. (1992). "'Codimers' of N-(pyrid-2-yl) amides and ethyl cyanoacetate". Russ. Chem. Bulletin. 41 (2): 287–291. doi:10.1007/bf00869516.
  9. Zheng, Shuyan; Yu, Chunhui; Shen, Zhengwu (2012). "Ethyl Cyanoacetate: A New Cyanating Agent for the Palladium-Catalyzed Cyanation of Aryl Halides". Org. Lett. 14 (14): 3644–3647. doi:10.1021/ol3014914.
  10. Mary Eagleson: Concise encyclopedia chemistry, Walter de Gruyter, Berlin - New York 1994, ISBN 3-11-011451-8.
  11. Axel Kleemann, Jürgen Engel: "Pharmazeutische Wirkstoffe", 2. Aufl., Georg Thieme, Stuttgart - New York 1982, ISBN 3-13-558402-X.
  12. Beyer-Walter: "Lehrbuch der Organischen Chemie", 24. Aufl., S. Hirzel, Stuttgart - Leipzig 2004.
  13. Avetisyan, A. A.; Vanyan, É. V.; Dangyan, M. T. (1980). "Synthesis of functionally substituted coumarins". Chem. Heterocycl. Compounds. 15 (9): 959–960. doi:10.1007/BF00473834.
  14. Harald Strittmatter, Stefan Hildbrand and Peter Pollak "Malonic Acid and Derivatives" in Ullmann's Encyclopedia of Industrial Chemistry 2007, Wiley-VCH, Weinheim. doi: 10.1002/14356007.a16_063.pub2
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