Quenching carbodiimides

December 7th, 2012 Leave a reply »

Carbodiimides are widely available and relatively inexpensive reagents that are often used to generate amides from the corresponding amines and carboxylic acids.  Such carbodiimides include dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), and N-ethyl –N’-(3-dimethyaminopropyl)-carbodiimide (available as free base or HCl salt; a.k.a. EDC, EDCI, EDAC, water-soluble carbodiimide, and WSC).  EDC can couple amines and carboxylic acids in predominantly aqueous solutions,[1] and is also widely used as a crosslinking reagent in biochemistry.[2]

Carbodiimides are known to be relatively toxic.  For instance, EDC is irritating to the skin and may cause severe eye damage.[3]  DCC is a known skin sensitizer.[4]  Exposure to DIC led to temporary blindness to a worker who cleaned up a spill of 1 L while wearing a respirator and gloves.[5]  On a molecular level EDC has been shown to crosslink double-stranded DNA, which could be responsible for cell death;[6] little has been published on the genotoxicity of carbodiimides.  People should undertake precautions to avoid contact with carbodiimides, and to quench reactions containing carbodiimides as part of workups.

Treatment with carboxylic acids or aqueous acids can decompose carbodiimides, thus affording effective quenches.  Oxalic acid, acetic acid, and phosphoric acid have been used to quench DCC.[7],[8]  The decomposition of EDC in aqueous solutions has been studied quantitatively: decomposition occurred in minutes at pH 4.0, and was said to be instantaneous at pH 2.8 (1% aq. AcOH) and pH 2.2 (1% aq. HCO2H).[9]  Using the kinetic data in the latter paper it may be possible to develop a QbD argument for the decomposition of EDC.

[1] Merck used EDC to prepare initial batches of a sitagliptin intermediate: Hansen, K. B.; Balsells, J.; Dreher, S.; Hsiao, Y.; Kubryk, M.; Palucki, M.; Rivera, N.; Steinhuebel, D.; Armstrong, J. D., III; Askin, D.; Grabowski, E. J. J. Org. Process Res. Dev. 2005, 9, 634.

[2] http://www.piercenet.com/browse.cfm?fldID=F3305493-0FBC-93DA-2720-4412D198A9C9

[3] See MSDS for EDC at http://www.sigmaaldrich.com/catalog/product/sial/e7750?lang=en&region=US

[4] See MSDS for DCC at http://www.sigmaaldrich.com/catalog/product/fluka/36650?lang=en&region=US

[5] http://ntp.niehs.nih.gov/ntp/htdocs/Chem_Background/ExecSumm/Diisopropylcarbodiimide/DIC_carc.html

[6] Moshnikova, A. B., et al., Cell. Mol. Life Sci. 2006, 63, 229.

[7] Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; Vol. 1; Wiley: New York, 1967; p 231.

[8] Anderson, N. G., Practical Process Research & Development – A Guide for Organic Chemists; 2nd edition; Academic Press: San Diego; 2012; pp 291, 297-8.

[9] Lei, Q. P.; Lamb, D. H.; Heller, R. K.; Shannon, A. G.; Ryall, R.; Cash, P. Anal. Biochem. 2002, 310, 122.

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