Amide Formation: Choosing the Safer Carbodiimide in Combination with OxymaPure to Avoid HCN Release

Abstract

It has been reported that DIC can react with OxymaPure to render an oxadiazole compound with the concomitant formation of HCN. Here we demonstrate that this reaction is not a feature of all carbodiimides but rather depends on the alkyl structure that flanks the two N atoms of the carbodiimide. Furthermore, we have identified two carbodiimides, TBEC and EDC•HCl, whose reaction with OxymaPure is exempt from HCN formation.

Understanding OxymaPure as a Peptide Coupling Additive: A Guide to New Oxyma Derivatives

“…Although, in this case, the formation of the adduct takes place to a much lesser extent than with HONM, it can cyclize with the generation of HCN (Figure ). These results have been corroborated by Pawlas and co-workers, and our own group. , …”

“…These results have been corroborated by Pawlas 54 and co-workers, and our own group. 55,56 In this context, and although this side reaction takes place to a very low extent and in only certain cases, there is interest in finding oxime derivatives with no cyano groups. Taking into account both the availability of their synthesis and the pK a , out of four nitro derivatives (46−49) only one ethyl2-(hydroxyimino)-2-nitroacetate (46)fulfils those requirements.…”

tert-Butylethylcarbodiimide as an Efficient Substitute for Diisopropylcarbodiimide in Solid-Phase Peptide Synthesis: Understanding the Side Reaction of Carbodiimides with OxymaPure

“…Furthermore, we addressed the reactions between OxymaPure and several carbodiimides, such as DIC, DCC, N,N′ -disecbutylcarbodiimide (DSBC), N,N′ -di- tert -butyl carbodiimide (DTBC), N - tert -butyl- N ′-ethyl carbodiimide (TBEC), and N -ethyl- N ′-(3-(dimethylamino)­propyl) carbodiimide hydrochloride (EDC·HCl or WSC), to study the extension of that side reaction (oxadiazole and HCN formation) with other carbodiimide congeners . Briefly, we have demonstrated that the reactivity of carbodiimides with OxymaPure depends on the steric hindrance around the carbodiimide backbone.…”

Sustainability in peptide chemistry: current synthesis and purification technologies and future challenges

“…The primary carbodiimide, EDC, and hybrid, TBEC, outperformed the other reagents with less adduct formation. 134 In addition, it was discovered very recently by the same research group how the generation of HCN could be reduced or suppressed according to the sequence of adding reagents. The optimal conditions call for pre-activation of the Fmoc-amino acid with DIC, subsequent addition of the mixture onto the resin, followed by insertion of OxymaPure® directly on the resin.…”