Uncovering the Most Kinetically Influential Reaction Pathway Driving the Generation of HCN from Oxyma/DIC Adduct: A Theoretical Study

Lingfeng Gui, Claire S. Adjiman, Amparo Galindo, Fareed Bhasha Sayyed, Stanley P. Kolis, Alan Armstrong*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)
6 Downloads (Pure)

Abstract

The combination of ethyl (hydroxyimino)cyanoacetate (Oxyma) and diisopropylcarbodiimide (DIC) has demonstrated superior performance in amino acid activation for peptide synthesis. However, it was recently reported that Oxyma and DIC could react to generate undesired hydrogen cyanide (HCN) at 20 °C, raising safety concerns for the practical use of this activation strategy. To help minimize the risks, there is a need for a comprehensive investigation of the mechanism and kinetics of the generation of HCN. Here we show the results of the first systematic computational study of the underpinning mechanism, including comparisons with experimental data. Two pathways for the decomposition of the Oxyma/DIC adduct are derived to account for the generation of HCN and its accompanying cyclic product. These two mechanisms differ in the electrophilic carbon atom attacked by the nucleophilic sp2-nitrogen in the cyclization step and in the cyclic product generated. On the basis of computed “observed” activation energies, ΔGobs, the mechanism that proceeds via the attack of the sp2-nitrogen at the oxime carbon is identified as the most kinetically favorable one, a conclusion that is supported by closer agreement between predicted and experimental 13C NMR data. These results can provide a theoretical basis to develop a design strategy for suppressing HCN generation when using Oxyma/DIC for amino acid activation.

Original languageEnglish
Pages (from-to)874-880
Number of pages7
JournalIndustrial and Engineering Chemistry Research
Volume62
Issue number2
Early online date5 Jan 2023
DOIs
Publication statusPublished - 18 Jan 2023

ASJC Scopus subject areas

  • General Chemistry
  • General Chemical Engineering
  • Industrial and Manufacturing Engineering

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