Controlling the outcome of an N-alkylation reaction by using N-oxide functional groups.
Covalent modifiers of proteins are of importance in chemical proteomics, an emerging chemical technology used to assign protein function. In this study, high-field (1)H NMR techniques were used to analyze the reaction of the bioactive compound, 2,3-bis(bromomethyl)quinoxaline 1,4-dioxide, with amines (a model system for proteins containing nitrogen-based nucleophiles). Unexpectedly, the results show that a double nucleophilic substitution reaction involving 2 equiv of the amine is preferred to an intramolecular cyclization pathway. A direct comparison with the reaction carried out on a substrate lacking the N-oxide functional groups is also provided. X-ray crystal structures and computational studies are used to rationalize the observed differences in reactivity between the two systems.
Pearson
Russell J
RJ
Centre for Biomolecular Sciences, School of Chemistry, University of St. Andrews, North Haugh, St. Andrews KY16 9ST, United Kingdom.
Evans
Kathryn M
KM
Slawin
Alexandra M Z
AM
Philp
Douglas
D
Westwood
Nicholas J
NJ
D000478:Alkylation; D000588:Amines / Q000737:chemistry; D018360:Crystallography, X-Ray; D003497:Cyclic N-Oxides / Q000737:chemistry*; D003500:Cyclization; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011506:Proteins / Q000737:chemistry; D011810:Quinoxalines / Q000737:chemistry*
C502067:2,3-bis(bromomethyl)quinoxaline-1,4-dioxide; D000588:Amines; D003497:Cyclic N-Oxides; D011506:Proteins; D011810:Quinoxalines