Journal
POLYMER CHEMISTRY
Volume 6, Issue 18, Pages 3415-3430Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c5py00168d
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Funding
- Wesleyan University
- National Science Foundation CAREER program [CHE-1352239]
- NSF [CNS-0619508]
- Division Of Chemistry
- Direct For Mathematical & Physical Scien [1352239] Funding Source: National Science Foundation
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The mechanism and kinetics of thiol-maleimide click reactions carried out under a variety of conditions have been investigated computationally and using experimental competition reactions. The influence of three different solvents (chloroform, ethane thiol, and N,N-dimethylformamide), five different initiators (ethylamine, diethylamine, triethylamine, diazabicyclo[2.2.2]octane, and dimethylphenyl-phosphine), and seven different thiols (methyl mercaptan, beta-mercaptoethanol, thioacetic acid, methyl thioglycolate, methyl 3-mercaptopropionate, cysteine methyl ester, and thiophenol) on the energetics and kinetics of thiol-maleimide reactions have been examined using density functional methods. Computational and kinetic modeling indicate that the choice of solvent, initiator, and thiol directly influences whether product formation follows a base-, nucleophile-, or ion pair-initiated mechanism (or some combination thereof). The type of mechanism followed determines the overall thiol-maleimide reaction kinetics. Insights from computational studies are then used to understand the selectivity of ternary thiol-maleimide reactions between N-methyl maleimide, thiophenol, and 1-hexanethiol in different combinations of solvents and initiators. The results provide considerable insight into the interplay between reaction conditions, kinetics, and selectivity in thiol-maleimide reactions in particular and thiol-Michael reactions in general, with implications ranging from small molecule synthesis to bioconjugation chemistry and multifunctional materials.
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