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Issue 32, 2020
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Decomplexation as a rate limitation in the thiol-Michael addition of N-acrylamides

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The thiol-Michael addition is a popular, selective, high-yield “click” reaction utilized for applications ranging from small-molecule synthesis to polymer or surface modification. Here, we combined experimental and quantum mechanical modeling approaches using density functional theory (DFT) to examine the thiol-Michael reaction of N-allyl-N-acrylamide monomers used to prepare sequence-defined oligothioetheramides (oligoTEAs). Experimentally, the reaction was evaluated with two fluorous tagged thiols and several monomers at room temperature (22 °C and 40 °C). Using the Eyring equation, the activation energies (enthalpies) were calculated, observing a wide range of energy barriers ranging from 28 kJ mol−1 to 108 kJ mol−1 within the same alkene class. Computationally, DFT coupled with the Nudged Elastic Band method was used to calculate the entire reaction coordinate of each monomer reaction using the B97-D3 functional and a hybrid implicit-explicit methanol solvation approach. The thiol-Michael reaction is traditionally rate-limited by the propagation or chain-transfer steps. However, our test case with N-acrylamides and fluorous thiols revealed experimental and computational data produced satisfactory agreement only when we considered a previously unconsidered step that we termed “product decomplexation”, which occurs as the product physically dissociates from other co-reactants after chain transfer. Five monomers were investigated to support this finding, capturing a range of functional groups varying in alkyl chain length (methyl to hexyl) and aromaticity (benzyl and ethylenephenyl). Increased substrate alkyl chain length increased activation energy, explained by the inductive effect. Aromatic ring-stacking configurations significantly impacted the activation energy and contributed to improved molecular packing density. Hydrogen-bonding between reactants increased the activation energy emphasizing the rate-limitation of the product decomplexation. Our findings begin to describe a new structure-kinetic relationship for thiol-Michael acceptors to enable further design of reactive monomers for synthetic polymers and biomaterials.

Graphical abstract: Decomplexation as a rate limitation in the thiol-Michael addition of N-acrylamides

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Supplementary files

Article information

06 Apr 2020
31 Jul 2020
First published
31 Jul 2020

Org. Biomol. Chem., 2020,18, 6364-6377
Article type

Decomplexation as a rate limitation in the thiol-Michael addition of N-acrylamides

J. S. Brown, A. W. Ruttinger, A. J. Vaidya, C. A. Alabi and P. Clancy, Org. Biomol. Chem., 2020, 18, 6364
DOI: 10.1039/D0OB00726A

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