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

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