Water‐Assisted and Catalyst‐Free Hetero‐Michael Additions: Mechanistic Insights from DFT Investigations

Abstract

The reaction mechanism of six catalyst‐free hetero‐Michael addition reactions in water has been investigated using DFT calculations. Our theoretical results revealed the direct involvement of multiple water molecules in the transition states. The water molecules play a catalytic role in lowering the activation barrier for the three thia‐Michael reactions. Concerted transition state with two bridging water molecules yields the lowest energy barrier. The formation of a hydrogen bonding network via one or more water molecules in the transition state facilitates proton shuttling from the nucleophile to the electrophile. For the aza‐Michael reactions considered, they follow a stepwise mechanism involving the formation of a stable zwitterionic intermediate. In these cases, water influences the reactions via strong (nonspecific) solvent effect and the catalytic role of water is less important for enones that adopt a stable s‐cis conformation. The calculated low reaction barriers (44–83 kJ/mol) of the six studied reactions are in excellent accord with the observed facile hetero‐Michael reactions in water.

Mechanistic aspects of thiol additions to Michael acceptors: Insights from computations

“…Wong et al 19 used explicitly solvated models to study systems where solvent molecules play an integral role in the TS. They used a combination of MN15 density functional and GFN2‐xTB semiempirical calculations (using their QMTSDock program) to analyze the impact of water molecules on transition states of catalyst‐free, water‐assisted thiol additions.…”

Three-Dimensional Quantitative Structure and Activity Relationship of Flavones on Their Hypochlorite Scavenging Capacity

“…Accordingly, the intermediates formed are neutral species, not the typical high-energy carbocations. The involvement of a water molecule, via multiple hydrogen bonds (Figure ), is crucial for the stabilization of the transition states and intermediates . This is the reason why the mono- and di-chlorination reactions are characterized a low activation barrier.…”

“…The involvement of a water molecule, via multiple hydrogen bonds (Figure 7), is crucial for the stabilization of the transition states and intermediates. 54 This is the reason why the mono-and di-chlorination reactions are characterized a low activation barrier. Moreover, the computational result supported the idea that the actual reactive species is hypochlorous acid instead of the hypochlorite anion.…”

Discovering and Evaluating the Reducing Abilities of Polar Alkanes and Related Family Members as Organic Reductants Using Thermodynamics

“…Polar alkane (YH 2 ) is one of the significant bioactive molecules as well as polar alkene (Y), and many clinical drugs have the polar alkane and polar alkene structures as key core skeletons (Scheme ). − Polar alkanes could be easily prepared from polar alkenes by Michael addition reactions , or hydrogenation reactions. − Since our group have long been interested in the elementary step thermodynamics on hydride transfer of NADH models and unsaturated compounds, in 2013, we focused on determining the thermodynamic driving forces on 12 elementary steps of the mutual transformation between Y or YH – in acetonitrile (Scheme ). It is well-known that the hydrogenation reactions always consist of two hydrogen ions (H – –H + ) or two hydrogen atoms (H • –H • ) transferring from organic hydrogen molecule reductants, such as Hantzsch ester (HEH 2 ), , benzothiazoline (BTH 2 ), , and dihydro-phenanthridine (PH 2 ), to unsaturated chemical bonds.…”

“…Since the thermodynamic driving forces of the one-step hydride transfer step (step 3, −3.8 kcal/mol) is 30. 4 and hydrogen atom transfer step (step 2), respectively, the mechanism of the hydride transfer reaction from 29H − to BNA + should be one-step hydride transfer.…”