Thermodynamic Parameters of Elementary Steps for 3,5-Disubstituted 1,4-Dihydropyridines To Release Hydride Anions in Acetonitrile

Abstract

A series of 3,5-disubstituted 1,4-dihydropyridine derivatives including the derivative with two chiral centers, 6H (R 2 = CH 3 , CH 2 Ph), as a new type of organic hydride source were synthesized and characterized. The thermodynamic driving forces (defined as enthalpy changes or standard redox potentials) of the 6 elementary steps for the organic hydrides to release hydride ions in acetonitrile were measured by isothermal titration calorimetry and electrochemical methods. The impacts of the substituents and functional groups bearing the N1 and C3/C5 positions on the thermodynamic driving forces of the 6 elementary steps were examined and analyzed. Moreover, the results showed that the reaction mechanism between the chiral organic hydride and activated ketone (ethyl benzoylformate) was identified as the concerted hydride transfer pathway based on the thermodynamic analysis platform. These valuable and crucial thermodynamic parameters will provide a broadly beneficial impact on the applications of 3,5-disubstituted 1,4-dihydropyridine derivatives in organic synthesis and pharmaceutical chemistry.

Comparison between 1,2-Dihydropyridine and 1,4-Dihydropyridine on Hydride-Donating Ability and Activity

“…Two dihydrogen isomers of PNAH, HEH, and PYH were synthesized according to the literature methods and were identified by 1H NMR; the detailed data are listed in the Supporting Information [ 20 , 22 , 28 , 29 , 30 , 31 ]. The enthalpy change of the two dihydrogen isomers reacting with hydride acceptors was determined in acetonitrile using an isothermal titration calorimeter (CSC-4200 ITC) at 298 K as described previously ( Figure 1 ) [ 32 ]. All kinetic tests were monitored in 298 K dry and anaerobic acetonitrile using an Applied Photophysics SX.18MV-R stopped-flow apparatus ( Figure 2 ).…”

Thermodynamics of the elementary steps of organic hydride chemistry determined in acetonitrile and their applications

“…•+ ) and ΔH PD (DH [60][61][62][63] and great reduction ability. 24,25 Given that our research interest has been focused on exploring the thermodynamic driving forces on each elementary step of organic hydride compounds releasing hydride, in 2018, we successfully synthesized 23 3,5-disubstituted-1,4-dihydropyridines (denoted as OH 2 here for clarity) with diverse electron-withdrawing groups at the 3,5position and N 1 -position (Scheme 9), 39 and established 23 "Molecule ID Cards" of OH 2 to quantitatively scale the ) hydride-, hydrogen-, proton-, and electron-donating abilities of OH 2 and its reaction active intermediates in acetonitrile to be used to accurately deduce the reduction mechanism. The thermodynamic results are displayed in Table 5.…”

“…24,25 A series of organic hydride compounds (abbreviated as hydrides and denoted as XH 2 herein) has been designed and synthesized as models to mimic the NADH coenzyme and further investigate the hydride transfer thermodynamics and mechanisms. 26–50…”

“…Zhu's group designed and synthesized a series of organic hydride compounds (XH 2 ) as models to mimic the NADH coenzyme and typical unsaturated compounds (Y) as hydride acceptors, and systematically investigated the thermodynamics of the elementary steps by combining isothermal titration calorimetry (ITC) and electrochemical techniques, and the mechanisms of hydride transfer. 26–50 To clearly show all the important data and the relations, interaction, interdependence and conversion among organic hydride compounds (XH 2 ) and related intermediates, Zhu's group created the “Molecule ID Card” to display the thermodynamic data for XH 2 releasing hydride and XH + accepting hydride in acetonitrile. 26–50…”

“…26–50 To clearly show all the important data and the relations, interaction, interdependence and conversion among organic hydride compounds (XH 2 ) and related intermediates, Zhu's group created the “Molecule ID Card” to display the thermodynamic data for XH 2 releasing hydride and XH + accepting hydride in acetonitrile. 26–50…”