Abstract

Choosing a suitable hydride reducing agent and thermodynamic analysis of reduction mechanisms is facilitated by experimental hydride affinities ΔH, which are reported herein for 28 polarized olefins 1 in acetonitrile (see scheme). The method should also be applicable to ketones, aldehydes, and imines.

Die Wahl eines Hydridreagens und die thermodynamische Analyse des Reduktionsmechanismus werden durch die experimentellen Hydridaffinitäten ΔH erleichtert, die für 28 polarisierte Olefine 1 in Acetonitril ermittelt wurden (siehe Schema). Diese Methode sollte auch auf Ketone, Aldehyde und Imine anwendbar sein.

Five 1-(p-substituted phenyl)-1,4-dihydronicotinamides (GPNAH-1,4-H₂) and five 1-(p-substituted phenyl)-1,2-dihydronicotinamides (GPNAH-1,2-H₂) were synthesized, which were used to mimic NAD(P)H coenzyme and its 1,2-dihydroisomer reductions, respectively. When the 1,4-dihydropyridine (GPNAH-1,4-H₂) and the 1,2-dihydroisomer (GPNAH-1,2-H₂) were treated with p-trifluoromethylbenzylidenemalononitrile (S) as a hydride acceptor, both reactions gave the same products: pyridinium derivative (GPNA⁺) and carbanion SH⁻ by a hydride one-step transfer. Thermodynamic analysis on the two reactions shows that the hydride transfer from the 1,2-dihydropyridine is much more favorable than the hydride transfer from the corresponding 1,4-dihydroisomer, but the kinetic examination displays that the former reaction is remarkably slower than the latter reaction, which is mainly due to much more negative activation entropy for the former reaction. When the formed pyridinium derivative (GPNA⁺) was treated with SH⁻, the major reduced product was the corresponding 1,4-dihydropyridine along with a trace of the 1,2-dihydroisomer. Thermodynamic and kinetic analyses on the hydride transfer from SH⁻ to GPNA⁺ all suggest that the 4-position on the pyridinium ring in GPNA⁺ is much easier to accept the hydride than the 2-position, which indicates that when the 1,4-dihydropyridine is used the hydride donor to react with S, the formed pyridinium derivative GPNA⁺ may return to the 1,4-dihydropyridine by a hydride transfer cycle; but when the 1,2-dihydropyridine is used as the hydride donor, the formed pyridinium derivative can not return to the 1,2-dihydropyridine by the hydride reverse transfer from SH⁻ to GPNA⁺. These results clearly show that the hydride-transfer cycle is favorable for the 1,4-dihydronicotinamides, but unfavorable for the corresponding 1,2-dihydroisomers.

Heterolytic and homolytic bond dissociation energies of the C4H bonds in ten NADH models (seven 1,4-dihydronicotinamide derivatives, two Hantzsch 1,4-dihydropyridine derivatives, and 9,10-dihydroacridine) and their radical cations in acetonitrile were evaluated by titration calorimetry and electrochemistry, according to the four thermodynamic cycles constructed from the reactions of the NADH models with N,N,N′,N′-tetramethyl-p-phenylenediamine radical cation perchlorate in acetonitrile (note: C9H bond rather than C4H bond for 9,10-dihydroacridine; however, unless specified, the C9H bond will be described as a C4H bond for convenience). The results show that the energetic scales of the heterolytic and homolytic bond dissociation energies of the C4H bonds cover ranges of 64.2–81.1 and 67.9–73.7 kcal mol⁻¹ for the neutral NADH models, respectively, and the energetic scales of the heterolytic and homolytic bond dissociation energies of the (C4H)^.+ bonds cover ranges of 4.1–9.7 and 31.4–43.5 kcal mol⁻¹ for the radical cations of the NADH models, respectively. Detailed comparison of the two sets of C4H bond dissociation energies in 1-benzyl-1,4-dihydronicotinamide (BNAH), Hantzsch 1,4-dihydropyridine (HEH), and 9,10-dihydroacridine (AcrH₂) (as the three most typical NADH models) shows that for BNAH and AcrH₂, the heterolytic C4H bond dissociation energies are smaller (by 3.62 kcal mol⁻¹) and larger (by 7.4 kcal mol⁻¹), respectively, than the corresponding homolytic C4H bond dissociation energy. However, for HEH, the heterolytic C4H bond dissociation energy (69.3 kcal mol⁻¹) is very close to the corresponding homolytic C4H bond dissociation energy (69.4 kcal mol⁻¹). These results suggests that the hydride is released more easily than the corresponding hydrogen atom from BNAH and vice versa for AcrH₂, and that there are two almost equal possibilities for the hydride and the hydrogen atom transfers from HEH. Examination of the two sets of the (C4H)^.+ bond dissociation energies shows that the homolytic (C4H)^.+ bond dissociation energies are much larger than the corresponding heterolytic (C4H)^.+ bond dissociation energies for the ten NADH models by 23.3–34.4 kcal mol⁻¹; this suggests that if the hydride transfer from the NADH models is initiated by a one-electron transfer, the proton transfer should be more likely to take place than the corresponding hydrogen atom transfer in the second step. In addition, some elusive structural information about the reaction intermediates of the NADH models was obtained by using Hammett-type linear free-energy analysis.