Temperature dependence of the primary kinetic isotope effect for hydride transfer mediated by a NAD(P)H‐model; discrimination between bent and linear transition states

Heterolytic and homolytic bond dissociation energies of the C4-H 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: C9-H bond rather than C4-H bond for 9,10-dihydroacridine; however, unless specified, the C9-H bond will be described as a C4-H bond for convenience). The results show that the energetic scales of the heterolytic and homolytic bond dissociation energies of the C4-H 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 (C4-H)(.+) 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 C4-H bond dissociation energies in 1-benzyl-1,4-dihydronicotinamide (BNAH), Hantzsch 1,4-dihydropyridine (HEH), and 9,10-dihydroacridine (AcrH(2)) (as the three most typical NADH models) shows that for BNAH and AcrH(2), the heterolytic C4-H bond dissociation energies are smaller (by 3.62 kcal mol(-1)) and larger (by 7.4 kcal mol(-1)), respectively, than the corresponding homolytic C4-H bond dissociation energy. However, for HEH, the heterolytic C4-H bond dissociation energy (69.3 kcal mol(-1)) is very close to the corresponding homolytic C4-H 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 AcrH(2), 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 (C4-H)(.+) bond dissociation energies shows that the homolytic (C4-H)(.+) bond dissociation energies are much larger than the corresponding heterolytic (C4-H)(.+) 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.

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Determination of the C4H Bond Dissociation Energies of NADH Models and Their Radical Cations in Acetonitrile

Zhu

et al. 2003

Chemistry A European J

151

134

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Nicotinamide Coenzyme Models, I. Synthesis and Molecular Structure of Four Isomeric Bis(methoxycarbonyl)[2.2](2,5)pyridinophanes

1986

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As nicotinamide coenzyme models the [2.2](2,5)pyridinophanes 3 -6 were prepared which consist of two interacting nicotinic ester units in the four different orientations possible. 3 -6 were obtained by photolytic sulfur extrusion from the corresponding dithia-[3.3](2,5)pyridinophanes 18-21 the syntheses of which are described. -The molecular structures for all four isomers 3-6 were determined by X-ray analysis. The sterical interactions and some spectroscopic properties of these compounds are discussed on the basis of the structure determinations. Since, 50 years ago, the classical work of Warburg and Karrer') established the structure and coenzyme function of nicotinamide adenine dinucleotide (NAD+) and nicotinamide adenine dinucleotide phosphate (NADP+) the biological importance of these coenzymes has been stressed by the discovery of several hundreds of NAD + -or NADP+-depending enzymatic reactions2). Concerning the mechanism of redox-equivalent transfer in these reactions early experiments led to the conclusion that 1,Cdihydropyridine structures are involved3), and that hydrogen transfer between coenzymes and substrates occurs directly4' and stereo~pecifically~.~). Although a hydride migration is quite generally postulated for this hydrogen transfer, alternative mechanisms like stepwise electron-proton-electron or electron-hydrogen atom transfers have not been ruled out definitely6). Recently, Nikotinamid-Coenzym

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Linear versus bent transition‐state structures in hydride‐transfer processes mediated by NAD(P)H model systems; a theoretical investigation

Kerk

Gerresheim

Verhoeven

1984

Recl. Trav. Chim. Pays‐Bas

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A b s t r a c t : The reaction-coordinate for degenerate hydride-transfer between l,4-dihydropyridine and the pyridinium-ion was searched by MNDO calculations. A linear transition-state (TS) structure is found to be strongly ( 2 16 kcal/mole) preferred over a bent TS. In the former. rotation about the C-hvdride-C axis occurs unimDeded. thus creating a continuum of linear between exo and endo.In the past years, hydride-transfer processes, mediated by 1,4-dihydropyridines related to the NAD(P)H coenzymes have elicited much interest. Mechanistic shows that, for the majority of hydride-acceptors, these processes involve a single-step mechanism. In this context, insight into the factors governing the catalysis and stereochemistry of hydride-transfer under both enzymatic and non-enzymatic conditions, appears to be offered by elucidation of the transition-state (TS) geometry. Temperature dependence of the primary kinetic isotope effect (TDKIE6) was recently introduced5 9' as a tool to revea.1 the TS geometry of hydridetransfer under non-enzymatic conditions. Although the parameters obtained'q systems, both involving a positively charged hydride-acceptor, matched within experimental error, the conclusions drawn were not the same. Thus, while van Gerresheim et a 1 . 7 interpreted their data as indicating a linear "parallel-exo" TS, Powell and Bruice' inferred the occurrence of significant tunneling across a barrier corresponding to a bent "parallel-endo" 'l'S! Therefore it appeared desirable to obtain an impression of the preferred relative orientation of hydride-donor and positively charged substrate in the TS via quantum-chemical calculations on the semi-empirical SCF level. Related calculations on the cyclopropene/cyclopropenium system were recently carried out by Donkersloot and Buck', where a limited search of the configurational space revealed a linear hydride-transfer with a parallelexo TS.In the present approach the complete 1,4-dihydropyridine molecule was chosen as the hydride-donor since it represents the reactive part of NAD(P)H but for the CONH2 group. As extensive modifications of the latter, including substitution by e.g. COCH and CN, have been shown to leave the stereochemica? course of enzymatic hydride-transfer unchanged', its omission in the present calculations appears acceptable. As a model for the positively charged acceptor the pyridinium cation was chosen, which offered the additional advantage of symmetrical transition states. For the calculations, a local version of the MNDO was used. The first series of calculations were carried out with partial geometry optimization: both rings were given a fixed geometry, corresponding to that of pyridineU, except for the C(4)-H bonds. Table I under the heading part. These results suggest that the parallel-endo arrangement indeed enforces a bent TS but at the expense of a much higher barrier than the linear TS resulting from the parallel-exo arrangement. Next, it was studied whether the two transition states described could transform into each other. Thi...

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Temperature dependence of the primary kinetic isotope effect for hydride transfer mediated by a NAD(P)H‐model; discrimination between bent and linear transition states

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References 19 publications

Determination of the C4H Bond Dissociation Energies of NADH Models and Their Radical Cations in Acetonitrile

Determination of the C4H Bond Dissociation Energies of NADH Models and Their Radical Cations in Acetonitrile

Nicotinamide Coenzyme Models, I. Synthesis and Molecular Structure of Four Isomeric Bis(methoxycarbonyl)[2.2](2,5)pyridinophanes

Linear versus bent transition‐state structures in hydride‐transfer processes mediated by NAD(P)H model systems; a theoretical investigation

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