- Intramolecular kinetic isotope effect in hydride transfer from dihydroacridine to a quinolinium ion. Rejection of a proposed two-step mechanism with a kinetically significant intermediate
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The intramolecular kinetic isotope effect (KIE) for hydride transfer from 10-methyl-9,10-dihydroacridine to 1-benzyl-3-cyanoquinolinium ion has been found to be 5-6 by both 1H NMR and mass spectrometry. This KIE is consistent with other hydride transfers. It is inconsistent with the high intermolecular KIEs derived by fitting to a two-step mechanism with a kinetically significant intermediate complex, and it is inconsistent with the strong temperature dependence of those KIEs. We therefore reject the two-step mechanism for this reaction, and we suggest that other cases proposed to follow this mechanism are in error.
- Perrin, Charles L.,Zhao, Chen
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Read Online
- Nonconventional versus conventional application of pseudo-first-order kinetics to fundamental organic reactions
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Three new analysis procedures for pseudo-first-order kinetics are introduced and applied to eight different fundamental organic reactions. The reactions belong to the following classes: nitroalkane proton transfer, formal hydride ion transfers from NADH model compounds, and SN2 reactions of alkyl halides with ionic and neutral nucleophiles. The three methods consist of (1) half-life dependence of kapp, (2) sequential linear pseudo-first-order correlation, and (3) revised instantaneous rate constant analysis. Each of the three procedures is capable of distinguishing between one- and multistep mechanisms, and the combination of the three procedures provides a powerful strategy for differentiating between the two mechanistic possibilities. The data from the eight reactions chosen as examples clearly show how the procedures work in practice.
- Parker, Vernon D.,Hao, Weifang,Li, Zhao,Scow, Russell
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experimental part
p. 2 - 12
(2012/03/22)
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- The tightness contribution to the Bronsted α for hydride transfer between NAD+ analogues
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It has been shown that the rate of symmetrical hydride transfer reaction varies with the hydride affinity of the (identical) donor and acceptor. In that case, Marcus theory of atom and group transfer predicts that the Bronsted α depends on the location of the substituent, whether it is in the donor or the acceptor, and the tightness of the critical configuration, as well as the resemblance of the critical configuration to reactants or products. This prediction has now been confirmed for hydride transfer reactions between heterocyclic, nitrogen-containing cations, which can be regarded as analogues of the enzyme cofactor, nicotinamide adenine dinucleotide (NAD+). A series of reactions with substituents in the donor gives Bronsted α of 0.67 ± 0.03 and a tightness parameter, τ of 0.64 ± 0.06. With substituents in the acceptor α = 0.32 ± 0.03 and τ = 0.68 ± 0.08. The reactions are all spontaneous, with equilibrium constants between 0.4 and 3 x 104, and the two sets span about the same range of equilibrium constants. The two τ values are essentially identical with an average value of 0.66 ± 0.05. These results can be semiquantitatively mimicked by rate constants calculated for a linear, triatomic model of the reaction. Variational transition state theory and a physically motivated but empirically calibrated potential function were used. The computed rate constants generate an α value of 0.56 if the hydride affinity of the acceptor is varied and an α of 0.44 if the hydride affinity of the donor is varied. The calculated kinetic isotope effects are similar to the measured values. A previous error in the Born charging term of the potential function has been corrected. Marcus theory can be successfully fitted to both the experimental and computed rate constants, and appears to be the most compact way to express and compare them. The success of the linear triatomic model in qualitatively reproducing these results encourages the continued use of this easily conceptualized model to think about group, ion, and atom transfer reactions.
- Lee, In-Sook Han,Chow, Kim-Hung,Kreevoy, Maurice M.
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p. 7755 - 7761
(2007/10/03)
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- Steric and kinetic isotope effects in the deprotonation of cation radicals of NADH synthetic analogues
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The deprotonation rate constants and kinetic isotope effects of the cation radicals have been determined by combined use of direct electrochemical techniques at micro- and ultramicroelectrodes, redox catalysis, and laser flash photolysis, over a extended
- Anne, Agnès,Fraoua, Sylvie,Hapiot, Philippe,Moiroux, Jacques,Savéant, Jean-Michel
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p. 7412 - 7421
(2007/10/02)
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- SIMPLE PREPARATIONS OF C-4-TERT-BUTYLATED NADH/NAD+ ANALOGS
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The addition of tert-butyl Grignard reagent to the 1-benzyl-3-carbamoylpyridinium salt (1) gives a mixture C-4-(2), C-6-(3), and C-2-tert-butylated dihydronicotinamides (4) in which the desired 1,4-isomer predominates.Stable cristalline 1-benzyl-4-tert-butyl-1,4-dihydronicotinamide (2) can be easily isolated.Oxidation of the product with the 1-benzyl-3-cyanoquinolinium ion (6) was found to be strongly solvent-dependent.In acetonitrile, exclusive hydride transfer gives the corresponding C-4-tert-butylated pyridinium ion (5).In methanol, an interesting tert-butyl transfer from 1,4-dihydronicotinamide (2) to quinolinium (6) occurs competitively, and predominates in the presence of a catalytic amount of formic acid; the resulting C-4-tert-butylated 1,4-dihydroquinoline derivative (8) can be readily isolated.
- Anne, Agnes
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p. 2331 - 2337
(2007/10/02)
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- Dynamics of hydride transfer between NAD+ analogues
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Primary kinetic isotope effects (KIE) for hydride transfer between 10-methylacridan and 1-benzyl-3-cyanoquinolinium perchlorate have been measured in 15 different solvents. There is a reduction of the KIE from 5.2 to about 2.9 in the more viscous, nonhydroxylic solvents. Hydroxylic solvents give the larger KIE regardless of their viscosity. These results suggest a three-step process. In the first step, the heavy atoms and solvent are reorganized to a configuration intermediate between reactants and products, while the hydride retains its original attachment. In the second stage, the hydride is transferred, probably by tunneling. In the final step the products are stabilized by further solvent and heavy-atom reorganization. For nonhydroxylic solvents, translational and rotational diffusion governs the heavy-atom reorganization steps and, therefore, determines which step is rate-limiting. Only when the heavy-atom reorganizations are fast is the second step rate-limiting and the KIE maximized. The rate constant for the tunneling process is assumed to be solvent-independent. It is of the right order of magnitude to compete with solvent relaxation. Changes in rate constant, k, and equilibrium constant, K, are modest, but there is a linear correlation between ln k and ln K, with a slope of 0.87. This slope suggests that it is the third step, rather than the first, which shares rate-limiting character with the second. There is no visible trend toward a maximum isotope effect at K = 1.
- Kreevoy, Maurice M.,Kotchevar, Ann T.
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p. 3579 - 3583
(2007/10/02)
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- Structure Sensitivity of the Marcus λ for Hydride Transfer between NAD+ Analogues
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Thirty-five rate constants, kij, for transfer of hydride between various pyridinium, quinilinium, acridinium, and phenantridinium ions spanning a range of over 10E11 in their equilibrium constants Kij and over 10E6 in kij
- Kreevoy, Maurice M.,Ostovic, Drazen,Lee, In-Sook Han,Binder, David A.,King, Gary W.
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p. 524 - 530
(2007/10/02)
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- Marcus Theory of Hydride Transfer from an Anionic reduced Deazaflavin to NAD+ Analogues
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Eighteen rate constants, kij for hydride transfer from the conjugate base of 1,5-dihydro-3,10-dimethyl-5-diazaisoalloxazine to a variety of pyridinium, quinolinium, phenanthridinium, and acridinium ions have been determined. (All the oxidizing agents can be regarded as analogues of NAD+.) The kij values span 7 powers of 10 and the corresponding equilibrium constants, Kij, span more than 13 powers of 10.For reactions with ΔG0 near zero, the kij values are close to those given by modified Marcus theory (ref 10).However, with more negative ΔG0 values, the observed kij increase more strogly than the calculated values.Agreement can be produced by making the standard free energy of precursor complex formation, symbolized WT +- here, to indicate that it applies to reactants of opposite charge, a linear function of ΔG0, and treating the slope and interrcept of the linear relation as adjustable parameters.The best fit is obtained with WT+-(in kJ*mol-1)=-9.4+0.11ΔG0.An avarage discrepancy between calculated and observed ln kij values of 0.5 is achieved, which is a good as the overall fit achieved for hydride transfer from neutral NADH analogues to NAD+ analogues (ref 10).The form and the parameterization of Wf are shown to be a physically reasonable approximation for reactions with ΔG00.These results strengthen the conclusion (ref 10) that a wide range of hydride transfer rates can be quantitavely understood without introducing high-energy metastable intermediates (radicals and radical ions).
- Lee, In-Sook Han,Ostovic, Drazen,Kreevoy, Maurice
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p. 3989 - 3993
(2007/10/02)
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- Hydride Transfer and Oxyanion Addition Equilibria of NAD+ Analogues
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Equilibrium constants, K, have been determined for the reduction of 10-methylacridinium ion by 15 N-heterocyclic hydride donors: acridine, quinoline, pyridine, and phenanthridine derivatives.The solvent was a mixture of 2-propanol and water in the ratio 4 : 1 by volume.Reduction potentials have been estimated for the corresponding cations in aqueous solution by assuming that the K's would be the same and accepting -361 mV as the reduction potential of the 3-(aminocarbonyl)-1-benzylpyridinium ion.These reduction potentials span 430 mV.Values of pKR have also been determined for six of the cations in the same solvent.For derivatives of the same ring system, -ΔlogK is approximately equal to ΔpKR, but a 4 log unit discrepancy appears when phenanthridine derivatives are compared with the 9-methylacridinium ion.
- Ostovic, Drazen,Lee, In-Sook Han,Roberts, Roger M. G.,Kreevoy, Maurice M.
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p. 4206 - 4211
(2007/10/02)
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- Regioselectivity of Hydride Transfer to and between NAD+ Analogues
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The reaction of 1-methyl- or 1-benzylquinolinium compounds, also bearing an electron-withdrawing substituent in the 3-position, with NaBH4, gives mixtures of the corresponding 1,2-dihydroquinolines and 1,4-dihydroquinolines in which the 1,2-dihydro derivatives usually predominate.The 1,2-derivatives can be isolated.The 1,2-isomers react with the quinolinium salts, giving the 1,4-isomers and regenerating quinolinium salts.This bimolecular isomerization can be used to convert a mixture of isomers to the 1,4-isomer on a preparative scale. 3-Cyano-1,2-dihydro-1-methylquinoline also isomerizes to the 1,2-isomer in the crystalline solid.The major first product of NaBH4 reduction of 3-(aminocarbonyl)-1-benzylpyridinium ion is the 1,6-dihydro derivative.This also isomerizes to the 1,4-dihydro compound in the presence of the pyridinium ion.Reduction of quinolinium derivatives with Na2S2O4 or a dihydropyridine directly produces the 1,4-isomer predominantly.Reduction of 3-(aminocarbonyl)-1-benzylpyridinium ion with Na2S2O4 in D2O gives the 1,4-dihydro derivative, but 8percent of the deuterium is in the 2-position; presumably by reversible isomerization.This deuterium redistribution may have important consequences for the interpretation of isotope effects.
- Roberts, R. M. G.,Ostovic, D.,Kreevoy, M. M.
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p. 2053 - 2056
(2007/10/02)
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- Pseudobases from Quinolinium-Salts and Alcoxides
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The quaternary 3-cyano-quinolinium salt (1b) reacts in aqueous buffer solution (pH 7.5-12) to oxy-di(1,4-dihydroquinoline) (7), which gives on addition of alcohols or oximes in high yields the alcoxy-dihydroquinolines (8a-c) or dihydroquinolyl-oximethers (8d-f). - Key words: Quinolinium Salts, Pseudobases, Insertion Reaction
- Guendel, Wolf-H.,Berenbold, Helmut
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p. 745 - 749
(2007/10/02)
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