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Electron transfer to [(C5H5)Fe(CO)2] 2 gives an anion radical in which the electronic configuration of one Fe no longer conforms to the '18 e' rule and which undergoes cleavage of the metal-metal bond with a rate constant equal to 1060 s-1 at 273 K and an activation energy of 15.7 kcal mol-1 (1 kcal = 4.18 kJ) in acetonitrile.

A reinvestigation of the formal hydride transfer reaction of 1-benzyl-3-cyanoquinolinium ion (BQCN(+)) with N-methyl-9,10-dihydroacridine (MAH) in acetonitrile (AN) confirmed that the reaction takes place in more than one step and revealed a new mechanism that had not previously been considered. These facts are unequivocally established on the basis of conventional pseudo-first-order kinetics. It was observed that even residual oxygen under glovebox conditions initiates a chain process leading to the same products and under some conditions is accompanied by a large increase in the apparent rate constant for product formation with time. The efficiency of the latter process, when reactions are carried out in AN with rigorous attempts to remove air, is low but appears to be much more pronounced when MAH is the reactant in large excess. On the other hand, the intentional presence of air in AN ([air] = half-saturated) leads to a much greater proportion of the chain pathway, which is still favored by high concentrations of MAH. The latter observation suggests that a reaction intermediate reacts with oxygen to initiate the chain process in which MAH participates. Kinetic studies at short times show that there is no kinetic isotope effect on the initial step in the reaction, which is the same for the two competing processes. Our observation of the chain pathway of an NADH model compound under aerobic conditions is likely to be of importance in similar biological processes where air is always present.

One representative type of heterocyclic compound that can release a hydride ion is 7,8-dihydro-9-methylcaffeine (CAFH). The one-electron oxidation potential of CAFH [-0.294 (V vs Fc(+/0))] and the one-electron reduction potential of CAF(+) [-2.120 (V vs Fc(+/0))] were obtained using two different methods, CV and OSWV. Applying titration calorimetry data in thermodynamic cycles, the enthalpies of CAFH releasing a hydride ion [57.6 kcal/mol] and releasing a hydrogen atom [80.3 kcal/mol] and of its radical cation CAFH(•+) releasing a proton [33.0 kcal/mol] and releasing a hydrogen atom [38.4 kcal/mol] have been determined. Several conclusions can be drawn from the thermodynamic results: (1) CAFH is a very good single-electron donor whose single-electron oxidation potential is much less positive than that of NAD(P)H model compound BNAH [E(ox) = 0.219 V vs Fc(+/0)]. (2) The single-electron reduction potential of CAF(+) is much more negative than that of BNA(+) [E(red) = -1.419 V], which means that CAF(+) is not a good electron acceptor. Furthermore, CAFH is a very good hydride donor compared to BNAH. The results of non-steady-state kinetic studies, for the reaction of CAFH and AcrH(+)ClO(4)(-), show that the ratio of t(0.50)/t(0.05) is larger than 13.5 and the ratio of k(init)/k(pfo) is larger than 1. The pseudo-first-order rate constants obtained at different reaction stages decrease with the time, and the kinetic isotope was observed to be small at a short reaction time and slowly increases to 3.72 with the progress of the reaction. These kinetic results clearly display that the hydride transfer of CAFH to AcrH(+) in acetonitrile is not a one-step mechanism, while the thermodynamic results show that CAFH is a very good electron donor. The combination of the kinetic results with the thermodynamics analysis shows that the hydride transfer of the caffeine derivative CAFH takes place by a two-step reversible mechanism and there is an intermediate in the reaction.

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. © 2011 Wiley Periodicals, Inc. Int J Chem Kinet 44: 2–12, 2012

The instantaneous rate constant (IRC)–time profiles for single-step mechanisms are straight lines with zero slope. The IRC–time profiles for reactions taking place in more than a single step depend upon whether decay of reactant or evolution of product concentration is monitored. When reactant decay is monitored, the IRC–time plot extrapolated to zero time is equal to the rate constant for the initial step (kf) in the reaction while the IRC–time profile for product evolution extrapolates to zero at t = 0. The IRC–time profiles for monitoring reactant decay and product evolution converge to a plateau value which can be equated to the rate constant under steady-state conditions (ks.s). Two independent procedures for calculating IRC–time profiles were developed and tested for both simple and complex mechanisms. The first method is initiated with a least squares correlation over the first 11 points of a 2000-point ln(1−ER)−time profile (ER designates extent of reaction). The IRC at the midpoint (IRC(6)) of the time interval is assigned the value of −S (where S is the slope of the correlation). The second correlation is over points 2–12 and provides a value of IRC(7). This procedure is continued until IRC(6) to IRC(1995) have been generated. The second method involves a 5th order polynomial smooth of the (1−ER)/time profile before calculating IRC at the midpoints between successive points. The limitations of the two IRC procedures are discussed. The IRC procedures are applied to experimental absorbance–time profiles for the acyl transfer reactions of p-nitrophenyl acetate to hydroxide ion in water and in aqueous acetonitrile. In water, no significant deviations from pseudo first-order kinetics were observed. A dramatic change in IRC/time profiles was observed on changing solvents to aqueous acetonitrile. Under the latter conditions the IRC analyses were observed to be consistent with a 2-step mechanism. Copyright © 2006 John Wiley & Sons, Ltd.

In recent years, we have reported that a number of organic reactions generally believed to follow simple second-order kinetics actually follow a more complex mechanism. This mechanism, the reversible consecutive second-order mechanism, involves the reversible formation of a kinetically significant reactant complex intermediate followed by irreversible product formation. The mechanism is illustrated for the general reaction between reactant and excess reagent under pseudo-first-order conditions in eq. i where k f' is the pseudo-first-order rate constant equal to k f[Excess Reagent]. Reactant + Excess reagent = Reactant complex = Products (i) The mechanisms are determined for the various systems, and the kinetics of the complex mechanisms are resolved by our "non-steady-state kinetic data analysis". The basis for the non-steady-state kinetic method will be presented along with examples. The problems encountered in attempting to identify intermediates formed in low concentration will be discussed.

Charge-transfer (CT) spectra of the π−π complexes formed by several aromatic amines and nitrogen heterocycles [acting as donors (Ds)] with acceptor A [A = tetracyanoethylene (TCNE), chloranil (CA)]...

Establishing thermodynamic parameters for electron transfer reactions involving redox proteins is essential for a complete description of these important reactions. While various methods have been developed for measuring the Gibbs free energy change (Delta G(HR) or E(m)) for the protein half-reactions, deconvolution of the respective contributions of enthalpy (Delta H(HR)) and entropy (Delta S(HR)) changes is much more challenging. In the present work, an approach is developed using isothermal titration calorimetry (ITC) that allows accurate determination of all of these thermodynamic parameters for protein electron transfer half-reactions. The approach was validated for essentially irreversible and reversible electron transfer reactions between well-characterized mediators and between mediators and the protein cytochrome c. In all cases, the measured thermodynamic parameters were in excellent agreement with parameters determined by electrochemical methods. Finally, the calorimetry approach was used to determine thermodynamic parameters for electron transfer reactions of the nitrogenase Fe protein [4Fe-4S](2+/+) couple in the absence or presence of MgADP or MgATP. The E(m) value was found to change from -290 mV in the absence of nucleotides to -381 mV with MgATP and -423 mV with MgADP, consistent with earlier values. For the first time, the enthalpy (Delta H(HR)) and entropy (Delta S(HR)) contributions for each case were established, revealing shifts in the contribution of each thermodynamic parameter induced by nucleotide binding. The results are discussed in the context of current models for electron transfer in nitrogenase.

The kinetics of the hydride exchange reaction between NADH model compound 10-methyl-9,10-dihydroacridine (MAH) and 1-benzyl-3-cyanoquinolinium (BQCN+) ion in acetonitrile were studied at temperatures ranging from 291 to 325 K. The extent of reaction-time profiles during the first half-lives are compared with theoretical data for the simple single-step mechanism and a 2-step mechanism involving initial donor/acceptor complex formation followed by unimolecular hydride transfer. The profiles for the reactions of MAH deviate significantly from those expected for the simple single-step mechanism with the deviation increasing with increasing temperature. The deviation from simple mechanism behavior is much less pronounced for the reactions of 10-methyl-9,10-dihydroacridine-10,10-d2 (MAD) which gives rise to extent of reaction dependent apparent kinetic isotope effects (KIEapp). Excellent fits of the experimental extent of reaction-time profiles with theoretical data for the 2-step mechanism, in the pre-steady-state time period, were observed in all cases. Resolution of the kinetics of the hydride exchange reaction into the microscopic rate constants over the entire temperature range resulted in real kinetic isotope effects for the hydride transfer step ranging from 40 (291 K) to 8.2 (325 K). That the reaction involves significant hydride tunnelling was verified by the magnitudes of the Arrhenius parameters; Ea D - EaH = 8.7 kcal mol-1 and AD/AH = 8 x 10(4). An electron donor acceptor complex (lambda max = 526 nm) was observed to be a reaction intermediate. Theoretical extent of reaction-time profile data are discussed for the case where a reaction intermediate is formed in a non-productive side equilibrium as compared to the case where it is a real intermediate on the reaction coordinate between reactants and products. The common assumption that the two cases are kinetically indistinguishable is shown to be incorrect.

The experimental recording of spectrophotometric data suitable for detailed kinetic analysis and reaction mechanism determination is covered early in the chapter with examples of experiments and subsequent data treatment on a variety of different chemical systems. Several new methods to distinguish between single-step and complex reaction mechanisms are described in detail. The fundamental organic reactions covered in more detail were limited to recent work on four general reaction types. These include (1) proton transfer reactions of nitroalkanes and related compounds, (2) S N 2 reactions of CH 3 -X where X is the leaving group, (3) electrophilic aromatic substitution, and (4) hydride transfer reactions of NADH/NAD + model systems. In all cases possible, discussion of the experimental studies was complemented by computational studies on the same reaction systems. The experimental kinetic studies all involved short-lived intermediates and could only distinguish the complex mechanisms involved from the mechanism with a single transition state. Computational studies confirmed the complex nature of the mechanisms and provided structures for the likely intermediates in the experimental reactions. The energies of the noncovalently bonded intermediates were highly dependent on the computational method and therefore could not confirm the apparent Gibbs free energies of the transition states.

The resolution of the kinetics of the reversible consecutive second-order reaction mechanism involving the formation of a kinetically significant intermediate, which does not reach steady state before late in the first half-life, followed by an irreversible product-forming reaction is discussed. It is shown that an apparent second-order rate constant kapp and an extent of reaction–time profile are the only experimental data necessary for the evaluation of kf and kb (the forward and reverse rate constants) as well as kp (the microscopic rate constant for the product forming reaction). When the product-forming step involves the cleavage of a CH bond, for which there is a deuterium kinetic isotope effect on kp, the resolution of the kinetics is enhanced. In this case, the experimental data include two apparent rate constants ( and ) and two extent of reaction–time profiles, one for normal reactants and the other for isotopically substituted reactants. Under these circumstances, a unique highly resolved experimental to theoretical data fit is found that results in the evaluation of all four microscopic rate constants: and . An alternative, when a kinetic isotope effect is not involved, is to fit the extent of reaction–time profiles for two or more concentrations of reactants concurrently. This procedure results in the resolution of the three microscopic rate constants for the reaction. Copyright © 2001 John Wiley & Sons, Ltd.

9-Substituted acridine radical cations undergo facile hydrogen atom abstraction reactions with cyclohexa-1,4-diene in dichloromethane–Bu4NPF6 (0.2 M). The kinetics of the reaction were studied by derivative cyclic voltammetry and observed to conform to the EC mechanism (charge transfer followed by irreversible first-order reaction). The products of the reactions are the protonated acridine substrate and dimer–substrate adducts of cyclohexa-1,4-diene. A comparison is made between the reactions of 9-phenylacridine and 9-phenylanthracene radical cations. The former undergoes rapid hydrogen atom abstractions, while the latter slowly dimerizes in the absence of nucleophiles. It is suggested that localization of the odd electron in a p-orbital on nitrogen imparts the hydrogen abstraction activity of the radical cation. Since there are no free p-orbitals on the carbon atoms of the aromatic rings in arene radical cations the hydrogen atom abstraction reaction pathway is not observed.

The kinetics of the reactions between 9,10-dimethylanthracene radical cation and 2,6-diethylpyridine (DEP) in dichloromethane–Bu4NPF6 (0.2 M) as well as that with 2,6-dimethylpyridine (LUT) in acetonitrile–Bu4NPF6 (0.1 M) were studied at temperatures ranging from 252 to 312 K. In the time period before steady-state was reached for both reaction systems at all temperatures, the apparent deuterium kinetic isotope effects (KIEapp) were observed to increase with extent of reaction. The KIEapp–extent of reaction profiles provide strong evidence for a two-step mechanism [eqns. (i),(ii)] consisting of reversible complex formation prior to rate determining proton transfer.(i) ArCH3+˙ + B ⇌ ArCH3+˙/B Keq = kf/kb(ii) ArCH3+˙/B → ArCH2˙ + BH+ kp(iii) ArCH2˙ + ArCH3+˙ + B → Products fast Resolution of the kinetics into the relevant microscopic rate constants resulted in real deuterium kinetic isotope effects (KIEreal) which are much larger than KIEapp and were observed to increase markedly with decreasing temperature. Values of KIEreal ranged from 62 to 247. It is concluded that a significant degree of quantum mechanical tunneling is involved for both reaction systems. Activation parameters for apparent and microscopic rate constants are discussed with reference to the proton tunneling effect.

Stopped-flow spectrophotometry was examined as a tool to assign midpoint potentials to protein redox half-reactions. The method involves the rapid mixing of protein and electron transfer mediator solutions and the determination of the absorbance of at least one of the reacting species or products at equilibrium. The utility of the method was demonstrated with two different redox proteins (nitrogenase iron protein and cytochrome c ) with very different midpoint potentials. The overall errors ranged from about ±0.5 to 3 mV. Advantages of the method include short times required for the experiments, the precision and accuracy of the method in comparison to other methods, the conservative use of valuable protein in the experiments and the ease of obtaining midpoint potentials for redox protein half-reactions, and the potential range covered by a single electron transfer mediator when the method involves mediated electron transfer. It is concluded that the stopped-flow spectrophotometry should be considered the method of choice for determining protein midpoint potentials.

The nitrogenase iron (Fe) protein binds two molecules of MgATP or MgADP, which results in protein conformational changes that are important for subsequent steps of the nitrogenase reaction mechanism. In the present work, isothermal titration calorimetry has been used to deconvolute the apparent binding constants (K'a1 and K'a2) and the thermodynamic terms (delta H' degree and delta S' degree) for each of the two binding events of MgATP or MgADP to either the reduced or oxidized states of the Fe protein from Azotobacter vinelandii. The Fe protein was found to bind two nucleotides with positive cooperativity and the oxidation state of the [4Fe-4S] cluster of the Fe protein was found to influence the affinity for binding nucleotides, with the oxidized ([4Fe-4S]2+) state having up to a 15-fold higher affinity for nucleotides when compared to the reduced ([4Fe-4S]1+) state. The first nucleotide binding reaction was found to be driven by a large favorable entropy change (delta S' degree = 10-21 cal mol-1 K-1), with a less favorable or unfavorable enthalpy change (delta H' degree = +1.5 to -3.3 kcal mol-1). In contrast, the second nucleotide binding reaction was found to be driven by a favorable change in enthalpy (delta H' degree = -3.1 to -13.0 kcal mol-1), with generally less favorable entropy changes. A plot of the associated enthalpy (-delta H' degree) and entropy terms (-T delta S' degree) for each nucleotide and protein binding reaction revealed a linear relationship with a slope of 1.12, consistent with strong enthalpy-entropy compensation. These results indicate that the binding of the first nucleotide to the nitrogenase Fe protein results in structural changes accompanied by the reorganization of bound water molecules, whereas the second nucleotide binding reaction appears to result in much smaller structural changes and is probably largely driven by bonding interactions. Evidence is presented that the total free energy change (delta G' degree) derived from the binding of two nucleotides to the Fe protein accounts for the total change in the midpoint potential of the [4Fe-4S] cluster.

Apparent deuterium kinetic isotope effects (KIEapp) of four different methylarene radical cation−pyridine base reactions in dichloromethane (0.2 M tetrabutylammonium hexafluorophosphate) were observed to increase toward a constant value with increasing extent of reaction. The reactions were studied by derivative cyclic voltammetry (DCV), and rate constants were assigned by comparing the experimental with the theoretical DCV data. The kinetic results rule out a simple second-order proton-transfer reaction and implicate a mechanism in which a complex is first formed that then undergoes proton transfer, followed by separation of the products. That KIEapp are extent of reaction-dependent is observed before steady-state is reached. The concurrent analysis of kinetic data for the reactions of both ArCH3•+ and ArCD3•+ with bases under non-steady-state conditions facilitates the resolution of the apparent rate constant [kapp = kfkp/(kb + kp)] into the microscopic rate constants (kf, kb, and kp) for the individual...

Radical cations of 9-aryl- and 9,10-diarylanthracenes with substituents on the 4 position of the aryl rings (PA-X+ and DPA-X+, respectively) have been generated by photoionization in acetonitrile. Their reactivity with n-butylamine (n-BuNH2) and 1,4-diazabicyclo[2.2.2]octane (DABCO) and a number of anions (CH3CO2-, Br-, CN-, N3-) has been studied using nanosecond laser flash photolysis. Reactions proceed by electron transfer and/or nucleophilic addition. Using PA-X and DPA-X as chemical probes, simple criteria are established that allow one mechanistic pathway to be distinguished from another. When electron transfer is thermodynamically feasible, this pathway dominates (e.g., DABCO and azide). For endothermic electron transfer, addition is not necessarily the preferred ultimate reaction pathway and an inner sphere process (addition/homolysis) can compete. In these cases other, criteria including steric factors and the strength of the incipient bond become important. Simple kinetic criteria and an approach to estimate the thermochemistry of the addition process are developed. It is clear from these studies that reactivity trends in the radical cation chemistry cannot be generalized as easily as those in carbocation chemistry. This has some implications concerning the development and utility of "clock" reactions in radical cation chemistry.

It is proposed that both polar and radical reactions should be considered when discussing radical ion reactivity. The fact that only the polar reactivity has dominated previous discussions is pointed out. It is argued that if the configuration mixing model is applicable for the estimation of radical cation-nucleophile (or cation-nucleophile) combination reaction barriers, the theory should also explain the reactivity of the proton toward anionic nucleophiles. The model severely overestimates reaction barriers for the latter reactions. The discussion is centered around the following hypothesis: In the absence of severe steric effects, the reactivity of radical ions, especially evident in the reactions with radicals (for example very few radical cations react with dioxygen at measurable rates), is dominated by the degree of coupling between charge and radical centers. Evidence from the literature supporting the hypothesis is presented for a number of different classes of radical ion reactions. Further work to test the validity of the hypothesis is proposed for many of the reaction types. Triarylmethyl radicals and carbenium ions are suggested as models to which the radical and polar reactivities of 9,10-diarylanthracene radical cations may be compared. It is concluded that the radical cation/carbenium ion comparison (for the reaction with acetate ion) would show similar reactivities while the radical cation/free radical comparison (for the reaction with dioxygen) would fail, since no reaction at all would be observed with the radical cation while the free radical reacts rapidly.

Nitrogenase-catalyzed substrate reduction reactions require electron transfer between two component proteins, the iron (Fe) protein and the molybdenum-iron (MoFe) protein, in a reaction that is coupled to the hydrolysis of MgATP. In the present work, electron transfer (Marcus) theory has been applied to nitrogenase electron transfer reactions to gain insights into possible roles for MgATP in this reaction. Evidence is presented indicating that an event associated with either MgATP binding or hydrolysis acts to gate electron transfer between the two component proteins. In addition, evidence is presented that the reaction mechanism can be fundamentally changed such that electron transfer becomes rate-limiting by the alteration of a single amino acid within the nitrogenase Fe protein (deletion of Leu 127, L127 Delta). These studies utilized the temperature dependence of intercomponent electron transfer within two different nitrogenase complexes: the wild-type nitrogenase complex that requires MgATP for electron transfer and the L127 Delta Fe protein-MoFe protein complex that does not require MgATP for electron transfer. It was found that the wild-type nitrogenase electron transfer reaction did not conform to Marcus theory, suggesting that an adiabatic event associated with MgATP interaction precedes electron transfer and is rate-limiting. Application of transition state theory provided activation parameters for this rate-limiting step. In contrast, electron transfer from the L127 Delta Fe protein variant to the MoFe protein (which does not require MgATP hydrolysis) was found to be described by Marcus theory, indicating that electron transfer was rate-limiting. Marcus parameters were determined for this reaction with a reorganization energy (lambda) of 2.4 eV, a coupling constant (HAB) of 0.9 cm-1, a free energy change (Delta G' degrees ) of -22.0 kJ/mol, and a donor-acceptor distance (r) of 14 A. These values are consistent with parameters deduced for electron transfer reactions in other protein-protein systems where electron transfer is rate-limiting. Finally, the electron transfer reaction within the L127 Delta Fe protein-MoFe protein complex was found to be reversible. These results are discussed in the context of models for how MgATP interactions might be coupled to electron transfer in nitrogenase.

Venlafaxine is a new antidepressant with a unique mode of action. Because many patients taking antidepressant therapy may self-medicate with ethanol, this study was undertaken to assess the possible pharmacokinetic and pharmacodynamic interactions between venlafaxine and ethanol. This randomized, double-blind, placebo-controlled, two-period crossover study was conducted with 16 healthy men. Multiple doses of venlafaxine (50 mg every 8 hours) or placebo were administered for 7 days. On days 5 and 7 a single dose of 0.5 g/kg of ethanol or a placebo solution was administered in a randomized fashion. Pharmacokinetic data indicated that ethanol administration did not affect the disposition of venlafaxine or O-desmethylvenlafaxine. Similarly, venlafaxine administration did not affect the pharmacokinetic disposition of ethanol. Ethanol produced its expected effects on the eight psychometric tests administered. Venlafaxine produced small effects on the results of the Digit Symbol Substitution Test, the Divided Attention Reaction Time, and the Profile of Mood States. No pharmacodynamic interaction was detected between venlafaxine and ethanol.

The temperature dependencies of the reversible electrode potentials for a number of charge transfer reactions of redox mediators were used to evaluate the corresponding charge transfer entropies in Tris-HCl (pH 8) buffer. The redox mediator thermodynamic data, along with reaction enthalpy data for mediator redox protein electron transfer, were used to evaluate the charge transfer entropy for the cytochrome c redox couple [(cytc)ox/(cytc)red] in Tris-HCl (pH 8) buffer and were found to be equal to -16 cal/degrees K mol. Reversible electrode potentials at 298 degrees K for the redox mediator half-reactions were observed to vary from -528 to +657 mV (vs NHE). Charge transfer entropies were observed to depend upon the structure of the redox mediators and to vary from -13.8 to -29.7 cal/degrees K mol for a closely related series of organic dications (viologens) and a value of -43.6 cal/degrees K mol was observed for the [Fe(CN)6]3-/[Fe(CN)6]4- couple under the same conditions. A procedure for determining charge transfer entropies of protein redox couples which cannot be studied by direct electrochemical methods is outlined. The factors contributing to the magnitude of the charge transfer entropies are discussed.

The nitration of benzene by nitronium ion in the gas phase has been re-examined. New features have been revealed; in particular, three transition states have been detected along the reaction coordinate. These have been shown by IRC analysis to connect an initially formed π complex (pi1) to a σ complex (sig1) (via ts1), sig1 to sig2 (via ts2), and finally sig2 to the product (via ts3). Sig2 also connects to another isomeric σ complex sig3 (via sig23ts), which connects to sig4 (via sig34ts).

Background Many antidepressants are extensively metabolized in the liver, requiring dose adjustments in individuals with hepatic impairment. Clinical studies indicate that the serotonin-norepinephrine reuptake inhibitor desvenlafaxine is metabolized primarily via glucuronidation, and ∼45% is eliminated unchanged in urine. Objective The objectives of this study were to assess the pharmacokinetic profile, safety, and tolerability of desvenlafaxine in adults with chronic Child-Pugh class A, B, and C hepatic impairment. Methods Subjects (aged 18–65 years) with mild (Child-Pugh class A, n = 8), moderate (Child-Pugh class B, n = 8), and severe (Child-Pugh class C, n = 8) hepatic impairment and 12 healthy matched subjects received a single 100-mg oral dose of desvenlafaxine. Disposition of (R)-, (S)-, and (R+S)-enantiomers of desvenlafaxine were examined in plasma and urine. Geometric least squares (GLS) mean ratios and 90% CIs for AUC, AUC0–τ, Cmax, and Cl/F were calculated; comparisons were made by using a 1-factor ANOVA. Safety was evaluated according to adverse events, physical examination, vital signs, and laboratory assessments. Results Healthy participants had a mean age of 51 years (range, 36–62 years) and weight of 79.1 kg (range, 52.5–105.0 kg); hepatically impaired participants had a mean age of 52 years (range, 31–65 years) and weight of 80.9 kg (range, 50.2–119.5 kg). In both groups, 67% of participants were male. No statistically significant differences (≥50%) in the disposition of desvenlafaxine were detected between hepatically impaired patients and healthy subjects based on GLS mean ratios for Cmax, AUC0–τ, AUC, or Cl/F (P > 0.05 for each comparison). Median Tmax was similar for all groups (range, 6–9 hours). A nonsignificant increase was observed for desvenlafaxine exposure in patients with moderate or severe hepatic impairment (GLS mean ratios [90% CIs] for AUC, 31% [93.2–184], 35% [96.5–190], respectively). The most common adverse events were nausea (n = 2, healthy subjects; n = 3, hepatically impaired subjects) and vomiting (n = 1, healthy subjects; n = 2, hepatically impaired subjects). Conclusions A single 100-mg dose of desvenlafaxine was well tolerated in healthy subjects and hepatically impaired patients. A mild increase in exposure was observed for moderate and severe hepatically impaired subjects (Child-Pugh class B and C).

Tolrestat is an aldose reductase inhibitor undergoing clinical trials in diabetic subjects that may reduce the severity of chronic tissue damage associated with hyperglycemia. These studies were conducted to evaluate the pharmacokinetics of tolrestat in healthy young and elderly male and female subjects and in young and elderly subjects with diabetes. The drug was administered in a multiple-dose regimen, and steady-state parameters were obtained. There were no important gender-related differences, but mean values for apparent oral clearance, renal clearance, and corresponding unbound parameters were significantly lower for the elderly healthy subjects than for the young healthy subjects. The drug is highly bound to plasma proteins, and the unbound fraction (0.75%) did not differ among the subjects. The results from young and elderly diabetic subjects suggest that diabetes per se has no influence on tolrestat disposition but that there is an age-related reduction in apparent oral clearance (30 versus 18 ml/hr/kg) and a corresponding increase in the minimum steady-state plasma concentration (1.2 versus 1.9 μg/ml). These data indicate a possible need to reduce the dose of tolrestat in elderly subjects, assuming the same concentration-response relationship. Clinical Pharmacology & Therapeutics (1996) 59, 603–612; doi

Redox-active iron on the surface of asbestos fibers was detected and quantified using a thin-layer cell, coulometric method with soluble mediators to shuttle electrons between the mineral fibers and the solid electrode. The working and counter electrodes consisted of gold films on a glass slide with reference electrodes of silver. Asbestos fibers were entrapped in a thin-layer cell of 25 microns thickness. Hexaammineruthenium(II) or o-dianisidine (dication) was used as the reducing or oxidizing mediator, respectively. Hexaammineruthenium(III) undergoes a one-electron reduction, and protonated o-dianisidine undergoes a sequential two-electron oxidation. The measurement involved determination of the total charge for the oxidation or reduction of surface-immobilized Fe(II) or Fe(III) on the asbestos fibers. Analysis of the results showed that crocidolite and amosite have 4.3 +/- 0.7 and 3.3 +/- 0.7 nmol/mg of total redox-active iron that is accessible to the mediators, respectively. This corresponded to a surface coverage of accessible redox-active iron of approximately 4.3 x 10(-11) mol/cm2 for crocidolite and 9.5 x 10(-11) mol/cm2 for amosite. Furthermore, Fe(II) constituted 76% or 25% of the accessible redox-active iron on the surface of crocidolite or amosite, respectively. The method may be applied to other types of solid materials with redox-active species on their surfaces.

Background and Objective: Desvenlafaxine (administered as desvenlafaxine succinate) is approved for the treatment of major depressive disorder (MDD). If eliminated by the kidney, desvenlafaxine may have more favorable pharmacokinetic or drug-drug interaction profiles compared to its parent compound, venlafaxine, which depends primarily on the CYP2D6 enzyme system. Therefore, the pharmacokinetics and bioavailability of desvenlafaxine was assessed in healthy human subjects. Methods: In a single-dose, open-label, crossover study, subjects were randomly assigned to 100 mg/d of oral desvenlafaxine or intravenous (50 mg/1 hr) desvenlafaxine. Plasma and urine were collected for 72 hours postdosing and assayed to determine pharmacokinetics and bioavailability of (R)-, (S)-, and (R+S)-desvenlafaxine and N,O-didesmethylvenlafaxine. Results and Discussion: Pharmacokinetic parameters for (R)- and (S)-desvenlafaxine enantiomers were approximately equivalent for the oral and intravenous formulations of desvenlafaxine. Compared with 50 mg intravenous desvenlafaxine, 100 mg oral desvenlafaxine had a higher area under the plasma concentration-time curve and an absolute bioavailability of 80.5%. Urinary excretion of total desvenlafaxine and N,O-didesmethylvenlafaxine accounted for 69% of the orally administered desvenlafaxine dose, with the majority of a dose being excreted unchanged or as the glucuronide conjugate (66%). Conclusion: Desvenlafaxine has high oral bioavailability and provides an evenly balanced enantiomeric ratio.

A single-dose, randomized, two-period, crossover study was conducted to compare the pharmacokinetics and relative bioavailability of the estrogens in Estratab® (esterified estrogens) with those in Premarin® (conjugated estrogens). Twenty-five healthy, postmenopausal women completed both study periods. Plasma concentration versus time profiles of four estrogens were examined over 48 hours using sensitive and specific gas chromatography/mass spectrophotometry/mass spectrophotometry methods. The conjugated and unconjugated estrogens generally showed slow absorption (t max , 5 to 9 hours), slow elimination (half-life, 10 to 18 hours), and lengthy mean residence times (MRT, 13 to 28 hours). The relative bioavailability (100 · AUC Estratab /AUC Premarin ) for the estrogens was 146% for total (conjugated plus unconjugated) estrone, 150% for estrone, 36% for total equilin, and 29% for equilin. Differences in peak plasma concentrations (C max ) of the estrogens were similar to the differences seen in the area under the concentration versus time curve (AUC). The time of maximum concentration (t max ) of the estrogens was approximately 1 to 2 hours shorter following Estratab administration. Estratab and Premarin have differences in the rate and extent of both the absorption of estrogens and the formation of the unconjugated metabolites. Thus these two agents cannot be considered bioequivalent, and therapeutic substitution should not be made.

Non-steady-state kinetic studies reveal that the elimination of HBr from 2-(p-nitrophenyl)ethyl bromide in alcohol/alkoxide media, the classical concerted E2 reaction, actually takes place by a two-step mechanism involving the intermediate formation of the carbanion.

Although the competitive mechanism for Meisenheimer complex formation during the reaction of 2,4,6-trinitroanisole with methoxide ion in methanol is generally accepted, no kinetic evidence has been presented to rule out a reversible consecutive mechanism. Simulation of the competitive mechanism revealed that a fractional order in [MeO(-)] is predicted by the latter. Conventional pseudo-first-order analysis of the kinetics resulted in cleanly first-order in [MeO(-)], which rules out the competitive mechanism. The kinetic data are consistent with the reversible consecutive mechanism, which is proposed for this important reaction. An intermediate is required for this mechanism, and we propose that a dianion complex (III) is formed reversibly from the initial 1,3-σ complex (I). The trimethoxy complex (III), the (1)H NMR spectrum of which was observed earlier by Servis (Servis, K. L. J. Am. Chem. Soc. 1965, 87, 5495; 1967, 89, 1508), then eliminates methoxide ion reversibly to form the 1,1-σ complex product (II).

Halide affinities [ΔG halide (R + )] of simple carbenium ions (R + +X - ⇄RX ΔG halide (R + ) (i)) in both the gas phase and in aqueous solution were obtained from the corresponding hydride affinities [ΔG hybride (R + )] along with the differences in free energies of formation of RX and RH (ΔΔG o f [RX-RH]) and the differences in free energies of formation of hydride and halide ions (ΔΔG o f [H - -X - ]) using eq ii (ΔG halide (R+)-ΔG hybride (R+)=ΔΔG o f [RX-RH]+ΔΔG o f [H - -X - ] (ii))

Free energy hydride affinities in solution defined by reaction i [(i) Q s +H - s ⇄(QH - ) s , ΔG hybride (Q) s ] were evaluated for a number of quinones (Q) in dimethyl sulfoxide solution using reaction ii [(ii) -ΔG hybride (Q) s =2.303 RTpK a +FΔE o NHE [Q .- /Q 2- ) s +(Q/Q .- ) s ]+C] derived from a thermochemical cycle. The constant c corresponds to -FE o NHE [(H + /H - ) s +(H . /H - ) s ] which is equal to 69.9 kcal/mol in dimethyl sulfoxide

Second-order rate constants for the reactions of radical cations of a number of haloanthracenes with pyridine and 2-substituted pyridines were determined in acetonitrile and dichloromethane using electrochemical techniques. Attack at the ipso positions was observed to be less favorable than attack at positions bearing hydrogen. The halo-substituents were observed to exert opposing electronic and steric effects on the second-order rate constants. The 10-positions of 9-haloanthracene radical cations were observed to be nearly 2 orders of magnitude more susceptible to nucleophilic attack by pyridine than the 9,10-positions of the parent radical cation

Crystal structure: P1, a=15.541, b=10.196, c=9.360A, α=110.46, β=97.51, γ=94.94°, Z=1, R=0.028 for 7222 reflections. The Ni ions are on symmetry centers and are octahedrally coordinated by four water molecules and two oxygen atoms from tertiary phosphate groups. The molybdenum atoms are octahedrally coordinated. The octahedra build two rings, each containing five octahedra which share edges or apices with each other or share apices with the phosphate groups

Free energies of solvation [ΔG solv (gas) aq 's] of the noble gases in water are linearly related to the atomic radii. These data allow ΔG solv (H . ) aq to be calculated from the correlation line. The standard potential [E o (H + /H . aq ] for reduction of the proton in water (reaction i) was then determined using eq ii

The differences between charge-transfer transition energies calculated for donor-acceptor pairs at infinite separation and values determined experimentally for the charge-transfer complex geometry vary according to the charge type of the pairs and within a group of fixed charge type. It is argued that these differences provide a guide to the slope of the state-correlation curves for the product configuration in electrophile-nucleophile reactions of the corresponding charge type and that the observed variation invalidates the use of the simple expression ΔE=fΛ-β with constant f, derived from the curve-crossing model, to estimate energy barriers to reaction.

The oxidation chemistry of the organometallic hydride complexes ({eta}{sup 5}C{sub 5}H{sub 5})M(CO){sub 3}H (M = Cr, 1; Mo, 2; W, 3), ({eta}{sup 5}-C{sub 5}Me{sub 5})Mo(CO){sub 3}H (4), and ({eta}{sup 5}-C{sub 5}H{sub 5})W(CO){sub 2}(PMe{sub 3})H (5) has been investigated in acetonitrile solution by electrochemical and other methods. The thermodynamic acidities of the cation radicals of 1-5 have been estimated by the use of a thermochemical cycle based on the oxidation potentials of 1-5 and their conjugate bases (anions) as well as the solution pK{sub a} values of 1-5. The metal hydride cation radical pK{sub a} estimates fall in the range {minus}10 to +5, which makes these complexes the most acidic hydrides for which pK{sub a} values have been determined. Coulometric measurements show that 1-5 undergo overall two-electron oxidations. Chemical oxidation of 5 gives a 1:1 mixture of dihydride ({eta}{sup 5}-C{sub 5}H{sub 5})W(CO){sub 2}(PMe{sub 3})H{sub 2}{sup +} (13) and ({eta}{sup 5}-C{sub 5}H{sub 5})W(CO){sub 2}(PMe{sub 3})(NCMe){sup +} (10), the latter as a mixture of cis and trans isomers in the thermodynamic 95:5 ratio.