Kinetic Hydrogen Isotope Effects Research Articles

A theoretical MNDO and AM1 SCF-MO study of dihydrogen transfer reactions

The mechanisms of concerted and stepwise dihydrogen transfer reactions have been studied for a wide variety of hydrogen donors and acceptors using the MNDO and AM1 semiempirical SCF-MO methods. The calculated barriers for concerted [1,2]dihydrogen transfer from cis-di-imide were sensitive to the strain and geometry of the π acceptor but less so to polar substituents, and with the exception of sterically hindered alkenes and systems with silicon and phosphorus double bonds, the energy differences between this route and an alternative stepwise process were surprisingly constant. The AM1 method tends to favour a concerted and essentially synchronous transfer of hydrogen whereas MNDO tends to favour a stepwise mechanism, with signficiant differences also for sterically hindered systems, for the barriers to the concerted hydrogen transfer, and in the disproportionation energies of the intermediate radical pairs involved in the stepwise mechanistic pathway. Highly strained alkene acceptors induce asymmetry in the concerted transfer, and such alkenes also form hydrogen bonded complexes with diimide. Transition state frontier orbitals are shown to give a simple interpretation of selectivity and reactivity, particularly for strained systems and allene it acceptors. The entropy of activation is suggested to be important in rationalising cis/trans alkene selectivity. Bis-α(oxy-anion) substituents on the donor significantly decrease the activation barriers, but induce a stepwise transfer of hydride anion rather than a concerted dihydrogen transfer. Hydrogen kinetic isotope effects show significantly different behaviour for the concerted and stepwise transfer. The concerted [1,4] reduction of butadiene proceeds antarafacially with a much higher barrier than [1,2] reduction. Dimethyl transfer from diazomethane proceeds with double inversion rather than with double retention of configuration at the methyl groups.

19- 14C]androstenedione: A new substrate for assaying aromatase and studying its reaction mechanism

[19-14C]Androstenedione has been prepared and utilized as a substrate for assaying microsomal human placental aromatase. Enzyme activity is determined by measuring the rate at which [14C]formate is produced by aromatization of this 14C-labeled steroid. Isotope ratio experiments using [19-14C]androstenedione and [1 beta-3H]androstenedione demonstrate that an apparent kinetic hydrogen isotope effect exists for the aromatization of the tritiated steroid with kH/kT approximately 1.09. Metabolic switching occurs to a minor extent (approximately 3%) during aromatization of [1 beta-3H]androstenedione, but not during the aromatization of [19-14C]androstenedione.

Cytochrome P-450-catalyzed dehydrogenation of 1,4-dihydropyridines.

A variety of different 4-substituted 1,4-dihydropyridine Hantzsch esters are substrates for ring dehydrogenation by a cytochrome P-450 (P-450) enzyme (P-450 UT-A); the substitutent could be varied from a hydrogen to a naphthalenyl, but a pyrenyl derivative was not dehydrogenated. When a 4-alkyl group is present, both the P-450 which oxidizes the substrate and other P-450s can be inactivated (by putative alkyl radicals). P-450s did not discriminate with regard to removal of the 4-H atoms from an enantiomeric pair of dihydropyridines. Losses of the 4-proton and N-methyl from a N-methyl-1,4-dihydropyridine occur at similar rates. The calculated intrinsic kinetic hydrogen isotope effect (Dk) for dehydrogenation of 1,4-dihydro-2,6-dimethyl-4-phenyl-3,5-pyridinedicarboxylic acid dimethyl ester was 2.9 in a reconstituted P-450 UT-A enzyme system. No significant kinetic hydrogen isotope effect was observed in microsomal incubations for the dehydrogenation of this compound or 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester in a variety of competitive and noncompetitive experiments. In light of previous studies on the magnitude of kinetic hydrogen isotope effects in P-450 systems (e.g. Miwa et al., 1983 (Miwa, G. T., Walsh, J. S., Kedderis, G. L., and Hollenberg, P. F. (1983) J. Biol. Chem. 258, 14445-14449], the mechanistic proposals of Augusto et al., 1982 (Augusto, O., Beilan, H. S., and Ortiz de Montellano, P. R. (1982) J. Biol. Chem. 257, 11288-11295)) for enzyme inactivation by 4-alkyl-substituted Hantzsch pyridine esters, and other precedents for sequential electron transfer in amine oxidation by P-450s, we interpret these results as being consistent with P-450-mediated 1-electron oxidation of dihydropyridines followed by the facile loss of the 4-proton, with subsequent electron transfer to complete the reaction.

Primary kinetic isotope effects in hydride transfer: experimental studies of intramolecular hydride migration and ab initio molecular orbital calculations of model systems

Measurements of the primary kinetic hydrogen isotope effects for the intramolecular migration of hydride accompanying the rearrangements of (i) hydroxy-ketones involving 1,4-migration of hydride between ketonic carbonyl groups and (ii) phenylglyoxal hydrates to their corresponding mandelic acids are described. The results are discussed using ab initio MO calculations of model systems, with a variety of basis sets. The value of such model calculations is demonstrated.

Temperature dependences of hydrogen kinetic isotope effect in reactions of cyclohexane with Mn(VII), Cr(VI) and NO 2 + in solutions

Temperature dependences of hydrogen kinetic isotope effect (KIE) in reactions of cyclohexane with Mn(VII), Cr(VI) and NO 2 + in solutions have been studied. With increasing temperature from −10° to 140°C, KIE decreases and the equation kH/kD=AH/ADexp(ΔE/RT) is met.

Kinetic hydrogen isotope effects: An organic/physical laboratory experiment

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTKinetic hydrogen isotope effects: An organic/physical laboratory experimentPatricia McGuiggan , Robert Eliason , Ben Anderson , and Beatrice Botch Cite this: J. Chem. Educ. 1987, 64, 8, 718Publication Date (Print):August 1, 1987Publication History Received3 August 2009Published online1 August 1987Published inissue 1 August 1987https://doi.org/10.1021/ed064p718RIGHTS & PERMISSIONSArticle Views250Altmetric-Citations3LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (2 MB) Get e-Alerts Get e-Alerts

Hydrogen isotope effects in hydride transfer reactions of formaldehyde and glyoxal. An Ab initio and MNDO SCF-M.O. study

Ab initio and MNDO calculations predict the hydroxide anion-catalysed intramolecular hydride transfer reaction of glyoxal to exhibit a larger kinetic hydrogen isotope effect than the intermolecular Cannizzaro reaction of formaldehyde.

Primary kinetic hydrogen isotope effects in hydride transfer: ab initio MO and experimental studies

Measurement of the primary kinetic hydrogen isotope effects for the intramolecular migration of hydride from alcohol methine to ketonic carbonyl in hydroxy-ketones and their interpretation using ab initio MO calculations show good agreement between theory and experiment.

Kinetic hydrogen isotope effect

This note describes three simple demonstrations or laboratory exercises that illustrate kinetic hydrogen isotopic effects.

Rapid-scan stopped-flow studies of the pH dependence of the reaction between mercuric reductase and NADPH.

The reaction of NADPH with the flavoenzyme mercuric reductase has been studied by rapid-scan stopped-flow spectrophotometry at 5 degrees C in the pH range 5.1-9.5. An intermediate formed within the dead time of the apparatus, and proposed to be an NADPH complex of oxidized enzyme, has an almost pH-independent spectrum. At pH 5.1 the formation of this species is followed by a rapid bleaching (k = 145 s-1) of the main flavin absorption band at 455 nm concomitantly with an absorbance increase around 395 nm. This process, which has a kinetic hydrogen isotope effect of 2.4, becomes less prominent at higher pH values and is not detectable above pH 7. It is suggested that this process includes the formation of a covalent thiol-flavin C-4a derivative stabilized by protonation of the active site. In the presence of an excess of NADPH, the final product of the reaction is probably an NADPH complex of two-electron-reduced enzyme, but below pH 6 the final spectrum becomes less intense suggesting a partial formation of four-electron-reduced enzyme. The spectral changes observed above pH 7 are nearly independent of pH. The first measurable step (k = 48 s-1 at pH 9.5) is thought to include the formation of an NADP+ complex of two-electron-reduced enzyme, while the final step (k = 6.3 s-1 at pH 9.5) results in the above-mentioned NADPH complex with two-electron-reduced enzyme. A minimal kinetic scheme rationalizing the observed pH dependence of the reaction and the observed isotope effects is presented.

Dehydrogenation of formate by 10-methylacridinium ion

Formate is dehydrogenated to CO 2 by 10-methylacridinium ion, mimicking formate dehydrogenase. The hydrogen and carbon kinetic isotope effects are 2.74 and 1.027 in a mixed solvent consisting of di-methylformamide and water in a 4:1 ratio, at 50°. These values are similar to those observed in the enzymatic reaction (2.27 and 1.042, respectively) suggesting that the mechanisms of enzymatic and nonenzymatic reactions are the same, and transition state structures not too different. Marcus theory of atom and group transfer is used to locate the transition state for the nonenzymatic reaction 0.4 of the distance along the minimum energy path from precursor configuration to successor configuration. It is concluded, following Cleland and coworkers, that the protein of the enzyme dehydrates the formate and deforms the cofactor NAD + so as to make the reaction more spontaneous. This produces an enzymatic transition state in which the covalency changes around hydrogen are less advanced than in the non-enzymatic transition state, but the environment of the carboxylate is much more suitable to the product, CO 2.

PHYTOCHROME MODELS, PART 9. CONFORMATION SELECTIVITY OF THE PHOTOCYCLIZATION OF THE BILIVERDIN IX γ and IX δ DIMETHYL ESTERS*

Abstract— The photocyclization of the biliverdin IX γ and IX δ dimethyl esters to phorcabilin and neobiliverdin IX δ dimethyl ester, respectively, markedly depends on the irradiation wavelength within the first electronic absorption band. The quantum yields of reaction are highest on irradiation at575–600 nm. As judged from fluorescence excitation studies, absorption by the stretched conformations of the biliverdins is relatively important at these wavelengths. At longer wavelengths, where the reaction efficiency sharply declines, absorption by the coiled form predominates. Based on these findings and on supporting evidence from the solvent and temperature influence on the reaction, the photocyclization is proposed to occur selectively from a stretched conformation (an example of the principle of nonequilibration of excited rotamers), competing with E‐Z isomerization of the centralC–10 double bond. A kinetic hydrogen isotope effect on the photochemical reaction rate of N,N,N‐trideuteriated biliverdin IX δ dimethyl ester indicates that the primary photoproduct in the cyclization reaction is labile and reacts via two competing processes: reopening to the starting material and a solvent‐mediated proton shift. The latter process leads to the phorcabilin and neobiliverdin IX δ esters. The results suggest, as a general rule, that the stretching of coiled biliverdins is confined to thermal and photochemical transformations within the B/C partial structure, while the Z‐syn geometry of the A/B and C/D moieties is retained.

Kinetic hydrogen isotope effects in the reaction between 2,4,6-trinitrotoluene and 1-ethylpiperidine in acetonitrile. The effect of pressure

The effect of pressure on the kinetic isotope ratio kH/kD and tunnelling factor Q has been examined for proton and deutron transfer from 2,4,6-trinitrotoluene (TNT) to 1-ethylpiperidine in acetonitrile. The reaction rate has been measured in the pressure range 1–1000 bar and in the temperature range 15–35 °C by means of a high-pressure stopped-flow method. Even at 1000 bar, the kinetic isotope ratio kH/kD(16.4), the activation energy difference Ea(D)–Ea(H)(10.0 kJ mol–1) and the ratio of Arrhenius pre-exponential factor A(D)/A(H)(4.0) are large, suggesting a considerable tunnelling contribution. However, the tunnelling factor Q(H), calculated according to Bell's equation, hardly changes with pressure (being 2.39 at 1 bar and 2.26 at 1000 bar). Tunnelling phenomena and related pressure effects are discussed in relation to the curvature of potential-energy barriers. The present results lead us to conclude that large changes of kH/kD with pressure do not always confirm the occurrence of tunnelling.

An MNDO SCF-MO study of the mechanism of the Cannizzaro reaction

The mechanism of the Cannizzaro reaction has been studied using the MNDO SCF-MO method. A hydride transfer between the intermediate (1) to the aldehyde (2)(R =R1=H) was calculated to proceed via a symmetrical transition state with a barrier of 72 kJ mol–1. Alternative mechanisms involving a single-electron transfer between (1) and (2) are predicted to be less favourable, particularly for aliphatic aldehydes. A radical chain mechanism involving a single-electron-transfer step is proposed as an alternative. Mechanisms involving dianions are discussed, in which single-electron transfers are particularly favourable, and radicals such as H˙ should be formed at high pH. Primary hydrogen kinetic isotope effects are calculated for all the steps involving hydrogen transfers and the results discussed in terms of the symmetry and properties of the transition states.

Transition-state structure and the temperature dependence of the kinetic isotope effect

The underlying theory of the temperature dependence of the kinetic hydrogen isotope effect (KIE) is presented herein. The implications of this technique as a mechanistic criterion are pointed out in a straightforward manner. Some model calculations referring to the intramolecular proton transfer in the monoprotonated methylenediamine are included. The results of this investigation indicated that the temperature dependence of the KIE should not be used as a mechanistic tool in differentiating between linear and bent transition states.

The reaction of PtCl 62− with aromatic compounds to afford anionic σ-aryl complexes of platinum(IV) : VIII. Kinetics and mechanisms of thermal, photochemical and γ-induced reactions with arenes and arylmercury compounds (electrophilic substitution involving electron transfer)

The kinetics of the thermal reaction of the PtCl 6 2− ion with various aromatic compounds in CF 3COOH/H 2O or CH 3COOH to afford σ-aryl complexes of platmum(IV) have been studied at temperatures of 60–100 °C. The reaction is first order both in PtCl 6 2− and arene. The process of formation of platinated toluene (as well as some other complexes) is accompanied with its para-meta isomerisation. The rate of formation of the σ-aryl complexes decreases with increasing concentration of LiCl added to the reaction mixture. Additions of AgNO 3, Na 2PtCl 4, Hg(OCOCH 3) 2, NaOCOCH 3, BF 3 · OEt 2 and SeO 2 accelerate the reaction. The activation energies of the formation and the para-meta isomerisation are ca. 100 kJ mol −1. The relative rates of the reaction with different aromatic compounds (C 6H 5X) decrease in the following sequence of X: OH > OCH 3 > CH 3 > C 2H 5 > OC 6H 5 > CH(CH 3) 2 > H > C 6H 5 > F > COCH 3 > COOH > Cl > NO 2. The logarithms of the relative rates correlate with Hammett's σ and Brown's σ + constants (ϱ = −3.0 and ϱ + = −1.5). The kinetic hydrogen isotope effect of the reaction is small ( ∼ 3 for benzene and ∼ 2.3 for toluene). The following mechanism of the reaction is proposed. The first stage is the dissociation of PtCl 6 2− followed by coordination with arene to form a π-complex. The π-complex then transforms into a Wheland-type complex, which gives a σ-aryl complex of platmum(IV) after proton elimination. The reaction of PtCl 6 2− with arenes may be carried out at room temperature if it is induced by light or γ-irradiation. The relative rates of the photoinduced reaction decrease in the following sequence: OH > OC 2H 5 > OCH 3 > OC 6H 5 > CH 3 (ϱ + = −1.5). The isotope effect for the reaction with toluene ( k H/ k D ∼ 2) was determined. No para-meta isomerisation was observed in the photoinduced reaction at room temperature. The ESR spectra of frozen solutions of PtCl 6 2− and arenes irradiated at 77 K exhibited signals due to platinum(III) complexes and organic radicals. The proposed mechanism involves electron transfer from an arene to a platinum(IV) complex to give an intermediate ion-radical pair, [ArH] + [Pt IIICl 5 2− ]. The latter may then be transformed into a Wheland-type complex. Such a mechanism may be termed the S E2e.t. mechanism. The thermal reaction of PtCl 6 2− with Ar 2Hg in aqueous acetone to afford σ-aryl complexes of platinum(IV) is first order in the platinum(IV) complex and zero order in the aryl mercurial. The rate of the reaction decreases upon addition of LiCl. The mechanism of the reaction with Ar 2Hg appears to involve an electron-transfer stage.

Isotope effects on hydride transfer between NAD+ analogs

Primary kinetic hydrogen isotope effects (KIE's) for hydride transfer between NAD/sup +/ analogues have been measured for reactions with equilibrium constants ranging from 0.7 to 10/sup 16/. There is no sign of the sharp change in KIE which would signal the change of a rate limiting step in a multistep mechanism, and other evidence also indicates a one-step mechanism. The secondary KIE produced by changing the hydrogen already attached at the acceptor site from H to D is about 10% smaller when the transferred atom is D than when it is H. These results, combined with the values of the primary KIE's, strongly suggest some nuclear tunneling in the reaction coordinate.

ChemInform Abstract: KINETIC HYDROGEN ISOTOPE EFFECTS FOR PROTON TRANSFER BETWEEN CARBOXYLIC ACIDS AND THE MONOPROTONATED CRYPTAND (2,1,1)H+ IN METHANOL

Chemischer InformationsdienstVolume 14, Issue 30 Preparative Organic Chemistry ChemInform Abstract: KINETIC HYDROGEN ISOTOPE EFFECTS FOR PROTON TRANSFER BETWEEN CARBOXYLIC ACIDS AND THE MONOPROTONATED CRYPTAND (2,1,1)H+ IN METHANOL B. G. COX, B. G. COXSearch for more papers by this authorNGUYEN VAN TRUONG NGUYEN VAN TRUONG, NGUYEN VAN TRUONG NGUYEN VAN TRUONGSearch for more papers by this authorH. SCHNEIDER, H. SCHNEIDERSearch for more papers by this author B. G. COX, B. G. COXSearch for more papers by this authorNGUYEN VAN TRUONG NGUYEN VAN TRUONG, NGUYEN VAN TRUONG NGUYEN VAN TRUONGSearch for more papers by this authorH. SCHNEIDER, H. SCHNEIDERSearch for more papers by this author First published: July 26, 1983 https://doi.org/10.1002/chin.198330121Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume14, Issue30July 26, 1983 RelatedInformation

Kinetic hydrogen isotope effects for proton transfer between carboxylic acids and the monoprotonated crysptand (2,1,1)H+ in methanol

The rates of proton transfer from substituted acetic and benzoic acids, HA, to the monoprotonated cryptand (2,1,1)H+ have been measured in methanol. The reaction involves a slow direct proton transfer from HA into the ligand cavity to give the di-endo-protonated cryptand (2,1,1)H22+. The measured rates are several orders of magnitude lower than those expected for diffusion-controlled proton transfer between oxygen and nitrogen bases. Good Bronsted plots with α values close to 0.5 are observed for both series of acids. The reactions show substantial kinetic hydrogen isotope effects which pass through a maximum with increassing strength of HA.

Model calculations of isotope effects. IX. Origin of large hydrogen and carbon isotope effects in the deprotonation of 2-nitropropane by pyridine bases

The abnormally large primary hydrogen and carbon kinetic isotope effects found in the deprotonation of 2-nitropropane by hindered pyridine bases are investigated by means of model calculations. Transition-state models have been varied between tight and loose extremes, and between carbanion-like and nitronate-like structures. The only models that reproduce the experimental findings are those in which the sum of the bond orders to the transferring proton is less than unity (loose transition states) and which are subject to tunnelling corrections.