Large Kinetic Deuterium Isotope Effect Research Articles

Revisiting Alkane Hydroxylation with m-CPBA (m-Chloroperbenzoic Acid) Catalyzed by Nickel(II) Complexes.

Mechanistic studies are performed on the alkane hydroxylation with m-CPBA (m-chloroperbenzoic acid) catalyzed by nickel(II) complexes, NiII (L). In the oxidation of cycloalkanes, NiII (TPA) acts as an efficient catalyst with a high yield and a high alcohol selectivity. In the oxidation of adamantane, the tertiary carbon is predominantly oxidized. The reaction rate shows first-order dependence on [substrate] and [NiII (L)] but is independent on [m-CPBA]; vobs =k2 [substrate][NiII (L)]. The reaction exhibited a relatively large kinetic deuterium isotope effect (KIE) of 6.7, demonstrating that the hydrogen atom abstraction is involved in the rate-limiting step of the catalytic cycle. Furthermore, NiII (L) supported by related tetradentate ligands exhibit apparently different catalytic activity, suggesting contribution of the NiII (L) in the catalytic cycle. Based on the kinetic analysis and the significant effects of O2 and CCl4 on the product distribution pattern, possible contributions of (L)NiII -O. and the aroyloxyl radical as the reactive oxidants are discussed.

Structure and Reactivity of Copper Complexes Supported by a Bulky Tripodal N4 Ligand: Copper(I)/Dioxygen Reactivity and Formation of a Hydroperoxide Copper(II) Complex

A copper(I) complex, [CuI(TIPT2aped)(CH3CN)]ClO4 (1), and two copper(II) complexes, [CuII(TIPT2aped)(Cl)]PF6 (2) and [CuII(TIPT2aped)(ClO4)]ClO4 (3), were synthesized and characterized. The reaction of 1 with dioxygen in acetone at –90 °C gave an end‐on superoxide copper(II) complex 4. The superoxide copper(II) complex 4 reacted with 2,2,6,6‐tetramethylpiperidin‐1‐ol (TEMPO‐H) and 2,6‐di‐tert‐butyl‐4‐methoxyphenol (DTBMP) to generate a hydroperoxide copper(II) complex 6. These copper‐oxygen adducts were thoroughly characterized by UV/Vis, resonance Raman, EPR, and NMR spectroscopic techniques. Complex 6 was also synthesized from the copper(II) complex 3 in the presence of hydrogen peroxide and triethylamine. The reaction of 4 with TEMPO‐H showed a relatively large kinetic deuterium isotope effect (kH/kD = 5.8) and a largely negative activation enthalpy (ΔH‡). Based on the kinetic data, the reaction mechanism for the conversion of 4 to 6 is discussed.

Loss of water and hydrogen atom from the n-propanol molecular cation: A theoretical study

The unimolecular dissociation of n-propanol molecular cation ( 1) has been investigated theoretically. Density functional theory (DFT) molecular orbital calculations have been performed at the UB3LYP/aug-cc-pVQZ//UB3LYP/6-31 + G(d) level to obtain pathways for water and hydrogen atom loss from 1. On the basis of the DFT results, the rate-energy dependences have been calculated for water and hydrogen atom loss from various deuterated analogues of 1 by Rice–Ramsperger–Kassel–Marcus modeling. The large kinetic deuterium isotope effects on the metastable water and hydrogen atom loss reported previously are rationalized from the obtained rate-energy dependences.

Synthetic, Structural, and Mechanistic Aspects of an Amine Activation Process Mediated at a Zwitterionic Pd(II) Center

A zwitterionic palladium complex [[Ph(2)BP(2)]Pd(THF)(2)][OTf] (1) (where [Ph(2)BP(2)] = [Ph(2)B(CH(2)PPh(2))(2)](-)) reacts with trialkylamines to activate a C-H bond adjacent to the amine N atom, thereby producing iminium adduct complexes [Ph(2)BP(2)]Pd(N,C:eta(2)-NR(2)CHR'). In all cases examined the amine activation process is selective for the secondary C-H bond position adjacent to the N atom. These palladacycles undergo facile beta-hydride elimination/olefin reinsertion processes as evident from deuterium scrambling studies and chemical trap studies. The kinetics of the amine activation process was explored, and beta-hydride elimination appears to be the rate-limiting step. A large kinetic deuterium isotope effect for the amine activation process is evident. The reaction profile in less polar solvents such as benzene and toluene is different at room temperature and leads to dimeric [[Ph(2)BP(2)]Pd](2) (4) as the dominant palladium product. Low-temperature toluene-d(8) experiments proceed more cleanly, and intermediates assigned as [Ph(2)BP(2)]Pd(NEt(3))(OTf) and the iminium hydride species [[Ph(2)BP(2)]Pd(H)(Et(2)N=CHCH(3))][OTf] are directly observed. The complex (Ph(2)SiP(2))Pd(OTf)(2) (14) was also studied for amine activation and generates dimeric [(Ph(2)SiP(2))Pd](2)[OTf](2) (16) as the dominant palladium product. These collective data are discussed with respect to the mechanism of the amine activation and, in particular, the influence that solvent polarity and charge have on the overall reaction profile.

Borderline between E1cB and E2 mechanisms. Chlorine isotope effects in base-promoted elimination Reactions.

The chlorine leaving group isotope effect has been measured for the base-promoted elimination reaction of 1-(2-chloro-2-propyl)indene (1-Cl) in methanol at 30 degrees C: k(35)/k(37) = 1.0086 +/- 0.0007 with methoxide as the base and k(35)/k(37) = 1.0101 +/- 0.0001 with triethylamine (TEA) as the base. These very large chlorine isotope effects combined with large kinetic deuterium isotope effects of 7.1 and 8.4, respectively, are consistent not with the irreversible E1cB mechanism proposed previously (J. Am. Chem. Soc. 1977, 99, 7926) but with the E2 mechanism with transition states having large amounts of hydron transfer and very extensive cleavage of the bond to chlorine.

Localized control of proton transfer through the D-pathway in cytochrome c oxidase: application of the proton-inventory technique.

In the reaction cycle of cytochrome c oxidase from Rhodobacter sphaeroides, one of the steps that are coupled to proton pumping, the oxo-ferryl-to-oxidized transition (F --> O), displays a large kinetic deuterium isotope effect of about 7. In this study we have investigated in detail the dependence of the kinetics of this reaction step ¿k(FO)(chi) on the fraction (chi) D(2)O in the enzyme solution (proton-inventory technique). According to a simplified version of the Gross-Butler equation, from the shape of the graph describing k(FO)(chi)/k(FO)(0), conclusions can be drawn concerning the number of protonatable sites involved in the rate-limiting proton-transfer reaction step. Even though the proton-transfer reaction during the F --> O transition takes place over a distance of at least 30 A and involves a large number of protonatable sites, the proton-inventory analysis displayed a linear dependence, which indicates that the entire deuterium isotope effect of 7 is associated with a single protonatable site. On the basis of experiments with site-directed mutants of cytochrome c oxidase, this localized proton-transfer rate control is proposed to be associated with glutamate (I-286) in the D-pathway. Consequently, the results indicate that proton transfer from the glutamate controls the rate of all events during the F --> O reaction step. The proton-inventory analysis of the overall enzyme turnover reveals a nonlinear plot characteristic of at least two protonatable sites involved in the rate-limiting step in the transition state, which indicates that this step does not involve proton transfer through the same pathway (or through the same mechanism) as during the F --> O transition.

Solvent-promoted E1cB/E2 reactions competing with stepwise solvolysis through homoallylic carbocations

The water-promoted elimination reactions of (R,S)-1-(1-X-ethyl)indene 1-X [X = Cl, Br, I, OBs (4-bromophenylsulfonyloxy)] and the corresponding (R,R) isomers 2-X in 25 vol% acetonitrile in water exhibit non-stereospecific and stereospecific 1,2 elimination, respectively. The reactions are E1cB and E2 type reactions; the conclusion is based upon measured large kinetic deuterium isotope effects and Bronsted β parameters. The rate of the competing solvolytic substitution, which occurs through homoallylic carbocations, increases with the leaving group in the order Br–, I– and BsO–. The spontaneous reactions in methanol are slow; the anti stereochemistry increases with increasing basicity of added base and is favored by negative charge of the base.

Kinetic Site of Protonation in Transition Metal Clusters and Its Possible Relationship to Large Kinetic Deuterium Isotope Effects in Hydrogen Transfer Processes

The protonation of Ru3(CO)10(μ-NO)- (1) has been reexamined using CF3CO2X and CF3SO3X (X = H or D) in the temperature range of −80 to +25 °C using 13C NMR techniques. For both acids, the kinetic site of protonation is the oxygen of the nitrosyl group, giving Ru3(CO)9(μ3-CO)(μ3-NOH) (2). The rate of proton transfer to the metal core, to give Ru3(CO)10(μ-NO)(μ-H) (3), is approximately the same for both the protic and deuterated cases. These results are contrasted with previous proton transfer studies of other metal clusters which exhibit anomalously large kinetic deuterium isotope effects, and it is tentatively concluded that these effects are associated with strictly intramolecular hydrogen transfer as opposed to the anion-assisted intermolecular process reported here. The carbonyl group ligand dynamics for 1−3 are reported.

Unusually large kinetic deuterium isotope effects on oxidation reactions. 1. The mechanism of hydroxide‐catalysed permanganate oxidation of PhCD(CF3)OH and PhCD(CH3)OH in Water

AbstractThe oxidation of 1‐phenyl‐2,2,2‐trifluoroethanol (ROH) with potassium permanganate in 0.2 M aqueous sodium hydroxide solution at 25 °C provides 2,2,2‐trifluoroacetophenone as the sole product. The reaction rate constant, which was measured under pseudo‐first order conditions by following the decrease in substrate concentration as a function of time, was found to be substantially smaller than previously reported. The primary kinetic deuterium isotope effect was measured as k/k = 14·7 ± 1·0. A hydrogen‐transfer mechanism involving significant tunnelling is proposed. The oxidation of 1‐phenylethanol under similar reaction conditions yields acetophenone as the initial product. The kinetic deuterium isotope effect was found to be k/k = 5·2 ± 0·8.

Oxidation of 4‐methylcatechol by dioxygen studied by ESR spectroscopy. The different regioselectivity of OH− and MeO− nucleophilic attack and kinetic deuterium isotope effects

AbstractThe oxidation of 4‐methylcatechol by dioxygen and the subsequent reactions of the two nucleophiles OH− and MeO− with the oxidation products were studied by electron spin resonance (ESR) spectroscopy. These reactions are models for those of skin proteins with substituted 1,2‐dihydroxybenzenes (catechols) which produce the severe allergic contact dermatitis associated with plants such as poison ivy, poison oakd and the Japanese lac tree. The rates of formation of the primary and secondary semiquinone radical anions show a large kinetic deuterium isotope effect (ca 10) at 20°C, which is ascribed to a slow deprotonation of the hydrogen bridged 4‐methylcatechol monoanion. There is a marked difference in regioselectivity for OH− and MeO− substitution of the 4‐methylcatechol monoanione; OH− reacts exclusively at the 3‐position whereas MeO− attacks at the 5‐position. This dissimilarity between two normally similar nucleophiles is also ascribed to the occurrence of hydrogen bridging between the substituting OH− at the 3‐position and the adjacent quinone oxygen at the 2‐position. The expected attack at the more electropositive 5‐position occurs with MeO− because no such hydrogen bonding can occur. Disubstitution occurs for OH− but not for MeO−, probably reflecting the greater nucleophilicity of the former.

Ligand dynamics and reactivity in trimetallic clusters

The general relationships between trinuclear cluster reactivity and the ligand dynamical processes in these systems are explored. Three specific mechanistic studies are presented: (1) the rate and stereochemistry of ligand addition to μ3-imidoyl complexes, (2) the factors influencing the rate of carbon-hydrogen bond activation in μ3-alkyne complexes, and (3) the origin of anomalously large kinetic deuterium isotope effect in metal to ligand and ligand to metal hydrogen transfer in trinuclear and binuclear complexes. In all three cases, the current state of the mechanistic studies are summarized and the possible rate of specific ligand dynamical processes in controlling the mechanism are put forth.

Acid-catalyzed trans to cis isomerization of [C5H5(CO)Fe]2(.mu.-CO)(.mu.-CH2)

The isomerization of trans-[C 5 H 5 (CO)Fe] 2 (μ-CO)(μ-CH 2 ) (trans-1) to an equilibrium mixture of cis- and trans-2 occurs prior to hydride abstraction by (C 6 H 5 ) 3 C + PF 6 − , which produces [C 5 H 5 (CO)Fe] 2 (μ-CO)(μ-CH) + PF 6 − (1). The isomerization of 2 was shown to be an acid-catalyzed process. Second-order kinetic were observed for isomerization of 2 by HBF 4 •Et 2 O and by CF 3 CO 2 H in CD 2 Cl 2 . An extremely large kinetic deuterium isotope effect (k H /k D =70−105) was observed for the isomerization of 2 by CF 3 CO 2 D. A mechanism involving protonation at iron followed by bridge opening and rotation is proposed to explain the isomerization of 2

Oxidative cleavage of carboxylic esters by cytochrome P-450.

Cytochrome P-450 was demonstrated to catalyze the oxidative cleavage of carboxylic acid esters to the corresponding carboxylic acids. 2,6-Dimethyl-4-phenyl-3,5-pyridinedicarboxylic acid diethyl ester and related dialkyl esters were shown to serve as substrates in NADPH-fortified rat liver microsomes and reconstituted systems containing purified cytochrome P-450 enzymes. The ethyl group gave rise to acetaldehyde. The reactions proceed with large kinetic deuterium isotope effects, consistent with the view that P-450 abstracts a hydrogen atom in the mechanism. Oxygen rebound to the radical site is then postulated to complete the reaction and lead to a hemiacetal-like structure which collapses to give the products. Rate studies with differing alkyl substituents showed that the reaction was more rapid with removal of an ethyl than a methyl or isopropyl group, consistent with the view that the ethyl optimizes steric and inductive effects. Oxidative cleavage of carboxylic acid esters has little biochemical precedent, due to the difficult character of the reaction, and should be considered as an alternative to direct hydrolysis.

The substrate-dependent steric course of the ethanolamine ammonia-lyase reaction.

The adenosylcobalamin‐dependent ethanolamine ammonia‐lyase from Clostridium sp. deaminates (2S)‐2‐aminopropanol to propionaldehyde about three times faster than it does (2R)‐2‐aminopropanol. (2S)‐2‐Amino(1‐2H2)propanol and (1S, 2S)‐2‐amino(1‐2H1)propanol are deaminated by the enzyme with a large kinetic deuterium isotope effect (kH/k2H∼ 6), whereas (1R, 2S)‐2‐amino(1‐2H1)‐propanol behaves like the unlabelled substrate. (2R)‐2‐Amino(1‐2H2)propanol reacts about 1.7 times more slowly than unlabelled (2R)‐2‐aminopropanol or (1R, 2R)‐2‐amino(1‐2H1)propanol. From the above results it follows that the enantiomeric 2‐amino(1‐2H2)propanols react at the same rate, irrespective of their absolute configuration and the lyase reaction involves the 1‐Hsi atom in both enantiomers. (2S)‐2‐Amino[U‐14C, 2‐3H, 3‐3H]propanol was prepared by a combination of enzymic and chemical reactions and the distribution of tritium between C‐2 and C‐3 was determined by its degradation to acetic acid. This doubly labelled substrate was converted on ethanolamine ammonia‐lyase into (2R)‐[U‐14C, 2‐3H, 3‐3H]propionaldehyde. On the other hand, the (2S) configuration was proved for all three samples of [2‐3H]propionaldehyde recovered from incubations of [5′‐3H]adenosylcobalamin with ethanolamine ammonia‐lyase irrespective of whether the (2S) or (2R) enantiomer of 2‐aminopropanol or propionaldehyde itself (in the presence of ammonium ions) were used as substrates. Incubations with enzyme plus [5′‐3H]adenosylcobalamin also yielded tritiated 2‐amino‐propanols. These were in turn incubated with horse liver alcohol dehydrogenase and diaphorase in deuterium oxide, which lead to exchange of the 1‐HRe atom with deuterium. Retention of the tritium in the samples provided evidence for the (1S) configuration. By co‐crystallization as the 4‐methyl‐oxazolidone derivative the (2S) configuration of the tritiated 2‐aminopropanol samples was also proved. These results show that ethanolamine ammonia‐lyase deaminates (2S)‐2‐aminopropanol with retention, whereas (2R)‐2‐aminopropanol reacts with inversion of configuration. Tritium from [5′‐3H]adenosylcobalamin is transferred in all cases to the 2‐pro‐S position of propionaldehyde and to the 1‐pro‐S position of 2‐aminopropanol. In the case of (2R)‐2‐aminopropanol, tritium transfer is accompanied by inversion at the asymmetric centre. All these results, together with the previously reported racemization during the conversion of 2‐aminoethanol, can be explained by a simple mechanistic scheme.