Α-deuterium Kinetic Isotope Effects Research Articles

Secondary Kinetic Isotope Effects in Oxidative Addition of Benzyl Bromide to Dimethylplatinum(II) Complexes

The secondary α-deuterium kinetic isotope effects (KIEs), (kH/kD)α, have been determined, at different temperatures and in solvents having different polarities, for reaction of PhCH2Br/PhCD2Br with the dimethylplatinum(II) complexes [PtMe2(NN)], in which the bidentate NN ligand is bpy (=2,2′-bipyridine) or bu2bpy (=4,4′-di-tert-butyl-2,2′-bipyridine). The values obtained for the secondary α-deuterium KIEs in acetone solution are close to 1 and may be normal or inverse, but much larger values are found for the reactions in benzene. An explanation is presented on the basis of solvent dependence of the degree of looseness of the transition state in the SN2 mechanism.

Mechanism of a Chemical Glycosylation Reaction

Glycosylation is arguably the most important reaction in the field of glycochemistry, yet it involves one of the most empirically interpreted mechanisms in the science of organic chemistry. The beta-mannopyranosides, long considered one of the more difficult classes of glycosidic bond to prepare, were no exception to this rule. A number of logical but circuitous routes for their preparation were described in the literature, but they were accompanied by an even greater number of mostly ineffective recipes with which to access them directly. This situation changed in 1996 with the discovery of the 4,6-O-benzylidene acetal as a control element permitting direct entry into the beta-mannopyranosides, typically with high yield and selectivity. The unexpected nature of this phenomenon demanded study of the mechanism, leading first to the demonstration of the alpha-mannopyranosyl triflates as reaction intermediates and then to the development of alpha-deuterium kinetic isotope effect methods to probe their transformation into the product glycosides. In this Account, we assemble our observations into a comprehensive assessment consistent with a single mechanistic scheme. The realization that in the glucopyranose series the 4,6-O-benzylidene acetal is alpha- rather than beta-directing led to further investigations of substituent effects on the stereoselectivity of these glycosylation reactions, culminating in their explanation in terms of the covalent alpha-glycosyl triflates acting as a reservoir for a series of transient contact and solvent-separated ion pairs. The function of the benzylidene acetal, as explained by Bols and co-workers, is to lock the C6-O6 bond antiperiplanar to the C5-O5 bond, thereby maximizing its electron-withdrawing effect, destabilizing the glycosyl oxocarbenium ion, and shifting the equilibria as far as possible toward the covalent triflate. beta-Selective reactions result from attack of the nucleophile on the transient contact ion pair in which the alpha-face of the oxocarbenium ion is shielded by the triflate counterion. The alpha-products arise from attack either on the solvent-separated ion pair or on a free oxocarbenium ion, according to the dictates of the anomeric effect. Changes in selectivity from varying stereochemistry (glucose versus mannose) or from using different protecting groups can be explained by the shifting position of the key equilibria and, in particular, by the energy differences between the covalent triflate and the ion pairs. Of particular note is the importance of substitutents at the 3-position of the donor; an explanation is proposed that invokes their evolving torsional interaction with the substituent at C2 as the chair form of the covalent triflate moves toward the half-chair of the oxocarbenium ion.

Secondary α-deuterium kinetic isotope effects in [2+4] cycloaddition of (E)-2-phenylnitroethene to cyclopentadiene

Secondary a-deuterium kinetic isotope effects confirm that (2?4) cycloaddition between (E)-2-phenylni- troethene and cyclopentadiene occurs in concerted manner, on both the pathway leading to 6-endo-phenyl-5-exo-nitro- norbornene and the pathway leading to the corresponding 6- exo-phenyl-5-endo-nitro isomer. According to Hammond terminology the transition states on competitive pathways should be considered in terms of symmetrical early states.

2,3-Anhydrosugars in Glycoside Bond Synthesis: Mechanism of 2-Deoxy-2-thioaryl Glycoside Formation

A series of investigations probing the mechanism of the 2,3-anhydrosugar migration-glycosylation reaction were performed using a thioglycoside with the D-lyxo stereochemistry as the substrate. Among the work reported are the results of quantum mechanical calculations, NMR studies, the measurement of alpha-deuterium kinetic isotope effects, and the synthesis of a series of substrate analogues. All studies point to a consistent finding: that the reaction proceeds through an oxocarbenium ion intermediate, not an episulfonium ion as previously suggested. It is proposed that the high stereoselectivity of the reaction arises from a preferred "inside attack" of the nucleophile onto the oxocarbenium ion intermediate.

Mechanistic Studies on the Stereoselective Formation of β-Mannosides from Mannosyl Iodides Using α-Deuterium Kinetic Isotope Effects

Stereoselective synthesis of beta-mannosides is one of the most challenging linkages to achieve in carbohydrate chemistry. Both the anomeric effect and the C2 axial substituent favor the formation of the axial glycoside (alpha-product). Herein, we describe mechanistic studies on the beta-selective glycosidation of trimethylene oxide (TMO) using mannosyl iodides. Density functional calculations (at the B3LYP/6-31+G(d,p):LANL2DZ level) suggest that formation of both alpha- and beta-mannosides involve loose S(N)2-like transition-state structures with significant oxacarbenium character, although the transition structure for formation of the alpha-mannoside is significantly looser. alpha-Deuterium kinetic isotope effects (alpha-DKIEs) based upon these computed transition state geometries match reasonably well with the experimentally measured values: 1.16 +/- 0.02 for the beta-linkage (computed to be 1.15) and 1.19 +/- 0.05, see table 2 for the alpha-analogue (computed to be 1.26). Since it was unclear if beta-selectivity resulted from a conformational constraint induced by the anomeric iodide, a 4,6-O-benzylidine acetal was used to lock the iodide into a chairlike conformation. Both experiments and calculations on this analogue suggest that it does not mirror the behavior of mannosyl iodides lacking bridging acetal protecting groups.

Catalytic Mechanism of Glycosyltransferases: Hybrid Quantum Mechanical/Molecular Mechanical Study of the Inverting N-Acetylglucosaminyltransferase I

The Golgi glycosyltransferase, N-acetylglucosaminyltransferase I (GnT-I), catalyzes the transfer of a GlcNAc residue from the donor UDP-GlcNAc to the C2-hydroxyl group of a mannose residue in the trimannosyl core of the Man5GlcNAc2-Asn-X oligosaccharide. The catalytic mechanism of GnT-I was investigated using a hybrid quantum mechanical/molecular mechanical (QM/MM) method with a QM part containing 88 atoms treated with density functional theory (DFT) at the BP/TZP level. The remaining parts of a GnT-I complex, altogether 5633 atoms, were modeled using the AMBER molecular force field. A theoretical model of a Michaelis complex was built using the X-ray structure of GnT-I in complex with the donor having geometrical features consistent with kinetic studies. The QM(DFT)/MM model identified a concerted SN2-type of transition state with D291 as the catalytic base for the reaction in the enzyme active site. The TS model features nearly simultaneous nucleophilic addition and dissociation steps accompanied by the transfer of the nucleophile proton Hb2 to the catalytic base D291. The structure of the TS model is characterized by the Ob2-C1 and C1-O1 bond distances of 1.912 and 2.542 A, respectively. The activation energy for the proposed reaction mechanism was estimated to be approximately 19 kcal mol-1. The calculated alpha-deuterium kinetic isotope effect of 1.060 is consistent with the proposed reaction mechanism. Theoretical results also identified interactions between the Hb6 and beta-phosphate oxygen of the UDP and a low-barrier hydrogen bond between the nucleophile and the catalytic base D291. It is proposed that these interactions contribute to a stabilization of TS. This modeling study provided detailed insight into the mechanism of the GlcNAc transfer catalyzed by GnT-I, which is the first step in the conversion of high mannose oligosaccharides to complex and hybrid N-glycan structures.

Secondary Kinetic Deuterium Isotope Effects in the Reaction of MeI with Organoplatinum(II) Complexes

Secondary α-deuterium (α-D) kinetic isotope effects (KIEs) have been determined for the reactions of the (diimine)diarylplatinum(II) complexes [Pt(p-MeC6H4)2(NN)] (NN = bipyridine (bpy), 1a; NN = 4...

The Mechanism Study of Free Radical SH2′ Reactions by Leaving Group Effect and Secondary α‐Deuterium Kinetic Isotope Effect

AbstractThe reactions of free radical addition to allylic compounds are believed to proceed the SH2′ mechanism. It is not clear whether the SH2′ mechanism is concerted or stepwise. The leaving group effects and the secondary α‐deuterium kinetic isotope effects in free radical SH2′ reactions have been determined. The leaving group effect, kBr/kCl, is from 1.88 to 14.3. The secondary α‐deuterium kinetic isotope effects, kH/kD, are 1.20 for 2‐methylallyl chloride and 1,1‐d2‐2‐methylallyl chloride and 1.22 for allyl chloride and 1,1‐d2‐allyl chloride. The free radical SH2′ reactions seem to favor the concerted mechanism.

Secondary alpha-deuterium kinetic isotope effects: assumptions simplifying interpretations of mechanisms of solvolyses of secondary alkyl sulfonates.

For solvolyses of 2-propyl and cyclopentyl sulfonates, logarithms of alpha-deuterium kinetic isotope effects (alpha-KIE) correlate linearly with logarithms of nucleophilic solvent assistance (NSA); correlations have the same slopes, but different intercepts, consistent with both solvent and structural effects on alpha-KIEs for heterolysis, further supported by recent theoretical and experimental data. It is argued that alpha- and beta-KIEs cannot yet distinguish between mechanisms proceeding via one or more transition states of similar energies. Structural, solvent, and isotope effects can be rationalized by heterolysis accompanied by NSA.

Mechanism of Thermoanaerobacterium saccharolyticum beta-xylosidase: kinetic studies.

The catalytic mechanism of Thermoanaerobacterium saccharolyticum beta-xylosidase (XynB) from family 39 of glycoside hydrolases has been subjected to a detailed kinetic investigation using a range of substrates. The enzyme exhibits a bell-shaped pH dependence of k(cat)/K(m), reflecting apparent pK(a) values of 4.1 and 6.8. The k(cat) and k(cat)/K(m) values for a series of aryl xylosides have been measured and used to construct two Brønsted plots. The plot of log(k(cat)/K(m)) against the pK(a) of the leaving group reveals a significant correlation (beta(lg) = -0.97, r(2) = 0.94, n = 8), indicating that fission of the glycosidic bond is significantly advanced in the transition state leading to the formation of the xylosyl-enzyme intermediate. The large negative value of the slope indicates that there is relatively little proton donation to the glycosidic oxygen in the transition state. A biphasic, concave-downward plot of log(k(cat)) against pK(a) provides good evidence for a two-step double-displacement mechanism involving a glycosyl-enzyme intermediate. For activated leaving groups (pK(a) < 9), the breakdown of the xylosyl-enzyme intermediate is the rate-determining step, as indicated by the absence of any effect of the pK(a) of the leaving group on log(k(cat)) (beta(lg) approximately 0). However, a strong dependence of the first-order rate constant on the pK(a) value of relatively poor leaving groups (pK(a) > 9) suggests that the xylosylation step is rate-determining for these substrates. Support for the dexylosylation chemical step being rate-determining for activated substrates comes from nucleophilic competition experiments in which addition of dithiothreitol results in an increase in turnover rates. Normal secondary alpha-deuterium kinetic isotope effects ((alpha-D)(V) or (alpha-D)(V/K) = 1.08-1.10) for three different substrates of widely varying pK(a) value (5.15-9.95) have been measured and these reveal that the transition states leading to the formation and breakdown of the intermediate are similar and both steps involve rehybridization of C1 from sp(3) to sp(2). These results are consistent only with "exploded" transition states, in which the saccharide moiety bears considerable positive charge, and the intermediate is a covalent acylal-ester where C1 is sp(3) hybridized.

Kinetic isotope effects for gas phase SN2 methyl transfer: a computational study of anionic and cationic identity reactions

The relationship between energy barriers, transition-state looseness and 2° α-deuterium kinetic isotope effects (KIEs) has been re-evaluated for a range of identity SN2 methyl transfer reactions that extends to “exploded” transition structures (TSs). Ab initio MP2/6-311+G* molecular orbital calculations have been performed for reactions involving the neutral nucleophiles X = CO, N2, NH3, N(CH3)3, OH2, Kr, Ar, Ne and He, along with anionic nucleophiles X− = F, Cl, Br, CN, NC, CCH, and OH. The behaviour previously noted by Wolfe and co-workers, from MP2/6-31+G* studies of identity and non-identity methyl transfers with anionic nucleophiles and neutral electrophiles only, does not apply to the broader range which also includes neutral nucleophiles and cationic electrophiles: a looser TS is not associated with a higher energy barrier and a more inverse 2° α-D KIE. Moreover, when the interaction of the nucleophile with the electrophile in the reactant complex (RC) is considered, no simple relationships between “looseness” or “tightness” and either energy barriers or KIEs are found. The variation in energy barriers may be understood by means of a simple model involving the distance travelled by the methyl group within the encounter complex from RC to the product complex (PC) and the force constant for stretching the bond to the leaving group in RC. There is a fair linear correlation between the 2° α-D KIE and the change in this same stretching force constant, from RC to TS. The methyl group in the SN2 TS does not resemble an isolated methyl cation, even for systems showing “SN1-like” properties, owing to the significant influence of the nucleophile and leaving group. Consideration of the unusual range of nucleophiles X = Kr, Ar, Ne and He in identity reactions with CH3X+ shows a mechanistic changeover from a double-well potential with a true SN2 TS to a single-well potential with a symmetric intermediate corresponding to a solvated methyl cation.

The nature of the transition state in diarylmethyl cation – nucleophile combination reactions as probed by secondary α-deuterium isotope effects

Transition-state structures for the carbocation–nucleophile combination reactions of (4-substituted-4'- methoxydiphenyl)methyl cations with water, chloride, and bromide ions in acetonitrile–water mixtures have been investigated by measuring the secondary α-deuterium kinetic and equilibrium isotope effects. Rate constants in the combination direction were measured with laser flash photolysis. Equilibrium constants were measured for the water reaction by a comparison method in moderately concentrated sulfuric acid solutions, for the bromide reaction via the observation of reversible combination, and for the chloride reaction from the ratio of the combination rate constant and the rate constant for the ionization of the diarylmethyl chloride product. The fraction of bond making in the transition state has been calculated as the ratio log (kinetic isotope effect):log (equilibrium isotope effect). For the water reaction, there is 50–65% bond making in the transition state; this is also true for cations that are many orders of magnitude less reactive. The same conclusions, 50–65% bond formation in the transition state independent of reactivity, have previously been made in correlations of log kw vs. log KR. Thus, two quite different measures of transition structure provide the same result. The kH:kD values for the halide combinations in 100% acetonitrile are within experimental error of unity. This is consistent with suggestions that these reactions are occurring with diffusional encounter as the rate-limiting step. Addition of water has a dramatic retarding effect on the halide reactions, with rate constants decreasing steadily with increased water content. Small inverse kinetic isotope effects are observed (in 20% acetonitrile:80% water) indicating that carbon—halogen bond formation is rate-limiting. Comparison of the kinetic and equilibrium isotope effects shows ~25 and ~40% bond formation in the transition states for the reactions with bromide and chloride, respectively.Key words: carbocation, isotope effect, transition state, halide.

Deuterium kinetic isotope effects in gas phase SN2 reactions

Rate coefficients and secondary α-deuterium kinetic isotope effects (KIEs) for the nucleophilic substitution (SN2) reactions of Cl− + CH3Br → CH3Cl + Br−, Cl− + CH3I → CH3Cl + I−, Br− + CH3I → CH3Br + I−, and their perdeuterated analogs are remeasured in the gas phase at 300 K. The measurements confirm our previous results [Gronert et al., J. Am. Chem. Soc. 113 (1991) 4009] and substantial inverse KIEs are measured with an improved accuracy: kH/kD = 0.77 (±0.03), 0.84 (±0.01), and 0.76 (±0.01), respectively, for the above systems. Thus, the experimentally observed effect of deuterium substitution in these reactions is considerably more dramatic than predicted previously by transition state theory where KIEs are calculated to be closer to unity. The experimental KIE values for the series of SN2 reactions, F−, Cl−+CH3Br and F−, Cl−, Br−+CH3I are both found to decrease (i.e. become more inverse) with an increase in the transition-state looseness parameter (RTS) for larger halide anions, in contrast to those for lighter methyl halides which show the expected positive correlations with RTS.

An unusually large secondary α-deuterium kinetic isotope effect in hydride ion SN2 reactions

Theoretical calculations at the HF/6-31+G* level suggest the secondary α-deuterium kinetic isotope effects for hydride ion SN2 reactions are much larger than expected for the structure of the transition state. The secondary α-deuterium kinetic isotope effects for the SN2 reactions between sodium borohydride (hydride ion) and para-methyl- and para-chlorobenzyl chlorides are much larger than expected as the theoretical calculations suggest. It appears the secondary α-deuterium isotope effects are larger than expected for the structure of the SN2 transition state because the hydride ion is too small to affect the Cα—H(D) out-of-plane bending vibrations in the transition state.Key words: secondary α-deuterium kinetic isotope effects, SN2, nucleophilic substitution, transition state, substituent effects.

An unusually large secondary α-deuterium kinetic isotope effect in hydride ion S&lt;sub&gt;N&lt;/sub&gt;2 reactions

An unusually large secondary α-deuterium kinetic isotope effect in hydride ion S&lt;sub&gt;N&lt;/sub&gt;2 reactions

Kinetic Isotope Effects in the Reduction of Methyl Iodide

α-Deuterium (α-D) kinetic isotope effects (KIEs) have been determined for the reaction of methyl iodide with a series of reducing agents. Reagents which transfer hydride ion in an SN2 reaction show small inverse or small normal KIEs. Reagents which transfer an electron to methyl iodide to produce methyl radical show large normal KIEs up to 20% per α-D. Large KIEs were found for the reaction of methyl iodide with sodium, for Pd-catalyzed reaction of methyl iodide with hydrogen, for electron transfer (ET) at a platinum cathode, for ET from benzophenone ketyl or from sodium naphthalenide, for iron-catalyzed ET from a Grignard reagent to methyl iodide, and for reduction of methyl iodide with tributyltin hydride or with gaseous hydrogen iodide. Very small KIEs were found for electron transfer to methyl iodide from magnesium in ether or from sodium in ammonia. The reason may be that these reactions are transport or diffusion controlled.

Thermal Isomerizations of Substituted Benzyl Isocyanides: Relative Rates Controlled Entirely by Differences in Entropies of Activation

The absolute and relative rates of thermal rearrangments of substituted benzyl isocyanides were obtained at the temperatures between 170 and 230 °C. The relative rates are independent of temperature and exhibit excellent Hammett correlations (ρ+ = −0.24). The temperature studies yielded activation parameters ( and ) and their differential counterparts ( and ). The differential terms were plotted against σ+. The secondary α-deuterium kinetic isotope effects (kD/kH = 1.11) were measured at several temperatures. The rate data can be rationalized with the cyclic TS. The substituent effects on the rates are due to the entropic contributions.

Nucleophilic solvent participation in the solvolysis of 4-methoxybenzyl bromide and chloride

The solvolysis of 4-methoxybenzyl chloride (1) and bromide (3), and 1-(4-methoxyphenyl)ethyl chloride (4) in a variety of solvents were carried out. The observation of linear correlation using the dual-parameter Grunwald–Winstein equation, and the positive azide salt effect indicate significant nucleophilic solvent participation for 1 and 3. A smaller deviation of log k (in 100% 2,2,2-trifluoroethanol) for the bromide 3 than chloride 1 in the log k – YBnX plots reveals a lesser extent of nucleophilic participation and is also in harmony with the greater nucleofugality of the bromide ion. The use of a low kBr/kCl ratio as evidence for the presence of solvent participation is discussed. The observed α-deuterium kinetic isotope effect of 1.08 to 1.21 measured for 1 and 3 is inconsistent with the magnitude generally considered for a concerted mechanism.

Secondary α-deuterium kinetic isotope effects in the decomposition of simple α-acetoxydialkylnitrosamines: Nitrosiminium ion intermediates

Abstract Secondary α-deuterium kinetic isotope effects for the pH independent decay of two (N-nitrosoalkylamino)methylacetates (4) and two (N-nitrosoalkylamino)propyl acetates (5) have been determined at 52 °C in aqueous solution, ionic strength 1 M. In all cases the isotope effects are kobsdH/kobsdD ∼ 1.1 – 1.2 (per hydrogen). It is concluded that the direction and magnitude of the isotope effects are inconsistent with mechanisms involving rate limiting reaction at the carbonyl group; and, are consistent with the formation of N-nitrosiminium ions in, or prior to, the rate limiting step.

Isotopic labelling studies of the deaminative fragmentation of N-nitrosohydroxylamines and related compounds by kinetics, millimetre-wave spectroscopy and 17O NMR spectroscopy

Nitrous oxide enriched with 18 O has been identified by millimetre-wave spectroscopy from the acid-induced hydrolysis of N 1 -(2-adamantyl)-N 2 -[ 18 O]hydroxydiazen-1-ium N 1 -oxide 2 which, along with 17 O NMR studies and an α-deuterium kinetic isotope effect of k H /k D = 0.98 (±0.02) for N-nitroso-N-(2-[2- 2 H]adamantyl)-O-b enzylhydroxylamine 4, confirms (i) that nitrous oxide is liberated in these reactions, and (ii) that the fragmentations in these reactions are step-wise and not concerted.