Transverse compression and the secondary H/D isotope effects in intramolecular SN2 methyl-transfer reactions

1998 ◽  
Vol 76 (1) ◽  
pp. 102-113
Author(s):  
Saul Wolfe ◽  
Chan-Kyung Kim ◽  
Kiyull Yang ◽  
Noham Weinberg ◽  
Zheng Shi
Keyword(s):  
Transition State ◽  
Isotope Effect ◽  
Isotope Effects ◽  
High Energy ◽  
Retention Mechanism ◽  
Sigmatropic Rearrangement ◽  
Orbital Theory ◽  
Bending Vibration ◽  
Kinetic Isotope ◽  
Methyl Transfer

Using ab initio molecular orbital theory mainly at the 3-21 + G level, intramolecular SN2 methyl transfer between two oxygens confined within a rigid template is found to proceed exclusively by a high energy retention mechanism when the oxygens are separated by three or four bonds, and by a high energy inversion mechanism when the oxygens are separated by six bonds. Both mechanisms exist when the oxygens are separated by five bonds. The CH3/CD3 kinetic isotope effects are normal (1.21-1.34) in the retention processes and inverse (0.66-0.81) in the inversion reactions. In the case of inversion, compression of C-H bonds of the transition state by structural effects in the plane perpendicular to the O-C-O plane increases the inverse isotope effect. The retention barriers are high because retention is inherently unfavorable, even when pericyclic stabilization of the transition state is possible. The inversion barriers are high because a rigid template cannot accommodate a linear O-CH3-O structure, and the O-C-O bending vibration is stiff (the Eschenmoser effect). Using a novel design strategy, a nonrigid template has been found in which the barrier and the CH3/CD3 kinetic isotope effect are the same as in an intermolecular reaction.Key words: Eschenmoser effect, isotope effect, compression, SN2, sigmatropic rearrangement.

Additions and corrections: Transverse compression and the secondary H/D isotope effects in intramolecular SN2 methyl-transfer reactions

1998 ◽  
Vol 76 (3) ◽  
pp. 359-370 ◽  
Author(s):  
Saul Wolfe ◽  
Chan-Kyung Kim ◽  
Kiyull Yang ◽  
Noham Weinberg ◽  
Zheng Shi
Keyword(s):  
Transition State ◽  
Isotope Effect ◽  
Isotope Effects ◽  
High Energy ◽  
Retention Mechanism ◽  
Sigmatropic Rearrangement ◽  
Orbital Theory ◽  
Bending Vibration ◽  
Kinetic Isotope ◽  
Methyl Transfer

Using ab initio molecular orbital theory mainly at the 3-21+G level, intramolecular SN2 methyl transfer between two oxygens confined within a rigid template is found to proceed exclusively by a high energy retention mechanism when the oxygens are separated by three or four bonds, and by a high energy inversion mechanism when the oxygens are separated by six bonds. Both mechanisms exist when the oxygens are separated by five bonds. The CH3/CD3 kinetic isotope effects are normal (1.21-1.34) in the retention processes and inverse (0.66-0.81) in the inversion reactions. In the case of inversion, compression of C-H bonds of the transition state by structural effects in the plane perpendicular to the O-C-O plane increases the inverse isotope effect. The retention barriers are high because retention is inherently unfavorable, even when pericyclic stabilization of the transition state is possible. The inversion barriers are high because a rigid template cannot accommodate a linear O-CH3 -O structure, and the O-C-O bending vibration is stiff (the Eschenmoser effect). Using a novel design strategy, a nonrigid template has been found in which the barrier and the CH3/CD3 kinetic isotope effect are the same as in an intermolecular reaction.Key words: Eschenmoser effect, isotope effect, compression, SN2, sigmatropic rearrangement.

scholarly journals Human DNMT1 transition state structure

2016 ◽  
Vol 113 (11) ◽  
pp. 2916-2921 ◽  
Author(s):  
Quan Du ◽  
Zhen Wang ◽  
Vern L. Schramm
Keyword(s):  
Transition State ◽  
Dna Methyltransferase ◽  
Catalytic Mechanism ◽  
Isotope Effects ◽  
Nucleophilic Attack ◽  
Kinetic Isotope ◽  
Methyl Transfer ◽  
Major Transition ◽  
Methylation Patterns ◽  
Rate Limiting

Human DNA methyltransferase 1 (DNMT1) maintains the epigenetic state of DNA by replicating CpG methylation signatures from parent to daughter strands, producing heritable methylation patterns through cell divisions. The proposed catalytic mechanism of DNMT1 involves nucleophilic attack of Cys1226 to cytosine (Cyt) C6, methyl transfer from S-adenosyl-l-methionine (SAM) to Cyt C5, and proton abstraction from C5 to form methylated CpG in DNA. Here, we report the subangstrom geometric and electrostatic structure of the major transition state (TS) of the reaction catalyzed by human DNMT1. Experimental kinetic isotope effects were used to guide quantum mechanical calculations to solve the TS structure. Methyl transfer occurs after Cys1226 attack to Cyt C6, and the methyl transfer step is chemically rate-limiting for DNMT1. Electrostatic potential maps were compared for the TS and ground states, providing the electronic basis for interactions between the protein and reactants at the TS. Understanding the TS of DNMT1 demonstrates the possibility of using similar analysis to gain subangstrom geometric insight into the complex reactions of epigenetic modifications.

scholarly journals Isotope effect analyses provide evidence for an altered transition state for RNA 2′-O-transphosphorylation catalyzed by Zn2+

2016 ◽  
Vol 52 (24) ◽  
pp. 4462-4465 ◽  
Author(s):  
Shuming Zhang ◽  
Hong Gu ◽  
Haoyuan Chen ◽  
Emily Strong ◽  
Edward W. Ollie ◽  
...  
Keyword(s):  
Transition State ◽  
Isotope Effect ◽  
Isotope Effects ◽  
Kinetic Isotope Effects ◽  
Base Catalysis ◽  
Kinetic Isotope

Solvent D2O and18O kinetic isotope effects on RNA 2′-O-transphosphorylation catalyzed by Zn2+demonstrate an altered transition state relative to specific base catalysis.

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

2001 ◽  
Vol 79 (12) ◽  
pp. 1887-1897
Author(s):  
Thuy Van Pham ◽  
Robert A McClelland
Keyword(s):  
Transition State ◽  
Isotope Effect ◽  
Rate Constant ◽  
Rate Constants ◽  
Flash Photolysis ◽  
Isotope Effects ◽  
Equilibrium Constants ◽  
Bond Formation ◽  
Kinetic Isotope ◽  
Rate Limiting

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.

Unequal primary kinetic isotope effects in the base-catalysed H–D exchange of diastereotopic protons

1980 ◽  
Vol 58 (1) ◽  
pp. 72-78 ◽  
Author(s):  
Robert R. Fraser ◽  
Philippe J. Champagne
Keyword(s):  
Transition State ◽  
Exchange Reaction ◽  
Isotope Effect ◽  
Isotope Effects ◽  
Kinetic Isotope Effects ◽  
Deuterium Isotope Effect ◽  
Kinetic Isotope

Primary kinetic isotope effects have been measured for the base-catalyzed exchange reaction of 4′,1″-dimethyl-1,2,3,4-dibenzcyclohepta-1,3-diene-6-one, 1. It was found that the isotope effects kH/kT and kD/kT for the faster exchanging protons (13.6 and 3.8 respectively) are significantly larger than the corresponding values for the slower exchanging protons (4.6 and 1.6 respectively). These differences could result from truly unequal isotope effects due to transition state differences or intrusion of a second pathway for exchange of the less reactive proton in the dedeuteration reaction. The data appear to support the latter interpretation. The secondary deuterium isotope effect was found to be 1.18.

Kinetic evidence for the importance of solvent-separated ion pairs during the solvolyses of adamantylideneadamantyl derivatives

2004 ◽  
Vol 82 (9) ◽  
pp. 1336-1340
Author(s):  
Xicai Huang ◽  
Andrew J Bennet
Keyword(s):  
Ionic Strength ◽  
Transition State ◽  
Isotope Effect ◽  
Kinetic Isotope Effect ◽  
Isotope Effects ◽  
Ion Pairs ◽  
Kinetic Isotope Effects ◽  
Ion Pair ◽  
Salt Effects ◽  
Kinetic Isotope

The aqueous ethanolysis reactions of adamantylideneadamantyl tosylate, -bromide, and -iodide (1-OTs, 1-Br and 1-I) were monitored as a function of ionic strength. Special salt effects are observed during the solvolyses of both homoallylic halides, but not in the case of the tosylate 1-OTs. The measured α-secondary deuterium kinetic isotope effects for the solvolysis of 1-Br in 80:20 and 60:40 v/v ethanol–water mixtures at 25 °C are 1.110 ± 0.018 and 1.146 ± 0.009, respectively. The above results are consistent with the homoallylic halides reacting via a virtual transition state in which both formation and dissociation of a solvent-separated ion pair are partially rate-determining. While the corresponding transition state for adamantylideneadamantyl tosylate involves formation of the solvent-separated ion pair.Key words: salt effects, kinetic isotope effect, internal return, solvolysis, ion pairs.

Isotope Effect Studies on Elimination Reactions. IX. The Nature of the Transition State for the E2 Reaction of 2-Arylethylammonium Ions with Ethoxide in Ethanol

1974 ◽  
Vol 52 (5) ◽  
pp. 749-760 ◽  
Author(s):  
P. J. Smith ◽  
A. N. Bourns
Keyword(s):  
Transition State ◽  
Isotope Effect ◽  
Isotope Effects ◽  
Nitrogen Isotope ◽  
Kinetic Isotope Effects ◽  
Ammonium Ions ◽  
Nitrogen Effect ◽  
Kinetic Isotope ◽  
Leaving Group ◽  
Hydrogen Deuterium

Kinetic isotope effects have been determined for the E2 reaction of some 2-arylethyltrimethyl-ammonium ions with ethoxide in ethanol at 40°. The nitrogen effect, (k14/k15 − 1)100, decreased with increasing electron-withdrawing ability of the para substituent; i.e. 1.37, 1.33, 1.14, and 0.88 for p-OCH3, p-H, p-Cl, and p-CF3, respectively. Furthermore, the primary hydrogen–deuterium isotope effects increased for the same substituents, respectively; i.e. kH/kD = 2.64, 3.23, 3.48, and 4.16. A large positive ρ value of 3.66 was found as well as a small secondary α-deuterium effect of 1.02 for p-H. In addition, the nitrogen isotope effect decreased with increasing strength of the abstracting base for the reaction of ethyltrimethylammonium ion; i.e. 1.86 and 1.41 at 60° for reaction with EtO−–EtOH and t-BuO−–t-BuOH, respectively. The results are discussed in terms of recent theoretical treatments of the effect of base, substituents, and nature of the leaving group on the nature of the transition state for an E2 process. The conclusion is reached that any structural change which causes one bond (C—H) to be weakened more at the transition state will have a corresponding effect on the other bond [Formula: see text]

Isotope effects in nucleophilic substitution reactions. VI. The effect of ion pairing on the transition state structure of SN2 reactions

1988 ◽  
Vol 66 (5) ◽  
pp. 1263-1271 ◽  
Author(s):  
Kenneth Charles Westaway ◽  
Zhu-Gen Lai
Keyword(s):  
Transition State ◽  
Isotope Effect ◽  
Kinetic Isotope Effect ◽  
Isotope Effects ◽  
Ion Pair ◽  
State Structure ◽  
Transition State Structure ◽  
Substitution Reactions ◽  
Sn2 Reactions ◽  
Kinetic Isotope

Spectroscopic and conductivity studies of sodium thiophenoxide solutions in four different solvents and the secondary α-deuterium kinetic isotope effects found in the presence of 15-crown-5 ether demonstrate that the secondary α-deuterium kinetic isotope effect and transition state structure for the SN2 reaction between sodium thiophenoxide and n-butyl chloride are significantly different, depending on whether the ionic reactant is a solvent-separated ion-pair complex or a free ion. In all three solvents in which the form of the ionic reactant changes, a smaller isotope effect and tighter transition state are found for the reaction with the ion-pair complex.

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