Using secondary alpha deuterium kinetic isotope effects to determine the stereochemistry of an E2 reaction; the stereochemistry of the E2 reaction of 1-chloro-2-phenylethane with potassium tert-butoxide in tert-butyl alcohol

2001 ◽  
Vol 79 (7) ◽  
pp. 1145-1152 ◽  
Author(s):  
Peter James Smith ◽  
David AJ Crowe ◽  
Kenneth Charles Westaway
Keyword(s):  
Transition State ◽  
Isotope Effects ◽  
Kinetic Isotope Effects ◽  
Butyl Alcohol ◽  
State Structure ◽  
Transition State Structure ◽  
Isotopic Labelling ◽  
Tert Butyl ◽  
Kinetic Isotope ◽  
Tert Butyl Alcohol

Isotopic labelling studies have shown that the E2 reaction of 1-chloro-2-phenylethane with potassium tert-butoxide in tert-butyl alcohol occurs via an anti-periplanar stereochemistry. This demonstrates that the different secondary alpha deuterium kinetic isotope effects found for the high and low base concentrations and in the presence of 18-crown-6 ether are because of changes in transition state structure that occur when the form of the reacting base changes rather than to a change in the stereochemistry of the reaction.Key words: E2 reaction, stereochemistry, secondary alpha deuterium kinetic isotope effects, transition state.

Secondary Kinetic Isotope Effects in Bimolecular Nucleophilic Substitutions. V. The Role of the Solvent in the Reaction Between Methyl Iodide and Pyridine

1972 ◽  
Vol 50 (7) ◽  
pp. 982-985 ◽  
Author(s):  
K. T. Leffek ◽  
A. F. Matheson
Keyword(s):  
Transition State ◽  
Isotope Effects ◽  
Kinetic Isotope Effects ◽  
State Structure ◽  
Transition State Structure ◽  
Initial State ◽  
Nucleophilic Substitutions ◽  
Kinetic Isotope ◽  
Deuterium Isotope Effects

Secondary kinetic deuterium isotope effects are presented for the reaction of methyl-d3 iodide and pyridine in four different solvents. Calculations on mass and moment of inertia change with deuteration in the initial state and an assumed tetrahedral transition state, together with internal rotational effects, are used to rationalize the inverse isotope effects. It is concluded from the variation of the isotopic rate ratio, that the transition state structure varies with solvent.

scholarly journals Transition state for the NSD2-catalyzed methylation of histone H3 lysine 36

2016 ◽  
Vol 113 (5) ◽  
pp. 1197-1201 ◽  
Author(s):  
Myles B. Poulin ◽  
Jessica L. Schneck ◽  
Rosalie E. Matico ◽  
Patrick J. McDevitt ◽  
Michael J. Huddleston ◽  
...  
Keyword(s):  
Transition State ◽  
Isotope Effects ◽  
Histone H3 ◽  
Kinetic Isotope Effects ◽  
Chemical Mechanism ◽  
State Structure ◽  
Transition State Structure ◽  
Chemical Modeling ◽  
Kinetic Isotope ◽  
Human Multiple Myeloma

Nuclear receptor SET domain containing protein 2 (NSD2) catalyzes the methylation of histone H3 lysine 36 (H3K36). It is a determinant in Wolf–Hirschhorn syndrome and is overexpressed in human multiple myeloma. Despite the relevance of NSD2 to cancer, there are no potent, selective inhibitors of this enzyme reported. Here, a combination of kinetic isotope effect measurements and quantum chemical modeling was used to provide subangstrom details of the transition state structure for NSD2 enzymatic activity. Kinetic isotope effects were measured for the methylation of isolated HeLa cell nucleosomes by NSD2. NSD2 preferentially catalyzes the dimethylation of H3K36 along with a reduced preference for H3K36 monomethylation. Primary Me-14C and 36S and secondary Me-3H3, Me-2H3, 5′-14C, and 5′-3H2 kinetic isotope effects were measured for the methylation of H3K36 using specifically labeled S-adenosyl-l-methionine. The intrinsic kinetic isotope effects were used as boundary constraints for quantum mechanical calculations for the NSD2 transition state. The experimental and calculated kinetic isotope effects are consistent with an SN2 chemical mechanism with methyl transfer as the first irreversible chemical step in the reaction mechanism. The transition state is a late, asymmetric nucleophilic displacement with bond separation from the leaving group at (2.53 Å) and bond making to the attacking nucleophile (2.10 Å) advanced at the transition state. The transition state structure can be represented in a molecular electrostatic potential map to guide the design of inhibitors that mimic the transition state geometry and charge.

Secondary α-deuterium kinetic isotope effects for the E2 reaction of the 2-phenylethyl halides with tert-butoxide ion in tert-butyl alcohol

1985 ◽  
Vol 63 (1) ◽  
pp. 100-102 ◽  
Author(s):  
Peter James Smith ◽  
Kanchugarakoppal S. Rangappa ◽  
Kenneth Charles Westaway
Keyword(s):  
Isotope Effects ◽  
Kinetic Isotope Effects ◽  
Order Rate Constant ◽  
Butyl Alcohol ◽  
Tert Butyl ◽  
Kinetic Isotope ◽  
Tert Butyl Alcohol ◽  
Elimination Reactions ◽  
Leaving Groups ◽  
High Base

Secondary α-deuterium kinetic isotope effects have been determined for the elimination reactions of 2-phenylethyl halides with tert-butoxide in tert-butyl alcohol at 40 °C in the presence and absence of the crown ether 18C6. The second-order rate constant k2 and the normal (kH/kD)α effect remained constant when the tert-butoxide concentration was varied for reaction of the iodo and bromo compounds. However, both the magnitude of k2 and the secondary α-deuterium isotope effect were significantly dependent on [t-BuO−] when chlorine and fluorine are the leaving groups. It is noteworthy that (kH/kD)α is inverse for the reaction of both the chloro and fluoro compounds at "low" base concentrations and normal at "high" base concentrations. These results are discussed in terms of both syn- and anti-elimination pathways promoted by various associated and dissociated base species. It is suggested that the (kH/kD)α effect may be useful as a criterion for determining the stereochemistry of E2 elimination reactions.

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