Secondary Kinetic Isotope Effects in Bimolecular Nucleophilic Substitutions. VI. Effect of α and β Deuteration of Alkyl Halides in their Menschutkin Reactions with Pyridine in Nitrobenzene

1972 ◽  
Vol 50 (7) ◽  
pp. 986-991 ◽  
Author(s):  
K. T. Leffek ◽  
A. F. Matheson
Keyword(s):  
Isotope Effects ◽  
Side Reaction ◽  
Kinetic Isotope Effects ◽  
Alkyl Halides ◽  
State Structure ◽  
Transition State Structure ◽  
Nucleophilic Substitutions ◽  
Kinetic Isotope ◽  
Deuterium Isotope Effects ◽  
Rate Ratios

A survey of kinetic, secondary deuterium isotope effects, for α, β, and γ deuterated alkyl halides reacting with pyridine in nitrobenzene solvent has been made. α-Deuterium effects have been measured for eight compounds, β-deuterium effects for four compounds, and one rate ratio for γ-deuteration is reported. The possible errors in the rate ratios for β-deuterated compounds, resulting from the elimination side reaction have been determined. The results are discussed in terms of transition state structure.

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.

SECONDARY KINETIC ISOTOPE EFFECTS IN BIMOLECULAR NUCLEOPHILIC SUBSTITUTIONS: I. DEUTERIUM EFFECTS IN THE BUNTE SALT REACTION

1964 ◽  
Vol 42 (4) ◽  
pp. 851-855 ◽  
Author(s):  
K. T. Leffek
Keyword(s):  
Aqueous Ethanol ◽  
Isotope Effects ◽  
Kinetic Isotope Effects ◽  
Sodium Thiosulphate ◽  
Deuterium Isotope Effect ◽  
Nucleophilic Substitutions ◽  
Kinetic Isotope ◽  
Deuterium Isotope Effects ◽  
Rate Ratios ◽  
Aqueous Ethanol Solvent

The secondary deuterium isotope effects have been measured for the reaction between sodium thiosulphate and α-deuterated methyl, ethyl, and n-propyl bromide, and also for β- and γ-deuterated n-propyl bromide, in aqueous ethanol solvent. The α-deuterium isotopic rate ratios (kH/kD) are all greater than unity. These unexpected results are discussed with respect to the suggested use of the α-deuterium isotope effect as a test of mechanism in nucleophilic substitutions.

SOME DEUTERIUM KINETIC ISOTOPE EFFECTS: IV. β-DEUTERIUM EFFECTS IN WATER SOLVOLYSIS OF ETHYL, ISOPROPYL, AND tert-BUTYL COMPOUNDS

1960 ◽  
Vol 38 (11) ◽  
pp. 2171-2177 ◽  
Author(s):  
K. T. Leffek ◽  
J. A. Llewellyn ◽  
R. E. Robertson
Keyword(s):  
Isotope Effect ◽  
Kinetic Isotope Effect ◽  
Isotope Effects ◽  
Kinetic Isotope Effects ◽  
Alkyl Halides ◽  
Tert Butyl ◽  
Kinetic Isotope ◽  
Deuterium Isotope Effects ◽  
Intramolecular Forces

The secondary β-deuterium isotope effects have been measured in the water solvolytic reaction of alkyl halides and sulphonates for primary, secondary, and tertiary species. In every case the kinetic isotope effect was greater than unity (kH/kD > 1). This isotope effect may be associated with varying degrees of hyperconjugation or altered non-bonding intramolecular forces. The experiments make it difficult to decide which effect is most important.

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.

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