Experimental and Theoretical Multiple Kinetic Isotope Effects for an S<sub>N</sub>2 Reaction. An Attempt to Determine Transition‐State Structure and the Ability of Theoretical Methods to Predict Experimental Kinetic Isotope Effects

Fang, Yuqiang; Gao, Ying; Ryberg, Per; Eriksson, Jonas; Kołodziejska-Huben, Magdalena; Dybała-Defratyka, Agnieszka; Soundararajan, M.; Danielsson, Rolf; Paneth, Piotr; Matsson, Olle; Westaway, Kenneth Charles

doi:10.1002/chem.200204119

Cited by 50 publications

(84 citation statements)

References 90 publications

(97 reference statements)

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“…Furthermore, in both the gas phase and solution, the sums of the bond‐forming and bond‐breaking distances for the O atom reactions are less than 4 Å, while those for the N atom reactions are greater than 4 Å, suggesting that the transition states for reactions at O atoms are tighter than those for reactions at N atoms. This conclusion is also indicated by an analysis of reactant and product bond elongation in the transition states 68…”

Section: Discussionmentioning

confidence: 63%

Activation barriers for DNA alkylation by carcinogenic methane diazonium ions

Ekanayake

Lebreton

2005

J Comput Chem

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Methylation reactions of the DNA bases with the methane diazonium ion, which is the reactive intermediate formed from several carcinogenic methylating agents, were examined. The SN2 transition states of the methylation reactions at N7, N3, and O6 of guanine; N7, N3, and N1 of adenine; N3 and O2 of cytosine; and O2 and O4 of thymine were calculated using the B3LYP density functional method. Solvation effects were examined using the conductor-like polarizable continuum method and the combined discrete/SCRF method. The transition states for reactions at guanine N3, adenine N7, and adenine N1 are influenced by steric interactions between the methane diazonium ion and exocyclic amino groups. Both in the gas phase and in aqueous solution, the methylation reactions at N atoms have transition states that are looser, and generally occur earlier along the reaction pathways than reactions at O atoms. The forming bonds in the transition states in water are 0.03 to 0.13 A shorter than those observed in the gas phase, and the activation energies are 13 to 35 kcal/mol higher. The combined discrete/SCRF solvation energy calculations using base-water complexes with three water molecules yield base solvation energies that are larger than those obtained from the CPCM continuum method, especially for cytosine. Reactivities calculated using barriers obtained with the discrete/SCRF method are consistent with the experimentally observed high reactivity at N7 of guanine.

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Section: Discussionmentioning

confidence: 63%

Activation barriers for DNA alkylation by carcinogenic methane diazonium ions

Ekanayake

Lebreton

2005

J Comput Chem

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“…In order to predict isotope effects using DFT, 51 we need information about the putative transition states. In order to predict isotope effects using DFT, 51 we need information about the putative transition states.…”

Section: S-o Cleavagementioning

confidence: 99%

Search for a Symmetrical C–F–C Fluoronium Ion in Solution: Kinetic Isotope Effects, Synthetic Labeling, and Computational, Solvent, and Rate Studies

et al. 2015

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Recently, we reported evidence for the generation of a symmetrical fluoronium ion (a [C-F-C](+) interaction) in solution from a cage-like precursor, relying heavily on a single isotopic-labeling experiment. Paraphrasing the axiom that a strong claim must be met by as much evidence as possible, we seek to expand upon our initial findings with comprehensive labeling studies, rate measurements, kinetic isotope effect (KIE) experiments, synthetic studies, and computations. We also chronicle the development of the system, our thought process, and how it evolved from a tantalizing indication of fluoronium ion assistance in a dibromination reaction to the final, optimized system. Our experiments show secondary KIE experiments that are fully consistent with a transition state involving fluorine participation; this is also confirmed by a significant remote isotope effect. Paired with DFT calculations, the KIE experiments are indicative of the trapping of a symmetrical intermediate. Additionally, starting with an epimeric in-triflate precursor that hydrolyzes through a putative frontside SNi mechanism involving fluorine participation, KIE studies indicate that an identical intermediate is trapped (the fluoronium ion). Studies also show that the rate-determining step of the fluoronium forming SN1 reaction can be changed on the basis of solvent and additives. We also report the synthesis of a nonfluorinated control substrate to measure a relative anchimeric role of the fluorine atom in hydrolysis versus μ-hydrido bridging. After extensive testing, we can make the remarkable conclusion that our system reacts solely through a "tunable" SN1 mechanism involving a fluoronium ion intermediate. Alternative scenarios, such as SN2 reactivity, do not occur even under forced conditions where they should be highly favored.

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“…Experimental values of isotope effects can test the proposed mechanism as well as the applied theoretical protocol [6][7][8].…”

Section: Introductionmentioning

confidence: 98%

Kinetic isotope effects of nitrogen and hydrogen in reaction of N-tert-butyl-P-phenylphosphonamidothioic acid with alcohols

Jankowski

Mazur

Nonas

et al. 2005

Journal of Organometallic Chemistry

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Experimental and Theoretical Multiple Kinetic Isotope Effects for an S_N2 Reaction. An Attempt to Determine Transition‐State Structure and the Ability of Theoretical Methods to Predict Experimental Kinetic Isotope Effects

Cited by 50 publications

References 90 publications

Activation barriers for DNA alkylation by carcinogenic methane diazonium ions

Activation barriers for DNA alkylation by carcinogenic methane diazonium ions

Search for a Symmetrical C–F–C Fluoronium Ion in Solution: Kinetic Isotope Effects, Synthetic Labeling, and Computational, Solvent, and Rate Studies

Kinetic isotope effects of nitrogen and hydrogen in reaction of N-tert-butyl-P-phenylphosphonamidothioic acid with alcohols

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Experimental and Theoretical Multiple Kinetic Isotope Effects for an SN2 Reaction. An Attempt to Determine Transition‐State Structure and the Ability of Theoretical Methods to Predict Experimental Kinetic Isotope Effects

Cited by 50 publications

References 90 publications

Activation barriers for DNA alkylation by carcinogenic methane diazonium ions

Activation barriers for DNA alkylation by carcinogenic methane diazonium ions

Search for a Symmetrical C–F–C Fluoronium Ion in Solution: Kinetic Isotope Effects, Synthetic Labeling, and Computational, Solvent, and Rate Studies

Kinetic isotope effects of nitrogen and hydrogen in reaction of N-tert-butyl-P-phenylphosphonamidothioic acid with alcohols

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Experimental and Theoretical Multiple Kinetic Isotope Effects for an S_N2 Reaction. An Attempt to Determine Transition‐State Structure and the Ability of Theoretical Methods to Predict Experimental Kinetic Isotope Effects