E2 Transition State Research Articles

The Impact of Substituents on the Transition States of SN2 and E2 Reactions in Aliphatic and Vinylic Systems: Remarkably Facile Vinylic Eliminations

For a series of α and β substituted haloethanes and haloethenes, gas-phase experiments and computational modeling have been used to characterize their nucleophilic substitution and elimination reactions. Despite being less thermodynamically favorable, the vinylic eliminations have rate constants and computed barriers that are similar to those of analogous aliphatic eliminations. This is the result of the vinylic systems shifting to more E1(cb)-like transition states and exploiting the inherent greater acidity of vinylic hydrogens. In general, the α-substituents have a greater impact on the S(N)2 pathways and stabilize the transition states via field and polarizability effects. Substantial stabilization is also provided to the E2 transition states by the α-substituents, but they have surprisingly little impact on the geometries of the transition states of either pathway. The β-substituents generally lead to a strong bias toward elimination and greatly affect the synchronicity of the elimination (more E1(cb)-like) as well as its location on the reaction coordinate (early). The experimental and computational data are in good accord, and the full data set provides a comprehensive picture of substituent effects on solvent-free S(N)2 and E2 processes.

The Nucleotide, Inhibitor, and Cation Binding Sites of P‐type II ATPases

P-type ATPases constitute a ubiquitous superfamily of cation transport enzymes, responsible for carrying out actions of paramount importance in biology such as ion transport and expulsion of toxic ions from cells. The harmonized toggling of gates in the extra- and intracellular domains explain the phenomenon of specific cation binding in selective physiological states. A quantitative understanding of the fundamental aspects of ion transport mechanism and regulation of P-type ATPases requires detailed knowledge of thermodynamical, structural, and functional properties. Computational studies have made significant contributions to our understanding of biological ion pumps. Various 3D structures of Ca(2+) -ATPase between E1 and E2 transition states have given a impetus to the theorists to work on the Na(+) K(+) - and H(+) K(+) -ATPase to address important questions about their function. The current review delineates the importance of cation, nucleotide, and inhibitor binding domains, with a focus on the therapeutic potential and biological relevance of the three P-type II ATPases. This will give an insight into the ion selectivity and their conduction across the transmembrane helices of P-type II ATPases, which may pave the way to a range of fundamental questions about the mechanism and aid in the efforts of structure- and analog-based drug design.

E1-E2 Interactions in Ubiquitin and Nedd8 Ligation Pathways

Initial rates of E1-catalyzed E2 transthiolation have been used as a reporter function to probe the mechanism of 125I-ubiquitin transfer between activation and ligation half-reactions of ubiquitin conjugation. A functional survey of 11 representative human E2 paralogs reveals similar Km for binding to human Uba1 ternary complex (Km(ave)=121±72 nm) and kcat for ubiquitin transfer (kcat(ave)=4.0±1.2 s(-1)), suggesting that they possess a conserved binding site and transition state geometry and that they compete for charging through differences in intracellular concentration. Sequence analysis and mutagenesis localize this binding motif to three basic residues within Helix 1 of the E2 core domain, confirmed by transthiolation kinetics. Partial conservation of the motif among E2 paralogs not recognized by Uba1 suggests that another factor(s) account for the absolute specificity of cognate E2 binding. Truncation of the Uba1 carboxyl-terminal β-grasp domain reduces cognate Ubc2b binding by 31-fold and kcat by 3.5×10(4)-fold, indicating contributions to E2 binding and transition state stabilization. Truncation of the paralogous domain from the Nedd8 activating enzyme has negligible effect on cognate Ubc12 transthiolation but abrogates E2 specificity toward non-cognate carrier proteins. Exchange of the β-grasp domains between ubiquitin and Nedd8 activating enzymes fails to reverse the effect of truncation. Thus, the conserved Helix 1 binding motif and the β-grasp domain direct general E2 binding, whereas the latter additionally serves as a specificity filter to exclude charging of non-cognate E2 paralogs in order to maintain the fidelity of downstream signaling.

Chemical reactions inside structured nano-environment: SN2vs. E2 reactions for the F−+ CH3CH2Cl system

A new receptor for S(N)2 transition states, named NPTROL, is proposed. This molecule has a cavity and four hydroxyl groups that are able to interact with ionic S(N)2 and E2 transition states. Its catalytic effect and selectivity was investigated through high level ab initio calculations using the fluoride ion plus ethyl chloride in DMSO solution as a model system. Calculations at the ONIOM[CCSD(T)/6-311+G(2df,2p) : MP2/BASIS1] level of theory and solvent effects, included through a continuum solvation model, indicate that NPTROL is able to catalyze the S(N)2 pathway and has an inverse effect on the E2 pathway. Inside the NPTROL cavity, the ΔG(‡) for the S(N)2 transition state is 5.00 kcal mol(-1) lower than that for E2, and as a consequence this reaction becomes highly selective toward the S(N)2 product.

VBSCF Calculations on the Bimolecular (E2) Elimination Reaction. The Nature of the Transition State

Valence bond calculations utilizing the Xiamen package have been carried out on the bimolecular (E2) elimination reaction X(-) + HCH(2)CH(2)Y --> XH + CH(2)=CH(2) + Y(-) where X,Y = F,F; F,Cl; Cl,F; Cl,Cl for anti and syn reactant complexes, transition states, and product complexes. The calculations were supplemented by MO-based calculations at MP2/6-311++G**//MP2/6-311++G**. The valence bond calculations give reasonable energies with eight contributors to the resonance hybrid. Charge-localized contributors dominate the transition states. NPA charges from the MO calculations confirm that the transition states possess a significant degree of localized charge and can be described by the key resonance structure X(-)-H(+)-CH(2)(-)-CH(2)(+)-Y(-). At the same time, the MO calculations show that electronically and geometrically the reactions are clearly concerted though not synchronous. Valence bond state correlation diagrams (VBSCD) show that a simple proton transfer such as that in the E1cB irreversible reaction is predicted to have a lower barrier than a synchronous concerted (E2) reaction. The E2 transition state evidently avoids this energetic disadvantage by becoming localized and nonsynchronous, though with important electronic and geometric changes at all of the reacting centers.

Eliminations from aryl bis(p-chlorophenyl)acetates promoted by R2NH in MeCN. Effects of base-solvent and β-aryl group

Elimination reactions of (4′-ClC6H4)2CHCO2C6H3-2-X-4-NO2 promoted by R2NH in MeCN have been studied kinetically. The observed second-order kinetics, Bronsted β = 0.44–0.86 and |βblog| = 0.46–0.69 are consistent with the E2 mechanism. The Bronsted β decreased as the leaving group was made more nucleofugic and the |βlog| increased with a weaker base. Comparison with existing data reveals that the structure of the transition state is relatively insensitive to the base-solvent and β- aryl substituent on the E2 transition state.

Exploring the Reactivity Trends in the E2 and SN2 Reactions of X(-) + CH3CH2Cl (X = F, Cl, Br, HO, HS, HSe, NH2 PH2, AsH2, CH3, SiH3, and GeH3).

The reactivity order of 12 anions toward ethyl chloride has been investigated by using the G2(+) method, and the competitive E2 and SN2 reactions are discussed and compared. The reactions studied are X(-) + CH3CH2Cl → HX + CH2═CH2 + Cl(-) and X(-) + CH3CH2Cl → CH3CH2X + Cl(-), with X = F, Cl, Br, HO, HS, HSe, NH2 PH2, AsH2, CH3, SiH3, and GeH3. Our results indicate that there is no general and straightforward relationship between the overall barriers and the proton affinity (PA) of X(-); instead, discernible linear correlations only exist for the X's within the same group of the periodic table. Similar correlations are also found with the electronegativity of central atoms in X, deformation energy of the E2 transition state (TS), and the overall enthalpy of reaction. It is revealed that the electronegativity will significantly affect the barrier height, and a more electronegative X will stabilize the E2 and SN2 transition states. Multiple linear regression analysis shows that there is a reasonable linear correlation between E2 (or SN2) overall barriers and the linear combination of PA of X(-) and electronegativity of the central atom.

Deuterium Kinetic Isotope Effects in Microsolvated Gas-Phase E2 Reactions: Methanol and Ethanol as Solvents

The gas-phase reactions of F−(CH3OH) and F−(C2H5OH) with t-butyl bromide have been investigated to explore the effect of the solvent on the E2 transition state. Kinetic isotope effects (KIEs) were measured using a flowing afterglow-selected ion flow tube (FA-SIFT) mass spectrometer upon deuteration of both the alkyl halide and the alcohol. Kinetic isotope effects are significantly more pronounced than those previously observed for similar reactions of F−(H2O) with t-butyl halides. KIEs for the reaction of F−(CH3OH) with t-butyl bromide are 2.10 upon deuteration of the neutral reagent and 0.74 upon deuteration of the solvent. KIEs for the reaction of F−(C2H5OH) with t-butyl bromide are 3.84 upon deuteration of the neutral reagent and 0.66 upon deuteration of the solvent. The magnitude of these effects is discussed in terms of transition-state looseness. Additionally, deuteration of the neutral regent and deuteration of the solvent do not produce completely separable isotope effects, which is likely due to a crowded transition state. These results are compared to our previous work on SN2 and E2 solvated systems.

Ketene-Forming Elimination Reactions from Aryl Thienylacetates Promoted by R2NH/R2NH2+ in 70 mol % MeCN(aq). Effect of the β-Aryl Group

Ketene-forming eliminations from ArCH2CO2C6H3-2-X-4-NO2 (Ar = thienyl, 1) promoted by R2NH/R2NH2+ in 70 mol % MeCN(aq) have been studied kinetically. When X = CF3 and NO2, the reactions exhibit second-order kinetics as well as beta = 0.30-0.64 and |betalg| = 0.31-0.52 that decrease with a better leaving group. Hence, an E2 mechanism is evident. As the leaving group is made poorer (X = H, OCH3, and Cl), E2 transition state becomes more skewed toward the proton transfer, as revealed by the increase in Brönsted beta to 0.5-0.64, and the E1cb mechanism competes. The changes in the k1 and k-1/k2 values with the reactant structure variation provide additional support for the competing E1cb mechanism. By comparing with existing data for 4-YC6H4CH2CO2C6H3-2-X-4-NO2, the effect of beta-aryl group on ketene-forming elimination is assessed.

Theoretical study of bimolecular elimination (E2) reactions. Possibility ofsyn E2 elimination in the series of 2-R-2-R'-1-halocyclopropanes

Reactions of the methoxide ion with substituted halocyclopropanes, which result in E2 elimination, have been studied by the semiempirical quantum-chemical AM1 method. The transition states corresponding totrans andcis routes have been localized. The energetic predominance of thetrans route over thecis route is reduced by 2.6 kcal mol−1 on going from 1-chloropropane to chlorocyclopropane because of the features of cyclopropane geometry. It has been demonstrated that, in the gas phase,cis elimination may predominate overtrans elimination for a particular stereoisomer of 2-cyano-2-methyl-1-halocyclopropanes due to weakening of orbital interactions and Coulomb repulsion between the cyano group and the MeO− anion in thetrans E2 transition state.

The effect of the nature of the amine leaving group on the nature of the E2 transition state for the reaction of 1-phenylethylammonium ions with sodium ethoxide in ethanol

To investigate the effect of the leaving group on the elimination reaction of 1-phenylethylammonium ions with sodium ethoxide in ethanol at 60 °C, the reaction of seven different quaternary ammonium salts and their β-deuterated analogues with trimethylamine, N-methylpiperidine, N-methyldiethylamine, triethylamine, N,N-dimethylbenzylamine, tripropylamine, and N,N-diethylbenzylamine as leaving groups has been studied. In all cases the elimination, which was shown to proceed via the concerted E2 process, was accompanied by competing substitution reactions. Although a significant dependence of the rate of the elimination process on the nature of the leaving group was noted, there was not any linear correlation with the basicity of the amine leaving group. The primary hydrogen–deuterium kinetic isotope effect for the elimination process, (kH/kD)E, was found to increase initially with an increase of reaction rate, [Formula: see text] for substrates containing the leaving groups trimethylamine, N-methylpiperidine, N-methyldiethylamine, triethylamine, and N,N-dimethylbenzylamine; i.e., (kH/kD)E = 5.03, 5.26, 5.40, 5.83, and 5.85, respectively. A further increase in rate, using substrates with tripropylamine and N,N-diethylbenzylamine as leaving groups resulted in a decrease of the magnitude of the hydrogen–deuterium isotope effect; i. e., (kH/kD)E = 5.42 and 4.67, respectively. It is concluded that steric effects mainly determine leaving group ability. As well, it is concluded that the leaving group ability of the amine determines the structure of the E2 transition state. For the reaction of the poorer leaving groups, trimethylamine, N-methylpiperidine, and N-methyldiethylamine, the proton is morethan one-half transferred at the transition state while for reaction involving the two best leaving groups, tripropylamine and N,N-diethylbenzylamine, the Cβ—H bond is lessthan one-half broken at the transition state. The conclusions are considered in the light of the More O'Ferrall – Jencks potential energy surface diagram. Keywords: elimination mechanism, transition state, isotope effects, leaving group, quaternary salts.

The E2 transition state: elimination reactions of 2-(2,4-dinitrophenyl)ethyl halides

The E2 transition state: elimination reactions of 2-(2,4-dinitrophenyl)ethyl halides

Heavy atom isotope effect studies of elimination reaction mechanisms. 1. A kinetic and carbon-14 kinetic isotope effect study of the base-promoted dehydrochlorination of substituted 1-phenylethyl-2-14C chlorides

Upon treatment with the solvent conjugate base, the primary reaction of substituted 1-phenylethyl chlorides is elimination to substituted styrenes in tert-butanol (t-BuOH)-10% v/v dimethyl sulfoxide (Me/sub 2/SO) at 60/sup 0/C and in bis(2-hydroxyethyl) ether-10% v/v Me/sub 2/SO at 45/sup 0/C. Kinetic studies using eight substituted chlorides show that these reactions are strongly accelerated by both electron-donating and electron-withdrawing substituents, probably indicating a fairly reactant-like E2 transition state with the mechanism changing from El-like E2 to ElcB-like E2 as the substituents change from electron donating group (EDG) to electron withdrawing (EWG). In this first carbon isotope effect study of an elimination reaction of an alkyl chloride, carbon-14 kinetic isotope effects have been measured in the alkoxide/bis(2-hydroxyethyl) ether-Me/sub 2/SO system for 1-(4-methylphenyl)ethyl-2-/sup 14/C chloride, k/sup ..beta../k = 1.038, 1-phenylethyl-2-/sup 14/C chloride, k/sup ..beta../k = 1.058, and 1-(4-chlorophenyl)ethyl-2-/sup 14/C chloride, k/sup ..beta../k = 1.068. Clearly none of these compounds reacts by an irreversible El mechanism, for which no ..beta..-carbon isotope effect should be observed. The trend in the results is what would be expected from increased C/sub ..beta../-H bond rupture as the E2 transition state shifts from El-like to ElcB-like. Theoretical calculations involving El-like E2 transition-state models show that in this region onlymore » for a reaction coordinate motion tht strongly couples C/sub ..beta../-H bond rupture, C/sub ..cap alpha../-C/sub ..beta../ double bond formation, and C/sub ..cap alpha../-Cl bond rupture does the calculated value for k/sup ..beta../k come into the experimentally observed range, and then only for reactant-like models. 2 figures, 5 tables.« less

The effect of the leaving group on the nature of the E2 transition state for reaction of 2-aryl-1-phenylethylammonium ions with ethoxide in ethanol

The reaction of 2-aryl-1-phenylethylammonium salts with ethoxide in ethanol at 40 °C for five different amine leaving groups has been investigated. A significant dependence of the rate of reaction on the basicity of the leaving group was found. The variation of the primary hydrogen–deuterium isotope effect and pKa of the leaving group was not linear and it is concluded that the proton is less than one-half transferred to base at the transition state for reactions involving the best two leaving groups. In support of this conclusion is the observed opposite variation of kH/kD with ring substituents for the various leaving groups, i.e., for N-methylpyrrolidine, kH/kD = 4.58, 4.72, and 5.01 for p-Me, H, and p-Cl, respectively; for N-methylmorpholine, kH/kD = 6.13, 5.73, and 5.50 for p-Me, H, and p-Cl, respectively.

The carbanion mechanism of olefin-forming elimination. Part 10. Isotope effects in the dehydrochlorination of 1,1-diaryl-2,2-dichloroethanes

Intramolecular primary chlorine isotope effects have been measured for the base-induced dehydrochIorination reactions of (p-YC6H4)2CH·CHCl2(YMeO, H, orCl) in –OMe–MeOH, –OMe–MeOH–Me2SO, and ButO––ButOH. All isotope effects are small (ca. 0.14–0.37%). suggesting that the E2 transition states have nearly intact Cα–-Cl bonds. Trends in k35/k37 with changing substituent, base, and solvent are interpreted in terms of current theories of E2 transition-state character. An isotope effect of unity for the reaction of (p-NO2C6H4)2CH·CHCl2 with –OMe–MeOH confirms an earlier suggestion that the mechanism here is E1cB with rate-determining proton transfer.

ChemInform Abstract: THE EFFECT OF STERIC CROWDING ON AN E2 TRANSITION STATE

Chemischer InformationsdienstVolume 7, Issue 45 Physical Organic Chemistry ChemInform Abstract: THE EFFECT OF STERIC CROWDING ON AN E2 TRANSITION STATE G. S. DYSON, G. S. DYSONSearch for more papers by this authorP. J. SMITH, P. J. SMITHSearch for more papers by this author G. S. DYSON, G. S. DYSONSearch for more papers by this authorP. J. SMITH, P. J. SMITHSearch for more papers by this author First published: November 9, 1976 https://doi.org/10.1002/chin.197645091Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume7, Issue45November 9, 1976 RelatedInformation

The effect of steric crowding on an E2 transition state

The mechanism of the reaction of 9-(4-substituted benzyl)fluorene-9-trimethylammonium ions with ethoxide is a normal E2 process. The magnitude of the primary hydrogen–deuterium isotope effect at 60 °C increased with increasing electron-donating ability of the 4-substituent, i.e., 4.15, 5.10, 5.34, 5.65, 5.75, and 5.91 for the 4-CF3, 4-Br, 4-Cl, 4-H, 4-CH3, and 4-OCH3 substituents, respectively. The magnitude of the nitrogen isotope effect at 70 °C decreased with increased electron-donating power of the 4-substituent, i.e., [(k14/k15)–1]100 = 1.24, 0.95, 0.92, 0.91, and 0.80 for the 4-CF3, 4-F, 4-H, 4-CH3, and 4-OCH3 substituents, respectively. A small Hammett ρ value of +1.33 was observed for the reaction. It is concluded that the reaction proceeds via a transition state where the proton is more than one-half transferred to base. It is further concluded that for a reaction in which the 4-substituents decrease the rate, both carbon–hydrogen and carbon–nitrogen bond rupture is more advanced in the transition state. This variance with Hammond's postulate is discussed in the light of steric crowding at the transition state.

The E2C mechanism of elimination reactions. 9. Secondary deuterium isotope effects on rates of bimolecular reactions in alicyclic systems

Secondary ..cap alpha..-deuterium isotope effects on the rates of NBu/sub 4/OAc and NBu/sub 4/Cl promoted bimolecular reactions (E2 and SN2) of cyclohexyl tosylate and cyclohexyl bromide have been studied. The E2 reactions, previously categorized as E2C-like, show ..cap alpha..-deuterium isotope effects in the range 1.14--1.22, while the related SN2 reactions give values in the range 1.05--1.08. The discrepancy in the magnitude of the ..cap alpha..-deuterium isotope effect for the E2 and SN2 processes is consistent with the view that E2C-like reactions use ''looser'' transition states than those used in the concurrent SN2 reactions. While the reported ..cap alpha..-d isotope effects do not provide positive evidence to support the idea that the base interacts with C/sub ..cap alpha../ in the E2 transition states of the reactions studied, neither do they substantiate claims for dismissal of the concept. A comparison of the secondary ..gamma..-deuterium and ..beta..'-deuterium isotope effects arising in the reaction of cyclohexyl tosylate with NBu/sub 4/OAc in acetone indicates the two isotope effects to be of equivalent magnitude (k/sub ..beta..'-d/k/sub ..gamma..-d/ = 0.98). This observation can only be rationalized for this reaction in terms of a transition state structure in which there is extensive double bond development. It provides compellingmore » evidence against the involvement of any transition state structure which accommodates extensive positive charge development at C/sub ..cap alpha../.« less

E2 reactions of menthyl and neoisomenthyl Toluene-p-sulphonates

The reaction of menthyl toluene-p-sulphonate (7) with potassium t-butoxide in benzene-dimethyl sulphoxide proceeds regiospecifically to afford trans-p-menth-2-ene (1). Mixtures of olefins are obtained when sodium ethoxide in ethanol, potassium t-butoxide in t-butyl alcohol or tetrabutylammonium bromide in acetone are used. Neoisomenthyl toluene-p-sulphonate (9), prepared by a stereospecific route from piperitone, affords mixtures of cis-p-menth-2-ene (2) and p-menth-3-ene(3) when treated with strong bases. The results are consistent with the concept of variable E2 transition states.

Isotope effects in E2 transition states with non-linear proton abstraction

Calculations show that E2 transition states in which the base, β-hydrogen and β-carbon forms a right or acute angle give β-deuterium isotope effects substantially smaller than those normally found experimentally.