The mechanism of base-promoted HF elimination from 4-fluoro-4-(4-nitrophenyl)butan-2-one is E1cB. evidence from double isotopic fractionation experiments

Leaving-group fluorine and secondary deuterium multiple kinetic isotope effects (KIEs) have been determined for the base-promoted HF elimination from the 4-fluoro-4-(4'-nitrophenyl)-(1,1,1,3,3-(2)H(5))butan-2-one. The fluorine KIE was determined by using the accelerator-produced short-lived radionuclide (18)F in combination with the naturally abundant (19)F. The (19)F substrate was labeled with (14)C in a remote position to enable radioactivity measurements of both substrates. The size of the determined fluorine KIE is 1.0009 +/- 0.0010 when acetate is used as base. The secondary deuterium KIEs are 1.009 +/- 0.017, 1.000 +/- 0.018, and 1.010 +/- 0.023 for formate, acetate, and imidazole, respectively. The magnitudes of these KIEs are significantly smaller compared to the corresponding KIEs that we recently reported for the protic substrate. This new data clearly demonstrates that the elimination proceeds via an E1cB mechanism.     

Primary and secondary kinetic isotope effects in E2 elimination reactions

Primary and secondary deuterium kinetic isotope effects have been measured for elimination of LCl (L = H or D) from some substituted 1,2-diaryl-1-chloroethanes. Although changes in these effects are in agreement with theoretical predictions, the high values of (E_H-E_D)_β and the significantly low A_H/A_D may suggest that either proton tunnelling or an internal return mechanism is complicating this E2 elimination.     

P(v) intermediate-mediated E1cB elimination for the synthesis of glycals

Glycals are highly versatile and useful building blocks in the chemistry of carbohydrate and natural products. However, the practical synthesis of glycals remains a long-standing and mostly unsolved problem in synthetic chemistry. Herein, we present an unprecedented approach to make a variety of glycals using phosphonium hydrolysis-induced, P(v) intermediate-mediated E1cB elimination. The method provides a highly efficient, practical and scalable strategy for the synthesis of glycals with good generality and excellent yields. Furthermore, the strategy was successfully applied to late-stage modification of complex drug-like molecules. Additionally, the corresponding 1-deuterium-glycals were produced easily by simple ^tBuONa/D₂O-hydrolysis–elimination. Mechanistic investigations indicated that the oxaphosphorane intermediate-mediated E1cB mechanism is responsible for the elimination reaction.

A novel glucosylphosphonium-hydrolysis induced E1cB-elimination provides a highly efficient, practical and scalable method for the synthesis of glycals with good compatibility and excellent yields.     

Chlorine kinetic isotope effects on the haloalkane dehalogenase reaction.

We have found chlorine kinetic isotope effects on the dehalogenation catalyzed by haloalkane dehalogenase from Xanthobacter autotrophicus GJ10 to be 1.0045 +/- 0.0004 for 1,2-dichloroethane and 1.0066 +/- 0.0004 for 1-chlorobutane. The latter isotope effect approaches the intrinsic chlorine kinetic isotope effect for the dehalogenation step. The intrinsic isotope effect has been modeled using semiempirical and DFT theory levels using the ONIOM QM/QM scheme. Our results indicate that the dehalogenation step is reversible; the overall irreversibility of the enzyme-catalyzed reaction is brought about by a step following the dehalogenation.     

Ab initio molecular dynamics simulations of elimination reactions in water solution: exploring the borderline region between the E1cb and E2 reaction mechanisms

We report a theoretical study, based on ab initio molecular dynamics simulations in water solution, of the mechanism of base-induced beta-elimination reactions in systems activated by the pyridyl ring, with halogen leaving groups. The systems investigated represent borderline cases, where it is uncertain whether the reaction proceeds via a carbanion intermediate (E1cb, A(xh)D(H) + D(N)) or via the concerted loss of a proton and the halide (E2, A(N)D(E)D(N)) upon base attack. Recent theoretical and experimental evidence points toward the lack of a net distinction between the E1cb and E2 reaction paths, which seem to merge smoothly into each other in these borderline cases (Alunni, S.; De Angelis, F.; Ottavi, L.; Papavasileiou, M.; Tarantelli, F. J. Am.Chem. Soc. 2005, 127, 15151-15160). In this study, we explore the dynamics on the potential energy surface for the reaction of 2-(2-fluoroethyl)-1-methyl pyridinium with OH- by means of Car-Parrinello simulations in water solution. Our results indicate that the reaction mechanism effectively evolves through the potential energy region of the carbanion: the carbon-fluoride bond breaks only after the carbon-hydrogen bond, confirming the conclusions of a recently reported study of the potential energy surface for this system.     

Deuterium kinetic isotope effects in microsolvated gas-phase E2 reactions

This work describes the first experimental studies of deuterium kinetic isotope effects (KIEs) for the gas-phase E2 reactions of microsolvated systems. The reactions of F(-)(H(2)O)(n) and OH(-)(H(2)O)(n), where n = 0, 1, with (CH(3))(3)CX (X = Cl, Br), as well as the deuterated analogs of the ionic and neutral reactants, were studied utilizing the flowing afterglow-selected ion flow tube technique. The E2 reactivity is found to decrease with solvation. Small, normal kinetic isotope effects are observed for the deuteration of the alkyl halide, while moderately inverse kinetic isotope effects are observed for the deuteration of the solvent. Minimal clustering of the product ions is observed, but there are intriguing differences in the nature and extent of the clustering process. Electronic structure calculations of the transition states provide qualitative insight into these microsolvated E2 reactions.     

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.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 620–623, April, 1995.     

Stereochemistry of 1,2-elimination reactions at the E2-E1cB interface--tert-butyl 3-tosyloxybutanoate and its thioester

Experimental data on the stereoselectivity of base-catalyzed 1,2-elimination reactions that produce conjugated carbonyl compounds are scarce in spite of the importance of these reactions in organic and biochemistry. As part of a comprehensive study in this area, we have synthesized stereospecifically-deuterated beta-tosyloxybutanoate esters and thioesters and studied the stereoselectivity of their elimination reactions under non-ion pairing conditions. With the availability of both the (2R*,3R*) and (2R*,3S*) diastereomers the innate stereoselectivity could be determined unambiguously. (1)H and (2)H NMR data show that these substrates produce 5-6% syn elimination, the usual amount for acyclic substrates undergoing E2 reactions. Contrary to earlier suggestions, activation by a carbonyl group has virtually no influence upon the stereoselectivity. Elimination of the (2R*,3R*) diastereomer of the beta-tosyloxyester and thioester produces 21-25% of the (Z)-alkene, much more than observed with a poorer beta-nucleofuge. A relatively large amount of (Z)-alkene product seems to be a good marker for an E2 pathway, in which the transition state is E1cB-like, rather than an E1cB(irrev) mechanism. Syn KIE values were higher than those for anti elimination for the esters as well as the thioesters. Experimental challenges to the synthesis of stereospecifically-deuterated beta-tosyloxyesters are discussed.     

Dynamics effects on an E2/E1cb borderline mechanism: unimolecular elimination of 2-aryl-3-chloro-2-R-propanols

The mechanistic dichotomy between concerted E2 and stepwise E1cb of the base-promoted elimination of 2-aryl-3-chloro-2-R-propanols was examined computationally at the HF, M05-2X, and MP2 levels of theory. Optimizations of transition states (TSs) and reaction intermediates, and intrinsic reaction coordinates (IRC) calculations showed that there was a single reaction route for each substrate, and that the mechanism could be changed from E2 to E1cb by making a carbanion intermediate more stable through the introduction of electron-withdrawing substituents. Molecular dynamics simulations revealed that trajectories started at a single TS led directly to two product regions; the carbanion intermediate region in the E1cb mechanism, and the alkene product region in the E2 mechanism, through path bifurcation after the TS. The present system is a new example of bifurcation in reactions of closed-shell molecules. The overall reaction mechanism changes dynamically from E2 to E1cb by a gradual change in the ratio of E2 and E1cb trajectories, rather than a path switch in concurrent pathways.     

Evidence of a borderline region between E1cb and E2 elimination reaction mechanisms: a combined experimental and theoretical study of systems activated by the pyridine ring

We report a combined experimental and theoretical study to characterize the mechanism of base-induced beta-elimination reactions in systems activated by the pyridyl ring, with halogen leaving groups. The systems investigated represent borderline cases, where it is uncertain whether the reaction proceeds via a carbanion intermediate (E1cb, A(xh)D(H) + D(N)) or via the concerted loss of a proton and the halide (E2, A(N)D(E)D(N)) upon base attack. Experimentally, the Taft correlation for H/D exchange, in OD(-)/D(2)O with noneliminating substrates (1-methyl-2-(2-Xethyl)pyridinium iodide), is used to predict the expected values of the rate constants for the elimination reactions with N-methylated substrates and F, Cl, Br as the leaving group. The comparison indicates an E1cb irreversible mechanism with F, but the deviation observed with Cl and Br does not allow a conclusive assignment. The theoretical calculations show that for the N-methylated substrate with a fluoride leaving group the elimination proceeds via formation of a moderately stable carbanion. No stable anionic intermediate is instead found when the leaving group is Cl or Br, as well as for any of the nonmethylated species, indicating a concerted elimination. The methylated substrate with Cl shows however only a moderate increase in reactivity compared to the fluorinated substrate, despite the change in mechanism. Very interestingly, our analysis of the computed two-dimensional potential energy surface for the reaction with a F leaving group indeed evidences the lack of a net distinction between the E1cb and E2 reaction paths, which appear to merge smoothly into each other in these borderline cases.     

Transition state structure and isotope effects in unimolecular hydrogen elimination from carbocations

1,1 unimolecular hydrogen eliminations from carbocations are currently interpreted in terms of a concerted mechanism in which two CH bonds are synchronously stretched. Here we show, through MNDO and RRKM computations, that the available experimental data are compatible with all the reaction mechanisms in which both the CH bonds are significantly distorted in the transition state, irrespective of the synchronous or non-synchronous character of the reaction.     

Change in rate-determining step in an E1cB mechanism during aminolysis of sulfamate esters in acetonitrile

The kinetics of the reactions of the nitrogen-sulfur(VI) esters 4-nitrophenyl N-methylsulfamate (NPMS) with a series of pyridines and a series of alicyclic amines and of 4-nitrophenyl N-benzylsulfamate (NPBS) with pyridines, alicyclic amines, and a series of quinuclidines have been investigated in acetonitrile (ACN) in the presence of excess amine at various temperatures. Pseudo-first-order rate constants (k(obsd)) have been obtained by monitoring the release of 4-nitrophenol/4-nitrophenoxide. From the slope of a plot of k(obsd) vs [amine], second-order rate constants (k'(2)) have been obtained for the pyridinolysis of NPMS, and a Br?nsted plot of log k'(2) vs pK(a) of pyridine gave a straight line with beta = 0.45. However, aminolysis with alicyclic amines of NPMS gave a biphasic Br?nsted plot (beta(1) = 0.6, beta(2) approximately equal to 0). Pyridinolysis and aminolysis with alicyclic amines and quinuclidines of NPBS also gave similar biphasic Br?nsted plots. This biphasic behavior has been explained in terms of a mechanistic change within the E1cB mechanism from an (E1cB)(irrev) (less basic amines) to an (E1cB)(rev) (more basic amines), and the change occurs at approximately the pK(a)'s (in ACN) of NPMS (17.94) and NPBS (17.68). The straight line Br?nsted plot for NPMS with pyridines occurs because the later bases are not strong enough to substantially remove the substrate proton and initiate the mechanistic change observed in the reaction of NPMS with the strong alicyclic amines and quinuclidines. An entropy study supports the change from a bimolecular to a unimolecular mechanism. This is the first clear demonstration of this E1cB mechanistic changeover involving a nitrogen acid substrate.     

E2反应中的反式共平面构象

研究总结了E2反应中离去基团L和H的"反式共平面"构象与产物结构、产物组成、反应速度之间的对应关系.提出了让学生在参与中学习有机立体化学的新方法,具体的参与方式为"看、画、做".     

Reactions between Molecular Chlorine and Acrylates over a Wide Range of Temperatures

EPR, UV, VIS spectroscopy, chromatography, calorimetry, elemental analysis, and gravimetry are used to show that radicals formed spontaneously upon low temperature (77 K) interaction between molecular chlorine and methyl acrylate and/or methyl methacrylate initiate reactions of polymerization and chlorination that proceed under heating in a monomer system + Cl₂ prepared at 77 K. It is established that beginning at the premelting temperature of chlorine, both reactions mostly proceed at the temperatures of monomer melting, and the main reaction products are oligomers. It is concluded that chloroalkyl radicals formed spontaneously at 77 K react more readily with monomer molecules than do chlorine radicals in a cell.     

Deuterium kinetic isotope effects in microsolvated gas-phase E2 reactions: Methanol and ethanol as solvents

The gas-phase reactions of F(-)(CH(3)OH) and F(-)(C(2)H(5)OH) 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(-)(H(2)O) with t-butyl halides. KIEs for the reaction of F(-)(CH(3)OH) 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(-)(C(2)H(5)OH) 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 S(N)2 and E2 solvated systems.     

Reactions of CF3CH2I+O(3P): competing mechanisms of HF elimination

Ab initio density functional and molecular orbital calculations provide singlet and triplet electronic potential energy surfaces for the reactions of CF3CH2I+O(3P) leading to OI and HF eliminations, reactions which have been the subject of recent experimental studies. A barrier to OI formation occurs on the triplet potential energy surface; there is no reverse barrier to OI formation on the singlet pathway. Findings suggest that two competing pathways may form HF. One is an addition-insertion-elimination process involving insertion of O into the C-I bond. The alternate path involves OI elimination, addition of an O atom to CF3CH2, and subsequent HF elimination. The computed reactant pathways and energetics are discussed in relation to recent experiments.