A comparison of the Cope rearrangements of cis-1,2-divinylcyclopropane, cis-2,3-divinylaziridine, cis-2,3-divinyloxirane, cis-2,3-divinylphosphirane, and cis-2,3-divinylthiirane: a DFT study

Transition structures, energetics, and nucleus-independent chemical shifts (NICS) for Cope rearrangements of cis-2,3-divinylaziridine (1N), cis-2,3-divinyloxirane (1O), cis-2,3-divinylphosphirane (1P), and cis-2,3-divinylthiirane (1S), leading to 4,5-dihydro-1H-azepine (3N), 4,5-dihydrooxepine (3O), 4,5-dihydro-1H-phosphepine (3P), and 4,5-dihydrothiepine (3S), respectively, are reported at the (U)B3LYP/6-31G level and compared to those of cis-1,2-divinylcyclopropane (1C). The minimum energy path for all rearrangements proceeds through an endo-boatlike, aromatic transition structure. The predicted activation barriers increase in the order of 1C < 1N < 1O < 1P < 1S, which agrees qualitatively with the decreasing ring strain order of reference compounds (cyclopropane > aziridine > oxirane > phosphirane > thiirane). The exothermicities for these rearrangements decrease in the order of 1N > 1O > 1C > 1P > 1S. If the place of 1C in this sequence is ignored, the decreasing reaction exothermicity order correlates well with the increasing activation barrier order and with decreasing strain order of reference compounds. NICS values calculated for transition structures are typical of highly aromatic transition structures of thermally allowed pericyclic reactions.     

Base-Catalyzed Dehydration of 3-Substituted Benzene cis-1,2-Dihydrodiols: Stabilization of a Cyclohexadienide Anion Intermediate by Negative Aromatic Hyperconjugation

Evidence that a 1,2-dihydroxycyclohexadienide anion is stabilized by aromatic "negative hyperconjugation" is described. It complements an earlier inference of "positive" hyperconjugative aromaticity for the cyclohexadienyl cation. The anion is a reactive intermediate in the dehydration of benzene cis-1,2-dihydrodiol to phenol. Rate constants for 3-substituted benzene cis-dihydrodiols are correlated by σ(-) values with ρ = 3.2. Solvent isotope effects for the reactions are k(H(2)O)/k(D(2)O) = 1.2-1.8. These measurements are consistent with reaction via a carbanion intermediate or a concerted reaction with a "carbanion-like" transition state. These and other experimental results confirm that the reaction proceeds by a stepwise mechanism, with a change in rate-determining step from proton transfer to the loss of hydroxide ion from the intermediate. Hydrogen isotope exchange accompanying dehydration of the parent benzene cis-1,2-dihydrodiol was not found, and thus, the proton transfer step is subject to internal return. A rate constant of ～10(11) s(-1), corresponding to rotational relaxation of the aqueous solvent, is assigned to loss of hydroxide ion from the intermediate. The rate constant for internal return therefore falls in the range 10(11)-10(12) s(-1). From these limiting values and the measured rate constant for hydroxide-catalyzed dehydration, a pK(a) of 30.8 ± 0.5 was determined for formation of the anion. Although loss of hydroxide ion is hugely exothermic, a concerted reaction is not enforced by the instability of the intermediate. Stabilization by negative hyperconjugation is proposed for 1,2-dihydroxycyclohexadienide and similar anions, and this proposal is supported by additional experimental evidence and by computational results, including evidence for a diatropic ("aromatic") ring current in 3,3-difluorocyclohexadienyl anion.     

The synthesis of cis- and trans-1,2-dibromocyclopropane

A preparative route to cis- and trans-1,2-dibromocyclopropane ($\text{1}$) was developed via the Hunsdiecker reaction of silver cyclopropane-1,2-dicarboxylate ($\text{2}$). Cis- and trans-$\text{2}$ gave the same ratio of cis- and trans-$\text{1}$ (1:3.2). The mechanism of this reaction is briefly discussed.     

Mechanistic study of stereoselective gas-phase reactions of phosphenium ions with cis- and trans-1,2-diaminocyclohexanes

The 1,3-dioxolane-2-phosphenium ion, 1,3-benzodioxole-2-phosphenium ion, and o-biphenylenephosphenium ion are reported to react in a stereoselective manner with cis- and trans-1,2-diaminocyclohexanes in the gas phase in a Fourier transform ion cyclotron resonance mass spectrometer. Elimination of NH3 from an addition product was observed only for the trans isomer. Several reaction mechanisms were experimentally and computationally examined (B3LYP/6-31G(d)//HF/6-31G(d) + ZPVE level of theory). The most plausible mechanism is initiated by addition of one of the amino groups to the electrophilic phosphorus atom followed by proton transfer between the amino groups. A change to a diaxial conformation for the trans isomer facilitates anchimeric assistance by the now nucleophilic phosphorus atom as the C-N bond breaks to release NH3. Intramolecular proton transfer competes with the conformational change and ultimately leads to ethylene glycol elimination. The transition states for the critical steps of these two reactions are calculated to be nearly equal in magnitude, which rationalizes the observation of both reactions for the trans-diamine. In contrast, the adduct of the cis isomer can eliminate NH3 via a concerted 1,2-hydride shift without a need for a conformational change. However, the barrier associated with this reaction was found to be substantially greater than for proton transfer between the N- and O-atoms. The latter reaction dominates and ultimately leads to ethylene glycol elimination.     

Synthesis,stereochemistry, and isomeric transformations of cis- and trans-1,2-dimethyl-4-aryl-5-aroyl-2-imidazolines

The corresponding trans- and cis-1,2-dimethyl-4-aryl-5-aroyl-2-imidazolines were obtained from complexes of cis- and trans-1-methyl-2-aryl-3-aroylaziridines with BF₃ by heating with acetonitrile. The reaction proceeds with inversion of the configuration of the starting 3-aroylaziridines. In the presence of bases the complexes of cis-1,2-dimethyl-4-aryl-5-aroyl-2-imidazolines readily undergo isomerization to the corresponding trans analogs. The structures of the products were established on the basis of the IR, PMR, and mass spectra and the results of elementary analysis. The configurations of the compounds were determined by means of the Overhauser nuclear effect.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 952–957, July, 1981.     

The effect of solvent on the structure of the transition state for the S(N)2 reaction between cyanide ion and ethyl chloride in DMSO and THF probed with six different kinetic isotope effects

The secondary alpha- and beta-deuterium, the alpha-carbon, the nucleophile carbon, the nucleophile nitrogen, and the chlorine leaving group kinetic isotope effects for the S(N)2 reaction between cyanide ion and ethyl chloride were determined in the very slightly polar solvent THF at 30 degrees C. A comparison of these KIEs with those reported earlier for the same reaction in the polar solvent DMSO shows that the transition state in THF is only slightly tighter with very slightly shorter NC-C(alpha) and C(alpha)-Cl bonds. This minor change in transition state structure does not account for the different transition structures that were earlier suggested by interpreting the experimental KIEs and the gas-phase calculations, respectively. It therefore seems unlikely that the different transition states suggested by the two methods are due to the lack of appropriate solvent modeling in the theoretical calculations. Previously it was predicted that the transition state of S(N)2 reactions where the nucleophile and the leaving group have the same charge would be unaffected by a change in solvent. The experimental KIEs support this view.     

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

The secondary alpha-deuterium, the secondary beta-deuterium, the chlorine leaving-group, the nucleophile secondary nitrogen, the nucleophile (12)C/(13)C carbon, and the (11)C/(14)C alpha-carbon kinetic isotope effects (KIEs) and activation parameters have been measured for the S(N)2 reaction between tetrabutylammonium cyanide and ethyl chloride in DMSO at 30 degrees C. Then, thirty-nine readily available different theoretical methods, both including and excluding solvent, were used to calculate the structure of the transition state, the activation energy, and the kinetic isotope effects for the reaction. A comparison of the experimental and theoretical results by using semiempirical, ab initio, and density functional theory methods has shown that the density functional methods are most successful in calculating the experimental isotope effects. With two exceptions, including solvent in the calculation does not improve the fit with the experimental KIEs. Finally, none of the transition states and force constants obtained from the theoretical methods was able to predict all six of the KIEs found by experiment. Moreover, none of the calculated transition structures, which are all early and loose, agree with the late (product-like) transition-state structure suggested by interpreting the experimental KIEs.     

Isotope effects and heavy-atom tunneling in the Roush allylboration of aldehydes

Intermolecular (13)C kinetic isotope effects (KIEs) for the Roush allylboration of p-anisaldehyde were determined using a novel approach. The experimental (13)C KIEs fit qualitatively with the expected rate-limiting cyclic transition state, but they are far higher than theoretical predictions based on conventional transition state theory. This discrepancy is attributed to a substantial contribution of heavy-atom tunneling to the reaction, and this is supported by multidimensional tunneling calculations that reproduce the observed KIEs.     

The effect of solvent on a Lewis acid catalyzed Diels-Alder reaction,using computed and experimental kinetic isotope effects

A new transition structure for the Diels-Alder reaction between isoprene and acrolein catalyzed by Et(2)AlCl is found to reconcile reported discrepancies between computed and observed secondary kinetic isotope effects (KIEs). Including the effect of solvent realigns the computed results with experiment demonstrating the importance of nonbond interactions at transition structures. Comparison of experimental and newly predicted KIE data reaffirms the ability of theory and experiment to probe the mechanism and transition structure geometry of organic reactions.     

Asymmetric synthesis of cis-1,2-dialkenyl-substituted cyclopentanes via (-)-sparteine-mediated lithiation and cycloalkylation of a 9-chloro-2,7-nonadienyl carbamate

Herein we report our comprehensive results in enantioselective cyclopentane synthesis via stereogenic allyllithium compounds. The described cycloalkylation reaction starts with a (-)-sparteine-mediated asymmetric deprotonation of the 2,7-alkadienyl carbamate 7e and leads to the enantioenriched (80% ee) and diastereomerically pure (dr = 99:1) cis-1,2-divinyl-cyclopentane 8, by a subsequent cyclization and elimination of lithium chloride. The reaction mechanism has been investigated by silylation and lithiodestannylation experiments and was found to represent a completely regioselective anti-S(N)'S(E)'-reaction. Trapping of the vinyllithium intermediate 12 with various electrophiles under retention of the configuration at the double bond extends the field of application for this cyclization. We also applied this reaction as the key step in the enantioselective synthesis of (+)-dihydromultifidene (17).     

Vibrational spectra and structure of cis- and trans-1,2- dimethoxyethylenes

The vapor, liquid and CCl₄ solution infrared spectra of cis- and trans-1,2-dimethoxyethylene were recorded in the region 250–4000 cm^?1. The laser-Raman spectra were obtained in the liquid state only. The vibrational spectra show that at least two rotational isomers exist for each molecule. Further, the spectra indicate that for both the cis- and trans molecules, one of the rotational isomers has at least one planar conformer. Some vibrational assignments are made for the observed infrared and Raman bands of the cis- and trans- 1,2-dimethoxyethylenes.     

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.     

Kinetic isotope effects in the active site of B. subtilis chorismate mutase

Kinetic isotope effects are determined for the enzyme‐catalyzed Claisen rearrangement of chorismate to prephenate using computational methods. The calculated kinetic isotope effects (KIEs) compare reasonably with the few available experimental values with both the theory and experiment obtaining a large KIE for the ether oxygen, indicating large polarization of the transition‐state geometry. Because there is a question of the extent that the experimental rate constants are for chemistry as the rate‐limiting step, the KIEs for all the atoms of the substrate are reported with the exception of the carboxylate groups. A substantial number of large regular and inverse isotope effects are predicted for the hydrogens on the cyclohexadienyl ring related to activation of the reactant and charge reorganization in the transition state. A large KIE is predicted for the hydrogen atom bound to the ether carbon atom because the largest valency change and charge transfer occurs at the ether bond in both the reactant and tansition state. Observation of the overall pattern of predicted KIEs would ensure that conditions are favorable for the rate‐limiting chemistry. © 2003 Wiley Periodicals, Inc. Int J Quantum Chem 94: 287–292, 2003     

Primary semiclassical kinetic hydrogen isotope effects in identity carbon-to-carbon proton- and hydride-transfer reactions, an ab initio and DFT computational study

Enthalpies of activation, transition state (ts) geometries, and primary semiclassical (without tunneling) kinetic isotope effects (KIEs) have been calculated for eleven bimolecular identity proton-transfer reactions, four intramolecular proton transfers, four nonidentity proton-transfer reactions, eleven identity hydride transfers, and two 1,2-intramolecular hydride shifts at the HF/6-311+G, MP2/6-311+G, and B3LYP/6-311++G levels. We find the KIEs to be systematically smaller for hydride transfers than for proton transfers. This outcome is not the result of "bent" transition states, although extreme bending can lower the KIE. Rather, it is a consequence of generally greater total bonding in a hydride-transfer ts than in a proton-transfer ts, most prominently manifested as a reduced contribution from the zero-point vibrational energy difference between reactant and transition states (the DeltaZPVE factor) for hydride transfers relative to proton transfers. This and other differences between proton and hydride transfers are rationalized by modeling the central .C...H...C unit of a proton-transfer ts as a 4-electron, 3-center (4-e 3-c) system and the same unit of a hydride-transfer ts as a 2-e 3-c system. Inclusion of tunneling is most likely to magnify the observed differences between proton-transfer and hydride-transfer KIEs, leaving our qualitative conclusions unchanged.     

Analysis of classical and quantum paths for deprotonation of methylamine by methylamine dehydrogenase.

The hydrogen-transfer reaction catalysed by methylamine dehydrogenase (MADH) with methylamine (MA) as substrate is a good model system for studies of proton tunnelling in enzyme reactions--an area of great current interest--for which atomistic simulations will be vital. Here, we present a detailed analysis of the key deprotonation step of the MADH/MA reaction and compare the results with experimental observations. Moreover, we compare this reaction with the related aromatic amine dehydrogenase (AADH) reaction with tryptamine, recently studied by us, and identify possible causes for the differences observed in the measured kinetic isotope effects (KIEs) of the two systems. We have used combined quantum mechanics/molecular mechanics (QM/MM) techniques in molecular dynamics simulations and variational transition state theory with multidimensional tunnelling calculations averaged over an ensemble of paths. The results reveal important mechanistic complexity. We calculate activation barriers and KIEs for the two possible proton transfers identified-to either of the carboxylate oxygen atoms of the catalytic base (Asp428beta)-and analyse the contributions of quantum effects. The activation barriers and tunnelling contributions for the two possible proton transfers are similar and lead to a phenomenological activation free energy of 16.5+/-0.9 kcal mol(-1) for transfer to either oxygen (PM3-CHARMM calculations applying PM3-SRP specific reaction parameters), in good agreement with the experimental value of 14.4 kcal mol(-1). In contrast, for the AADH system, transfer to the equivalent OD1 was found to be preferred. The structures of the enzyme complexes during reaction are analysed in detail. The hydrogen bond of Thr474beta(MADH)/Thr172beta(AADH) to the catalytic carboxylate group and the nonconserved active site residue Tyr471beta(MADH)/Phe169beta(AADH) are identified as important factors in determining the preferred oxygen acceptor. The protein environment has a significant effect on the reaction energetics and hence on tunnelling contributions and KIEs. These environmental effects, and the related clearly different preferences for the two carboxylate oxygen atoms (with different KIEs) in MADH/MA and AADH/tryptamine, are possible causes of the differences observed in the KIEs between these two important enzyme reactions.     

Transition-state analysis of S. pneumoniae 5'-methylthioadenosine nucleosidase

Kinetic isotope effects (KIEs) and computer modeling are used to approximate the transition state of S. pneumoniae 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN). Experimental KIEs were measured and corrected for a small forward commitment factor. Intrinsic KIEs were obtained for [1'-3H], [1'-14C], [2'-3H], [4'-3H], [5'-3H(2)], [9-15N] and [Me-3H(3)] MTAs. The intrinsic KIEs suggest an SN1 transition state with no covalent participation of the adenine or the water nucleophile. The transition state was modeled as a stable ribooxacarbenium ion intermediate and was constrained to fit the intrinsic KIEs. The isotope effects predicted a 3-endo conformation for the ribosyl oxacarbenium-ion corresponding to H1'-C1'-C2'-H2' dihedral angle of 70 degrees. Ab initio Hartree-Fock and DFT calculations were performed to study the effect of polarization of ribosyl hydroxyls, torsional angles, and the effect of base orientation on isotope effects. Calculations suggest that the 4'-3H KIE arises from hyperconjugation between the lonepair (n(p)) of O4' and the sigma* (C4'-H4') antibonding orbital owing to polarization of the 3'-hydroxyl by Glu174. A [methyl-3H(3)] KIE is due to hyperconjugation between np of sulfur and sigma* of methyl C-H bonds. The van der Waal contacts increase the 1'-3H KIE because of induced dipole-dipole interactions. The 1'-3H KIE is also influenced by the torsion angles of adjacent atoms and by polarization of the 2'-hydroxyl. Changing the virtual solvent (dielectric constant) does not influence the isotope effects. Unlike most N-ribosyltransferases, N7 of the leaving group adenine is not protonated at the transition state of S. pneumoniae MTAN. This feature differentiates the S. pneumoniae and E. coli transition states and explains the 10(3)-fold decrease in the catalytic efficiency of S. pneumoniae MTAN relative to that from E. coli.     

Correction of pre-steady-state KIEs for isotopic impurities and the consequences of kinetic isotope fractionation

We show, both experimentally and by kinetic modeling, that enzymatic single-turnover (pre-steady-state) H-transfer reactions can be significantly complicated by kinetic isotope fractionation. This fractionation results in the formation of more protiated than deuterated product and is a unique problem for pre-steady-state reactions. When observed rate constants are measured using rapid-mixing (e.g., stopped flow) methodologies, kinetic isotope fractionation can lead to a large underestimation of both the magnitude and temperature dependence of kinetic isotope effects (KIEs). This fractionation is related to the isotopic purity of the substrates used and highlights a major problem with experimental studies which measure KIEs with substrates that are not isotopically pure. As it is not always possible to prepare isotopically pure substrates, we describe two general methods for the correction, for known isotope impurities, of KIEs calculated from pre-steady-state measurements.     

Transition structures, energetics, and nucleus-independent chemical shifts for divinylcyclobutene-to-cyclooctatriene rearrangement: a DFT study

The minimum energy reaction paths and nucleus-independent chemical shifts (NICS) for the Cope rearrangement of cis-3,4-divinylcyclobutene, obtained by (U)B3LYP/6-31G calculations, are reported. Three transition structures (endo-boatlike, chairlike, and exo-boatlike) have been located, giving rise to formation of cis,cis,cis-, cis,cis,trans-, and trans,cis,trans-1,3,5-cyclooctatrienes, respectively. The minimum energy path proceeds through an endo-boatlike, aromatic transition structure. The reaction path of the rearrangement is intervened by enantiomerization saddle point of the product. NICS values calculated for transition structures agree qualitatively with their activation energy and reaction exothermicity orders. Cope rearrangement and electrocyclic ring-opening processes of cis-3,4-divinylcyclobutene are competitive, but the former is relatively more favored and exothermic than the latter.     

The structure of aqueous pentaoxo silicon complexes with cis-1,2-dihydroxycyclopentane and furanoidic vicinal cis-diols

Addition of cis-1,2-dihydroxycyclopentane to aqueous alkaline silicate solutions results in the spontaneous formation of three organosilicate species, each with a 2:1 ligand to Si ratio and a pentacoordinated silicon centre. By using a mixture of both cis-1,2-dihydroxycyclopentane and 1,4-anhydroerythritol we show unambiguously that all three species are diastereomers of the monomeric bis(diolato)-hydroxo complex, [(L=)(2)SiOH](-)(where L represents the cis-diol ligand), thus clarifying the general assignment of (29)Si NMR spectra reported for silicate solutions containing furanoidic sugars with vicinal cis-diol functionality, such as ribose.     

Transition-state structure of human 5'-methylthioadenosine phosphorylase

Kinetic isotope effects (KIEs) and computer modeling using density functional theory were used to approximate the transition state of human 5'-methylthioadenosine phosphorylase (MTAP). KIEs were measured on the arsenolysis of 5'-methylthioadenosine (MTA) catalyzed by MTAP and were corrected for the forward commitment to catalysis. Intrinsic KIEs were obtained for [1'-(3)H], [1'-(14)C], [2'-(3)H], [4'-(3)H], [5'-(3)H(2)], [9-(15)N], and [Me-(3)H(3)] MTAs. The primary intrinsic KIEs (1'-(14)C and 9-(15)N) suggest that MTAP has a dissociative S(N)1 transition state with its cationic center at the anomeric carbon and insignificant bond order to the leaving group. The 9-(15)N intrinsic KIE of 1.039 also establishes an anionic character for the adenine leaving group, whereas the alpha-primary 1'-(14)C KIE of 1.031 indicates significant nucleophilic participation at the transition state. Computational matching of the calculated EIEs to the intrinsic isotope effects places the oxygen nucleophile 2.0 Angstrom from the anomeric carbon. The 4'-(3)H KIE is sensitive to the polarization of the 3'-OH group. Calculations suggest that a 4'-(3)H KIE of 1.047 is consistent with ionization of the 3'-OH group, indicating formation of a zwitterion at the transition state. The transition state has cationic character at the anomeric carbon and is anionic at the 3'-OH oxygen, with an anionic leaving group. The isotope effects predicted a 3'-endo conformation for the ribosyl zwitterion, corresponding to a H1'-C1'-C2'-H2' torsional angle of 33 degrees. The [Me-(3)H(3)] and [5'-(3)H(2)] KIEs arise predominantly from the negative hyperconjugation of the lone pairs of sulfur with the sigma (C-H) antibonding orbitals. Human MTAP is characterized by a late S(N)1 transition state with significant participation of the phosphate nucleophile.