Isotope effects and the nature of enantioselectivity in the shi epoxidation. The importance of asynchronicity

The epoxidation of beta-methylstyrene catalyzed by the Shi fructose-derived ketone is studied using experimental kinetic isotope effects and DFT calculations. The observation of a large beta olefinic (13)C isotope effect and small alpha carbon isotope effect is indicative of an asynchronous transition state with more advanced formation of the C-O bond to the beta olefinic carbon. By varying the catalyst conformation and alkene orientation, diverse transition structure geometries were located calculationally, and the lowest-energy structure leads to an accurate prediction of the isotope effects. Given this support for the accuracy of the calculations employed, the nature of enantioselectivity in this and related epoxidations is considered. The lowest-energy transition structures are generally those in which the differential formation of the incipient C-O bonds, the "asynchronicity," resembles that of an unhindered model, and the imposition of greater or less asynchronicity leads to higher barriers. In reactions of cis-disubstituted and terminal alkenes using Shi's oxazolidinone catalyst, the asynchronicity of the epoxidation transition state leads to increased steric interaction with the oxazolidinone when a pi-conjugating substituent is distal to the oxazolidinone but decreased steric interaction when the pi-conjugating substituent is proximal to the oxazolidinone. Overall, the asynchronicity of the transition state must be considered carefully to understand the enantioselectivity.     

Remote electronic effects in the rhodium-catalyzed nucleophilic ring opening of oxabenzonorbornadienes

We report the application of our rhodium-catalyzed nucleophilic ring-opening methodology to unsymmetrically arene-substituted oxabenzonorbornadienes. The regioselectivity of the ring opening was investigated using a variety of nucleophiles that led to a broad selection of dihydronaphthalene products. It was found that good to excellent regioselectivities are obtained using strongly pi-donating substituents, whereas sigma-donating and electron-withdrawing functionalities have a minimal effect. Post ring-opening manipulations of functional groups in the dihydronaphthalene products were shown to give efficient access to mono- and diamine tetrahydronaphthalene building blocks.     

Substituent effects on rates of rhodium-catalyzed allene cyclopropanation

Rates of cyclopropanation for mono- and disubstituted allenes have been measured relative to standard substrates in reaction with aryldiazoacetate esters catalyzed by Rh₂(S-DOSP)₄. Phenylallene derivatives exhibited a linear correlation of rate with σ⁺ coefficients, indicating a resonance-based effect, though the magnitude of the effect for allenes is less than that reported for other cyclopropanations. Relative reaction rates for aliphatic allenes were found to be similar to those for aryl-substituted allenes, but silicon substitution was found to give a 5- to 14-fold rate increase. The rate enhancement effect for 1-silyl allenes can partially make up for loss of rate and regioselectivity, with 1-trimethylsilyl-1,2-butadiene exhibiting high levels of enantioselectivity and diastereoselectivity in reaction with the chiral catalyst.     

Ligand and substrate effects on the mechanism of rhodium-catalyzed hydrogenation of enamides

The rhodium-catalyzed hydrogenation reaction of enamides is studied computationally using the B3LYP/LACVP** level of theory for a range of ligands and substrates. Two model bidentate phosphine ligands, 1,2-bis(dimethylphosphino)ethane (DMPE) and (Z)-1,2-bis(dimethylphosphino) ethene (ZDMP), and two chiral bidentate phosphine ligands, (R,R)-MeDuPHOS and (R,R)-tetramethylbisoxaphospinane (TMBOP), are investigated in the hydrogenation of alpha-formamidoacrylonitrile as a model substrate. The ZDMP ligand is then studied for three additional substrates: N-(2-propenyl)formamide, (Z)-3-formamido-2-butenenitrile, and (E)-3-formamido-2-butenenitrile. The potential-energy surfaces calculated for the four ligands and alpha-formamidoacrylonitrile are in general agreement with previous computational studies using QM/MM (ONIOM) methods but show consistently higher relative barriers rather than lower. The calculated potential-energy surfaces of hydrogenations of various substrates with a common ligand indicate a mechanistic change based on substrate. The sequence of hydrogen transfer to the two olefinic carbons is calculated to change based on substrate electronics. This has a significant impact on the origins of enantioselectivity for such varied substrates as the first hydride transfer to the substrate is calculated to be irreversible for all substrates, independent of whether it occurs at the alpha or beta carbon of the olefin.     

Isotope effects and the nature of stereo- and regioselectivity in hydroaminations of vinylarenes catalyzed by palladium(ii)-diphosphine complexes

[reaction: see text] The hydroamination of styrene with aniline catalyzed by phosphine-ligated palladium triflates exhibits a substantial (13)C isotope effect at the benzylic carbon. This supports rate-determining nucleophilic attack of amine on a eta(3)-phenethyl palladium complex. Deuterium exchange observations and predicted isotope effects based on DFT calculations support this mechanism. Selectivity in these reactions is determined by the facility of palladium displacement after reversible hydropalladation of the alkene.     

A theoretical study of steric and electronic effects in the rhodium-catalyzed carbonylation reactions.

We present a QM and QM/MM study of steric and electronic effects in the main steps of Rh-catalyzed carbonylation reactions. All the considered systems adopt a square-planar geometry prior to CH(3)I oxidative addition. As regards the octahedral complexes after CH(3)I oxidative addition, a comparison between the various models indicates that the energy gain due to the CH(3)I oxidative addition is reduced by the steric pressure of the substituents on the ligand. The substantially similar results obtained with the QM/MM and QM models indicate that electronic effects are not particularly relevant in determining the energetic of oxidative addition. As regards the P,P-Ph octahedral complex, the geometries in which the CO group is trans to the added CH(3) group, or trans to one of the P atoms, are of similar energy. A comparison between the various models indicates that the energy barrier of the CO insertion reaction is lowered by the presence of substituents on the chelating ligands. This effect is related to a relief of the steric pressure on the complex as the systems move from a six-coordinated octahedral geometry toward a five-coordinated square-pyramidal geometry. The energy barrier calculated for the P,S-Ph system is in rather good agreement with the experimental value, whereas that of the P,P-Ph system is somewhat underestimated. Inclusion of solvent effects with a continuum model leads to a slightly better agreement. The thermodynamic products adopt a square-pyramidal geometry with the COCH(3) group in the apical position.     

Diastereoselective Simmons-Smith cyclopropanations of allylic amines and carbamates

Cyclopropanation of 3-(N,N-dibenzylamino)cyclohexene with either Zn(CH(2)I)(2)(Wittig-Furukawa reagent) or CF(3)CO(2)ZnCH(2)I (Shi's reagent) gives the corresponding syn-cyclopropane as a single diastereoisomer, whilst cyclopropanation of 3-(N-tert-butoxycarbonylamino)cyclohexene with CF(3)CO(2)ZnCH(2)I gives the corresponding anti-cyclopropane exclusively; facile N-deprotection gives access to either diastereoisomer of the trifluoroacetic acid salt of 2-aminobicyclo[4.1.0]heptane.     

Scope and limitations of cyclopropanations with sulfur ylides

The rates of the reactions of the stabilized and semistabilized sulfur ylides 1a-g with benzhydrylium ions (2a-e) and Michael acceptors (2f-v) have been determined by UV-vis spectroscopy in DMSO at 20 °C. The second-order rate constants (log k(2)) of these reactions correlate linearly with the electrophilicity parameters E of the electrophiles 2 as required by the correlation log k(2) = s(N + E), which allowed us to calculate the nucleophile-specific parameters N and s for the sulfur ylides 1a-g. The rate constants for the cyclopropanation reactions of sulfur ylides with Michael acceptors lie on the same correlation line as the rate constants for the reactions of sulfur ylides with carbocations. This observation is in line with a stepwise mechanism for the cyclopropanation reactions in which the first step, nucleophilic attack of the sulfur ylides at the Michael acceptors, is rate determining. As the few known pK(aH) values for sulfur ylides correlate poorly with their nucleophilic reactivities, the data reported in this work provide the first quantitative approach to sulfur ylide reactivity.     

Isotope effects in the hydrogen exchange reaction

The PODSs of the H₃ system and its isotopic derivatives are used for computing exact adiabatic barriers. We find good agreement with experimentally measured ground and vibrationally excited activation energies. The theoretical results should stimulate further measurements of activation energies of vibrationally excited species.     

Influence of electrolyte nature on the separation selectivity of amphetamines in nonaqueous capillary electrophoresis: protonation degree versus ion pairing effects

The simultaneous analysis of Ecstasy and its derivatives in an acetonitrile-methanol (80:20 v/v) mixture was previously shown to be strongly dependent on the nature of the electrolyte (acetate versus formate). To elucidate the phenomena involved, systematic experiments were conducted in this solvent medium. Conductivity measurements allowed to evaluate the ion-pairing rate in the background electrolyte (BGE) and thereby distinguish between electrolyte concentration and ionic strength. The influence of electrolyte concentration on analyte effective mobilities micro(eff)) was studied by capillary electrophoresis (CE). As micro(eff) extrapolated to infinite dilution proved to be independent of the nature of the electrolyte, selectivity changes could not be attributed to a modification in the protonation degree of amphetamines. Experimental mobility data were then confronted to existing theoretical mobility models to discriminate between ion pairing or simple ionic strength effect. Ion-pair formation in a BGE containing acetate was highlighted with an ion-pairing model and ion-pair formation constants between each amphetamine and acetate ion were calculated.     

Matrix effects and selectivity issues in LC-MS-MS

Summary Chlorobenzenes, triazine and phenylurea herbicides were separated by normal micellar electrokinetic chromatography (MEKC) and by micellar electrokinetic chromatography with reversed flow (RF-MEKC) in running buffers containing organic solvents. The relationship between the two techniques is similar to that between reversed-phase and normal-phase HPLC. Using RF-MEKC, the separation of lipophilic compounds is often improved compared to normal MEKC. The migration in MEKC and in RF-MEKC was characterised by lipophilic and polar indices. The experimental values of the lipophilic indices of the compounds tested in the two techniques were close to the indices in reversed-phase HPLC (RP-HPLC). This enables the use of the indices determined in RP-HPLC for predicting the effects of changing composition of the running buffers on migration times in MEKC and in RF-MEKC. Presented at Balaton Symposium '01 on High-Performance Separation Methods, siófok, Hungary, September 2–4, 2001     

Isotope effects and the mechanism of palladium-catalyzed allylic alkylation

The palladium-catalyzed allylic alkylation reaction of 1,1-dimethylallyl acetate with dimethyl malonate is studied by a combination of isotope effects and theoretical calculations. A large ¹³C isotope effect of ≈1.037 is observed at the tertiary carbon, while small isotope effects are observed at the olefinic carbons. These results support rate-limiting ionization of a η²-Pd complex. The observed isotope effects are compared with predictions from calculational models employing either solvent models or ionization of an amidinium ion. The calculated transition structures are notably η² in character, and the implications of this observation are discussed.     

Isotope effects in photofragmentation of linear triatomics

We report the results of a theoretical study of isotope effects on the predissocation lifetimes, on the absorption cross sections for direct photodissociation and on the vibrational distribution of the photofragments in the photofragmentation of HCN and DCN. The deuterium isotope effect on the photofragmentation probability at 1.45 eV above the thréshold for production of CN (B²Σ) is γ_s(DCN)/γ_s(HCN) ≈ 0.2.     

Isotope effects in the bonds of α-CrOOH and α-CrOOD

Samples of rhombohedral chromium oxide hydroxide, α-CrOOH, and the deuterated compound, α-CrOOD, were prepared hydrothermally. The crystal structures were determined by powder profile refinement technique using neutron diffraction data. The crystallographic data are: α-CrOOH: a = 2.979(5)Å, c = 13.37(2)Å, z = 3, space group $\text{R}\text{3}\text{m}$ (No. 166). α-CrOOD: a = 2.985(4)Å, c = 13.48(3)Å, z = 3, space group R3m (No. 160). Distances found for the hydrogen (deuterium) atoms are: OD···O: 2.57(2) Å; OD: 1.05(2) Å; OH···O: 2.47(1) Å; and OH: 1.16(1) Å, showing large isotope effects.     

Isotope effects in the infrared spectra of OCS-He complexes and clusters

Infrared spectra of the OCS-He van der Waals complex and of OCS-He(N) clusters have been studied in the region of the OCS nu1 fundamental band using a tunable diode laser to probe a pulsed supersonic slit jet. For the complex, the spectrum of the normal isotope, 16O12C32S-4He, has been considerably extended and the 34S- and 13C-substituted forms have been recorded for the first time. The data could be analyzed satisfactorily using a conventional asymmetric rotor Hamiltonian with sextic centrifugal distortion terms. For the clusters, the 34S- and 13C-substituted forms have been observed and assigned for N = 2-7, including some transitions with higher J values than previously reported for the normal isotope, e.g., R5. The observed vibrational shifts, relative to the free OCS molecule, were very similar to those of the normal isotope, and most of the difference could be explained by simple scaling. These results constitute a subtle and precise probe of intermolecular forces and dynamical effects in a system which is of current interest for cluster studies.     

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.     

Electronic and steric effects of ligands as control elements for rhodium-catalyzed asymmetric hydrogenation

Electronic and steric effects in the rhodium diphosphinite catalyzed asymmetric hydrogenation were investigated. A series of electronically and sterically modified (S)-BINOL and (S)-H₈-BINOL ligands was synthesized and effects on the catalytic performance were studied. Phosphinite basicity was varied by using p-CH₃O, p-CH₃, p-H, p-CF₃, 3,5-(CH₃)₂, 3,5-(CF₃)₂ substituents on the diphenylphosphine moieties. In the hydrogenation of dimethyl itaconate and methyl (Z)-α-acetamido cinnamate an increase in enantioselectivity and activity was observed with increasing phosphine basicity.     

Isotope effects and medium effects on sulfuryl transfer reactions

Kinetic isotope effects and medium effects have been measured for sulfuryl-transfer reactions of the sulfate ester p-nitrophenyl sulfate (pNPS). The results are compared to those from previous studies of phosphoryl transfer, a reaction with mechanistic similarities. The N-15 and the bridge O-18 isotope effects for the reaction of the pNPS anion are very similar to those of the p-nitrophenyl phosphate (pNPP) dianion. This indicates that in the transition states for both reactions the leaving group bears nearly a full negative charge resulting from a large degree of bond cleavage to the leaving group. The nonbridge O-18 isotope effects support the notion that the sulfuryl group resembles SO(3) in the transition state. The reaction of the neutral pNPS species in acid solution is mechanistically similar to the reaction of the pNPP monoanion. In both cases proton transfer from a nonbridge oxygen atom to the leaving group is largely complete in the transition state. Despite their mechanistic similarities, the phosphoryl- and sulfuryl-transfer reactions differ markedly in their response to medium effects. Increasing proportions of the aprotic solvent DMSO to aqueous solutions of pNPP cause dramatic rate accelerations of up to 6 orders of magnitude, but only a 50-fold rate increase is observed for pNPS. Similarly, phosphoryl transfer from the pNPP dianion to tert-amyl alcohol is 9000-fold faster than the aqueous reaction, while the sulfuryl transfer from the pNPS anion is some 40-fold slower. The enthalpic and entropic contributions to these differing medium effects have been measured and compared.