Search

The reactions of dimethyl phosphinic chloride (1) and methyl phenyl phosphinic chloride (2) with X-anilines have been studied kinetically in acetonitrile at 15.0 and 55.0 °C, respectively. The deuterium kinetic isotope effects (KIEs) involving deuterated aniline nucleophiles (XC6H4ND2) are also reported for the same reactions. The obtained KIEs for 1 are secondary inverse (kH/kD = 0.703–0.899 1). A concerted mechanism involving predominantly backside nucleophilic attack is proposed for the anilinolysis of 1. A concerted mechanism involving predominantly frontside attack via a hydrogen-bonded four-center-type transition state is proposed for the anilinolysis of 2. The degree of steric hindrance is the major factor that determines both the reactivity of the phosphinates and the direction of the nucleophilic attack on the phosphinates. Copyright © 2008 John Wiley & Sons, Ltd.

Aryl Phenylphosphono-chloridothioates, were prepared by the following single-stepreaction. The equimolar starting materials of phenylthio-phosphonic dichloride, substituted phenols, and triethylamine were mixed and stirred in methylene chloride solventfor 2 hrs, all kept in an ice bath.GR grade phenylthio-phosphonic dichloride (TCI, Japa n), substituted phenols, andtriethylamine (Aldrich) were used without further purifi-cation. The physical constants of the substrates were asfollows

Theoretical studies on the un-catalyzed and catalyzed aminations of ketene with NH3 and (NH3)2, respectively, were studied using MP2 and hybrid density functional theory of B3LYP at the 6-31+G(d,p) and 6311+G(3df,2p) basis sets in the gas phase and in benzene and acetonitrile solvents. In the gas phase reaction, the un-catalyzed mechanism was the same as those previously reported by others. The catalyzed mechanism, however, was more complicated than expected requiring three transition states for the complete description of the C=O addition pathways. In the un-catalyzed amination, rate determining step was the breakdown of enol amide but in the catalyzed reaction, it was changed to the formation of enol amide, which was contradictory to the previous findings. Starting from the gas-phase structures, all structures were re-optimized using the CPCM method in solvent medium. In a high dielectric medium, acetonitrile, a zwitterions formed from the reaction of CH2=C=O with (NH3)2, I(d), exists as a genuine minimum but other zwitterions, I(m) in acetonitrile and I(d) in benzene become unstable when ZPE corrected energies are used. Structural and energetic changes induced by solvation were considered in detail. Lowering of the activation energy by introducing additional NH3 molecule amounted to ca. −20 ~ −25 kcal/mol, which made catalyzed reaction more facile than un-catalyzed one.

The deuterium kinetic isotope effects (KIEs) involving deuterated aniline nucleophiles (XC6H4ND2) are reported for the reactions of dimethyl chlorophosphate (1), dimethyl chlorothionophosphate (2), diethyl chlorophosphate (3) and diethyl chlorothionophosphate (4) in acetonitrile at 55.0 °C. The obtained kH/kD values are 0.798–0.979, 0.945–1.06, 0.714–0.919 and 1.01–1.10 for 1, 2, 3 and 4, respectively. A concerted mechanism with dominant backside nucleophilic attack is proposed for the reactions of 1 and 3. A concerted mechanism involving partial frontside attack through a hydrogen-bonded four-centre-type transition state (TS) is proposed for the reactions of 2 and 4. Copyright © 2008 John Wiley & Sons, Ltd.

substituent (Y) variations in the substrate (log kN vs. σY) are biphasic concave upwards/downwards with breaks at Y = 4-Cl (σY = 0.23). The Hammett coefficients ρY and the cross-interaction constant ρXY (= +0.16) are positive for σY ≤ 0.23, while the ρY values are positive/negative [ρY > 0 for X = (4-MeO and 4-Me) and ρY < 0 for X = (H, 4-Cl and 3-Cl)] and the ρXY (= −1.51) value is negative for σY ≥ 0.23. Based on these and other results, the benzylaminolyses of α-bromoacetanilides are proposed to proceed through rate-limiting expulsion of the bromide leaving group from a zwitterionic tetrahedral intermediate, T ± , with a bridged transition state for σ Y ≤ 0.23, while the reaction proceeds through concerted mechanism with an enolate-like TS in which the nucleophile attacks the α-carbon for σY ≥ 0.23.

Molecular modeling study has been performed to assist in the design of PTP1B inhibitors using FlexX. FlexX dockings with 19 test ligands, whose structures have been determined by X-ray crystallography, were successful in reproducing the experimental conformations within the protein. An increase in biological activity is observed as hydrophobic character of formylchromone derivatives increases. Most ligands bind to the activesite regions of the protein successfully in two different score runs. The Drug score run gave better results than the FlexX score run based on the score, rank, binding modes and bond distance of docked structures. Consensus values from the CScore scoring function are between 3 and 5, suggesting that the scoring scheme is reliable. All formylchromone inhibitors considered in this work show unidirectional binding modes in the active site pocket, which is contrary to the bidirectional X-ray results by Malamas et al. and amino acid residues responsible for such orientation are identified to help further development of the inhibitors.

) were well consistent with experimental results,although the R-substituent effect was underestimated theoretically. No correlations were found betweenactivation enthalpies and reaction enth alpies. The substituent ef fects on reactivity seemed to be complicated ata glance, but were understandable by c oncurrent electronic and steric factors. Variations of bond lengths at TSstructures were well correlated with the Taft’s σ

Kinetic studies of the reactions of aryl phenyl chlorothiophosphates (1) and aryl 4-chlorophenyl chlorothiophosphates (2) with substituted anilines in acetonitrile at 55.0 degrees C are reported. The negative values of the cross-interaction constant rhoXY (rhoXY = -0.22 and -0.50 for 1 and 2, respectively) between substituents in the nucleophile (X) and substrate (Y) indicate that the reactions proceed by concerted SN2 mechanism. The primary kinetic isotope effects (kH/kD = 1.11-1.13 and 1.10-1.46 for 1 and 2, respectively) involving deuterated aniline nucleophiles are obtained. Front- and back-side nucleophilic attack on the substrates is proposed mainly on the basis of the primary kinetic isotope effects. A hydrogen-bonded, four-center-type transition state is suggested for a front-side attack, while the trigonal bipyramidal pentacoordinate transition state is suggested for a back-side attack. The MO theoretical calculations of the model reactions of dimethyl chlorothiophosphate (1') and dimethyl chlorophosphate (3') with ammonia are carried out. Considering the specific solvation effect, the front-side nucleophilic attack can occur competitively with the back-side attack in the reaction of 1'.

Substrate specificity of the omega-aminotransferase obtained from Vibrio fluvialis (omega-ATVf) was rationally redesigned for the kinetic resolution of aliphatic chiral amines. omega-ATVf showed unique substrate specificity toward aromatic amines with a high enantioselectivity (E > 100) for (S)-enantiomers. However, the substrate specificity of this enzyme was much narrower toward aliphatic amines. To overcome the narrow substrate specificity toward aliphatic amines, we redesigned the substrate specificity of omega-ATVf using homology modeling and the substrate structure- activity relationship. The homology model and the substrate structure-activity relationship showed that the active site of omega-ATVf consists of one large substrate-binding site and another small substrate-binding site. The key determinant in the small substrate-binding site was D25, whose role was expected to mask R415 and to generate the electrostatic repulsion with the substrate's alpha-carboxylate group. In the large substrate-binding site, R256 was predicted to recognize the alpha-carboxylate group of substrate thus obeying the dual substrate recognition mechanism of aminotransferase subgroup II enzymes. Among the several amino acid residues in the large substrate-binding site, W57 and W147, with their bulky side chains, were expected to restrict the recognition of aliphatic amines. Two mutant enzymes, W57G and W147G, showed significant changes in their substrate specificity such that they catalyzed transamination of a broad range of aliphatic amines without losing the original activities toward aromatic amines and enantioselectivity.

3D-QSAR model that correlates the biological activities with the chemical structures of quipazine derivatives acting on the serotonine transporter (SERT) was developed by comparative molecular field analysis (CoMFA). Total 8 models were constructed and a more accurate model, using close 1 grid spacing and StDev*Coefficients weight value gave better results. The contour maps with the best model, the resulting cross-validated correlation ( : 0.744), and non-cross-validated correlation ( : 0.966) indicate the steric and electrostatic environment of inhibitors in the SERT binding pocket. This study can be used as a putative picture of the pharmacophore in the design of novel and potent inhibitors.

A practical neutral aromatic nitration process using nitrogen dioxide in the presence of FeCl3 · 6H2O under 40–100 psig of oxygen was developed, and nitration of several aromatic compounds, including the deactivated nitrobenzene, was performed in a successful manner. The correlation of reaction rate with equivalents nitrogen dioxide, oxygen pressure, amount of catalyst and temperature was investigated through the nitration of benzene. Following the optimization of reaction conditions, the nitration of benzene was scaled up to 476 mol. Furthermore, inorganic solid catalysts with pore size over 5 A and surface area over 100 m2/g were applied to newly developed neutral nitration.

Three dimensional quantitative structure-activity relationship studies for a series of isatin derivatives as a non-peptidyl caspase-3 enzyme inhibitor were investigated using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The first approach of non-peptidyl small molecules by 3D QSAR may be useful in guiding further development of potent caspase-3 inhibitors.

The kinetic studies of the reactions of -chloroacetanilides (5)) with pyridines have been carried out in dimethyl sulfoxide at 95 . The pyridinolysis rates are faster with 4 than with 5 whereas the aminolysis rates with benzylamines are faster with 5 than with 4. The Bronsted values are in the range from 0.30 to 0.32 and the cross-interaction constants, , are small negative values; = -0.06 and -0.10 for 4 and 5, respectively. Based on these and other results, the pyridinolyses of -chloroacetanilides are proposed to proceed via a stepwise mechanism with rate-limiting addition of the nucleophile to the carbonyl group to form zwitterionic tetrahedral intermediate () followed by a bridged type transition state to expel the leaving group.

Department of Chemistry, Inha University, Incheon 402-751, KoreaReceived June 30, 2004Ligand-based quantitative structure-activity relationship (QSAR) studies were performed on indolinonesderivatives as a potential inhibitor of the protein tyrosine kinase of fibroblast growth factor receptor (FGFR) bycomparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis(CoMSIA) implemented in the SYBYL packages. The initial X-ray structure of docked ligand (Su5402) toFGFR was used to minimize the 27 training set molecules using TRIPOS force field. Seven models weregenerated using CoMFA and CoMSIA with grid spacing 2 A. After the PLS analysis the best predictedCoMSIA model with hydrophobicity, hydrogen bond donor and acceptor property showed that a leave-one out(LOO) cross validated value (r

Receptor-based (RB) quantitative structure-activity relationship (QSAR) studies were performed on the peroxisome proliferator-activated receptors gamma (PPAR γ ) agonists with antihyperglycemic property using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) implemented in the SYBYL packages. The initial X-ray structure of PPAR γ with GI262570 agonist was used to sketch 36 training set molecules having the receptor bound conformation. These structures were subjected to subset energy minimization using TRIPOS force field and aligned against an α-helix of PPAR γ receptor. Four models were generated using CoMFA and CoMSIA with two different grid spacing, 2 A and 1 A. After PLS analysis, the best predicted CoMSIA model with grid spacing 1 A, Model 4, showed that a leave-one out (LOO) cross validated value (r 2 c v ) and non-cross validated conventional value (r 2 n c v ) are 0.758 and 0.994, respectively. From the CoMFA and CoMSIA contour maps, important interactions crucial to strong binding to the receptor can be identified and verified. This information on the pharmacophore models can be used to design new ligands. Traditional ligand-based (LB) QSAR studies were also performed using the global minima of the same training set molecules. Compared to LB QSAR study, advantage of using subset-minimized RB QSAR study is discussed in detail.

The characteristics of back-bonding in metal–olefin complexes have been studied by using the NBO analyses. In metal–olefin complexes, the evidence for back-bonding is only possible from the d M–C and/or d CC bond length variations. However, these bond lengths might be ambiguous in explaining the extents of back-bonding, since both bond lengths are dependent upon the extents of the σ-bonding as well as the π-back-bonding. Instead, the explanation and prediction using the NBO analyses of electron populations in π * -orbitals of olefin ligands and of the second-order charge transfer interactions between metal d-orbitals and olefins π * -orbitals could be more efficient and correct.

3-(3-[ 18 F]Fluoropropyl)-6-nitroquipazine ([ 18 F]FPNQ) as a 5-HT transporter imaging agents was designed, synthesized, and evaluated. FPNQ was selected due to its potent in vitro biological activity ( K i =0.32 nM) in rat brain cortical membranes. The 18 F-labeled FPNQ was prepared by reaction of the propyl mesylate as a precursor with tetra- n -butylammonium [ 18 F]fluoride generated under NCA conditions. The precursor mesylate was synthesized from commercially available hydrocarbostyril in nine steps in 21% overall yield. The specific activity of the [ 18 F]FPNQ determined by radioreceptor assay was 27.0 GBq/μmol. Tissue distribution studies in mice showed the highest uptake in the frontal cortex (5.79 %ID/g) at 60 min post-injection.

The gas phase identity nucleophilic substitution reactions of halide anions (X = F, Cl, Br) with cyclopentadienyl halides (I) are investigated at the B3LYP/6-311+G**, MP2/6-311+G** and G2(+)MP2 levels involving five reaction pathways: σ attack S N 2, β-S N 2'-syn, β-S N 2'-anti, γ-S N 2'-syn and γ-S N 2'-anti paths. In addition, the halide exchange reactions at the saturated analogue, cyclopentyl halides (2), and the monohapto circumambulatory halide rearrangements in 1 are also studied at the same three levels of theory. In the σ-attack S N 2 transition state for 1 weak positive charge develops in the ring with X = F while negative charge develops with X = Cl and Br leading to a higher energy barrier with X = F but to lower energy barriers with X = Cl and Br than for the corresponding reactions of 2. The π-attack β-S N 2' transition states are stabilized by the strong n C - π* C = C charge transfer interactions, whereas the π-attack γ-S N 2' transition states are stabilized by the strong n C -σ* C - X interactions. For all types of reaction paths, the energy barriers are lower with X = F than Cl and Br due to the greater bond energy gain in the partial C-X bond formation with X = F. The β-S N 2' paths are favored over the γ-S N 2' paths only with X = F and the reverse holds with X = Cl and Br. The σ-attack S N 2 reaction provides the lowest energy barrier with X = Cl and Br, but that with X = F is the highest energy barrier path. Activation energies for the circumambulatory rearrangement processes are much higher (by more than 18 kcal mol - 1 ) than those for the corresponding S N 2 reaction path. Overall the gas-phase halide exchanges are predicted to proceed by the σ-attack S N 2 path with X = Cl and Br but by the β-S N 2'-anti path with X = F. The barriers to the gas-phase halide exchanges increase in the order X = F < Br < Cl, which is the same as that found for the gas-phase identity methyl transfer reactions.

Kinetic studies of the reactions of alpha-chloroacetanilides (YC6H4NRC(=O)CH2Cl; R = H (5) and CH3 (6)) with benzylamines (NH2CH2C6H4X) were carried out in dimethyl sulfoxide at 55.0 degrees C. The Brønsted betaX values were in the range from 0.6 to 0.9 and cross-interaction constants phoXY were positive: phoXY = +0.21 and +0.18 for 5 and 6, respectively. The rates were faster with 6 than with 5 and inverse secondary kinetic isotope effects involving deuterated benzylamine (ND2CH2C6H4X) nucleophiles, kH/kD1.0, were obtained. Based on these and other results, a stepwise mechanism with rate-limiting expulsion of the chloride leaving group from a zwitterionic tetrahedral intermediate, T+/-, is proposed. In this mechanism, a prior carbonyl addition to T+/- is followed by a bridged type transition state to expel the chloride. An enolate-like transition state in which the developing negative charge on C(alpha) delocalizes toward the carbonyl group (nC--pi*(C=O) interaction) is not feasible for the present series of reactions due to a stronger charge transfer involving the lone pair on the anilino nitrogen (nAN--pi*(C=O) interaction).

3′- N -Substituted-3′- N -debenzoylpaclitaxel analogues were synthesized and investigated for their 3-D QSAR by using comparative molecular field analysis (CoMFA). The CoMFA model obtained from receptor(microtubule)–paclitaxel binding structure displays an excellent predictive power to forecast the biological activity of new 3′- N -substituted-3′- N -debenzoylpaclitaxel analogues as well as the ability to explain the activity of the known paclitaxel analogues. The cross-validated r 2 cv values of the selected models are 0.835 and 0.616 for A549 and SK-OV-3, respectively, and the non-cross-validated r 2 ncv values of them are 0.992 and 0.974.

Eleven 4-substituted derivatives of 6-nitroquipazine were synthesized and evaluated for their abilities to displace [ 3 H]citalopram binding to the rat cortical synaptic membranes. Among them, 4-chloro-6-nitroquipazine was shown to possess the highest binding affinity ( K i= 0.03 nM) which was approximately 6 times higher than that of 6-nitroquipazine ( K i =0.17 nM) itself. In this paper, we describe the syntheses of 4-substituted 6-nitroquipazine derivatives, the results of corresponding biological evaluation and the SAR study.

The gas-phase hetero Diels–Alder cycloaddition reactions of the sulfur diimides HNS+N−X, where X = CH3, H, Cl, CN and NO2, with 1,3-butadiene were investigated theoretically at the B3LYP/6-31G* level. The most stable isomers of sulfur diimides have Z,Z-forms, which are more stable than the least stable E,E-forms by 6–11 kcal mol−1. The reactions proceed mostly with HNS+N−X (2) rather than HN−S+NX (2′), even with an electron-donor X (=CH3). The activation free energy (ΔG‡) is lower, the stronger the electron-accepting ability of X. The lowest cycloaddition barriers are obtained in the exo-additions of the E,E-isomers, which are lower by ca. 10–13 kcal mol−1 than the highest barrier exo-processes of the Z,Z-isomers. The repulsive interactions between the diene π electrons and the endo lone pair on N (nN), and the steric hindrance of a bulky group, are the two major factors that are responsible for the cycloaddition barrier heights.

Facilitated olefin transport has been observed through membranes containing AgBF4 dissolved in poly(ethylene oxide) (PEO), but not through ones containing AgNO3 according to the previous studies. The difference in facilitated transport behavior between the two systems was theoretically investigated in terms of the mechanism on facilitated transport, in particular, the interaction of the silver cation with olefin using the density functional theory (DFT) method. It was found that the reaction of silver cation with ethylene occurred through two steps: (i) addition of one ethylene molecule to a silver cation dissolved in PEO, (ii) replacement of the ethylene molecule coordinated on the silver cation with another ethylene molecule. In the two-step mechanism of the addition and replacement reactions, the addition reaction is a nonactivated, preequilibrium process and the replacement reaction occurred through a transition state of two ethylene molecules coordinated to a silver cation dissolved in PEO. It was a...

Gas-phase nucleophilic substitution reactions at the imidoyl carbon have been investigated using chloride exchanges, Cl- + RY=CHCl right harpoon over left harpoon RY=CHCl + Cl- with Y = N and R = F, H or CH3, at the MP2, B3LYP and G2(+) levels using the MP2/6-311+G geometries. The results are compared with those for the vinyl (Y = CH) and carbonyl (Y = O) carbon substitution. The mechanism and reactivity of substitution at the imidoyl carbon are intermediate between those of carbonyl (SNpi) and vinyl carbon (SNsigma) substitution, which is directly related to the electronegativity of Y, CH < N < O. The prediction of competitive SNsigma with SNpi path for the imidoyl chloride is consistent with the S(N)1-like mechanism proposed for reactions in solution. The important factors in favor of an in-plane concerted SN2 (SNsigma) over an out-of-plane pi-attack (SNpi) path are (i) lower proximate sigma-sigma* charge-transfer energies (DeltaECT), (ii) stronger electrostatic stabilization (DeltaENCT), and (iii) larger lobe size on C(alpha) for the sigma*- than pi*-LUMO despite the higher sigma* than pi* level. The electron correlation energy effects at the MP2 level are overestimated for the relatively delocalized structure (S(N)pi TS) but are underestimated for the localized structure (SNsigma TS) so that the MP2 energies lead to a wrong prediction of preferred reaction path for the vinyl chloride. The DFT at the B3LYP level predicts correct reaction pathways but overestimates the electron correlation effects.

Mechanisms of the gas-phase acyl group transfers, Cl- + R(XY)Cl, involving various acyl functional groups, >XY with X = C, S, or P and Y = O or S, are investigated theoretically at the MP2/6-31+G* and B3LYP/6-31+G* levels (additionally with extended basis sets of B3LYP/6-311+G(3df,2p)), and the effects of solvent (e = 78.5) are calculated with the SCIPCM model at the isodensity level of 0.0004 au. The tetrahedral adducts formed in the carbonyl (RCO) and thiocarbonyl (RCS) group transfers are either transition states (double-well PES) or intermediates (single- or triple-well PES) depending on R, a stronger electron acceptor R favoring the intermediate. However, all of the sulfonyl (RSO2) and phosphoryl ((RO)2PO) transfers proceed with trigonal bipyramid (TBP)-type transition states, in contrast to the stepwise mechanism through TBP-type intermediates for the sulfinyl (RSO) (and sulfonyl transfers between F-) transfers. The most important factor determining whether an adduct in an acyl-group-transfer reacti...

Characterization of the stationary points in a flat transition structure region of the potential energy surface for the HCOCl+Cl − reaction has been carried out at the MP2/6-311+G∗∗ level. Two stationary points are found: an intermediate with C S symmetry and all positive eigenvalues in the Hessian and a transition state with C 1 symmetry and only one negative eigenvalue in the Hessian. The MP2/6-311+G∗∗ electronic energies of these two only differ by δΔ E (=Δ E TS −Δ E Int )=0.01 kcal mol −1 . The zero-point and thermal energy corrections to the electronic energy lead to an inversion of levels: δΔ E ZPE =−0.06 and δΔ H =−0.59 kcal mol −1 , which becomes normal when the − T Δ S term is added to obtain δΔ G =+0.90 kcal mol −1 (+0.80 kcal mol −1 at the G2(+)MP2 level). This inversion arises solely from one less vibrational mode in the TS on the flat transition structure region.

Both the α-protons and carbons of β-propiothiolactones exhibit atypical downfield chemical shifts. The α-protons of β-propiothiolactones with no heteroatom at the α-position appear at 3.53–5.35 ppm, whereas the α-carbons appear at 56.9–86.2 ppm. The major cause of the unexpected deshielding effect was rationalized by assuming a through-space interaction between the occupied orbital of the α-carbon and the vacant orbital of sulfur. Copyright © 2000 John Wiley & Sons, Ltd.

The aminolysis of Z-aryl cyclobutanecarboxylates (II) with X-benzylamines is investigated in acetonitrile at 55.0 °C. The rates are uniformly greater by 2.2 times than the corresponding rates of aryl cyclopropanecarboxylates (III). All the selectivity parameters, ρX (βX), ρZ (βZ) and ρXZ, are quite similar for the two substrates II and III. The kH/kD values involving deuterated benzylamines (XC6H4CH2ND2) are greater than unity, but are marginally smaller than those for the reactions of III. Low ΔH‡ and large negative ΔS‡ values are obtained and adherence to the reactivity–selectivity principle is observed. All these results are consistent with a stepwise mechanism with rate-limiting expulsion of a leaving group (aryl oxides) from a tetrahedral intermediate, T±, with a hydrogen-bonded, four-center transition state.

Transition structures for hetero-Diels–Alder reactions involving the heteroatoms O, S and N in dienes as well as in dienophiles have been determined at the MP2 (MP2/6-31G*//MP2/6-31G*) and hybrid DFT (B3LYP/6-31G*//B3LYP/6-31G*) levels of theory. The transition structures are predicted to be relatively early, concerted and asynchronous in all cases, with the DFT transition structures being more asynchronous than the MP2 ones. The reactions of butadiene with formaldehyde, thioformaldehyde and formaldimine proceed by diene HOMO–dienophile LUMO interactions whereas those of ethylene with acrolein, 1-thiabutadiene and 1-azabutadiene proceed by reverse electron demand interactions. In all the hetero-Diels–Alder reactions, the C–C bond is more fully formed than the heteroatom–carbon bond in the transition structure with the exception of the reaction between formaldimine and butadiene for which C–N bond formation is ahead of C–C bond making. All the reactions are highly exothermic. The reactions are facilitated by heteroatoms in both the diene and dienophile, and bond formation between two heteroatoms is disfavored. The reaction of formaldimine shows an endo preference whereas that of 1-azabutadiene leads to an exo preference of the imino hydrogen; these preferences of ca. 4 kcal mol-1 are caused mostly by inter-hydrogen steric effects in the transition structures. We conclude that the DFT calculations provide an economical way of accounting for electron correlation effects at nearly the same level as the MP2 ones in the investigations of hetero-Diels–Alder reactions.

Three-membered ring (3MR) forming processes of −X(SINGLE BOND)CH2(SINGLE BOND)CH2(SINGLE BOND)F and −CH2(SINGLE BOND)C((SINGLE BOND)Y)(SINGLE BOND)CH2(SINGLE BOND)F (X(DOUBLE BOND)CH2, O, or S and Y(DOUBLE BOND)0 or S) through a gas phase neighboring group mechanism (SNi) are studied theoretically using the ab initio molecular orbital method with the 6–31+G* basis set. When electron correlation effects are considered, the activation (ΔG≠) and reaction energies (ΔG0) are lowered by ca. 10 kcal mol−1, indicating the importance of the electron correlation effect in these reactions. The contribution of entropy of activation (−TΔS≠) at 298 K to ΔG≠ is very small, and the reactions are enthalpy controlled. The ΔG≠ and ΔG0 values for these ring closure processes largely depend on the stabilities of the reactants and the heteroatom acting as a nucleophilic center. The Bell–Evans–Polanyi principle applies well to all these reaction series. © 1997 John Wiley & Sons, Inc. J Comput Chem18: 1773–1784, 1997

The gas-phase reactions of OH- and SH- with NCCH2CH2Cl have been studied with ab initio methods using the 6-31+G* basis sets. The electron correlation effect was accounted for at the MP2 level of theory. Both the SN2 and E2(anti) reactions are exothermic and have negative activation barriers when Cl- is the leaving group. Overall, E2 is preferred to SN2, and E2(anti) is favored over E2(gauche) for both OH- and SH-, indicating the preference of an antiperiplanar transition state in the gas phase. Since SH- is a weaker gas-phase nucleophile than OH-, the transition state occurs later on the reaction coordinate. The results of this work are consistent with those of gas-phase experimental studies which indicated that first-row nucleophiles undergo both SN2 and E2 reactions, whereas second-row nucleophiles have lower abilities to induce elimination reactions. Substitution of a CN group for a β-hydrogen of CH3CH2Cl to NCCH2CH2Cl is found to enhance both the SN2 and E2 reactivities and makes the β-H-elimination ...

Understanding the origin of the regioselectivity of inositol derivatives is essential to the synthetic design of these biologically important molecules. We have undertaken a study of the regioselectivities displayed by the myo-inositol derivatives toward electrophiles using various levels of quantum mechanical calculation: Hartree−Fock (HF) theory, Moller-Plesset second-order perturbation (MP2) theory, density functional theory (DFT), and self-consistent reaction field (SCRF) theory. Various basis sets were also tested. The systems investigated here are 1,2:4,5-di-O-methylidene-myo-inositol and its probable intermediates (deprotonated and sodium-chelated species). In experiments the O3 position was the major site for derivatization of the molecule. However, the MP2 and DFT results could not explain the experiments. Taking into account that the myo-inositol derivatives were highly insoluble with the exception of some polar solvents, we performed the SCRF calculations using the dielectric constant (e) of 4...

The ring opening reaction of 3,4-epimino-1-butene (EIP), 3,4-epoxy-1-butene (EOB) and 3,4-epithio-1-butene (ETB) initiated by the attack of hydroxide ion at three carbons (Cα, Cγ, and Cδ) have been investigated using MP2/6-31+G*//MP2/6-31+G* ab initio molecular orbital theory. The CαCβCγCδX process by the α-attack is favored by the strong frontier orbital interactions due to the low π* orbital, but is disfavored by a lower degree of progress in the developing π orbital as well as in the ring opening. In contrast, the processes by the γ-and δ-attacks are disfavored by the high σ* orbitals, but are favored by a greater strain energy release in a greater degree of ring opening in the transition state. The barriers to the ring opening processes are found to depend on the strain energy of the three-membered heterocycles, bond strength of the C−X bonds, frontier orbital (π*, σ*(1), and σ*(2)) levels, exothermicity of the reaction, and steric and entropy effects.

The base-catalysed rearrangements of disubstituted aryl benzils in the gas phase and in solution (water) have been investigated theoretically by the AM1 method. The solvent effects were accounted for using the Cramer–Truhlar SM2.1 solvation model. The calculated Gibbs free energy changes (ΔG‡) for the overall reactions (kobs) are dissected into component parts, i.e. for the equilibrium step(K) of reactants ⇌ intermediate (ΔGIo) and rearrangement step (k2) of intermediate → transition state (ΔGI‡); ΔG‡=ΔGIo+ΔGI‡. The Hammett ρ values for the migrating (ρX) and non-migrating rings (ρY) are then calculated for each step. Thus, the overall ρ(kobs) value can be dissected into two components, ρ(K)+ρ(k2). It has been shown that (i) the substituent effects of the 4,4′-disubstituted aryl benzils are not in general additive, ρ(kobs)≠ρX+ρY, due to the cross-interaction term, ρXY, and (ii) in the gas phase, the equilibrium step is considerably more important than the rearrangement step, ρ(K)ρ(k2), whereas in solution (water) the two steps contribute comparably, ρ(K)≃ρ(k2). It is also notable that in the rearrangement step (k2) the carbonyl carbon of the non-migrating ring actually becomes more electron-deficient [ρY(k2) 0]. Fair agreement of the ρ(kobs) values are obtained between those for the theoretical solution phase (6.7 in water) and for the experimentally observed [5.7 in 7%(v/v) aqueous Me2SO] for the symmetrically disubstituted aryl benzils (σX=σY).

Ab initio studies on the SN2 identity exchange reactions RCH2X + X− X− + RCH2X for R = CH2CH with X− = H, NH2, OH, F, PH2, SH and Cl, and for R = CH3 and CHC with X− = Cl were carried out at the HF and MP2 levels using the 6–31 ++ G** basis sets. The activation barriers, ΔE≠, and major structural changes, Δd≠ (C–X), in the activation process are closely related to the electronegativity of the R and X groups. The effect of electronegativity is twofold: a stronger electronegativity of R and/or X leads to a lesser electronic as well as structural reorganization required in the activation and to a greater correlation energy in the transition state. The former effect lowers the energy barriers at both the HF and MP2 levels whereas the latter lowers only the correlated (MP2) activation energies. Results with R = CH2CH, as a model for R = C6H5, indicate that ‘benzylic effect’ arises mainly from the relatively stronger electron acceptor ability of the phenyl group.

Semiempirical MO (PM3) studies are reported on the reactions of 18 substituted phenolate anions with m-(MNPF), p-(PNPF) and 3,4-dinitrophenyl formates (DNPF). The mechanistic change from rate-limiting formation to breakdown of the anionic intermediate (T−) can occur in the gas phase, especially for MNPF, at approximately an equal proton affinity (PA) of the nucleophile and leaving group phenolates, i.e. ΔPA = 0 as the PA of the phenolate anion is decreased. In solution, however, owing to the low stability of T and a greater stabilization by solvation of the transition state for the breakdown step (TS2), all three formate esters are predicted to proceed by a concerted mechanism, which is in agreement with the experimental results. The low stability of T can be ascribed to the relatively high electron affinity of the phenolate anions.