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The cyclization of a series of nonheterocyclic allenyl aryl ketones was examined using boron trifluoride etherate and indium triflate to mediate the reaction. Yields with BF3 were low in most instances due mainly to competitive destruction of the substrates. With In(OTf)3, there was less decomposition, and the yields of the cyclized product were much higher, but only for substrates with electron-donating substituents. Cyclization did not occur without those substituents. A computational study using the ωB97X-D/6-311+G(2d,p)//ωB97X-D/6-31+G(d,p) method confirmed better stability of the σ-complexed substrate by indium(III) and that meta-substituents on the phenyl ring of the substrate significantly influenced the activation barrier of the cyclization, whereas the effect of para-substituents was almost negligible. The computational results supported the idea that the cyclization is a 4π-electrocyclization and not a 5-endo-dig ring closure as had been proposed in the literature.

Cytochrome P450 enzymes were recently engineered to catalyze the C-H amination reaction of aryl sulfonyl azides with excellent regio- and stereoselectivity (Arnold and co-workers J. Am. Chem. Soc. 2014 , 136 , 15505 ). The mechanism of this reaction was studied by quantum mechanical (QM)/molecular mechanical (MM) calculations in this work. The C-H activation is found to be a stepwise process consisting of hydrogen abstraction (H-abstraction) of the reactive C-H bond by an iron nitrenoid cofactor to produce the biradical intermediate and subsequent radical rebinding to form the final product. The rate of rotation of the carbon radical center was estimated to be much faster than that of radical rebinding, which implies that the H-abstraction does not determine the stereoselectivity. For mutant A, the H-abstraction step has a barrier of 16.7 kcal/mol, which is 3.0 kcal/mol higher than that of the following radical rebinding step. The H-abstraction step determines the regioselectivity, but the radical rebinding step determines the stereoselectivity. Barriers of these two steps are 16.1 and 27.5 kcal/mol, respectively, for mutant B. It is different from mutant A in that the radical rebinding step has the higher barrier and determines both the regio- and stereoselectivity. The initial distances between the hydrogens of reactive C-H bonds and the iron nitrenoid were found to not correlate with their reactivities. The calculated barriers are qualitatively consistent with the experimentally observed regio- and stereoselectivity with the exception of the stereoselectivity of mutant B. The lower barriers of mutant A presumably come from the stabilization effect of the H-bond between G265 and the sulfone O. This H-bond does not exist in mutant B. The conformation of the protein backbone, with the exception of the active site, does not change much (RMSD0.05) along the reaction pathway.

Since the 1960s, dithiolene complexes have been intensely studied; however, the same cannot be said about diselenolene complexes. Thus, the chemistry associated with the reduction of several Mo- and W-tris(diselenolene) complexes was investigated. In particular, relative reduction potentials, changes in key geometrical properties, the contribution of the metal center to the redox active MO, and HOMO–LUMO energy gaps are investigated. It is noted that the results obtained for the tris(diselenolene) complexes are compared to analogous Mo- and W-tris(dithiolene) complexes to understand the effect of substituting the sulfur atoms with selenium atoms. The reduction potentials of the complexes are more dependent upon the choice of the ligand than the metal. Overall, it is found that the substitution of chalcogen atom for the tris complexes investigated herein has only a subtle effect on the calculated reduction potentials between analogous redox couples. Upon reduction of the neutral and mono-anionic complexes, it is found that changes in key bond lengths, fold angles (θ), and trigonal twist angles (ΦAvg) are very similar for the tris(diselenolene) complexes investigated. Such changes have been previously observed for several Mo- and W-tris(dithiolene) complexes. Comparing the HOMO–LUMO energy gaps of the tris(diselenolene) complexes to the tris(dithiolene) complexes, the former complexes have on average a 0.07-eV smaller energy gap and are thus expected to be slightly more reactive to reduction. Lastly, in the neutral complexes, the Mo and W atoms contribute at most 26% to the redox active MO; thus, in the case of the tris(diselenolene) complexes, it can be concluded that the redox active MO is predominantly ligand based. The contribution of the metal-based AO becomes less as the complexes are reduced. In summary, given the high interest of dithiolene complexes in the areas of alternative energy and material science, the results presented herein provide motivation to further investigate the chemistry of diselenolene complexes.

A computational examination of the tandem Nazarov/cycloaddition process involving an allenyl vinyl ketone with a diene has been carried out using the ωB97X-D/6-311++G(d,p)//ωB97X-D/6-31+G(d,p) method with solvation modeled by SMD-PCM. The barrier for the initial Lewis acid mediated Nazarov reaction, which provided the intermediate cyclic oxylallyl cation, was higher than that for any subsequent cycloaddition. The barrier for the first step of a subsequent stepwise reaction did not vary much with the diene, and the lowest barrier was with the diene in its s-trans conformation. Stepwise formation of a (4 + 3) cycloaddition product was not energetically feasible, but (3 + 2) cycloaddition products could have been produced through low energy pathways. The barrier for a concerted (4 + 3) cycloaddition did depend upon the diene, which was always in an s-cis geometry. The barriers for the compact and the extended geometries for the transition states of (4 + 3) cycloadditions were not much different.

The full catalytic mechanism for nitrile hydratase is explored, involving cysteine-sulfenic acid acting as a nucleophile, activating a water molecule to attack nitrile substrates. The iminol intermediate undergoes tautomerization to form the amide product. The computed enthalpies are closely related to experimental values, suggesting the current mechanism with two water molecules should be further investigated.

Predicting the correct ground-state multiplicity for iron(II) porphyrin, a high-spin quintet, remains a significant challenge for electronic-structure methods, including commonly employed density functionals. An even greater challenge for these methods is correctly predicting favorable binding of O2 to iron(II) porphyrin, due to the open-shell singlet character of the adduct. In this work, the performance of a modest set of contemporary density-functional approximations is assessed and the results interpreted using Bader delocalization indices. It is found that inclusion of greater proportions of Hartree-Fock exchange, in hybrid or range-separated hybrid functionals, has opposing effects; it improves the ability of the functional to identify the ground state but is detrimental to predicting favorable dioxygen binding. Because of the uncomplementary nature of these properties, accurate prediction of both the relative spin-state energies and the O2 binding enthalpy eludes conventional density-functional approximations.

Capture of the cyclic oxyallyl cation intermediates from the BF3-mediated Nazarov reactions of three allenyl vinyl ketones with various dienes was accomplished by (3+2)- and (4+3)-cycloaddition. The relative amounts of these types of products were dependent on the substitution on the diene, and this could be linked to steric hindrance. Treatment of the (3+2)-cycloaddition products with BF3·Et2O led mainly to decomposition but also to ring-opened molecules and ring-enlarged structures. The computed Gibbs energies of the (3+2)-cycloaddition products, the products of the acid treatment and of some transition states leading to rearranged products were compared.

The local and regional stabilities in clusters of water, methanol, and formaldehyde up to the tetramers have been analyzed from an atomic energy perspective. We optimize structures at the MP2/6-311++G(d,p) level with some CCSD(T)/6-311++G(d,p) single point energies, and then decompose the electronic densities into atomic parts using the atoms in molecules (AIM) approach. We consider the changes in atomic energy in the clusters vs. the isolated monomer. This method of analysis allows us to reveal the variety of stabilities within these hydrogen-bonded clusters, including indications of cooperative, anti-cooperative, and non-cooperative interactions. Cooperatively interacting clusters have increasing stability at the atomic level as the cluster size grows. This is not observed in the anti- and non-cooperative arrangements of water and formaldehyde clusters. The cooperativity in methanol clusters is dominated by the OH regions, with negligible energy change in the methyl regions. Formaldehyde clusters, including the lowest minimum “bucket” cluster, do not show significant cooperativity. Atomic energy analysis is supported with bond critical point data as well as charge and geometric values. We represent the local stability in the clusters using a simple visual approach that allows areas of increased or decreased stability to be easily interpreted.

We performed an assessment of 10 common DFT functionals to determine their suitability for calculating the reduction potentials of the ([M(S2C2H2)2](0)/[M(S2C2H2)2](1-)), ([M(Se2C2H2)2](0)/[M(Se2C2H2)2](1-)), ([M(S2C2H2)2](1-)/[M(S2C2H2)2](2-)), and ([M(Se2C2H2)2](1-)/[M(Se2C2H2)2](2-)) redox couples (M = Ni, Pd, and Pt). Overall it was found that the M06 functional leads to the best agreement with the gold standard CCSD(T) method with an average difference of only +0.07 V and a RMS of 0.07 V in calculated reduction potentials. The variability in calculated reduction potentials between the various DFT functionals arise, in part, from the multireference character of these systems, which was determined by the T1 diagnostic values. Thus, the bisdiselenolene complexes show similar multireference character as the bisdithiolene complexes, which were previously shown to have such character. In particular, for the Ni-, Pd-, and Pt-bisdiselenolene complexes the average T1 values are 0.05, 0.03, and 0.02, respectively. For the CCSD(T) calculations the similarities in the reduction potentials between analogous bisdithiolene and bisdiselenolene redox couples, which appear to be independent of the metal, is a result of the noninnocence of the dithiolene and diselenolene ligands. Thus, the reduction potential is more dependent on the ligand than the metal.

Nazarov reactions mediated by BF3-etherate of a series of carbon-substituted allenyl vinyl ketones provided intermediates in which substituents on the termini of the allenes had rotated away from the vinyl moieties, and these intermediates were trapped by (4 + 3)-cyclizations. A computational examination of the torquoselectivity of these Nazarov reactions confirmed a kinetic preference for the observed isomers and pointed to steric interactions and the degree of allene deformation as significant factors in determining the torquoselectivity. The study also suggested that the high proportion of one geometrical isomer in the Nazarov products might also be due to some preferential trapping of the major Nazarov intermediate.

The reactions of XSeSX, XSeSY, and YSeSX (X, Y = CH3, NH2, OH, F) with F− and CN− nucleophiles have been investigated by means of B3PW91/6-311+G(2df,p) and G4 calculations. In systems where the two substituents are not identical (XSeSY), the more stable of the two possible isomers corresponds to those in which the most electronegative substituent is attached to Se. Nucleophilic attack takes place at Se, independent of the nature of the nucleophile, with the only exception being XSeSF (X = CH3, NH2, OH), in which case the attack occurs at S. In agreement with recent results for disulfide and diselenide linkages, the mechanisms leading to Se—S bond cleavage are not always the more favorable ones because for highly electronegative substituents the most favorable process is fission of the chalcogen-substituent bond. These dissimilarities in the observed reactivity pattern as a function of the electronegativity of the substituents are due to the fact that the σ-type Se—S antibonding orbital, which for low-electronegative substituents is the lowest unnoccupied molecular orbital (LUMO), becomes strongly destabilized when the electronegativity of the substituent increases, and is replaced by an antibonding π-type Se-X (or S-X) orbital. In contrast, however, with what has been found for disulfide and diselenide derivatives, the observed reactivity does not change with the nature of the nucleophile. The activation strain model provides interesting insight into these processes, showing that in most cases the activation barriers are the consequence of subtle differences in the strain or in the interaction energies. © 2013 Wiley Periodicals, Inc.

Analogues of the antioxidant ethoxyquin are studied to determine the effects of changing the group 16 element in the reacting center of a glutathione peroxidase mimic. The energy barrier for hydrogen peroxide reduction decreases along the group, with sulfur showing the highest, selenium intermediate, and tellurium the lowest barrier. The ethyl side chain on the chalcogen is substituted with methyl and tertiary-butyl groups to determine the degree of steric effects on the barrier. A phenyl substituent results in a higher barrier than the alkyl side chains.

The potential energy surfaces of methanol clusters, (CH3OH)n, n = 2-12, have been studied using density functional theory at the B3LYP/6-31G(d) and higher levels of theory. Cyclic clusters in which n methanol molecules are joined in a ring structure formed by n hydrogen bonds are shown to be more stable than structures of the same number of methanol molecules where one or more methanol molecules are outside the ring and are hydrogen-bonded to oxygens of methanols in rings of n - 1, n - 2, and so forth. So-called chain structures are generally even less stable. Furthermore, the hydrogen-bonding energy per methanol molecule of the n-ring clusters is shown to converge to an asymptotic value of about 27 kJ/mol at B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) after five to six methanols are included in the cluster. As expected, there are many minima on the potential energy surfaces of the methanol clusters, the number increasing rapidly with n. A cyclic cluster of five to six methanol molecules appears to be sufficient to mimic liquid behavior as far as vibrational frequencies are concerned.

Inspired by the helical structure as well as the conductivity of DNA and substituted polyphenylacetylenes, a new kind of substituted polyacetylene is introduced. More specifically, polycytosineacetylene ((RC CH) n , R = cytosine) with a trans-polyacetylene backbone is investigated theoretically. The neutral and cationic geometries are optimized as single helical chains with n = 20. It is found that when an electron is removed the polymer stretches from 19.80 A to 28.41 A. The polyacetylene backbone in the optimized cationic polymer exhibits the formation of a soliton. It is predicted that a doped polycytosineacetylene would have good conductivity, and would also behave as a nanomechanical spring and as a piezoelectric material.

Polaron formation in poly(G)-poly(C) cations is investigated with density functional theory (DFT) and molecular mechanics (MM) employing a two-layer ONIOM method. In these calculations, the high layer, composed of all complementary base pairs, is treated by a DFT method, while the low layer, which includes the sugar-phosphate backbone, counterions and water molecules, is described by the AMBER force field. The high layer is the model system in which the charge transfer takes place. According to our calculations, three or four guanines move in a paddle-like fashion when an electron is removed from the neutral model system. In the cation model system, about 80% of the charge is delocalized onto the guanine residues, and the remaining charge is delocalized onto the cytosine residues. This happens because guanine has a lower ionization potential (IP) than cytosine. The counterions and water molecules in the low layer are important in the geometry optimization. The optimized geometry of the model system is closer to the standard B-form structure when counterions and water molecules are included than when they are omitted. Comparison of the optimized neutral and cationic model systems reveals a polaron in poly(G)-poly(C) cations extending from the first to the third guanine. It is demonstrated that the position of counterions and the number of surrounding water molecules can affect polaron formation.

The structures and relative stabilities of the complexes formed by uracil and its thio- and seleno-derivatives with the Sr(2+) cation, in the gas phase, have been analyzed by means of G96LYP density functional theory (DFT) calculations. The attachment of the Sr(2+) cation to the heteroatom at position 4 is preferred systematically. Although the enolic forms of uracil and its derivatives should not be observed in the gas phase, the corresponding Sr(2+) complexes are the most stable. The enhanced stability of these tautomers is two-fold, on the one hand Sr(2+) interacts with two basic sites simultaneously, and on the other hand an aromatization of the six-membered ring takes place upon Sr(2+) association. Sr(2+) attachment also has a clear catalytic effect in the tautomerization processes involving uracil and its derivatives. This catalytic effect increases when oxygen is replaced by sulfur or selenium. The Sr(2+) binding energy with uracil and its derivatives is bigger than the tautomerization barriers connecting the dioxo forms with the corresponding enolic tautomers. Consequently, when associated with Sr(2+), all tautomers are energetically accessible and should all be observed in the gas phase.

The effects of introducing electron-donating (NH(2), OCH(3), CH(3)) and electron-withdrawing (NO(2), CF(3), CN, F) groups to N,N-dimethylbenzylamine-2-selenol are studied to determine the effect of the selenium electron density on the efficiency of the reduction of hydrogen peroxide. Introducing substituents in the meta and para positions decreases or increases the energy barrier of the reaction in the expected way, due to changes in the electronic environment of the reacting selenium center. Ortho substituents are found to have a greater effect on the electronic environment of the selenium center, which is mitigated by changing the steric environment. Insight into the origins of the substituent effects is obtained through quantum theory of atoms in molecules (QTAIM) and electrostatic potential analysis.

The displacement of the iron(II) atom from the porphyrin plane in iron(II) porphyrin complexes is investigated with respect to the spin state of iron(II) employing density functional theory. In this study the quantum theory of atoms in molecules (QTAIM) is used to show that the atomic volume of iron is smaller in the quintet state of imidazolium ligated iron(II) porphyrin than in the triplet state. This is consistent with what has been found for free atoms and contradicts the original interpretation of structural studies with X-rays, which assumed that the out-of-plane displacement of iron from the porphyrin ring in the quintet state is due to the increased spatial size of the high-spin iron atom. The bonding environment of the iron atom is analyzed with respect to the electron density (ρ) at the bond critical points (BCPs). It is found that in the quintet state, relative to the triplet state, there is a stronger bonding interaction between iron and the nitrogen atoms of the porphyrin despite a longer bond length. It has previously been suggested that the weakening of these bonds is the cause of the out-of-plane displacement of iron. Since this is not the case, this implies that the magnitude of the bonding interaction between the iron atom and the axial ligand has a more significant role in the domed structure of the quintet state.

The reaction mechanism for the reduction of hydrogen peroxide by N,N-dimethylbenzylamine diselenide, its selenol analogue, and the charged analogues of the diselenide and selenol are elucidated using reliable electronic structure techniques. It is found that the reaction using the diselenide has a large Gibbs energy barrier of 173.5 kJ/mol. The cationic diselenide, with both amines protonated, shows a lower barrier of 103.5 kJ/mol. Both diselenide species show significant Se-Se bond lengthening upon oxidation. An unusual two-step mechanism is found for the selenol with barriers of 136.3 and 141.9 kJ/mol, respectively, showing that it is unlikely that the selenol is the active form. The zwitterion, selenolate, and protonated amine analogues of the selenol show one-step reactions with energy barriers of 82.7, 92.7, and 102.3 kJ/mol, respectively. The zwitterion of the selenol shows the most favorable reaction energies, which is in good agreement with proposed mechanisms for this reaction.

We discuss the exact Coulomb hole for the ground state of the helium atom and helium-like ions. We find that the correlated wavefunction yields a smaller probability of finding the electrons at large separations than does the Hartree–Fock wavefunction, leading to the counterintuitive conclusion that correlation brings distant electrons closer together. This effect becomes less pronounced as the nuclear charge increases.

Protein tyrosine phosphatase 1B (PTP1B) functions by removing the phosphoryl group from tyrosinephosphorylated proteins in insulin signaling and metabolism. The regeneration of the active site involves a sulphenylamide intermediate derived from the intrastrand cross-linking between the catalytic serine and the neighboring backbone nitrogen. Two mechanisms have been proposed for the formation of the sulphenylamide intermediate and the subsequent reactivation of the catalytic site. In the current work, the proposed mechanisms have been investigated by the use of density functional theory calculations. Our results suggest that these two mechanisms have similar overall energy barriers and that the preferred route will be determined by the availability of hydrogen peroxide or other oxidizing reagents.

The Paal–Knorr pyrrole synthesis, which involves the reaction of 1,4-dicarbonyls with amines, is among the most classical methods of heterocyclic pyrrole ring synthesis. The detailed sequence and the nature of the intermediates that occur in the Paal–Knorr reaction mechanism are not well understood. Density functional theory methods have been employed to investigate the nature of the intermediates and transition states in the Paal–Knorr pyrrole mechanism. Two mechanistic pathways for the reaction were examined: hemiaminal cyclization vs. enamine cyclization. Our calculated reaction potential energy surfaces suggest that the hemiaminal cyclization is the preferred pathway for the reaction both in gas phase and in solution. This conclusion is consistent with the experimental results which suggest that the hemiaminal intermediate undergoes cyclization in the rate-limiting step in the Paal–Knorr reaction mechanism. The preferred mechanism for the Paal–Knorr reaction consists of hemiaminal formation, hemiaminal cyclization and a dehydration step to form the pyrrole ring. Water and hydrogen-bonding interactions play a key role in catalyzing the hydrogen-transfer steps of the reaction.

Density functional theory calculations at the B3LYP/6-311++G(3df,3pd)//B3LYP/6-31G(d,p) level have been performed to elucidate the mechanism and reaction energetics for the reduction of hydrogen peroxide by ebselen, ebselen diselenide, ebselen selenol, and their sulfur analogues. The effects of solvation have been included with the CPCM model, and in the case of the selenol anion reaction, diffuse functions were used on heavy atoms for the geometry optimizations and thermochemical calculations. The topology of the electron density in each system was investigated using the quantum theory of atoms in molecules, and a detailed interpretation of the electronic charge and population data as well as the atomic energies is presented. Reaction free energy barriers for the oxidation of ebselen, ebselen diselenide, and ebselen selenol are 36.8, 38.4, and 32.5 kcal/mol, respectively, in good qualitative agreement with experiment. It is demonstrated that the oxidized selenium atom is significantly destabilized in all cases and that the exothermicity of the reactions is attributed to the peroxide oxygen atoms via reduction. The lower barrier to oxidation exhibited by the selenol is largely due to entropic effects in the reactant complex.

The addition of enols and [(trimethylsilyl)oxy]alkenes, bearing methyl substituents at various positions, to a cyclic, BF3-complexed oxyallyl cation has been studied at the M06/6-311G(d)//B3LYP/6-31G(d) level of theory. The reactions with the [(trimethylsilyl)oxy]alkenes are homologous Mukaiyama reactions, which have not been examined computationally previously. In most instances a number of transition states were located, and the difference in energy between these transition states was not large, which pointed to low levels of diastereoselectivity in the reactions of the oxyallyl cation model compound. The lowest energy transition states were those with a synclinal geometry in which the alkene was positioned over the cyclic oxyallyl cation, and the relative orientation of the alkene and the oxyallyl cation was rationalized in terms of stabilizing intermolecular interactions, revealed by NBO analysis, between one or more fluorines of the complexed BF3 and hydrogens on the alkene moiety, and between the oxygen on the alkene and the π-system of the oxyallyl cation. Because, in most instances with these simple models, two or more transition states of relatively low energy were located, predictions of diastereoselectivity in more complex examples that are based on simple models cannot be recommended.

The most common method for achieving the regioselective monoalkylation of diols involves formation of dialkylstannylene acetals as intermediates. Reactions of dialkylstannylene acetals with alkyl halides are slow, but rates are enhanced by addition of fluoride or other nucleophiles. The mechanism of the fluoride-accelerated alkylation of dialkylstannylene acetals was studied at several levels of theory in the gas phase, in N,N-dimethylformamide (DMF) solution, and in DMF solution in the presence of tetramethylammonium ions. The reactive species were adducts involving addition of fluoride to tin. Under the conditions that most closely simulated experiment, reactions from fluoridated monomers and monofluoridated dimers were calculated to have similar activation energies. In the transition states in the rate-determining steps for the two pathways, carbon-oxygen bond formation was between 60 and 75% complete while tin-oxygen bond cleavage was much less advanced, between 6 and 16% complete. A test of Sn-O bond dissociation indicated that the "Sn-O bond cleavage first" mechanism is not a minimum energy pathway.

Theoretical calculations have been performed on three model reactions representing the reduction of hydrogen peroxide by ebselen, ebselen selenol, and ebselen diselenide. The reaction surfaces have been investigated at the B3PW91/6-311G(2df,p) level, and single-point energies were calculated using the 6-311++G(3df,3pd) basis set. Solvent effects were included implicitly with the conductor-like polarizable continuum model and in one case with explicit inclusion of three water molecules. Mechanistic information is gained from investigating the critical points using the quantum theory of atoms in molecules. The barriers for the reduction of hydrogen peroxide with the ebselen, ebselen selenol, and ebselen diselenide models are 56.7, 53.4, and 35.3 kcal/mol, respectively, suggesting that ebselen diselenide may be the most active antioxidant in the ebselen GPx redox pathway. Results are also compared to that of the sulfur analogues of the model compounds.

Electron-withdrawing groups (EWGs) on the nitrogen atom of pyrroles have significant effects on the properties of the pyrrole. It has been suggested that the experimental 13C chemical shifts show a general increase in deshielding effect with the increase of N-EWGs strength [A. Thompson, S. Gao, G. Modzelewska, D.S. Hughes, B. Patrick, D. Dolphin, Org. Lett., 2, 3587 (2000)]. However, recently observed 15N chemical shifts of pyrroles do not correlate with the N-EWG strength. To elucidate the relationship between the electronic structures of pyrroles and their nitrogen and carbon chemical shifts, density functional theory calculations were performed on pyrroles with various substituents. A correlation between the paramagnetic shift and the 15N chemical shift was observed for the pyrroles, indicating that the nitrogen chemical shift trend for the pyrroles arises entirely from variations of the paramagnetic shift contribution. However, a general correlation between the 15N chemical shifts and the EWG strength...

We report a detailed characterization of the valence shell charge concentration (VSCC) of fluorine in methyl fluoride through the atoms in molecules theory. A comparison between the VSCCs of fluorine and neighboring elements (N, O, P, S, Cl) in the periodic table is also presented. The fluorine VSCC is shown to be tetrahedral and the most compact with the highest values of ρ and −∇ 2 ρ . Our results calculated at several post Hartree–Fock levels of theory using a large basis set show a remarkable insensitivity to the level of theory.

The question of why the iron displacement out of the porphyrin plane is enhanced in quintet states of singly ligated iron-porphyrin complexes compared to lower spin states and unligated iron-porphyrin is addressed. The spatial size of the Fe2+ atom is analyzed with respect to different spin states, and it is shown that the ion size decreases with increasing spin state for the d6 electronic configuration. This contradicts the common belief that the iron out-of-plane location in the quintet state of ligated Fe(II)-porphyrins is due to an increased required space of the iron within the porphyrin ring. Therefore, the singlet, triplet, and quintet ground states of imidazole-ligated iron-porphyrin have been calculated employing density functional theory, and the relevant molecular orbitals have been analyzed. Additional comparison with the unligated iron-porphyrin molecules reveals that the enhanced doming in the quintet state is the result of a combination of the weakening of the iron-ring nitrogen bonds by oc...

The proline-catalyzed direct aldol reaction between acetone and acetaldehyde has been investigated using density functional theory. Proline catalyzes the reaction according to the enamine mechanism characteristic of the natural class I aldolase enzymes. Although it has been postulated that the rate-limiting step in the proposed mechanism is enamine and/or C−C bond formation, the initial reaction between proline and acetone is accompanied by a very large barrier which may inhibit further progression of the reaction. However, an alternative lower energy reaction pathway is utilized when the ionizing solvent DMSO is present to assist in the formation and stabilization of separated charges. The direct aldol reaction between acetone and acetaldehyde illustrates the catalytic potential of simple organic molecules in asymmetric synthesis.

DNA-protein cross-linking is one of the many DNA lesions mediated by hydroxyl radicals, the most damaging among the reactive oxygen species in biological systems. Density functional theory methods are employed to investigate the complex reaction mechanisms of the formation of cytosine-tyrosine cross-links as observed in gamma-irradiated aqueous solutions of cytosine and tyrosine, as well as in gamma-irradiated nucleohistone. The majority of the radical addition mechanisms considered are found to have significant barriers and therefore to be thermodynamically unfavorable for the formation of the initial cross-linked product. Our calculated reaction potential energy surfaces suggest that a feasible complete mechanism consists of radical combination forming the initial cross-linked product, a hydrogen shuffle within the initial cross-linked product, and an acid-catalyzed dehydration reaction. Water and hydrogen-bonding interactions are suggested to play a key role in catalyzing the hydrogen-transfer step of the reaction.

Density functional theory is used to study a series of model iron porphyrins in the gas phase. In the first part of this study, three range-separated hybrid density functionals developed by Chai and Head-Gordon were assessed; ωB97, ωB97X, and ωB97XD. The effects of including full Hartree-Fock exchange at long-range and dispersion corrections are reported with respect to the geometries and binding energies of oxygen to the iron porphyrin systems. The functionals all correctly predict the quintet ground state for the deoxy-iron porphyrins, where typically hybrid functionals fail and predict a triplet ground state. Including dispersion in ωB97XD is shown to give the best results for the O2 binding energy and geometrical parameters. The second part of the study employs ωB97XD to study iron porphine systems with different amino acids in the axial position. Geometrical parameters are reported and compared to experimental data, where available. Binding energies of the systems with oxygen are also reported and discussed.

Leukotrienes (LT) are a family of drug-like molecules involved in the pathobiology of bronchial asthma and are responsible for smooth muscle contraction. Leukotriene C4 synthase (LTC4S) is a nuclear-membrane enzyme responsible for the conjugation of leukotriene A4 (LTA4) to glutathione to form LTC4, a cysteinyl leukotriene. In this study, the mechanism of LTA4 binding by LTC4S has been computationally examined. More specifically, docking and molecular dynamics simulations were used to gain insight into the substrate-bound active site. These studies identified two possible orientations for bound LTA4: ‘tail-to-head’ and ‘head-to-tail’. An ONIOM(QM/MM) approach was then used to elucidate the mechanism by which glutathione may add to LTA4. In particular, the thiolate of glutathione acts as a nucleophile attacking C6 of LTA4 forming a S–C6 bond. Concomitantly, a proton is transferred from the guanidinium of Arg31 to the epoxide ring oxygen. This results in opening of the epoxide ring and stabilization of the LTC4 product complex. Within the present computational methodology the ‘tail-to-head’ orientation appears to be the most likely substrate orientation.

Herein we present an assessment to determine which of nine well-established DFT functionals best describes the reduction of C2H2Se2(-)˙. In addition, we have also studied the effects of changing the substituents bound to the alkene functional group of dithiolene and diselenolene ligands. Such ligands are important due to their unique electrochemical and physical properties when ligated to metals. The M06-L functional shows best agreement with the QCISD/cc-pVTZ value of -2.45 V for the reduction potential of the (C2H2Se2˙(-)/C2H2Se2(-2)) redox couple. At the M06-L/6-311+G(d,p) level of theory the calculated reduction potential for the (C2H2Se2˙(-)/C2H2Se2(-2)) redox couple is only 0.09 V in error. However, as a result of the nature of the oxidized species for the respective ligands the absolute reduction potential of the (C2H2Se2˙(-)/C2H2Se2(-2)) redox couple is 0.57 V more oxidizing than the (C2H2S2˙(-)/C2H2S2(-2)) redox couple. This is due to the radical electron in C2H2S2˙(-) being delocalized within the alkene backbone, whereas in C2H2Se2˙(-) the electron is largely localized on the Se atoms. The relative reducing power of the S- and Se-containing redox couples is shown to vary depending on the choice of substituents. In particular the reduction potential of the various S-containing redox couples range from being 0.34 V more reducing to 0.28 V more oxidizing than the analogous Se-containing redox couples. This difference in the relative reducing power appears to be a result of the nature of the oxidized ligand. Thus, depending on the choice of moiety very different chemistry is seen between the analogous dithiolate and diselenolate ligands.

In the present study, ab initio methods have been used to study the OH hydrogen-abstraction reaction from two substituted aldehydes: FCHO and ClCHO. A complex mechanism in which the overall rate depends on the rates of two competitive reactions, a reversible step where a reactant (or prereactive) complex is formed, followed by the irreversible hydrogen abstraction to form the products, is corroborated. This mechanism was previously shown to describe accurately the kinetics of the OH hydrogen-abstraction reaction from formaldehyde and acetaldehyde. Classical transition state theory (TST) rate constants calculated with tunneling corrections, assuming an unsymmetrical Eckart barrier, agree very well with experimental upper bound values. Activation energy barriers and enthalpies of reaction have been estimated through CCSD(T) single point calculations using MP2 geometries and frequencies and the 6-311++G(d,p) basis set.

The gas phase and solution electron affinities and ionization potentials of uracil, thymine and a series of 5-halouracils ( 5XU, X=F, Cl, Br ) are investigated with B3LYP. Halogen substitution has a smaller effect on the IP than the EA of U . The EAs are calculated to increase according to T U 5FU 5ClU 5BrU . The calculated barriers for the dissociation of the resulting 5XU anions to X − plus uracil-centered radicals decrease along the series 5FU − > 5ClU − > 5BrU − . The calculated trends are consistent with suggestions that 5XUs enhance the sensitivity of deoxyribonucleic acid, DNA (ribonucleic acid, RNA) to ionizing radiation and that 5BrU leads to the greatest enhancement.

In this work, the OH + formaldehyde and OH + acetaldehyde reactions have been characterized using accurate ab initio methods with large basis sets. The results clearly indicate that the reaction occurs by hydrogen abstraction, and that the OH addition channel is unfavorable. Close to zero (for formaldehyde) and negative (for acetaldehyde) activation energy values are obtained, which are in excellent agreement with the experimentally observed values. The reaction rate constants, calculated using the classical transition-state theory as applied to a complex mechanism involving the formation of a prereactive complex, reproduce very well the reported experimental results. Consideration of the prereactive complex is shown to be essential for the determination of the height of the energy barrier and thus for the correct calculation of the tunneling factor.

The aminolysis of 6-chloropyrimidine and 2-amino-6-chloropyrimidine has been examined by using density functional theory. Relative to the aminolysis of 6-chloropyrimidine, the addition of an electron-donating NH(2) group to C(2) increases the barrier to aminolysis, indicating that the third hydrogen bond does not play a catalytic role but introduces additional rigidity into the system. However, the computations suggest that there is an interesting correlation between the barrier to aminolysis and the proton affinity of the species that interacts with the incoming NH(3). To extend the range of proton affinities, the aminolysis of 6-chloropyrimidine was examined by using fluoro, imine, and thioketo derivatives of the uracil-derived bases. The proton affinity of the moiety that hydrogen bonds with NH(3) is decreased by fluoro substitution, and thus the aminolysis barriers are increased. Similarly, imine substitution enhances the PA of the moiety, which is reflected in a decrease in the aminolysis barriers. The same correlation exists for the thioketo-derived bases, whose PAs are intermediate between the fluoro and imine derivatives. Thus, the aminolysis of 6-chloropryimidine and 2-amino-6-chloropyrimidine demonstrates the importance of a well-chosen proton acceptor and the catalytic possibilities associated with the formation of multiple hydrogen bonds.

The structure sensitivity and cluster size convergence for formate adsorption on the Cu(100), Cu(110) and Cu(111) surfaces have been investigated systematically using density functional theory and the cluster model containing up to 40 Cu atoms. The copper core–valence correlation effect on the adsorbate–surface interaction is examined by using three different basis sets and effective core potentials. The calculated geometries and vibrational frequencies are in good agreement with experimental data even on the small clusters and are not surface sensitive. However, the adsorption energies show strong dependence on the surface structure and the cluster size. The adsorption energies are shown to converge very well for the large clusters, and the activity of the Cu planes for formate adsorption is in the order of Cu(110)>Cu(100)>Cu(111), the same as that observed experimentally for methanol synthesis. Regardless of the basis set, cluster size and surface structure, all results show an anionic formate adsorption species. The chemisorption mechanism and the local structure of formate on the three copper surfaces are essentially very similar. Some discussion about cluster modeling is presented.

Density-functional theory (B3LYP functional) is used to investigate the ionization potentials and electron affinities of the DNA and RNA nucleotide bases. For the first time, anions lying lower in energy than the neutral species have been calculated for both thymine and uracil (i.e., positive adiabatic electron affinities). Additionally, the calculations show that anion formation leads to significant geometrical changes to the nucleobases. This is a very important finding as previous calculations have indicated that the anions are very similar in geometry to the neutral species and reported negative valence adiabatic electron affinities.

The effects of the successive addition of alkyl substituents (methyl and reduced rings) on the excited states of naphthalene are reported. The calculated electronic states of all the reduced derivatives with two, three, and four substituents are compared with the excited states of their methylated analogues. The excited states of several reduced derivatives with seven and eight substituents are also studied. The AM1 method was used to optimize the geometry of 57 naphthalene derivatives, and excited states were calculated with the ZINDO/S (INDO/S) method. ZINDO/S calculations on naphthalene gave excited states in better agreement with experimental results than with results of other semiempirical (CNDO/S and CNDOL) and ab initio (CIS, TD-HF, and TD-DFT) methods. Successive alkyl substitutions are accompanied by bathochromic displacements of the UV-visible bands, since the occupied orbitals are raised in energy more than the unoccupied orbitals. However, not all available substituent positions in naphthalene alter its orbital energy distribution in the same way when they are occupied by alkyl substituents. Distortion from planarity of the naphthalene skeleton of some reduced derivatives is the cause of “anomalous” bathochromic displacements of the absorption bands.

The geometries, spin density distributions, and hyperfine coupling constants (HFCC) in possible radiation products of guanine are studied through the use of density functional theory. Numerous hydrogenated, dehydrogenated, and hydroxylated radicals are ex

Possible radical reaction products observed when subjecting monohydrate crystals of the DNA base cytosineto ionizing radiation are characterized and analyzed by means of density functional theory. Comparison ismade with data from a recently published detailed ESR and ENDOR study by Sagstuen et al. (Sagstuen, E.;Hole, E. O.; Nelson, W. H.; Close, D. M. J. Phys. Chem. 1992, 96, 8269), as well as earlier studies onmethylcytosine and cytidine monophosphates. For cytosine monohydrate it is found, when comparing computedand measured radical hyperfine coupling constants, that products other than those initially assumed are possiblybeing formed. Instead of the original model that irradiation leads to the net reaction of dehydrogenation atthe N1 position of one cytosine molecule and hydrogenation at the N3 position of a second cytosine, wepresent an alternative mechanism where water is involved in the process. This alternative mechanism leadsto the formation of N3 hydrogenation and C5 hydroxylation net products, as the main reactions. Not only dothe hyperfine couplings provide a better match for the latter but they are also energetically favored over thefirst mechanism.

Quantum-chemical studies (UMP2/6-311G*//UHF/6-311G*) on a series of phosphenium and arsenium derivatives confirm singlet ground states and reveal an unexpected model for the bonding in their lowest triplet state. Models of the novel solid-state dimer structures that are experimentally observed for some arsolanium cations reveal large positive dimerization energies (P, 3, 277 kJ/mol; As, 7, 207 kJ/mol), implying that the observed dimers are imposed by crystal-packing phenomena. The surprising contrast observed in the butadiene cycloaddition reactivities for phosphenium and arsenium cations are understood in terms of the calculated absolute energies of the observed structural arrangements for the cycloadducts in each case; the cheletropic adduct 4 is 52 kJ/mol more stable than the Diels−Alder adduct for the phospholanium cation, while in the case of the arsolanium cation the Diels−Alder adduct 9 is favored by 59 kJ/mol.

The geometries, relative energies, and hyperfine coupling constants of dehydrogenated, hydrogenated, and hydroxylated radiation products, as well as the anion and the cation, of thymine (T), 1-methylthymine (1-MeT), and uracil (U) are calculated through the use of density functional theory. The results for T and 1-MeT are subsequently compared to accurate ENDOR experiments performed by Sagstuen and co-workers (Sagstuen, E.; Hole, E. O.; Nelson, W. H.; Close, D. M. J. Phys. Chem. 1989, 93, 5974 and references therein). The theoretical coupling constants support the experimental assignment of the observed radicals. It is suggested that the hydrogen added to form the O4-hydrogenated product is located at an angle of 50° out of the molecular plane in T. Unfavorable interactions of this hydrogen with the N3 and the methyl hydrogens are shown to lead to this out-of-plane position for O4−H. For the similar radical in 1-MeT, hydrogen bonding in the crystal leads to an in-plane hydrogen position. Notable geometry ...

The molecular quadrupole moments of benzene and naphthalene are calculated using a range of ab initio and density functional methods, with basis sets as large as aug-CC-PVTZ for benzene and CC-PVTZ for naphthalene. The quadrupole moments calculated using Hartree-Fock wavefunctions are lower than the experimentally determined values, and all DFT values are higher than the experimental values. The use of the hybrid B3P86 and B3PW91 functionals, with a large basis set, produce quadrupole moments which are within experimental error for these two small aromatic molecules.

The interactions between polycyclic aromatic hydrocarbons (with up to four rings) and dinitrobenzene have been calculated using semiempirical methods and shown to give poor correlation with experimental stability constants. Quadrupole moments for these molecules have been calculated at the HF/6-31G(d,p) and BLYP/6-31G(d,p) levels of theory. The interaction between polycyclic aromatic hydrocarbons and nitrated benzenes is found to be dependent on the quadrupole moment. Dispersion interactions are estimated to be considerably smaller than quadrupole interactions and not a significant influence on the binding energy. The two methods used show the same trends in the calculated quadrupole moment, and it is shown that a method involving electron correlation may not be necessary for prediction of stability constants.

Dialkylstannylene acetals are organotin intermediates widely used to facilitate regioselective monofunctionalization of diols or polyols by electrophiles. Alkylation is both the slowest and the most useful reaction of these intermediates, and this reaction is markedly accelerated by the addition of nucleophiles to the reaction media, usually cesium fluoride in dimethylformamide (DMF) or tetrabutylammonium iodide or bromide in toluene. The regioselectivity may be influenced by aggregation of the dialkylstannylene acetals into dimers and higher oligomers, and by the addition of these nucleophiles. The stabilities and the geometries of the species potentially involved in these processes were examined by using theoretical chemistry methods with di-n-butyldialkoxytin derivatives as examples and fluoride as the nucleophile. Geometry optimizations were performed at B3LYP/6-31G(d,p) level, and single point energies obtained at the MP2/6-311G(2d,p) level with diffuse functions added for fluorine. The LANL2DZdp basis set with diffuse and polarization functions and its effective core potential were used to describe tin. The addition of fluoride to monomeric di-n-butyldialkoxytin derivatives to give fluoridated monomers is predicted to be strongly exothermic, by 187 to 209 kJ/mol, depending on the alkoxyl group. The fluoridated monomers are calculated to react with monomers exothermically to give monofluoridated dimers, except for the di-t-butoxy derivative. Dimer formation on average is about 20 kJ mol(-1) more exothermic than for the nonfluoridated monomers alone. Monofluoridated monomers strongly prefer to exist as monomers because the difluoridated dimers are estimated to be 209 to 278 kJ mol(-1) less stable at 298 K.

The structures and relative stabilities of the four different forms of hydroxypyridine and hydroxyquinoline (normal, protonated cation, deprotonated anion and zwitterion) in the gas phase have been calculated at the Moller-Plesset (MP) perturbation and coupled-cluster theory levels with basis sets up to 6–31+ G ∗∗ . The solvation free energies of the reactions were treated with the SMx series of aqueous solvation models by Cramer and Truhlar. By combining the PM3-SM3 model for solvation with the MP 2/6–31+ G ∗∗ level treatment for the gass-phase species, it is found that the free energy changes of the proton transfer reactions can be predicted reasonably well.

Properties of the bond critical points, including the electron density and its Laplacian, and distances to bonded nuclei, for all species (reactants, transition states, and products) in the reactions of the hydroxyl radical with the series C2HnF6−nn = 1–6 were calculated using Bader's atoms-in-molecules methodology. The electron density and its Laplacian at the bond critical points correlate with bond strength, as measured by bond dissociation energies. The positions of the bond critical points vary with the electronegativity of surrounding atoms. Charge development in the course of the reactions was monitored using Mulliken population analysis at the HF/6-31G(d), HF/6-311G(d,p)//HF/6-31G(d), MP2/6-311G(d,p)//HF/6-31G(d), and HF/6-311G(d,p)//MP2/6-31G(d,p) levels of theory, and natural population analysis and Bader population analysis at the highest common level of theory, MP2/6-311G(d,p)//HF/6-31G(d). In general, there is a buildup of charge in the transition states, concentrated near the reaction centre, which dissipates somewhat as the reaction proceeds to products. The description of charge transfer varies somewhat with the three methods. Key words: topological properties, atomic charges, charge development, reactions of the hydroxyl radical with fluorinated ethanes.