A Selective and Functional Group-Tolerant Ruthenium-Catalyzed Olefin Metathesis/Transfer Hydrogenation Tandem Sequence Using Formic Acid as Hydrogen Source.

A ruthenium-catalyzed transfer hydrogenation of olefins utilizing formic acid as a hydrogen donor is described. The application of commercially available alkylidene ruthenium complexes opens access to attractive C(sp3)-C(sp3) bond formation in an olefin metathesis/transfer hydrogenation sequence under tandem catalysis conditions. High chemoselectivity of the developed methodology provides a remarkable synthetic tool for the reduction of various functionalized alkenes under mild reaction conditions. The developed methodology is applied for the formal synthesis of the drugs pentoxyverine and bencyclane.

Electrophilicity of oxalic acid monomer is enhanced in the dimer by intermolecular proton transfer.

We have analyzed the effect of excess electron attachment on the network of hydrogen bonds in the oxalic acid dimer (OA)2. The most stable anionic structures may be viewed as complexes of a neutral hydrogenated moiety HOA˙ coordinated to an anionic deprotonated moiety (OA-H)-. HOA˙ acts as a double proton donor and (OA-H)- as a double proton acceptor. Thus the excess electron attachment drives intermolecular proton transfer. We have identified several cyclic hydrogen bonded structures of (OA)2-. Their stability has been analyzed in terms of the stability of the involved conformers, the energetic penalty for deformation of these conformers to the geometry of the dimer, and the two-body interaction energy between the deformed HOA˙ and (OA-H)-. There are at least seven isomers of (OA)2- with stabilization energies in the range of 1.26-1.39 eV. These energies are dominated by attractive two-body interaction energies. The anions are vertically bound electronically by 3.0-3.4 eV and adiabatically bound by at least 1.6 eV. The computational predictions are consistent with the anion photoelectron spectrum of (OA)2-. The spectrum consists of a broad feature, with an onset of 2.5 eV and spanning to 4.3 eV. The electron vertical detachment energy (VDE) is assigned to be 3.3 eV.

Different Conformations of 2'-Deoxycytidine in the Gas and Solid Phases: Competition between Intra- and Intermolecular Hydrogen Bonds.

Computational results have been reported for 2'-deoxycytidine (dC), its gas phase isomers, tautomers, and their conformers, as well as for the crystalline phase. In addition to the neutral gas phase molecules, we have also considered associated radical anions and cations. The structural calculations were performed at the density functional and MP2 levels of theory. Vertical electron ionization energies and excess electron binding energies were determined using electron propagator theory. The α-anomer proved to be more stable by a fraction of kcal/mol than the biologically relevant canonical ß-anomer. The conformational space of canonical dC has been systematically probed. dC in the crystalline phase or DNA structures favors canonical anti conformations. These structures were used in past computational studies to model gas phase characteristics of dC. Our findings indicate, however, that the gas phase dC favors syn conformations. It has repercussions for earlier interpretations of gas phase experimental results based on these computational results. The thermodynamic dominance of syn conformations results from the formation of an intramolecular O5'-H13···O2 hydrogen bond. The IR spectra of the most stable syn and anti canonical conformers differ markedly in the region of frequencies corresponding to NH/OH stretching modes. The MP2 value of deprotonation enthalpy of dC of 1411.7 kJ/mol is in very good agreement with the experimental value of 1409 ± 2.5 kJ/mol. The most stable valence anions are characterized by electron vertical detachment energies (VDE) in the 0.8-1.0 eV range, in good agreement with the experimental VDE of 0.87 eV. The barrier for the glycosidic bond cleavage is significant in the neutral canonical dC, 40.0 kcal/mol, and it is reduced to 22 and 16 kcal/mol for the anionic and cationic radicals of dC, respectively. The cleavage reaction is exothermic by 4 kcal/mol for dC- and endothermic by 7 and 9 kcal/mol for dC+ and dC, respectively. We decomposed the crystal cohesive energy into repulsive one-body terms associated with the syn-anti conformational changes, and the attractive intermolecular interaction term. We exposed that the syn-anti conformational changes are very favorable for intermolecular interactions; in particular they make the imino-amino side of the cytosine residue accessible to intermolecular interactions.

Importance of Time Scale and Local Environment in Electron-Driven Proton Transfer. The Anion of Acetoacetic Acid.

Anion photoelectron spectroscopy (PES) and electron energy-loss spectroscopy (EELS) probe different regions of the anionic potential energy surface. These complementary techniques provided information about anionic states of acetoacetic acid (AA). Electronic structure calculations facilitated the identification of the most stable tautomers and conformers for both neutral and anionic AA and determined their relative stabilities and excess electron binding energies. The most stable conformers of the neutral keto and enol tautomers differ by less than 1 kcal/mol in terms of electronic energies corrected for zero-point vibrations. Thermal effects favor these conformers of the keto tautomer, which do not support an intramolecular hydrogen bond between the keto and the carboxylic groups. The valence anion displays a distinct minimum which results from proton transfer from the carboxylic to the keto group; thus, we name it an ol structure. The minimum is characterized by a short intramolecular hydrogen bond, a significant electron vertical detachment energy of 2.38 eV, but a modest adiabatic electron affinity of 0.33 eV. The valence anion was identified in the anion PES experiments, and the measured electron vertical detachment energy of 2.30 eV is in good agreement with our computational prediction. We conclude that binding an excess electron in a π* valence orbital changes the localization of a proton in the fully relaxed structure of the AA(-) anion. The results of EELS experiments do not provide evidence for an ultrarapid proton transfer in the lowest π* resonance of AA(-), which would be capable of competing with electron autodetachment. This observation is consistent with our computational results, indicating that major gas-phase conformers and tautomers of neutral AA do not support the intramolecular hydrogen bond that would facilitate ultrarapid proton transfer and formation of the ol valence anion. This is confirmed by our vibrational EELS spectrum. Anions formed by vertical electron attachment to dominant neutrals undergo electron autodetachment with or without vibrational excitations but are unable to relax to the ol structure on a time scale fast enough to compete with autodetachment.

Intermolecular interactions between molecules in various conformational states: the dimer of oxalic acid.

We considered stability of the dimer of oxalic acid. The global minimum energy structure identified by us is stabilized by two inter- and four intramolecular hydrogen bonds, whereas the most stable structure identified in previous studies is supported by two inter- and three intramolecular hydrogen bonds. The latter structure proves to be less stable by 25 meV than the former. The global minimum stability results from a balancing act between a moderately attractive two-body interaction energy and small repulsive one-body terms. We have analyzed zero-point vibrational corrections to the stability of various conformers of oxalic acid and their dimers. We have found that minimum energy structures with the most stabilizing sets of hydrogen bonds have the largest zero-point vibrational energy, contrary to a naive anticipation based on red shifts of OH stretching modes involved in hydrogen bonds.

Communication: Remarkable electrophilicity of the oxalic acid monomer: an anion photoelectron spectroscopy and theoretical study.

Our experimental and computational results demonstrate an unusual electrophilicity of oxalic acid, the simplest dicarboxylic acid. The monomer is characterized by an adiabatic electron affinity and electron vertical detachment energy of 0.72 and 1.08 eV (±0.05 eV), respectively. The electrophilicity results primarily from the bonding carbon-carbon interaction in the singly occupied molecular orbital of the anion, but it is further enhanced by intramolecular hydrogen bonds. The well-resolved structure in the photoelectron spectrum is reproduced theoretically, based on Franck-Condon factors for the vibronic anion → neutral transitions.

Discovery of Most Stable Structures of Neutral and Anionic Phenylalanine through Automated Scanning of Tautomeric and Conformational Spaces.

We have developed a software tool for combinatorial generation of tautomers and conformers of small molecules. We have demonstrated it by performing a systematic search for the most stable structures of neutral and anionic phenylalanine (Phe) using electronic structure methods. For the neutral canonical tautomer we found out that the conformers with and without the intramolecular (O)H···NH2 hydrogen bond are similarly stable, within the error bars of our method. A unique IR signature of the conformer without the hydrogen bond has been identified. We also considered anions of Phe, both valence type and dipole-bound. We have found out that tautomers resulting from proton transfer from the carboxylic OH to the phenyl ring do support valence anions that are vertically strongly bound, with electron vertical detachment energies (VDE) in a range of 3.2-3.5 eV. The most stable conformer of these valence anions remains adiabatically unbound with respect to the canonical neutral by only 2.17 kcal/mol at the CCSD(T)/aug-cc-pVDZ level. On the basis of our past experience with valence anions of nucleic acid bases, we suggest that the valence anions of Phe identified in this report can be observed experimentally. The most stable conformer of canonical Phe is characterized by an adiabatic electron affinity of 53 meV (a dipole-bound state).

Is electronegativity a useful descriptor for the pseudo-alkali metal NH4?

Molecular ions in the form of "pseudo-atoms" are common structural motifs in chemistry, with properties that are transferrable between different compounds. We have determined one such property--the electronegativity--for the "pseudo-alkali metal" ammonium (NH(4)), and evaluated its reliability as a descriptor versus the electronegativities of the alkali metals. The computed properties of ammonium's binary complexes with astatine and of selected borohydrides confirm the similarity of NH(4) to the alkali metal atoms, although the electronegativity of NH(4) is relatively large in comparison to its cationic radius. We have paid particular attention to the molecular properties of ammonium (angular anisotropy, geometric relaxation and reactivity), which can cause deviations from the behaviour expected of a conceptual "true alkali metal" with this electronegativity. These deviations allow for the discrimination of effects associated with the molecular nature of NH(4).

SSC: a tool for constructing libraries for systematic screening of conformers.

Even a relatively small molecule with 10-20 atoms might have a few local minima, which correspond to different conformers. The number of local minima quickly increases with molecular size and the most common algorithms, driven by calculated forces, frequently identify a minimum, which is closest to the initial structure, rather than the most stable conformer. Here we discuss how to perform a systematic search of the conformational space for a chain-like molecule. Our approach is fully automated and a user has control which chemical bonds will be probed and with which increments. Moreover, whole fragments of the molecule, which are adjacent to each selected rotational bond, are rotated in a properly selected cylindrical coordinate system and unchemical hybridizations and some "clashes" between neighboring groups, which are common when standard Z-matrices are used, are avoided. A library of potentially relevant conformers is created with a tool, which we call SSC, denoting Systematic Screening of Conformers. Each member of the library is prescreened at a predefined level of theory and the most promising conformers are identified. Finally, they are further evaluated at a higher level of theory to identify the most stable structures and their physicochemical properties. As an example, we demonstrate the results of this approach for 2'-deoxycytidine.

The anionic (9-methyladenine)-(1-methylthymine) base pair solvated by formic acid. A computational and photoelectron spectroscopy study.

The photoelectron spectrum for (1-methylthymine)-(9-methyladenine)...(formic acid) (1MT-9MA...FA) anions with the maximum at ca. 1.87 eV was recorded with 2.54 eV photons and interpreted through the quantum-chemical modeling carried out at the B3LYP/6-31+G(d,p) level. The relative free energies of the anions and their calculated vertical detachment energies suggest that only seven anionic structures contribute to the observed PES signal. We demonstrate that electron binding to the (1MT-9MA...FA) complex can trigger intermolecular proton transfer from formic acid, leading to the strong stabilization of the resulting radical anion. The SOMO distribution indicates that an excess electron may localize not only on the pyrimidine but also on the purine moiety. The biological context of DNA-environment interactions concerning the formation of single-strand breaks induced by excess electrons has been briefly discussed.

Theoretical investigations on the formation and dehydrogenation reaction pathways of H(NH2BH2)(n)H (n = 1-4) oligomers: importance of dihydrogen interactions.

The H(NH(2)BH(2))(n)H oligomers are possible products from dehydrogenation of ammonia borane (NH(3)BH(3)) and ammonium borohydride (NH(4)BH(4)), which belong to a class of boron-nitrogen-hydrogen (BNH(x)) compounds that are promising materials for chemical hydrogen storage. Understanding the kinetics and reaction pathways of formation of these oligomers and their further dehydrogenation is essential for developing BNH(x)-based hydrogen storage materials. We have performed computational modeling using density functional theory (DFT), ab initio wave function theory, and Car-Parrinello molecular dynamics (CPMD) simulations on the energetics and formation pathways for the H(NH(2)BH(2))(n)H (n = 1-4) oligomers, polyaminoborane (PAB), from NH(3)BH(3) monomers and the subsequent dehydrogenation steps to form polyiminoborane (PIB). Through computational transition state searches and evaluation of the intrinsic reaction coordinates, we have investigated the B-N bond cleavage, the reactions of NH(3)BH(3) molecule with intermediates, dihydrogen release through intra- and intermolecular hydrogen transfer, dehydrocoupling/cyclization of the oligomers, and the dimerization of NH(3)BH(3) molecules. We find that the formation of H(NH(2)BH(2))(n+1)H oligomers occurs first through reactions of the H(NH(2)BH(2))(n)H oligomers with BH(3) followed by reactions with NH(3) and the release of H(2), where the BH(3) and NH(3) intermediates are formed through dissociation of NH(3)BH(3). We also find that the dimerization of the NH(3)BH(3) molecules to form cyclic c-(NH(2)BH(2))(2) is slightly exothermic, with an unexpected transition state that leads to the simultaneous release of two H(2) molecules. The dehydrogenations of the oligomers are also exothermic, typically by less than 10 kcal/(mol of H(2)), with the largest exothermicity for n = 3. The transition state search shows that the one-step direct dehydrocoupling cyclization of the oligomers is not a favored pathway because of high activation barriers. The dihydrogen bonding, in which protic (H(N)) hydrogens interact with hydridic (H(B)) hydrogens, plays a vital role in stabilizing different structures of the reactants, transition states, and products. The dihydrogen interaction (DHI) within the R-BH(2)(eta(2)-H(2)) moiety accounts for both the formation mechanisms of the oligomers and for the dehydrogenation of ammonia borane.

Combinatorial-computational-chemoinformatics (C3) approach to finding and analyzing low-energy tautomers.

Finding the most stable tautomer or a set of low-energy tautomers of molecules is critical in many aspects of molecular modelling or virtual screening experiments. Enumeration of low-energy tautomers of neutral molecules in the gas-phase or typical solvents can be performed by applying available organic chemistry knowledge. This kind of enumeration is implemented in a number of software packages and it is relatively reliable. However, in esoteric cases such as charged molecules in uncommon, non-aqueous solvents there is simply not enough available knowledge to make reliable predictions of low energy tautomers. Over the last few years we have been developing an approach to address the latter problem and we successfully applied it to discover the most stable anionic tautomers of nucleic acid bases that might be involved in the process of DNA damage by low-energy electrons and in charge transfer through DNA. The approach involves three steps: (1) combinatorial generation of a library of tautomers, (2) energy-based screening of the library using electronic structure methods, and (3) analysis of the information generated in step (2). In steps 1-3 we employ combinatorial, computational and chemoinformatics techniques, respectively. Therefore, this hybrid approach is named "Combinatorial*Computational*Chemoinformatics", or just abbreviated as C(3) (or C-cube) approach. This article summarizes our developments and most interesting methodological aspects of the C(3) approach. It can serve as an example how to identify the most stable tautomers of molecular systems for which common chemical knowledge had not been sufficient to make definite predictions.

Electrostatic potential maps of damaged DNA studied by image analysis tools. 8-Oxoguanine and abasic site lesions.

Changes of electrostatic potential around the DNA molecule resulting from chemical modifications of nucleotides may play a role in enzymatic recognition of damaged sites. The electrostatic potential around the DNA fragments containing either the intact guanine-cytosine pair or 8-oxoguanine-cytosine or the guanine-abasic site was projected on a cylindrical surface around the double helix. The 2D maps of EP of intact and damaged DNA fragments were compared using image analysis methods. Occurrence of abasic site and 8-oxoguanine lesions were found to be reflected in the EP maps. In the case of the 8-oxoguanine lesion, the two phosphate groups and countercations of the damaged strand are moved away from the lesion in opposite directions, whereas they are moved in the same direction in the case of the abasic site lesion. The characteristic features of 8-oxoguanine lesion might be identified in the major groove, whereas the features of abasic site lesion the minor groove.

Comparison of some representative density functional theory and wave function theory methods for the studies of amino acids.

Energies of different conformers of 22 amino acid molecules and their protonated and deprotonated species were calculated by some density functional theory (DFT; SVWN, B3LYP, B3PW91, MPWB1K, BHandHLYP) and wave function theory (WFT; HF, MP2) methods with the 6-311++G(d,p) basis set to obtain the relative conformer energies, vertical electron detachment energies, deprotonation energies, and proton affinities. Taking the CCSD/6-311++G(d,p) results as the references, the performances of the tested DFT and WFT methods for amino acids with various intramolecular hydrogen bonds were determined. The BHandHLYP method was the best overall performer among the tested DFT methods, and its accuracy was even better than that of the more expensive MP2 method. The computational dependencies of the five DFT methods and the HF and MP2 methods on the basis sets were further examined with the 6-31G(d,p), 6-311++G(d,p), aug-cc-pVDZ, 6-311++G(2df,p), and aug-cc-pVTZ basis sets. The differences between the small and large basis set results have decreased quickly for the hybrid generalized gradient approximation (GGA) methods. The basis set convergence of the MP2 results has been, however, very slow. Considering both the cost and the accuracy, the BHandHLYP functional with the 6-311++G(d,p) basis set is the best choice for the amino acid systems that are rich in hydrogen bonds.

Photoelectron spectrum of valence anions of uracil and first-principles calculations of excess electron binding energies.

The photoelectron spectrum (PES) of the uracil anion is reported and discussed from the perspective of quantum chemical calculations of the vertical detachment energies (VDEs) of the anions of various tautomers of uracil. The PES peak maximum is found at an electron binding energy of 2.4 eV, and the width of the main feature suggests that the parent anions are in a valence rather than a dipole-bound state. The canonical tautomer as well as four tautomers that result from proton transfer from an NH group to a C atom were investigated computationally. At the Hartree-Fock and second-order Moller-Plesset perturbation theory levels, the adiabatic electron affinity (AEA) and the VDE have been converged to the limit of a complete basis set to within +/-1 meV. Post-MP2 electron-correlation effects have been determined at the coupled-cluster level of theory including single, double, and noniterative triple excitations. The quantum chemical calculations suggest that the most stable valence anion of uracil is the anion of a tautomer that results from a proton transfer from N1H to C5. It is characterized by an AEA of 135 meV and a VDE of 1.38 eV. The peak maximum is as much as 1 eV larger, however, and the photoelectron intensity is only very weak at 1.38 eV. The PES does not lend support either to the valence anion of the canonical tautomer, which is the second most stable anion, and whose VDE is computed at about 0.60 eV. Agreement between the peak maximum and the computed VDE is only found for the third most stable tautomer, which shows an AEA of approximately -0.1 eV and a VDE of 2.58 eV. This tautomer results from a proton transfer from N3H to C5. The results illustrate that the characteristics of biomolecular anions are highly dependent on their tautomeric form. If indeed the third most stable anion is observed in the experiment, then it remains an open question why and how this species is formed under the given conditions.

Solvation free energies of molecules. The most stable anionic tautomers of uracil.

Anionic states of nucleic acid bases are suspected to play a role in the radiation damage processes of DNA. Our recent studies suggested that the excess electron attachment to the nucleic acid bases can stabilize some rare tautomers, i.e. imine-enamine tautomers and other tautomers with a proton being transferred from nitrogen sites to carbon sites (with respect to the canonical tautomer). So far, these new anionic tautomers have been characterized by the gas-phase electronic structure calculations and photoelectron spectroscopy experiments. In the current contribution we explore the effect of water solvation on the stability of the new anionic tautomers of uracil. The accurate free energies of solvation are calculated in a two step approach. The major contribution was calculated using the classical free-energy perturbation adiabatic-charging approach, where it is assumed that the solvated molecule has the charge distribution given by the polarizable continuum model. In the second step the free energy of solvation is refined by taking into account the real, average solvent charge distribution. This is done using our accelerated QM/MM simulations, where the QM energy of the solute is calculated in the mean potential averaged over many MD steps. We found that in water solution three of the recently identified anionic tautomers are 6.5-3.6 kcal mol(-1) more stable than the anion of the canonical tautomer.

Effect of excess electron and one water molecule on relative stability of the canonical and zwitterionic tautomers of glycine.

The anionic and neutral complexes of glycine with water were studied at at the coupled cluster level of theory with single, double, and perturbative triple excitations. The most stable neutral complex has a relatively small dipole moment (1.74 D) and does not bind an electron. Other neutral complexes involve a polar conformer of canonical glycine and support dipole-bound anionic states. The most stable anion is characterized by an electron vertical detachment energy of 1576 cm(-1), in excellent agreement with the experimental result of 1573 cm(-1). The (Gly.H(2)O)(-) complex supports local minima, in which the zwitterionic glycine is stabilized by one water and one excess electron. They are, however, neither thermodynamically nor kinetically stable with respect to the dipole-bound states based on the canonical tautomers of glycine. The electron correlation contributions to excess electron binding energies are important, in particular, for nonzwitterionic complexes. Our results indicate that the condensation energies for Gly((0,-))+H(2)O-->(Gly.H(2)O)((0,-)) are larger than the adiabatic electron affinity of Gly.H(2)O. The above results imply that collisions of Gly(-) with H(2)O might effectively remove Gly(-) from the ion distribution. This might explain why formation of Gly(-) and (Gly.H(2)O)(-) is very sensitive to source conditions. We analyzed shifts in stretching mode frequencies that develop upon formation of intra- and intermolecular hydrogen bonds and an excess electron attachment. The position of the main peak and a vibrational structure in the photoelectron spectroscopy spectrum of (Gly.H(2)O)(-) are well reproduced by our theoretical results.

Electron-driven acid-base chemistry: proton transfer from hydrogen chloride to ammonia.

In contrast to widely familiar acid-base behavior in solution, single molecules of NH3 and HCl do not react to form the ionic salt, NH+4Cl-, in isolation. We applied anion photoelectron spectroscopy and ab initio theory to investigate the interaction of an excess electron with the hydrogen-bonded complex NH3...HCl. Our results show that an excess electron induces this complex to form the ionic salt. We propose a mechanism that proceeds through a dipole-bound state to form the negative ion of ionic ammonium chloride, a species that can also be characterized as a deformed Rydberg radical, NH4, polarized by a chloride anion, Cl-.

Cylindrical projection of electrostatic potential and image analysis tools for damaged DNA: the substitution of thymine with thymine glycol.

Changes of electrostatic potential around the DNA molecule resulting from chemical modifications of nucleotides may play a role in enzymatic recognition of damaged sites. Effects of chemical modifications of nucleotides on the structure of DNA have been characterized through electronic structure computations. Quantum mechanical structural optimizations of fragments of five pairs of nucleotides with thymine or thymine glycol were performed at the density functional level of theory with a B3LYP exchange-correlation functional and 6-31G(d,p) basis sets. The electrostatic potential (EP) around DNA fragments was projected on a cylindrical surface around the double helix. The 2D maps of EP of intact and damaged DNA fragments were compared using image analysis methods to identify and measure modifications of the EP that result from the occurrence of thymine glycol. It was found that distortions of phosphate groups and displacements of the accompanying countercations by up to approximately 0.5 angstroms along the axis of DNA are clearly reflected in the EP maps. Modifications of the EP in the major groove of DNA near the damaged site are also reported.

Structure and singly occupied molecular orbital analysis of anionic tautomers of guanine.

Recently, we reported the discovery of adiabatically bound anions of guanine that might be involved in the processes of DNA damage by low-energy electrons and in charge transfer through DNA. These anions correspond to some tautomers that have been ignored thus far. They were identified using a hybrid quantum mechanical-combinatorial approach in which an energy-based screening was performed on the library of 499 tautomers with their relative energies calculated with quantum chemistry methods. In the current study, we analyze the adiabatically bound anions of guanine in two aspects: (1) the geometries and excess electron distributions are analyzed and compared with anions of the most stable neutrals to identify the sources of stability; (2) the chemical space of guanine tautomers is explored to verify if these new tautomers are contained in a particular subspace of the tautomeric space. The first task involves the development of novel approaches-the quantum chemical data like electron density, orbital, and information on its bonding/antibonding character are coded into holograms and analyzed using chemoinformatics techniques. The second task is completed using substructure analysis and clustering techniques performed on molecules represented by 2D fingerprints. The major conclusion is that the high stability of adiabatically bound anions originates from the bonding character of the pi orbital occupied by the excess electron. This compensates for the antibonding character that usually causes significant buckling of the ring. Also, the excess electron is more homogenously distributed over both rings than in the case of anions of the most stable neutral species. In terms of 2D substructure, the most stable anionic tautomers generally have additional hydrogen atoms at C8 and/or C2 and they do not have hydrogen atoms attached to C4, C5, and C6. They also form an "island of stability" in the tautomeric space of guanine.