Lewis Acid-Mediated Cyclization of Allenyl Aryl Ketones.

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 BF were low in most instances due mainly to competitive destruction of the substrates. With In(OTf), there was less decomposition, and the yields of the cyclized product were much higher, but only for substrates with electron-donating substituents.

An Electron Density Source-Function Study of DNA Base Pairs in Their Neutral and Ionized Ground States.

The source function (SF) decomposes the electron density at any point into contributions from all other points in the molecule, complex, or crystal. The SF "illuminates" those regions in a molecule that most contribute to the electron density at a point of reference. When this point of reference is the bond critical point (BCP), a commonly used surrogate of chemical bonding, then the SF analysis at an atomic resolution within the framework of Bader's Quantum Theory of Atoms in Molecules returns the contribution of each atom in the system to the electron density at that BCP.

Computational Study of Engineered Cytochrome P450-Catalyzed C-H Amination: The Origin of the Regio- and Stereoselectivity.

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.

Computational Examination of (4 + 3) versus (3 + 2) Cycloaddition in the Interception of Nazarov Reactions of Allenyl Vinyl Ketones by Dienes.

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.

Balancing Exchange Mixing in Density-Functional Approximations for Iron Porphyrin.

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.

The Importance of the MM Environment and the Selection of the QM Method in QM/MM Calculations: Applications to Enzymatic Reactions.

In this chapter, we discuss the influence of an anisotropic protein environment on the reaction mechanisms of saccharopine reductase and uroporphyrinogen decarboxylase, respectively, via the use of a quantum mechanical and molecular mechanical (QM/MM) approach. In addition, we discuss the importance of selecting a suitable DFT functional to be used in a QM/MM study of a key intermediate in the mechanism of 8R-lipoxygenase, a nonheme iron enzyme. In the case of saccharopine reductase, while the enzyme utilizes a substrate-assisted catalytic pathway, it was found that only through treating the polarizing effect of the active site, via the use of an electronic embedding formalism, was agreement with experimental kinetic data obtained.

Density Functional Theory Study of BF3-Mediated Additions of Enols and [(Trimethylsilyl)oxy]alkenes to an Oxyallyl Cation: Homologous Mukaiyama Reactions.

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.

Molecular docking study of macrocycles as Fk506-binding protein inhibitors.

To prepare for future resistance, new methods are being explored for novel treatment of malaria. The current work uses high performance docking methods to model different substrates binding into the active sites of varying Homo sapien and Plasmodium peptidyl-prolyl cis/trans isomerase enzymes and compares their subsequent docking scores. This approach has shown that the substrates ILS-920 and WYE-592 will bind less-favourably with hFKBP12 and PfFKBP35 compared to a competing substrate rapamycin; however, the binding appears to be more favourable in PvFKBP35.

Role of fluoride in accelerating the reactions of dialkylstannylene acetals.

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.

Assessment of several DFT functionals in calculation of the reduction potentials for Ni-, Pd-, and Pt-bis-ethylene-1,2-dithiolene and -diselenolene complexes.

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.

Torquoselectivity in the Nazarov reactions of allenyl vinyl ketones.

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 catalytic formation of leukotriene C4: a critical step in inflammatory processes.

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.

Effect of amino acid ligands on the structure of iron porphyrins and their ability to bind oxygen.

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 one-electron oxidation of a dithiolate molecule: the importance of chemical intuition.

A series of nine commonly used density functional methods were assessed to accurately predict the oxidation potential of the (C2H2S2(-2)/C2H2S2(•-)) redox couple. It was found that due to their greater tendency for charge delocalization the GGA functionals predict a structure where the radical electron is delocalized within the alkene backbone of C2H2S2(•-), whereas the hybrid functionals and the reference QCISD/cc-pVTZ predict that the radical electron remains localized on the sulfurs. However, chemical intuition suggests that the results obtained with the GGA functionals should be correct.

Changing weak halogen bonds into strong ones through cooperativity with beryllium bonds.

The mutual interaction between beryllium bonds and halogen bonds within H2Be···FCl···Base complexes, where Base includes a wide set of N- and O-containing Lewis bases, has been studied at the M06-2X/6-31+G(d,p) level of theory. The reliability of this theoretical model was assessed by comparison with ab initio CCSD/aug-cc-pVTZ reference calculations. Cooperative effects were investigated within the framework of the atoms in molecules theory (AIM) by analyzing the topology of the electron density and the changes in the atomic energy components.

The one-electron reduction of dithiolate and diselenolate ligands.

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.

How do nucleophiles accelerate the reactions of dialkylstannylene acetals? The effects of adding fluoride to dialkoxydi-n-butylstannanes.

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.

Hydrogen bond cooperativity in water hexamers: atomic energy perspective of local stabilities.

Atomic energies are used to describe local stability in eight low-lying water hexamers: prism, cage, boat 1, boat 2, bag, chair, book 1, and book 2. The energies are evaluated using the quantum theory of atoms in molecules (QTAIM) at MP2/aug-cc-pVTZ geometries. It is found that the simple, stabilizing cooperativity observed in linear hydrogen-bonded water systems is diminished as clusters move from nearly planar to three-dimensional structures.

Dramatic substituent effects on the mechanisms of nucleophilic attack on Se-S bridges.

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.

Revealing unexpected mechanisms for nucleophilic attack on S-S and Se-Se bridges.

The reactivity of disulfide and diselenide derivatives towards F(-) and CN(-) nucleophiles has been investigated by means of B3PW91/6-311+G(2df,p) calculations. This theoretical survey shows that these processes, in contrast with the generally accepted view of disulfide and diselenide linkages, do not always lead to SS or SeSe bond cleavage. In fact, SS or SeSe bond fission is the most favorable process only when the substituents attached to the S or the Se atoms are not very electronegative.

Mechanism of the Reduction of an Oxidized Glutathione Peroxidase Mimic with Thiols.

N,N-dimethylbenzylamine-2-selenol is a well-known, efficient glutathione peroxidase mimic. This compound reduces peroxides through a three-step catalytic mechanism, of which the first step has been well-characterized computationally. The mechanism for the reaction of N,N-dimethylbenzylamine-2-selenenic acid with a thiol, the second step in the catalytic cycle, is studied using reliable electronic structure techniques.

Cooperativity between hydrogen bonds and beryllium bonds in (H2O)(n)BeX2 (n = 1-3, X = H, F) complexes. A new perspective.

The interaction of BeX(2) (X = H, F) with water molecules has been analyzed at the B3LYP/6-311+G(3df,2p)//B3LYP/6-311+G(d,p) level of theory. The formation of strong beryllium bonds between water molecules and the BeX(2) derivative triggers significant electron density redistribution within the whole system, resulting in significant changes in the proton donor and proton acceptor capacity of the water molecules involved. Hence, significant cooperative and anti-cooperative effects are present, explaining why there is no case in which the global minimum corresponds to a tetracoordinated beryllium atom.

Self-assembling ADADA helices formed by hydrogen bonding.

A computational investigation of the electronic properties of an experimentally prepared ADADA helix indicates that the helix is held together with four strong hydrogen bonds as well as many other weak interactions. Determination of the electronic energy changes, as well as thermodynamic parameters, suggests that helix formation is a favorable process, driven by the formation of the hydrogen bonds. For instance, the unsubstituted helix has an electronic binding energy of -85.