Chiral Diselenophosphoric Acids for Ion Pair Catalysis: A Novel Approach to Enhance Both Proton Donating and Proton Accepting Properties.

The activation of poorly reactive substrates via strong chiral acids is a central topic in asymmetric ion pair catalysis these days. Despite highly successful scaffolds such as N-triflylphosphoramides, these catalysts either lack C2-symmetry or provide multiple H-bond acceptor sites, leading to lower ee values for certain reactions. We present BINOL-based diselenophosphoric acids (DSA) as an extremely promising alternative. Using an intertwined approach of synthesis and NMR studies, we developed a synthetic approach to DSA with up to 98% NMR yield. The obtained acids provide both very high proton donor and proton acceptor properties, a bifunctionality, which is key to catalytic applications. Indeed, first reactivity test proved the much higher acidity of DSA and its ability to initiate Mukaiyama-Mannich reaction and protodesilylation of silyl ethers. Together with their C2-symmetry, the single donor and single acceptor situation, the decreased tendency of self-association, and the straightforward synthesis with potential 3,3'-substitution, the DSA provide all features ideal for the further development of ion pair catalysis.

Charge Relay Without Proton Transfer: Coupling of Two Short Hydrogen Bonds via Imidazole in Models of Catalytic Triad of Serine Protease Active Site.

A homologous series of 20 substituted alcohol-imidazole-acetate model complexes imitating the charge relay system in Ser-His-Asp catalytic triad of serine proteases is considered quantum-chemically. We show qualitatively that the geometries of alcohol-imidazole and imidazole-acetate short hydrogen bonds are strongly coupled via the central imidazole and such complexes are capable of effectively relaying the charge from acetate to alcohol moiety upon relatively small concerted proton displacements. We hypothesize an alternative catalytic mechanism of serine proteases that does not require two complete proton transfers or hydrogen bond breakage between Ser and His residues.

NMR detection of the strained metallacycles in organolithiums: theoretical study.

For the first time through quantum chemistry methods, the effective use of 1JCLi spin-spin coupling constants as descriptors for assessing the formation of strained metallacycles is demonstrated. Both acyclic organolithiums and 3- to 7-membered metallacycles are examined. 80 organolithium compounds, including both monomeric and dimeric species, with ligands containing fluorine, nitrogen, oxygen, and carbon (in the form of carbanions), are tested. In general, the 1JCLi values below 12 Hz for monomeric species and below 6 Hz for dimeric species serve as clear indicators of strained monomeric metallacycle formation (for 6Li nuclei). The primary contributor to the overall 1JCLi value is the Fermi-contact term, which correlates directly with the carbon-lithium interatomic distance and allows to distinguish between dimers and monomers.

Mutual influence of non-covalent interactions formed by imidazole: A systematic quantum-chemical study.

Imidazole is a five-membered heterocycle that is part of a number of biologically important molecules such as the amino acid histidine and the hormone histamine. Imidazole has a unique ability to participate in a variety of non-covalent interactions involving the NH group, the pyridine-like nitrogen atom or the π-system. For many biologically active compounds containing the imidazole moiety, its participation in formation of hydrogen bond NH⋯O/N and following proton transfer is the key step of mechanism of their action. In this work a systematic study of the mutual influence of various paired combinations of non-covalent interactions (e.g., hydrogen bonds and π-interactions) involving the imidazole moiety was performed by means of quantum chemistry (PW6B95-GD3/def2-QZVPD) for a series of model systems constructed based on analysis of available x-ray data. It is shown that for considered complexes formation of additional non-covalent interactions can only enhance the proton-donating ability of imidazole. At the same time, its proton-accepting ability can be both enhanced and weakened, depending on what additional interactions are added to a given system. The mutual influence of non-covalent interactions involving imidazole can be classified as weak geometric and strong energetic cooperativity-a small change in the length of non-covalent interaction formed by imidazole can strongly influence its strength. The latter can be used to develop methods for controlling the rate and selectivity of chemical reactions involving the imidazole fragment in larger systems. It is shown that the strong mutual influence of non-covalent interactions involving imidazole is due to the unique ability of the imidazole ring to effectively redistribute electron density in non-covalently bound systems with its participation.

The Role of Conjugation in the Halogen-Lithium Exchange Selectivity: Lithiation of 4,6,7,9-Tetrabromo-1,3-dimethyl-2,3-dihydro-1H-perimidine.

The first case of successful suppression of the coordination of a lithium atom with a dialkylamino group by the effective conjugation of the latter with the aromatic core has been discovered. This effect controls regioselectivity of the bromine-lithium exchange in 4,6,7,9-tetrabromo-1,3-dimethyl-2,3-dihydro-1H-perimidine, which leads to products with the most effective conjugation. As a result, the product of this quadruple exchange demonstrates no tendency of the coordination of the NMe groups to neighboring lithium atoms despite the absence of steric restrictions. Experimental results are explained by means of quantum chemical calculations: geometry optimization, natural bond analysis and scans using the modredundant scheme.

Evolution of vibrational bands upon gradual protonation/deprotonation of arsinic acid H2As(O)OH in media of different polarity.

This computational work is devoted to the investigation (MP2/def2-TZVP) of the geometry and IR parameters of arsinic acid H2AsOOH and its hydrogen-bonded complexes under vacuum and in media with different polarity. The medium effects were accounted for in two ways: (1) implicitly, using the IEFPCM model, varying the dielectric permittivity (ε) and (2) explicitly, by considering hydrogen-bonded complexes of H2As(O)OH with various hydrogen bond donors (41 complexes) or acceptors (38 complexes), imitating a gradual transition to the As(OH)2+ or AsO2- moiety, respectively. It was shown that the transition from vacuum to a medium with ε > 1 causes the As(O)OH fragment to lose its flatness. The solvent polar medium introduces significant changes in the geometry and IR spectral parameters of hydrogen-bonded complexes too: as the polarity of a medium increases, weak hydrogen bonds become weaker, and strong and medium hydrogen bonds become stronger; in the case of a complex with two hydrogen bonds cooperativity effects are observed. In almost all cases the driving force of these changes appears to be preferential solvation of charge-separated structures. In the limiting case of complete deprotonation (or conversely complete protonation) the vibrational frequencies of νAsO and νAs-O turn into νAs-O(asym) and νAs-O(sym), respectively. In the intermediate cases the distance between νAsO and νAs-O is sensitive to both implicit solvation and explicit solvation and the systematic changes of this distance can be used for estimation of the degree of proton transfer within the hydrogen bond.

Spontaneous Cyclization of peri-Diiminonaphthalenes Leading to the Formation of Benzo[de]isoquinolines and Stable Benzo[de]isoquinoliniums.

The interaction of peri-dilithionaphthalenes with organic cyanides was studied. Instead of the expected peri-diimines, the reaction leads to the formation of three types of benzo[de]isoquinolines. Treatment of unsubstituted 1,8-dilithionaphthalene with aromatic nitriles results in the formation of 1-amino-1,3-diaryl-1H-benzo[de]isoquinolines. In contrast, 4,5-dilithio-1,8-bis(dimethylamino)naphthalene gives an aromatic isoquinolonium cation via elimination of ammonia under the same condition. Upon treatment with tert-butylcyanide, both dilithionaphthalenes undergo a transformation to 1-amino-3,4-di-tert-butyl-4H-benzo[de]isoquinolines. The observed reactivity was supported by quantum chemical calculations.

Organometallic Synthesis of 2,3,6,7-Tetrasubstituted 1,8-Bis(dimethylamino)naphthalenes for Investigation of the Double Buttressing Effect in Proton Sponges.

The lithiation of 2,7-disubstituted derivatives of 1,8-bis(dimethylamino)naphthalene (DMAN, proton sponge) bearing potentially ortho-directing OMe, NMe2, and SMe groups was studied. It has been shown that OMe groups facilitate selective dual ß-lithiation of the naphthalene moiety while the 2(7)-NMe2 groups allow only monolithiation presumably due to the decreased acidity of the ring C-H bonds and conformational immobilization after coordination to the lithium atom. In contrast, the SMe groups provided no ring lithiation and underwent deprotonation of their methyl fragment. The first representatives of previously unknown 2,3,6,7-tetrasubstituted DMANs have been synthesized in good yield after treatment of 2,7-dimethoxy-3,6-dilithio DMAN with the appropriate electrophiles (MeI, Me2S2, Me3SiCl, DMF, etc.). Because the exceedingly high basicity of 2,7-dimethoxy DMAN is commonly attributed to the so-called "buttressing effect" (BE), the availability of 2,3,6,7-tetrasubstituted species provided the first opportunity to study the double BE version. Using X-ray diffraction and basicity measurements, we showed that due to the high conformational mobility of the methoxy groups, the most striking manifestations of double BE are the strong planarization of peri-NMe2 groups and a significant decrease in basicity, while the length and the other properties of the intramolecular NHN hydrogen bond in the corresponding protonated species undergo minor changes.

Halogen Bonding Involving Gold Nucleophiles in Different Oxidation States.

A single-crystal X-ray diffraction (XRD) study of diaryliodonium tetrachloroaurates (or, in the recent terminology, tetrachloridoaurates), [(p-XC6H4)2I][AuCl4] (X = Cl, 1; Br, 2), was performed for 1 (the structure is denoted as 1a to show similarity with the isomorphic structure 2a) and two polymorphs─2a (obtained from MeOH) and 2b (from 1,2-C2H4Cl2). Examination of the XRD data for these three structures revealed 2-center C-X···AuIII (X = Cl and Br) and 3-center bifurcated C-Br···(Cl-Au) halogen bonding (abbreviated as XB) between the p-Cl or p-Br atoms of the diaryliodonium cations and the gold(III) atom of [AuCl4]-. The noncovalent nature of AuIII-involving interactions, the nucleophilicity of the gold(III) atoms, and the electrophilic role of p-X atoms of the diaryliodonium cations in the XBs were studied by a set of complementary computational methods. Combined experimental and theoretical studies allowed the recognition of the d-nucleophilicity of the [d8AuIII] atom which, regardless of its rather substantial formal 3+ charge, can function as a d-nucleophilic partner of XB. This conclusion was also supported by theoretical calculations performed for the structures' refcodes BINXOM and ICSD 62511; the obtained data verified the nucleophilicity of AuIII toward a K+ ions or a σ-(Cl)-hole, respectively. All our results, together with consideration of relevant literature, indicate that gold atoms in the three oxidation states (0, I, and even III) exhibit nucleophilicity in XBs.

The Distance between Minima of Electron Density and Electrostatic Potential as a Measure of Halogen Bond Strength.

In this study, we present results of a detailed topological analysis of electron density (ED) of 145 halogen-bonded complexes formed by various fluorine-, chlorine-, bromine-, and iodine-containing compounds with trimethylphosphine oxide, Me3PO. To characterize the halogen bond (XB) strength, we used the complexation enthalpy, the interatomic distance between oxygen and halogen, as well as the typical set of electron density properties at the bond critical points calculated at B3LYP/jorge-ATZP level of theory. We show for the first time that it is possible to predict the XB strength based on the distance between the minima of ED and molecular electrostatic potential (ESP) along the XB path. The gap between ED and ESP minima exponentially depends on local electronic kinetic energy density at the bond critical point and tends to be a common limiting value for the strongest halogen bond.

Non-covalent interactions in the glutathione peroxidase active center and their influence on the enzyme activity.

In this computational work, the structure of the active center of the enzyme glutathione peroxidase (in three forms -SeH, -SeOH and -Se(O)OH) and the non-covalent interactions in it were investigated using modern quantum chemistry methods. The non-covalent interactions are described in detail. The presence of σ-hole interactions (chalcogen, tetrel and pnictogen bonds) formed mostly by a selenium atom as an electrophile in the glutathione peroxidase active center is confirmed for the first time. It is shown that a number of non-covalent interactions stabilize intermediates along the catalytic cycle and that modelling of the whole enzyme active center is necessary for accurate predictions of thermodynamic parameters, in particular, activation barriers.

Choice of computational protocol for carbon-lithium spin-spin coupling constants 1 JCLi.

In this work, we tested various computational schemes for calculations of 1 JCLi constants with a high accuracy. On the example of six organolithium reagents (phenyllithium monomer and dimer, monomer s-butyllithium, monomers of 1- and 2-lithionaphthalenes, and a methyllithium tetramer), the following aspects are discussed: (i) the role of a model system geometry, (ii) influence of solvent effects, and (iii) the choice of a functional and basis set. Practical recommendations for calculation of 1 JCLi with an accuracy ±2 Hz are formulated.

Simultaneous Estimation of Two Coupled Hydrogen Bond Geometries from Pairs of Entangled NMR Parameters: The Test Case of 4-Hydroxypyridine Anion.

The computational method for estimating the geometry of two coupled hydrogen bonds with geometries close to linear using a pair of spectral NMR parameters was proposed. The method was developed based on the quantum-chemical investigation of 61 complexes with two hydrogen bonds formed by oxygen and nitrogen atoms of the 4-hydroxypyridine anion with OH groups of substituted methanols. The main idea of the method is as follows: from the NMR chemical shifts of nuclei of atoms forming the 4-hydroxylpyridine anion, we select such pairs, whose values can be used for simultaneous determination of the geometry of two hydrogen bonds, despite the fact that every NMR parameter is sensitive to the geometry of each of the hydrogen bonds. For these parameters, two-dimensional maps of dependencies of NMR chemical shifts on interatomic distances in two hydrogen bonds were constructed. It is shown that, in addition to chemical shifts of the nitrogen atom and quaternary carbon, which are experimentally difficult to obtain, chemical shifts of the carbons and protons of the CH groups can be used. The performance of the proposed method was evaluated computationally as well on three additional complexes with substituted alcohols. It was found that, for all considered cases, hydrogen bond geometries estimated using two-dimensional correlations differed from those directly calculated by quantum-chemical methods by not more than 0.04 Å.

Self-association of diphenylpnictoginic acids in solution and solid state: covalent vs. hydrogen bonding.

Triphenylpnictogens were oxidized to access diphenylpnictioginic acids Ph2XOOH (X = P, As, Sb, Bi). It was shown that oxidation with chloramine-T does not lead to the cleavage of a C-pnictogen bond. The preliminary reductive cleavage with sodium in liquid ammonia followed by the oxidation with hydrogen peroxide was successfully utilised for the synthesis of diphenylphosphinic and diphenylarsinic acids. It was shown that in solid state (by means of XRD), all diphenylpnictoginic acids form polymeric chains. Diphenylbismuthinic and diphenylantimonic acids form polymeric covalent adducts, while diphenylphosphinic and diphenylarsinic chains are associated through hydrogen bonding. Unlike diphenylphosphinic acid, diphenilarsinic acid forms two polymorphs of hydrogen-bonded infinite chains. In solution in a polar aprotic solvent diphenylarsinic acid, similarly to dimethylarsinic, forms hydrogen-bonded cyclic dimers together with a small amount of cyclic trimers.

Metal-Involving Halogen Bonding Including Gold(I) as a Nucleophilic Partner. The Case of Isomorphic Dichloroaurate(I)·Halomethane Cocrystals.

Three isomorphic cocrystals were obtained via the crystallization of [PPN][AuCl2] (1) from CHBr3 (1·CHBr3), or CHCl3/1,2-C2F4Br2 (1·CHCl3) and CH2Cl2/Et2O (1·CH2Cl2) mixtures. Analysis of the single-crystal X-ray diffraction data for these cocrystals revealed a gold(I)-involving two-center C-X···Au halogen bond (abbreviated as XB; X = Cl, Br) and a three-center bifurcated C-Br···(Cl-Au) XB; in the latter, the gold(I)-chloride linkage functions as an integrated XB acceptor. The noncovalent nature and energies [spanning from -1.58 to -5.52 kcal/mol for C-X···Au and -6.37 kcal/mol for C-Br···(Cl-Au) XBs] of these noncovalent interactions were studied by density functional theory calculations and topological analysis of the electron density distribution in the framework of the quantum theory of atoms-in-molecules (QTAIM) followed by noncovalent interaction (NCI) analysis at the B3LYP-D3/jorge-TZP-DKH level of theory. The nucleophilicity of the gold(I) centers toward halogens of halomethanes was verified by a set of independent methods including electrostatic potential surfaces, electron localization function projection, natural bond orbital charge transfer, electron density/electrostatic potential profile, Wiberg bond indexes, natural population analysis, and atoms-in-molecules charge analyses.

Hydration of selenolate moiety: Ab initio investigation of properties of O-H⋯Se(-) hydrogen bonds in CH3 Se(-)⋯(H2 O)n clusters.

This work is devoted to investigations of the influence of O-H···Se(-) hydrogen bonds on the electronic shells of selenolate R-Se(-) fragment (R═CH3 ). The geometric, energetic and nuclear magnetic resonance (NMR) spectral parameters for various conformers of CH3 Se(-)⋯(H2 O)n clusters with n = 0-6 were calculated at CCSD/aug-cc-pVDZ level of theory. For selenolate anion CH3 Se(-) solvation free energy was calculated, and for water media it is equal to -71.41 kcal/mol. For O-H···Se(-) hydrogen bonds the proportionality coefficients between QTAIM parameters at (3; -1) bond critical point and the strength of an individual hydrogen bond ∆E were proposed. It was shown, that despite a relative weakness of O-H···Se(-) hydrogen bonds, the outer electronic shell of the selenium atom changes significantly upon formation of each hydrogen bond. This, in turn, cause the dramatic change of NMR parameters of selenium nuclei.

On the influence of water molecules on the outer electronic shells of R-SeH, R-Se(-) and R-SeOH fragments in the selenocysteine amino acid residue.

In this computational work (MP2/aug-cc-pVTZ) we investigated the features of the outer electronic shells of R-SeH, R-Se(-) and R-SeOH fragments (R = CH3), which can be considered as simplified models for the forms of the active centres of glutathione peroxidases GPx along their catalytic pathway (reduction of peroxides). It is shown that the preferential direction of a nucleophilic attack on the R-Se(-) fragment by a peroxide molecule is determined by the presence of the electron-depleted region of the selenium atom in front of the C-Se bond and nucleophilic attack can be facilitated by the solvation of R-Se(-) by water molecules. Such solvation does not block the direction of potential nucleophilic attack and also leads to the increase of the maximal value of the molecular electrostatic potential on the selenium atom. It was shown that the 77Se NMR chemical shift is sensitive both to the oxidation state and the hydration state of the selenium-containing fragment.

Estimations of FH···X hydrogen bond energies from IR intensities: Iogansen's rule revisited.

In this work the possibility of using the IR intensity of the stretching vibration νs of proton donor group for estimation of hydrogen bond strength was investigated. For a set of complexes with FH···X (X = F, N, O) hydrogen bonds in the wide range of energies (0.1-49.2 kcal/mol) vibrational frequencies νs and their intensities A were calculated (CCSD at complete basis set limit). The validity of the previously proposed linear proportionality between the intensification of the stretching vibration νs in IR spectra and hydrogen bond enthalpy -ΔH = 12.2 ∆ A (A. V. Iogansen, Spectrochimica Acta A 1999) was examined. It is shown that for a range of similar hydrogen bond types with complexation energies ∆E <15 kcal/mol the ∆E( ∆ A ) function remains similar to that proposed in the Iogansen's work, while upon strengthening this dependency becomes significantly nonlinear. We examined two other parameters ( ∆ A ν s and ∆ A ∙ m R ) related to IR intensity as descriptors of hydrogen bond strength which are proportional to transition dipole moment matrix element and mass-independent dipole moment derivative. It was found that the dependency ∆E( ∆ A ν s ) stays linear in the whole studied range of complexation energies and it can be used for evaluation of ∆E from infrared spectral data with the accuracy about 2 kcal/mol. The mass-independent product ∆ A ∙ m R is an appropriate descriptor for sets of complexes with various hydrogen bond types. Simple equations proposed in this work can be used for estimations of hydrogen bond strength in various systems, where experimental thermodynamic methods or direct calculations are difficult or even impossible.

Sterically Facilitated Intramolecular Nucleophilic NMe2 Group Substitution in the Synthesis of Fused Isoxazoles: Theoretical Study.

The influence of steric repulsion between the NMe2 group and a second ortho-(peri-)substituent in the series of 1-dimethylaminonaphthalene and N,N-dimethylanilene ortho-oximes on the ease of the NMe2 group's intramolecular nucleophilic substitution is studied. Possible reaction intermediates for three mechanisms are calculated (ωB97xd/def-2-TZVP), and their free Gibbs energies are compared to model reaction profiles. Supporting experiments have proved the absence of studied reactivity in the case of simple 2-dimethylaminobenzaldoxime, which allowed us to establish reactivity limits. The significant facilitation of NMe2 group displacement in the presence of bulky substituents is demonstrated. The possibility of fused isoxazoles synthesis via the intramolecular nucleophilic substitution of a protonated NMe2 group in the aniline and naphthalene series is predicted.

Stretching force constants as descriptors of energy and geometry of F···HF hydrogen bonds.

In this work applicability of proton donor group stretching vibration force constants ks and intermolecular stretching force constants kσ for evaluations of hydrogen bond strength and geometry are discussed. For a set of 30 complexes with F···HF hydrogen bonds in a wide range 0.5-48 kcal/mol by means of quantum chemical calculations equilibrium geometries, complexation energies, vibrational frequencies and corresponding force constants were calculated (MP2/aug-cc-pVTZ). It is shown, that properties of a hydrogen bond are more strictly correlated with the values of force constants than with vibrational frequencies. Easy-to-use equations for estimations of hydrogen bond energy ∆E and geometry (rFH, rFF) based on ks and kσ values are proposed.