Bifunctional Hydrogen Bond Research Articles

Thiourea as Bifunctional Hydrogen Bond Donor and Brønsted Base Catalyst for Green One-Pot Synthesis of 2-Aryl/Heteroaryl/Styryl Benzothiazoles in the Aqueous Medium under Ultrasound Irradiation.

A green organocatalysis cascade strategy using thiourea in catalytic amounts as both a hydrogen bond donor and a Brønsted base bifunctional catalyst was utilized to synthesize a series of 2-aryl/heteroaryl/styryl benzothiazole derivatives. This strategy involved an ultrasound-irradiated one-pot two-component reaction between substituted aldehydes and 2-amino thiophenols in an aqueous medium at 60 °C, using air as an oxidant. At the gram-scale, this protocol yielded 87% of the desired product, making it suitable for production at a larger scale. This green and mild protocol offers excellent yields, cost-effectiveness, atom economy, step economy, and a simple operation that does not require extra purification steps. Furthermore, the catalyst is easily recoverable and can be used for up to five cycles without a significant loss of any activity.

Cover Feature: Bifunctional Hydrogen Bond Donor‐Catalyzed Diels–Alder Reactions: Origin of Stereoselectivity and Rate Enhancement (Chem. Eur. J. 16/2021)

Cover Feature: Bifunctional Hydrogen Bond Donor‐Catalyzed Diels–Alder Reactions: Origin of Stereoselectivity and Rate Enhancement (Chem. Eur. J. 16/2021)

Bifunctional Hydrogen Bond Donor-Catalyzed Diels-Alder Reactions: Origin of Stereoselectivity and Rate Enhancement.

The selectivity and rate enhancement of bifunctional hydrogen bond donor‐catalyzed Diels–Alder reactions between cyclopentadiene and acrolein were quantum chemically studied using density functional theory in combination with coupled‐cluster theory. (Thio)ureas render the studied Diels–Alder cycloaddition reactions exo selective and induce a significant acceleration of this process by lowering the reaction barrier by up to 7 kcal mol−1. Our activation strain and Kohn–Sham molecular orbital analyses uncover that these organocatalysts enhance the Diels–Alder reactivity by reducing the Pauli repulsion between the closed‐shell filled π‐orbitals of the diene and dienophile, by polarizing the π‐orbitals away from the reactive center and not by making the orbital interactions between the reactants stronger. In addition, we establish that the unprecedented exo selectivity of the hydrogen bond donor‐catalyzed Diels–Alder reactions is directly related to the larger degree of asynchronicity along this reaction pathway, which is manifested in a relief of destabilizing activation strain and Pauli repulsion.

An octahedral cobalt(iii) complex based on cheap 1,2-phenylenediamine as a bifunctional metal-templated hydrogen bond donor catalyst for fixation of CO2 with epoxides under ambient conditions

An octahedral cobalt(iii) complex based on cheap 1,2-phenylenediamine operates as an efficient bifunctional hydrogen bond donor catalyst in cycloaddition of epoxides with CO2 under ambient conditions and solvent- and co-catalyst-free conditions.

ELECTRONIC ABSORPTION SPECTRA AND INTERMOLECULAR HYDROGEN BONDING IN MESOGEN–NONMESOGEN SYSTEMS

The TD-DFT/B97-D/6-311G** method is used to calculate the electronic absorption spectra of А⋯Х⋯А supramolecules with intermolecular hydrogen bonds (HBs), where А is 4-n-propoxycinnamic acid, Х is a nonmesogen molecule with bifunctional HB acceptors. Nonmesogens Х (B, C, D, E) consist of two pyridyl fragments connected by bridging groups of different natures: 4,4′-bipyridine (В), 1,2-bis(4-pyridyl)ethane (С), 1,2-bis(4-pyridyl)ethylene (D), 4,4′-azopyridine (Е). It is shown that the introduction of bridging groups (–CН2–CН2–, –CН=СН–, –N=N–) significantly affects the energy of frontier orbitals and electronic absorption spectra (EAS) of nonmesogens Х in the near-UV region. The EAS of two structural units A⋯В⋯A, A⋯A, which may be formed due to the self-assembly in two-component mesogen А–nonmesogen В systems, are compared. Due to hydrogen bonds (O–H⋯N and O–H⋯O), having different types and strengths in these complexes, the high-intensity band shifts to shorter wavelengths in complex А⋯В⋯А and to longer wavelengths in complex А⋯А with respect to the λ = 333 nm band of monomer А. It is shown that EAS of hydrogen-bonded complexes А⋯Х⋯А are not superpositions of EAS of individual components. The spectra show electronic transitions related to charge transfer between the components of the complexes. Using nonmesogens Х of different nature in supramolecules А⋯Х⋯А will allow one to change purposefully their electro-optical properties and to achieve intense absorption in particular regions of UV spectra.

Connecting and Analyzing Enantioselective Bifunctional Hydrogen Bond Donor Catalysis Using Data Science Tools.

The generalization of related asymmetric processes in organocatalyzed reactions is an ongoing challenge due to subtle, noncovalent interactions that drive selectivity. The lack of transferability is often met with a largely empirical approach to optimizing catalyst structure and reaction conditions. This has led to the development of diverse structural catalyst motifs and inspired unique design principles in this field. Bifunctional hydrogen bond donor (HBD) catalysis exemplifies this in which a broad collection of enantioselective transformations has been successfully developed. Herein, we describe the use of data science methods to connect catalyst and substrate structural features of an array of reported enantioselective bifunctional HBD catalysis through an iterative statistical modeling process. The computational parameters used to build the correlations are mechanism-specific based on the proposed transition states, which allows for analysis into the noncovalent interactions responsible for asymmetric induction. The resulting statistical models also allow for extrapolation to out-of-sample examples to provide a prediction platform that can be used for future applications of bifunctional hydrogen bond donor catalysis. Finally, this multireaction workflow presents an opportunity to build statistical models unifying various modes of activation relevant to asymmetric organocatalysis.

Ascorbic Acid as a Bifunctional Hydrogen Bond Donor for the Synthesis of Cyclic Carbonates from CO2 under Ambient Conditions

Readily available ascorbic acid was discovered as an environmentally benign hydrogen bond donor for the synthesis of cyclic organic carbonates from CO2 and epoxides in the presence of nucleophilic cocatalysts. The ascorbic acid/TBAI (TBAI: tetrabutylammonium iodide) binary system could be applied for the cycloaddition of CO2 to various epoxides under ambient or mild conditions. Density functional theory calculations and catalysis experiments revealed an intriguing bifunctional mechanism in the step of CO2 insertion involving different hydroxyl moieties (enediol, ethyldiol) of the ascorbic acid scaffold.

Supramolecular Synthesis Based on a Combination of Se···N Secondary Bonding Interactions with Hydrogen and Halogen Bonds

Examination of the solid state structures of 2,1,3-benzoselenadiazole complexes with hydrogen or halogen bond donors has demonstrated that the 2,1,3-benzoselenadiazole molecules preferably form centrosymmetric dimers with use of [Se–N]2 supramolecular synthon, whereas the two remaining nitrogen atoms not involved in the [Se–N]2 supramolecular interactions can act as acceptors of hydrogen or halogen bonds. Cocrystallization of selenadiazoles with monofunctional hydrogen or halogen bond donors like pentafluorophenol, pentafluorobenzoic acid, or pentafluoroiodobenzene results in formation of binary discrete complexes. One- or two-dimensional aggregates based on selenadiazole [Se–N]2 dimers as building blocks were prepared using bifunctional hydrogen or halogen bond donors like resorcinol, tetrafluororesorcinol, tetrafluorohydroquinone, and 1,4-diiodotetrafluorobenzene. During the complexation of selenadiazoles with hydroquinone, anilic acid, or chloranilic acid a competition between Se···N and Se···O interac...

Adsorption of 2-Chloroethyl Ethyl Sulfide on Silica: Binding Mechanism and Energy of a Bifunctional Hydrogen-Bond Acceptor at the Gas–Surface Interface

This work investigates the fundamental nature of sulfur mustard surface adsorption by characterizing interfacial hydrogen bonding and other intermolecular forces for the surrogate molecule (simulant) 2-chloroethyl ethyl sulfide (2-CEES). Adsorption at the surface of amorphous silica is the focus of this work because of silica’s low chemical reactivity, well-known properties, and abundance in the environment. 2-CEES has two polar functional groups, the chloro and thioether moieties, available to accept hydrogen bonds from free surface silanol groups. Diethyl sulfide and chlorobutane are also investigated to independently assess the role of the chloro and thioester functionalities in the overall adsorption mechanism and to explore the interplay between the charge transfer and electrostatic contributions to total hydrogen-bond strength. Our approach utilizes infrared spectroscopy to study specific surface–molecule interactions and temperature-programmed desorption to measure the activation energy for desorption of adsorbed molecules. Our results indicate that 2-CEES adsorbs to silica by hydrogen bonding through either the chloro or thioether moieties but is unable to form a more stable configuration in which both polar groups interact simultaneously with adjacent silanol groups. The activation energy for desorption of 2-CEES is nearly 43 kJ/mol, driven by both strong hydrogen bonding and other non-bonding interactions. A systematic study of chloroalkanes reveals that each methylene group contributes approximately 5–8 kJ/mol to the overall desorption energy.

複素環骨格を基盤とする新規水素結合供与型有機分子触媒の開発と不斉反応への応用

We have designed and synthesized novel bifunctional hydrogen-bond (HB) donor catalysts bearing a benzothiadiazine or a quinazoline scaffold, whose HB-donating activity as well as recognition modes of the substrates were found to be significantly different from thiourea-typed organocatalysts by comparison of their 1H NMR studies, X-ray crystallographic analyses, spectrophotometric analyses, and computational investigations. We found that quinazoline-typed catalysts were effective for the highly enantioselective hydrazination of 1,3-dicarbonyl compounds and that benzothiadiazine-type catalysts showed great activity for the asymmetric isomerization of alkynoates to allenoates. In both cases, these newly developed catalysts were much more efficient than thiourea-typed organocatalysts, indicating that the HB-donating moiety of the catalysts was important for the recognition and activation of the substrates to facilitate the reaction.

Bifunctional Hydrogen Bonds in Monohydrated Cycloether Complexes

In this work, the cooperative effects implicated in bifunctional hydrogen bonds (H-bonds) were studied (in monohydrated six-membered cycloether) within the framework of the atoms in molecules (AIM) theory and of the natural bond orbitals (NBO) analysis. The study was carried out in complexes formed by six-membered cycloether compounds (tetrahydropyrane, 1,4-dioxane, and 1,3-dioxane) and a water molecule. These compounds were used as model systems instead of more complicated molecules of biological importance. All the results were obtained at the second-order Møller-Plesset (MP2) level theory using a 6-311++G(d,p) basis set. Attention was focused on the indicators of the cooperative effects that arise when a water molecule interacts simultaneously with a polar and a nonpolar portion of a six-membered cycloether (via bifunctional hydrogen bonds) and compared with conventional H-bonds where the water molecule only interacts with the polar portion of the cycloether. Different indicators of H-bonds strength, such as structural and spectroscopic data, electron charge density, population analysis, hyperconjugation energy and charge transference, consistently showed significant cooperative effects in bifunctional H-bonds. From the AIM, as well as from the NBO analysis, the obtained results allowed us to state that in the monohydrated six-membered cycloether, where the water molecule plays a dual role, as proton acceptor and proton donor, a mutual reinforcement of the two interactions occurs. Because of this feature, the complexes engaged by bifunctional hydrogen bonds are more stabilized than the complexes linked by conventional hydrogen bonds.

Asymmetric Diels-Alder Reactions of Vinylindoles Using Organocatalysis

The different behavior of 3- and 2-vinylindoles in Diels-Alder cycloaddition reactions in the presence of bifunctional hydrogen bond donor organocatalysts is described.

Synthesis, in Vivo Evaluation, and Molecular Modeling Studies of New Pyrazolo[5,1-c][1,2,4]benzotriazine 5-Oxide Derivatives. Identification of a Bifunctional Hydrogen Bond Area Related to the Inverse Agonism

A new series of pyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide 8-alkyloxy-/aryloxy-/arylalkyloxy and 8-aryl-/arylalkylderivatives variously substituted at the 3-position were synthesized and binding studies at the benzodiazepine site on GABA(A) receptor were carried out. The pharmacological profile was identified for compounds 10, 11, 16(+), 16(-), and 17 by considering six potential benzodiazepine actions: motor coordination, anticonvulsant action, spontaneous motility and explorative activity, potential anxiolytic-like effects, mouse learning and memory modulation, and finally, ethanol-potentiating action. Compound 17 stands out as the compound that improves mouse memory processes selectively, safely, and in a statistically significant manner. From a ligand-based pharmacophoric model, we identified a hydrogen bond interaction area HBp-3 near the lipophilic area. This new pharmacophoric model allowed us to identify four structural compound typologies and thus to rationalize the affinity data of all compounds.

Mutational, kinetic, and NMR studies of the mechanism of E. coli GDP-mannose mannosyl hydrolase, an unusual Nudix enzyme.

GDP-mannose mannosyl hydrolase (GDPMH) is an unusual Nudix family member, which catalyzes the hydrolysis of GDP-alpha-D-mannose to GDP and the beta-sugar by nucleophilic substitution at carbon rather than at phosphorus (Legler, P. M., Massiah, M. A., Bessman, M. J., and Mildvan, A. S. (2000) Biochemistry 39, 8603-8608). Using the structure and mechanism of MutT, the prototypical Nudix enzyme as a guide, we detected six catalytic residues of GDPMH, three of which were unique to GDPMH, by the kinetic and structural effects of site-specific mutations. Glu-70 (corresponding to Glu-57 in MutT) provides a ligand to the essential divalent cation on the basis of the effects of the E70Q mutation which decreased kcat 10(2.2)-fold, increased the dissociation constant of Mn2+ from the ternary E-Mn2+-GDP complex 3-fold, increased the K(m)Mg2+ 20-fold, and decreased the paramagnetic effect of Mn2+ on 1/T1 of water protons, indicating a change in the coordination sphere of Mn2+. In the E70Q mutant, Gln-70 was shown to be very near the active site metal ion by large paramagnetic effects of Mn2+ on its side chain -NH2 group. With wild-type GDPMH, the effect of pH on log(kcat/K(m)GDPmann) at 37 degrees C showed an ascending limb of unit slope, followed by a plateau yielding a pK(a) of 6.4, which increased to 6.7 +/- 0.1 in the pH dependence of log(kcat). The general base catalyst was identified as a neutral His residue by the DeltaH(ionization) = 7.0 +/- 0.7 kcal/mol, by the increase in pK(a) with ionic strength, and by mutation of each of the four histidine residues of GDPMH to Gln. Only the H124Q mutant showed the loss of the ascending limb in the pH versus log(kcat) rate profile, which was replaced by a weak dependence of rate on hydroxide concentration, as well as an overall 10(3.4)-fold decrease in kcat, indicating His-124 to be the general base, unlike MutT, which uses Glu-53 in this role. The H88Q mutant showed a 10(2.3)-fold decrease in kcat, a 4.4-fold increase in K(m)GDPmann, and no change in the pH versus log(kcat) rate profile, indicating an important but unidentified role of His-88 in catalysis. One and two-dimensional NMR studies permitted the sequence specific assignments of the imidazole HdeltaC, H(epsilon)C, N(delta), and N(epsilon) resonances of the four histidines and defined their protonation states. The pK(a) of His-124 (6.94 +/- 0.04) in the presence of saturating Mg2+ was comparable to the kinetically determined pK(a) at the same temperature (6.40 +/- 0.20). The other three histidines were neutral N(epsilon)H tautomers with pK(a) values below 5.5. Arg-52 and Arg-65 were identified as catalytic residues which interact electrostatically with the GDP leaving group by mutating these residues to Gln and Lys. The R52Q mutant decreased kcat 309-fold and increased K(m)GDPmann 40.6-fold, while the R52K mutant decreased kcat by only 12-fold and increased K(m)GDPmann 81-fold. The partial rescue of kcat, but not of K(m)GDPmann in the R52K mutant, suggests that Arg-52 is a bifunctional hydrogen bond donor to the GDP leaving group in the ground state and a monofunctional hydrogen bond donor in the transition state. Opposite behavior was found with the Arg-65 mutants, suggesting this residue to be a monofunctional hydrogen bond donor to the GDP leaving group in the ground state and a bifunctional hydrogen bond donor in the transition state. From these observations, a mechanism for GDPMH is proposed involving general base catalysis and electrostatic stabilization of the leaving group.

One-Dimensional Hydrogen Bonded Polymers Based on C-Methyl-Calix[4]Resorcinarene and a Crystal Engineering Design Strategy

The X-ray crystal structures of co-crystals involving C-methylcalix[4]resorcinarene 1 and exo-bidentate pyridines 2 are reported. The components assemble such that the calixarenes adopt a C 2v conformation and the pyridines serve as bifunctional hydrogen bond acceptors. In the case of linear bridging units, 4,4′-bipyridine 2a and 4,4′-dipyridyl butanedioate 2b, the assembly process yields 1D wave-like hydrogen bonded polymers 4a and 4b, respectively, which include guest solvent molecules within 1. In the case of an angular bridging unit, pyrimidine 2c, the assembly process yields a 1D chain 5 which exhibits self-inclusion. Thermal analysis of 4a demonstrates that the thermal behavior of these compounds is independent of the nature of the included guest, the solvent-included lattices being stable up to 190°C.

Conjugated Dual Hydrogen Bonds Mediating 2-Pyridone/2-Hydroxypyridine Tautomerism

Tautomeric equilibria of 2-pyridone (PD) and 2-hydroxypyridine (HP) dimeric forms as well as PD/HP complexes mediated by the conjugated dual hydrogen-bonding (CDHB) formation have been studied by ab initio molecular orbital calculations up to the 6-31+G** basis set at the Moller−Plesset level. The result in combination with the semiempirical solvation free-energy calculation reasonably predicts the relative free energy and consequently the tautomeric equilibria between PD, HP, their corresponding dimers and PD/HP complex in the gas phase as well as in solution. The results also indicate that the strength of dual hydrogen bonding resonantly affects the PD and HP electronic structures upon CDHB formation, resulting in an additional stabilization energy. Further calculation shows that the tautomeric equilibria can be fine-tuned by the formation of a hydrogen-bonded complex with guest molecules possessing bifunctional hydrogen bonds. The results lead to a possible mechanism suggesting that the tautomerization...

Supramolecular mesomorphic structures based on 2,5-dialkoxyterephthalicacid derivatives

Self-assembly of 2,5-di-n-alkoxyterephthalic acids (CnOTpA) and 2,5-di-n-hexylterephthalic acid (C6TpA) as bifunctional hydrogen bond donors with bifunctional acceptors 1,3-diaminopropane (Dap), piperazine (Pip) and 4,4′-bipyridine (Bipy) has been investigated, both in the crystal lattice and in the mesophase. Stoichiometric mixtures of compounds CnOTpA with diamine Dap form mesophases with a lamellar-type structure and constitute, to the best of our knowledge, the first examples of the generation of mesophases from 2,5-di-n-alkoxyterephthalic acids and bifunctional diamines. The liquid crystalline behaviour of these mixtures was characterized using X-ray scattering, DSC and polarizing microscopy. The self-assembly of complexes C6TpA·Bipy and C6TpA·Pip in the crystal lattice was characterized using single crystal X-ray structural analysis. In the crystal lattice of C6TpA·Bipy, only hydrogen bonding interactions between the neutral acid and the base were observed. However, in the crystal structure of cocrystals of C6TpA with Pip, an ionic interaction was observed due to proton transfer from the acid group to the basic nitrogen atoms of the base.

Approaches to supramolecular structures with various topologies in the crystal lattice

AbstractSimple molecular building blocks for creating supramolecular architectures in the crystal lattice are described. Combination of hydrogen bonding and alkyl chain crystallization is used to explore self‐assembly1 of molecular building blocks 1, 2, 3 and 4 in the crystal lattice. The crystal lattice of pure acids and its equimolar mixtures with bifunctional hydrogen bond acceptors are characterized by singe crystal analysis.

NMR docking of the competitive inhibitor thymidine 3',5'-diphosphate into the X-ray structure of staphylococcal nuclease.

In the X-ray structure of the ternary staphylococcal nuclease-Ca(2+)-3',5'-pdTp complex, the conformation of the bound inhibitor 3',5'-pdTp is distorted by Lys-70* and Lys-71* from an adjacent molecule of the enzyme in the crystal lattice (Loll, P. J. and Lattman, E. E. Proteins 5:183-201, 1989; Serpersu, E. H., Hibler, D. W., Gerlt, J. A., and Mildvan, A. S. Biochemistry 28:1539-1548, 1989). Since this interaction does not occur in solution, the NMR docking procedure has been used to correct this problem. Based on 8 Co(2+)-nucleus distances measured by paramagnetic effects on T1, and 9 measured and 45 lower limit interproton distances determined by 1D and 2D NOE studies of the ternary Ca2+ complex, the conformation of enzyme-bound 3',5'-pdTp is high-anti (chi = 58 +/- 10 degrees) with a C2' endo/O1' endo sugar pucker (delta = 143 +/- 2 degrees), (-) synclinal about the C3'-O3' bond (epsilon = 273 +/- 4 degrees), trans, gauche about the C4'-C5' bond (gamma = 301 +/- 29 degrees) and either (-) or (+) clinal about the C5'-O5' bond (beta = 92 +/- 8 degrees or 274 +/- 3 degrees). The structure of 3',5'-pdTp in the crystalline complex differs due to rotations about the C4'-C5' bond (gamma = 186 +/- 12 degrees, gauche, trans) and the C5'-O5' bond [beta = 136 +/- 10 degrees, (+) anticlinal]. The undistorted conformation of enzyme-bound metal-3',5'-pdTp determined by NMR was docked into the X-ray structure of the enzyme, using 19 intermolecular NOEs from ring proton resonances of Tyr-85, Tyr-113, and Tyr-115 to proton resonances of the inhibitor. van der Waals overlaps were then removed by energy minimization. Subsequent molecular dynamics and energy minimization produced no significant changes, indicating the structure to be in a global rather than in a local minimum. While the metal-coordinated 5'-phosphate of the NMR-docked structure of 3',5'-pdTp overlaps with that in the X-ray structure, and similarly receives bifunctional hydrogen bonds from both Arg-35 and Arg-87, the thymine, deoxyribose, and 3'-phosphate are significantly displaced from their positions in the X-ray structure, with the 3'-phosphate receiving hydrogen bonds from Lys-49 rather than from Lys-84 and Tyr-85. The repositioned thymine ring permits hydrogen bonding to the phenolic hydroxyl of Tyr-115.(ABSTRACT TRUNCATED AT 400 WORDS)

Differentiation of antihemophilic factor (AHF) and von Willebrand factor (vWF) by their interaction with urea and selected amino acids

The interaction of urea with antihemophilic factor (AHF), von Willebrand factor (vWF) and and von Willebrand factor antigen (vWF-Ag) was studied in fresh plasma, fresh-frozen plasma, and high-purity preparations of factor VIII (AHF/vWF). About 1.5 M urea resulted in complete loss of vWF activity (100%), partial loss of AHF (70%) and vWF-Ag (35%) in 2 hrs, and even 3 M urea resulted in complete loss of vWF activity and incomplete loss of AHF (90%) and vWF-Ag (45%) after 3 hrs. vWF and vWF-Ag partially inactivated by urea could be fully recovered after dialysis, while the AHF activity returned to about 75% of the initial value. When acetamide was substituted for urea the AHF loss was about 50% and the vWF loss was 70% of that observed with urea at each concentration, suggesting that urea may interact with these proteins through the formation of bifunctional hydrogen bonds. Lysine and structural analogs of lysine with free amino groups prevented urea inactivation of the AHF but not the vWF. These data imply that regions on the molecule(s) essential for the biologic activity of AHF, vWF and vWF-Ag are probably denatured by direct interaction with urea. Since vWF-Ag and AHF are more resistant than vWF to reaction with urea, several other bonds or groups may be involved. The difference in denaturation, renaturation and protection against urea inactivation of AHF and vWF by selected amino acids could be explained if the reactive sites for the two activities were located on different molecules, as suggested by other in vitro and in vivo observations, or were on different regions of one molecule.