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.

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.

2H-Indazole Tautomers Stabilized by Intra- and Intermolecular Hydrogen Bonds.

2-[(2H-Indazol-3-yl)methylene]-1H-indene-1,3(2H)-dione 6 and (E)-2-[(2H-indazol-3-yl)methylene]-2,3-dihydro-1H-inden-1-one 7 have been synthesized. In the crystal, the NH hydrogen atom of 6 is disordered between the N(1) and N(2) atoms with the population ratio of 0.69:0.31. Molecule 7 crystallizes in two tautomeric polymorphs: 7-1H tautomer (yellow) and 7-2H tautomer (red). Both 6 and 7 form centrosymmetric dimers in the crystal with the monomeric units linked by C═O···H···N bifurcated hydrogen bonds in 6 and N-H···N hydrogen bonds in 7. According to 1H and 13C NMR data, in DMSO-d6 solution, the 6-1H tautomer predominates, whereas in less polar CDCl3 or CD2Cl2, the 6-2H tautomer is stabilized by a strong N-H···O═C intramolecular hydrogen bond. Compound 7 in dimethyl sulfoxide (DMSO) or ethanol solutions exists in the form of 7-1H and 7-2H tautomers. On the example of the 7-2H tautomer, it was shown for the first time that the 2H tautomers of 3-substituted indazoles can be stabilized by an intermolecular hydrogen bond and may remain in aprotic solvents almost indefinitely. However, in the open air or in water, fast 2H → 1H tautomerization occurs. As follows from density functional theory calculations, the high stability of the 2H form in solution is due to the formation of centrosymmetric dimers, which are more stable than the corresponding dimers of the 1H tautomer.

Crystal structure determination of rac-11'-(1-acetyl-1H-indazol-3-yl)-11',11a'-di-hydro-10'H,17'H-spiro-[indene-2,18'-[5a,16b]methano-tri-indeno[1,2-b:1',2'-d:2'',1''-g]oxocine]-1,3,10',12',17'(10a'H)-penta-one aceto-nitrile 1.5-solvate.

The title compound, C46H26N2O7·1.5CH3CN, is the aldol condensation product of bindone with indazole-3-carbaldehyde followed by double inter-molecular cyclization. The asymmetric unit, which has monoclinic P21/c symmetry, contains two independent mol-ecules of the title compound and three aceto-nitrile mol-ecules. The title mol-ecule comprises a central eight-membered ring, which contains an enol-ester, from which five arms extend. The arms exhibit inter-molecular inter-actions within the crystal lattice between mol-ecules of the title compound and with co-crystallized solvent mol-ecules (aceto-nitrile).

Photoinduced Intramolecular Bifurcate Hydrogen Bond: Unusual Mutual Influence of the Components.

A series of 7-hydroxy-2-methylidene-2,3-dihydro-1H-inden-1-ones with 2-pyrrolyl (3), 4-dimethylaminophenyl (4), 4-nitrophenyl (5), and carboxyl group (6) as substituents at the exocyclic double bond was synthesized in the form of the E-isomers (4-6) or predominantly as the Z-isomer (3) which in solution is converted to the E-isomer. The synthesized compounds and their model analogues were studied by NMR spectroscopy, X-ray analysis, and MP2 theoretical calculations. The E-isomers having intramolecular O-H···O═C hydrogen bond are converted by UV irradiation to the Z-isomers having bifurcated O-H···O···H-X hydrogen bond. Unexpected shortening (and, thus, strengthening) of the O-H···O═C component of the bifurcated hydrogen bond upon the formation of the C═O···H-X hydrogen bond was found experimentally, proved theoretically (MP2), and explained by a roundabout interaction of the H-donor (HX) and H-acceptor (C═O) via the system of conjugated bonds.

Estimating the energy of intramolecular hydrogen bonds from 1H NMR and QTAIM calculations.

The values of the downfield chemical shift of the bridge hydrogen atom were estimated for a series of compounds containing an intramolecular hydrogen bond O-HO, O-HN, O-HHal, N-HO, N-HN, C-HO, C-HN and C-HHal. Based on these values, the empirical estimation of the hydrogen bond energy was obtained by using known relationships. For the compounds containing an intramolecular hydrogen bond, the DFT B3LYP/6-311++G(d,p) method was used both for geometry optimization and for QTAIM calculations of the topological parameters (electron density ρBCP and the density of potential energy V in the critical point of the hydrogen bond). The calculated geometric and topological parameters of hydrogen bonds were also used to evaluate the energy of the hydrogen bond based on the equations from the literature. Comparison of calibrating energies from the 1H NMR data with the energies predicted by calculations showed that the most reliable are the linear dependence on the topological ρBCP and V parameters. However, the correct prediction of the hydrogen bond energy is determined by proper fitting of the linear regression coefficients. To obtain them, new linear relationships were found between the calculated ρBCP and V parameters and the hydrogen bond energies obtained from empirical 1H NMR data. These relationships allow the comparison of the energies of different types of hydrogen bonds for various molecules and biological ensembles.

Hydrogen Bonding in Bis(6-amino-1,3-dimethyluracil-5-yl)-methane Derivatives: Dynamic NMR and DFT Evaluation.

Three bis(6-amino-1,3-dimethyluracil-5-yl)-methane derivatives were studied experimentally by variable-temperature (1)H NMR in polar aprotic solutions (CD2Cl2, C5D5N, C2D2Cl4) and computationally by DFT. The unusual for diarylmethanes coplanar conformation of dimethyluracil rings of each molecule is held by a pair of unequal intramolecular N-H···O hydrogen bonds. We show the presence of two dynamic processes involving breakage/formation of these bonds. First, it is two independent NH2 group rotations, each coupled to nitrogen inversion. Second, it is uracil ring rotations (ring flips). The thermodynamic parameters (ΔH(‡), ΔS(‡), and ΔG(‡)) of both processes were estimated by the full line shape analysis of NMR signals and also by DFT calculations. We demonstrate that, though the ring flips exchange pairs of NH protons, the two processes are not coupled: during the ring flip NH2 groups do not rotate, and during the NH2 rotation the rings do not necessarily rotate. Unlike in many other diarylmethanes, the ring flips in the studied compounds are happening stepwise; i.e., the configuration when both rings are "in flight" at the same time is energetically unfavorable (small degree of "cog wheel effect"). The signs of the ΔS(‡) values indicate that the molecular flexibility increases during the NH2 rotations, but decreases during the ring flips.

Keto-enol tautomerism of phenindione and its derivatives: an NMR and density functional theory (DFT) reinvestigation.

Keto-enol tautomerism of phenindione (2-phenyl-1,3-indandione) and of its 4-phenyl-substituted derivatives was reinvestigated by NMR, supported by density functional theory (DFT) quantum-mechanical calculations. The calculated data quantitatively confirmed the stabilization in DMSO solution of the enol form by a strong hydrogen bond. The symmetry of the NMR spectra of the enol forms was explained by a fast proton transfer between carbonyl oxygen atoms, which is facilitated by the formation of a strong ionic complex of the enol form and an anion. It was shown that keto-enol tautomerization also proceeds with the participation of a similar complex between an anion and the diketo form of 2-phenyl-1,3-indandione.

Intra- and intermolecular hydrogen bonds in pyrrolylindandione derivatives and their interaction with fluoride and acetate: possible anion sensing properties.

The series of push-pull compounds containing the pyrrole ring as a donor and the 1,3-indandione derived moieties as the acceptor unit were synthesized, and strong intramolecular hydrogen bonding in their molecules was studied. In the presence of fluoride and acetate anions their solutions undergo color changes. It was shown by NMR, UV-vis, and quantum chemical calculations including AIM analysis that all these compounds undergo solvent-assisted rupture of the intramolecular hydrogen bond followed by the formation of a strong intermolecular hydrogen bond with fluoride and acetate anions which finally abstract a proton from the pyrrole ring. The insensitivity of the studied compounds to other anions (Cl, Br, HSO4, PF6) is consequence of the instability of the corresponding hydrogen-bonded complexes.

C(Ar)-H···O hydrogen bonds in substituted isobenzofuranone derivatives: geometric, topological, and NMR characterization.

Substituted isobenzofuranone derivatives 1a-3a and bindone 4 are characterized by the presence of an intramolecular C(Ar)-H···O hydrogen bond in the crystal (X-ray), solution ((1)H NMR and specific and nonspecific IEF-PCM solvation model combined with MP2 and B3LYP methods), and gas (MP2 and B3LYP) phases. According to geometric and AIM criteria, the C(Ar)-H···O interaction weakens in 1a-3a (independent of substituent nature) and in 4 with the change in media in the following order: gas phase > CHCl(3) solution > DMSO solution > crystal. The maximum value of hydrogen bond energy is 4.6 kcal/mol for 1a-3a and 5.6 kcal/mol for 4. Both in crystals and in solutions, hydrogen bond strength increases in the order 1a < 2a < 3a with the rising electronegativity of the ring substituents (H < OMe < Cl). The best method for calculating (1)H NMR chemical shifts (δ(calcd) - δ(expl) < 0.7 ppm) of hydrogen bonded and nonbonded protons in 1a-3a and 1b-3b (isomers without hydrogen bonds) is the GIAO method at the B3LYP level with the 6-31G** and 6-311G** basis sets. For the C-H moiety involved in the hydrogen bond, the increase of the spin-spin coupling constant (1)J((13)C-(1)H) by about 7.5 Hz is in good agreement with calculations for C-H bond shortening and for blue shifts of C-H stretching vibrations (by 55-75 cm(-1)).