Very Strong Hydrogen Bond in Nitrophthalic Cocrystals.

This work presents the studies of a very strong hydrogen bond (VSHB) in biologically active phthalic acids. Research on VSHB comes topical due to its participation in many biological processes. The studies cover the modelling of intermolecular interactions and phthalic acids with 2,4,6-collidine and N,N-dimethyl-4-pyridinamine complexes with aim to obtain a VSHB. The four synthesized complexes were studied by experimental X-ray, IR, and Raman methods, as well as theoretical Car-Parrinello Molecular Dynamics (CP-MD) and Density Functional Theory (DFT) simulations. By variation of the steric repulsion and basicity of the complex' components, a very short intramolecular hydrogen bond was achieved. The potential energy curves calculated by the DFT method were characterized by a low barrier (0.7 and 0.9 kcal/mol) on proton transfer in the OHN intermolecular hydrogen bond for 3-nitrophthalic acid with either 2,4,6-collidine or N,N-dimethyl-4-pyridinamine cocrystals. Moreover, the CP-MD simulations exposed very strong bridging proton dynamics in the intermolecular hydrogen bonds. The accomplished crystallographic and spectroscopic studies indicate that the OHO intramolecular hydrogen bond in 4-nitrophthalic cocrystals is VSHB. The influence of a strong steric effect on the geometry of the studied cocrystals and the stretching vibration bands of the carboxyl and carboxylate groups was elaborated.

UV Laser-Induced Phototransformations of Matrix-Isolated 5-Chloro-3-nitro-2-hydroxyacetophenone.

Conformational changes of 5-chloro-3-nitro-2-hydroxyacetophenone were studied by experimental and theoretical methods. Phototransformations of the compound were induced in low-temperature argon matrices by using UV radiation, which was followed by FT-IR measurements. Two types of changes within the molecule were detected: rotations of the hydroxyl and acetyl groups. A new conformer without an intramolecular hydrogen bond was generated upon irradiation with λ = 330 nm, whereas the reverse reaction was observed at 415 nm.

Inter- vs. Intra-Molecular Hydrogen Bond in Complexes of Nitrophthalic Acids with Pyridine.

This study covers the analysis of isomeric forms of nitrophthalic acids with pyridine. This work dwells on the complementary experimental (X-ray, IR and Raman) and theoretical (Car-Parrinello Molecular Dynamics (CPMD) and Density Functional Theory (DFT)) studies of the obtained complexes. The conducted studies showed that steric repulsion between the nitro group in ortho-position and the carboxyl group causes significant isomeric changes. Modeling of the nitrophthalic acid-pyridine complex yielded a short strong intramolecular hydrogen bond (SSHB). The transition energy from the isomeric form with an intermolecular hydrogen bond to the isomeric form with an intramolecular hydrogen bond was estimated.

Comparison of Proton Acceptor and Proton Donor Properties of H2O and H2O2 in Organic Crystals of Drug-like Compounds: Peroxosolvates vs. Crystallohydrates.

Two new peroxosolvates of drug-like compounds were synthesized and studied by a combination of X-ray crystallographic, Raman spectroscopic methods, and periodic DFT computations. The enthalpies of H-bonds formed by hydrogen peroxide (H2O2) as a donor and an acceptor of protons were compared with the enthalpies of analogous H-bonds formed by water (H2O) in isomorphic (isostructural) hydrates. The enthalpies of H-bonds formed by H2O2 as a proton donor turned out to be higher than the values of the corresponding H-bonds formed by H2O. In the case of H2O2 as a proton acceptor in H-bonds, the ratio appeared reversed. The neutral O∙∙∙H-O/O∙∙∙H-N bonds formed by the lone electron pair of the oxygen atom of water were the strongest H-bonds in the considered crystals. In the paper, it was found out that the low-frequency Raman spectra of isomorphous crystalline hydrate and peroxosolvate of N-(5-Nitro-2-furfurylidene)-1-aminohydantoin are similar. As for the isostructural hydrate and peroxosolvate of the salt of protonated 2-amino-nicotinic acid and maleic acid monoanion, the Raman spectra are different.

Combination of "Buttressing" and "Clothespin" Effects for Reaching the Shortest NHN Hydrogen Bond in Proton Sponge Cations.

A series of previously unknown 2,4,5-tri- and 2,4,5,7-tetrasubstituted 1,8-bis(dimethylamino)naphthalenes and their salts with HBF4 containing bulky spherically shaped substituents (Me, Br, and SiMe3) in the naphthalene ring has been synthesized. Using XRD analysis of 11 samples, the influence of the so-called "buttressing" and "clothespin" effects on their molecular structure and the NHN hydrogen bond geometry in the solid cations were investigated. The combined action of both effects has been shown to significantly increase the compression of the hydrogen bond. As a result, the previous record of the hydrogen bond shortness (N···N = 2.524 Å) has been surpassed in favor of 2.502 Å found for the tetrafluoroborate of 2,4,5,7-tetramethyl-1,8-bis(dimethylamino)naphthalene. The molecular structure of the latter differs by perfect symmetry and practically barrier-free proton transfer in the [NHN]+ bond. On the basis of the results of quantum-chemical calculations, it is suggested that the value of 2.502 Å likely represents or lies very close to the theoretical limit for the short hydrogen bonds between the amine-type nitrogen atoms.

Spectroscopic Identification of Hydrogen Bond Vibrations and Quasi-Isostructural Polymorphism in N-Salicylideneaniline.

The ortho-hydroxy aryl Schiff base 2-[(E)-(phenylimino)methyl]phenol and its deutero-derivative have been studied by the inelastic incoherent neutron scattering (IINS), infrared (IR) and Raman experimental methods, as well as by Density Functional Theory (DFT) and Density-Functional Perturbation Theory (DFPT) simulations. The assignments of vibrational modes within the 3500-50 cm-1 spectral region made it possible to state that the strong hydrogen bond in the studied compound can be classified as the so-called quasi-aromatic bond. The isotopic substitution supplemented by the results of DFT calculations allowed us to identify vibrational bands associated with all five major hydrogen bond vibrations. Quasi-isostructural polymorphism of 2-[(E)-(phenylimino)methyl]phenol (SA) and 2-[(E)-(phenyl-D5-imino)methyl]phenol (SA-C6D5) has been studied by powder X-ray diffraction in the 20-320 K temperature range.

Polymorphism and Conformational Equilibrium of Nitro-Acetophenone in Solid State and under Matrix Conditions.

Conformational and polymorphic states in the nitro-derivative of o-hydroxy acetophenone have been studied by experimental and theoretical methods. The potential energy curves for the rotation of the nitro group and isomerization of the hydroxyl group have been calculated by density functional theory (DFT) to estimate the barriers of the conformational changes. Two polymorphic forms of the studied compound were obtained by the slow and fast evaporation of polar and non-polar solutions, respectively. Both of the polymorphs were investigated by Infrared-Red (IR) and Raman spectroscopy, Incoherent Inelastic Neutron Scattering (IINS), X-ray diffraction, nuclear quadrupole resonance spectroscopy (NQR), differential scanning calorimetry (DSC) and density functional theory (DFT) methods. In one of the polymorphs, the existence of a phase transition was shown. The position of the nitro group and its impact on the crystal cell of the studied compound were analyzed. The conformational equilibrium determined by the reorientation of the hydroxyl group was observed under argon matrix isolation. An analysis of vibrational spectra was achieved for the interpretation of conformational equilibrium. The infrared spectra were measured in a wide temperature range to reveal the spectral bands that were the most sensitive to the phase transition and conformational equilibrium. The results showed the interrelations between intramolecular processes and macroscopic phenomena in the studied compound.

Modeling Biologically Important NH···π Interactions Using peri-Disubstituted Naphthalenes.

For the first time, systematic studies of 8-aryl and 8-pyrrolyl derivatives of 1-aminonaphthalene as simple, synthetically available, and nicely preorganized models were conducted for a better understanding the properties of NH···π interactions involved in the stabilization of the secondary and tertiary protein structures as well as the recognition of guest molecules by biological receptors. It was shown that the NH···π binding is especially effective when the NH-donor is a positively charged group, for example, Me2NH+, and the π-donor is an electron-rich aromatic substituent, in particular, the 1-pyrrolyl or the 4-hydroxyphenyl group. Using protonated tetrafluoroborate salts, a strong counterion effect was demonstrated by means of theoretical calculations. Through several mechanisms, including short CH···F contacts, bifurcation, and long-range dispersion, the counterion promotes considerable structural changes and weakens the NH···π interactions from 12-15 kcal mol-1 in "naked" cations to 5-9 kcal mol-1 in the salts. To this end, 8-(2,5-dimethylpyrrol-1-yl)-N,N-dimethylnaphthalene-1-ammonium tetrafluoroborate, with the record linearity and shortness (2.07 Å) of the NH···π-centroid bond, was recognized as the most appropriate model with the strongest NH···π interaction ever described.

H/D Isotope Effects on 1H-NMR Chemical Shifts in Cyclic Heterodimers and Heterotrimers of Phosphinic and Phosphoric Acids.

Hydrogen-bonded heterocomplexes formed by POOH-containing acids (diphenylphosphoric 1, dimethylphosphoric 2, diphenylphosphinic 3, and dimethylphosphinic 4) are studied by the low-temperature (100 K) 1H-NMR and 31P-NMR using liquefied gases CDF3/CDF2Cl as a solvent. Formation of cyclic dimers and cyclic trimers consisting of molecules of two different acids is confirmed by the analysis of vicinal H/D isotope effects (changes in the bridging proton chemical shift, δH, after the deuteration of a neighboring H-bond). Acids 1 and 4 (or 1 and 3) form heterotrimers with very strong (short) H-bonds (δH ca. 17 ppm). While in the case of all heterotrimers the H-bonds are cyclically arranged head-to-tail, ···O=P-O-H···O=P-O-H···, and thus their cooperative coupling is expected, the signs of vicinal H/D isotope effects indicate an effective anticooperativity, presumably due to steric factors: when one of the H-bonds is elongated upon deuteration, the structure of the heterotrimer adjusts by shortening the neighboring hydrogen bonds. We also demonstrate the formation of cyclic tetramers: in the case of acids 1 and 4 the structure has alternating molecules of 1 and 4 in the cycle, while in case of acids 1 and 3 the cycle has two molecules of 1 followed by two molecules of 3.

Inter- vs. Intramolecular Hydrogen Bond Patterns and Proton Dynamics in Nitrophthalic Acid Associates.

Noncovalent interactions are among the main tools of molecular engineering. Rational molecular design requires knowledge about a result of interplay between given structural moieties within a given phase state. We herein report a study of intra- and intermolecular interactions of 3-nitrophthalic and 4-nitrophthalic acids in the gas, liquid, and solid phases. A combination of the Infrared, Raman, Nuclear Magnetic Resonance, and Incoherent Inelastic Neutron Scattering spectroscopies and the Car-Parrinello Molecular Dynamics and Density Functional Theory calculations was used. This integrated approach made it possible to assess the balance of repulsive and attractive intramolecular interactions between adjacent carboxyl groups as well as to study the dependence of this balance on steric confinement and the effect of this balance on intermolecular interactions of the carboxyl groups.

Neutral Pyrrole Nitrogen Atom as a π- and Mixed n,π-Donor in Hydrogen Bonding.

9-Dimethylaminobenzo[ g]indoles 3-6 and 1-dimethylamino-8-(pyrrolyl-1)naphthalene 7 were examined as possible models for establishing the ability of the pyrrole nitrogen atom to participate in [NHN]+ hydrogen bonding as a proton acceptor. Indoles 3-5 (to a lesser extent 6) form rather stable tetrafluoroborates, with the proton mostly located on the NMe2 group but simultaneously engaged in the formation of a charged intramolecular [NHN]+ hydrogen bond (IHB) with the pyrrole N atom. The theoretically estimated energies of IHB in salts 3H+BF4--6H+BF4- vary between 7.0-10.7 and 6.2-7.0 kcal mol-1 in vapor and MeCN, respectively. The pyrrole N atom undergoes a perceptible pyramidalization but still remains involved in the 6π-electron aromatic system, suggesting that the hydrogen bonding in salts 3H+BF4--6H+BF4- represents a previously unknown mixed NH···N(n,π) interaction. Despite the favorable orientation of the N-H bond and the pyrrole ring in salt 7H+BF4-, no signs of NH···N(n) bonding in it were noticed, and the existing interaction was classified as pure NH···N(π). The results obtained may be useful in studies of secondary protein structures, especially those α-helix sections which contain tryptophan residues.

Impact of the Keto-Enol Tautomeric Equilibrium on the BODIPY Chromophore.

An intramolecular tautomeric fluorescent BODIPY sensor has been designed and synthesized. The obtained BODIPY dye is a combination of the 4-bora- 3a, 4a-diaza- s-indacene core and a diketone fragment. The study of conformational equilibria in the ground and excited states has been completed for a broad range of solvent polarity by steady state and NMR methods as well as by DFT and TD-DFT calculations. The interpretation of the unique emission observed in hydrogen bond accepting solvents upon the excitation of the fluorescent dye in the S0-S2 transition has been accomplished. The Jablonski diagram has been analyzed for the observed processes in the BODIPY dye studied on the basis of DFT and TD-DFT calculations.

Some Brief Notes on Theoretical and Experimental Investigations of Intramolecular Hydrogen Bonding.

A review of selected literature data related to intramolecular hydrogen bonding in ortho-hydroxyaryl Schiff bases, ortho-hydroxyaryl ketones, ortho-hydroxyaryl amides, proton sponges and ortho-hydroxyaryl Mannich bases is presented. The paper reports on the application of experimental spectroscopic measurements (IR and NMR) and quantum-mechanical calculations for investigations of the proton transfer processes, the potential energy curves, tautomeric equilibrium, aromaticity etc. Finally, the equilibrium between the intra- and inter-molecular hydrogen bonds in amides is discussed.

Comparison of resonance assisted and charge assisted effects in strengthening of hydrogen bonds in dipyrrins.

This paper deals with the study of two types of hydrogen bonding: a quasi-aromatic hydrogen bonding in dipyrromethene and the ionic one in dipyrromethane. The study focuses on two phenomena-the proton transfer process and tautomeric equilibrium. Metric parameters and spectroscopic assignments have been calculated; this allowed a further comparison of spectral features calculated with four methods (Car-Parrinello molecular dynamics (CPMD), ab initio, density functional theory (DFT), and numerical calculation of anharmonic vibrational levels via a solution of the corresponding 1D Schrödinger equation). A significant dynamics of the bridged proton and bent vibration of pyrrole fragments in dipyrromethane have been exposed by the CPMD calculations. The prevailing of the ionic effect over the π-electronic coupling in the strengthening of the hydrogen bonding has been shown on the basis of the calculated structural, electron-topological, and spectral data as well as potential energy surface (PES). The analysis of the aromaticity and electronic state of pyrrole and chelate moieties depending on the tautomeric equilibrium by the quantum theory of atoms in molecules (QTAIM) method was conducted. The principle divergence in the behavior of aromaticity of the chelate chains in the analyzed compounds was demonstrated.

Renewed spectroscopic and theoretical research of hydrogen bonding in ascorbic acid.

The studies of two isomers of ascorbic acid and their deuteroanalogues, presented in the paper, have been accomplished by vibrational spectroscopy methods and quantum-chemical simulations. The spectroscopic research of L-ascorbic and D-isoascorbic acids have been carried out by the infrared (IR) and Raman (R) techniques. On the basis of the obtained results the spectral interpretation of the hydrogen bonded groups of ascorbic acids has been performed. Car-Parrinello Molecular Dynamics (CPMD) and Density Functional Theory (DFT) have been employed to support spectroscopic experimental findings and shed light onto the bridged proton dynamics in the L- and D- isomers of ascorbic acids. The accurate assignments of the hydrogen bond modes have been accomplished with the application of deuterosubstitution, CPMD-solid state simulations and Potential Energy Distribution (PED) analysis. The spectral and structural results have shown that dependency ν(OH) = f(γ(OH)) is the most common for the OHO hydrogen bond, whereas dependency d(OO) = f(γ(OH)) differs as for the ionic and resonance assisted hydrogen bonds.

Impact of proton transfer phenomena on the electronic structure of model Schiff bases: an AIM/NBO/ELF study.

Understanding of the electronic structure evolution due to a proton dynamics is a key issue in biochemistry and material science. This paper reports on density functional theory calculations of Schiff bases containing short, strong intramolecular hydrogen bonds where the bridged proton is located: (i) at the donor site, (ii) strongly delocalized, and (iii) at the acceptor site. The mobility of the bridged proton and its influence on the molecular structure and properties of the chosen Schiff base derivatives have been investigated on the basis of Atoms in Molecules, Natural Bond Orbitals, and Electron Localization Function theories. It has been observed that the extent of the bridged proton delocalization is strongly modified by the steric and inductive effects present in the studied compounds introduced by various substituents. It has been shown that: (i) potential energy profiles for the proton motion are extremely dependent on the substitution of the aromatic ring, (ii) the topology of the free electron pairs present at the donor∕acceptor site, as well as their electron populations, are affected qualitatively by the bridged proton position, (iii) the distortion of the molecular structure due to the bridged proton dynamics includes the atomic charge fluctuations, which are in some cases non-monotonic, and (iv) topology of the ELF recognizes events of proton detachment from the donor and attachment to the acceptor. The quantitative and qualitative results shed light onto molecular consequences of the proton transfer phenomena.

Photochromic cycle of 2'-hydroxyacetophenone azine studied by absorption and emission spectroscopy in different solvents.

This paper reports on the investigations of the synthesized di-(o-hydroxyaryl ketoimine) compound by the steady state absorption and emission techniques as well as picosecond time resolved emission and femtosecond transient absorption methods in different solvents. The results of the experimental observation have been supported by the theoretical DFT and TD-DFT calculations. The theoretical data have revealed the completed influence of the environmental polarity on particular conformers of studied compound. Dependencies between the activation rate constant and polarizability function as well as Kamlet-Abbond-Taft hydrogen-bonding parameter have been obtained in different solvent. The mechanism of photodynamic changes of di-(o-hydroxyaryl ketoimine) is presented.

H/D isotope effects in hydrogen bonded systems.

An extremely strong H/D isotope effect observed in hydrogen bonded A-H…B systems is connected with a reach diversity of the potential shape for the proton/deuteron motion. It is connected with the anharmonicity of the proton/deuteron vibrations and of the tunneling effect, particularly in cases of short bridges with low barrier for protonic and deuteronic jumping. Six extreme shapes of the proton motion are presented starting from the state without possibility of the proton transfer up to the state with a full ionization. The manifestations of the H/D isotope effect are best reflected in the infra-red absorption spectra. A most characteristic is the run of the relationship between the isotopic ratio nH/nD and position of the absorption band shown by using the example of NHN hydrogen bonds. One can distinguish a critical range of correlation when the isotopic ratio reaches the value of ca. 1 and then increases up to unusual values higher than . The critical range of the isotope effect is also visible in NQR and NMR spectra. In the critical region one observes a stepwise change of the NQR frequency reaching 1.1 MHz. In the case of NMR, the maximal isotope effect is reflected on the curve presenting the dependence of Δd (¹H,²H) on d (¹H). This effect corresponds to the range of maximum on the correlation curve between dH and ΔpKa that is observed in various systems. There is a lack in the literature of quantitative information about the influence of isotopic substitution on the dielectric properties of hydrogen bond except the isotope effect on the ferroelectric phase transition in some hydrogen bonded crystals.

Triple hydrogen bonding in a circular arrangement: ab initio, DFT and first-principles MD studies of tris-hydroxyaryl enamines.

First-principles Car-Parrinello molecular dynamics, ab initio (MP2) and density functional schemes have been used to explore the tautomeric equilibrium in three tris(amino(R)methylidene)cyclohexane-1,3,5-triones (R = hydrogen, methyl or phenyl group). The dynamic nature of the cyclic hydrogen bonding has been studied by the first-principles MD method. The comparison of the results obtained by aforesaid methods has been accomplished on the basis of calculations of structural and spectroscopic characteristics of the compounds. The conformational analysis of the studied compounds has been carried out at the MP2/6-31+G(d,p) and B3LYP/6-31+G(d,p) levels of theory. The influence of steric and electronic effects on the cyclic hydrogen bonding has been analysed. The extent of the proton delocalization has been modified by the substituents according to the sequence: hydrogen < phenyl < methyl. This fact is verified by the spectroscopic and structural data as well as the energy potential curve. A prevalence of the keto-enamine tautomeric form has been observed in the static ab initio and DFT models, and confirmed by the first-principles MD.

Rational design, synthesis, and spectroscopic and photophysical properties of a visible-light-excitable, ratiometric, fluorescent near-neutral pH indicator based on BODIPY.

A visible-light-excitable, ratiometric, brightly fluorescent pH indicator for measurements in the pH range 5-7 has been designed and synthesized by conjugatively linking the BODIPY fluorophore at the 3-position to the pH-sensitive ligand imidazole through an ethenyl bridge. The probe is available as cell membrane permeable methyl ester 8-(4-carbomethoxyphenyl)-4,4-difluoro-3-[2-(1H-imidazol-4-yl)ethenyl]-1,5,7-trimethyl-3a,4a-diaza-4-bora-s-indacene (I) and corresponding water-soluble sodium carboxylate, sodium 8-(4-carboxylatophenyl)-4,4-difluoro-3-[2-(1H-imidazol-4-yl)ethenyl]-1,5,7-trimethyl-3a,4a-diaza-4-bora-s-indacene (II). The fluorescence quantum yield Φ(f) of ester I is very high (0.8-1.0) in the organic solvents tested. The fluorescence lifetime (ca. 4 ns) of I in organic solvents with varying polarity/polarizability (from cyclohexane to acetonitrile) is independent of the solvent with a fluorescence rate constant k(f) of 2.4×10(8) s(-1). Probe I is readily loaded in the cytosol of live cells, where its high fluorescence intensity remains nearly constant over an extended time period. Water-soluble indicator II exhibits two acid-base equilibria in aqueous solution, characterized by pK(a) values of 6.0 and 12.6. The Φ(f) value of II in aqueous solution is high: 0.6 for the cationic and anionic forms of the imidazole ligand, and 0.8 for neutral imidazole. On protonation-deprotonation in the near-neutral pH range, UV/Vis absorption and fluorescence spectral shifts along with isosbestic and pseudo-isoemissive points are observed. This dual-excitation and dual-emission pH indicator emits intense green-yellow fluorescence at lower pH and intense orange fluorescence at higher pH. The influence of ionic strength and buffer concentration on the absorbance and steady-state fluorescence of II has also been investigated. The apparent pK(a) of the near-neutral acid-base equilibrium determined by spectrophotometric and fluorometric titration is nearly independent of the added buffer and salt concentration. In aqueous solution in the absence of buffer and in the pH range 5.20-7.45, dual exponential fluorescence decays are obtained with decay time τ(1)=4.3 ns for the cationic and τ(2)=3.3 ns for the neutral form of II. The excited-state proton exchange of II at near-neutral pH becomes reversible on addition of phosphate (H(2)PO(4)(-)/HPO(4)(2-)) buffer, and a pH-dependent change of the fluorescence decay times is induced. Global compartmental analysis of fluorescence decay traces collected as a function of pH and phosphate buffer concentration was used to recover values of the deactivation rate constants of the excited cationic (k(01)=2.4×10(8) s(-1)) and neutral (k(02)=3.0×10(8) s(-1)) forms of II.