Solute-solvent Hydrogen Bonds Research Articles

Study on the formation mechanism and effective manipulation of polymorphs and solvates in Osimertinib-Caffeic acid multi-component crystal with distinct properties.

Investigating the formation mechanism and effective manipulation of multi-component crystal polymorphs is crucial for facilitating industrial drug development. Herein, five novel Osimertinib-caffeic acid forms were first strategically tailored by varying solvent selection. Theoretical analysis demonstrated this polymorphism is correlated with multiple hydrogen bond donors-acceptors within multi-component system, which provides manipulation space for reconfiguration of intermolecular interactions and structural competition, while solvent further induced or involved in hydrogen-bonded rearrangements. Molecular dynamics simulation and solvent characterization revealed strong solute-solvent interaction and hydrogen bond donor propensity promoted the generation of hydrate. Small molecular size or large cavity of crystal facilitated solvent entry, resulting in the generation of channel-type solvates. Higher solvation free energy implied faster reaction rate and poorer solvent removal ability for solvates. Thermal analysis confirmed removal of the solvent occupying crystal channels for precursor solvates led to polymorph formation while maintaining the structure. Properties assessments revealed multi-component crystals significantly enhanced the physicochemical properties of Osimertinib. Polymorphs and hydrate exhibited remarkable distinctions in solubility, dissolution rate and physical stability. Nanoindentation and tableting tests confirmed distinct mechanical properties of different forms. Overall, this exploration has the potential to reshape the landscape of multi-component crystal polymorph development, paving the way for manipulating intermolecular interactions.

Role of explicit hydrogen bonding in solvation calculation on the photophysics of 2-(2′-Hydroxyphenyl)oxazolo[4,5-b]pyridine

The photophysics of 2-(2′-hydroxyphenyl)oxazolo[4,5-b]pyridine (HPOP) was theoretically examined by employing the integral equation formalism variant of polarizable continuum model (PCM) at the level of density functional theory with M06 functional. Polar protic methanol and water and aprotic acetonitrile and tetrahydrofuran, which have varied dielectric constants, were considered to study the role of polarity on the photophysics of HPOP and was compared with the results obtained in vacuum. Six different structural forms of HPOP were observed: cis and trans-closed enol, cis and trans-open enol, and cis and trans-keto. cis-closed enol is the most stable and trans-keto the least in the ground state. In the S1 state, cis-keto is the most stable and cis-open enol the most unstable. The relative stabilities of the different structures increase with the polarity of the solvent. The calculations were extended to vacuum and methanol environments by adding two methanol molecules, and similarly done with two water molecules in vacuum and water environments which are explicitly hydrogen bonded to HPOP at different hydrogen bonding centres of HPOP to study the role of solute–solvent hydrogen bond on its photophysics and the changes in results obtained under the PCM formalism. The hydrogen bond between the solute and solvent molecules further increases the relative stabilities of the different hydrogen bonded clusters. The calculations show that the intramolecular proton transfer (IPT) between cis-closed enol and cis-keto is a barrierless process with the transition state displaying a submerged barrier both in S0 and S1 states where the IPT occurs within a single OH stretching vibration. The IPT trajectory is shorter in the S1 state.

The Solvation Shell of Small Solutes in Aqueous-Organic Solvent Mixtures and Its Implications for Reversed-Phase Liquid Chromatography.

Reversed-phase liquid chromatography (RPLC) operates with water-organic solvent (W-OS) mobile phases where preferential solvation (PS) of solutes is likely. To investigate the relevance of the solute solvation shell in the mobile phase for RPLC retention, we combine data from molecular dynamics simulations of small, neutral solutes (six analytes and two dead time markers) in W-methanol (MeOH) and W-acetonitrile (ACN) mixtures with corresponding retention data obtained on an RPLC column over a wide range of W/OS ratios. Data derived from Kirkwood-Buff integrals show PS by the OS for analytes vs low or negative PS for dead time markers. W-ACN mixtures generate a higher amount of PS than W-MeOH mixtures, which contributes to the higher eluent strength of ACN in RPLC. Difference spatial distribution functions reveal anisotropic solvation shells with OS excess at hydrocarbon elements and W excess at functional groups, predicting that retention by the hydrophobic stationary phase is favored by hydrocarbon elements and limited by functional groups. Analysis of solute-solvent hydrogen bonds pinpoints the hydrogen-bond requirements toward W as the retention-limiting factor. The relation between the solute solvation shell and retention confirms the importance of W-OS and solute-W hydrogen bonding for RPLC retention.

Computational analysis of the vibrational spectra and structure of aqueous cytosine.

The recently developed efficient protocol for the explicit quantum mechanical modeling of the structure and IR spectra of liquids and solutions [Katsyuba et al., J. Phys. Chem. B, 2020, 124, 6664-6670] is used to describe aqueous solutions of cytosine. The same cluster model of a solute surrounded by the first solvation shell of solvent molecules was shown to be sufficient to reproduce experimental vibrational frequencies and relative IR and Raman intensities. An equally good quality of Raman spectra was provided by B3LYP-D3/def2-TZVP and B3LYP-D3/aug-cc-pVDZ simulations. Computations using the PBE functional were sufficient for modeling of the IR spectra but failed in the simulations of Raman scattering. It is shown that strong changes of frequencies and relative intensities of Raman and IR bands of cytosine, caused by its hydration, cannot be completely assigned to the influence of hydrogen bonds (HBs) with 7 or 8 closest water molecules. They are rather ascribed to the combined effect of solute-solute and solute-solvent HBs with the participation of at least 30 water molecules separating cytosine from the bulk solvent. This suggests that the vibrational modes and derivatives of the polarizability and dipole moment of the solute are mainly locally influenced by its first hydration shell, while the influence of bulk water is rather modest.

Solvation of serine-based model peptides and the role of the intramolecular OH·O hydrogen bond in interpreting VCD spectra.

Infrared and vibrational circular dichroism (VCD) spectra are occasionally very sensitive to solute-solvent interactions and show distinct spectral changes when strong solute-solvent hydrogen bonds give rise to conformational changes. In this regard, small peptides are ideal model systems to investigate such solvent effects on IR and VCD spectra as they possess several hydrogen bonding donor sites. In the present study, we investigate serine and serine-phenylalanine, which both are N-protected with Boc and C-capped with n-propylamine. Compared to previously studied model peptides, the serine residue introduces a strong hydrogen bonding site that competes with the amides for intra- and intermolecular interactions. For both compounds, we computationally found that the intramolecular OH·O interactions are preferentially broken by DMSO, but it was not sufficient to model only this particular interaction. Instead, depending on the conformer family, it was necessary to consider different numbers of solvent molecules in the computed structures and the experimental spectra were found to be best described by assuming mixed solvation states. Our analyses show that the IR and VCD spectra of molecules with multiple hydrogen bonding cannot be simulated by simply solvating all donor sites as this would neglect the presence of important conformer families. In turn, these results stresss the need for novel routines to account for solvation in IR and VCD spectra, that help estimating the contributions of different solvations states to the conformational distribution.

Free-Energy Landscape of the SN2 Reaction CH3Br + Cl- → CH3Cl + Br- in Different Liquid Environments.

This work describes in detail the reaction path of the well-known SN2 reaction CH3Br + Cl- → CH3Cl + Br-, whose reaction rate has a huge variation with the solvent in the gas phase and in protic and aprotic liquid environments. We employed the ASEC-FEG method to optimize for minima (reactants and products) and saddle points (transition states) in the in-solution free-energy hypersurface. The method takes atomistic details of the solvent into account. A polarizable continuum model (PCM) has also been employed for comparison. The most perceptive structural changes are noted in aqueous solution by using the ASEC-FEG approach. The activation energies in all solvents, estimated by means of free-energy perturbation calculations, are in good agreement with the experimental data. The total solute-solvent hydrogen bonds play an important role in the increased barrier height observed in water and are therefore crucial to explain the huge decrease in the kinetic constant. It is also found that the hydration shell around the ions breaks itself spontaneously to accommodate the molecule, thus forming minimum energy complexes.

Unlocking the power of resonance Raman spectroscopy: The case of amides in aqueous solution

We report a joined experimental and computational study of Raman and Resonance Raman spectra of amides in aqueous solution. By employing state-of-the-art QM/MM methods combined with synchrotron–based UV Resonance Raman spectroscopy, we propose a protocol to interpret and reliably predict Resonance Raman spectra for amide systems in water, which are prototypical system for the peptide bond. We demonstrate that the main experimental spectral features can be correctly reproduced by simultaneously taking into account the dynamical aspects of the solvation phenomenon, specific solute–solvent hydrogen bond interactions and mutual solute–solvent polarization effects.

Peptide-based chiral derivatizing reagents in nano-scale liquid chromatography: Effect of the oxidation state of cysteine moiety on enantioseparation of ibuprofen

Mass spectrometry is a powerful instrument for identifying the structures of target compounds. However, one of the major disadvantages is that mass spectrometry could not directly distinguish between enantiomers. Cysteine, a special amino acid containing a thiol group, can undergo a variety of oxidative modifications. The different redox states of cysteine existing in a peptide or protein may interact differently with the stationary phase in a chromatographic column. In this study, we developed a peptide that can be used as a chiral derivatization reagent for the enantioseparation of drugs using nano-scale liquid chromatography. Ibuprofen, a model analyte to evaluate the chiral separation efficiency of peptide-based derivatizing reagents, is a widely used anti-inflammatory drug. After the peptide derivatizing reagents were micro-coupled with ibuprofen, the solution was injected into a nano-flow column. The separation of the (R) and (S) forms of ibuprofen was performed on the nano-scale, using a C18 75 μm capillary column at a flow rate of 400 nL/min. The results indicated that the peptide AAAACAAAR comprising tri-oxidized cysteine is most suitable for separating (R)- and (S)-ibuprofen at the nano-scale flow rate without using a chiral column. The detection of (R)- and (S)-ibuprofen in only 10 μL human plasma (by pricking the finger) was sufficient with an injection volume of 200 nL. The linear range for detecting the (R) and (S) forms of ibuprofen in plasma was 1–100 μg/mL, the relative standard deviation (RSD) for the precision analyses was below 17 %, and the recovery for the method was 86%–109%. Using the peptide as a chiral derivatization reagent with a suitable cysteine oxidation state, we successfully separated and quantitated the (R) and (S) forms of ibuprofen in commercial tablets and plasma samples. Finally, our computation simulations suggested that the oxidization state of cysteine affects the formation of solute–solvent hydrogen bonds, which might influence the separation efficiency on the C18 column by changing the molecular binding affinity with the column stationary phase.

Understanding the solid-liquid phase equilibrium of 3,5-dimethoxybenzoic acid in thirteen pure solvents by thermodynamic analysis and molecular simulation

The solubility of 3,5-dimethoxybenzoic acid in 13 pure solvents range from 283.15 K to 323.15 K was investigated by the experiments and molecular simulations. Interestingly, its solubility in ethanol shows a particularity that is larger than that in n-butanol, which may be different from the expectation. This phenomenon was analyzed by molecular electrostatic potential surface (MEPs), Hirschfeld surface (HS), and radial distribution function (RDF) simulated by molecular dynamics (MD). The results indicate that the higher solubility of 3,5-dimethoxybenzoic acid in ethanol is due to the solute-solvent and solvent-solvent intermolecular hydrogen bonds. While in the investigation of the solubility in the esters, the relevant results of solvation free energy demonstrate that the solute-solvent interaction is dominant. The experimental data were further correlated with the van't Hoff model, λh model, the modified Apelblat equation and the NRTL model. All the overall ARD values are less than 4%. The modified Apelblat equation presents the best fitting effect. Furthermore, based on the NRTL model, the order of the obtained mixing Gibbs energy is consistent with the solubility order. Besides, its negative value indicates that the mixing process is spontaneous. The solubility of 3,5-dimethoxybenzoic acid in different solvents increases from 2-folds to 5-folds with the increasing temperature, which provides favorable conditions for the separation and purification of 3,5-dimethoxybenzoic acid in industrial production.

Insights on the crossing of the two lowest [formula omitted] and [formula omitted] absorption lines of thieno[3,4-b]pyrazine in an aqueous environment

Different degrees of quantum mechanics and solvation based on a polarizable continuum model and a sequential-QM/MM methodology is applied to investigate the two lowest singlet excited states in the UV–vis spectra of thieno[3,4-b]pyrazine (TPy). The results show that the solvent affects the solute’s photophysics severely, reversing the order of the lowest n-π∗ and π-π∗ lines compared to vacuum conditions. The best description of the crossing-effect between n-π∗ and π-π∗ lines must reconcile explicit solute-solvent hydrogen-bonds (HB) coupled to electrostatic interactions from the bulk. Long-range interactions play a fundamental role in TPy’s photophysics.

Insights into the structural and thermodynamic properties of fullerols [C60(OH)n, n = 12, 14, 16, 18, 20, 22, 24] in aqueous media

In recent years, fullerenes and their amphiphilic derivatives fullerols [C60(OH)n] have received considerable attention of researchers worldwide because of their unique structural and electronic properties that enables numerous industrial and medicinal applications. Because of surface hydroxylation in fullerols [C60(OH)n], one might expect a different behaviour of these hydrophobic-hydrophilic solutes in water. In the present study, we have performed classical molecular dynamics simulations of three different isomers of fullerols [C60(OH)n, where n = 12–24]. Hydration shells of water around these nanoparticles are characterized with the help of radial distribution functions (RDFs) and hydrogen bonding. RDFs indicate the presence of two hydration shells around the central solute molecule for all the isomers. Hydrogen bonding studies reveal that with uniform distribution of hydroxyl groups on fullerene cage, the average number of solute-solvent hydrogen bond increases with an increasing number of hydroxyl groups. The hydration free energy for the isomer with uniform distribution of hydroxyl group is found to be highly negative compared to all other isomers for all the fullerols, which suggests that the effect of surface hydroxylation is more dominant where the hydroxyl groups are uniformly distributed on the fullerene cage.

Free energy gradient for understanding the stability and properties of neutral and charged L-alanine molecule in water

Amino acids exhibit their most important properties in aqueous environment in physiological conditions. These properties are related to their structural changes in water. Although several studies have been performed earlier for obtaining the structure of alanine in a solvent environment, an explicit consideration of the solvent molecular system is still in need. This work uses a Free Energy Gradient method to obtain the structures of alanine with an explicit consideration of the water environment. This is combined with a QM/MM method. Next, the electronic and vibrational properties of L-Alanine in water solution at different pH scales are obtained. The equilibrium structures of L-alanine are obtained in its neutral, anionic and cationic form. A systematic study of the solute-solvent hydrogen bonds was performed to predict the stability of neutral and charged L-alanine molecules. Quantum mechanical calculations were also performed to obtain the infrared spectrum, pH induced changes and to predict NMR parameters such as chemical shifts, magnetic shieldings and spin-spin coupling constants.

CPL Spectra of Camphor Derivatives in Solution by an Integrated QM/MD Approach.

We extend a recently proposed computational strategy for the simulation of absorption spectra of semi-rigid molecular systems in condensed phases to the emission spectra of flexible chromophores. As a case study, we have chosen the CPL spectrum of camphor in methanol solution, which shows a well-defined bisignate shape. The first step of our approach is the quantum mechanical computation of reference spectra including vibrational averaging effects and taking bulk solvent effects into account by means of the polarizable continuum model. In the present case, the large amplitude inversion mode is explicitly treated by a numerical approach, whereas the other small-amplitude vibrational modes are taken into account within the harmonic approximation. Next, the snapshots of classical molecular dynamics computations are clusterized and one representative configuration from each cluster is used to compute a reference spectrum. In the present case, different clusters correspond to the two stable conformers of camphor in the S1 excited electronic state and, for each of them, to different numbers of strong solute-solvent hydrogen bonds. Finally, local fluctuation effects within each cluster are taken into account by means of the perturbed matrix model. The overall procedure leads to good agreement with experiment for absorption and emission spectra together with their chiral counterparts, thus allowing to analyze the role of different effects (stereo-electronic, vibrational, environmental) in tuning the overall experimental spectra.

Atom-Condensed Fukui Function in Condensed Phases and Biological Systems and Its Application to Enzymatic Fixation of Carbon Dioxide.

Local reactivity descriptors such as atom-condensed Fukui functions are promising computational tools to study chemical reactivity at specific sites within a molecule. Their applications have been mainly focused on isolated molecules in their most stable conformation without considering the effects of the surroundings. Here we propose to combine quantum mechanics/molecular mechanics Born-Oppenheimer molecular dynamics simulations to obtain the microstates (configurations) of a molecular system using different representations of the molecular environment and calculate Boltzmann-weighted atom-condensed local reactivity descriptors based on conceptual density functional theory. Our approach takes the conformational fluctuations of the molecular system and the polarization of its electron density by the environment into account, allowing us to analyze the effect of the molecular environment on reactivity. In this contribution, we apply the method mentioned above to the catalytic fixation of carbon dioxide by crotonyl-CoA carboxylase/reductase and study if the enzyme alters the reactivity of its substrate compared with an aqueous solution. Our main result is that the protein environment activates the substrate by the elimination of solute-solvent hydrogen bonds from aqueous solution in the two elementary steps of the reaction mechanism: the nucleophilic attack of a hydride anion from NADPH on the α,β-unsaturated thioester and the electrophilic attack of carbon dioxide on the formed enolate species.

Solvent-Dependent Structures of Natural Products Based on the Combined Use of DFT Calculations and 1H-NMR Chemical Shifts.

Detailed solvent and temperature effects on the experimental 1H-NMR chemical shifts of the natural products chrysophanol (1), emodin (2), and physcion (3) are reported for the investigation of hydrogen bonding, solvation and conformation effects in solution. Very small chemical shift of │Δδ│ < 0.3 ppm and temperature coefficients │Δδ/ΔΤ│ ≤ 2.1 ppb/K were observed in DMSO-d6, acetone-d6 and CDCl3 for the C(1)–OH and C(8)–OH groups which demonstrate that they are involved in a strong intramolecular hydrogen bond. On the contrary, large chemical shift differences of 5.23 ppm at 298 K and Δδ/ΔΤ values in the range of −5.3 to −19.1 ppb/K between DMSO-d6 and CDCl3 were observed for the C(3)–OH group which demonstrate that the solvation state of the hydroxyl proton is a key factor in determining the value of the chemical shift. DFT calculated 1H-NMR chemical shifts, using various functionals and basis sets, the conductor-like polarizable continuum model, and discrete solute-solvent hydrogen bond interactions, were found to be in very good agreement with the experimental 1H-NMR chemical shifts even with computationally less demanding level of theory. The 1H-NMR chemical shifts of the OH groups which participate in intramolecular hydrogen bond are dependent on the conformational state of substituents and, thus, can be used as molecular sensors in conformational analysis. When the X-ray structures of chrysophanol (1), emodin (2), and physcion (3) were used as input geometries, the DFT-calculated 1H-NMR chemical shifts were shown to strongly deviate from the experimental chemical shifts and no functional dependence could be obtained. Comparison of the most important intramolecular data of the DFT calculated and the X-ray structures demonstrate significant differences for distances involving hydrogen atoms, most notably the intramolecular hydrogen bond O–H and C–H bond lengths which deviate by 0.152 tο 0.132 Å and 0.133 to 0.100 Å, respectively, in the two structural methods. Further differences were observed in the conformation of –OH, –CH3, and –OCH3 substituents.

Critical assessment of solvent effects on absorption and fluorescence of 3HF in acetonitrile in the QM/PCM framework: A synergic computational and experimental study

Absorption and fluorescence properties of 3-hydroxyflavone (3HF) dissolved in the polar aprotic solvent acetonitrile have been investigated by electronic spectroscopies, associated to mixed quantum mechanical (QM)/classical calculations, where the effect of the solvent is included at the classical level by means of the polarizable continuum model (QM/PCM).Whereas absorption and fluorescence (λexc = 342 nm) spectra confirmed previous results, a detailed spectrofluorimetric investigation of the anion, deriving from solvent-induced deprotonation of the OH group of 3-hydroxyflavone, showed for the first time that a single anionic form is present in solution, differently from what observed in another polar aprotic solvent, DMSO.A detailed computational study based on Density Functional Theory (DFT), using five different functionals, has been carried out in order to reproduce and better understand absorption and emission bands on the different existing forms for 3HF in solution: Normal (N), Tautomer (T), Anion (A).The results are discussed in terms of solvent effects on 3HF spectroscopic properties. It was found that simulations are in good agreement with the spectroscopic data for the N and T forms, whereas for the A form larger discrepancies are observed, especially for absorption properties. The effect of specific solute solvent hydrogen bond interactions involving the CO and OH moieties of 3HF was also explored, aiming to better simulate anionic spectroscopic properties. Results suggest that a more complete description of the whole solvation shell is necessary.

Unprecedented O:⇔:O compression and H↔H fragilization in Lewis solutions.

Charge injection in terms of lone pairs ':', protons, and ions upon acid and base solvation mediates the hydrogen bonding network and properties of Lewis solutions, and is ubiquitously important in many subject areas of Chemical Physics. This work features the recent progress and future trends in this aspect with a focus on the solute-solvent interactions and hydrogen bond (O:H-O or HB) transition from the vibration mode of ordinary water to the hydrating states. A combination of the O:H-O bond cooperativity notion, differential phonon spectrometrics, calorimetric detection, and quantum computations clarified the solute capabilities of O:H-O bond transition in HX and YOH (X = Cl, Br, I and Y = Li, Na, K) solutions. The H+ and the lone pair do not stay alone to move or shuttle freely between adjacent H2O molecules, but they are attached to a H2O molecule to form (H3O+ and OH-)·4H2O tetrahedral motifs, which transits an O:H-O bond into the H↔H anti-HB point breaker in acidic solutions and into the O:⇔:O super-HB compressor and polarizer in basic solutions, respectively. H↔H disrupts the solvent network and surface stress, having the same effect of liquid heating on HB bond relaxation and thermal fluctuation on surface stress. The O:⇔:O compression lengthens and weakens the solute H-O bond, which heats up the solution during solvation. The H-O bonds due to H3O+ contract by 3% and due to OH- shrink by 10%. The Y+ and X- ions perform in the same manner as they do in salt solutions to form hydration shells through electrostatic polarization and hydrating H2O dipolar screen shielding. Focusing more on the O:H-O bond transition would be even more promising and revealing than on the manner and mobility of lone pair and proton transportation.

Studies of Volumetric and Viscosity Properties in Aqueous Solutions of Imidazolium Based Ionic Liquids at Different Temperatures and at Ambient Pressure

The ionic liquids (ILs) 1,3-dimethyl imidazolium methyl sulfate [MIm][MeSO4] and 1-ethyl-3-methyl imidazolium ethyl sulfate [EMIm][EtSO4] have been synthesized and characterized by 1H NMR, 13C NMR, mass spectrometry, TGA and DSC methods. The densities and viscosities of binary aqueous solutions of [MIm][MeSO4] (0.02458 to 0.18922 mol·kg−1) and [EMIm][EtSO4] (0.01044 to 0.21261 mol·kg−1) are reported at (293.15, 298.15 and 303.15) K and at ambient pressure. Apparent and partial molar volumes of the studied ILs are calculated at the studied concentrations. The limiting partial molar volumes of the studied ILs were obtained using an appropriate extrapolation method. The limiting apparent molar expansivity values at 298.15 K are also obtained. The relative viscosity data are analyzed by applying the Jones–Dole equation and Vand’s equations. Positive viscosity A and B coefficients were observed for both studied ILs, while the D coefficients were also found to be necessary, showing specific behavior depending upon the solute–solute interactions. Calculations of the B coefficients for anions are reported. The application of Vand’s equation to the viscosity data enabled us to calculate the Einstein–Simha factor (ν) and particle interaction coefficient ( $$Q$$ ) for the ion-pairs. The calculated ν values are found to be less than Einstein’s value of 2.5. The results are discussed from the points of view of the water structure making effect, solute–solvent hydrogen bond interaction and the presence of hydrophobic interaction.

DFT-calculated structures based on 1H NMR chemical shifts in solution vs. structures solved by single-crystal X-ray and crystalline-sponge methods: Assessing specific sources of discrepancies

DFT calculations of 1H NMR chemical shifts, using various functionals and basis sets, the conductor-like polarizable continuum model and discrete solute-solvent hydrogen bond interactions have been used to derive the solution structures of methyl salicylate and methyl 2,5-dihydroxybenzoate. We demonstrate that very good agreement between experimental and computed 1H NMR chemical shifts can be obtained for various basis sets. The DFT structures in solution were compared with the recently reported X-ray structure, solved by the crystalline-sponge method, of the methyl salicylate and the single-crystal X-ray structure of methyl 2,5-dihydroxybenzoate. It is demonstrated that the information provided by 1H NMR chemical shifts about the solution structure is significantly more precise than that obtained by the single-crystal X-ray and the crystalline-sponge methods.

Role of solute-solvent hydrogen bonds on the ground state and the excited state proton transfer in 3-hydroxyflavone. A systematic spectrophotometric study.

A detailed account on the photophysics of 3-hydroxyflavone (3HF) in 27 organic solvents is reported. Dual fluorescence of neutral 3HF was observed in protic, polar, and weakly polar solvents, endowed with sufficiently high hydrogen bond accepting and/or donating capabilities. Ground-state solvent-induced 3HF deprotonation was reported in 14 cases. 3HF anion photophysics was investigated, and the deprotonation constant Kdep calculated. Previously reported models (based on solute-solvent intermolecular hydrogen bonds) to explain solvent effects on Excited-State Intramolecular Proton Transfer (ESIPT) and on solvent-induced deprotonation have been re-examined and improved in order to rationalize the observed photophysical behaviour in all the studied solvents. Hydrogen bond donor acidity and hydrogen bond acceptor basicity are shown to be key parameters. The results are discussed in the framework of the use of 3HF as an environment-sensitive fluorescent sensor in several research fields, and as a model system in the study of ESIPT reactions. Solvent effects on 3HF reactivity are also discussed, as the role of the surrounding media on the chemistry of flavonols is an emerging topic in natural product research.