Solvent Shifts Research Articles

Investigation on the performance of PCM/TD-DFT functionals (standard pure, hybrid and long-range corrected) in simulating the absorption and emission spectra of 1-(2,5-dimethylfuran-3-yl)-3-(2,4,5-trimethoxyphenyl)prop-2-en-1-one dye in different solvents

The question investigated in this study is which functional/s of the twelve tested density functionals in combination with PCM-LR can reproduce the absorption and emission spectra of DFTP dye in three solvents with different polarity. DFTP is an abbreviation of 1-(2,5-dimethylfuran-3-yl)-3-(2,4,5-trimethoxyphenyl)prop-2-en-1-one, and it is with D-π-A structure. The twelve functionals range from standard pure to hybrid and long-range corrected functionals. The simulation of the experimental data included the ability to reproduce the maximum wavelength/transition energy of the absorption and emission spectra as well as the Stokes shift in CCL4, ethanol and DMSO solvents. The geometrical parameters and dipole moments of the ground and first excited singlet states were compared and discussed too. The PBE0 functional appears as the best one in reproducing the absorption, emission and Stokes shifts.

Comparison of measured and predicted specific optical rotation in gas and solution phases: A test for the polarizable continuum model of solvation.

A comparative theoretical and experimental study of dispersive optical activity is presented for a set of small, rigid organic molecules in gas and solution phases. Target species were chosen to facilitate wavelength-resolved measurements of specific rotation in rarefied vapors and in organic solvents having different polarities, while avoiding complications due to conformational flexibility. Calculations were performed with two density functionals (B3LYP and CAM-B3LYP) and with the coupled-cluster singles and doubles (CCSD) ansatz, and solvent effects were included through use of the polarizable continuum model (PCM). Across the various theoretical methods surveyed, CCSD with the modified velocity gauge provided the best overall performance for both isolated and solvated conditions. Zero-point vibrational corrections to equilibrium calculations of chiroptical response tended to improve agreement with gas-phase experiments, but the quality of performance realized for solutions varied markedly. Direct comparison of measured and predicted specific-rotation suggests that PCM, in general, is not able to reproduce attendant solvent shifts (neither between gas and solution phases nor among solvents) and fares better in estimating actual medium-dependent values of this property (although the error is rather system dependent). Thus, more elaborate solvation models seem necessary for a proper theoretical description of solvation in dispersive optical activity.

Photo-physics study of a styrylquinoline as inhibitor of Pim-1 kinase: Solvent and concentration effects

7-Nicotinoyl-styrylquinoline (MB96) displays an antiviral activity on HIV-1 infected CEM cell lines and is a promising inhibitor of the serine/threonine-protein Pim-1 kinase. By means of UV–vis spectroscopy supported by theoretical calculations this styrylquinoline is shown to exist in different conformations: the s-trans planar conformation along with other twisted ones with respect to the torsion around the single bond between the quinoline and the phenylethenyl appendage. Hydrogen bonding interactions with the solvent shift the skeleton of the MB96 towards the planar form, enhancing conjugation of π-electrons between the quinoline and the catechol parts, while self-association process seems furthering this planar conformation.

Is there a correlation between the glass forming ability of a drug and its supersaturation propensity?

The use of an enabling formulation technique, such as amorphization of a poorly water-soluble crystalline drug, can result in supersaturation with respect to the crystalline form of the drug and thus potentially in a higher degree of absorption after oral administration. The ease with which such drugs can be amorphized is known as their glass forming ability (GFA). In this study, a potential correlation between GFA and supersaturation propensity is investigated. The GFA of 23 different drugs was determined by melt quenching or milling the crystalline drugs to obtain their respective amorphous forms. The inherent propensity of the drug to supersaturate, i.e. the maximal apparent degree of supersaturation (aDS), and the time until precipitation at a given aDS were determined. Supersaturation was induced via a solvent shift method where the drug was initially dissolved in dimethyl sulfoxide and then added to a biorelevant medium (fasted state simulated intestinal fluid).The study showed that drugs which are good glass formers also have the potential to supersaturate to a high degree (high maximal aDS) whereas drugs that are modest glass formers supersaturate only to a low degree. This correlation was confirmed by principal component analysis, which also indicated that melt enthalpy inversely correlated with both GFA and maximal aDS. However, no correlation between GFA of a drug and the time until precipitation at a given aDS was found.

Computational Design, Synthesis, and Structure Property Evaluation of 1,3-Thiazole-Based Color-Tunable Multi-heterocyclic Small Organic Fluorophores as Multifunctional Molecular Materials.

Probing the chemical space of luminescent organic materials built on novel cores is highly imperative for its potential to expand the horizons of advanced functional materials. Small organic fluorophores possessing therapeutic traits can contribute to theranostics. We coupled computational and classical synthetic chemistry strategies for the rational design of 5-(hetero-2-yl)-1,3-thiazoles as color-tunable fluorophore core. With the aid of DFT and TD-DFT, we prove that the multi-heterocyclic system is built on a thiazole-het core with three inherent tunable sites on thiazole (C2, C4, and C5) capable of accommodating a panoply of substituents as a multifunctional molecular materials' platform. This de novo design offered unprecedented freedom to control strength and direction of charge transfer by varying donor-acceptor fragments. A 30-member fluorophore library built on thiazole-thiophene/furan core was accomplished using commercial reagents by a simple [4 + 1] synthesis. Structure-photophysical property studies revealed large Stokes shift, positive solvatochromism, acidochromism, and color tunability in different solvents and were rationalized using computational calculations. In vitro studies indicated 1a to be active against HL-60 cell lines, suggesting the possibility of expanding the core for theranostics. The lower values of computed hole reorganization energies indicated their potential as hole transporting materials in optoelectronics and widen the scope of these molecules as advanced functional materials.

Photochemistry and photopolymerisation of substituted 2-methylanthraquinones and novel 2-acryloxymethylanthraquinone in radiation curing

Anthraquinones have been the subject of numerous photochemical studies and their photopolymerization activities have been examined under various conditions to improve more efficient photochemical systems. This article involves further detailed investigations into the photophysical, photochemistry and photopolymerisation properties of 4 commercial derivatives of 2-substituted anthraquinone, namely, 2-Bromomethylanthraquinone (2BA), 2-Chloromethylanthraquinone (2CA), 2-Ethylanthraquinone (2EA), 2-Hydroxymethylanthraquinone (2HA) and one novel synthesized anthraquinone, 2-Acryloxymethylanthraquinone (2AA). 2AA is synthesized from 2HA. The results from both spectroscopic and analysis studies proved the 2AA to having the ester link. Absorption spectroscopy and solvent shift data are used to characterise their spectral activity. Luminescence studies involving fluorescence and phosphorescence analysis indicates efficient intersystem crossing to triplet state and n-π* nature of the lowest excited triplet state. The polymerisation activity was studied using methyl methacrylate (MMA) and analysis of the cure rate was measured using the gravimetric method. All the compounds are shown to be highly dependent on the structure. However, the rate of polymerisation (Rp) was reduced in the presence of amine. This is consistent with other results, proving the behaviour of derivatives with n-π* configuration. Hardness tests for all compounds took place using a different formula of acrylated resin/monomer systems. The excited state characteristics of the methyl derivatives have also been examined using micro and nanosecond flash photolysis. Triplet absorption spectra of all the anthraquinone derivatives show a significant red shift in the region of 340–370 nm with increasing solvent polarity due to stabilisation of the lowest triplet state by solvent reorganization. Hydrogen atom abstraction takes place in 2-propanol, forming a semiquinone radical. In the presence of the tertiary amine, triethylamine, all anthraquinone derivatives show the formation of intermediary species related to either the exciplex or the radical ion pair. Under aerobic conditions, the first decay rate for all anthraquinone derivatives increases and showed oxygen to be a good quencher with a bimolecular rate constant of around 2 × 108 mol. dm−3 s−1. Relative to benzophenone, the molar absorption coefficient, ε, and quantum yield of intersystem crossing, ΦISC were calculated, and it is summarised that the value for ΦISC for all compound is less than 1.00 and controls to a major extent their photochemical activities.

Novel nonequilibrium solvation theory for calculating the vertical ionization energies of alkali metal cations and DNA bases in aqueous

Quantitative evaluation of vertical ionization energy (VIE) of solute in solution is a challenge for modern computational chemistry. We derived the expression of VIE in solution and found that the nonequilibrium solvation free energy plays a key role. Using the novel nonequilibrium solvation theory developed by our group, we established the expression of nonequilibrium solvation free energy and implemented its numerical algorithm in PCM part of Q-Chem package. To prove its correctness, the solvation shifts of VIE for alkali metal cations were calculated. The obtained results are in good agreement with available experimental findings. Finally, we investigated the vertical ionization processes of four DNA bases: guanine, adenine, cytosine and thymine. The computed results can reasonably explain the experimental findings and indicate that nonequilibrium polarization is crucial to VIE in solution.

31P NMR Chemical Shifts of Solvents and Products Impurities in Biomass Pretreatments

The identification of chemical impurities is crucial in elucidating the structures of biorefinery products using nuclear magnetic resonance (NMR) spectroscopic analysis. In the current biorefinery platform, contaminants derived from pretreatment solvents and decomposition byproducts may lead to misassignment of the NMR spectra of biorefinery products (e.g, lignin and bio-oils). Therefore, we investigated 54 commonly reported compounds including alcohols, carbohydrates, organic acids, aromatics, aldehydes, and ionic liquids associated with biomass pretreatment using 31P NMR. The chemical shifts of these chemicals after derivatizing with 2-chloro-4,4,5,5-tetramethyl-1,3,2-dioxaphospholane (TMDP) were provided. The 31P NMR signals of these derivatives could serve as valuable and informative spectral data in characterizing lignocellulose-based compounds.

Substituent Effect on Intramolecular Charge Transfer of Symmetric Methoxy-Substituted Bi-1,3,4-oxadiazole Derivatives.

Intramolecular charge-transfer characteristics of a series symmetric methoxy -substituted bi-1,3,4-oxadiazole derivatives with various substituted positions and quantities have been studied with a combination of experimental techniques and theoretical calculations to investigate the substituent effect. Different degrees of fluorescence red shift in polar solvents are observed in these compounds. The meta-substituted molecule (BOXD-m-OCH3) exhibits a larger red shift (82 nm) than the other two monosubstituted molecules, BOXD-o-OCH3 (40 nm) and BOXD-p-OCH3 (37 nm); the polysubstituted molecules BOXD-D1 and BOXD-T1 show 80 and 104 nm red shifts, respectively, which are obviously larger than the monosubstituted molecules. The changes of molecular dipole moment between the ground state and charge transfer (CT) excited state are calculated to be on the same order with the degree of red shift (7.56 D in BOXD-o-OCH3, 12.07 D in BOXD-m-OCH3, 7.38 D in BOXD-p-OCH3, 14.79 D in BOXD-D1, and 16.80 D in BOXD-T1). Theoretical calculations at the density functional theory level reveal that the first singlet excited state of all of these compounds shows both π-π* and CT characteristics and the charge has been proven to transfer from the terminal methoxy phenyl group to the central bioxadiazole group. The analysis of charge transfer based on electron density shows that the greater the amount substituent, the more charge would be involved in the intramolecular charge transfer. In addition, the negative barycenter has a tendency to locate close to the methoxy substituent, which would cause the difference in the charge-transferred distance. The transferred charge and CT distance work jointly and finally lead to differences in dipole moment variation. These findings could provide very good guidance for the design of molecules with intramolecular charge-transfer characteristics.

Electronically Excited States in Solution via a Smooth Dielectric Model Combined with Equation-of-Motion Coupled Cluster Theory.

We present a method for computing excitation energies for molecules in solvent, based on the combination of a minimal parameter implicit solvent model and the equation-of-motion coupled-cluster singles and doubles method (EOM-CCSD). In this method, the solvent medium is represented by a smoothly varying dielectric function, constructed directly from the quantum mechanical electronic density using only two tunable parameters. The solvent-solute electrostatic interactions are computed by numerical solution of the nonhomogeneous Poisson equation and incorporated at the Hartree-Fock stage of the EOM-CCSD calculation by modification of the electrostatic potential. We demonstrate the method by computing excited state transition energies and solvent shifts for several small molecules in water. Results are presented for solvated H2O, formaldehyde, acetone, and trans-acrolein, which have low-lying n → π* transitions and associated blue shifts in aqueous solution. Comparisons are made with experimental data and other theoretical approaches, including popular implicit solvation models and QM/MM methods. We find that our approach provides surprisingly good agreement with both experiment and the other models, despite its comparative simplicity. This approach only requires modification of the Fock operator and total energy expressions at the Hartree-Fock level-solvation effects enter into the EOM-CCSD calculation only through the Hartree-Fock orbitals. Our model provides a theoretically and computationally simple route for accurate simulations of excited state spectra of molecules in solution, paving the way for studies of larger and more complex molecules.

Development of a Video-Microscopic Tool To Evaluate the Precipitation Kinetics of Poorly Water Soluble Drugs: A Case Study with Tadalafil and HPMC.

Many drug candidates today have a low aqueous solubility and, hence, may show a low oral bioavailability, presenting a major formulation and drug delivery challenge. One way to increase the bioavailability of these drugs is to use a supersaturating drug delivery strategy. The aim of this study was to develop a video-microscopic method, to evaluate the effect of a precipitation inhibitor on supersaturated solutions of the poorly soluble drug tadalafil, using a novel video-microscopic small scale setup. Based on preliminary studies, a degree of supersaturation of 29 was chosen for the supersaturation studies with tadalafil in FaSSIF. Different amounts of hydroxypropyl methyl cellulose (HPMC) were predissolved in FaSSIF to give four different concentrations, and the supersaturated system was then created using a solvent shift method. Precipitation of tadalafil from the supersaturated solutions was monitored by video-microscopy as a function of time. Single-particle analysis was possible using commercially available software; however, to investigate the entire population of precipitating particles (i.e., their number and area covered in the field of view), an image analysis algorithm was developed (multiparticle analysis). The induction time for precipitation of tadalafil in FaSSIF was significantly prolonged by adding 0.01% (w/v) HPMC to FaSSIF, and the maximum inhibition was reached at 0.1% (w/v) HPMC, after which additional HPMC did not further increase the induction time. The single-particle and multiparticle analyses yielded the same ranking of the HPMC concentrations, regarding the inhibitory effect on precipitation. The developed small scale method to assess the effect of precipitation inhibitors can speed up the process of choosing the right precipitation inhibitor and the concentration to be used.

A series of terpyridine containing flexible amino diethylacetate derivatives with large two-photon action cross-sections for effective mitochondrial imaging in living liver cancerous cells

Small molecules possess large two-photon action cross sections (Φσ) are highly demanded for biological purpose. Herein, three novel terpyridine containing flexible amino diethylacetate organic small molecules (A1, A2 and A3) were rationally designed and their photophysical properties were investigated both experimentally and theoretically. The results revealed that the three chromophores possess large Φσ and remarkable Stokes' shift in high polar solvents, which are particularly benefit for further biological imaging application. One chromophore (A1) displayed an effective intracellular uptake against lung cancerous living cells A549. Colocalization studies suggested the internalized subcellular compartment was mitochondria. Consequently, chromophore A1 provides a promising platform to directly monitor mitochondria in living cells under two-photon confocal laser scanning microscopy.

High-level Ab Initio Absorption Spectra Simulations of Neutral, Anionic and Neutral+ Chromophore of Green Fluorescence Protein Chromophore Models in Gas Phase and Solution.

Semiclassical ab initio simulations of the absorption spectra of neutral and anionic p-hydroxybenzylidene-2,3-dimethylimidazolinone (p-HBDI), a model chromophore of green fluorescent protein (GFP) and of a positively charged neutral (N+)-HBDI chromophore model, were performed in gas phase with the resolution-of-identity algebraic diagrammatic construction through second-order (RI-ADC(2)) method. The calculated absorption spectra in gas phase are composed of one band centered at 3.51 eV (HBDI), 2.50 eV (HBDI- ) and 3.02 eV ((N+)-HBDI) owing to the absorption of the first 1 ππ* transition. Band maxima are redshifted by ~0.1 eV with respect to the corresponding vertical energies. The COSMO-RI-ADC(2) calculations of the first vertical excitation energy of HBDI, HBDI- and (N+)-HBDI forms in polar solution including microsolvation simulate the observed solvent redshift for neutral HBDI and the solvent blueshift of the HBDI- and (N+)-HBDI forms. The state-specific solvation approach applied to TDDFT calculations reproduced the experimental solvent shifts for the three HBDI forms, demonstrating a more accurate theoretical description as compared to the linear-response TDDFT approach.

A theoretical study of the low-lying excited states and the photophysics of dimethoxy curcumin in cyclohexane and acetonitrile

Two important aspects of the photophysics of dimethoxy curcumin in solvents are theoretically analysed. First, the large Stokes shift in cyclohexane and in acetonitrile is calculated using time-dependent density functional theory with large basis set. Second, a possible explanation is given for the considerable decrease of the nonradiative decay rate in changing from the nonpolar cyclohexane to polar acetonitrile. The solvent is treated using the polarizable continuum model. We analyse different isomers and obtain the absorption transition energies. Similarly, after obtaining the relaxed geometry of the excited state, the emission transition is obtained. In both cases, a red shift of the singlet transition is obtained with increasing solvent polarity. In contrast, the low-lying triplet states are essentially solvent independent. The calculated solvent shift in the emission is in very good agreement with experiment. The Stokes shifts are also in fair agreement with experiment when long-range or dispersion-corrected functionals are used. There are three calculated triplet states lying below the S 1 state. As they are π → π* states, they cannot participate in the intersystem crossing by the El-Sayed rule. However, a fourth triplet state of n → π* nature is found only slightly above the Franck–Condon position of the S 1 state, and the S 1 → T 4 separation increases with the solvent polarity, this being a possible explanation for the decrease of the nonradiative transition.

Automated Supersaturation Stability Assay to Differentiate Poorly Soluble Compounds in Drug Discovery

Increasingly, in vitro assays evaluate a compound's tendency to maintain supersaturation toward improving oral absorption. Throughput remains a challenge and only small sets of compounds are evaluated in reported studies. The present work describes an automated workflow and data analysis approach to determine supersaturation stability after 16 min. Eight increasing concentrations were targeted and supernatant concentration was measured following solvent shift in fasted-state simulated intestinal fluid. The effect of dimethyl sulfoxide both on equilibrium solubility and on induced supersaturation was addressed, whereas the change in concentration was evaluated over time. Our sample set included 24 commercial compounds, along with comparison to literature results. To demonstrate in vivo relevance of in vitro supersaturation, classification of supersaturation stability was proposed based on the target concentration achieved and the percentage of area under the curve dose proportionality in 42 preclinical and clinical studies. Eighty-one percent of low supersaturation stability compounds (target concentrations ≤50 μM) had proportionality <0.8, whereas 100% of high supersaturation stability compounds (target concentrations ≥200 μM) demonstrated proportionality ≥0.8. The robust, automated assay and its impact on dose proportionality downstream make this approach applicable in drug discovery where low-soluble compounds with otherwise attractive properties may be differentiated on the basis of supersaturation stability.

Excited states study reveals the twisted geometry induced large stokes shift in DCM fluorescent dye

The fluorescent dye DCM represents a large Stokes shift in polar solvents which makes it a very attractive material for applications such as solar cells, laser and metal-enhanced fluorescence spectroscopy. The molecular mechanism by which this large Stokes shift is induced is currently not well understood. In this work, we examined the experimental Stokes shift of 162nm (0.69eV) for DCM in ethanol as a commonly used polar solvent and investigated the molecular basis of the underlying shift using a TD-DFT approach. TD-DFT calculations showed the intramolecular charge transfer (ICT) from donor segment (dimethylamino) toward acceptor segment (dicyano) upon S0→S1 excitation. We propose two ICT minima states out of six conceivable twisted emitting S1 minima as the most likely emitting species for the fluorescence emission. These minima correspond to twisting of either the dimethylanilino group or the dimethylamino group (δ and μ torsion, respectively). The adiabatic pathway between LE and twisted dimethylanilino-ICT minimum is energetically preferred to similar pathway between LE and dimethylamino-ICT minima. Our results strongly suggest that the twisted geometry, δ-S1-TransCis geometry, is the emitting S1 state of DCM in ethanol. Molecular understanding of the twisted geometry induced large Stokes shift in DCM dye will help in the design of better strategies for new fluorescent dyes for future applications.

TD-DFT and GIAO-NMR spectroscopy studies for maltose and (α- and β)-glucose in water solution using S-MC/QM polarization methodology

We investigate the behavior of the spectroscopic properties of (α-)β-glucose and maltose in water solution using the S-MC/QM method. TD-CAM-B3LYP/6-311++G(2d,2p) and TD-B3LYP/6-311++G(2d,2p) electronic transitions show strong dependence with the solute polarization in water, indicating a blue shift of the λwater in comparison with λgas–phase results. The NMR spectroscopy shows that the inclusion of the polarization effect and solvent medium - treated as point charge - is essential for a more appropriate description of the variation of the magnetic signature of oxygen atoms. Our results show variations up to 16ppm on the solvent shift for σ(17O) values with CAM-B3LYP functional.

Nuclear Magnetic Shieldings of Stacked Aromatic and Antiaromatic Molecules

Nuclear magnetic shieldings have been calculated at the density functional theory (DFT) level for stacks of benzene, hexadehydro[12]annulene, dodecadehydro[18]annulene, and hexabenzocoronene. The magnetic shieldings due to the ring currents in the adjacent molecules have been estimated by calculating nucleus independent molecular shieldings for the monomer in the atomic positions of neighbor molecules. The calculations show that the independent shielding model works reasonably well for the 1H NMR shieldings of benzene and hexadehydro[12]annulene, whereas for the larger molecules and for the 13C NMR shieldings the interaction between the molecules leads to shielding effects that are at least of the same size as the ring current contributions from the adjacent molecules. A better agreement is obtained when the nearest neighbors are also considered at full quantum mechanical (QM) level. The calculations suggest that the nearest solvent molecules must be included in the quantum mechanical system, at least when estimating solvent shifts at the molecular mechanics (MM) level. Current density calculations show that the stacking does not significantly affect the ring current strengths of the individual molecules, whereas the shape of the ring current for a single molecule differs from that of the stacked molecules.

Modeling the absorption spectrum of the permanganate ion in vacuum and in aqueous solution.

The absorption spectrum of the MnO4- ion has been a test-bed for quantum-chemical methods over the last decades. Its correct description requires highly-correlated multiconfigurational methods, which are incompatible with the inclusion of finite-temperature and solvent effects due to their high computational demands. Therefore, implicit solvent models are usually employed. Here we show that implicit solvent models are not sufficiently accurate to model the solvent shift of MnO4-, and we analyze the origins of their failure. We obtain the correct solvent shift for MnO4- in aqueous solution by employing the polarizable embedding (PE) model combined with a range-separated complete active space short-range density functional theory method (CAS-srDFT). Finite-temperature effects are taken into account by averaging over structures obtained from ab initio molecular dynamics simulations. The explicit treatment of finite-temperature and solvent effects facilitates the interpretation of the bands in the low-energy region of the MnO4- absorption spectrum, whose assignment has been elusive.

ChemInform Abstract: Excited States Behavior of Nucleobases in Solution: Insights from Computational Studies

AbstractReview: 139 refs.