The structural role of solvation phenomena in bioorganic compounds has been documented sporadically over the last two decades, although they are of fundamental importance in a variety of chemical, physical, and biological processes. NMR chemical shifts depend on the electron densities around the nuclei, which can be influenced by the surrounding environment. Solvent-dependent chemical shift variations, therefore, can provide important structural information on solute-solvent interactions, especially nuclei, which belong to polar groups, such as OH, NH, CONH, COOH, etc. Recent developments in quantum chemical methods for calculating NMR chemical shifts, especially those incorporating explicit solvent effects, and the exponential advances in computer power can provide an excellent methodology for the accurate calculation of chemical shifts in solution. Furthermore, comparison of density functional theory (DFT) calculated activation free energies with NMR experimentally determined values can provide a reliable method for investigating the role of solvents in various atomistic reaction mechanisms. It has been demonstrated that the combined use of NMR and DFT calculations represents the new frontier of our understanding of the role of solvents, at the atomic level, in molecular structures and in catalytic reactions of bioorganic molecules, natural products and model compounds.

Conjugated polymer nanoparticles (CPNs) have gained significant attention as promising nanomaterials for cancer theranostics, particularly in fluorescence imaging and therapy, where early detection and image-guided surgery are crucial for effective treatment. Despite growing interest, there remains a notable gap in the literature regarding rational design strategies and clear structure-property relationships for CPN development. Comprehensive design rules that guide the production of CPNs with optimized performance are still lacking, hindering the systematic advancement of this field. Addressing this gap, we synthesized a series of new donor-acceptor (D-A) conjugated polymers (CPs), each incorporating a common acceptor unit paired with three distinct donor groups to assess their impact on optical and biological properties. The resulting nanoparticles exhibited excellent characteristics as fluorescent contrast agents, including enhanced fluorescence intensity in aqueous media along with favorable photostability. Studies using human colorectal carcinoma (HCT-116) and human umbilical vein endothelial cells (HUVEC) confirmed the CPNs' nontoxic nature, strong fluorescence, and biocompatibility. Notably, this study is the first to investigate the cellular uptake mechanism of CPNs in HCT-116 cells, offering valuable insights into their biological interactions. These findings not only demonstrate the potential of these newly developed CPNs for fluorescence imaging of HCT-116 but also underscore the urgent need for rational design frameworks to guide the future development of next-generation CPNs.

Accurate dissociation constants of the carboxylic groups of free fatty acids in aqueous solution are unknown, and a wide range of values extending over 5 pKa units have been suggested. We reinvestigated the problem with the use of 1H and 13C NMR and DFT methods and demonstrate that the pKa values fall within those of typical organic acids.

Overcoming line broadening of labile protons and achieving high-resolution NMR spectra is crucial for the structural and conformational analysis of organic molecules. Recently, Ma et al. (Magn. Reson. Chem. 2024, 62, 198-207) demonstrated the effectiveness of 2,2,2-trifluoroacetic acid (TFA) in sharpening NMR signals for nitrogen-containing compounds which exhibit prototropic tautomerization or conformational isomerism using high molar ratio of [acids]/[solute] similar to 5 to 200. In this commentary, we provide an overview of earlier publications and highlight the extensive applications of TFA in enhancing NMR resolution across a variety of organic functional groups, with the use of very small ratios of [acids]/[solute] similar to 10(-3) to 10(-2). The prospects for the unequivocal structure analysis using labile protons as the starting point will be analyzed.

Base-catalyzed H/D exchange reactions through keto-enol tautomeric equilibrium are a textbook example in mechanistic organic chemistry. The pH effect of H2O catalysis, however, is largely unknown. We report, herein, variable temperature and pD 1H NMR studies of the experimental activation enthalpy , entropy , and Gibbs free energy of H/D exchange reactions of the H-6 and H-8 protons belonging to ring A of the natural product taxifolin. The experimental values range from similar to 25 to 23 kcal mol-1 for pD values of 6.1 to 9.6 and a buffer concentration in the range of 25 to 1000 mM. Differences in values of neutral and anionic taxifolin and phloroglucinol were found to be very small (<= 1.5 kcal mol-1). The experimental data of taxifolin and phloroglucinol were compared with DFT calculations with two up to four H2O molecules explicitly present, which demonstrate a unique catalytic role of H2O of over 35 kcal mol-1. Excellent agreement between and DFT calculated Gibbs free activation energies, , was obtained with the use of three molecules of H2O for the neutral state of phloroglucinol (with the "in-in" configuration of the phenol OH groups) and taxifolin. In the ionic form of phloroglucinol, the mechanistic pathway with two molecules of H2O in the transition state (one of which involves the C 00000000 00000000 00000000 00000000 11111111 00000000 11111111 00000000 00000000 00000000 O moiety) showed very good agreement with the experimental data. For the anionic form of taxifolin, the mechanistic pathway with three molecules of H2O in the transition state showed excellent agreement with the experimental values. Among the various functionals used, the APFD/6-31+G(d) and B3LYP/6-31+G(d)/GD3BJ resulted in optimum agreement with . The enthalpic term is considerably larger than the entropic term , in agreement with the experimental data. This indicates a dissociative mechanism of the loosely bound activated complex. The present results demonstrate the unique catalytic role of two and/or three molecules of H2O, through keto-enol tautomerization, with minor contribution of base-catalysis, in H/D exchange reactions in aromatic systems.

Phytochemical investigation of the n-hexane-soluble fraction of the aqueous ethanol extract of the aerial parts of Hypericum helianthemoides (Spach) Boiss. (Hypericaceae), furnished four undescribed polycylic polyprenylated benzoylphloroglucinols (PPBPs) 1-4, together with phytyl formate (5) and thirteen previously reported prenylated phloroglucinol derivatives, including yezo'otogirin C (6), hyperibrins A (7) and F (8), hyperibones G (9), J (10), La (11a)/Lb (11b), 7-epi-clusianone a (12a)/7-epi-clusianone b (12b), and hypermongones A (13), C (14), E (15), G (16), H (17), and sampsonione L (18). The structures of 1-4 were established by extensive 1D and 2D NMR spectral analysis as well as HREI-MS. The absolute configurations of the stereogenic carbons in 1 were established by X-ray crystallographic analysis, while the stereochemistry of 2 was assigned by quantum chemical calculation of its 1H and 13C NMR chemical shift values using DP4+ probability analysis. The isolated compounds were assayed for antileishmanial activity on Leishmania tropica and L. major parasites. Compounds 9 and 16 displayed activities against L. tropica, with IC50 values of 17.7 and 31.5 μM, respectively. Moreover, 9 was only active against L. major, with IC50 value of 34.2 μM.

Detailed DFT studies of 1H and 13C NMR chemical shifts of hydroxy secondary oxidation products of various geometric isomers of conjugated linolenic acids methyl esters are presented. Several low energy conformers were identified for model compounds of the central dienenol OH moiety, which were found to be practically independent on the various functionals and basis sets used. This greatly facilitated the minimization process of the geometric isomers of conjugated linolenic acids methyl esters. Several regularities of the literature experimental H-1 and C-13 chemical shifts were reproduced very accurately with the computational chemical shifts of the Gibbs low energy DFT optimized conformers, after a Boltzmann analysis. 5(C-13) and 5(H-1) of the methine CH- OH group are highly diagnostic for the trans/trans and cis/trans geometric isomerism of the adjacent double bond. 5(C-13) of the -CH2- group adjacent to the terminal double bond of the conjugated system strongly depend on the cis/trans geometric isomerism of this bond and, thus, could be of importance in structural analysis. Ambiguities in the reported literature resonance assignments of olefinic carbons had been resolved. Computational 5(H-1) and 5(C-13) can be utilized for the identification of geometric isomerism and structural and conformational elucidation of hydroxy derivatives of conjugated linoleic acids and their ester derivatives.

Encouraged by the excellent antiplatelet properties of novel imatinib and nilotinib analogues in our previous study and based on a fact that slight structural changes, such as the incorporation of different substituents at the final phenyl ring of imatinib and nilotinib, have a strong impact on their antiplatelet potency, two pairs of constitutional isomers of the imatinib analogues 1, 2 and 3, 4, have been designed, synthesized and evaluated for their antiplatelet characteristics. The structure geometry of the imatinib analogues 1-4 and NBO (Natural Bond Orbital) charges of the lower energy conformation each of the analogues were explored by DFT. Molecular docking studies were also performed. All compounds were less efficient in inhibiting platelet aggregation induced by ADP or TRAP-6 in comparison with arachidonic acid (AA). Similar results were obtained for the membrane expression of P-selectin. The most active compound was also tested to inhibit c-Src kinase. The present study demonstrates that appropriate modifications of the imatinib structure, may confer on this molecule potent antiplatelet characteristics.

Structures of low-energy conformers of caproleic acid (CA; 10:1 cis-9), oleic acid (OA; 18:1 cis-9),alinolenic acid (ALA; 18:3 cis-9,12,15 co-3), eicosapentaenoic acid (EPA; 20:5 cis-5,8,11,14,17 co-3), and docosahexaenoic acid (DHA; 22:6 cis-4,7,10,13,16,19 co-3) in the liquid state, based on detailed 1D NOE and density functional theory calculations of 1H NMR chemical shifts are presented. Transient 1D NOE experiments with variable mixing time showed significant through-space proximity of the CH2- COOH protons and the terminal CH3- groups. Variable temperature 1H NMR experiments revealed strong intermolecular centro-symmetric cyclic hydrogen bond interactions of the carboxylic groups of the monounsaturated oleic and caproleic acids (8(COOH) ti 12.0-12.4 ppm), ALA and EPA (8(COOH) ti 11.0 ppm). On the contrary, the carboxylic proton of DHA is strongly shielded with 8(COOH) ti 8.5 ppm. DFT calculations were interpreted in terms of aggregates of dimerized fatty acids with parallel and antiparallel interdigitated structures. The antiparallel arrangement was found to be in excellent agreement with experimental 1D NOE NMR data. For the dimeric DHA, a flip-flop process between a classical intermolecular centro-symmetric hydrogen bond through carboxylic groups and a novel intramolecular hydrogen bond between the carboxylic group and the terminal co-3 double bond is demonstrated. (c) 2023 Elsevier B.V. All rights reserved.

Molecular structures, in chloroform and DMSO solution, of the free fatty acids (FFAs) caproleic acid, oleic acid, α-linolenic acid, eicosapentanoic acid (EPA) and docosahexaenoic acid (DHA) are reported with the combined use of NMR and DFT calculations. Variable temperature and concentration chemical shifts of the COOH protons, transient 1D NOE experiments and DFT calculations demonstrate the major contribution of low molecular weight aggregates of dimerized fatty acids through intermolecular hydrogen bond interactions of the carboxylic groups, with parallel and antiparallel interdigitated structures even at the low concentration of 20 mM in CDCl3. For the dimeric DHA, a structural model of an intermolecular hydrogen bond through carboxylic groups and an intermolecular hydrogen bond between the carboxylic group of one molecule and the ω-3 double bond of a second molecule is shown to play a role. In DMSO-d6 solution, NMR and DFT studies show that the carboxylic groups form strong intermolecular hydrogen bond interactions with a single discrete solvation molecule of DMSO. These solvation species form parallel and antiparallel interdigitated structures of low molecular weight, as in chloroform solution. This structural motif, therefore, is an intrinsic property of the FFAs, which is not strongly affected by the length and degree of unsaturation of the chain and the hydrogen bond ability of the solvent.

In this work, a series of Type I photoinitiators (PIs), based on the naphthoquinone scaffold, were designed and synthesized for the first time in order to induce photopolymerization under visible light.

DFT calculations of δ(13 C) and δ(1 H) chemical shifts and 3 J(13 C-O-O-1 H) coupling constants of three model hydroperoxides of the naturally occurring cis-11-OOH and trans-9-OOH isomers of oleate and 9-cis, 11-trans-16-OOH endo hydroperoxide of methyl linolenate are reported. The computational δ (OOH) for various functionals and basis sets, were found to be nearly identical for the cis/trans geometric isomers. Τhe chemical shifts of the methine CH-OOH protons and carbons, οn the contrary, are highly diagnostic for the identification of cis/trans geometric isomerism. The chemical shifts of the olefinic protons and carbons strongly depend on the orientation of the hydroperoxide unit relative to the double bond and, thus, of importance in conformational analysis. The results are in very good agreement with the available experimental data. For the various diastereomeric pairs of the model endo-hydroperoxide, the strongly deshielded OOH resonances, due to the presence of an intramolecular hydrogen bond between the hydroperoxide proton and an oxygen of the endo-peroxide ring, along with the δ (CH-OOH), are highly diagnostic for identification and structure elucidation of complex erythro- and threo- diastereomeric pairs of endo-hydroperoxides; the computational results are in very good agreement with the available experimental data. The 3 J(13 C-O-O-1 H) coupling constants were found to be < 2 Hz for the cis-trans geometric models and < 0.5 Hz for the endo-hydroperoxide and, thus, unimportant in stereochemical analysis. Sharp resonances of the hydroperoxide protons, with Δν1/2 < 3 Hz, are required for the successful implementation of the 1 H-13 C HMBC technique.

Density functional theory (DFT) calculations of delta(C-13) and delta(H-1) chemical shifts and (3)J(C-13-O-O-H-1) coupling constants of three model hydroperoxides of the naturally occurring cis-11-OOH and trans-9-OOH isomers of oleate and 9-cis, 11-trans-16-OOH endo hydroperoxide of methyl linolenate are reported. The computational delta(OOH) for various functionals and basis sets were found to be nearly identical for the cis/trans geometric isomers. The chemical shifts of the methine CH-OOH protons and carbons, on the contrary, are highly diagnostic for the identification of cis/trans geometric isomerism. The chemical shifts of the olefinic protons and carbons strongly depend on the orientation of the hydroperoxide unit relative to the double bond and, thus, of importance in conformational analysis. The results are in very good agreement with the available experimental data. For the various diastereomeric pairs of the model endo-hydroperoxide, the strongly deshielded OOH resonances, due to the presence of an intramolecular hydrogen bond between the hydroperoxide proton and an oxygen of the endo-peroxide ring, along with the delta(CH-OOH), are highly diagnostic for identification and structure elucidation of complex erythro- and threo- diastereomeric pairs of endo-hydroperoxides; the computational results are in very good agreement with the available experimental data. The (3)J(C-13-O-O-H-1) coupling constants were found to be < 2$$ \left|2\right| $$ Hz for the cis-trans geometric models and < 0.5$$ \left|0.5\right| $$ Hz for the endo-hydroperoxide and, thus, unimportant in stereochemical analysis. Sharp resonances of the hydroperoxide protons, with Delta nu(1/2) < 3 Hz, are required for the successful implementation of the H-1-C-13 heteronuclear multiple bond correlation (HMBC) technique.

A new organic material with three 4,4-difluoro-4-borata-3a-azonia-4a-aza-s-indacene dyes (BODIPYs) at the periphery of the central core is successfully synthesized (3BDP3T) and its corresponding aqueous nanoparticles are prepared via the encapsulation approach and characterized in detail both experimentally and theoretically with the aid of the Density Functional Theory (DFT). The linear and non-linear optical properties of the synthesized material are also studied. Until now, the development of organic materials with three BODIPYs as substituents is limited and their properties are not fully resolved. The obtained 3BDP3T-based nanoparticles exhibit far-red and near infrared (NIR) emission with photoluminescence quantum yields of 0.021, which is promising as a new fluorescent contrast agent in the far-red and NIR spectral regions.

A DFT study of the 1H NMR chemical shifts, δ(1H), of geometric isomers of 18:3 conjugated linolenic acids (CLnAs), hexadecatrienyl pheromones, and model triene-containing compounds is presented, using standard functionals (B3LYP and PBE0) as well as corrections for dispersion interactions (B3LYP-D3, APFD, M06–2X and ωB97XD). The results are compared with literature experimental δ(1H) data in solution. The closely spaced “inside” olefinic protons are significantly more deshielded due to short-range through-space H…H steric interactions and appear close to or even beyond δ-values of aromatic systems. Several regularities of the computational δ(1H) of the olefinic protons of the conjugated double bonds are reproduced very accurately for the lowest-energy DFT-optimized single conformer for all functionals used and are in very good agreement with experimental δ(1H) in solution. Examples are provided of literature studies in which experimental resonance assignments deviate significantly from DFT predictions and, thus, should be revised. We conclude that DFT calculations of 1H chemical shifts of trienyl compounds are powerful tools (i) for the accurate prediction of δ(1H) even with less demanding functionals and basis sets; (ii) for the unequivocal identification of geometric isomerism of conjugated trienyl systems that occur in nature; (iii) for tackling complex problems of experimental resonance assignments due to extensive signal overlap; and (iv) for structure elucidation in solution.

NMR and DFT studies of phenol compounds as molecular sensors were carried out to investigate H2O/DMSO eutectic mixtures at a molecular level. The experimental 1H NMR chemical shifts of the OH groups, δexp(OH), of phenol, paracoumaric acid, and vanillic acid show maximum deshielding and, thus, hydrogen bond interactions in the range of mole fractions 0.20 < χ(DMSO) < 0.33. In the mole fractions χ(DMSO) < 0.2, a progressive decrease in δexp(OH) was observed which demonstrates a decrease in hydrogen bond interactions at infinite dilution in H2O, despite the increase in the number of available hydrogen bond acceptor and donor sites. DFT calculated δcalc(OH) of minimum energy solvation clusters were shown to be in reasonable agreement with the pattern in experimental δexp(OH) data. The chemical shift deshielding and, thus, increased hydrogen bond interactions in the natural product + DMSO + nH2O (n = 2, 3) solvation clusters, relative to complexes in DMSO or H2O solutions, cannot be attributed to a single structural parameter of the cooperative interactions between H2O and DMSO molecules with the phenol OH groups of the natural products. The minimum energy conformers of phenol compounds + 2H2O + DMSO complexes are in excellent agreement with a recent low temperature neutron diffraction experiment of 3D2O + DMSO and demonstrate a general structural motif of solvation complexes. The combined use of 1H NMR and DFT studies with emphasis on δ(OH) of phenol compounds, as molecular sensors, can provide an effective method for the study of solute-solvent interactions at the atomic level.

The development of new aqueous conjugated polymer nanoparticles with high photoluminescence quantum yields (PLQYs) at the far red and near infrared (NIR) spectral regions (>650 nm) as alternative polymer probes for fluorescence imaging is reported.

A density functional theory (DFT) study of the 1H- and 13C-NMR chemical shifts of the geometric isomers of 18:2 ω-7 conjugated linoleic acid (CLA) and nine model compounds is presented, using five functionals and two basis sets. The results are compared with available experimental data from solution high resolution nuclear magnetic resonance (NMR). The experimental 1H chemical shifts exhibit highly diagnostic resonances due to the olefinic protons of the conjugated double bonds. The "inside" olefinic protons of the conjugated double bonds are deshielded than those of the "outside" protons. Furthermore, in the cis/trans isomers, the signals of the cis bonds are more deshielded than those of the trans bonds. These regularities of the experimental 1H chemical shifts of the olefinic protons of the conjugated double bonds are reproduced very accurately for the lowest energy DFT optimized single conformer, for all functionals and basis sets used. The other low energy conformers have negligible effects on the computational 1H-NMR chemical shifts. We conclude that proton NMR chemical shifts are more discriminating than carbon, and DFT calculations can provide a valuable tool for (i) the accurate prediction of 1H-NMR chemical shifts even with less demanding functionals and basis sets; (ii) the unequivocal identification of geometric isomerism of CLAs that occur in nature, and (iii) to derive high resolution structures in solution.

An approach for investigating the impacts of hydrogen bonding and stereochemical interactions of enol-enol tautomeric equilibria of β-dicarbonyl compounds is presented. DFT quantum chemical calculations of O–H⋯O 1H NMR chemical shifts of enol pairs, weighted by their proportions.as predicted by the relative free energies computed for them at the DFT level, agree well with experimental NMR chemical shifts. The main parameters affecting equilibrium constants for a set of eleven compounds, each one of which exists in two tautomeric forms in CHCl3 solution, are ring strain and steric repulsion of substituents with differences in O–H⋯O hydrogen bond lengths playing a secondary role.

Application of the Restricted Active Space Self-Consistent Field Theory on the S-2 excited state potential energy surface of benzene shows the existence of three minima. Of these, the first one is planar with a D-6h molecular point group, while the other two have a boat type structure with an approximate C-2v symmetry. All three minima have a biradicaloid structure and constitute potential candidates for new photochemical pathways on the S-2 surface. A common S-2/S-1 Conical Intersection, which is accessible from all three S-2 minima has been found which decays to the S-1 potential energy surface (PES) giving benzene S-1 minimum as the only photoproduct.