Clofazimine pKa Determination by Potentiometry and Spectrophotometry: Reverse Cosolvent Dependence as an Indicator of the Presence of Dimers in Aqueous Solutions.

The weakly basic antibiotic and anti-inflammatory drug, clofazimine (CFZ), was first described in 1957. It has been used therapeutically, most notably in the treatment of leprosy. However, the compound is extremely insoluble in aqueous media, and, indeed, there is poor consensus about what its intrinsic solubility is since the reported values range from 0.04 to 11 ng/mL. To understand the speciation and solubilization of CFZ as a function of pH, it is of paramount importance to know the true aqueous pKa. However, there is also poor consensus about the value of the pKa (reported measured values range from 6.08 to 9.11). In the present study, we report the determination of the CFZ ionization constant using two independent techniques. A state-of-the-art potentiometric analysis was performed, drawing on titration data in methanol-water solutions (46-75 wt % MeOH) of CFZ, using the bias-reducing consensus of two different procedures of extrapolating the apparent psKa values to zero cosolvent to approximate the true aqueous pKa as 9.43 ± 0.12 (25 °C, I = 0.15 M reference ionic strength). In parallel, spectrophotometric UV/vis titration data were acquired (250-600 nm at different pH) in 10 mM HEPES buffer solutions containing up to 54 wt % MeOH. The alternating least squares (ALS) method was used in the analysis of the absorbance-pH spectra. Uncharacteristically, the cosolvent UV/vis data in our study showed reverse cosolvent dependence (apparent pKa values increased with increasing cosolvent) which could be explained by a dimerization of the free base. The analysis of UV/vis data obtained from 54 wt % MeOH-water solution containing 20 µM CFZ yielded the apparent pKa 9.51 ± 0.17 (I ≈ 0.005 M). To assess whether self-assembly of CFZ was energetically feasible, density functional theory (DFT) calculations were used to study the putative CFZ dimers in aqueous and methanol media. The DFT-optimized geometries and infrared spectra of CFZ dimers using water and methanol as solvents were calculated and analyzed. Based on the lack of negative frequencies in calculated infrared spectra, it was confirmed that optimized geometries correspond to the true energetic minima. Visual analysis of optimized structures indicates the presence of stacking interactions between two CFZ molecules. The protonation site (the imine nitrogen atom) was determined by 1H NMR spectroscopy.

Chelate Coordination Compounds as a New Class of High-Energy Materials: The Case of Nitro-Bis(Acetylacetonato) Complexes.

The existence of areas of strongly positive electrostatic potential in the central regions of the molecular surface of high-energy molecules is a strong indicator that these compounds are very sensitive towards detonation. Development of high-energy compounds with reduced sensitivity towards detonation and high efficiency is hard to achieve since the energetic molecules with high performance are usually very sensitive. Here we used Density Functional Theory (DFT) calculations to study a series of bis(acetylacetonato) and nitro-bis(acetylacetonato) complexes and to elucidate their potential application as energy compounds with moderate sensitivities. We calculated electrostatic potential maps for these molecules and analyzed values of positive potential in the central portions of molecular surfaces in the context of their sensitivity towards detonation. Results of the analysis of the electrostatic potential demonstrated that nitro-bis(acetylacetonato) complexes of Cu and Zn have similar values of electrostatic potential in the central regions (25.25 and 25.06 kcal/mol, respectively) as conventional explosives like TNT (23.76 kcal/mol). Results of analysis of electrostatic potentials and bond dissociation energies for the C-NO2 bond indicate that nitro-bis(acetylacetonato) complexes could be used as potential energetic compounds with satisfactory sensitivity and performance.

Can the sensitivity of energetic materials be tuned by using hydrogen bonds? Another look at the role of hydrogen bonding in the design of high energetic compounds.

Strongly positive electrostatic potential in the central areas of molecules of energetic materials is one of the most important factors that determines the sensitivity of these molecules towards detonation. Quantum chemical and density functional theory calculations were used to reveal the influence of hydrogen bonding on the values of electrostatic potential above the central areas of molecules of three conventional explosives: 1,3,5-trinitrobenzene, 2,4,6-trinitrophenol, and 2,4,6-trinitrotoluene. Both the case when energetic molecules act as hydrogen atom donors and when they act as hydrogen atom acceptors were considered. Results of the calculations performed using the M06/cc-PVDZ level of theory showed that there are significant differences in the influence of hydrogen bonding on the electrostatic potential of energetic molecules acting as hydrogen atom donors and hydrogen atom acceptors. In the case when energetic molecules act as hydrogen acceptors, an increase of 10% in the strength of positive electrostatic potential was identified. In the case when energetic molecules act as hydrogen atom donors, a significant decrease (20-25%) in the strength of the positive potential on the molecular surface was calculated. These differences give an opportunity for fine-tuning the impact sensitivities of energetic compounds and provide new guidelines for the design of explosives with desirable characteristics.

How aromatic system size affects the sensitivities of highly energetic molecules?

Positive values of electrostatic potentials above the central regions of the molecular surface are strongly related to the high sensitivities of highly energetic molecules. The influence of aromatic system size on the positive values of electrostatic potentials and bond dissociation energies of C-NO2 bonds was studied by Density Functional Theory (DFT) calculations on a series of polycyclic nitroaromatic molecules. Calculations performed at PBE/6-311G** level showed that with the increase of the aromatic system size, values of positive electrostatic potential above the central areas of selected energetic molecules decrease from 32.78 kcal mol-1 (1,2,4,5-tetranitrobenzene) to 15.28 kcal mol-1 (2,3,9,10-tetranitropentacene) leading to the decrease in the sensitivities of these molecules towards detonation. Results of the analysis of electrostatic potential maps were in agreement with the trends in bond dissociation energies calculated for C-NO2 bonds of studied nitroaromatic molecules. Bond dissociation energies values indicate that the C-NO2 bond in the molecule of 1,2,4,5-tetranitrobenzene (56.72 kcal mol-1) is weaker compared to the nitroaromatic molecules with the additional condensed aromatic rings and with a similar arrangement of -NO2 groups (59.75 kcal mol-1 in the case of 2,3,9,10-tetranitropentacene). The influence of the mutual arrangement of -NO2 groups on the sensitivity of nitroaromatic molecules was also analyzed. Results obtained within this study could be of great importance for the development of new classes of highly energetic molecules with lower sensitivity towards detonation.

Influence of chelate ring type on chelate-chelate and chelate-aryl stacking: the case of nickel bis(dithiolene).

Chelate-aryl and chelate-chelate stacking interactions of nickel bis(dithiolene) were studied at the CCSD(T)/CBS and DFT levels. The strongest chelate-aryl stacking interaction between nickel bis(dithiolene) and benzene has a CCSD(T)/CBS stacking energy of -5.60 kcal mol-1. The strongest chelate-chelate stacking interactions between two nickel bis(dithiolenes) has a CCSD(T)/CBS stacking energy of -10.34 kcal mol-1. The most stable chelate-aryl stacking has the benzene center above the nickel atom, while the most stable chelate-chelate dithiolene stacking has the chelate center above the nickel atom. Comparison of chelate-aryl stacking interactions of dithiolene and acac-type nickel chelate shows similar strength. However, chelate-chelate stacking is stronger for dithiolene nickel chelate than for acac-type nickel chelate, which has a CCSD(T)/CBS interaction energy of -9.50 kcal mol-1.

Strong CH/O interactions between polycyclic aromatic hydrocarbons and water: Influence of aromatic system size.

Energies of CH/O interactions between water molecule and polycyclic aromatic hydrocarbons with a different number of aromatic rings were calculated using ab initio calculations at MP2/cc-PVTZ level. Results show that an additional aromatic ring in structure of polycyclic aromatic hydrocarbons significantly strengthens CH/O interactions. Calculated interaction energies in optimized structures of the most stable tetracene/water complex is -2.27 kcal/mol, anthracene/water is -2.13 kcal/mol and naphthalene/water is -1.97 kcal/mol. These interactions are stronger than CH/O contacts in benzene/water complex (-1.44 kcal/mol) while CH/O contacts in tetracene/water complex are even stronger than CH/O contacts in pyridine/water complexes (-2.21 kcal/mol). Electrostatic potential maps for different polycyclic aromatic hydrocarbons were calculated and used to explain trends in the energies of interactions.

Nature of the water/aromatic parallel alignment interactions.

The water/aromatic parallel alignment interactions are interactions where the water molecule or one of its O-H bonds is parallel to the aromatic ring plane. The calculated energies of the interactions are significant, up to ΔE(CCSD)(T)(limit) = -2.45 kcal mol(-1) at large horizontal displacement, out of benzene ring and CH bond region. These interactions are stronger than CH···O water/benzene interactions, but weaker than OH···π interactions. To investigate the nature of water/aromatic parallel alignment interactions, energy decomposition methods, symmetry-adapted perturbation theory, and extended transition state-natural orbitals for chemical valence (NOCV), were used. The calculations have shown that, for the complexes at large horizontal displacements, major contribution to interaction energy comes from electrostatic interactions between monomers, and for the complexes at small horizontal displacements, dispersion interactions are dominant binding force. The NOCV-based analysis has shown that in structures with strong interaction energies charge transfer of the type π → σ*(O-H) between the monomers also exists.

The effect of substituents on the surface modification of anatase nanoparticles with catecholate-type ligands: a combined DFT and experimental study.

The surface modification of nanocrystalline TiO2 particles (45 Å) with catecholate-type ligands having different electron donating/electron withdrawing substituent groups, specifically 3-methylcatechol, 4-methylcatechol, 3-methoxycatechol, 3,4-dihydroxybenzaldehyde and 4-nitrocatechol, was found to alter the optical properties of nanoparticles in a similar way to catechol. The formation of the inner-sphere charge-transfer (CT) complexes results in a red shift of the semiconductor absorption compared to unmodified nanocrystallites and a reduction of the effective band gap, being slightly less pronounced in the case of electron withdrawing substituents. The investigated ligands have the optimal geometry for binding to surface Ti atoms, resulting in ring coordination complexes of the catecholate type (binuclear bidentate binding-bridging) thus restoring six-coordinated octahedral geometry of surface Ti atoms. From the absorption measurements (Benesi-Hildebrand plot), the stability constants in methanol/water = 90/10 solutions at pH 2 in the order of 10(3) M(-1) have been determined. The binding structures were investigated by using FTIR spectroscopy. Thermal stability of CT-complexes was investigated by using TG/DSC/MS analysis. Quantum chemical calculations on model systems using density functional theory (DFT) were performed to obtain the vibrational frequencies of charge transfer complexes, and the calculated values were compared with the experimental data.

Surface modification of anatase nanoparticles with fused ring salicylate-type ligands (3-hydroxy-2-naphthoic acids): a combined DFT and experimental study of optical properties.

The surface modification of nanocrystalline TiO2 particles (45 Å) with salicylate-type ligands consisting of an extended aromatic ring system, specifically 3-hydroxy-2-naphthoic acid, 3,5-dihydroxy-2-naphthoic acid and 3,7-dihydroxy-2-naphthoic acid, was found to alter the optical properties of nanoparticles in a similar way to salicylic acid. The formation of the inner-sphere charge-transfer (CT) complexes results in a red shift of the semiconductor absorption compared to unmodified nanocrystallites and a reduction in the band gap upon the increase in the electron delocalization when including an additional ring. The investigated ligands have the optimal geometry for binding to surface Ti atoms, resulting in ring coordination complexes of a salicylate-type (binuclear bidentate binding-bridging) thus restoring the six-coordinated octahedral geometry of surface Ti atoms. From both absorption measurements in methanol/water = 90/10 solutions and steady-state quenching measurements of modifier fluorescence upon binding to TiO2 in aqueous solutions, stability constants in the order of 10(3) M(-1) have been determined at pH 2 and pH 3. Fluorescence lifetime measurements, in the presence and absence of colloidal TiO2 nanoparticles, indicated that the fluorescence quenching process is primarily static quenching, thus proving the formation of a nonfluorescent CT complex. The binding structures were investigated by using FTIR spectroscopy. Quantum chemical calculations on model systems using density functional theory (DFT) were performed to obtain the vibrational frequencies of charge transfer complexes, and the calculated values were then compared with the experimental data.

Surface modification of anatase nanoparticles with fused ring catecholate type ligands: a combined DFT and experimental study of optical properties.

Surface modification of nanocrystalline TiO(2) particles (45 Å) with catecholate-type ligands consisting of an extended aromatic ring system, i.e., 2,3-dihydroxynaphthalene and anthrarobin, was found to alter the optical properties of the nanoparticles in a similar way to modification with catechol. The formation of inner-sphere charge-transfer (CT) complexes results in a red shift of the semiconductor absorption compared to unmodified nanocrystallites and the reduction of the band gap upon the increase of the electron delocalization on the inclusion of additional rings. The binding structures were investigated by FTIR spectroscopy. The investigated ligands have the optimal geometry for binding to surface Ti atoms, resulting in ring coordination complexes of catecholate type (binuclear bidentate binding-bridging) thus restoring the six-coordinated octahedral geometry of surface Ti atoms. From the Benesi-Hildebrand plot, stability constants in methanol/water = 90/10 solutions at pH 2 of the order 10(3) M(-1) have been determined. Quantum chemical calculations on model systems using density functional theory (DFT) were performed to obtain vibrational frequencies of charge transfer complexes, and the calculated values were compared with the experimental data.