Health is the greatest wealth: Quest for a diagnostic check for thermochemistry of pure drug compounds.

The development of pharmaceutical formulations and the optimisation of drug synthesis are not possible without knowledge of thermodynamics. At the same time, the quantity and quality of the available data is not at a level that meets modern requirements. A convenient diagnostic approach is desirable to assess the quality of available experimental thermodynamic data of drugs. A comprehensive set of available data on phase transitions of profens family drugs was analysed using new complementary measurements and structure-property correlations. The consistent sets of solid-gas, liquid-gas and solid-liquid phase transitions were evaluated for twelve active pharmaceutical ingredients based on alkanoic acid derivatives and recommended for the calculations of the pharmaceutical processes. A "centerpiece approach" proposed in this work helped to perform the "health check" of the thermochemical data. The evaluated data on the sublimation enthalpies were used to derive the crystal lattice energies of the profens and to correlate the water solubilities with the sublimation vapour pressures and molecular parameters. A "paper-and-pen" approach proposed in this work can be extended to the diagnosis of "sick" or "healthy" thermodynamic data for drugs with a different structure than those studied in this work.

Thermodynamics of reversible hydrogen storage: Does alkoxy-substitution of naphthalene yield functional advantages for LOHC systems?

The reversible hydrogenation/dehydrogenation of aromatic molecules, known as liquid organic hydrogen carriers (LOHCs), is considered an attractive option for the safe storage and release of elemental hydrogen. The LOHC systems based on the alkoxy-naphthalene/alkoxy-decalin studied in this work can become potentially attractive from the point of view of the thermodynamic conditions of the reversible hydrogenation/dehydrogenation processes. This work reports the results of a complex experimental investigation of the thermochemical properties of the reactants of the LOHC systems. The enthalpies of formation were measured using high-precision combustion calorimetry, the enthalpies of vaporization and sublimation were derived from the vapor pressure-temperature dependencies measured using the transpiration method, and the melting temperatures and enthalpies of fusion were measured using the differential scanning calorimetry method. The liquid-phase enthalpies of formation of methoxy- and ethoxy-substituted naphthalenes and methoxy- and ethoxy-substituted decalins were derived and used for the thermodynamic analysis of hydrogenation/dehydrogenation reactions and transferhydrogenation reactions.

Quantum Chemistry and Pharmacy: Diagnostic Check of the Thermochemistry of Ibuprofen.

The thermodynamic data on ibuprofen available in the literature shows that the disarray of experimental results is unacceptable for this very important drug. The data on ibuprofens available in the literature were collected, combined with our complementary experimental results and evaluated. The enthalpies of combustion and formation of the crystalline RS-(±)- and S-(+)-ibuprofens were measured using high-precision combustion calorimetry. The temperature dependence of the vapour pressure of S-(+)-ibuprofen was measured using the transpiration method and the enthalpy of vaporization was derived from this measurement. The enthalpies of fusion of both compounds were measured using DSC. The G4 calculations have been carried out to determine the enthalpy of formation in the gaseous state of the most stable conformer. Thermochemical properties of the compounds studied were evaluated and tested for consistency with the "centerpiece approach". A set of reliable and consistent values of thermodynamic properties of ibuprofens at 298.15 K is recommended for thermochemical calculations of the pharmaceutical processes. The diagnostic protocol was developed to distinguish between the "sick" or "healthy" thermodynamic data. This diagnostic is also applicable to other drugs with a different structure than ibuprofen.

Combined Spectroscopic, Thermodynamic, and Theoretical Approach for Detecting and Quantifying Hydrogen Bonding and Dispersion Interaction in Ionic Liquids.

ConspectusIonic liquids (ILs) are attracting increasing interest in science and engineering due to their unique properties that can be tailored for specific applications. Clearly, a better understanding of their behavior on the microscopic scale will help to elucidate macroscopic fluid phenomena and thereby promote potential applications. The advantageous properties of these innovative fluids arise from the delicate balance of Coulomb interactions, hydrogen bonding, and dispersion forces. The development of these properties requires a fundamental understanding of the strength, location, and direction of the different types of interactions and their contribution to the overall phase behavior. Contrary to expectations, hydrogen bonding and dispersion interactions have a significant influence on the structure, dynamics, and phase behavior of ILs.The synergy between experimental and theoretical methods has now advanced to a stage where hydrogen bonds and dispersion effects as well as the competition between the two can be studied in detail. In this account, we demonstrate that a suitable combination of spectroscopic, thermodynamic, and theoretical methods enables the detection, dissection, and quantification of noncovalent interactions, even in complex systems such as ionic liquids. This approach encompasses far-infrared vibrational spectroscopy (FIR), various thermodynamic methods for determining enthalpies of vaporization, and quantum chemical techniques that allow us to switch dispersion contributions on or off when calculating the energies and spectroscopic properties of clusters.We briefly discuss these experimental and theoretical methods, before providing various examples illustrating how the mélange of Coulomb interaction, hydrogen bonds, and dispersion forces can be analyzed, and their individual contributions quantified. First, we demonstrated that both hydrogen bonding and dispersion interactions are manifested in the FIR spectra and can be quantified by observed shifts of characteristic spectral signatures. Through the selection of suitable protic ionic liquids (PILs) featuring anions with varying interaction strengths and alkyl chain lengths, we were able to demonstrate that dispersion interactions can compete with hydrogen bonding. The resultant transition enthalpy serves as a measure of the dispersion interaction. Contrary to expectations, PILs possess lower enthalpies of vaporization compared with aprotic ILs (AILs). The reason for this is simple: In protic ILs, ion pairs carry both the hydrogen bond and attractive dispersion between the cation and anion into the gas phase. By utilizing a well-curated set of protic ILs and molecular analogues, we successfully disentangled Coulomb interaction, hydrogen bonding, and dispersion interaction through purely thermodynamic methods.

Experimental and computational thermochemistry: how strong is the intramolecular hydrogen bond in alkyl 2-hydroxybenzoates (salicylates).

Hydrogen bonding (HB) is a fascinating phenomenon that exhibits unusual properties in organic and biomolecules. The qualitative manifestation of hydrogen bonds is known in numerous chemical processes. However, quantifying HB strength is a challenging task, especially in the case of intra-molecular hydrogen bonds. It is qualitatively well established that the alkyl 2-hydroxybenzoates have strong intra-HB. The thermochemical methods suitable for the determination of intra-HB strength were the focus of this study. The experimental gas phase formation enthalpies for alkyl 2-hydroxybenzoates (including methyl, ethyl, n-propyl and n-butyl) at 298.15 K were derived from a combination of vapour pressure measurements and high-precision combustion calorimetry and validated by the quantum chemical methods G3MP2 and G4. The intra-HB strength in methyl 2-hydroxybenzoate was determined from the evaluated gas-phase enthalpies of formation by comparing the energies of cis- and trans- conformers, by well-balanced reactions, the "para-ortho" method and the "HB and Out" method. All these methods give a common level of intra-molecular hydrogen bond strength of -43 kJ mol-1. The intra-HB strength was found to be independent of the chain length of the alkyl 2-hydroxybenzoates.

Thermodynamic Analysis of Chemical Hydrogen Storage: Energetics of Liquid Organic Hydrogen Carrier Systems Based on Methyl-Substituted Indoles.

Liquid organic hydrogen carriers can store hydrogen in a safe and dense form through covalent bonds. Hydrogen uptake and release are realized by catalytic hydrogenation and dehydrogenation, respectively. Indoles have been demonstrated to be interesting candidates for this task. The enthalpy of reaction is a crucial parameter in this regard as it determines not only the heat demand for hydrogen release, but also the reaction equilibrium at given conditions. In this work, a combination of experimental measurements, quantum chemical methods and a group-additivity approach has been applied to obtain a consistent dataset on the enthalpies of formation of different methylated indole derivatives and their hydrogenated counterparts. The results show a namable influence of the number and position of methyl groups on the enthalpy of reaction. The enthalpy of reaction of the overall hydrogenation reaction varies in the range of up to 18.2 kJ·mol-1 (corresponding to 4.6 kJ·mol(H2)-1). The widest range of enthalpy of reaction data for different methyl indoles has been observed for the last step (hydrogenation for the last double bond in the five-membered ring). Here a difference of up to 7.3 kJ·mol(H2)-1 between the highest and the lowest value was found.

Molecular Liquids versus Ionic Liquids: The Interplay between Inter-Molecular and Intra-Molecular Hydrogen Bonding as Seen by Vaporisation Thermodynamics.

In this study, we determined the enthalpies of vaporisation for a suitable set of molecular and ionic liquids using modern techniques for vapour pressure measurements, such as the quartz crystal microbalance, thermogravimetric analysis (TGA), and gas chromatographic methods. This enabled us to measure reasonable vapour pressures, avoiding the problem of the decomposition of the ionic liquids at high temperatures. The enthalpies of vaporisation could be further analysed by applying the well-known "group contribution" methods for molecular liquids and the "centerpiece" method for ionic liquids. This combined approach allowed for the dissection of the enthalpies of vaporisation into different types of molecular interaction, including hydrogen bonding and the dispersion interaction in the liquid phase, without knowing the existing species in both the liquid and gas phases.

Nearest-Neighbour and Non-Nearest-Neighbour Non-Covalent Interactions between Substituents in the Aromatic Systems: Experimental and Theoretical Investigation of Functionally Substituted Benzophenones.

Benzophenone derivatives exhibit not only biological activity but also act as photo initiator and UV blocker. We carried out experimental and theoretical thermochemical studies of hydroxy- and methoxy-substituted benzophenones. Standard molar enthalpies of vaporisation were obtained from the temperature dependence of vapour pressures measured by the transpiration method. The thermodynamic data on phase transitions available in the literature (crystal-gas, crystal-liquid, and liquid-gas) were also collected and evaluated. High-level quantum chemical methods G3MP2 and G4 were used to estimate the standard molar enthalpies of formation of substituted benzophenones in the gas phase and establish agreement between experimental and theoretical results. The application of the "centrepiece" group-contribution approach to hydroxy- and methoxy-substituted benzophenones was demonstrated. A quantitative assessment of the hydrogen bond was carried out using various approaches based on experimental data and quantum chemical calculations.

Dissecting Noncovalent Interactions in Carboxyl-Functionalized Ionic Liquids Exhibiting Double and Single Hydrogens Bonds Between Ions of Like Charge.

We show that the carboxyl-functionalized ionic liquid 1-(carboxymethyl)pyridinium bis(trifluoromethylsulfonyl)imide [HOOC-CH2 -py][NTf2 ] exhibits three types of hydrogen bonding: the expected single hydrogen bonds between cation and anion, and, surprisingly, single and double hydrogen bonds between the cations, despite the repulsive Coulomb forces between the ions of like charge. Combining X-ray crystallography, differential scanning calorimetry, IR spectroscopy, thermodynamic methods and DFT calculations allows the analysis and characterization of all types of hydrogen bonding present in the solid, liquid and gaseous states of the ionic liquid (IL). We find doubly hydrogen bonded cationic dimers (c+ =c+ ) in the crystalline phase. With increasing temperature, this binding motif opens in the liquid and is replaced by (c+ -c+ -a- species, with a remaining single cationic hydrogen bond and an additional hydrogen bond between cation and anion. We provide clear evidence that the IL evaporates as hydrogen-bonded ion pairs (c+ -a- ) into the gas phase. The measured transition enthalpies allow the noncovalent interactions to be dissected and the hydrogen bond strength between ions of like charge to be determined.

"In Vitro" and "In Vivo" Diagnostic Check for the Thermochemistry of Metal-Organic Compounds.

Volatile metal ß-diketonates are of interest from both practical and theoretical perspectives (manufacturing of film materials, catalysis, and the nature of metal-ligand bonding). Knowledge of their reliable thermochemical properties is essential for effective applications. However, there is an unacceptable scattering of the available data on the enthalpies of formation. In this work, we proposed "in vitro" and "in vivo" diagnostic tools to verify the available enthalpies of formation in both the crystalline and gaseous states for metal tris-ß-diketonates. The "in vitro" procedure involved high-level quantum-chemical calculations and was applied to define a consistent data set on the enthalpies of formation for iron(III) ß-diketonates. This data set has provided the basis for "in vivo" structure-property-based diagnostics to evaluate the robustness of the thermochemical data for ß-diketonate tris-complexes with metals other than iron.

Aprotic Ionic Liquids: A Framework for Predicting Vaporization Thermodynamics.

Ionic liquids (ILs) are recognized as an environmentally friendly alternative to replacing volatile molecular solvents. Knowledge of vaporization thermodynamics is crucial for practical applications. The vaporization thermodynamics of five ionic liquids containing a pyridinium cation and the [NTf2] anion were studied using a quartz crystal microbalance. Vapor pressure-temperature dependences were used to derive the enthalpies of vaporization of these ionic liquids. Vaporization enthalpies of the pyridinium-based ionic liquids available in the literature were collected and uniformly adjusted to the reference temperature T = 298.15 K. The consistent sets of evaluated vaporization enthalpies were used to develop the "centerpiece"-based group-additivity method for predicting enthalpies of vaporization of ionic compounds. The general transferability of the contributions to the enthalpy of vaporization from the molecular liquids to the ionic liquids was established. A small, but not negligible correction term was supposed to reconcile the estimated results with the experiment. The corrected "centerpiece" approach was recommended to predict the vaporization enthalpies of ILs.

Non-Covalent Interactions in Molecular Systems: Thermodynamic Evaluation of the Hydrogen-Bond Strength in Amino-Ethers and Amino-Alcohols.

The intramolecular hydrogen bond (intra-HB) is one of the best-known examples of non-covalent interactions in molecules. Among the different types of intramolecular hydrogen bonding, the NH⋅⋅⋅O hydrogen bond in amino-alcohols and amino-ethers is one of the weakest. In contrast to the strong OH⋅⋅⋅N intramolecular hydrogen bond, the strength of the NH⋅⋅⋅O bond can hardly be measured with conventional spectroscopic methods, even for simple amino-alcohols, since the band belonging to the NH⋅⋅⋅O conformer merges with the free OH band. In this work, we developed a combination of G4 calculations, and a method based on experimental vaporization enthalpies to determine the NH⋅⋅⋅O hydrogen bonding strength. The archetypal compounds for this study are 2-amino-1-ethanol and 3-amino-1-propanol as well as their respective methoxy analogs. Based on these molecules, different series were studied to investigate various factors influencing NH⋅⋅⋅O intra-HB strength. In the first series, the influence of alkylation near the hydroxy or methoxy group and the amino group in sterically hindered aminoalcohols was examined. In the second series, the influence of alkylation of the amino-group was investigated. In the third series, the effect of extending the alkyl chain between functional groups was studied.

Non-covalent interactions in molecular systems: thermodynamic evaluation of the hydrogen bond strength in aminoalcohols.

In molecules with two functional groups that form hydrogen bonds, the structure-property relationship can depend significantly on the strength of intra-molecular hydrogen bonding. This bonding can cause a substantial conformational change that is accompanied by a frequency shift in the infrared spectrum, which provides the basis for experimental studies. Despite its great importance in biological systems, the available literature data for the strength of this bonding are scarce and not in agreement. In this work, we present the results of four thermodynamic methods for the determination of the strength of intramolecular hydrogen bonds. Comprehensive thermochemical analysis of 1-amino-2-alcohols and 2-amino-1-alcohols was performed with Fourier-transform infrared spectroscopy, high-level G4 quantum-chemical calculations, the homomorph scheme with enthalpies of vaporization and a group contribution method. With the combination of these four thermodynamic methods, the strength of intramolecular hydrogen bonding in 1,2-aminoalcohols and 2,1-aminoalcohols was evaluated quantitatively. The results were correlated with NBO parameters to find an explanation for the different strengths of intramolecular hydrogen bonds in total charge transfer and second order stabilization energies.

Imidazolium Based Ionic Liquids: Unbiased Recovering of Vaporization Enthalpies from Infinite-Dilution Activity Coefficients.

We propose and test an efficient approach for the assessment of the enthalpies of vaporization of ionic liquids at the reference temperature 298.15 K. The approach is based on activity coefficients at infinite dilution of volatile organic solutes in ionic liquids bearing the imidazolium cation of the general formula [Cnmim][Anion].

Determination of the dispersion forces in the gas phase structures of ionic liquids using exclusively thermodynamic methods.

Ionic liquids are described by a delicate balance of Coulomb interaction, hydrogen bonding and dispersion forces. Dissecting the different types of interactions from thermodynamic properties is still a challenge. Here, we show that comparison of vaporization enthalpies of tetra-alkyl-ammonium ionic liquids with bis(trifluoromethylsulfonyl)imide [NTf2]- anions and the related molecular liquids, trialkylamines, allows for determining dispersion interactions in the gas phase ion-pairs. For this purpose, we measured vapor pressures and vaporization enthalpies of these ionic and molecular liquids by using a quartz-crystal microbalance. For supporting these data, we determined the vaporization enthalpies additionally from experimental activity coefficients at infinite dilution. Characteristic alkyl chain length dependences of the vaporization enthalpies have been established and were used for quantifying the dispersion forces in the gas phase species. The dissected dispersion contributions suggest that the alkyl chains do not show star-like topologies but embrace the anion maximizing the dispersion interactions. For the longest alkyl chains with eight carbon atoms, the dispersion interaction is as strong as two and a half hydrogen bonds. The proportion of dispersion in the gas phase species depending on the number of methylene groups in the ammonium cations is strongly supported by quantum chemical calculations.

Extremely Low Vapor-Pressure Data as Access to PC-SAFT Parameter Estimation for Ionic Liquids and Modeling of Precursor Solubility in Ionic Liquids.

Precursor solubility is a crucial factor in industrial applications, dominating the outcome of reactions and purification steps. The outcome and success of thermodynamic modelling of this industrially important property with equations of states, such as Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT), vastly depends on the quality of the pure-component parameters. The pure-component parameters for low-volatile compounds such as ionic liquids (ILs) have been commonly estimated using mixture properties, e. g. the osmotic pressure of aqueous solutions. This leads to parameters that depend on the solvent, and transferability to other mixtures often causes poor modeling results. Mixture-independent experimental properties would be a more suitable basis for the parameter estimation offering a way to universal parameter sets. Model parameters for ILs are available in the literature [10.1016/j.fluid.2012.05.029], but they were estimated using pure-IL density data. The present work focuses on a step towards a more universal estimation strategy that includes new experimental vapor-pressure data of the pure IL. ILs exhibit an almost negligible vapor pressure in magnitude of usually 10-5  Pa even at elevated temperatures. In this work, such vapor-pressure data of a series of 1-ethyl-3-methyl-imidazolium-based [C2 mim]-ILs with various IL-anions (e. g. tetrafluoroborate [BF4 ]- , hexafluorophosphate [PF6 ]- , bis(trifluoromethylsulfonyl)imide [NTf2 ]- ) were experimentally determined and subsequently used for PC-SAFT parameter estimation. The so-determined parameters were used to predict experimental molecular precursor solubility in ILs and infinitely diluted activity coefficients of various solvents in ILs. The parameters were further compared to modeling results using classical parametrization methods (use of liquid-density data only for the molecular PC-SAFT and the ion-based electrolyte PC-SAFT). As a result, the modeled precursor solubilities using the new approach are much more precise than using the classical parametrization methods, and required binary parameters were found to be much smaller (if needed). In sum, including the pure-component vapor-pressure data of ILs opens the door towards parameter estimation that is not biased by mixture data. This procedure might be suitable also for polymers and for all kind of ionic species but needs extension to ion-specific parametrization in the long term.

In the footsteps of August Michaelis: Syntheses and Thermodynamics of Extremely Low-Volatile Ionic Liquids.

A series of nine different known ionic liquids or low melting salts was synthesised and purified. They are composed of the [NTf2 ]- (bis(trifluoromethane)sulfonimide), [OTf]- (trifluoro-methane-sulfonate), or [B(CN)4 ]- (tetracyanidoborate) anion and [Ph4 P]+ (tetraphenylphosphonium), [Ph3 BzP]+ (triphenylbenzyl phosphonium), [n Bu4 P]+ (tetra-n butylphosphonium), [n BuPh3 P]+ (tri-phenyl-n butylphosphonium), [n Bu4 N]+ (tetra-n butylammonium), or the [PPN]+ (bis(triphenylphosphine)iminium) cation. Precise vapour pressure data and enthalpies of vaporisation were measured using the Quartz Crystal Microbalance (QCM) method and evaluated. Structure-property relations are established using the obtained data as well as literature known data of ILs with alkyl-substituted imidazolium cations. It turns out that ILs with the tetracyanidoborate anion have even higher values of the enthalpy of vaporisation than those with the common [NTf2 ]- or [OTf]- anion and therefore are even less volatile.

Tetrahydrothiophene-Based Ionic Liquids: Synthesis and Thermodynamic Characterizations.

S-alkyltetrahydrothiophenium, [Cn THT]+ bis(trifluorosulfonyl)imide, [NTf2 ]- room temperature ionic liquids (ILs) and tetraphenylborate, [BPh4 ]- salts with alkyl chain lengths from C4 to C10 have been prepared. The ILs and salts were characterized and their purity verified by 1 H- and 13 C-nuclear magnetic resonance, elemental analysis, ion chromatography, Karl-Fischer titration, single crystal X-ray diffraction as well as thermogravimetric analysis. The experimentally determined density and viscosity decrease with increasing temperature. The experimental solubility of the [Cn THT][NTf2 ]-ILs in water (75 to 2.2 mg/L for C4 to C10 ) was modelled with very good agreement by Perturbed Chain Statistical Associating Fluid Theory (PC-SAFT), based on the extremely low vapor pressures for the [Cn THT][NTf2 ]-ILs measured in this work (4.15 to 0.037 ⋅ 10-7 ×psat for C4 to C10 ). PC-SAFT is able to predict and correlate different thermodynamic properties by estimating the Helmholtz residual energy.

Webbing a network of reliable thermochemistry around lignin building blocks: tri-methoxy-benzenes.

Methoxy-substituted benzenes are the simplest fragments from the lignin separation feedstock. Extensive experimental thermochemical studies of these compounds were carried out, including vapor pressure measurements, combustion and differential scanning calorimetry. These data were evaluated using empirical, semi-empirical and quantum chemical methods. The consistent sets of evaluated thermodynamic data were used to design the method for predicting enthalpies of vaporisation and enthalpies of formation of di- and tri-substituted benzenes. It has been found that the agglomeration of substituents on the benzene ring has dramatic consequences for the energetics of the molecule (in terms of the enthalpy of formation), as well as for the energetics of intermolecular interactions (in terms of the enthalpy of vaporisation). These observations are essential to reliably assess the energetics of the molecules that appear in reaction products of lignin transformations in value-adding chemicals and materials.

The Relative Thermodynamic Stability of Diamond and Graphite.

Recent density-functional theory (DFT) calculations raised the possibility that diamond could be degenerate with graphite at very low temperatures. Through high-accuracy calorimetric experiments closing gaps in available data, we reinvestigate the relative thermodynamic stability of diamond and graphite. For T<400 K, graphite is always more stable than diamond at ambient pressure. At low temperatures, the stability is enthalpically driven, and entropy terms add to the stability at higher temperatures. We also carried out DFT calculations: B86bPBE-25X-XDM//B86bPBE-XDM and PBE0-XDM//PBE-XDM results overlap with the experimental -TΔS results and bracket the experimental values of ΔH and ΔG, displaced by only about 2× the experimental uncertainty. Revised values of the standard thermodynamic functions for diamond are Δf Ho =-2150±150 J mol-1 , Δf So =3.44±0.03 J K-1 mol-1 and Δf Go =-3170±150 J mol-1 .