Crystal Engineering Studies of Squaric Acid Derivatives

[cat] Aquesta tesi presenta un estudi multidisciplinar de l’estat sòlid de derivats de l’àcid esquàric, enmarcat en diferents àrees com l’enginyeria cristal•lina, la química supramolecular i la cristal•lografia. Les esquaramides són compostos interessants per la seva capacitat doble donadora/acceptora d’enllaços d’hidrogen. En aquest treball s’han analitzat les característiques estructurals de les esquaramides en l’estat sòlid i s’han dissenyat nous materials cristal•lins derivats de l’àcid esquàric per tal d’estudiar nous sintons supramoleculars. L’estudi de la capacitat acceptora/donadora de compostos model a través de la determinació teòrica dels paràmetres d’enllaç d’hidrogen (a i ß), ha permès la racionalització dels aspectes estructurals d’aquesta família de compostos. A més, a través d’aquest estudi, s’han explorat fenòmens químics de rellevància com l’efecte template i la preorganització pel disseny de sals i cocristalls, la cooperativitat, responsable del sintó observat en estat sòlid de les diesquaramides secundàries, així com la compressió electrostàtica identificada en esquaramides zwitteriòniques i sals de l’àcid esquàric. En resum s’han obtingut 47 polimorfs, solvats, cocristalls i sals de 22 derivats de l’àcid esquàric i s’han resolt i analitzat 31 estructures cristal•lines. Per a l’anàlisi de les espècies sintetitzades s’han utilitzat diferents tècniques experimentals com la calorimetria diferencial d’escaneig, la termogravimetria, la termomicroscòpia, l’espectroscòpia de ressonància magnètica nuclear i la difracció de raigs X de pols i de monocristall. En aquest sentit, l’optimització de la metodologia de resolució d’estructures cristal•lines a partir de dades de difracció de raigs X de laboratori a través de mètodes d’espai directe ha permès superar les dificultats que presenten les esquaramides secundàries a cristal•litzant monocristalls de qualitat. A partir dels resultats d’aquesta tesi doctoral es pot concloure que el grup funcional esquàric/esquaramida, poc estudiat en l’estat sòlid, té unes propietats potencialment explotables en el disseny i la síntesi de nous i diversos materials cristal•lins.[eng] This thesis is a multidisciplinary study of the solid state of squaric acid derivatives which combines approaches from areas such as crystal engineering, supramolecular chemistry and crystallography. The structural preferences in the solid state of this family of compounds has been analyzed, new crystalline materials derived from squaric acid have been designed in order to study new supramolecular synthons and relevant chemical phenomena such as template effect, preorganization, cooperativity and electrostatic compression have been explored. In summary, 47 polymorphs, solvates, cocrystals and salts from 22 squaric acid derivative compounds have been obtained and 31 crystal structures have been solved and analyzed. Several experimental techniques such as differential scanning calorimetry, thermogravimetry, thermomicroscopy, NMR spectroscopy and X­ray diffraction have been used for the analysis of the squaric acid derivatives synthesized. In this sense, the optimization of a methodology for solving crystal structures from laboratory powder X­ray diffraction data by means of direct space methods has permitted to overcome the difficulty of growing good quality single crystals of disecondary squaramides. Squaramides are interesting compounds due to their double donor­acceptor hydrogen bond character. In this work, their structural characteristics in the solid state have been studied and cooperativity in hydrogen­bonded catemers has been observed to play a crucial role in defining the robust solid­state head­to­tail synthon in the anti/anti conformation of disecondary squaramides, overriding the preferred association mode anti/syn observed in solution. Consequently, the self­assembling of the squaramide rings is a very strong binding motif, which has been proven difficult to be perturbed by other competing functional groups in the solid state. Taking into account these characteristics, two different cocrystal design strategies have been developed: the first one considering the preorganization of a monosquaramide ester via intramolecular hydrogen bonding, and the second one, more successful, considering that secondary squaramides can act as molecular scaffolds which, with a suitable functionalization of their substituents, new multicomponent solids have been obtained with coformers interacting via peripheral hydrogen bonding. Moreover, the analysis of the hydrogen bonding donor/acceptor parameters (a and ß) has been conducted with some model compounds with the aim of explaining their structural preferences in the solid state. Understanding the preference of a functional group for a particular synthon is mandatory in order to design new crystalline materials. In this sense, an unprecedented squaramide helical topology driven by the head­to­tail interaction has been reported, revealing its potential use in the field of crystal engineering and supramolecular chemistry. In a second stage of this thesis, further inside has been given to squaric acid derivatives through the design of zwitterionic squaramides. This has permitted the analysis of the electrostatic compression phenomenon which is responsible for a robust dimeric supramolecular synthon which also allows the formation of multicomponent solids. Finally, a collaborative research has been conducted on the theoretical and experimental of the main interactions shown by squaric acid and amidosquaric acid salts in the solid state. In summary, it can be concluded that the squaric/squaramide functional group, poorly studied in the solid state, has interesting properties which can be potentially exploited for the design and synthesis of new and diverse crystalline materials

A combined crystallographic and theoretical study of weak intermolecular interactions in crystalline squaric acid esters and amides

We report the synthesis and X-ray solid state structures of five squaric acid derivatives, i.e. a zwitterionic compound, namely 3-hydroxy-4-(2-pyridin-2-yl-ethylamino)cyclobut-3-ene-1,2-dione (1), a squaramide monoester, 3-ethoxy-4-(2-pyridin-2-yl-ethylamino)cyclobut-3-ene-1,2-dione (2), two differently solvated (EtOH and DMSO/water) disquaramides 3,4-bisIJ(4-hydroxyphenethyl)amino)cyclobut-3-ene-1,2-dione (3 and 4, respectively), and a mixed hydrogen squarate and disquarate 2-(2-aminoethyl)pyridinium salt (5). All compounds form interesting supramolecular assemblies in the solid state that have been analyzed using high level DFT calculations and Bader's theory of 'atoms-in-molecules'. An intricate combination of ionpair and H-bonding interactions along with π-π stacking and anion-π contacts of the cyclobutenedione rings is crucial for the formation of the supramolecular assemblies in the solid state

Experimental and theoretical study of weak intermolecular interactions in crystalline tertiary squaramides

We report the X-ray solid state structures of two tertiary squaramides, i.e. 3-(diethylamino)-4-ethoxy-cyclobutene-1,2-dione (1) and bis-3,4-(diethylamino)-cyclobutene-1,2-dione (2). Compound 1 forms electrostatically compressed dimers in the solid state. Moreover, compound 2 exhibits a remarkable solid state architecture resembling a lipid bilayer. This supramolecular assembly has been analyzed using high level DFT calculations and Bader's theory of "atoms-in-molecules". The antiparallel CO⋯CO interactions of the cyclobutenedione rings and hydrophobic interactions involving the ethyl chains are crucial for the formation of the bilayer assembly in the solid stat

H-Bonded anion-anion complex trapped in a squaramido-based receptor

Herein we report the experimental observation (X-ray characterization) of an anion-anion complex (anion = hydrogen fumarate) stabilized by H-bonds that is trapped in a secondary squaramide receptor. High level ab initio calculations indicate that the anion- anion complex is thermodynamically unstable but kinetically stable with respect to the isolated anion

Entrapped Transient Chloroform Solvates of Bilastine

The knowledge about the solid forms landscape of Bilastine (BL) has been extended. The crystal structures of two anhydrous forms have been determined, and the relative thermodynamic stability among the three known anhydrous polymorphs has been established. Moreover, three chloroform solvates with variable stoichiometry have been identified and characterized, showing that S3CHCl3-H2O and SCHCl3 can be classified as transient solvateswhich transforminto the newchloroform solvate SCHCl3-H2O when removed fromthemother liquor. The determination of their crystal structures from combined single crystal/synchrotron X-ray powder diffraction data has allowed the complete characterization of these solvates, being two of them heterosolvates (S3CHCl3-H2O and SCHCl3-H2O) and SCHCl3 a monosolvate. Moreover, the temperature dependent stability and interrelation pathways among the chloroform solvates and the anhydrous forms of BL have been studied

Polymorphism in secondary squaramides: on the importance of π-interactions involving the four membered ring

We report the X-ray solid state structures of four new squaric acid derivatives, i.e. three polymorphs of 3,4-bisIJ(2-(dimethylamino)ethyl)amino)cyclobut-3-ene-1,2-dione (1a-c) and a co-crystal of compound 1 and resorcinol (2). All structures form interesting supramolecular assemblies in the solid state which have been analyzed using high level DFT calculations and molecular electrostatic potential (MEP) surface calculations. A combination of H-bonding and π-π stacking interactions of the cyclobutenedione rings are crucial for the formation of the supramolecular assemblies in the solid state. Moreover, unusual antiparallel CO⋯CO interactions observed in the X-ray structure of one of the polymorphs of 1 and the lp-π interactions between one oxygen atom of resorcinol and the squaramide ring in 2 have been characterized using Bader's theory of 'atoms-in-molecules' (AIM)

Expanding the Crystal Form Landscape of the Antiviral Drug Adefovir Dipivoxil

The solid state of adefovir dipivoxil (AD) has been revisited. In the present article we extend the knowledge about the solid state of this pharmaceutical prodrug. The stability landscape of the amorphous form with respect to the anhydrous and hydrate crystalline forms has been studied, and the use of an antiplasticizing agent to increase its Tg is described. The crystal structure of the elusive anhydrous form I has been determined from laboratory powder X-ray diffraction data by means of direct space methods using the computing program FOX. In addition, three new isostructural solvates of AD (methanol, ethylenglycol, and methylethylketone) have been discovered and structurally characterized by single cristal X-ray diffraction

Polymorphism of Cocrystals: The Promiscuous Behavior of Agomelatine

It has been traditionally suggested that polymorphism of cocrystals is a phenomenon seen less frequently than in monocomponent crystals. However, since the research on cocrystals has recently experienced a big growth, the number of solved structures of polymorphic cocrystals in the Cambridge Structural Database has increased, which can help to understand better whether a lower impact of this phenomenon exists or not in multicomponent crystals. In this paper we describe the cocrystal landscape of agomelatine, a particularly promiscuous drug able to cocrystallize with up to nine different coformers. Interestingly, two of those coformers have produced polymorphic cocrystals during the screening, which converts agomelatine into a new example that questions the traditional belief of the lesser impact of polymorphism in cocrystals and highlights the importance of polymorphism studies in cocrystal screening. Our work is completed with the determination of the crystal structures of the new forms from combined single crystal/laboratory X-ray powder diffraction data

Experimental and theoretical study of weak intermolecular interactions in crystalline tertiary squaramides

We report the X-ray solid state structures of two tertiary squaramides, i.e. 3-(diethylamino)-4-ethoxy-cyclobutene-1,2-dione (1) and bis-3,4-(diethylamino)-cyclobutene-1,2-dione (2). Compound 1 forms electrostatically compressed dimers in the solid state. Moreover, compound 2 exhibits a remarkable solid state architecture resembling a lipid bilayer. This supramolecular assembly has been analyzed using high level DFT calculations and Bader's theory of "atoms-in-molecules". The antiparallel CO⋯CO interactions of the cyclobutenedione rings and hydrophobic interactions involving the ethyl chains are crucial for the formation of the bilayer assembly in the solid stat