Riccardo Montis

Surprisingly complex supramolecular behaviour in the crystal structures of a family of mono-substituted salicylic acids

Crystal structure packing analyses of a family of monosubstituted salicylic acids, including some hydrates, show a surprisingly varied choice of supramolecular arrangements, even though the expected carboxyl–carboxyl dimer occurs in 17 of the 24 structures studied, and the 2-hydroxyl group hydrogen bonds with the carboxyl carbonyl oxygen in all molecules. In three of the four hydrates (3-MeO, 3NO2 and 5-Cl), the water molecules disrupt the carboxyl–carboxyl dimer to form a centrosymmetric [carboxyl–water]2 cluster. In the fourth hydrate, of the 5-acetamido (ACM) derivative, one water molecule forms an (ACM)CO⋯H–O(H)⋯H–O(carbox) single bridge. In the 4-ACM structure, the acetamido and carboxyl groups interact via (ACM)CO⋯H–O(carbox) and (ACM–Me)C–H⋯OC(carbox) double bridges, whilst the 6-MeO molecules, in which the carboxyl OH group is H-bonding intramolecularly to the MeO oxygen, forming catemers via bifurcating carboxyl OH and CO functions. The remaining outlier is the 5-amino (5-NH2) derivative, which exists in a zwitterionic form, with one carboxyl oxygen forming a short O⋯H–N intermolecular bond to an –NH3+ group, whilst the second oxygen forms three longer O⋯H–N bonds to three different –NH3+ groups. The larger, “normal” group of 17 derivatives adopt 16 different structures, generally comprising stacks of molecules with varying relative shifts of the molecular planes, and interactions involving the substituents. Surprisingly, the family contains only two polymorphic pairs, 5-Br α, β and 5-I α, β, in each of which the forms show low similarities, but two isostructures, the 5-Br α and 5-I β forms.

Crystalline adducts of some substituted salicylic acids with 4-aminopyridine, including hydrates and solvates: contact and separated ionic complexes with diverse supramolecular synthons

Co-crystallizations of some 3, 5 and 6 mono-substituted salicylic acids with 4-aminopyridine, using a variety of solvents, have yielded a number of new complex solid forms, mainly with the 5-halide-substituted acid, including some hydrates and solvates. In all cases, proton transfer occurs from the carboxyl group of the acid to the pyridine nitrogen of the base, with the COO−⋯H+NPy synthon being found in 12/14 cases. The prime exception is 4-aminopyridinium:5-aminosalicylate:pyridine solvate, where the carboxylate group forms a 2-point synthon with one hydrogen of the 4-amino group on the aminopyridinium supplemented by a C–H⋯O interaction involving an ortho hydrogen. This synthon is also found as one component of a disordered structure of the 4-aminopyridinium:5-chlorosalicylate. The other component adopts the normal pyridinium⋯carboxylate synthon. The adoption of 2-point or 1-point synthons, and the geometry of the former, is influenced by the presence of other hydrogen-bonding interactions involving hydrate water molecules or the amine of the 4-aminopyridinium group. A detailed packing analysis shows a number of similarities, partly linked to the synthon geometries. The structures generally fall into two groups, one derived from a simple zero-dimensional pyridinium–carboxylate monomer construct, the other from a zero-dimensional pyridinium–carboxylate centrosymmetric dimer construct. The former group contains most of the hydrates and the latter all of the 5-halide and methyl anhydrates, plus the 5-I pyridine solvate. The diversity of structures found confirm the frequent unpredictability in the structures adopted by products of co-crystallizations when ionic forms are produced.

Intriguing relationships and associations in the crystal structures of a family of substituted aspirin molecules

A number of ring-substituted aspirin molecules have been synthesised and their crystal structures determined. All contain the strongly H-bonded carboxylate dimer found in the two forms of aspirin itself. Detailed analysis of the further packing of this dimer reveals that the 5-chloro, 5-bromo and 5-iodo derivatives form an isostructural group, as do the 5-fluoro, 5-methyl and 5-nitro derivatives. The 3-methyl and 4-methyl structures have close 3D similarity and may be classified as pseudoisostructural. The structures of the first two groups have a common 1D stack of dimers which contributes to two different 2D layers. One of the 2D layers is found in the fluoro, nitro and 5-methyl isostructures and also in the 3-methyl and 4-methyl derivatives. The second layer motif is found in the chloro, bromo and iodo groups and is also present in the fluoro, nitro and 5-methyl structures. The 6-methyl structure shares a 1D motif with the chloro, bromo and iodo groups. The packing variations are linked to different types of intermolecular interactions. In the 5-Cl, Br, and I groups, we find short Hal⋯O contacts to the carboxylate carbonyl; in the 5-F, 5-NO2 and 5-Me derivatives we find the acyl⋯acyl dimer interaction, present also in aspirin form I. In addition, the 5-F structure contains F⋯O short contacts to a carboxylate hydroxyl oxygen and in the 5-NO2 we find N–O⋯H–C contacts to an acyl methyl group.

Non-symmetric substituted ureas locked in an (E,Z) conformation: an unusual anion binding via supramolecular assembly

Two new asymmetric ureidic receptors L1 (1-(1H-indol-7-yl)-3-(quinolin-2-yl)urea) and L2 (1-(quinolin-2-yl)-3-(quinolin-8-yl)urea) have been synthesised and their affinity towards different anions tested in DMSO-d6. L1 adopts both in solution and in the solid state an (E,Z) conformation. A moderate affinity for acetate has been observed for L1 while no interaction has been observed for L2. The different behaviour has been ascribed to the presence/absence of the indole group. In the case of L1 the indole group causes the formation of a peculiar supramolecular architecture with two molecules of the receptor binding the anions in the (E,Z) conformation via H-bonds. L2 also adopts an (E,Z) conformation in the solid state. However, the absence of the indole group in L2 hampers the formation of the supramolecular assembly with the participation of anionic species.

Experimental and theoretical investigations of the polymorphism of 5-chloroacetoxybenzoic acid (5-chloroaspirin)

From an initial crystallographic study of a large family of ring-substituted 2-acetoxybenzoic acids, only one member - the 5-chloro derivative - showed polymorphism, with two forms (α and β) identified, the former having a marginally higher melting point. The two structures show a close 1-D similarity through a row of carboxylic dimers connected viaCl⋯O halogen bonds, which assemble to give an approximate 2-D similarity by the stacking of these rows in a second direction. However, the further packing arrangement of the resulting 2-D stacks is significantly different in the two forms, through different symmetry arrangements and subtle variations in C–H⋯O weak hydrogen bonds. A parallel crystal structure prediction (CSP) calculation identified the two experimental polymorphs in the correct stability order with effective energy rankings of 2 and 3 (lattice energy difference of 0.2 kcal mol−1). The lowest energy crystal structure found during the CSP, as yet not found experimentally, is more stable than the lowest energy observed polymorph by 0.08 kcal mol−1. The predicted forms mostly comprise pairs of structures with nearly identical crystal structure arrangements, which differ only in the positioning of the carboxylate protons in the common carboxylate-carboxylate hydrogen-bonded dimers, relative to the positions of the neighboring acetyl substituents (syn or anti). The CSP calculations identify the correct isomer for each polymorph. One of the additional predicted forms is found to have 3-D packing similarity, and others partial similarities, with the crystal structures of particular members of the extended aspirin family.

Hydrogen- and halogen-bond cooperativity in determining the crystal packing of dihalogen charge-transfer adducts: a study case from heterocyclic pentatomic chalcogenone donors

Three new molecular CT adducts with dihalogens, based on 5,5-dimethyl-2-thiohydantoin (dth) and 1,5, 5-trimethyl-2-thiohydantoin (mdth) donor molecules have been synthesised and characterised by single crystal X-ray diffraction and their crystal structures compared with those of previously published analogous compounds to assess the role of molecular shape of the donors, and cooperativity and competition between hydrogen-bonds (HBs) and halogen-bonds (XBs) in defining the observed supramolecular architectures at the solid state. The study of the role played by these factors was supported by several computational tools. The structural feature at the base of the crystal packings observed is the formation of dimers of donor molecules via complementary N–H⋯O or N–H⋯S HBs. These dimers are arranged in space in 2D architectures via further interactions involving the S/Se⋯I–I/Br XBs. Interestingly, in most of the cases the XB interactions strengthen upon formation of the self-assembled H-bonded dimers, indicating a favourable cooperativity effect which is at the base of the supramolecular architectures formed.

Anion complexation, transport and structural studies of a series of bis-methylurea compounds

A new family of bis-methylureas () have been synthesised and their ability to bind anions both in solution and in the solid state and to transport them through lipid membrane have been studied. From the solid state studies it has emerged that various conformations can be adopted by the receptors allowing the isolation of complexes of different stoichiometries (from 1 : 1 to 1 : 3). The transport studies highlighted the possibility to use bis-methylureas to mediate Cl(-) transport across membranes.

Cationic and anionic 1D chains based on NH+⋯N charge-assisted hydrogen bonds in bipyridyl derivatives and polyiodides

The possibility of constructing extended networks based on NH+⋯N charge-assisted hydrogen bonding and N⋯I interactions was explored. The organic modules 3,5-di-(3-pyridyl)-1,2,4-thiadiazole (L1) and 3,5-di-(4-pyridyl)-1,2,4-thiadiazole (L2) possess two pyridyl groups, allowing them to act both as hydrogen-bond acceptors and hydrogen-bond donors with H+ acting as the main linker between the molecular units. The crystal structure of the ionic compounds (HL1)I3, (HL1)I5, (HL1)IBr2, (HL2)I3, and (HL2)IBr2 are described; the position of the nitrogen atoms in the outwards pyridyl rings in L1 and L2 leads to the formation of 1D helices of interacting cations (HL1)+ and zig-zag chains of interacting cations (HL2)+. In the case of (HL1)I5, cationic helices of (HL1)+ and helices of I5− take place in a highly shape-complementary arrangement. The crystal structure of the bis-adduct L1·2I2 features the presence of intermolecular iodine–iodine long contacts to form infinite I2 chains. A comparative structural analysis carried out using the XPac procedure identifies three common molecular arrangements and confirms the importance of directional interactions and molecular shape of the target molecules in directing the packing preferences of this family of structures.

Anhydrates and/or hydrates in nitrate, sulphate and phosphate salts of 4-aminopyridine, (4-AP) and 3,4-diaminopyridine (3,4-DAP): the role of the water molecules in the hydrates

Several salt forms of 4-aminopyridine and 3,4-diaminopyridine with nitric, sulfuric, and phosphoric acids, comprising anhydrates and some hydrates, have been prepared and structurally characterized, and the role of water assessed in the latter cases. Our study has confirmed that anhydrates can be obtained even when water is present in the crystallizing solution. Protonation of the aminopyridines is consistent with ΔpKa differences. 4-Aminopyridine uniquely forms a mono cation only, with protonation at the pyridine nitrogen, whilst 3,4-diaminopyridine forms both a mono cation, again with protonation at the pyridine nitrogen, and a dication, with the second protonation at the 3-amino position. Thus, 4-aminopyridine forms a 1 : 1 nitrate anhydrate, a 1 : 1 bisulphate anhydrate, a 2 : 1 sulfate hydrate and a 1 : 1 dihydrogen phosphate hydrate. 3,4-Diaminopyridine forms a 1 : 1 nitrate anhydrate and 1 : 2 nitrate anhydrate and hydrate, 2 : 1 and 1 : 1 sulfate hydrates and a 1 : 1 dihydrogen phosphate anhydrate. Analysis of the structures found suggests that the H-bonding capability of the water O–H donors and O acceptor components have similar tendencies to N–H donors and other O acceptors. At the same time, we recognise that, whilst water molecules may occasionally be structure forming, they also act as spacers or fillers in the development of the primary H-bonded assemblies. These will mainly be controlled by the stoichiometries and H-bonding possibilities of the anion/cation components. It is also possible that, in some circumstances, the inclusion or otherwise of water in structures may be competitive with supplementary weak interactions such as C–H⋯O hydrogen bonding.

Reactivity of the drug methimazole and its iodine adduct with elemental zinc

The reactivity of zinc complexes with N,S-donor molecules may be of relevance to the study of Zn-metalloproteins and -metalloenzymes. In this context, the zinc complex [Zn(MeImSH)2I2] was synthesised by the reaction of zinc powder with the 1:1 iodine adduct of the drug methimazole [(MeImSH)·I2]. The molecular structure of the complex, elucidated by X-ray diffraction analysis, showed a tetrahedral zinc(II) centre coordinated by two neutral methimazole units (through the sulfur atoms) and two iodides. From the reaction of MeImSH and Zn powder, the complex [Zn(MeImSH)(MeImS)2] (MeImS = deprotonated form of methimazole) was separated and characterised. An analysis of the crystal packing of the neutral complexes [Zn(MeImSH)2X2] (X = I, Br and Cl) and the ionic complex [Zn(MeImSH)3I]I showed that in all of the complexes the sulfur atom, in addition to binding to the metal centre, contributes to the formation of 1-D chains built via C(4)–H⋯S and N–H⋯X interactions in the neutral complexes, and via C(4)–H⋯S and N–CH3⋯S interactions in the ionic complex [Zn(MeImSH)3I]I. The deprotonation/protonation of the coordinated methimazole units can modulate the coordination environment at the Zn core. From the reaction of complex [Zn(MeImSH)3I]I with a strong non-coordinating organic base, we have shown that, as a consequence of the NH deprotonation of methimazole S-coordinated to zinc(II), the ligand coordination mode changes from S-monodentate to N,S-bridging. Correspondingly, in the complex [Zn(MeImSH)(MeImS)2], the MeImS that displays the N,S-bridging mode at zinc can be N-protonated and thereby changes to the S-monodentate coordination.