One barbiturate and two solvated thiobarbiturates containing the triply hydrogen-bonded ADA/DAD synthon, plus one ansolvate and three solvates of their coformer 2,4-diaminopyrimidine.

A path to new synthons for application in crystal engineering is the replacement of a strong hydrogen-bond acceptor, like a C=O group, with a weaker acceptor, like a C=S group, in doubly or triply hydrogen-bonded synthons. For instance, if the C=O group at the 2-position of barbituric acid is changed into a C=S group, 2-thiobarbituric acid is obtained. Each of the compounds comprises two ADA hydrogen-bonding sites (D = donor and A = acceptor). We report the results of cocrystallization experiments of barbituric acid and 2-thiobarbituric acid, respectively, with 2,4-diaminopyrimidine, which contains a complementary DAD hydrogen-bonding site and is therefore capable of forming an ADA/DAD synthon with barbituric acid and 2-thiobarbituric acid. In addition, pure 2,4-diaminopyrimidine was crystallized in order to study its preferred hydrogen-bonding motifs. The experiments yielded one ansolvate of 2,4-diaminopyrimidine (pyrimidine-2,4-diamine, DAPY), C4H6N4, (I), three solvates of DAPY, namely 2,4-diaminopyrimidine-1,4-dioxane (2/1), 2C4H6N4·C4H8O2, (II), 2,4-diaminopyrimidine-N,N-dimethylacetamide (1/1), C4H6N4·C4H9NO, (III), and 2,4-diaminopyrimidine-1-methylpyrrolidin-2-one (1/1), C4H6N4·C5H9NO, (IV), one salt of barbituric acid, viz. 2,4-diaminopyrimidinium barbiturate (barbiturate is 2,4,6-trioxopyrimidin-5-ide), C4H7N4(+)·C4H3N2O3(-), (V), and two solvated salts of 2-thiobarbituric acid, viz. 2,4-diaminopyrimidinium 2-thiobarbiturate-N,N-dimethylformamide (1/2) (2-thiobarbiturate is 4,6-dioxo-2-sulfanylidenepyrimidin-5-ide), C4H7N4(+)·C4H3N2O2S(-)·2C3H7NO, (VI), and 2,4-diaminopyrimidinium 2-thiobarbiturate-N,N-dimethylacetamide (1/2), C4H7N4(+)·C4H3N2O2S(-)·2C4H9NO, (VII). The ADA/DAD synthon was succesfully formed in the salt of barbituric acid, i.e. (V), as well as in the salts of 2-thiobarbituric acid, i.e. (VI) and (VII). In the crystal structures of 2,4-diaminopyrimidine, i.e. (I)-(IV), R2(2)(8) N-H...N hydrogen-bond motifs are preferred and, in two structures, additional R3(2)(8) patterns were observed.

6-Propyl-2-thiouracil versus 6-methoxymethyl-2-thiouracil: enhancing the hydrogen-bonded synthon motif by replacement of a methylene group with an O atom.

The understanding of intermolecular interactions is a key objective of crystal engineering in order to exploit the derived knowledge for the rational design of new molecular solids with tailored physical and chemical properties. The tools and theories of crystal engineering are indispensable for the rational design of (pharmaceutical) cocrystals. The results of cocrystallization experiments of the antithyroid drug 6-propyl-2-thiouracil (PTU) with 2,4-diaminopyrimidine (DAPY), and of 6-methoxymethyl-2-thiouracil (MOMTU) with DAPY and 2,4,6-triaminopyrimidine (TAPY), respectively, are reported. PTU and MOMTU show a high structural similarity and differ only in the replacement of a methylene group (-CH2-) with an O atom in the side chain, thus introducing an additional hydrogen-bond acceptor in MOMTU. Both molecules contain an ADA hydrogen-bonding site (A = acceptor and D = donor), while the coformers DAPY and TAPY both show complementary DAD sites and therefore should be capable of forming a mixed ADA/DAD synthon with each other, i.e. N-H...O, N-H...N and N-H...S hydrogen bonds. The experiments yielded one solvated cocrystal salt of PTU with DAPY, four different solvates of MOMTU, one ionic cocrystal of MOMTU with DAPY and one cocrystal salt of MOMTU with TAPY, namely 2,4-diaminopyrimidinium 6-propyl-2-thiouracilate-2,4-diaminopyrimidine-N,N-dimethylacetamide-water (1/1/1/1) (the systematic name for 6-propyl-2-thiouracilate is 6-oxo-4-propyl-2-sulfanylidene-1,2,3,6-tetrahydropyrimidin-1-ide), C4H7N4(+)·C7H9N2OS(-)·C4H6N4·C4H9NO·H2O, (I), 6-methoxymethyl-2-thiouracil-N,N-dimethylformamide (1/1), C6H8N2O2S·C3H7NO, (II), 6-methoxymethyl-2-thiouracil-N,N-dimethylacetamide (1/1), C6H8N2O2S·C4H9NO, (III), 6-methoxymethyl-2-thiouracil-dimethyl sulfoxide (1/1), C6H8N2O2S·C2H6OS, (IV), 6-methoxymethyl-2-thiouracil-1-methylpyrrolidin-2-one (1/1), C6H8N2O2S·C5H9NO, (V), 2,4-diaminopyrimidinium 6-methoxymethyl-2-thiouracilate (the systematic name for 6-methoxymethyl-2-thiouracilate is 4-methoxymethyl-6-oxo-2-sulfanylidene-1,2,3,6-tetrahydropyrimidin-1-ide), C4H7N4(+)·C6H7N2O2S(-), (VI), and 2,4,6-triaminopyrimidinium 6-methoxymethyl-2-thiouracilate-6-methoxymethyl-2-thiouracil (1/1), C4H8N5(+)·C6H7N2O2S(-)·C6H8N2O2S, (VII). Whereas in (I) only an AA/DD hydrogen-bonding interaction was formed, the structures of (VI) and (VII) both display the desired ADA/DAD synthon. Conformational studies on the side chains of PTU and MOMTU also revealed a significant deviation for cocrystals (VI) and (VII), leading to the desired enhancement of the hydrogen-bond pattern within the crystal.

Cocrystals of 6-chlorouracil and 6-chloro-3-methyluracil: exploring their hydrogen-bond-based synthon motifs with several triazine and pyrimidine derivatives.

In order to obtain complexes held together by hydrogen as well as halogen bonds, 6-chlorouracil [6-chloropyrimidin-2,4(1H,3H)-dione; 6CU] and its 3-methyl derivative [6-chloro-3-methylpyrimidin-2,4(1H,3H)-dione; M6CU] were cocrystallized with 2,4,6-triaminopyrimidine and the three triazine derivatives 2,4,6-triamino-1,3,5-triazine (melamine), 2,4-diamino-6-methyl-1,3,5-triazine and 2-chloro-4,6-diamino-1,3,5-triazine, which all offer complementary hydrogen-bonding sites. Three of these compounds form cocrystals with 6CU; however, melamine yielded only a new pseudopolymorph with 6CU, but formed a cocrystal with M6CU. All six cocrystals contain solvent molecules (N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidin-2-one), whose intermolecular interactions contribute significantly to the stabilization of the crystal packing. Each of these structures comprises chains, which are primarily formed by strong hydrogen bonds with a basic framework built by R2(2)(8) hydrogen bonds of either pure N-H...N or mixed patterns. Solvent molecules are aligned to the border of these chains via N-H...O hydrogen bonds. Two of the reported crystal structures containing 6CU show additional Cl...O halogen bonds, which connect the chains to two-dimensional layers, while one weak and one strong Cl...Cl interaction are observed in the two structures in which molecules of M6CU are present.

Cocrystals of 6-methyl-2-thiouracil: presence of the acceptor-donor-acceptor/donor-acceptor-donor synthon.

The results of seven cocrystallization experiments of the antithyroid drug 6-methyl-2-thiouracil (MTU), C(5)H(6)N(2)OS, with 2,4-diaminopyrimidine, 2,4,6-triaminopyrimidine and 6-amino-3H-isocytosine (viz. 2,6-diamino-3H-pyrimidin-4-one) are reported. MTU features an ADA (A = acceptor and D = donor) hydrogen-bonding site, while the three coformers show complementary DAD hydrogen-bonding sites and therefore should be capable of forming an ADA/DAD N-H...O/N-H...N/N-H...S synthon with MTU. The experiments yielded one cocrystal and six cocrystal solvates, namely 6-methyl-2-thiouracil-2,4-diaminopyrimidine-1-methylpyrrolidin-2-one (1/1/2), C(5)H(6)N(2)OS·C(4)H(6)N(4)·2C(5)H(9)NO, (I), 6-methyl-2-thiouracil-2,4-diaminopyrimidine (1/1), C(5)H(6)N(2)OS·C(4)H(6)N(4), (II), 6-methyl-2-thiouracil-2,4-diaminopyrimidine-N,N-dimethylacetamide (2/1/2), 2C(5)H(6)N(2)OS·C(4)H(6)N(4)·2C(4)H(9)NO, (III), 6-methyl-2-thiouracil-2,4-diaminopyrimidine-N,N-dimethylformamide (2/1/2), C(5)H(6)N(2)OS·0.5C(4)H(6)N(4)·C(3)H(7)NO, (IV), 2,4,6-triaminopyrimidinium 6-methyl-2-thiouracilate-6-methyl-2-thiouracil-N,N-dimethylformamide (1/1/2), C(4)H(8)N(5)(+)·C(5)H(5)N(2)OS(-)·C(5)H(6)N(2)OS·2C(3)H(7)NO, (V), 6-methyl-2-thiouracil-6-amino-3H-isocytosine-N,N-dimethylformamide (1/1/1), C(5)H(6)N(2)OS·C(4)H(6)N(4)O·C(3)H(7)NO, (VI), and 6-methyl-2-thiouracil-6-amino-3H-isocytosine-dimethyl sulfoxide (1/1/1), C(5)H(6)N(2)OS·C(4)H(6)N(4)O·C(2)H(6)OS, (VII). Whereas in cocrystal (I) an R(2)(2)(8) interaction similar to the Watson-Crick adenine/uracil base pair is formed and a two-dimensional hydrogen-bonding network is observed, the cocrystals (II)-(VII) contain the triply hydrogen-bonded ADA/DAD N-H...O/N-H...N/N-H...S synthon and show a one-dimensional hydrogen-bonding network. Although 2,4-diaminopyrimidine possesses only one DAD hydrogen-bonding site, it is, due to orientational disorder, triply connected to two MTU molecules in (III) and (IV).

Cocrystals of the antibiotic trimethoprim with glutarimide and 3,3-dimethylglutarimide held together by three hydrogen bonds.

The antibiotic trimethoprim [5-(3,4,5-trimethoxybenzyl)pyrimidine-2,4-diamine] was cocrystallized with glutarimide (piperidine-2,6-dione) and its 3,3-dimethyl derivative (4,4-dimethylpiperidine-2,6-dione). The cocrystals, viz. trimethoprim-glutarimide (1/1), C14H18N4O3·C5H7NO2, (I), and trimethoprim-3,3-dimethylglutarimide (1/1), C14H18N4O3·C7H11NO2, (II), are held together by three neighbouring hydrogen bonds (one central N-H...N and two N-H...O) between the pyrimidine ring of trimethoprim and the imide group of glutarimide, with an ADA/DAD pattern (A = acceptor and D = donor). These heterodimers resemble two known cocrystals of trimethoprim with barbituric acid and its 5,5-diethyl derivative. Trimethoprim shows a conformation in which the planes of the pyrimidine and benzene rings are approximately perpendicular to one another. In its glutarimide coformer, five of the six ring atoms lie in a common plane; the C atom opposite the N atom deviates by about 0.6 Å. The crystal packing of each of the two cocrystals is characterized by an extended network of hydrogen bonds and contains centrosymmetrically related trimethoprim homodimers formed by a pair of N-H...N hydrogen bonds. This structural motif occurs in five of the nine published crystal structures in which neutral trimethoprim is present.

Structural similarities among eight benzoylhydrazones.

The crystal structures of eight benzoylhydrazones with different substituents have been investigated, namely 1-benzoyl-2-(propan-2-ylidene)hydrazone, C(10)H(12)N(2)O, (I), 1-benzoyl-2-(1-cyclohexylethylidene)hydrazone, C(15)H(20)N(2)O, (II), 1-benzoyl-2-[1-(naphthalen-2-yl)ethylidene]hydrazone, C(19)H(16)N(2)O, (III), 1-benzoyl-2-(1-cyclohexylbenzylidene)hydrazone, C20H22N2O, (IV), 1-benzoyl-2-(1-phenylbenzylidene)hydrazone, C(20)H(16)N(2)O, (V), 1-benzoyl-2-[1-(4-chlorophenyl)benzylidene]hydrazone, C(20)H(15)ClN(2)O, (VI), 1-benzoyl-2-(4-hydroxybenzylidene)hydrazone methanol monosolvate, C(14)H(12)N(2)O(2) · CH(3)OH, (VII), and 1-benzoyl-2-(1,1-diphenylpropan-2-ylidene)hydrazone, C(22)H(20)N(2)O, (VIII). The ten molecules in the eight crystal structures [there are two independent molecules in the structures of (V) and (VI)] show similar conformations and hydrogen-bonding patterns. The C=N-NH-C=O group is planar, but the plane of the phenyl ring of the benzoyl group is rotated by about 30° with respect to that of the keto group [except for (IV), where the groups are coplanar]. Only in the amide group of (VIII) is the N-H group syn to the C=O bond, whereas the seven other compounds exhibit the anti conformation. Unless prevented by steric hindrance, N-H...O hydrogen bonds help to stabilize the crystal structure, which leads to infinite chains or dimers depending upon the molecular conformation. The molecular packing is supported by intermolecular C-H...O interactions. In the crystal structure of (VII), the methanol solvent molecule participates in two strong hydrogen bonds and two weak C-H...O interactions, thus acting as a link between the molecular chains.

N-H···S and N-H···O hydrogen bonds: 'pure' and 'mixed' R2(2)(8) patterns in the crystal structures of eight 2-thiouracil derivatives.

The preferred hydrogen-bonding patterns in the crystal structures of 5-propyl-2-thiouracil, C7H10N2OS, (I), 5-methoxy-2-thiouracil, C5H6N2O2S, (II), 5-methoxy-2-thiouracil-N,N-dimethylacetamide (1/1), C5H6N2O2S·C4H9NO, (IIa), 5,6-dimethyl-2-thiouracil, C6H8N2OS, (III), 5,6-dimethyl-2-thiouracil-1-methylpyrrolidin-2-one (1/1), C6H8N2OS·C5H9NO, (IIIa), 5,6-dimethyl-2-thiouracil-N,N-dimethylformamide (2/1), 2C6H8N2OS·C3H7NO, (IIIb), 5,6-dimethyl-2-thiouracil-N,N-dimethylacetamide (2/1), 2C6H8N2OS·C4H9NO, (IIIc), and 5,6-dimethyl-2-thiouracil-dimethyl sulfoxide (2/1), 2C6H8N2OS·C2H6OS, (IIId), were analysed. All eight structures contain R(2)(2)(8) patterns. In (II), (IIa), (III) and (IIIa), they are formed by two N-H···S hydrogen bonds, and in (I) by alternating pairs of N-H···S and N-H···O hydrogen bonds. In contrast, the structures of (IIIb), (IIIc) and (IIId) contain 'mixed' R(2)(2)(8) patterns with one N-H···S and one N-H···O hydrogen bond, as well as R(2)(2)(8) motifs with two N-H···O hydrogen bonds.

Pseudopolymorphs of chelidamic acid and its dimethyl ester.

Different tautomeric and zwitterionic forms of chelidamic acid (4-hydroxypyridine-2,6-dicarboxylic acid) are present in the crystal structures of chelidamic acid methanol monosolvate, C(7)H(5)NO(5)·CH(4)O, (Ia), dimethylammonium chelidamate (dimethylammonium 6-carboxy-4-hydroxypyridine-2-carboxylate), C(2)H(8)N(+)·C(7)H(4)NO(5)(-), (Ib), and chelidamic acid dimethyl sulfoxide monosolvate, C(7)H(5)NO(5)·C(2)H(6)OS, (Ic). While the zwitterionic pyridinium carboxylate in (Ia) can be explained from the pK(a) values, a (partially) deprotonated hydroxy group in the presence of a neutral carboxy group, as observed in (Ib) and (Ic), is unexpected. In (Ib), there are two formula units in the asymmetric unit with the chelidamic acid entities connected by a symmetric O-H···O hydrogen bond. Also, crystals of chelidamic acid dimethyl ester (dimethyl 4-hydroxypyridine-2,6-dicarboxylate) were obtained as a monohydrate, C(9)H(9)NO(5)·H(2)O, (IIa), and as a solvent-free modification, in which both ester molecules adopt the hydroxypyridine form. In (IIa), the solvent water molecule stabilizes the synperiplanar conformation of both carbonyl O atoms with respect to the pyridine N atom by two O-H···O hydrogen bonds, whereas an antiperiplanar arrangement is observed in the water-free structure. A database study and ab initio energy calculations help to compare the stabilities of the various ester conformations.

Cocrystals of 5-fluorocytosine. I. Coformers with fixed hydrogen-bonding sites.

The antifungal drug 5-fluorocytosine (4-amino-5-fluoro-1,2-dihydropyrimidin-2-one) was cocrystallized with five complementary compounds in order to better understand its drug-receptor interaction. The first two compounds, 2-aminopyrimidine (2-amino-1,3-diazine) and N-acetylcreatinine (N-acetyl-2-amino-1-methyl-5H-imidazol-4-one), exhibit donor-acceptor sites for R(2)(2)(8) heterodimer formation with 5-fluorocytosine. Such a heterodimer is observed in the cocrystal with 2-aminopyrimidine (I); in contrast, 5-fluorocytosine and N-acetylcreatinine [which forms homodimers in its crystal structure (II)] are connected only by a single hydrogen bond in (III). The other three compounds 6-aminouracil (6-amino-2,4-pyrimidinediol), 6-aminoisocytosine (2,6-diamino-3H-pyrimidin-4-one) and acyclovir [acycloguanosine or 2-amino-9-[(2-hydroxyethoxy)methyl]-1,9-dihydro-6H-purin-6-one] possess donor-donor-acceptor sites; therefore, they can interact with 5-fluorocytosine to form a heterodimer linked by three hydrogen bonds. In the cocrystals with 6-aminoisocytosine (Va)-(Vd), as well as in the cocrystal with the antiviral drug acyclovir (VII), the desired heterodimers are observed. However, they are not formed in the cocrystal with 6-aminouracil (IV), where the components are connected by two hydrogen bonds. In addition, a solvent-free structure of acyclovir (VI) was obtained. A comparison of the calculated energies released during dimer formation helped to rationalize the preference for hydrogen-bonding interactions in the various cocrystal structures.

Cocrystals of 5-fluorocytosine. II. Coformers with variable hydrogen-bonding sites.

Two flexible molecules, biuret and 6-acetamidouracil, were cocrystallized with 5-fluorocytosine to study their conformational preferences. In the cocrystal with 5-fluorocytosine (I), biuret exhibits the same conformation as in its hydrate. In contrast, 6-acetamidouracil can adopt two main conformations depending on its crystal environment: in crystal (II) the trans form characterized by an intramolecular hydrogen bond is observed, while in the cocrystal with 5-fluorocytosine (III), the complementary binding induces the cis form. Three cocrystals of 6-methylisocytosine demonstrate that complementary binding enables the crystallization of a specific tautomer. In the cocrystals with 5-fluorocytosine, (IVa) and (IVb), only the 3H tautomer of 6-methylisocytosine is present, whereas in the cocrystal with 6-aminoisocytosine, (V), the 1H tautomeric form is adopted. The complexes observed in the cocrystals are stabilized by three hydrogen bonds similar to those constituting the Watson-Crick C·G base pair.

Cocrystals of 6-propyl-2-thiouracil: N-H···O versus N-H···S hydrogen bonds.

In order to investigate the relative stability of N-H···O and N-H···S hydrogen bonds, we cocrystallized the antithyroid drug 6-propyl-2-thiouracil with two complementary heterocycles. In the cocrystal pyrimidin-2-amine-6-propyl-2-thiouracil (1/2), C(4)H(5)N(3)·2C(7)H(10)N(2)OS, (I), the `base pair' is connected by one N-H···S and one N-H···N hydrogen bond. Homodimers of 6-propyl-2-thiouracil linked by two N-H···S hydrogen bonds are observed in the cocrystal N-(6-acetamidopyridin-2-yl)acetamide-6-propyl-2-thiouracil (1/2), C(9)H(11)N(3)O(2)·2C(7)H(10)N(2)OS, (II). The crystal structure of 6-propyl-2-thiouracil itself, C(7)H(10)N(2)OS, (III), is stabilized by pairwise N-H···O and N-H···S hydrogen bonds. In all three structures, N-H···S hydrogen bonds occur only within R(2)(2)(8) patterns, whereas N-H···O hydrogen bonds tend to connect the homo- and heterodimers into extended networks. In agreement with related structures, the hydrogen-bonding capability of C=O and C=S groups seems to be comparable.

Five pseudopolymorphs and a cocrystal of nitrofurantoin.

The antibiotic nitrofurantoin {systematic name: (E)-1-[(5-nitro-2-furyl)methylideneamino]imidazolidine-2,4-dione} is not only used for the treatment of urinary tract infections, but also illegally applied as an animal food additive. Since derivatives of 2,6-diaminopyridine might serve as artificial receptors for its recognition, we crystallized one potential drug-receptor complex, nitrofurantoin-2,6-diacetamidopyridine (1/1), C(8)H(6)N(4)O(5)·C(9)H(11)N(3)O(2), (I·II). It is characterized by one N-H···N and two N-H···O hydrogen bonds and confirms a previous NMR study. During the crystallization screening, several new pseudopolymorphs of both components were obtained, namely a nitrofurantoin dimethyl sulfoxide monosolvate, C(8)H(6)N(4)O(5)·C(2)H(6)OS, (Ia), a nitrofurantoin dimethyl sulfoxide hemisolvate, C(8)H(6)N(4)O(5)·0.5C(2)H(6)OS, (Ib), two nitrofurantoin dimethylacetamide monosolvates, C(8)H(6)N(4)O(5)·C(4)H(9)NO, (Ic) and (Id), and a nitrofurantoin dimethylacetamide disolvate, C(8)H(6)N(4)O(5)·2C(4)H(9)NO, (Ie), as well as a 2,6-diacetamidopyridine dimethylformamide monosolvate, C(9)H(11)N(3)O(2)·C(3)H(7)NO, (IIa). Of these, (Ia), (Ic) and (Id) were formed during cocrystallization attempts with 1-(4-fluorophenyl)biguanide hydrochloride. Obviously nitrofurantoin prefers the higher-energy conformation in the crystal structures, which all exhibit N-H···O and C-H···O hydrogen-bond interactions. The latter are especially important for the crystal packing. 2,6-Diacetamidopyridine shows some conformational flexibility depending on the hydrogen-bond pattern.

New pseudopolymorphs of 5-fluorocytosine.

In order to better understand the interaction between the pharmaceutically active compound 5-fluorocytosine [4-amino-5-fluoropyrimidin-2(1H)-one] and its receptor, hydrogen-bonded complexes with structurally similar bonding patterns have been investigated. During the cocrystallization screening, three new pseudopolymorphs of 5-fluorocytosine were obtained, namely 5-fluorocytosine dimethyl sulfoxide solvate, C(4)H(4)FN(3)O.C(2)H(6)OS, (I), 5-fluorocytosine dimethylacetamide hemisolvate, C(4)H(4)FN(3)O.0.5C(4)H(9)NO, (II), and 5-fluorocytosine hemihydrate, C(4)H(4)FN(3)O.0.5H(2)O, (III). Similar hydrogen-bond patterns are observed in all three crystal structures. The 5-fluorocytosine molecules form ribbons with repeated R(2)(2)(8) dimer interactions. These dimers are stabilized by N-H...N and N-H...O hydrogen bonds. The solvent molecules adopt similar positions with respect to 5-fluorocytosine. Depending on the hydrogen bonds formed by the solvent, the 5-fluorocytosine ribbons form layers or tubes. A database study was carried out to compare the hydrogen-bond pattern of compounds (I)-(III) with those of other (pseudo)polymorphs of 5-fluorocytosine.