Crystal water as the molecular glue for obtaining different co-crystal ratios: the case of gallic acid tris-caffeine hexahydrate

This co-crystal structure consists of three caffeine molecules and one gallic acid molecule as well as six hydrate water molecules per formula unit. It can be described as being composed of two types of molecular layers connected via hydrogen-bonding interactions to solvent water. The two layers stack in an alternate manner between layers consisting solely of caffeine molecules and layers of caffeine and gallic acid molecules.


Chemical context
Gallic acid and its derivatives are widely known compounds in the pharmaceutical and chemical industry (Nayeem et al., 2016;Clarke et al., 2011). One such example is the dietary polyphenol found in Choerospondiatis fructus, a Mongolian medicinal herb used to treat conditions such as angina pectoris (Zhao et al., 2007). Lately, it has gained a lot of attention as a versatile component in crystal enineering, in particular with regards to co-crystallization and hydratation. Gallic acid could represent an entire microcosm of the special challenges and opportunities afforded by hydrates (Clarke et al., 2011) as it contains two of the most ubiquitous functional groups present in APIs: carboxylic acids and phenols. As part of a series of cocrystallization experiments in which both caffeine and gallic acid were used as coformers, single crystals of hydrated gallic acid and caffeine GAL3CAFÁ6H 2 O in the ratio gallic acid:caffeine:water of 1:3:6 were obtained and characterized by single-crystal X-ray diffraction. The crystal structure is reported herein and compared to the different hydrated forms of this co-crystal GALCAFÁ0.5H 2 O reported elsewhere (Clarke et al., 2010). The crystal structures differ greatly because of the different stoichiometry of the coformers. The different number of water molecules is necessary to act as structural glue, thereby facilitating crystallization.

Structural commentary
The asymmetric unit of the co-crystal GAL3CAFÁ6H 2 O consists of three independent caffeine molecules and one ISSN 2056-9890 gallic acid molecule as well as six hydrate water molecules. Gallic acid can be described as a thrice-substituted benzoic acid with hydroxyl groups in both the meta and para positons. Caffeine consists of a purine backbone with carbonyl substituents at positions 2 and 6 (C26, C28, C46, C48, C66, C68) and methyl groups connected to three out of four nitrogen atoms (Fig. 1).

Supramolecular features
As a result of the limited number of hydrogen-bond donors and acceptors in both gallic acid and caffeine, the packing strongly depends on (i) the concentration of each of the components in solution as well as (ii) other experimental conditions such as other components in solution, temperature, pressure, etc. In fact, there is a large difference in the way both molecules pack in the crystal lattice.
The crystal structure of GALCAFÁ0.5H 2 O (Clarke et al., 2010) has a 1:1:0.5 ratio of gallic acid, caffeine and water molecules. Both molecules form hydrogen-bonded tapes that are built by COO-HÁ Á ÁN and O-HÁ Á ÁO interactions [OÁ Á ÁN = 2.705 (2) Å and OÁ Á ÁO = 2.703 (2) and 2.750 (2) Å ] formed between the hydoxyl substituents on gallic acid molecules and the carbonyl moieties of adjacent caffeine molecules. These tapes are then cross-linked by water molecules that hydrogenbond with the third hydroxyl group in each gallic acid mol-ecule [OÁ Á ÁO = 2.857 (1) Å ]. The water molecules facilitate the formation of bilayers that stack in an ABAB manner sustained byinteractions. The distances between these layers of molecules can be calculated from the distances between the centroids of the aromatic rings of the two molecules and range from 3.3742 (14) to 4.3402 (14) Å . The ratio between classical hydrogen-bond donors and acceptors is 4:4 (four donors and one acceptor on the gallic acid molecule and three acceptors on the caffeine molecule).
The different balance of gallic acid and caffeine in GAL3CAFÁ6H 2 O affects the donor/acceptor ratio significantly. There are still only four classical hydrogen-bond Molecular structure of the GAL3CAFÁ6H 2 O showing the labelling scheme and displacement ellipsoids drawn at 50% probability level. Table 1 Hydrogen-bond geometry (Å , ). donors deriving from the hydroxyl groups on gallic acid, but ten hydrogen-bond acceptors (three on each caffeine and one on gallic acid). This discrepency is equilibrated by inclusion of additional solvent water molecules into the crystal structure. These act as structural glue enabling crystallization in different stoichiometries and thus, compensating for the above imbalance. The water molecules provide the additional hydrogen bonds required to form a crystalline solid. Thus, the majority of hydrogen bonds forming the intermolecular network between gallic acid and caffeine are formed by crystal water (Table 1) with d(DÁ Á ÁA) ranging from 2.643 (2) to 3.011 (2) Å . Direct classical hydrogen bonding between noncarbon atoms can only be observed between the carboxylic oxygen of gallic acid (O1) and the carbonyl oxygen of caffeine (O32) with d(DÁ Á ÁA) = 2.672 (2) Å ( Fig. 2). Additionally, there is a significant number of weak C-HÁ Á ÁO interactions present between gallic acid molecules and caffeine molecules and between caffeine molecules themselves ( Table 1). One of these interactions is between carboxylic acid and a carbonyl oxygen via hydrogen bonding that is almost parallel to an interaction between the carbonyl oxygen (O2) of the carboxylic group in gallic acid with the adjacent proton of a caffeine methyl substituent (C31) d(DÁ Á ÁA) 3.326 (3) Å . Another C-HÁ Á ÁO interaction is notable as it forms a linear chain connecting all caffeine molecules to each other (Fig. 3). These are formed between the only protonated carbon atom in the purine backbone (C22-H22, C42-H42, C62-H62) and the carbonyl oxygen of the next caffeine molecule (O32, O52, O72) with donor-acceptor distances ranging from 3.119 (3)  A comparable interaction between the protonated carbon of the purine ring does not exist in the GALCAFÁ0.5H 2 O structure.
The crystal structure of GAL3CAFÁ6H 2 O can be described as having two types of molecular layers connected via hydrogen-bonding interactions with solvent water molecules. Layers consisting solely of caffeine molecules are stacked alternately with layers composed of caffeine and gallic acid molecules (Fig. 4). The distances between the centroids of the aromatic rings are within the significance range at 3.231 (13) and 4.5028 (13) Å . Thus -stacking of the aromatic rings is both stronger and weaker in places.
The discussed crystal structure provides a good representation of the large impact of weak C-HÁ Á ÁO interactions and of how solvent molecules can play a crucial role in the formation of crystal structures. All our attempts at obtaining a solventless co-crystal with the same stoichiometry have failed so far.

Synthesis and crystallization
The crystals were obtained as a by-product in a reaction aiming for the synthesis of a lanthanide salt. Gel crystallizations were carried out in order to slow the crystallization process down. This technique involves a piece of glassware that allows two solutions to diffuse through a (tetramethylorthosilicate) gel medium. The two sets of reagents then react when they eventually diffuse through the gel. Crystal packing of GAL3CAFÁ6H 2 O viewed along b. Hydrogen-bonding interactions (Table 1) are shown as red dashed lines.

Figure 3
Crystal packing of GAL3CAFÁ6H 2 O. Hydrogen-bonding interactions (Table 1)   orthosilicate gel (10%) was prepared freshly from 7 mL in 63 mL distilled water using Na 2 CO 3 to make the gel approximately pH 8, and left to set overnight using U-tubes. Solutions were put into the two reservoirs: one contained caffeine (1 mmol, 0.2 g), while a solution containing an excess gallic acid and lanthanide was in the other.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. Methyl H atoms were refined as riding (C-H = 0.98 Å with U iso (H) = 1.5U eq (C).

Gallic Acid Tris-Caffeine hexahydrate
Crystal data Special details Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.