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Inversion dimers dominate the crystal packing in the structure of trimethyl citrate (trimethyl 2-hydroxypropane-1,2,3-tricarboxylate)

The molecular and crystal structure of trimethyl citrate is reported. The formation of inversion is the principal contributor to the crystal packing.


Chemical context
Esters of citric acid have received significant attention because of their many applications. Their use as plasticizers has grown because of their low toxicity, compatibility with the host materials and low volatility (Labrecque et al., 1997;Garg et al., 2014). They were investigated for use in degradable thermoset polymers (Halpern et al., 2014). In the biological field, trimethyl citrate is used to synthesize citrate-functionalized ciprofloxacin conjugates and their antimicrobial activities have been determined against a panel of clinically-relevant bacteria (Md-Saleh et al., 2009). Several different methods and catalysts have been employed for the synthesis of trimethyl citrate from citric acid and methanol using, for example, thionyl chloride (Ilewska & Chimiak, 1994) and zirconium(IV) dichloride oxide hydrate (Sun et al., 2006). We report here the esterification of citric acid to form trimethyl citrate, 2, together with its molecular and crystal structure.

Structural commentary
The title compound, 2, crystallizes in the triclinic space group P1, with one molecule in the asymmetric unit. The molecular structure of the compound, with the atom labelling, is shown in Fig. 1. The bond lengths and angles in 2 are comparable to those observed in citric acid, 1 (Glusker et al., 1969;Roelofsen & Kanters, 1972;King et al., 2011). The C2-C3 and C5-C6 bonds [1.506 (2) and 1.502 (2)  The central carboxylate group and the hydroxy group occur in the normal planar arrangement, with an O3-C4-C8-O6 torsion angle of À178.95 (11) and an r.m.s. deviation of only 0.0171 Å from the best-fit mean plane through the O3, C4, C8, O7, O6 and C9 atoms.

Figure 1
The structure of 2, showing the atom numbering, with ellipsoids drawn at the 50% probability level.

Figure 2
A view along c of chains of molecules of 2 formed along (101) from pairs of inversion dimers.

Figure 3
Chains of molecules of 2 along the a-axis direction formed from pairs of inversion dimers. molecular contacts generates a three-dimensional network structure with molecules stacked along the c-axis direction (Fig. 6).

Database survey
A search of the Cambridge Structural Database (Version 5.39, updated February 2018; Groom et al., 2016) for the title compound gave no hits. In contrast, a search for the O 2 CCH 2 C(O)(CO 2 )CH 2 CO 2 fragment incorporating both organic and metal organic structures gave an impressive 404 hits. Limiting the search to organic structures, which eliminates the numerous metals salts of the citrate anions and the use of citrate as a ligand, reduced the hits to 124. In what follows, with few exceptions, only one or two recent examples of the plethora of different related systems are cited. The structure of citric acid itself has been reported several times, both in isolation (Glusker et al., 1969) and as the monohydrate (Roelofsen & Kanters, 1972;King et al., 2011). Eighteen examples of citric acid cocrystallized with various organic bases are also found (see, for example, Kerr et al., 2016;Wang et al., 2016). This search also revealed a lone neutral 1,5-dimethyl citrate (Li et al., 2007a) and a single monoanionic dimethyl citrate derivative, (À)-brucinium (R)-1,2-dimethylcitrate hydrate (Bergeron et al., 1997), with no related dianions. No examples of 1-methyl citrate or any of its anions were found, but 6-methyl citrate with the carboxylate group on the central C atom has been reported (Li et al., 2007b;Aliyu et al., 2009). In contrast, structures of more than 80 citrate anions have been reported; these included 48 monoanions with the proton lost from both the central (Inukai et al., 2017;Wang et al., 2017) and peripheral carboxylate OH groups (Abraham et al., 2016;Rammohan & Kaduk, 2016a). Sixteen examples of citrate dianions (Rammohan & Kaduk, 2016b, 2017a and 17 citrate trianions (Rammohan & Kaduk, 2017b,c) were also found. The overall packing of 2 viewed along the c-axis direction.

Figure 7
The synthesis of the title compound (2).

Figure 4
Pairs of inversion dimers that link molecules of 2 into chains along the ac diagonal.

Figure 5
A view along c of the sheet of molecules of 2 formed in the ab plane by weak C-HÁ Á ÁO hydrogen bonds.

Synthesis and crystallization
Citric acid (0.01 mol, 2.00 g) was dissolved in absolute methanol (50 mL) and the solution was cooled in an ice-bath under a nitrogen atmosphere. To this solution, thionyl chloride (0.08 mol, 6.0 mL) was added dropwise with efficient stirring at 273 K for 1 h and the solution was left stirring overnight at 298 K (Fig. 7). The solvent was removed in vacuo and the solid residue was dissolved in ethyl acetate (15 mL), dried over MgSO 4 and filtered. The solvent was removed under reduced pressure and the solid residue was purified by recrystallization from hexane/ethyl acetate (1:3 v/v) to yield 1.6 g (80%) of the title compound as white crystals.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. Atom H3 of the OH group was located in a difference Fourier map and its coordinates refined with U iso (H) = 1.5U eq (O). The resulting O3-H3 distance of 0.80 (2) Å was acceptable. All H atoms bound to carbon were refined using a riding model, with C-H = 0.99 Å and U iso (H) = 1.2U eq (C) for CH 2 H atoms, and C-H = 0.98 Å and U iso (H) = 1.5U eq (C) for CH 3 H atoms.

Computing details
Data collection: APEX2 (Bruker, 2003); cell refinement: SAINT (Bruker, 2003); data reduction: SAINT (Bruker, 2003); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL2018 (Sheldrick, 2015); molecular graphics: Mercury (Macrae et al., 2008); software used to prepare material for publication: SHELXL2018 (Sheldrick, 2015), PLATON (Spek, 2009), publCIF (Westrip 2010) and WinGX (Farrugia 2012). 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.