The crystal structure, Hirshfeld surface analysis and energy frameworks of 2-[2-(methoxycarbonyl)-3,6-bis(methoxymethoxy)phenyl]acetic acid

The title compound, 2-(2-(methoxycarbonyl)-3,6-bis(methoxymethoxy)phenyl)acetic acid, was synthesized as an intermediate for a possible total synthesis of the isocoumarin 3-methyl-3,5,8-trihydroxy-3,4-dihydroisocoumarin.


Chemical context
Isocoumarins are among the phytotoxins produced by the Ceratocystis fimbriata species. The latter are pathogenic agents responsible for the infections of coffee and plane trees (Gremaud & Tabacchi, 1994;Bü rki et al., 2003). The analysis of the culture medium of Ophiostoma ulmi, a pathogenic agent responsible for elm disease and classified in the family of Ceratocystis, enabled Michel (2001) to isolate sixteen metabolites including four isocoumarins without apparent toxicity and a new natural product, 3-methyl-3,5,8-trihydroxy-3,4-dihydroisocoumarin, found in the extract of diseased wood. Qualitatively, the latter is present in trace amounts; however, the toxicity of this metabolite is possible, since the activity is not necessarily proportional to the concentration.
The title compound (I), is a key intermediate for the proposed total synthesis of 3-methyl-3,5,8-trihydroxy-3,4-dihydroisocoumarin, and its synthesis is illustrated in Fig. 1 (Tiouabi, 2005). It was synthesized from hydroquinone (1), which was first brominated to give compound 2. The latter was then reacted with NaH and ClCH 2 OCH 3 to give compound 3, so protecting the hydroxyl groups. Reacting 3 with tetramethylpiperidene with n-butyllithium and CH 2 (CO 2 CH 3 ) 2 resulted in the formation of compound 4. Finally 4 was reacted with various quantities of KOH in methanol/water (2:1) to give the title compound, I. The highest yield (81%) was obtained by reacting 20 equivalents of KOH in methanol/ water (2:1) at 298 K under stirring for 16 h. Interestingly, the same reaction with reflux for 30 minutes yielded the diacid, 2-(carboxymethyl)-3,6-dihydroxybenzoic acid (5), with a yield of 82% (Fig. 1).

Supramolecular features
In the crystal of I, molecules are linked by a pair of O-HÁ Á ÁO hydrogen bonds (O8-H8Á Á ÁO7 i ) forming an inversion dimer with an R 2 2 (8) ring motif ( Fig. 3 and Table 1). The dimers are linked by two C-HÁ Á ÁO hydrogen bonds (C9-H9BÁ Á ÁO6 ii and C11-H11AÁ Á ÁO1 iii ) and offsetinteractions between inversion-related benzene rings, so forming layers lying parallel to (101). The layers are linked by a third C-HÁ Á ÁO hydrogen bond (C13-H13BÁ Á ÁO4 iv ) and a C-HÁ Á Á interaction to form a supramolecular framework (Table 1  The molecular structure of compound I, with atom labelling. Displacement ellipsoids are drawn at the 50% probability level.

Figure 1
The reaction scheme resulting in the formation of the title compound, I. Table 1 Hydrogen-bond geometry (Å , ).

Hirshfeld surface analysis and two-dimensional fingerprint plots
The Hirshfeld surface analysis (Spackman & Jayatilaka, 2009), the associated two-dimensional fingerprint plots and the calculation of the energy frameworks (McKinnon et al., 2007) were performed with CrystalExplorer17.5 (Turner et al., 2017), following the protocol outlined in the recent article by Tiekink and collaborators (Tan et al., 2019). The Hirshfeld surface is colour-mapped with the normalized contact distance, d norm , from red (distances shorter than the sum of the van der Waals radii) through white to blue (distances longer than the sum of the van der Waals radii). The energy frameworks (Turner et al., 2015;Tan et al., 2019) are represented by cylinders joining the centroids of molecular pairs using red, green and blue colour codes for the electrostatic (E ele ), dispersion (E dis ) and total energy (E tot ) components, respectively. The radius of the cylinder is proportional to the magnitude of the interaction energy.
A view of the Hirshfeld surface of I mapped over d norm is shown in Fig. 5. The short interatomic OÁ Á ÁH/HÁ Á ÁO contacts are indicated by the large red spots. Other C-HÁ Á ÁO contacts are indicated by faint red spots. A full list of short interatomic contacts in the crystal of I are given in Table 2 A view along the b axis of the crystal packing of compound I. The hydrogen bonds (Table 1) are shown as dashed lines. The offsetinteractions are indicated by orange double arrows, and the C-HÁ Á Á interactions by blue dashed arrows. For clarity, only the H atoms involved in the intermolecular interactions have been included.

Figure 5
The Hirshfeld surface of compound I mapped over d norm , in the colour range À0.6996 to 1.3669 a.u..

Table 2
Short interatomic contacts (Å ) a in the crystal of compound I.
The principal intermolecular contacts for I are delineated into HÁ Á ÁH (48.0%) (Fig. 6b), OÁ Á ÁH/HÁ Á ÁO (41.1%) (Fig. 6c), CÁ Á ÁH/HÁ Á ÁC (7.2%) (Fig. 6d) and CÁ Á ÁC (2.7%) (Fig. 6e) contacts. The intermolecular contacts are therefore almost equally distributed between electrostatic and dispersion forces, as shown in Fig. 7a and 7b. The energy frameworks ( Fig. 7) were adjusted to the same scale factor of 80 with a cutoff value of 5 kJ mol À1 within a radius of 5 Å about a central molecule, and were obtained using the wave function calculated at the HF/3-21G level of theory. The calculation of the energy framework results in a colourcoded molecular cluster related to the specific interaction energy, see Fig. 8a. The individual energy components, electrostatic (E ele ), polarization (E pol ), dispersion (E dis ) and repulsion (E rep ) energies and the sum of these components (E tot ) for the interactions relative to a reference molecule (*) are shown in The energy frameworks for I viewed down the c-axis direction comprising, (a) electrostatic potential forces (E ele ), (b) dispersion forces (E dis ) and (c) total (E tot ) energy for a cluster about a reference molecule of I. The energy frameworks were adjusted to the same scale factor of 80 with a cut-off value of 5 kJ mol À1 within a 5 Å radius of a selected central molecule.

Figure 8
The colour-coding interaction mapping within 5 Å of the centering (*) molecular cluster.  Fig. 9 and Table 3. In GEZPUZ and GEZQAG these side chains are twisted and directed to the same side of the benzene ring. In IVIQIP they are also twisted but directed to opposite sides of the benzene ring as in compound I.

Database survey
A search of the CSD for the substructure 2-(2-(methoxycarbonyl)phenyl)acetic acid gave zero hits.

Synthesis and crystallization
The synthesis of compound I is illustrated in Fig. 1. Full details of the syntheses and spectroscopic and analytical data for compounds 2-5 and I are available in the PhD thesis of Tiouabi (2005). It can be downloaded from the website https:// doc.rero.ch/record, a digital library where many theses of Swiss universities are deposited. Colourless block-like crystals of I were obtained by slow evaporation of a solution in acetone-d 6 .

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 4. The OH and C-bound H atoms were included in calculated positions and treated as riding atoms: O-H = 0.84 Å , C-H = 0.95-0.99 Å with U iso (H) = 1.5U eq (OH and C-methyl) and 1.2U eq (C) for other H-atoms.
Intensity data were measured using a Stoe IPDS I, a onecircle diffractometer. For the triclinic system often only 93% of the Ewald sphere is accessible, which explains why the alert diffrn_reflns_laue_measured_fraction_full value (0.942) below minimum (0.95) is given. This involves 155 random reflections out of the expected 2692 for the IUCr cutoff limit of sin / = 0.60. Table 3 Selected torsion angles ( ) in compound I compared to those in compounds GEZPUZ, GEZQAG and IVIQIP.