Crystal structure of 4-(2-hydroxy-3-methoxybenzylamino)benzoic acid dimethylformamide monosolvate monohydrate

The title compound, C15H15NO4·C3H7NO·H2O, crystallizes with one molecule of water and one molecule of dimethylformamide (DMF) as solvate molecules. The molecule is non-planar, with a Caryl—CH2—NH—Caryl torsion angle of −66.3 (3)°.


Chemical context
Vanillin and vanillin derivatives are used in food and non-food applications, in fragrances and as flavouring agents for pharmaceutical products (Hocking, 1997;Walton et al., 2003). Synthetic vanillin is used as an intermediate in the chemical and pharmaceutical industries for the production of herbicides, antifoaming agents and drugs, such as papaverine, l-dopa and l-methyldopa, as well as antimicrobial agents such as trimethoprim (Fitzgerald et al., 2005), and as a bacterial cofactor involved in the synthesis of folic acid (Robinson, 1966). Another example is benzocaine, the ethyl ester of p-aminobenzoic acid, which is a local anaesthetic. The mechanism includes inhibiting voltage-dependent sodium channels on the nerve membrane, which results in stopping the signal propagation (Neumcke et al., 1981). The title compound (1) was synthesized by reduction of reported (E)-4-(2-hydroxy-3methoxybenzylideneamino)benzoic acid with sodium borohydride and crystallizes as a water and dimethylformamide solvate. The latter Schiff base is formed by condensation of 4-aminobenzoic acid with o-vanilline.
In this context and as part of an ongoing structural study of Schiff bases and secondary amines for their utilization in the synthesis of new organic compounds and the application of excited-state proton transfer and fluorescent chemosensors (Faizi et al., 2016a(Faizi et al., ,b, 2018aKumar et al., 2018;Mukherjee et al., 2018), we report here the molecular and crystal structure of (1), C 15 H 15 NO 4 ÁC 3 H 7 NOÁH 2 O.

Structural commentary
Compound (1) crystallizes in space group Pbca with one molecule of 4-(2-hydroxy-3-methoxybenzylamino)benzoic acid and one molecule each of DMF and water in the asymmetric unit (Fig. 1). The secondary amine has two substituted aromatic rings at either end of the -CH 2 -NH-linkage. As a result of the C aryl -CH 2 -NH-C aryl torsion angle of À66.3 (3) , the molecular shape of the title compound is bent around the central C8-N1 bond. The secondary amine N atom (N1) has a practically trigonal-planar configuration deviating by 0.02 (1) Å from the mean plane of the adjacent atoms, and N1-C5 is apparently less conjugated with the C2-C7 benzenecarboxylic acid ring. For comparison, the reported C-N distance in the crystal structure of the ethyl 4-[(E)-(4hydroxy-3-methoxybenzylidene)amino]benzoate Schiff base is 1.274 (2) Å (Ling et al., 2016), and in the zwitterionic form it is 1.312 Å (Kamaal et al., 2018). The benzene rings C2-C7 and C9-C14 are roughly perpendicular to each another, with a dihedral angle of 88.15 (10) between them.

Figure 2
A view of hydrogen-bonding interactions around the water molecule in the title structure.

Synthesis and crystallization
To a hot stirred solution of 4-aminobenzoic acid (PABA) (1.00 g, 7.2 mmol) in methanol (15 ml) was added vanillin (1.11 g, 7.2 mmol). The resultant mixture was then heated under reflux. After an hour, a precipitate was formed. The reaction mixture was heated for about a further 30 minutes for completion of the reaction, which was monitored through TLC. The reaction mixture was then cooled to room temperature, filtered and washed with hot methanol. It was then dried in vacuo to give (E)-4-(2-hydroxy-3-methoxybenzylideneamino) benzoic acid in 78% yield. The latter (1.00 g, 3.7 mmol) was dissolved in 25 ml of methanol and reduced by addition of excess sodium borohydride (0.28 g, 7.4 mmol). The solution was stirred until the yellow colour disappeared. Then the solution was diluted with 8-10 times the volume of water and the pH was adjusted to 6 by addition of 12% wt HCl. The white precipitate was collected and dried in air. Colourless single crystals of the title compound, suitable for X-ray analysis, were obtained by slow evaporation of a dimethylformamide solution.

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.