N-[2-(Trifluoromethyl)phenyl]maleamic acid: crystal structure and Hirshfeld surface analysis

The –COOH group of the title compound adopts a syn conformation (O= C—O—H = 0°) unlike the anti conformation observed in related maleamic acids. This is correlated with the formation of carboxylic acid inversion dimers linked by pairwise O—H⋯O hydrogen bonds in the crystal of the title compound rather than an intramolecular O—H⋯O hydrogen bond.


Chemical context
The development of pH-induced charge-conversion drugdelivery systems can help to overcome the intrinsic pH difference between tumor tissues (pH 6.5-6.8) and normal tissues or the blood stream (pH 7.2-7.4) (Ge et al., 2013). Reactions of 2,3-dimethylmaleic anhydride (DMMA) and amino groups on the particle surface have been used to shield the positive charge of nanoparticles (Du et al., 2010). The generated amide bond is cleavable under mildly acidic conditions but is stable at neutral or basic pH, whereas the DMMA-decorated nanoparticles are inert under physiological conditions. After accumulating into the acidic tumor tissue through the enhanced permeation and retention (EPR) effect, the amide bond slowly cleaves and thus exposes the positive charge, which eventually promotes cell internalization. Therefore, maleamic acids and their derivatives, by virtue of their unique weak acid sensitivity and charge conversion have been widely used as smart carriers to deliver nucleic acids (Meyer et al., 2009), proteins Lee et al., 2007) and drugs (Du et al., 2011;Chen et al., 2015;Han et al., 2015). Simple methods to control the ratio of two positional isomers of mono-substituted maleamic acids and a highly efficient way to synthesize di-substituted maleamic acids have been reported (Su et al., 2017). The hydrolysis profiles of mono-or di-substituted maleamic acids were studied by the same authors to elucidate their hydrolysis selectivity towards various physiologically available pH values (Su et al., 2017). As part our studies in this area, the synthesis and crystal structure of N-[2-(trifluoromethyl)phenyl]maleamic acid, (I), ISSN 2056-9890 is described and is further analysed using Hirshfeld surfaces and fingerprint plots and compared to related structures.

Hirshfeld surface analysis
In the Hirshfeld surface analysis, d norm surfaces and twodimensional fingerprint plots (FP) were generated to further investigate the intermolecular interactions in (I) and to provide quantitative data for the relative contributions to the surfaces (Turner et al., 2017). The appearance of both darkand faint-red spots near O1 and O3 support the involvement of each of these atoms in architectures involving the acceptance of a strong hydrogen bond and a weak intermolecular interaction (Fig. 3). Similarly, dark-red spots near the H1N and H2O hydrogen atoms are due to their involvement as donors in stronger hydrogen bonds, while faint spots near H8 and H9 atoms are due to the weak C-HÁ Á ÁO interactions involving these atoms (Fig. 3). Analysis of the fingerprint plots ( Fig. 4) showed that the major contributions to the overall Hirshfeld surfaces of (I) are from OÁ Á ÁH/HÁ Á ÁO ( Table 1 Hydrogen-bond geometry (Å , ).

Figure 1
A view of the molecular structure of (I), with displacement ellipsoids drawn at the 50% probability level.
interactions, with other contacts contributing the remaining 10.2%.

Synthesis and crystallization
The title compound was synthesized by following the same procedure that was employed for synthesizing N-(2-methyl- The Hirshfeld surface mapped with d norm for the molecule in (I) over the range À0.753 to 1.252 a.u., shown interacting with near-neighbour molecules connected through hydrogen bonds (dashed lines).

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. The carbon-bound H atoms were placed in calculated positions (C-H = 0.93 Å ) and were included in the refinement in the riding-model approximation, with U iso (H) set to 1.2U eq (C). The oxygen-and nitrogenbound H atoms were located from difference-Fourier maps and freely refined. Data collection: APEX2 (Bruker, 2009); cell refinement: SAINT-Plus (Bruker, 2009); data reduction: SAINT-Plus (Bruker, 2009); program(s) used to solve structure: SHELXT2016 (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2016 (Sheldrick, 2015b); molecular graphics: Mercury (Macrae et al., 2008); software used to prepare material for publication: SHELXL2016 (Sheldrick, 2015b). 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.