Crystal structures of three 6-substituted coumarin-3-carboxamide derivatives

Three coumarin derivatives display intramolecular N—H⋯O and weak C—H⋯O hydrogen bonds, which probably contribute to the approximate planarity of the molecules. The supramolecular structures feature C—H⋯O hydrogen bonds and π–π interactions, as confirmed by Hirshfeld surface analyses.


Chemical context
Benzopyrones are oxygen-containing heterocycles recognised as privileged structures for drug-discovery programs (Klekota & Roth, 2008;Lachance et al., 2012). Within this class of compounds, coumarin has emerged as an interesting building block due to its synthetic accessibility and substitution variability. Furthermore, coumarins display anticancer, antiviral, anti-inflammatory and anti-oxidant biological properties (Matos et al., 2009(Matos et al., , 2014Vazquez-Rodriguez et al., 2013).

Structural commentary
The structural analyses revealed that the molecules are coumarin derivatives with a phenylamide substituent at position 3 of the coumarin ring, as seen in the chemical scheme. The coumarin component rings are identified by the letters A and B while the exocyclic benzene ring is denoted C. Figs. 1-3 show the molecular structures of compounds 1-3, respectively: they differ in the type of substituents at the 6-position of the coumarin ring system and at the 3-position of the pendant benzene ring.
An inspection of the bond lengths shows that there is a slight asymmetry of the electronic distribution around the coumarin ring: the mean C3-C4 bond length [1.3517 (3) Å ] and the mean value for the C3-C2 bond length [1.461 (6) Å )] are shorter and longer, respectively, that those expected for an C ar -C ar bond, suggesting that there is an increased electronic density located in the C3-C4 bond at the pyrone ring.
The values for the distances of the C3-C31 bonds [mean value 1.508 (4) Å ] connecting the coumarin system to the amide spacer are of the same order as a Csp 3 -Csp 3 bond. This confers freedom of rotation of the phenylamide substituent around it. Despite that, the molecules are approximately planar, as can be inferred by the set of values of the dihedral angles in Table 1, which refer to the combination of the dihedral angles between the best planes formed by all non-H atoms of the 2H-chromen-2-one ring, the O31/C31/N32 atoms of the amide residue and the phenyl substituent, which are all less than 11 . This may be correlated with the conformation assumed by the amide group around the C-N rotamer which displays an Àanti orientation with respect to the oxo oxygen atom of the coumarin, thus allowing the establishment, in all three structures, of an intramolecular N-HÁ Á ÁO hydrogen bond between the amino group of the carboxamide and the oxo group at the O2 position of the coumarin and a weak C-HÁ Á ÁO intramolecular hydrogen bond between an ortho-CH group on the exocyclic phenyl ring and the O atom of the carboxamide. Thus these two interactions, which both form S(6) rings, probably contribute to the overall approximate planarity of the molecules since they may prevent the molecules from adopting some other possible conformations by restraining their geometry.

Supramolecular features
As mentioned above, the NH group is involved in an intramolecular hydrogen bond. It is not involved in any intermolecular interactions thus only carbon atoms may act as donors for the carbonyl and methoxy-type acceptors. Details A view of the asymmetric unit of 1 with the atom-numbering scheme. Displacement ellipsoids are drawn at the 70% probability level.

Figure 2
A view of the asymmetric unit of 2 with the atom-numbering scheme. Displacement ellipsoids are drawn at the 70% probability level.

Figure 3
A view of the asymmetric unit of 3 with the atom-numbering scheme. Displacement ellipsoids are drawn at the 70% probability level. Table 1 Selected dihedral angles ( ). 1 is the dihedral angle between the mean planes of the coumarin ring system and exocyclic phenyl ring. 2 is the dihedral angles between the mean plane of the coumarin ring system and the plane defined by the atoms O31/C31/N32. 3 is the dihedral angle between the mean planes of the exocyclic phenyl ring and the plane defined by atoms O31/C31/N32. of the hydrogen bonding for compounds 1, 2 and 3 are given in Tables 2, 3 and 4, respectively.

Figure 4
Compound 1, the simple chain formed by the C5-H5Á Á ÁO1 weak hydrogen bond. This chain extends by unit translation along the a axis. Symmetry codes: (i) x À 1, y, z; (ii) x + 1, y, z. H atoms not involved in the hydrogen bonding are omitted.
the FP plots are presented in Figs. 7 to 9 for 1, 2 and 3, respectively. They provide complementary information concerning the intermolecular interactions discussed above.
The contributions from various contacts, listed in Table 5, were selected by the partial analysis of the FP plots.
Forgetting the prevalence of the HÁ Á ÁH contacts on the surface, inherent to organic molecules, the most significant contacts are the HÁ Á ÁO/OÁ Á ÁH ones. Those appear as highlighted red spots on the top face of the surfaces (Fig. 7 to 9) that indicate contact points with the atoms participating in the C-HÁ Á ÁO intermolecular interactions. Those contacts correspond to weak hydrogen bonds, as seen in the FP plots where the pair of sharp spikes that would be characteristic of hydrogen bond are masked by the HÁ Á ÁH interactions appearing near d e 'd i = 1.20 Å . Compound 1 has the smallest percentage for HÁ Á ÁO/OÁ Á ÁH contacts since it has no methoxy substituents. The most representative of these corresponds to the C5-H5Á Á ÁO2 contact that links the molecules in the C6 chain. In the surface of 2, two red spots appear perpendicular to the C8-H8 bond and near O1 indicating the C8-H8Á Á ÁO1 contact that links the molecules into dimers. The red spots near O31 indicate that this atom establishes two weak contacts (C61-H61BÁ Á ÁO31 and C317-H31AÁ Á ÁO31). In 3, there are several contacts, three of those involving the oxygen atoms of the coumarin system and those directly connected to it that are acceptors for H atoms of the coumarin residue of another molecule. These multiple contacts result in chains of hydrogen-bonded rings, as described in the previous section, and seem to operate a co-operative effect since the hydrogen bonds in 3 are stronger than in 1 and 2 (see the well-defined sharp spikes in the FP plot of 3).
The values for the remaining contacts listed in Table 5 suggest that the supramolecular structure is built by HÁ Á ÁC/ CÁ Á ÁH and CÁ Á ÁC contacts. In 3, the percentage for HÁ Á ÁC/ CÁ Á ÁH contacts is higher than that for the other compounds. The FP plots also reveal a cluster at d e /d i ' 1.8 Å and d i /d e ' 1.2 Å characteristic of C-HÁ Á Á contacts that seem to assume higher importance in the supramolecular structure in 3. On the other hand, the CÁ Á ÁC contacts prevail in 1 and 2. In fact, the packing in 1 is built up by severalinteractions (Table 6). Also, when the surface is mapped with shape index, several complementary triangular red hollows and blue bumps appear that are characteristic of the six-ring stacking (Figs. 10 and 11). In 1, ring A stacks with ring C by a twofold rotation, and ring B with ring A when the molecule is placed above another centrosymmetrically related molecule. This gives rise to close CÁ Á ÁC contacts in the middle of the surface identified as red spots. Molecule 2 also displays a significant percentage of CÁ Á ÁC contacts on the Hirshfeld surface, resulting from the continuousstacking where ring C stacks with rings A and B (up and down) of centrosymmetrically related molecules.

Figure 9
A view of the Hirshfeld surface mapped over d norm (left) and fingerprint plot (right) for 3. The highlighted red spots on the bottom face of the surfaces indicate contact points with the atoms participating in the C-HÁ Á ÁO intermolecular interactions whereas those on the middle of the surface correspond to CÁ Á ÁC and CÁ Á ÁH contacts. The FP plot displays two couple of spikes (external ends corresponding to CÁ Á ÁH contacts and middle spikes corresponding to OÁ Á ÁH contacts).

Figure 8
A view of the Hirshfeld surface mapped over d norm (left) and fingerprint plot (right) for 2. The highlighted red spots on the top face of the surfaces indicate contact points with the atoms participating in the C-HÁ Á ÁO intermolecular interactions whereas those on the middle of the surface correspond to CÁ Á ÁC contacts consequent of thestacking. The CÁ Á ÁC contacts contribute to higher the frequency of the pixels at d e ' d i ' 1.8 Å on the FP plots.

Figure 7
A view of the Hirshfeld surface mapped over d norm (left) and fingerprint plot (right) for 1. The highlighted red spots on the top face of the surfaces indicate contact points with the atoms participating in the C-HÁ Á ÁO intermolecular interactions whereas those on the middle of the surface correspond to CÁ Á ÁC contacts consequent of thestacking. The CÁ Á ÁC contacts contribute to higher the frequency of the pixels at d e ' d i ' 1.8 Å on the FP plots (yellow spot).  Table 1. These compounds also had a short intramolecular contact between the ortho-C hydrogen atom of the exocyclic benzene ring and the carboxamide O atom as in the present compounds. Details of the searches can be found in the supporting information.

Synthesis and crystallization
The coumarin derivatives 1-3 were synthesized by a two-step process. In the first step, 5-methylsalicylaldehyde (1 mmol) and diethyl malonate (1 mmol) and catalytic amounts of piperidine were dissolved in ethanol (10 ml) and refluxed for 4 h. After cooling to room temperature, the suspension was filtered off and ethyl 6-methylcoumarin-3-carboxylate was obtained. This compound was then dissolved in 20 ml of an ethanolic solution with 0.5% NaOH (aq.) and hydrolyzed under reflux for 1h. After reaction, 10% HCl (aq.) was added and the desired carboxylic acid was then filtered and washed with water (Chimenti et al., 2010 Table 6 Selectedcontacts (Å ).
CgI(J) = plane number I(J); CgÁ Á ÁCg = distance between ring centroids; CgI perp = perpendicular distance of Cg(I) on ring J; CgJ perp = perpendicular distance of Cg(J) on ring I; Slippage = distance between Cg(I) and perpendicular projection of Cg(J) on ring I.

Figure 10
Surface of 1 mapped with shape index showing the complementary triangular red hollows and blue bumps that are characteristic of six-ring stacking.

Figure 11
Surface of 2 mapped with shape index showing the complementary triangular red hollows and blue bumps that are characteristic of six-ring stacking.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 7. H atoms were treated as riding atoms with C-H(aromatic) = 0.95 Å and U iso = 1.2U eq (C), C-H(methyl) 0.98 Å and U iso = 1.5U eq (C) The amino H atoms were refined.  (7), 100.009 (7), 113.042 (7) V (Å 3 ) 1367.31 (9) 714.10 (6) 171.38.41 (Rigaku Oxford Diffraction, 2015) Empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm. 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.

2) N-(3-Methoxyphenyl)-6-methyl-2-oxo-2H-chromene-3-carboxamide
Crystal data Empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm. 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.