Crystal structures of three 3,4,5-trimethoxybenzamide-based derivatives

These benzamide derivatives differ only in the substituent that terminates the hexyl chain and the nature of these substituents determines the differences in hydrogen bonding between the molecules.

The crystal structures of three benzamide derivatives, viz. N-(6-hydroxyhexyl)-3,4,5-trimethoxybenzamide, C 16 H 25 NO 5 , (1), N-(6-anilinohexyl)-3,4,5-trimethoxybenzamide, C 22 H 30 N 2 O 4 , (2), and N-(6,6-diethoxyhexyl)-3,4,5-trimethoxybenzamide, C 20 H 33 NO 6 , (3), are described. These compounds differ only in the substituent at the end of the hexyl chain and the nature of these substituents determines the differences in hydrogen bonding between the molecules. In each molecule, the m-methoxy substituents are virtually coplanar with the benzyl ring, while the p-methoxy substituent is almost perpendicular. The carbonyl O atom of the amide rotamer is trans related with the amidic H atom. In each structure, the benzamide N-H donor group and O acceptor atoms link the molecules into C(4) chains. In 1, a terminal -OH group links the molecules into a C(3) chain and the combined effect of the C(4) and C(3) chains is a ribbon made up of screw related R 2 2 (17) rings in which the Á Á ÁO-HÁ Á Á chain lies in the centre of the ribbon and the trimethoxybenzyl groups forms the edges. In 2, the combination of the benzamide C(4) chain and the hydrogen bond formed by the terminal N-H group to an O atom of the 4-methoxy group link the molecules into a chain of R 2 2 (17) rings. In 3, the molecules are linked only by C(4) chains.

Structural commentary
The molecular structures of compounds 1, 2 and 3 are shown in Figs. 1-3. The molecules consist of a trimethoxybenzamide 'head' that is linked to a six-carbon-atom alkyl chain 'tail' that ends with different functional groups: a hydroxyl group for 1, a phenylamino group for 2 and a diethoxy group for 3. In spite of having the same 'head' and 'tail', the differences observed for their molecular conformations are not only due to the different 'end tail' functional groups. Thus, the analysis of the molecular conformations will be performed on a comparative basis encompassing the following: (i) the relative positions of the methoxy substituents on the aromatic ring; (ii) the conformation of the amide unit and (iii) the conformation of the alkyl chain. The specifics of the substituents at the end of the alkyl chain determine the differences in the supramolecular structures, as discussed in the next section.
The m-methoxy substituents are virtually co-planar with the benzene ring and are trans related with respect to the p-carbon atom of the ring [the maximum deviation of the methoxy carbon atom to the best plane of the phenyl ring is 0.238 (1) Å in 2], while the p-methoxy group is nearly perpendicular [the minimum deviation of the methoxy carbon atom to the best plane of the benzene ring being 0.923 (2) Å , also in 2]. These relative positions agree with previous predictions of theoretical calculations for the stabilization energies for methoxygroup conformations attached to aromatic rings (Tsuzuki et al., 2002), which suggested that, while co-planarity is the most stable conformation when there is only one methoxy substituent on the aromatic ring, the perpendicular conformation may appear as an alternative one when two vicinal methoxy groups are present. According to these authors, this spatial arrangement is stabilized by a short C-HÁ Á ÁO contact between the neighbouring groups. As can be seen in Tables 4,  5 and 6, the shortest distances between a methyl H atom and a vicinal methoxy O atom are 2.44, 2.33 and 2.37 Å for 1, 2 and 3, respectively, which do suggest the possibility of a very weak interaction.
In the amide rotamer, the carbonyl oxygen atom is in a trans position with respect to the hydrogen atom of the amidic nitrogen atom for all compounds, and so, the trimethoxy phenyl group is also trans related to the alkyl chain. The rotation of the trimethoxy phenyl substituent with respect to the amide rotamer around the C11-C1 bond may be evaluated by the N12-C11-C1-C6 torsion angle, whose values are given in Tables 1-3. The mean planes between the C1 benzene ring and the mean plane of the three atoms O11, C11 and N12 are 35.1 (3), 12.00 (16)  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. less distorted than in the others. In 1 and in 2, the sense of rotation is anticlockwise.
The freedom of rotation around the N-C(alkyl) bond together with the regular tetrahedral geometry of the sp 3 -hybridized carbon atoms allows the molecules to acquire very different conformational profiles for the alkyl chain as is observed in the C11-N12-C13-C14 torsion angles [129.1 (3) for 1, À112.80 (13) for 2 and 114.65 (12) for 3], as well as the direction of the alkyl chain with respect to the N12-C13 bond, which primarily affects the relative position of the alkyl 'tail' with respect to the benzamide moiety. Considering the disposition of the amide rotamer: in 1 and in 3 the alkyl chain is directed backwards from the amide plane and in 2 forward from that plane. This affects the general shape of the molecules, as can be better visualized in Figs. 7-9. So, in spite of the consistent zigzag shape of the remaining alkyl chain those molecules have entirely different spatial arrangements.

Hydrogen Bonding and short contacts
Tables 4, 5 and 6 show the hydrogen-bonding details for 1, 2 and 3, respectively. In each compound, the amide group forms the common C(4) chain motif by an N-HÁ Á ÁO hydrogen bond. In 1, the N12--H12Á Á ÁO11 chain runs parallel to the b axis and adjacent molecules are at unit translation along this axis. The O19--H19Á Á ÁO19 hydrogen bond links the mol-ecules into a C(3) chain formed by the action of the twofold screw axis at ( 1 2 , y, 3 4 ). These two chains link the molecules to form a ribbon made up of screw-related R 2 2 (17) rings, which runs parallel to the b axis with the Á Á ÁO-HÁ Á Á chain running up the centre of the ribbon and the trimethoxybenzyl groups forming the edges (Fig. 4) Table 1 Selected torsion angles ( ) for 1. Table 2 Selected torsion angles ( ) for 2.

Hirshfeld Surfaces
Hirshfeld surfaces were generated using Crystal Explorer 3.1 (Wolff et al., 2012) mapped over d norm for the title compounds. The contact distances d i and d e from the Hirshfeld surface to the nearest atom inside and outside, respectively, were used to analyse the intermolecular interactions through the mapping of d norm and the plot of d i versus d e provides twodimensional fingerprint plots (Rohl et al., 2008) that are used to summarize those contacts. Figs. 7-9 are views of the Hirshfeld surfaces mapped over d norm for 1, 2 and 3 respectively. Since the molecules have a six-atom alkyl chain, most of the contacts are HÁ Á ÁH contacts. Leaving these aside, the remaining surface highlights the red areas that indicate contact points for the atoms participating in the (O/N/C)-HÁ Á ÁO intermolecular interactions. There are also significant contributions of C-HÁ Á ÁC contacts, as can be visualized in the figures for each compound. The percentages of (O/N/C)-HÁ Á ÁO and C-HÁ Á ÁC contacts are listed in Table 7.
In all three compounds, red spots near the amide indicate the N(amide)-HÁ Á ÁO hydrogen bonds that connect the amide groups in the classic fashion, making a C(4) chain for all  Compound 2: the chain of rings formed by the interaction of the N12-H12Á Á ÁO11 and N19-H19Á Á ÁO4 hydrogen bonds. This chain extends along the c axis and is generated by the c-glideplane at y = 1 4 . Hydrogen atoms not involved in the hydrogen bonding are omitted. Symmetry codes: (i) x, Ày À 1 2 , z À 1 2 ; (ii) x, Ày + 1 2 , z + 1 2 .

Figure 7
View of the Hirshfeld surface mapped over d norm for 1.
compounds. In 2 and 3, there are two pairs of red spots at the amide environment indicating that, in these structures, the carbonyl oxygen atom acts as the receptor for another H contact (the C6-H6Á Á ÁO11 contact). The classical O(hydroxy)-HÁ Á ÁO hydrogen bond is located at the chain 'tail' in 1 and is identified by two red spots indicating that the oxygen atom O19 acts as donor and acceptor making the C(3) chain. The red spots in structure 2 show another two hydrogen bonds: one of these involves the amine nitrogen atom of the end 'tail' phenylamine residue and the other also indicates the involvement of the p-methoxy group located at the trimethoxybenzamide 'head'. This behaviour contrasts with that observed for 1 and 3, in which the methoxy groups are not involved in classical hydrogen bonding.
The full fingerprint (FP) plots showing various crystal packing interactions are given in Figs. 10-12; the contributions from various contacts, listed in Table 7, were selected by the partial analysis of these plots. The FP plots show, for all compounds, a pair of long sharp spikes characteristic of a View of the Hirshfeld surface mapped over d norm for 2.

Figure 9
View of the Hirshfeld surface mapped over d norm for 3.

Figure 10
The full fingerprint (FP) plot showing various crystal packing interactions for 1. Dark blue corresponds to the low frequency of occurrence of a d i /d e pair, while light blue indicates a higher frequency for the occurrence.

Figure 11
The full fingerprint (FP) plot showing various crystal packing interactions for 2. Dark blue corresponds to the low frequency of occurrence of a d i /d e pair, while light blue indicates a higher frequency for the occurrence. strong hydrogen bond, in an area near 1.7-1.8 Å . The symmetry of the upper left/down right spikes is an indication for the balance between the donor and acceptor character of the atoms involved in the hydrogen bonding, as seen before. They correspond to the N-HÁ Á ÁO and O-HÁ Á ÁO contacts. The d e /d i points corresponding to HÁ Á ÁH interactions appear around the hydrogen atom van der Waals radius of 1.20 Å . The wings in the graphical representation of 2 indicate that C-HÁ Á Á interactions are more relevant in this crystal structure, highlighting the contribution of the C-HÁ Á Á interaction (Table 5) involving the phenylamide residue of the 'tail'. Structure 2 also displays the biggest percentage of HÁ Á ÁC/CÁ Á ÁH contacts: besides the C-HÁ Á Á contacts with the aromatic ring that define the supramolecular structure for all compounds, in 2 the benzene ring of the phenylamine forms an extra interaction of this kind

Database survey
A search made in the February 2016 version of the Cambridge Structural Database, (Groom et al., 2016), revealed the existence of 37 structures (containing 48 unique molecules) featuring the 3,4,5-trisubstituted benzamide scaffold.
ortho-C atom C2 was selected such that the amino N atom N12 was trans to it and in the following survey it is transrelated torsion angles which are discussed. The analysis of the torsion angles for the o-C atoms of the benzyl ring and the N atom of the benzamide group showed two distinct populations about 180 in the angular ranges À180 to À145 with a median value of À152.5 and 136-171 with a median value of 149.2 .
The value of À179.3 for HESLEX, N,N-(heptane-2,6-diyl)-N 0 -(3,4,5-methoxybenzoyl)thiourea (Dillen et al., 2006) is unusual: if this is excluded, then the lower limit for the negative range is À172 . The methyl groups attached to atoms C3 and C5 are inclined to the benzyl ring in the range À20 to 24 with a median values close to 0 . This excludes a molecule with a C5 methoxy torsion angle of À85.9 : PIDTEC, 4hydroxy-3,5-diethoxybenzaldehyde-3,4,5-trimethoxybenzoylhydrazone monohydrate (Sun et al., 2007). The methyl groups attached to atoms C4 are inclined to the benzyl ring in the ranges AE63 to AE122 with a median values close to AE90 . Of these 48 molecules, 16 participate in N-HÁ Á ÁO C(4) chains similar to those in the present compounds. In these structures, the torsion angles for the trans o-C atoms of the benzyl ring and the N atom of the benzamide group showed that, as above, the torsion angles lie in two populations: one in the range À153 to À145 and the other in the very similar positive range 142 to 165 with median values of À147.6 and 148.1 , respectively. The value for this torsion angle for 1, À149.3 (3) lies within the negative range, those for 2, À167.27 (12) and 3, À158.58 (10) lie outside this range.The results of the database searches are included in the supporting information.

Synthesis and crystallization
The title benzoic derivatives were obtained in moderate-tohigh yields via the synthetic strategy described in the Scheme below. Compound 1 was obtained from 3,4,5-trimethoxybenzoic acid by an amidation reaction using ethylchloroformate as coupling agent. After oxidation of compound 1 alcohol function to an aldehyde, compounds (2) and (3) could be obtained. Compound 2 was synthesized by a reductive amination reaction using sodium triacetoxyborohydride as reducing agent. Compound 3 was synthesized using an ethanolic solution of N-benzylhydroxylamine hydrochloride.
1: N-(6-hydroxyhexyl)-3,4,5-trimethoxybenzamide (1). The full fingerprint (FP) plot showing various crystal packing interactions for 3. Dark blue corresponds to the low frequency of occurrence of a d i /d e pair, while light blue indicates a higher frequency for the occurrence.
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )    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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )
x y z U iso */U eq O3 0.06047 (