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

Gomes, L.R.; Low, J.N.; Oliveira, C.; Cagide, F.; Borges, F.

doi:10.1107/S2056989016005958

research communications

CRYSTALLOGRAPHIC
COMMUNICATIONS

ISSN: 2056-9890

Volume 72| Part 5| May 2016| Pages 675-682

doi:10.1107/S2056989016005958

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

Ligia R. Gomes,^a,^b John Nicolson Low,^c ^* Catarina Oliveira,^d Fernando Cagide ^d and Fernanda Borges ^d

^aREQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade do Porto, Rua do Campo Alegre, 687, P-4169-007, Porto, Portugal, ^bFP-ENAS-Faculdade de Ciências de Saúde, Escola Superior de Saúde da UFP, Universidade Fernando Pessoa, Rua Carlos da Maia, 296, P-4200-150 Porto, Portugal, ^cDepartment of Chemistry, University of Aberdeen, Meston Walk, Old Aberdeen AB24 3UE, Scotland, and ^dCIQ/Departamento de Quιmica e Bioquιmica, Faculdade de Ciências, Universidade do Porto, 4169-007 Porto, Portugal
^*Correspondence e-mail: jnlow111@gmail.com

Edited by W. T. A. Harrison, University of Aberdeen, Scotland (Received 31 March 2016; accepted 10 April 2016; online 15 April 2016)

The crystal structures of three benzamide derivatives, viz. N-(6-hydroxyhexyl)-3,4,5-trimethoxybenzamide, C₁₆H₂₅NO₅, (1), N-(6-anilinohexyl)-3,4,5-trimethoxybenzamide, C₂₂H₃₀N₂O₄, (2), and N-(6,6-diethoxyhexyl)-3,4,5-trimethoxybenzamide, C₂₀H₃₃NO₆, (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 R₂²(17) rings in which the ⋯O—H⋯ 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 R₂²(17) rings. In 3, the molecules are linked only by C(4) chains.

Keywords: crystal structure; benzamide; hydrogen bonding.

CCDC references: 1473261; 1473260; 1473259

1. Chemical context

Phenolic acids are widely distributed in the plant kingdom and exist in significant quantities in the human diet (e.g. in fruits and vegetables). Like other phenolic compounds they are recognized for their health benefits, which are linked to their biological properties, particularly anti-oxidant, anti-inflammatory and anticancer properties (Benfeito et al., 2013 , Roleira et al., 2015 , Garrido et al., 2013 , Teixeira et al., 2013 ). Within this framework, our project has been focused on the synthesis of new molecules based on the benzoic acid scaffold. Accordingly, herein we describe the syntheses and structures of three new benzamide derivatives, viz. N-(6-hydroxyhexyl)-3,4,5-trimethoxybenzamide (1) N-(6-anilinohexyl)-3,4,5-trimethoxybenzamide (2) and N-(6,6-diethoxyhexyl)-3,4,5-trimethoxybenzamide (3).

2. 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.

Figure 1
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.

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 methoxy-group 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—H⋯O 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.

Table 4
Hydrogen-bond geometry (Å, °) for 1

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O19—H19⋯O19ⁱ	0.92 (4)	1.86 (4)	2.7799 (14)	176 (4)
N12—H12⋯O11ⁱⁱ	0.77 (3)	2.15 (3)	2.859 (3)	153 (3)
C18—H18B⋯O11ⁱⁱⁱ	0.99	2.64	3.614 (3)	168
C41—H41B⋯O3	0.98	2.44	3.010 (3)	117
Symmetry codes: (i) $[-x+1, y+{\script{1\over 2}}, -z+{\script{3\over 2}}]$ ; (ii) x, y-1, z; (iii) $[x, -y+{\script{3\over 2}}, z+{\script{1\over 2}}]$ .

Table 5
Hydrogen-bond geometry (Å, °) for 2

Cg is the centroid of the C111–C116 ring.

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N12—H12⋯O11ⁱ	0.867 (17)	2.052 (17)	2.9051 (14)	167.9 (15)
N19—H19⋯O4ⁱ	0.855 (17)	2.106 (17)	2.9436 (15)	166.3 (15)
C6—H6⋯O11ⁱ	0.95	2.33	3.2356 (15)	159
C41—H41C⋯O3	0.98	2.33	2.9287 (18)	119
C112—H112⋯O4ⁱ	0.95	2.65	3.3845 (16)	134
C13—H13A⋯Cgⁱⁱ	0.99	2.64	3.5272 (15)	148
C31—H31C⋯Cgⁱⁱⁱ	0.98	2.62	3.5205 (16)	152
Symmetry codes: (i) $[x, -y+{\script{1\over 2}}, z-{\script{1\over 2}}]$ ; (ii) -x+1, -y+1, -z+1; (iii) $[-x, y-{\script{1\over 2}}, -z+{\script{3\over 2}}]$ .

Table 6
Hydrogen-bond geometry (Å, °) for 3

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N12—H12⋯O11ⁱ	0.856 (16)	2.169 (16)	2.9890 (13)	160.2 (14)
C6—H6⋯O11ⁱ	0.95	2.34	3.2549 (14)	162
C15—H15B⋯O18ⁱⁱ	0.99	2.49	3.4239 (14)	157
Symmetry codes: (i) $[x, -y+{\script{3\over 2}}, z-{\script{1\over 2}}]$ ; (ii) $[x, -y+{\script{1\over 2}}, z-{\script{1\over 2}}]$ .

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) and 20.19 (14)°, respectively, for 1, 2 and 3, showing that the substituent in 2 is significantly less distorted than in the others. In 1 and in 2, the sense of rotation is anticlockwise.

Table 1
Selected torsion angles (°) for 1

C31—O3—C3—C4	176.7 (2)	C6—C1—C11—N12	35.6 (3)
C31—O3—C3—C2	−3.5 (4)	C11—N12—C13—C14	129.1 (3)
C41—O4—C4—C5	108.9 (3)	N12—C13—C14—C15	177.5 (2)
C41—O4—C4—C3	−74.4 (3)	C13—C14—C15—C16	65.7 (3)
C51—O5—C5—C4	−175.7 (2)	C14—C15—C16—C17	173.9 (2)
C51—O5—C5—C6	3.6 (4)	C15—C16—C17—C18	−174.4 (2)
C13—N12—C11—C1	−171.3 (2)	C16—C17—C18—O19	177.9 (2)
C2—C1—C11—N12	−149.3 (2)

Table 2
Selected torsion angles (°) for 2

C31—O3—C3—C2	−0.16 (17)	C2—C1—C11—N12	−167.30 (11)
C31—O3—C3—C4	178.57 (11)	C11—N12—C13—C14	−112.80 (13)
C41—O4—C4—C3	67.59 (16)	N12—C13—C14—C15	66.85 (14)
C41—O4—C4—C5	−118.62 (13)	C13—C14—C15—C16	−179.75 (11)
C51—O5—C5—C6	−11.14 (18)	C14—C15—C16—C17	−175.06 (11)
C51—O5—C5—C4	170.38 (11)	C15—C16—C17—C18	175.02 (11)
C13—N12—C11—C1	179.22 (10)	C111—N19—C18—C17	172.76 (11)
C6—C1—C11—N12	13.05 (17)	C16—C17—C18—N19	67.90 (15)

Table 3
Selected torsion angles (°) for 3

C31—O3—C3—C2	9.59 (16)	C2—C1—C11—N12	158.58 (10)
C31—O3—C3—C4	−171.49 (10)	C6—C1—C11—N12	−19.07 (15)
C41—O4—C4—C5	61.51 (15)	C11—N12—C13—C14	114.65 (12)
C41—O4—C4—C3	−124.05 (12)	N12—C13—C14—C15	175.72 (9)
C51—O5—C5—C6	9.66 (17)	C13—C14—C15—C16	67.27 (13)
C51—O5—C5—C4	−171.35 (11)	C14—C15—C16—C17	175.71 (10)
C13—N12—C11—C1	−170.25 (10)	C15—C16—C17—C18	−177.76 (10)

The freedom of rotation around the N—C(alkyl) bond together with the regular tetrahedral geometry of the sp³-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, −112.80 (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.

Figure 7
View of the Hirshfeld surface mapped over d_norm for 1.

Figure 8
View of the Hirshfeld surface mapped over d_norm for 2.

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

3. Supramolecular features

3.1. 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—H⋯O hydrogen bond. In 1, the N12—-H12⋯O11 chain runs parallel to the b axis and adjacent molecules are at unit translation along this axis. The O19—-H19⋯O19 hydrogen bond links the molecules into a C(3) chain formed by the action of the twofold screw axis at ( $[1\over2]$ , y, $[3\over4]$ ). These two chains link the molecules to form a ribbon made up of screw-related R₂²(17) rings, which runs parallel to the b axis with the ⋯O—H⋯ chain running up the centre of the ribbon and the trimethoxybenzyl groups forming the edges (Fig. 4). In 2, both the N12—H12⋯O11 and N19—H19⋯O4 hydrogen bonds link the molecules into a chain of R₂²(17) rings, which are bridged by the C11—N12 bond. This chain runs parallel to the c axis and is formed by the action of the c-glide plane at 1/4 along the b axis (Fig. 5). In 3, the N12—H12⋯O11 hydrogen bond links the molecules into a C(4) chain, which runs parallel to the c axis and which is formed by the action of the c-glide plane at 3/4 along the b axis, Fig. 6. Possible weak C—H⋯O interactions are detailed in the relevant Tables 4–6 .

Figure 4
Compound 1: view of the ribbon structure formed by the N12—H12⋯O11 and O19—H19⋯O19 hydrogen bonds. Hydrogen atoms not involved in the hydrogen bonding are omitted. Symmetry codes: (i) −x + 1, −y + $[{1\over 2}]$ , −z + $[{3\over 2}]$ ; (ii) −x, −y − 1, −z + 1; (iii) −x + 1, −y − $[{1\over 2}]$ , −z + $[{3\over 2}]$ ; (iv) −x + 1, −y + 1, −z + 1; (v) −x + 1, −y + $[{3\over 2}]$ , −z + $[{3\over 2}]$ .

Figure 5
Compound 2: the chain of rings formed by the interaction of the N12—H12⋯O11 and N19—H19⋯O4 hydrogen bonds. This chain extends along the c axis and is generated by the c-glideplane at y = $[1\over 4]$ . Hydrogen atoms not involved in the hydrogen bonding are omitted. Symmetry codes: (i) x, −y − $[{1\over 2}]$ , z − $[{1\over 2}]$ ; (ii) x, −y + $[{1\over 2}]$ , z + $[{1\over 2}]$ .

Figure 6
Compound 2: the simple C(4) chain formed by the N12—H12⋯O11 hydrogen bond. This chain extends along the c axis and is generated by the c glideplane at y = $[3\over4]$ . Hydrogen atoms not involved in the hydrogen bonding are omitted. Symmetry codes: (i) x, −y − $[{3\over 2}]$ , z − $[{1\over 2}]$ ; (ii) x, −y − $[{1\over 2}]$ , z + $[{1\over 2}]$ .

3.2. 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 two-dimensional 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 H⋯H contacts. Leaving these aside, the remaining surface highlights the red areas that indicate contact points for the atoms participating in the (O/N/C)—H⋯O intermolecular interactions. There are also significant contributions of C—H⋯C contacts, as can be visualized in the figures for each compound. The percentages of (O/N/C)—H⋯O and C—H⋯C contacts are listed in Table 7.

Table 7
The percentages of (O/N/C)–H⋯O and C—H⋯C contacts

Contact	1	2	3
H⋯H	60.0	60.8	68.9
H⋯O/O⋯H	25.4	16.0	19.0
H⋯C/C⋯H	13.0	21.4	10.1
H⋯N/N⋯H	0.03	1.7	0.8

In all three compounds, red spots near the amide indicate the N(amide)—H⋯O hydrogen bonds that connect the amide groups in the classic fashion, making a C(4) chain for all 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—H6⋯O11 contact).

The classical O(hydroxy)–H⋯O 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 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—H⋯O and O—H⋯O contacts. The d_e/d_i points corresponding to H⋯H 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—H⋯π interactions are more relevant in this crystal structure, highlighting the contribution of the C—H⋯π interaction (Table 5) involving the phenylamide residue of the `tail'. Structure 2 also displays the biggest percentage of H⋯C/C⋯H contacts: besides the C—H⋯π 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

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.

Figure 12
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.

4. 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 trans-related 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 −180 to −145° with a median value of −152.5° and 136–171° with a median value of 149.2°. The value of −179.3° for HESLEX, N,N-(heptane-2,6-diyl)-N′-(3,4,5-methoxybenzoyl)thiourea (Dillen et al., 2006 ) is unusual: if this is excluded, then the lower limit for the negative range is −172°. The methyl groups attached to atoms C3 and C5 are inclined to the benzyl ring in the range −20 to 24° with a median values close to 0°. This excludes a molecule with a C5 methoxy torsion angle of −85.9°: PIDTEC, 4-hydroxy-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 ±63 to ±122° with a median values close to ±90°. Of these 48 molecules, 16 participate in N—H⋯O 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 −153 to −145° and the other in the very similar positive range 142 to 165° with median values of −147.6° and 148.1°, respectively. The value for this torsion angle for 1, −149.3 (3)° lies within the negative range, those for 2, −167.27 (12)° and 3, −158.58 (10)° lie outside this range.The results of the database searches are included in the supporting information.

5. Synthesis and crystallization

The title benzoic derivatives were obtained in moderate-to-high 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). Overall yield 82%; m.p. 393–399 K; crystallization solvent: ethyl acetate, to yield colourless needles.

2: N-(6-anilinohexyl)-3,4,5-trimethoxybenzamide (2). Overall yield 51%; m.p. 376–388 K; crystallization solvent: ethyl acetate to yield colourless laths

3: N-(6,6-diethoxyhexyl)-3,4,5-trimethoxybenzamide (3). Overall yield 50%; m.p. 364–374 K; crystallization solvents: chloroform/n-hexane to yield colourless needles.

6. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 8. The N—H and O—H hydrogen atoms were located in difference Fourier maps and freely refined. The C-bound H atoms were included in calculated positions and treated as riding: C—H(aromatic) = 0.95 Å and C—H2(methylene) = 0.99 Å with U_iso = 1.2U_eq(C), C—H(methyl) = 0.98 Å with U_iso = 1.5U_eq(C).

Table 8
Experimental details

	1	2	3
Crystal data
Chemical formula	C₁₆H₂₅NO₅	C₂₂H₃₀N₂O₄	C₂₀H₃₃NO₆
M_r	311.37	386.48	383.47
Crystal system, space group	Monoclinic, P2₁/c	Monoclinic, P2₁/c	Monoclinic, P2₁/c
Temperature (K)	100	100	100
a, b, c (Å)	22.3351 (18), 5.0467 (4), 14.2265 (10)	11.5626 (8), 19.5328 (9), 9.5488 (7)	24.6345 (18), 8.4646 (5), 10.0598 (7)
β (°)	99.956 (7)	109.369 (8)	100.851 (2)
V (Å³)	1579.4 (2)	2034.5 (2)	2060.2 (2)
Z	4	4	4
Radiation type	Mo Kα	Mo Kα	Cu Kα
μ (mm⁻¹)	0.10	0.09	0.74
Crystal size (mm)	0.15 × 0.02 × 0.01	0.25 × 0.08 × 0.02	0.80 × 0.05 × 0.02

Data collection
Diffractometer	Rigaku AFC12	Rigaku AFC12	Rigaku Saturn944+
Absorption correction	Multi-scan (CrysAlis PRO; Agilent, 2014 )	Multi-scan (CrysAlis PRO; Agilent, 2014)	Multi-scan (CrystalClear-SM Expert; Rigaku, 2012 )
T_min, T_max	0.803, 1.000	0.384, 1.000	0.814, 1.000
No. of measured, independent and observed [I > 2σ(I)] reflections	19396, 3627, 2039	26057, 4655, 3869	18993, 3706, 3362
R_int	0.123	0.040	0.037
(sin θ/λ)_max (Å⁻¹)	0.649	0.649	0.602

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.062, 0.133, 0.97	0.041, 0.105, 1.04	0.035, 0.095, 1.05
No. of reflections	3626	4652	3706
No. of parameters	210	264	253
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement	H atoms treated by a mixture of independent and constrained refinement	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	0.25, −0.33	0.32, −0.18	0.23, −0.28
Computer programs: CrystalClear-SM Expert (Rigaku, 2012), CrysAlis PRO (Agilent, 2014), SHELXT (Sheldrick, 2015a ), Flipper 25 (Oszlányi & Sütő, 2004 ), OLEX2 (Dolomanov et al., 2009 ), OSCAIL (McArdle et al., 2004 ), ShelXle (Hübschle et al., 2011 ), SHELXL2014 (Sheldrick, 2015b ), Mercury (Macrae et al., 2006 ) and PLATON (Spek, 2009 ).

Supporting information

CCDC references: 1473261; 1473260; 1473259

Crystal structure: contains datablocks 1, 2, 3, global. DOI: 10.1107/S2056989016005958/hb7575sup1.cif

Structure factors: contains datablock 1. DOI: 10.1107/S2056989016005958/hb75751sup2.hkl

Structure factors: contains datablock 2. DOI: 10.1107/S2056989016005958/hb75752sup3.hkl

Structure factors: contains datablock 3. DOI: 10.1107/S2056989016005958/hb75753sup4.hkl

Supporting information file. DOI: 10.1107/S2056989016005958/hb75751sup5.cml

Supporting information file. DOI: 10.1107/S2056989016005958/hb75752sup6.cml

Supporting information file. DOI: 10.1107/S2056989016005958/hb75753sup7.cml

Supporting information file. DOI: 10.1107/S2056989016005958/hb7575sup8.pdf

Supporting information file. DOI: 10.1107/S2056989016005958/hb7575sup9.pdf

checkCIF report

Chemical context top

Phenolic acids are widely distributed in the plant kingdom and exist in significant quantities in the human diet (e.g. in fruits and vegetables). Like other phenolic compounds they are recognized for their health benefits, which are linked to their biological properties, particularly anti-oxidant, anti-inflammatory and anticancer properties (Benfeito et al., 2013, Roleira et al., 2015, Garrido et al., 2013, Teixeira et al., 2013). Within this framework, our project has been focused on preparing new molecules based on the benzoic acid scaffold. Accordingly, herein we describe the syntheses and structures of three new benzamide derivatives, viz. N-(6-hydroxyhexyl)-3,4,5-trimethoxybenzamide (1) N-(6-anilinohexyl)-3,4,5-trimethoxybenzamide (2) and N-(6,6-diethoxyhexyl)-3,4,5-trimethoxybenzamide (3).

Structural commentary top

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 comparative encompassing the following: (i) the relative positions of the methoxy substituents of the benzamide grouping; (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 their attached phenyl ring and are trans related with respect to the p-carbon atom of the ring [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 phenyl ring being 0.923 (2) Å, also in 2]. These relative positions agree with previous predictions of theoretical calculations for the stabilization energies for methoxy-group conformations attached to aromatic rings (Tsuzuki et al., 2002), which suggested that, while co-planarity is the most stable conformation when the methoxy substituent is isolated, 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—H···O 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 phenyl ring and the mean plane of the three atoms O11, C11 and N12 are 35.1 (3), 12.00 (16) and 20.19 (14)°, respectively, for 1, 2 and 3, showing that the substituent in 2 is significantly 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 sp³-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, –112.80 (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.

Supramolecular features top

Hydrogen Bonding and short contacts top

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—H···O hydrogen bond. In 1, the N12—-H12···O11 chain runs parallel to the b axis and adjacent molecules are at unit translation along this axis. The O19—-H19···O19 hydrogen bond links the molecules 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 R₂²(17) rings, which runs parallel to the b axis with the ···O—H··· chain running up the centre of the ribbon and the trimethoxybenzyl groups forming the edges (Fig. 4). In 2, both the N12—H12···O11 and N19—H19···O4 hydrogen bonds link the molecules into a chain of R₂²(17) rings, which are linked by the C11—N12 bond. This chain runs parallel to the c axis and is formed by the action of the c-glide plane at 1/4 along the b axis (Fig. 5). In 3, the N12—H12···O11 hydrogen bond links the molecules into a C(4) chain, which runs parallel to the c axis and which is formed by the action of the c-glide plane at 3/4 along the b axis, Fig. 6. Possible weak C—H···O interactions are detailed in the relevant Tables 4–6.

Hirshfeld Surfaces top

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 two-dimensional 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 H···H contacts. Leaving these aside, the remaining surface highlights the red areas that indicate contact points for the atoms participating in the (O/N/C)—H···O intermolecular interactions. There are also significant contributions of C—H···C contacts, as can be visualized in the figures for each compound. The percentages of (O/N/C)—H···O and C—H···C contacts are listed in Table 7.

In all three compounds, red spots near the amide indicate the N(amide)—H···O hydrogen bonds that connect the amide groups in the classic fashion, making the C(4) chain for all 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—H6···O11 contact).

The classical O(hydroxy)–H···O 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 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—H···O and O—H···O contacts. The d_e/d_i points corresponding to H···H 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—H ···π interactions are more relevant in this crystal structure, highlighting the contribution of the C—H ···π interaction (Table 5) involving the phenylamide residue of the `tail'. Structure 2 also displays the biggest percentage of H···C/C ···H contacts: besides the C—H···π 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 top

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-benzamide scaffold.

ortho-Atom C2 was selected such that the amino N atom N12 was trans to it and in the following survey it is trans-related 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 -180–145° with a median value of -152.5° and 136–171° with a median value of 149.2°. The value of -179.3° for HESLEX, N,N-(heptane-2,6-diyl)-N'-(3,4,5-methoxybenzoyl)thiourea (Dillen et al., 2006) is unusual: if this is excluded, then the lower limit for the negative range is -172°. The methyl groups attached to atoms C3 and C5 are inclined to the benzyl ring in the range -20 to 24° with a median values close to 0°. This excludes a molecule with a C5 methoxy torsion angle of -85.9°: PIDTEC, 4-hydroxy-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 ±63 to ±122° with a median values close to ±90°. Of these 48 molecules, 16 participate in N—H···O 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 -153 to -145° and the other in the very similar positive range 142 to 165° with median values of -147.6° and 148.1°, respectively. The value for this torsion angle for 1, -149.3 (3)° lies within the negative range, those for 2, -167.27 (12)° and 3, -158.58 (10)° lie outside this range.

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Synthesis and crystallization top

The title benzoic derivatives were obtained in moderate-to-high 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, N-(6-compounds (2) and (3) were 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). Overall yield 82%; m.p. 393–399 K; crystallization solvent: ethyl acetate, to yield colourless needles.

2: N-(6-anilinohexyl)-3,4,5-trimethoxybenzamide (2). Overall yield 51%; m.p. 376–388 K; crystallization solvent: ethyl acetate to yield colourless laths

3: N-(6,6-diethoxyhexyl)-3,4,5-trimethoxybenzamide (3). Overall yield 50%; m.p. 364–374 K; crystallization solvents: chloroform/n-hexane to yield colourless needles.

Refinement top

Crystal data, data collection and structure refinement details are summarized in Table 8. H atoms were treated as riding atoms with C—H(aromatic), 0.95 Å, with U_iso = 1.2U_eq(C), C—H2(methylene), 0.99 Å, with U_iso = 1.2U_eq(C),C—H(methyl) 0.98 Å with U_iso = 1.5U_eq(C). N—H and O—H hydrogen atoms were refined.

Structure description top