Unusual C–H···π Interactions in the Structure of 3,4,5-Trimethoxy-N-p-tolylbenzamide
3,4,5-trimethoxy-N-p-tolylbenzamide, C17H19NO4, (1), is a benzanilide derivative derived from p-toluidine and 3,4,5-trimethoxybenzoyl chloride. The structure was identified from spectroscopic and elemental analysis data and unambiguously confirmed by the single crystal X-ray diffraction studies in space group P21, with a = 5.1065(7) Å; b = 13.9148(18) Å; c = 11.2054(14) Å; β = 103.118(7)°; Z = 2. In the X-ray structure packing is predictably influenced by strong N–H···O hydrogen bonds, augmented by C–H···O contacts generating R12(6) ring motifs and forming chains of molecules along the b axis. Chains are also linked in a head-to-tail fashion by an additional weak Ar–C–H···O contact involving the tolyl methyl group. A particularly unusual feature of the packing in this structure however, is the extensive contribution of C–H···π interactions, involving two hydrogen atoms from each of the methyl groups of the 3- and 5-methoxy substituents. These link the chains into a three-dimensional network. A CSD investigation of intermolecular interactions involving both phenyl-bound and methoxy methyl groups is also presented.
KeywordsBenzamides Tri-methoxy benzene derivatives Spectroscopic characterisation Crystal structure Hydrogen bonding C–H···π interactions
N-substituted benzamides are an important class of structurally simple compounds with a wide range of medicinal, commercial and synthetic applications. For example declopramide (3-chloroprocainamide) is a well known anticancer compound . The cytotoxic effects of N-(3-chloro-1,4-dioxo, 4-dihydro-naphthalen-2-yl)-benzamide on androgen-dependent and independent prostate cancer cell lines have also been reported . 2-Oxy-6-fluoro-N-((S)-1-hydroxy-3-phenylpropan-2-yl)-benzamides are inhibitors of hepatitis C virus polymerase  while alo-nitrobenzamides find potential applications against human African trypanosomiasis  and aminopiperidine benzamides have been identified as MCHr1 antagonists .
Materials and Measurements
The melting points were recorded using a digital Gallenkamp (SANYO) model MPD.BM 3.5 apparatus and are uncorrected. 1H and 13C NMR spectra were determined in DMSO-d6 at 300 MHz and 75.4 MHz, respectively, using a Bruker spectrophotometer. The FTIR spectrum was recorded on an FTS 3000 MX spectrophotometer. The mass spectrum (EI, 70 eV) was obtained using a GC-MS instrument, Agilent technologies, and elemental analysis was conducted using a LECO-183 CHNS analyzer.
Synthesis and Characterization of 3,4,5-Trimethoxy-N-p-tolylbenzamide (1)
Freshly prepared 3,4,5-trimethoxybenzoyl chloride (1 mmol) in CHCl3 was treated with p-toluidine (1.0 mmol) under a nitrogen atmosphere at reflux for 3.5 h. Upon cooling, the reaction mixture was diluted with CHCl3 and washed consecutively with 1 M aqueous HCl and saturated aqueous NaHCO3. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Crystallization of the residue from ethanol twice afforded (1) (83 %) as colourless crystals. mp 168–169 °C; IR (ATR cm−1): 3273 (NH amide), 3096 (C sp2-H), 2918 (Csp3-H), 1681 (C=O amide), 1575 (C=C aromatic); 1H NMR (300 MHz, DMSO-d6): δ 8.65 (s, 1H, NH), 8.1 (d, 2H, J = 6.2, Ar), 7.83 (d, 2H, J = 6.2, Ar), 7.71 (s, 2H, Ar), 3.81 (s, 9H, OMe × 3), 2.51 (s, 3H, ArCH3), 13C NMR: (75.4 MHz, DMSO-d6): δ 169.9 (CONH), 167.2, 147.2, 148.11, 138.4, 134.42, 133.39, 128.92, 125.61, 114.69, 56.7 (OMe), 22.4 (ArCH3); GC–MS m/z (%) 301(36), 219 (28), 206 (52), 195 (100); Anal. calcd. for C17H19NO4: C, 67.76; H, 6.36; N, 4.65 %; found: C, 67.54; H, 6.67; N, 4.49 %.
Crystal data and structure refinement for (1)
Dc (g cm−3)
Absorption coeff. (mm−1)
Crystal size (mm)
0.30 × 0.26 × 0.10
Data collection and structure solution
−7/6; −19/18; −15/15
Observed reflections [I > 2σ(I)]
R1[I > 2σ(I)]b
wR2 (all data)c
GooF, S, on F2
Largest difference peak and hole (eÅ−3)
Results and Discussion
Synthesis and Characterization
In the FTIR spectrum, a broad signal attributed to the N–H stretch appeared at 3,273 cm−1 while the amide carbonyl and aromatic C=C stretching vibrations, were observed at 1,681 and 1,575 cm−1, respectively. The 1H-NMR spectrum of the compound was also consistent with the proposed structure. Thus, in addition to the signals for the amide N–H proton at δ 8.6, two 2H doublets typical of a p-disubstituted aromatic ring appeared at δ 8.1 and δ 7.83 together with a 2H singlet at δ 7.71 ppm, respectively. A singlet for the nine methoxy protons appeared at δ 3.81 with that for aromatic methyl group at δ 2.51 ppm. In the 13C NMR the amide carbonyl was observed at δ 169.9 with all other carbon resonances in their characteristic regions. The mass spectrum showed the molecular ion peak at m/z 301 and a base peak derived from the trimethoxycarbonyl cation at m/z 195.
Selected bond distances, angles and torsion angles (Å, °) for (1)
The CSD  reveals that bond distances in this molecule compare well with those reported for the 30 other structurally characterised 3,4,5-trimethoxybenzene structures with C(O)–NH substituents at position 1.
Hydrogen bond geometry (Å, °) for (1)
Potential C–H…π contacts (Å, °) for (1)
Doubts have been raised concerning the appropriateness of invoking any kind of intermolecular hydrogen bonding contact that involves methyl groups on the basis that, even at low temperatures, rapid rotation of the groups occurs reducing the possibility of meaningful non-classical hydrogen bonding contacts [24, 25]. As this structure appears to provide strong evidence for the involvement of both C–H···O and C–H···π contacts in the packing of these molecules, we have undertaken database searches targeting both types of methyl based contacts to examine their generality and applicability more closely. A recent detailed study has looked at the energetics of weak hydrogen bonding interactions as a function of D–H···A angles  and recommends limiting C–H···X angles to a minimum of no less than 120° for the contact to be considered significant. We have used these criteria as a guide to investigate initially C–H···O contacts involving phenyl bound methyl groups such as those as shown in Fig. 3.
Interrogating the CSD for Ar–CH3···O contacts involving a methyl group bound in a para position on a benzene ring as found in (1) with C···O distances in the range 2.7–3.5 Å and with C–H···O angles limited to 120°–180° (other search limitations: 3-D-coordinates determined; R < 0.1; only organics) produced 1,536 hits involving 1,815 discrete contacts. Analysis of the metrical data using Mercury  showed a mean C···O contact distance of 3.4(4) Å while the C–H···O angles examined in the same search over the range 120°–180° showed a mean angle of 140(14)° suggesting that there is some substance to the suggestion that such contacts can indeed support crystal packing. The distance observed here for (1), 3.409 (3) Å, is close to this mean bond distance, while the C–H···O angle, 128°, is at the lower end of the range suggesting that in this case the interaction may be relatively weak. Nonetheless this investigation confirms that this interaction will indeed contribute to the crystal packing in this instance.
Similarly we have also sought evidence for the involvement of intermolecular O–C–H···π contacts involving the methyl groups of methoxy substituents on aromatic rings. These interactions certainly appear to be fairly common, as a search of the CSD for Ar–O–CH3···π contacts involving one H atom from an individual methoxy group with C···Cg distances in the range 3.0–3.9 Å and C–H···Cg angles within the range 120–180° produced no fewer than 4,919 hits (limitations 3D coordinates determined; R < 0.1; only organics). Applying the same criteria, 212 of these structures were found to be 3,4,5-trimethoxybenzene derivatives. Restricting the search to 3,4,5-trimethoxybenzene compounds in which a methoxy group formed contacts via two discrete H atoms from different outer (3 & 5) methyl groups limited the number of contacts to 44. Analysis of these  gave mean C···centroid distances of 3.67(2) Å and 3.685(19) Å, respectively, with corresponding mean C–H···centroid angles of 144(12)° and 147(11)°. A similar search in which the two C–H···π contacts emanated from the same outer (3 or 5) methoxy group revealed 14 structures only one of which was a benzamide [3,4,5-trimethoxy-N-methyl-N-(4(1H-pyrrol-2-yl)phenyl)-benzamide] but its packing was not discussed . Similar analysis gave mean C···centroid distances of 3.66(16) Å and 3.75(11) Å, respectively, with corresponding mean C–H···centroid angles of 138(13)° and 141(14)°. This suggests that where two H atoms from the same methyl group are involved in such C–H···π interactions the resulting contacts are slightly weaker. Extending this search still further to include one or two additional C–H···π contacts involving both 3,5-methoxy substituents in 3,4,5-trimethoxybenzene compounds produced no hits demonstrating the complete novelty of the range of contacts observed in the crystal packing of (1). Clearly the metrical data for the compound reported here, Table 4, show that these contacts lie well within the norms observed previously in similar molecules. This is however the first situation where such an extensive set of O–C–H···π contacts have been observed in a 3,4,5-trimethoxybenzene derivative.
While the molecular structure of this compound is unremarkable, the crystal packing involves some novel interactions. Classical N–H···O hydrogen bonds are supported by C–H···O contacts from the adjacent tolyl ring. CH3···O contacts from the tolyl methyl group are also found. A significant contribution to the packing also comes from OCH3···π contacts involving two hydrogen atoms from each of the outer (3 & 5) methoxy groups. These provide a structural motif that is shown to be unique to this molecule.
We thank the University of Otago for purchase of the diffractometer.
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