Polar crystal of vanillylformamide through replacement of the alkene by an isosteric formamide group

Département de Chimie, Cégep de Sherbrooke, 475 Rue du Cégep, Sherbrooke, Québec, J1E 4K1, Canada, Laboratoire d’Analyses Structurales par Diffraction des rayons-X, Département de Chimie, Université de Sherbrooke, 2500, Boulevard de l’Université, Sherbrooke, Québec, J1K 2R1, Canada, and Laboratoire de Synthèse Supramoléculaire, Département de Chimie, Institut de Pharmacologie, Université de Sherbrooke, 3001 12e Avenue Nord, Sherbrooke, Québec, J1H 5N4, Canada. *Correspondence e-mail: Pierre.Baillargeon@usherbrooke.ca

Vanillylformamide [systematic name: N-(4-hydroxy-3-methoxybenzyl)formamide], C 9 H 11 NO 3 , (II), has been synthesized from vanillylamine hydrochloride and studied by single-crystal X-ray diffraction. Compound (II) and the well known biologically active eugenol compound (I) can be considered to be 'isosteres' of each other, since they share comparable molecular shape and volume. The product (II) crystallizes in the space group P1. In the crystal, the vanillylformamide molecules are linked mainly by N-HÁ Á ÁO, O-HÁ Á ÁO and Csp 2 -HÁ Á ÁO hydrogen bonds, forming infinite two-dimensional polar sheets. These two-dimensional layers pack in a parallel fashion, constructing a polar three-dimensional network. Except for van der Waals forces and weak Csp 3 -HÁ Á ÁO hydrogen bonds, there are no significant intermolecular interactions between the layers. A Cambridge Structural Database search revealed that vanillylamide-related crystals are scarce.

Structure description
Eugenol is a natural molecule that exhibits versatile properties useful in various domains. Indeed, there is increasing interest from the scientific and industrial community in eugenol-based polymers (Miao et al. 2017;Guzmá n et al., 2017;Chen et al., 2017;Modjinou et al., 2016;Wan et al., 2016a,b;Deng et al., 2015). Moreover, this bioactive compound has high potential as a therapeutic agent since it has antiparasitic, antiviral, antibacterial, antifungal, anticancer, antioxidant and anti-inflammatory activities (Raja et al., 2015;Khalil et al., 2017). On the other hand, to the best of our knowledge, no study on the bioisosteres of eugenol has been undertaken. The definition of bioisosterism has been data reports broadened by Burger (1991) as 'Compounds or groups that possess near-equal molecular shapes and volumes, approximately the same distribution of electrons, and which exhibit similar physical properties'. Thus, chemical modification of lead compounds represents a rational approach in drug design (Patani et al., 1996). Alkenes and amides are isosteric since they are both planar and possess two sp 2 -hybridized atoms in the main chain (Choudhary et al., 2011). In this context, effort has been focused in our group to determine the crystal structure of the vanillylformamide (II), which mimics eugenol (I) (Fig. 1) and could have some biological interest. We were also pleased that the title compound crystallized in a polar space group, since several functional properties of advanced materials (piezoelectricity, pyroelectricity, ferroelectricity, second harmonic generation, and electro-optic response) are only allowed or significantly enhanced in polar crystal structures (Centore et al., 2012(Centore et al., , 2016Takahashi et al., 2016).
The molecular structure of the title compound (II) is shown in Fig. 2. All bond lengths and angles are within normal ranges. Although the O3-H3Á Á ÁO1 angle [113 (5) ] is far from linear, we can consider that the phenol and methoxy group are partners in an intramolecular hydrogen bond (Hunt et al., 2005). The cis/trans conformational equilibrium of the formamide group is fixed in the solid state in the trans conformation, as can be confirmed by the torsion angle C5-N1-C6-O2 [1.3 (6) ].

Synthesis and crystallization
Vanillylformamide (II) was already characterized in the literature through NMR spectroscopy (Baldessari et al., 1987). However, this molecule has no known crystal structure.
Compound (II): To a solution of 4-nitrophenylformate (575 mg, 3.44 mmol) in ethyl acetate (10 ml) at room temperature was added potassium carbonate (715 mg, 5.17 mmol) and vanillylamine hydrochloride (717 mg, 3.78 mmol) under an argon atmosphere. After 1 h of stirring at room temperature, a catalytic amount of water (30 ml) was added, the resulting mixture was stirred for an additional 3 h.
The reaction was followed by TLC (30/70 acetone/DCM). The reaction mixture was poured in HCl 0.1M (15 ml) and then extracted twice with ethyl acetate (2 Â 15 ml). Hexane (50 ml) was added to the combined organic layers and the resulting organic phase was then filtrated directly through a silica gel pad, eluting with 100 ml of acetone/DCM (5:95) and 100 ml of acetone/DCM (30:70), to yield compound (II) as a yellowish white crystalline powder (485 mg, 78%). Single crystals suitable for X-ray diffraction were prepared by slow evaporation of an ether/acetone/hexane (70:5:25) solution of (II) at room temperature.

data-1
IUCrData (  where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max < 0.001 Δρ max = 0.25 e Å −3 Δρ min = −0.23 e Å −3 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.