Crystal structures of three new N-halomethylated quaternary ammonium salts

In the crystals of the title N-halomethylated quaternary ammonium salts, there are short I⋯I− interactions of 3.564 (4), 3.506 (1) and 3.55781) Å for compounds (I), (II) and (III), respectively. In (I), molecules are linked by C—H⋯I− and C—H⋯π interactions, together with the I⋯I− short contacts, forming ribbons along [100]. In (II), there are only C—H⋯I− interactions, which together with the I⋯I− short contacts, lead to the formation of helices along [010]. In (III), apart from the I⋯I− short contacts, there are no other significant intermolecular interactions present.


Chemical context and background to halogen bonding and cation-p interactions
Quaternary ammonium salts have been widely studied as anticancer (Wang et al., 2012;Song et al., 2013), anti-fungal (Ng et al., 2006), anti-HIV-1 (Shiraishi et al., 2000), anti-bacterial (Calvani et al., 1998), anti-malarial (Calas et al., 1997;Calas et al., 2000) and anti-leishmanial (Mavromoustakos et al., 2001) pharmaceuticals. Our research group has been working in the past few years on the activity of quaternary N-halomethyl ammonium salts for likely pharmaceutical purposes, specifically against axenic L. (V) panamensis and L. (L) amazonensis parasites, human pathogenic species that cause cutaneous and mucocutaneous leishmaniasis. The experiments proved that these compounds are very promising anti-leishmanial molecules, and very significant changes in their activity were observed upon a slight modification of the carbon skeleton by only a single methylene unit (Ríos-Vá squez et al., 2015). A preliminary effort at understanding a structure-activity relationship with three N-iodomethyl quaternary ammonium salts (I), (II) and (III) of the form [ICH 2 N(CH 3 ) 3 (CH 2 ) n CH C(Ph) 2 ] + ÁI À (with n = 2, 3 and 4, respectively) is currently being carried out. One possible approach to understand the different activities is to establish what kind of interactions are present in compounds (I)-(III), for example whether C-IÁ Á ÁI À (Desiraju et al., 2013), C-HÁ Á ÁI À (Glidewell et al., 1994), C-HÁ Á Á (Nishio et al., 1998) or cation- (Dougherty, 1996), and if so, how these interactions may affect their structure and biological properties. ISSN 2056-9890 As defined by International Union for Pure and Applied Chemistry (IUPAC): a halogen bond occurs when there is evidence of a net attractive interaction between an electrophilic region associated with a halogen atom in a molecular entity and a nucleophilic region in another, or the same, molecular entity (Desiraju et al., 2013). Halogen bonds are characterized by XÁ Á ÁX distances that are clearly shorter than the van der Waals radii sum (Formigué, 2009;Awwadi et al.;; otherwise this interaction is neglected. In a similar way, the existence of C-HÁ Á ÁX hydrogen bonds (X = F, Cl, Br or I) in neutral organic molecules (Aakerö y & Seddon, 1993) and even in organic salts has been recognized. On the other hand, a special kind of hydrogen bond, defined as a weak interaction between a soft acid (i.e. an sp 3 , sp 2 or sp C-H system) and a soft base (i.e. an aromatic, olefinic or acetilenic p system), with a significant role on diverse chemical and biological phenomena has recently been described (Nishio, 2012). In particular, this interaction exerts an observable influence on host-guest recognition and crystal packing in the solid state. A related attraction is the cation-interaction, which is regarded as an electrostatic attraction between a positive charge and the quadrupole moment of an aromatic ring (Dougherty, 1996). A cation-interaction between aromatic and ammonium ions is known to play an important role in many biological systems (Ma & Dougherty, 1997;Dougherty, 2013;Sussman et al., 1991;Chen et al., 2011). Part of our research interest is focused not only in understanding the reactive nature of alpha ammonium distonic radical cations which are generated from N-halomethylated quaternary ammonium salts (Ríos et al., 1996;Ríos, Bartberger et al., 1997), but also in trying to understand how these salts behave against Leishmania parasites (Ríos-Vá squez et al., 2015). The recognition of the occurrence of some supramolecular interactions in these salts may lead to a better understanding of the likely novel biological binding sites, and therefore to new suggestions about biocatalytic mechanisms.
The title N-iodomethyl quaternary ammonium salts, (I)-(III), were synthesized following standard procedures used for other related compounds (Newcomb et al., 1993;Horner et al., 1995) and suitable crystals were obtained (Mú nera-Orozco, 2014). This paper reports a comparative crystal structure and supramolecular interactions analysis for the aforementioned compounds.

Structural commentary
Compound (I), Fig. 1, crystallizes in the non-centrosymmetric monoclinic space group P2 1 and is therefore, a potential material for NLO properties. The asymmetric unit consists of an ammonium cation and an iodide anion. In the geminalsubstituted diphenylethene unit, the phenyl rings (C5-C10 and C11-C16) are inclined to one another by 74.6 (2) , and are twisted from the mean plane of the central C C bond fragment (C2-C5/C11) by 33.2 (2) and 61.4 (2) , respectively. Coplanarity of the olefin skeleton and the peripheral phenyl rings is prevented because of steric congestion between the associated phenyl rings. The conformation of the side chain reveals an all-trans extended conformation with the iodomethyl moiety on one side of the backbone chain, with bond lengths and angles in the expected ranges.
In compound (II), Fig. 2, the dihedral angles between the mean planes of the C C double-bond fragment (C3-C6/C12) and the two phenyl rings (C6-C11 and C12-C17) are 31.1 (4) The molecular structure of compound (I), showing the atom labelling. Displacement ellipsoids are drawn at the 50% probability level.

Figure 2
The molecular structure of compound (II), showing the atom labelling. Displacement ellipsoids are drawn at the 50% probability level. and 58.6 (4) , respectively, while the phenyl rings are inclined to one another by 76.2 (4) . The N-iodomethyl-N,N-dimethyl-N-propylammonium moiety adopts a fully extended conformation with one methyl group and the iodomethyl unit on opposite sides of the backbone of the side chain (Fig. 2). This conformation seems to be partially supported by a C-HÁ Á ÁI À hydrogen bond (Table 2 and Supramolecular features).
In compound (III), Fig. 3, the phenyl rings are twisted out of the plane defined by the ethylene moiety (C4-C7/C13), making dihedral angles of 38.7 (4) and 78.7 (6) for the trans (C7-C12) and cis (C13-C18) phenyl rings, respectively. The phenyl rings are inclined to one another by 78.5 (6) . The alkylamino side chain is almost fully extended away from the geminal-substituted ethene group.
In the crystal of (II), helical chains along the b-axis direction are formed by molecules linked via C-HÁ Á ÁI À (Table 2) and I1Á Á ÁI2 ii interactions [3.506 (1) Å ; symmetry code: (ii) Àx + 1 2 , y À 1 2 , Àz + 1 2 ]; as shown in Fig. 5. Here no C-HÁ Á Á interactions are present in the crystal packing. The closest distance between the ammonium substituents and any of the phenyl rings is ca 7.18 Å . These features clearly rule out an intramolecular cation-interaction for this molecule in the solid state. However, in studies of distonic radical cation (Ríos et al. 1996;Yates et al., 1986), evidence is presented that the active conformation of the alkylamino side chain is oriented  Table 1 Hydrogen-bond geometry (Å , ) for (I).

Table 2
Hydrogen-bond geometry (Å , ) for (II). The molecular structure of compound (III), showing the atom labelling. Displacement ellipsoids are drawn at the 50% probability level.

Figure 4
The crystal packing of compound (I), viewed along the b axis, showing the intermolecular contacts (dashed lines; see Table 1).

Figure 5
The crystal packing of compound (II), viewed along the b axis, showing the intermolecular contacts (dashed lines; see Table 2).
toward and above the plane of the C C double bond of the geminal-substituted ethene group. These results confirm that there is considerable freedom of rotation about the bonds separating the basic amino function and the tricyclic system, and thus numerous interconvertible side-chain conformations, differing only slightly in potential energy, may exist. In the crystal of (III), apart from the I1Á Á ÁI2 iii contact of 3.557 (1) Å [symmetry code: (iii) Àx, Ày + 1, Àz], there are no other significant intermolecular contacts present (Fig. 6). The only possible conclusion regarding the crystal structure of (III) is that the steric requirements in this molecule outweigh the additional stabilization obtained by an intramolecular cationinteraction.

Synthesis and crystallization
The general procedure for the preparation of the title quaternary ammonium salts is illustrated in Fig. 7 for compounds (I)-(III). The reactions were carried out following a standard literature method (Ríos et al., 1996) starting from the appropriate amine [N,N-dimethyl-4,4-diphenylbut-3-en-1amine 1(a), N,N-dimethyl-5,5-diphenylpent-4-en-1-amine 1(b) and N,N-dimethyl-6,6-diphenylhex-5-en-1-amine 1(c)]. Typically, CH 2 I 2 (4 eq) and 1 eq of the starting tertiary amine [for example, compound 1(a) for the synthesis of (I); as shown in Fig. 7] were dissolved in acetonitrile. The reactions were allowed to run overnight at room temperature, and the precipitated salts were filtered off and washed several times with diethyl ether, and then recrystallized from a binary mixture water-isopropanol. The desired products were obtained as colourless crystals.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3. For all three compounds the Cbound H atoms were included in calculated positions and treated as riding atoms: C-H = 0.93-0.99 Å with U iso (H) = 1.5U eq (C) for methyl H atoms and 1.2U eq (C) for other H atoms. Refining the structure of compound (I) in the noncentrosymmetric space group gives a value of 0.02 (3) for the Flack parameter (Flack & Bernardinelli, 1999), confirming that the direction of the polar axis has been correctly determined. The studied crystal of compound (III) was a nonmerohedral twin with a ratio of two major domains of 0.374 (2):0.626 (2). The two domains are rotated from each other by 180.0 about the reciprocal axis a*, as determined by the CELL NOW program (Sheldrick, 2004). The final refinement was carried out using the twinned data set. The crystal packing of compound (III), viewed along the b axis.