A new, deep quinoxaline-based cavitand receptor for the complexation of benzene

A new, deep tetraquinoxaline-based cavitand has been synthesized, and its solid-state complex with benzene has been studied through X-ray diffraction analysis.

We report the synthesis of a new macrocyclic receptor, namely 2,8,14,20tetrahexyl-4,24:6,10:12,16:18,22-O,O 0 -tetrakis[2,3-dihydro-[1,4]dioxino[2,3-g]quinoxalin-7,8-diyl]resorcin [4]arene, DeepQxCav, obtained by the addition of ethylene glycol ditosylate to an octahydroxy quinoxaline cavitand. A 1:1 supramolecular complex of this cavitand with benzene has been obtained and analysed through X-ray diffraction analysis. The complex, of general formula C 92 H 88 O 16 N 8 ÁC 6 H 6 , crystallizes in the space group C2/c, with the cavitand host located about a twofold rotation axis. The benzene guest, which is held inside the cavity by C-HÁ Á Á interactions and dispersion forces, is disordered over two equivalent sites, one in a general position and one lying on a twofold axis. The crystal structure features C-HÁ Á ÁO hydrogen bonds and C-HÁ Á Á interactions involving the alkyl chains, the aromatic rings, and the O atoms of the dioxane moiety of the resorcinarene scaffold. The crystal studied was refined as a twocomponent twin.

Chemical context
Resorcinarene-based cavitands are macrocyclic synthetic compounds (Cram, 1983;Cram & Cram, 1994), whose versatility primarily stems from the possibility of modifying the size and form of the cavity by choosing different bridging groups connecting the phenolic hydroxyl groups of the resorcinarene scaffold. This allows the tuning of the complexation properties of the cavity, which can thus interact with neutral and charged molecules through hydrogen bonding,stacking and C-HÁ Á Á interactions, but also forms coordinate bonds with metal centers to create discrete complexes, cages or extended networks. These properties have made cavitands useful receptors for molecular recognition and building blocks for crystal engineering Kane et al., 2015;Brekalo et al., 2018). In our group, we have been exploiting two main types of receptors, in which the bridging groups at the upper rim are either phosphonate RPO 3 moieties or quinoxaline ring systems. Both families have been extensively used in sensing in solution Liu et al. 2018) and in the gas phase (Melegari et al., 2013;Tudisco et al., 2016). Indeed, the demand for fast and reliable detection of biological and chemical hazards is rising continuously and optimal sensors for environmental, security and biomedical applications must be sufficiently responsive to allow detection of the target analyte at low concentrations, and selective enough to respond primarily to a single chemical species in the presence of interferents. In this respect, quinoxaline-based cavitands, exploiting the -basicity and hydrophobicity of their cavity are ideal hosts to interact with aromatic compounds (Pinalli et al., 2018). Following this line of ISSN 2056-9890 research, we have synthesized a new member of the quinoxaline family, DeepQxCav, in which the cavity has been made deeper by the addition of four 1,4 dioxane rings on the quinoxaline walls. In this paper we report and analyse the crystal structure of its complex with benzene as guest.

Structural commentary
The molecular structure of DeepQxCav is shown in Fig. 1. It consists of a 1:1 host-guest complex in which one molecule of benzene is engulfed inside the walls of the cavitand. The complex crystallizes in the monoclinic crystalline system, in space group C2/c. The asymmetric unit comprises half of a cavitand host in a general position, about a twofold rotation axis, and half a molecule of the benzene guest disordered over two sites, one in a general position and one lying on a twofold axis. Distances and angles are in good agreement with similar compounds reported in the literature (see Section 4). Fig. 2 shows two perspective views of the shape of the cavity (in a vase conformation) upon complexation of the guest. The depth of the cavity has been calculated as the distance between the mean plane passing through the groups of atoms C7 at the lower rim and C22-C23 of the upper rim, yielding a value of 10.290 (2) Å . The mean planes passing through the quinoxaline moieties are inclined with respect to the plane passing through the O1/O2 atoms (see Fig. 2), forming angles of 85.24 (3) and 75.16 (4) for the walls labelled A and B, respectively. The mouth of the cavity is roughly rectangular in shape, but because of the bending of the walls, the opening is blocked by the steric hindrance of the four 1,4 dioxane rings (see Table 1 for geometrical details).

Supramolecular features
The most interesting supramolecular feature of the title compound is the encapsulation of benzene inside the aromatic cavity of the host. As can be seen in Fig. 3, two orientations of the guest are present, from now on called I for ring C1S-C3S and II for ring C4S-C7S (the remaining atoms are generated by symmetry). I and II are rotated by ca 60 with respect to each other. In both cases, the benzene molecule is found deep inside the cavity, at the same level of the pyrazine rings, roughly parallel to the walls labelled B [the angles formed by the mean planes passing through the benzene rings and through the quinoxaline wall are 82.4 (5) and 84.2 (3) for I and II, respectively] and perpendicular to the walls labelled A [angles of 15.3 (2) and 15.0 (2) for I and II, respectively]. In particular, the distances of C1S and C7S from the mean plane passing through the resorcinarene oxygen atoms O1/O2 are Left: asymmetric unit of the title compound with labelling scheme and ellipsoids drawn at the 20% probability level. Right: molecular structure of the whole complex. The symmetry-related atoms are in position 1 À x, y, 1 2 À z. For both views, only one of the two disordered orientations has been shown for clarity.

Figure 2
Perspective views of the cavity of DeepQxCav with partial labelling scheme, referred only to atoms in general positions. H atoms and alkyl chains have been omitted for clarity. 1.128 (5) and 1.003 (9) Å , respectively. In the case of orientation I, two symmetry-related, equivalent C-HÁ Á Á interactions are present, between C2S-H2S and the centroid Cg2 of the ring (see Table 2). These interactions are absent in the case of orientation II, which is stabilized by van der Waals dispersion forces only.
In the crystal, the main interactions connecting the cavitands are C-HÁ Á ÁO hydrogen bonds, involving the C-H groups of the alkyl chains (C12B-H12D) and of the aromatic rings (C18A-H18A, C21B-H21B) with the oxygen atoms of the dioxane moiety (O3A) or of the resorcinarene scaffold (O1A, see Figs. 4 and 5 and Table 2). Further consolidation of the structure is provided by C-HÁ Á Á interactions (Fig. 4) due to the presence of aromatic rings in the cavitand scaffold.

Database survey
Several structures of quinoxaline-based cavitands have been published in recent years. A search in the Cambridge Structural Database (Version 5.38, update August 2018; Groom et al., 2016) yielded 20 hits, of which 15 were inclusion compounds. In particular, the group of Professor Dalcanale has reported compounds NUTBUB01 and GURLIQ  in which a singly or doubly 'roofed' quinoxaline cavitand forms a 1:1 complex with benzene; LIMFOE and LIMGAR  in which the guests are 1,3benzodioxole and 5-allyl-1,3-benzodioxole, respectively; and the fluorobenzene complex YAGVIL (Soncini et al., 1992). Other related compounds are BUJNUR (Ballistreri et al., 2016), a benzene clathrate co-crystallizing with fullerene; LUDJEA (Wagner et al., 2009), in which the guest is phenyl azide; and UNIFAY (Azov et al., 2003), an inclusion compound with acetonitrile, the only non-aromatic guest of the series.
Particularly interesting is a quinoxaline-based cavitand (EtQxBox) in which four ethylendioxy bridges between the quinoxaline wings have been introduced to obtain a rigidification of the cavity (Trzciń ski et al., 2017). Also in that case, the crystal structure of the inclusion compound with benzene has been obtained and analysed in detail in the solid state.  Table 2 Hydrogen-bond geometry (Å , ).

Figure 4
View of the relevant C-HÁ Á ÁO hydrogen bonds and C-HÁ Á Á interactions (light-blue and green dotted lines, respectively) stabilizing the crystal structure of the title compound. Only the H atoms involved in the interactions are shown. The benzene guest has been omitted for clarity.

Figure 5
View of the relevant C-HÁ Á ÁO hydrogen bonds (light-blue dotted lines) stabilizing the crystal structure of the title compound. Only the H atoms involved in the interactions are shown. The benzene guest has been omitted for clarity.

Figure 3
View of the interactions (green dotted lines) involving the benzene ring and the quinoxaline cavitand (both orientations of the guest are shown). Symmetry code: (i) 1 À x, y, 1 2 À z.
Differently from what happens in the title compound, the benzene molecule does not lie parallel to the quinoxaline walls of EtQxBox (Fig. 6) and is held inside the cavity by two C-HÁ Á Á interactions with the lower aromatic part of the cavitand, and two bifurcated C-HÁ Á Á N interactions with the nitrogen atoms of two adjacent quinoxaline moieties. The shortest distance of a carbon atom of the guest from the mean plane passing through the O1/O2 groups of atoms is 1.268 (8) Å .

Synthesis and crystallization
All commercial reagents were ACS reagent grade and used as received. Solvents were dried and distilled using standard procedures. 1 H NMR spectra were recorded on Bruker Avance 300 (300 MHz) and on Bruker Avance 400 (400 MHz) spectrometers. All chemical shifts () were reported in parts per million (ppm) relative to proton resonances resulting from incomplete deuteration of NMR solvents. The Matrix-assisted laser desorption/ionization analyses (MALDI TOF-TOF) were performed on an AB SCIEX MALDI TOF-TOF 4800 Plus using -cyano-4-hydroxycinnamic acid as a matrix. The GC-Mass analyses were performed on a Hewlett-Packard Agilent 6890 series equipped in Supelco1 SLBTM 5ms column and Hewlett-Packard 5973 MS Selective Mass Detector. Cavitand QxCav (7) was prepared according to the following convergent synthetic approach: (i) synthesis of the 2,3-dichloro-6,7-dimethoxy quinoxaline bridging unit 4 (Fig. 7); (ii) introduction of the dimethoxy-functionalized quinoxaline bridging unit onto the resorcinarene skeleton, deprotection of the methoxy groups and subsequent ring closure (Fig. 8).
The multistep synthesis of 4 started with nitration of veratrole following an electrophilic aromatic substitution reaction in concentrated nitric acid, under reflux. The obtained 1,2dimethoxy-4,5-dinitro benzene (1) was successively reduced using a catalytic amount of metallic Pd on activated carbon in an H 2 atmosphere to give 1,2-dimethoxy-4,5-diamino benzene (2). Due to the high reactivity of amino groups, compound 2 was used without any further purification for a condensation with oxalic acid under acidic conditions to give heterocycle 3. The final step was the chlorination of the 6,7-dimethoxyquinoxaline-2,3-dione (3) in the presence of POCl 3 as chlorinating agent, dimethylformamide as catalyst and dichloroethane as solvent. The functionalized bridging unit 4 was obtained in 80% yield after column chromatography.

Figure 6
View of the orientation of benzene (in space-filling mode) inside the rigidified cavitand EtQxBox. Alkyl chains and host H atoms have been omitted for clarity. feet was chosen as a compromise between solubility, which helps in the purification of intermediates and final products, and ease of crystallization. The synthesis consists of three steps ( Fig. 8): firstly the hexyl-footed resorcinarene 5 (Tunstad et al., 1989) was fourfold bridged with the 2,3-dichloro-5,8dimethoxy quinoxaline (4) under microwave irradiation, leading to octamethoxyquinoxaline cavitand (5) in 92% yield. The 1 H NMR studies showed the fluctional vase-kite conformation of the cavitand 5, due to the presence of the methoxy groups in the 6,7 positions relative to the quinoxaline moiety. The purified cavitand 6 was successively reacted with a Lewis acid (BBr 3 ) in dry chloroform under reflux, to cleave the methyl protecting groups of the quinoxaline walls. The deprotection of eight CH 3 groups influences the cavitand conformation, as observed by the 1 H NMR analysis, and the octahydroxy cavitand 6 is in the pure vase conformation. This change is due to the presence of hydrogen bonding between the hydroxyl groups placed at the cavity entrance. This strong interaction tightens the cavity, holding it in the vase form. The last reaction step was the closure of the 1,4 dioxane ring by reacting the octahydroxy cavitand 6 and ethylene glycol ditosylate under microwave irradiation in the presence of Cs 2 CO 3 as base and dimethylformamide as solvent. Both 1 H NMR and MALDI TOF-TOF analyses confirmed the formation of the desired compound.
DeepQxCav (7): Cavitand 6 (0.052 mmol, 1 eq.), ethylene glycol ditosylate (0.52 mmol, 10 eq.), dry Cs 2 CO 3 (0.63 mmol, 12 eq.) and dry DMF (5 mL) were added into an oven-dried microwave vessel under an Ar atmosphere and reacted under microwave irradiation at 393 K for 1.5 h. The reaction was quenched in water and extracted with DCM/H 2 O. The organic fractions were collected and dried over Na 2 SO 4 . After filtration the solvent was removed under reduced pressure and the crude was purified by flash chromatography. The final product 7 was obtained in 90% yield. Prismatic, colourless single crystals of the title compound suitable for X-ray analysis were obtained by slow evaporation of a benzene solution.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3.
The structure of the title compound was refined as a twocomponent twin with a BASF parameter of 0.572 (1). The last cycle of refinement was performed with a HKLF 5 dataset containing 12410 corrected reflections constructed from all observations involving domain 2.
A carbon atom (C23B) of one of the upper 1,4 dioxane rings was found to be disordered over two positions with occupancies of 0.547 (17) and 0.453 (17). The benzene guest was found disordered over two equally populated positions. For one of the two orientations (atoms C1S, C2S, C3S and their symmetry-generated analogues), the aromatic ring was modelled by fixing the bond distances to 1.380 (1) Å . The SIMU restraint (Sheldrick, 2015) was applied to atoms C4S-C7S of the second orientation.