Synthesis of Novel P-tert-butylcalix[4]arene Derivative: Structural Characterization of a Methanol Inclusion Compound

A p-tertbutylcalix[4]arene derivative was synthesized from a reaction of the diisothiocyanate p-tertbutylcalix[4]arene, obtaining crystals that were then characterized by mass spectroscopy, Raman spectroscopy, and single-crystal X-ray diffraction. The molecule presents two acid carbamothioic-n-ethoxy-methyl-ester substituent groups. Through crystallization of this compound, it was also found that it includes a methanol molecule within the aromatic cavity. The inclusion of the methanol molecule is due to favorable CH···π interactions.


Introduction
Calix [n]arenes constitute a family of well-known cyclic compounds that are synthesized by the base-catalyzed condensation of formaldehyde with para-substituted phenols, usually p-tert-butylphenol (cyclocondensation).Calix [n]arenes adopt a basket-shaped conformation in the solid state with a ring size that is dependent on the base that is used [1].These macrocycles have been the subject of a variety of studies because of their interesting and technologically useful properties [2][3][4].Their technological applications [5,6] include nanodevices with nanoparticles capable of detecting metal cations, polyaromatic hydrocarbons, and pesticides.The potential uses of chiral calix[n]arenes for enantioselective recognition [7], asymmetric catalysis [3], and as membrane carriers for the transport of chiral amino acids [8] are particularly interesting.
Different chemical modifications of calix [n]arenes have been used as artificial receptors for cations, anions, and neutral organic molecules.This is due to the interactions that occur between the hydrophilic areas of calix[n]arenes (lower rim) and different species.These interactions are primarily hydrogen bonds.Moreover, these compounds may host different molecules or ions within the hydrophobic cavity due to the interactions generated by the aromatic fraction.Different types of guests, including neutral molecules [9] such as acetonitrile [10], and various ions [11] such as the ammonium ion [12], have been reported.The crystal structures of calix[n]arenes makes them attractive building blocks, as they can easily be functionalized as required; for example, p-tert-butylcalix [4]arene is available through the functionalization of the hydroxyl groups (lower rim) or the para positions of the phenyl rings (upper rim).Additionally, intermolecular interactions lead to the formation of supramolecular arrays in crystal packing [13].
Compound (4) was obtained by stepwise substitution of its precursor, p-tert-butylcalix [4]arene (Scheme 1).The crystallographic analysis reveals the supramolecular array produced by the different interactions of XH•••π and inter-and intra-molecular hydrogen-bonds.The cone conformation of the derivative remains.
Compound (4) was obtained by stepwise substitution of its precursor, p-tert-butylcalix [4]arene (Scheme 1).The crystallographic analysis reveals the supramolecular array produced by the different interactions of XH•••π and inter-and intra-molecular hydrogen-bonds.The cone conformation of the derivative remains.
Compounds (3) and ( 4) were studied by Mass-Spectrometry Imaging.The spectrum, shown in Figure 1, clearly exhibited one peak at m/z 883.48.This analysis established the molecular mass of (4) which is consistent with the molecular formula determined by single-crystal diffraction (see Table 3).
Figure 2 shows the Raman spectra of the selected crystals of compounds (1), (3), and (4).The spectra may be qualitatively analyzed in terms of the vibration modes of the related substituted p-tert-butylcalix [4]arene.Vibrational modes of p-tert-butyl groups, hydroxyl groups, and aromatic rings (~1600 to 500 cm −1 ) are observed in the spectra.However, significance differences in the C=N stretching modes were observed (see inset of Figure 2).The absorption mode of the CN group in (1) (at 2258.2 cm −1 ) shifted to 2105.6 cm −1 in (3).In addition to shifting, the shapes of the peaks also changed (the CN group peak in 3 is broad).On the other hand, compound (4) did not show this vibration mode, implying the absence of the CN group in its structure.
Compounds (3) and (4) were studied by Mass-Spectrometry Imaging.The spectrum, shown in Figure 1, clearly exhibited one peak at m/z 883.48.This analysis established the molecular mass of (4) which is consistent with the molecular formula determined by single-crystal diffraction (see Table 3).
Figure 2 shows the Raman spectra of the selected crystals of compounds (1), (3), and (4).The spectra may be qualitatively analyzed in terms of the vibration modes of the related substituted p-tert-butylcalix [4]arene.Vibrational modes of p-tert-butyl groups, hydroxyl groups, and aromatic rings (~1600 to 500 cm −1 ) are observed in the spectra.However, significance differences in the C=N stretching modes were observed (see inset of Figure 2).The absorption mode of the CN group in (1) (at 2258.2 cm −1 ) shifted to 2105.6 cm −1 in (3).In addition to shifting, the shapes of the peaks also changed (the CN group peak in 3 is broad).On the other hand, compound (4) did not show this vibration mode, implying the absence of the CN group in its structure.

Crystal Structure
The crystal structure of (4) was determined by single crystal X-ray diffraction.The asymmetric unit consists of the p-tert-butylcalix [4]arene derivative and one methanol solvent molecule.The molecular structure with the atom labels is shown in Figure 3.

Crystal Structure
The crystal structure of (4) was determined by single crystal X-ray diffraction.The asymmetric unit consists of the p-tert-butylcalix [4]arene derivative and one methanol solvent molecule.The molecular structure with the atom labels is shown in Figure 3.

Crystal Structure
The crystal structure of (4) was determined by single crystal X-ray diffraction.The asymmetric unit consists of the p-tert-butylcalix [4]arene derivative and one methanol solvent molecule.The molecular structure with the atom labels is shown in Figure 3.In crystal packing, the calixarene molecules are linked by hydrogen bonds, weak intermolecular contacts, and N-H•••π and C-H•••π interactions (Table 2).The packing structure contains a C67-H67C•••O50 intermolecular contact with a bond distance of 2.26(4) Å, with H-acceptor distances that are less than the sum of the van der Waals radii.This intermolecular contact links two calixarenes, leading to the formation of dimers.These intermolecular interactions generate a graph-set descriptor D motif (see Figure 4) [15], which is an important influence on the orientation of calixarenes in crystal packing.In crystal packing, the calixarene molecules are linked by hydrogen bonds, weak intermolecular contacts, and N-H•••π and C-H•••π interactions (Table 2).The packing structure contains a C67-H67C•••O50 intermolecular contact with a bond distance of 2.26(4) Å, with H-acceptor distances that are less than the sum of the van der Waals radii.This intermolecular contact links two calixarenes, leading to the formation of dimers.These intermolecular interactions generate a graph-set descriptor D motif (see Figure 4) [15], which is an important influence on the orientation of calixarenes in crystal packing.5) motifs (Figure 5, Table 2).The three-dimensional supramolecular network is reinforced by C-H•••π interactions [16].The inclusion of the methanol molecule is due to favorable C1S-H1S1•••Cg2 interactions.The calixarene accommodates the methanol molecule between the channels (Figure 6, Table 2).A similar inclusion compound has been observed in tetraethyl p-tert-butylcalix [4]arene tetracarbonate in which one acetonitrile molecule lies within the cavity [10].Additionally, N-H•••π interactions generate N2-H2N•••Cg4 intermolecular interactions that connect the calixarenes (Figure 6, Table 2).2).The three-dimensional supramolecular network is reinforced by C-H•••π interactions [16].The inclusion of the methanol molecule is due to favorable C1S-H1S1•••Cg2 interactions.The calixarene accommodates the methanol molecule between the channels (Figure 6, Table 2).A similar inclusion compound has been observed in tetraethyl p-tert-butylcalix [4]arene tetracarbonate in which one acetonitrile molecule lies within the cavity [10].Additionally, N-H•••π interactions generate N2-H2N•••Cg4 intermolecular interactions that connect the calixarenes (Figure 6, Table 2).The intramolecular interactions involved in C69-H69A•••S2 and C67-H67A•••S1 generate graph-set descriptor S(5) motifs (Figure 5, Table 2).The three-dimensional supramolecular network is reinforced by C-H•••π interactions [16].The inclusion of the methanol molecule is due to favorable C1S-H1S1•••Cg2 interactions.The calixarene accommodates the methanol molecule between the channels (Figure 6, Table 2).A similar inclusion compound has been observed in tetraethyl p-tert-butylcalix [4]arene tetracarbonate in which one acetonitrile molecule lies within the cavity [10].Additionally, N-H•••π interactions generate N2-H2N•••Cg4 intermolecular interactions that connect the calixarenes (Figure 6, Table 2).
We performed the transformation of (2) into the corresponding diisothiocyanate derivative (3) with excellent yields using thiophosgene [17,18].The reaction was conducted in a round-bottom flask with 4.08 mmol of (2), 8.2 mmol of barium carbonate, and 20 mL of dichloromethane.The mixture was stirred at room temperature in a closed system.Then, 4.1 mmol of thiophosgene was added to the closed system, and the new mixture was stirred at room temperature for 24 h.After this reaction period time, dichloromethane was added and the mixture was filtered; the filtrate was extracted with water in a separating funnel.The organic phase was collected and dried with sodium sulfate, filtered, and evaporated under vacuum [2].The resulting yellowish solid was purified using a chromatographic column with dichloromethane as the mobile phase.Finally, single-crystals were obtained from a solution of (3) (0.6 mmol) in boiling chloroform (0.5 mL) with hot methanol added dropwise (1 mL).This solution was left for one week, at which point needle crystals were observed and dried.The product that was obtained corresponded to 5,11,17,23tetra-tert-butyl-25,27-di[acidcarbamothioic-n-ethoxy-methyl-ester]-26,28-dihydroxy calix [4]arene (4).The reaction yield was very low.The mechanism of step (d) is similar to the one reported by Katrtizky et al. [19].

Raman and Mass Spectroscopy
The Raman spectra in selected crystals were recorded in the frequency range between 150 and 3500 cm −1 using a micro-Raman Renishaw system 1000 (Barueri, SP, Brazil) equipped with a Leica-DMLM microscope (Barueri, SP, Brazil).The spectra data were collected at room temperature with a laser line of 633 nm and a laser power of 1 mW.The spectra of the samples are uniform throughout the scanned region of single crystals.
The ESI-MS experiments were performed on a Mass spectrometer LC/MSD-TOF (2006) Agilent Technologies (Santa Clara, CA, USA) with capillary voltage positive of 4 KV, fragmentor of 215 V, gas temperature 325 • C with double nebulizer.The sample is introduced into the source through a pumping system Agilent 1100 HPLC (Waldbronn, Germany) using a flow rate of 200 microliter/min of H 2 O:CH 3 CN 1:1.

Conclusions
A new p-tert-butylcalix [4]arene derivative has been obtained and characterized by Raman spectroscopy, ESI-MS, and single-crystal X-ray diffraction.The results showed an inclusion compound.Supramolecular arrays produced by different intra and intermolecular interactions, such as hydrogen bonds and (C,N)-H•••π interactions, were revealed.Raman analysis and mass spectroscopy confirmed the solved structure based on the obtained molecular weight and the absence of precursor signals on the carbamothioic derivative.The inclusion of a solvent molecule confirms the supramolecular nature of the derivative calix [4]arenes.This work demonstrates the possibility of the inclusion of a compound that is anchored in the cavity of calix [4]arene derivatives, which is crucial for their applications in pharmacology.

Figure 4 .
Figure 4. Dimers of compound (4).The methanol solvent molecule and H atoms not involved in the intermolecular interactions have been omitted for clarity.

Figure 4 .
Figure 4. Dimers of compound (4).The methanol solvent molecule and H atoms not involved in the intermolecular interactions have been omitted for clarity.

Figure 5 .
Figure 5.View of intramolecular interactions in compound (4).The H atoms not involved in the intermolecular interactions and the solvent methanol molecule have been omitted for clarity.

Figure 6 .
Figure 6.View of intermolecular interactions in compound (4): (top) Cavity and a methanol molecule through interaction of C-H•••π.(bottom) N-H•••π interactions.The H-atoms not involved in the intermolecular interactions have been omitted for clarity.

Figure 5 .
Figure 5.View of intramolecular interactions in compound (4).The H atoms not involved in the intermolecular interactions and the solvent methanol molecule have been omitted for clarity.

Figure 5 .
Figure 5.View of intramolecular interactions in compound (4).The H atoms not involved in the intermolecular interactions and the solvent methanol molecule have been omitted for clarity.

Figure 6 .
Figure 6.View of intermolecular interactions in compound (4): (top) Cavity and a methanol molecule through interaction of C-H•••π.(bottom) N-H•••π interactions.The H-atoms not involved in the intermolecular interactions have been omitted for clarity.

Figure 6 .
Figure 6.View of intermolecular interactions in compound (4): (top) Cavity and a methanol molecule through interaction of C-H•••π.(bottom) N-H•••π interactions.The H-atoms not involved in the intermolecular interactions have been omitted for clarity.