Syntheses and characterization of aryl-substituted pyrogallol[4]arenes and resorcin[4]arenes

Seven aryl-substituted pyrogallol[4]arenes and six aryl-substituted resorcin[4]arenes were synthesized through the acid catalyzed reaction of either pyrogallol or resorcinol with a specific alkoxybenzaldehyde. Single crystal X-ray data was obtained for all thirteen compounds. In order to determine the effect of the different pendent –R groups, four properties were investigated: π–π distance, inward tilt, twist angle, and the angle between the planes containing the pendent –R groups. Positioning of the –R groups, the carbon atom chain length of the –R groups, the number of upper-rim hydroxyl groups (resorcin[4]arene vs. pyrogallol[4]arene), and the number of substituted phenyl groups all influenced these four properties. The trends that develop are investigated and discussed.


Introduction
Due to their flexibility and bowl-shaped cavity, calix [4]arenes have garnered attention over the last forty years.They have found extensive applications in a range of fields due to their ability to act as host molecules for a variety of guest molecules. 1As a result of the considerable number of applications of calix [4]arenes, related hosts were synthesized, such as pyrogallol [4]arenes and resorcin [4]arenes (see Fig. 1).Pyrogallol [4]  arenes and resorcin [4]arenes imitate the conformation and shape of calix [4]arenes; however, the possibility of more hydrogen bonding due to the presence of more hydroxyl groups on the upper-rim (eight for resorcin [4]arenes and twelve for pyrogallol [4]arenes) has led to new chemistry and to supramolecular architectures such as metal-seamed dimers and hexamers. 2,3iedel and Vogel led the way in the 1940s with research in resorcin [4]arenes.Their work concentrated on the reactions of resorcinol with aliphatic aldehydes.These reactions resulted in the formation of the all-cis cone stereoisomer (see Fig. 2). 4,5ater research by Hoegberg exposed three more possible conformers of resorcin [4]arenes: boat, saddle, and chair. 6he orientations of the pendent -R groups for resorcin [4]  arene are given the nomenclature of rccc (cone), rcct (partial cone), rcct (saddle), and rctt (chair) and they describe the orientation of the aliphatic or aryl -R group (see Fig. 2).The reference point, r, is followed by stereochemical positions cis, c, or trans, t, going counterclockwise around the molecule.Vogel undertook further studies on the conformers of resorcin [4]arenes with variable temperature 1 H NMR studies.It was determined that the kinetic product was the chair isomer while the cone isomer was the thermodynamic product. 6yrogallol [4]arenes and resorcin [4]arenes have different bonding interactions and structure. 7Therefore, manipulation of the pyrogallol [4]arene and resorcin [4]arene conformers is most likely different from that with calix [4]arenes.For instance, for pyrogallol [4]arenes it was determined that in aprotic solvent the chair conformation was preferred, but in protic solvent the boat conformation was favored. 8It has been hypothesized that the pendent -R group also might have an impact on the resulting conformation. 9A good deal of information is known about the synthesis pathways for pyrogallol [4]arenes and resorcin [4]arenes; however, not much is known about the properties and interactions that govern these reactions.Thus, characterization and the creation of a database of modified pyrogallol [4]arenes and resorcin [4]  arenes is needed to provide insight into the interactions involved with these molecules and their adaptability and flexibility to specific applications.Accordingly, the work herein was carried out to uncover the properties and trends that arise from varying the phenyl substituent on pyrogallol [4]  arenes and resorcin [4]arenes.
Several studies have already been carried out with aryl-substituted C-phenylpyrogallolĳ4]arenes 10-13 and C-phenylresorcinĳ4]arenes. 14 These have all produced the chair conformer unless the hydroxyl group has been alkylated (see Table 1).Additionally, studies with C-fluorophenyl-pyrogallolĳ4]arene, C-chlorophenylpyrogallolĳ4]arene, and C-bromophenylpyrogallolĳ4]arene have been completed (see Table 1). 15The twist angle (the degree of rotation between two eclipsed benzene ring substituents) is greatest and smallest with bromophenyl and fluorophenyl substituents respectively.Furthermore, it was found that temperature also played a part in influencing the twist angle.The twist angle decreased as the temperature decreased from reflux to room temperature.
Herein seven aryl-substituted pyrogallol [4]arenes and six aryl-substituted resorcin [4]arenes have been synthesized and single crystal X-ray data for all thirteen structures has been collected.Both the pendent -R groups and whether the molecule is a pyrogallol [4]arene or resorcin [4]arene affect several properties of the resulting structures, including the π-π distance between pendent -R groups, the inward tilt of the pendent -R groups, the twist angle of the pendent -R groups, and the angle between the planes containing the pendent -R groups (ABP).The trends are investigated and discussed in detail (Table 2).

Experimental
Reagents and solvents were obtained commercially and used without additional purification.stirred until all 4-hydroxybenzaldehyde dissolved.To the reaction, 1.97 grams of sodium hydride was added and the solution was stirred at room temperature for ten minutes.To the solution, 3.05 mL of iodoethane was added and the solution was stirred at room temperature for one hour.The reaction was quenched with methanol then all solvent was rotovapped off.The product was washed with a 50/50 water/chloroform mixture.Since product dissolves in chloroform, the chloroform layer was removed and rotovapped off.The remaining liquid was dried with magnesium sulfate, filtered, and all remaining solvent was evaporated off yielding 8.3 grams of orange liquid.C-4-Methoxyphenylpyrogallolĳ4]arene.To a round bottom flask, 3.89 grams of pyrogallol and 50 mL of ethanol were added.The solution was stirred until the pyrogallol dissolved.To the solution, 3.75 mL of 4-methoxybenzaldehyde was added followed by 0.5 mL of concentrated hydrochloric acid.The solution was heated to 90 °C and refluxed for 8 hours.The solution was filtered and the powder dried yielding 1.8 grams of white precipitate.Colourless, plate-shaped crystals were obtained by dissolving the powder in DMSO and allowing the solution to slowly evaporate.

Synthesis of structures 2-13
Synthesis of structures 2-13 were synthesized with a similar method as structure 1. Complete synthesis information is described in ESI.†

Crystallography
Single crystal X-ray data for structures 2, 8, 10, and 13 were collected at 173 K on a Bruker Apex II CCD diffractometer using a CuKα radiation source (1.54178 Å).Data for all other cocrystals were collected at 100 K or 173 K on a Bruker Apex II CCD diffractometer, using a MoKα radiation source (0.71073 Å).

Results
All synthesized structures form the chair conformer pack in a bilayer arrangement.Four measurements are used to describe and compare the structures of the aryl-substituted pyrogallol [4]arenes and resorcin [4]arenes: π-π distance, the tilt inward, the twist angle, and the angle between the plane of the pendent -R groups (see Tables 3 and 4).(Note: there are two sets of pendent -R groups, four pendent -R groups total.Some of the molecules are symmetric through a C 2h plane so the two groups are equal and thus only one set of measurements is given.)First, the π-π distance is the distance measured from the calculated centroids of the phenyl groups of the pendent -R groups (see Fig. 3).This measurement describes the degree the pendent -R groups are rotated away from each other and is used with the tilt distance to express how much the pendent -R groups are tilted inwards (see Fig. 4).Tilt distance is the difference between the two C-C distances (see Fig. 5).The first C-C distance is the distance between the two C4 carbon atoms of the phenyl groups of the -R groups and the second C-C distance is the distance between the two C1 carbon atoms of the phenyl groups of the -R groups (see Fig. 5).The twist angle is found using equation 1. Angle 1 is the angle that is made up by the points C1, C2, and C3 (see Fig. 6).Angle 2 is the angle that is made up by the points C3, C4, and C5 (see Fig. 6).Along with the angle between the planes of the eclipsed pendent -R groups,  the angle describes the sterics and torsion between the two groups.The angle between the planes (ABP) of the eclipsed pendent -R groups is calculated with the MPLA command in X-Seed. 16The command creates two planes for the two phenyl groups and then calculates the angle between.
Fig. 6 Points C1 and C2 that make up angle 1 (blue atoms) and points C4 and C5 that make up angle 2 (green atoms).C3 is used to find both angles and is the orange atom.Hydrogen atoms are removed for clarity.
In order to compare these current results to previously published crystal structures of aryl-substituted pyrogallol [4]  arenes and resorcin [4]arenes, similar examinations were performed with the previously reported structures.The results can be found in Table 8.Comparing the substituted pyrogallol [4]arenes to the substituted resorcin [4]arenes, with a phenyl or fluoro -R group, the pyrogallol [4]arenes have a greater π-π distances and angle between the planes than the resorcin [4]arenes.However, the substituted resorcin [4]arenes have a greater inward tilt and twist angle than the substituted pyrogallol [4]arenes.This is similar to the trends found for alkoxy substituted pyrogallol [4]arenes and resorcin [4]arenes except for the angle between the planes.For chloro -R groups, the pyrogallol [4]arenes have a greater inward tilt and twist angle than the resorcin [4]arenes and the resorcin [4]  arenes have a greater π-π distances and angle between the planes.These trends are dissimilar to the trends found in the alkoxy substituted pyrogallol [4]arenes except for the angle between the planes (see Table 9 for a summary of the trends).

Conclusions
Thirteen new aryl-substituted pyrogallol [4]arenes and resorcin [4]arenes were synthesized.It was demonstrated that small changes in the substituted pendent -R group (positioning of alkoxy group and length of alkoxy group) led to structural changes and several trends arose in π-π distance, inward tilt, twist angle, and ABP.
Further studies are being undertaken to determine the effect of substitution on phenylpyrogallol [4]arenes.Longer alkoxy groups in different positions are being synthesized as only methoxyphenyl was done in all three (ortho, meta, and para) positions.Additionally, phenyl rings are being expanded to determine if anthracene and pyrene groups could be substituted.Furthermore, studies have been started to convert the chair conformer of all structures to the boat conformer.This is being attempted through refluxing, microwave synthesis, or changes in solvent system.With the boat conformers synthesized, these compounds will be used to create a library of metal-seamed dimeric and hexameric nano-capsules.
Table 9 Trends for π-π distance, inward tilt, twist angle, and the angle between the planes (ABP) containing the pendent -R groups for previously reported aryl substituted pyrogallol [4]arenes and resorcin [4]

Fig. 5
Fig. 5 C4 C-C distance (dashed blue bond) and C1 C-C distance (dashed green bond).C4 atoms are blue while C1 atoms are green.Hydrogen atoms are removed for clarity.

Table 2
Structures with corresponding name and -R group.-R groups attaches to bridging -CH linker through the top (top left, if more than one phenyl group) carbon atom Structure Name -R group This journal is © The Royal Society of 2016

Table 3 π
-π distance and inward tilt of aryl-substituted pyrogallol[4]arenes and resorcin[4]arenes a Tilt inward is calculated as the difference between C-C distance 2 and C-C distance 1.

Table 4
Twist angles and angle between the planes of eclipsed -R groups for aryl-substituted pyrogallol[4]arenes and resorcin[4]arenesThis journal is © The Royal Society of Chemistry 2016

Table 6
Comparison of twist angle and ABP for pyrogallol[4]arenes vs.