Pillararenes are macrocycles composed of hydroquinone or dialkoxybenzene units (5 to 10) linked in the para position by methylene bridges. They are structurally similar to the cucurbiturils and calixarenes that play an important part in host–guest chemistry. The first pillararene was the five membered dimethoxypillararene.Cao, D.; Kou, Y.; Liang, J.; Chen, Z.; Wang, L.; Meier, H.; A Facile and Efficient Preparation of Pillararenes and a Pillarquinone. Angew. Chem. Int. Ed. 2009, 48, 9721-9723.
History 1,4-Dimethoxypillararene, the first pillararene, was reported in 2008 by Tomoki Ogoshi et al. They catalyzed the condensation of 1,4-dimethoxybenzene and paraformaldehyde using a Lewis acid to obtain 1,4-dimethoxypillararene (DMpillararene). The methoxy groups of DMpillararene were then deprotected using boron tribromide and removed to give pillararene. Ogoshi and Kanai decided naming the new family of host macrocycles "pillararene", since they are cylindrical or pillar-like in shape and composed of aromatic or "arene" moieties. Chemists often refer to them as "pillarenes"Tan, L.-L.; Zhang, Y.; Li, B.; Wang, K.; Zhang, S. X.-A.; Tao, Y.; Yang, Y.-W. Selective Recognition of "Solvent" Molecules in Solution and the Solid State by 1,4-Dimethoxypillararene Driven by Attractive Forces. New J. Chem. 2014, 38, 845-851. orally as this is easier to pronounce and remember. It is pertinent to mention that Rathore and Kochi Rathore, R.; Kochi, J. K. Radical-Cation Catalysis in the Synthesis of Diphenylmethanes via the Dealkylative Coupling of Benzylic Ethers. J. Org. Chem. 1995, 60, 7479–7490. first observed pillararenes in 1995, but were unable to characterize, and reported as a polymer-like material being formed along with diarylmethanes during the transformation of bis(methoxymethyl)-p-hydroquinone ether.Ivanov, M. V.; Wang, D.; Navale, T. S.; Lindeman, S. V.; Rathore, R. From Intramolecular (Circular) in an Isolated Molecule to Intermolecular Hole Delocalization in a Two‐Dimensional Solid‐State Assembly: The Case of Pillarene. Angew. Chem. Int. Ed. 2018, 57, 2144-2149.
Structure Pillararenes are composed of hydroquinone units linked by methylene bridges at para-positions. It features a symmetrical pillar architecture with two identical cavity gates. Pillararene is the most conformationally stable member in this family. Due to the close proximity of many electron-rich hydroquinones, the cavity of pillararenes are able to form strong association complexes with electron-poor species. Also, derivatives of the pillararenes can be generated by modifying the hydroxyl groups at all positions or selectively on one or two positions.Strutt, N. L.; Forgan, R. S.; Spruell, J. M.; Botros, Y. Y.; Stoddart, J. F. Monofunctionalized Pillararene as a Host for Alkanediamines. J. Am. Chem. Soc. 2011, 133, 5668-5671.
Planar chirality
The orientation of the hydroquinone oxygens on both rims of the pillararene allow the macrocycle to exhibit planar chirality. When the substituent on the hydroquinone oxygen is small enough to fit through the cavity of the pillararene, allowing for oxygen-through-the-annulus rotation to occur, racemization occurs. If this substituent is large enough to prevent rotation, optically active pillararene macrocycles can be isolated.Ogoshi, T.; Masaki, K.; Shiga, R.; Kitajima, K.; Yamagishi, T.-a. Org. Lett. 2011, 13, 1264Strutt, N. L., Fairen-Jimenez, D.; Iehl, J.; Lalonde, M. B.; Snurr, R. Q.; Farha, O. K.; Hupp, J. T.; Stoddart, J. F. J. Am. Chem. Soc. 2012, 134, 17436.
A pillar[n]arene macrocycle, with n hydroquinone units, has n planes of chirality. DMpillararene has five planes of chirality which are "in sync" in the lowest energy conformational isomer due to unfavorable steric interactions between the methoxy groups of neighboring 1,4-dimethoxy-phenylene units. The absolute stereochemical designation of these planes of chirality in pillararene structures can be assigned following modified Cahn-Ingold-Prelog priority rules. The pilot atom for one of the five planes of chirality in pillararene is assigned to the highest priority atom that is not in the chiral plane - the first carbon atom of the neighboring phenylene unit. The three adjacent in-plane atoms are then assigned, starting with the methylene carbon attached to the pilot atom as priority 1, and the directly connected phenylene carbon as 2, and the carbon atom connected to the methoxy group as 3. When viewed from the side of the pilot atom, if the three atoms form a clockwise direction when followed in order of priority, the molecule is assigned as R(p), otherwise it is assigned as S(p).Strutt, N. L., Schneebeli, S. T.; Stoddart, J. F. Stereochemical Inversion in Difunctionalised Pillararenes. Supramol. Chem., 2013, 25, 596–608.Ke, C.; Strutt, N. L.; Li, H.; Hou, X.; Hartlieb, K.; McGonigal, P. R.; Ma, Z.; Iehl, J.; Stern, C. L.; Cheng, C.; Zhu, Z.; Vermeulen, N. A.; Meade, T. J.; Botros, Y. Y.; Stoddart, J. F. Pillararene as a Co-Factor in Templating Rotaxane Formation. J. Am. Chem. Soc. 2013, 135, 17019-17030.
Synthesis
Homopillararenes Three strategies are mainly used to obtain pillararenes (Scheme 1).Xue, M.; Yang, Y.; Chi, X.; Zhang, Z.; Huang, F., Pillararenes, A New Class of Macrocycles for Supramolecular Chemistry. Acc. Chem. Res. 2012, 45 (8), 1294–1308. All of three strategies use an acid as catalyst.
The Lewis acidLiu, L.; Cao, D.; Jin, Y.; Tao, H.; Kou, Y.; Meier, H., Efficient Synthesis of CopillarArenes and Their Host–Guest Properties with Dibromoalkanes. Org. Biomol. Chem. 2011, 9, 7007-7010. or trifluoromethanesulfonic acid catalyzed condensation of 1,4-dialkoxybenzene and paraformaldehyde at room temperature. The condensation of 1,4-dialkoxy-2,5bis(alkoxymethyl)benzene catalyzed by p-toluenesulfonic acid. Cyclooligomerization of 2,5-dialkoxybenzyl alcohols or 2,5-dialkoxybenzyl bromides with an appropriate Lewis acid as the catalyst.
Copillararenes In 2010, Feihe Huang et al.Zhang, Z.; Xia, B.; Han, C.; Yu, Y.; Huang, F. Syntheses of Copillararenes by Co-oligomerization of Different Monomers, Organic Letters, 2010, 12, 3285-3287. introduced three new ways to synthesize copillararenes, which are composed of different repeating units. It is easier to selectively functionalize copillararenes, helping to generate interesting physical properties, conformations, and host–guest binding interactions. There are two possible ways to make copillararenes: to selectively modify repeating monomers of homopillararenes, or to use two different monomers to carry out co-oligomerization.
Mechanism Pillararenes are traditionally formed through a thermodynamically controlled Friedel-Crafts cyclooligomerization.Holler, M.; Allenbach, N.; Sonet, J.; Nierengarten, J.-F. The high yielding synthesis of pillararenes under Friedel-Crafts conditions explained by dynamic covalent bond formation. Chem. Commun. 2012, 48, 2576. A practical and effective trifluoromethanesulfonic acid (TfOH)-catalyzed cyclooligomerization strategy was also developed for the synthesis of functionalized pillar[n]arenes and copillararenes from 1,4-dialkoxybenzenes with paraformaldehyde under mild reaction conditions, and the reaction mechanism of solution-phase catalytic synthesis of pillararenes was investigated by room-temperature X-band ESR spectroscopy, mass spectroscopy, NMR and control experiments, suggesting a free radical process initially and a Friedel–Crafts alkylation process during the consequent coupling and ring-closure stage.Wang, K.; Tan, L.-L.; Chen, D.-X.; Song, N.; Xi, G.; Zhang, S. X.-A.; Li, C.; Yang, Y.-W. One-Pot Synthesis of Pillar[n]arenes Catalyzed by a Minimum Amount of TfOH and a Solution-Phase Mechanistic Study. Org. Biomol. Chem. 2012, 10, 9405-9409.
Selective Synthesis of Pillararene Pillararene can be targeted as the major product of the Friedel-Crafts cyclooligomerization by using bulky alkoxy groups on the monomer, switching the Lewis acid catalyst Synthesis and host–guest properties of pillararenes. Sci. China Chem. 2012, 55, 223-228. or by using a bulky chlorinated solvent. Ogoshi and coworkers reported The template effect of solvents on high yield synthesis, co-cyclization of pillararenes and interconversion between pillar- and pillararenes. Chem. Commun. 2014, 50, 5774-5777. the synthesis of a pillararene with 1,4-Bis(methylcyclohexyl ether)phenylene units in an 87% yield by using chlorocyclohexane as the solvent. The bulky chlorinated solvent was suggested to act as a template for the formation of the larger pillar[n]arene.
Higher Pillar[n]arenes The higher pillar[n]arene homologues, pillar[6-15]arene, have been synthesized through the ring expansion of pillararene.Tomoki Ogoshi, Naosuke Ueshima, Fumiyasu Sakakibara, Tada-aki Yamagishi, and Takeharu Haino. Conversion from Pillararene to Pillar[6–15]arenes by Ring Expansion and Encapsulation of C60 by Pillar[n]arenes with Nanosize Cavities. Org. Lett. 2014, 16, 2896-2899. .
Biomedical applications
While native pillar[n]arenes display no solubility in water, and are therefore unsuitable for biomedical applications, a range of water-soluble pillar[n]arenes have been reported which have application in drug delivery. In particular, water-soluble carboxylated-pillar[n]arenes (where n = 6 or 7) have already shown potential in both drug delivery and bio-diagnostics because they are highly soluble, form host–guest complexes with a range of drug and medicine-based compounds, and appear to be relatively non-toxic. The cavity of carboxylated-pillararene is too small to include most drug molecules and therefore is not useful in drug delivery. To form a host–guest complex with the pillar[n]arenes, the drug must have a cationic charge; its ability to hydrogen-bond with the pillar[n]arenes is less important. Two planar dye molecules, like proflavine, can be simultaneously encapsulated within the cavity of a single caboxylated-pillararene. Because encapsulation within the cavity of carboxylated-pillararene quenches the fluorescence of proflavine, this gives rise to "on" and "off' states to the dye which may have application in bio-diagnostics.
Other potential applications