Pillararene

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 dimethoxypillar rene.

History

1,4-Dimethoxypillar rene, 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-dimethoxypillar rene (DMpillar rene). The methoxy groups of DMpillar rene were then deprotected using boron tribromide and removed to give pillar rene. 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.¹ Chemists often refer to them as "pillarenes" orally as this is easier to pronounce and remember. It is pertinent to mention that Rathore and Kochi 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.

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. Pillar rene 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.

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.

A pillar rene macrocycle, with ''n'' hydroquinone units, has ''n'' planes of chirality. DMpillar rene 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 pillar rene 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).

Synthesis

Homopillararenes

Three strategies are mainly used to obtain pillararenes (Scheme 1). All of three strategies use an acid as catalyst.

# The Lewis acid 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. 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. A practical and effective trifluoromethanesulfonic acid (TfOH)-catalyzed cyclooligomerization strategy was also developed for the synthesis of functionalized pillar renes and copillar renes 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.

Selective Synthesis of Pillar rene

Pillar rene 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 or by using a bulky chlorinated solvent. Ogoshi and coworkers reported the synthesis of a pillar rene 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 rene.

Higher Pillar renes

The higher pillar rene homologues, pillar -15rene, have been synthesized through the ring expansion of pillar rene.

Biomedical applications

A molecular model of carboxylated-pillar[7rene with the anti-Alzheimer drug memantine, showing the total encapsulation of the drug within the macrocycle's cavity. The host–guest complex is stabilized by hydrophobic effects within the cavity, hydrogen bonding, and electrostatic interactions.
While native pillar renes display no solubility in water, and are therefore unsuitable for biomedical applications, a range of water-soluble pillar renes have been reported which have application in drug delivery. In particular, water-soluble carboxylated-pillar renes (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-pillar rene 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 renes, the drug must have a cationic charge; its ability to hydrogen-bond with the pillar renes is less important. Two planar dye molecules, like proflavine, can be simultaneously encapsulated within the cavity of a single caboxylated-pillar rene. Because encapsulation within the cavity of carboxylated-pillar rene 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

Pillar renes have been shown to have potential applications in molecular machinery, sensing, nanoparticle synthesis, artificial transmembrane channels, as components in complex, supramolecular controlled drug delivery systems, construction of porous materials for gas/guest absorption, organic light-emitting materials, and ionic liquids. Binding with dibromoalkanes.

Researchers at Jilin University have reportedZheng, D.-D.; Fu, D.-Y.; Wu, Y.-Q.;* Sun, Y.-L.; Tan, L.-L.; Zhou, T.; Ma, S.-Q.; Zha, X.; Yang, Y.-W. Efficient Inhibition of Human Papillomavirus 16 L1 Pentamer Formation by a Carboxylatopillarene and a p-Sulfonatocalixarene. Chem. Commun. 2014, 50, 3201-3203. that a percarboxylated derivative of pillar rene inhibits the assembly of the human papillomavirus.

References

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Macrocycles
Hydroquinones
Cyclophanes