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DOI: 10.1055/s-0040-1738369
Copillar[5]arene Chemistry: Synthesis and Applications
China Scholarship Council for a PhD grant to W.C.
Abstract
Research on pillar[n]arenes has witnessed a very quick expansion. This emerging class of functionalized macrocyclic oligoarenes not only offers host–guest properties due to the presence of the central cavity, but also presents a wide variety of covalent functionalization possibilities. This short review focuses on copillararenes, a subfamily of pillar[n]arenes. In copillararenes, at least one of the hydroquinone units bears different functional groups compared to the others. After having defined the particular features of copillararenes, this short review compares the different synthetic strategies allowing their construction. Some key applications and future perspectives are also described.
1 Introduction
2 General Features of Pillar[5]arenes
3 Synthesis of Functionalized Copillar[4+1]arenes
4 Concluding Remarks
# 1
Introduction
Macrocyclic compounds are the main players in the field of supramolecular chemistry as they are able to form organized, non-covalent assemblies via cavity-size-dependent host–guest interactions.[1] [2] [3] As a result, the design and synthesis of new macrocyclic host molecules has attracted the interest of scientists because of their broad potential applications, for instance, for preparing mechanically interlocked molecules and supramolecular assemblies.[4,5] Numerous macrocyclic compounds, including the most familiar: cyclodextrins,[6] crown ethers,[7] cucurbit[n]urils,[8] and calix[n]arenes,[9] were discovered a long time ago, with some even dating back from the 19th century (Figure [1]).[10] Pillar[n]arenes were discovered very recently and have witnessed a very quick expansion.[11] [12] [13] [14] [15] [16] [17] [18] [19] This emerging class of functionalized macrocyclic oligoarenes not only offers host–guest properties due to the presence of the central cavity, but also presents a wide variety of covalent functionalization possibilities.




One strategy to achieve regioselective functionalization of pillar[5]arenes is the differentiation of the two rims of these macromolecules (A) (Figure [2]).[20] [21] [22] Another approach to display two distinct groups on a pillararene structure is to generate copillars B. In copillars, at least one of the hydroquinone units bears a different functional groups compared to the others.[23] Moreover, non-covalent functionalization can also be achieved by exploiting the cavity of the pillar to generate rotaxanes C.[24]


This short review intends to outline the state of the art of the chemistry of copillar[5]arenes. We first briefly describe the discovery and the main characteristics of the parent pillar[5]arenes, for which several review articles have already been published.[25] [26] [27] [28] After defining the particular features of copillararenes, we review and compare the different synthetic strategies allowing their construction. Finally, some key applications and future perspectives are described.
# 2
General Features of Pillar[5]arenes
2.1Discovery of Pillar[5]arene
Pillar[n]arenes are a new generation of macrocycles comprised of 1,4-dialkoxybenzene units linked by methylene bridges at para positions. They were discovered by serendipity by Ogoshi in 2008, and immediately attracted significant attention for their host–guest properties.[29] [30] Pillar[n]arenes and calix[n]arenes can both be considered as cyclic oligomers of para-substituted phenolic monomers, however, they differ in the positions of the methylene groups bridging the monomers.[26,31]
The first pillar[5]arene, DMpillar[5]arene, was obtained and characterized during an investigation into the synthesis of new phenolic resins via the reaction of 1,4-dimethoxybenzene with paraformaldehyde in the presence of a Lewis acid (Scheme [1]).[10]


The monomer, 1,4-dimethoxybenzene, has four electronically equivalent reaction sites (positions 2, 3, 5 and 6). Therefore, one of these reactive sites should react with formaldehyde to install a hydroxymethyl group on the benzene ring. After a series of condensation steps, linear polymers are formed and their NMR spectra proved the regioselectivity of the condensations.[29] Interestingly, by choosing appropriate reaction conditions, a new macrocyclic compound, DMpillar[5]arene, was obtained.[29] The discovery of this first pillar[5]arene was an essential starting point in the fascinating chemistry of pillar[n]arenes. Since then, pillar[n]arenes have become prevalent as they have opened new avenues in supramolecular chemistry.[32] Hence, the increasing interest in the chemistry of pillar[5]arenes can be mainly attributed to their unique advantages compared to other macrocyclic molecules, and which arise from their structural characteristics.[27]
# 2.2
Rim Functionalizations
Pillar[5]arenes are the most important members of the pillar[n]arene family (Figure [1a]).[33] [34] Interestingly, etherifications, esterifications, and oxidation reactions of the hydroquinone units ensure vast functionalization possibilities for pillar[n]arenes. In fact, the versatile functionalization of pillar[5]arenes has been exemplified in many studies, and has been already reviewed.[22,25,35]
# 2.3
Shape and Cavity of Pillar[5]arenes
1,4-Substituted phenols are key monomers for the synthesis of calix[n]arenes and pillar[n]arenes. Furthermore, they are connected by methylene bridges in both macrocyclic arenes.[27] The main structural difference is the position of the methylene bridges connecting the arene units. In pillar[n]arenes, the phenolic monomers are connected by methylene bridges at the para positions (positions 2 and 5), whereas the phenolic monomers in calix[n]arenes are linked through methylene bridges at the meta positions (positions 2 and 6), which results in different shapes (see Figure [1]). Calix[5]arenes have an asymmetrical calix-shaped structure when observed from the side and a cone shape when inspected from the bottom. In contrast, DMpillar[5]arene has a highly symmetrical hollow cylindrical structure.[36] Viewed from the top, DMpillar[5]arene appears as a pentagon.[36]
# 2.4
Pillar[5]arenes Possess an Electron-Rich Cavity
In pillar[5]arenes, the five hydroquinone units form a 4.7 Å π-electron-rich cavity.[30] [37] This allows the accommodation of a variety of suitable guest molecules, such as electron-deficient cationic guests and neutral linear molecules, eventually forming a stable complex.[38]
# 2.5
Planar Chirality of Pillar[5]arenes
Since the methylene bridges of pillar[5]arenes are sp3 hybridized, each hydroquinone unit can rotate along the axis of the methylene bridges.[39] [40] [41] The flipping of each unit can theoretically form 8 conformational isomers, including four pairs of enantiomers, and these conformations can interconvert under certain conditions.[42] However, not all of them are thermodynamically stable, and the preferred conformation depends on the type of substituent on the hydroquinones.[43] The conformational and planar chirality characteristics of pillar[5]arenes have been thoroughly addressed by Ogoshi et al.[36] [42]
In general, conformational isomers, in which at least one unit has a different orientation compared to the others, are unfavorable thermodynamically due to steric hindrance caused by the substituents on the hydroquinones, resulting in very short-lived states under normal conditions. Thus, the two most stable conformations in which all the arene units have the same orientations are enantiomers, identified as pS and pR, respectively (planar chirality). These observations have been further confirmed by theoretical calculations of the relative energies of the complete families of conformers.[44] Under certain conditions, the pS and pR conformers can interconvert with each other through the so-called oxygen-through-annulus rotation along the methylene bridges, preventing their separation. The prerequisite of isomer/enantiomer separations is thus to inhibit the rotation of the units, either by inserting a guest moiety in the pillar[5]arene cavity (rotaxane formation)[45] [46] or by introducing bulky substituents on one or several of the hydroquinones.[28,43] , [47–50]
# 2.6
Some Applications of Pillar[5]arenes in Chemical Biology
The convenience and variety of possible functionalizations of the two rims of pillar[n]arenes opens the way for the design of new architectures, topological isomers, and scaffolds, and offers a unique platform for biological purposes.[25] To date, pillar[5]arenes have been successfully applied in the fields of artificial membrane transport,[51] [52] [53] [54] drug delivery,[55–57] antibiofilm agents,[58] biosensors,[59] [60] [61] [62] [63] cell adhesion inhibitors,[24] [64] fluorescent sensing,[65] [66] [67] and pesticide detection.[68]
It is noteworthy that the multiple phenolic functions of pillar[5]arenes offer the possibility to link up to 10 ligands when both rims are functionalized, which may give rise to the so-called multivalent effect.[69] Multivalency most often results in a significant enhancement of the affinity of the multimer towards its biological targets, especially when the ligands have naturally low affinities, such as carbohydrates.[70] [71] The first evidence of a multivalent effect using a decaglycosylated pillar[5]arene was provided by our group.[72] Subsequently, other glycosylated pillars were generated and showed significant utility in chemical biology and medicinal chemistry.[24,73]
#
# 3
Synthesis of Functionalized Copillar[4+1]arenes
Shortly after the discovery of pillar[5]arenes, the search for methods allowing their selective functionalization quickly became an important synthetic objective, as it was evident that many applications of the resulting products would thus be enabled. Different synthetic strategies have been imagined, especially taking into account that a non-regioselective functionalization yields mixtures of constitutional isomers that are difficult to characterize.
One strategy to achieve regioselective bisfunctionalization of pillar[5]arenes is to differentiate the two rims of these macromolecules, as shown in A (Figure [2]).[20] [21] [22] A second strategy is to generate copillars B that display two different groups on the pillararene structure, in which at least one of the hydroquinone units bears distinct functional groups in comparison to the others.[23]
The synthesis of rim-differentiated pillar[5]arenes of type A usually results in low yields and separation difficulties. This is due to the inherent statistical nature of the cyclization of difunctionalized monomers that leads to the formation of four constitutional isomers.[74] For instance, the first rim-differentiated pillar[5]arene was synthesized by Ogoshi and co-workers using 1-ethoxy-4-methoxybenzene as the monomer, but this molecule could not be purified by standard silica gel chromatography.[39] Later on, Huang and co-workers successfully prepared and separated a rim-differentiated pillar[5]arene using 1-butoxy-4-methoxybenzene as the monomer and BF3O·Et2O as the Lewis acid, however, the yield was only 6% (Figure [3a]).[75] Recently, a preoriented synthetic protocol using a FeCl3-catalyzed cyclization of a heterosubstituted 2,5-dialkoxybenzyl alcohol was developed and applied to synthesize rim-differentiated pillar[5]arenes in yields of around 20%, as determined by HPLC (Figure [3b]).[74] [76] Such a method was very recently exploited for generating rim-differentiated copillararenes (see the previous section).[77]


As pillar[n]arenes have a central cavity, non-covalent assembly can also be exploited as a synthetic strategy to generate structures with several functional groups and with a controlled topology. For instance, the use of rotaxanes C (Figure [2]) to construct hetero-multivalent scaffolds was reported by our group.[24] Pillar[5]arene have excellent host–guest properties, thus rotaxanes can be generated when a functionalized linear guest molecule is bound inside the cavity of the pillar[5]arene and then ligated with two bulky molecules.[47] [78] However, if the pillar[5]arene bears bulky substituents, it can be difficult to form a rotaxane as the steric hindrance of the substituents may shield the cavity.
A third strategy consists of differentiating at least one of the hydroquinone units in the pillar core, thus generating copillar[n]arenes. Synthetic protocols for the preparation of copillar[5]arenes have been intensively investigated and a variety of copillar[5]arenes have been generated in moderate to high yields.[25] More importantly, in most cases, these copillar[5]arenes can be separated by silica gel chromatography depending on the substituents present on the copillar[5]arene. In the following section, we will first detail some of the most important achievements in copillar[5]arene synthetic chemistry and then illustrate some of their applications.
3.1Copillar[5]arenes
In copillar[5]arenes, at least one of the hydroquinone units bears different functional groups in comparison to the others. Thus, based on the number of functional groups in the copillar[5]arene, mono-, di-, tri-, tetrafunctionalized copillar[5]arenes can be defined according to the nomenclature system that was first proposed by Ogoshi and co-workers in 2011 (Figure [4]).[79] When the number of functional groups increases, the preparation of copillar[5]arenes is progressively more difficult due to all the possible constitutional isomers that can form. For instance, difunctionalized pillar[5]arenes have five isomers, and trifunctionalized pillar[5]arenes count 10 isomers.


Two main synthetic strategies have been proposed in the literature to prepare copillar[5]arenes in a selective manner. These two strategies are briefly described in the next paragraph.
# 3.2
Strategies to Synthesize Copillar[5]arenes
The first method to construct copillar[5]arenes is via post-functionalization of pre-formed pillar[5]arenes.
3.2.1Selective Modification of Homopillararenes
Hydroquinones are highly reactive compounds that can be engaged in etherification, esterification and oxidation reactions to obtain a wide range of derivatives.[34] Moreover, the transformation of the 1,4-dialkoxybenzene units of homopillar[5]arenes into phenols or hydroquinones may provide intermediates that allow a large variety of modifications. Along these lines, Ogoshi and co-workers initially developed mono-deprotection methods for the synthesis of mono-functionalized copillar[5]arenes.[80] In this work, 0.9 equivalents of the Lewis acid BBr3 was used to mono-demethylate DMpillar[5]arene (B1) to generate a single phenol unit that could be used for further functionalization (Scheme [2]). This pioneering methodology resulted in a reproducible and controllable 22% yield. The resulting monohydroxy pillar[5]arene was readily converted into copillar[5]arene B3 by etherification.[81]


While there is only one constitutional isomer in mono-functionalized pillar[5]arenes, five are possible when two functional groups are introduced into a homopillar[5]arene by a Lewis acid promoted deprotection. An initial difunctionalized pillar[5]arene was obtained by using AlBr3 as a Lewis acid to catalyze the cyclization to prepare DMpillar[5]arene.[79] However, the yield of the A1/B2 isomer was only 4%. When BBr3 was employed to produce dihydroxylated pillar[5]arenes, the A1/B1 and A1/C2 isomers were generated. Under optimized conditions, the A1/B1 and A1/C2 copillar[5]arenes could be separated by the ‘deprotection-followed-by-activation’ strategy proposed by Stoddart and co-workers (Scheme [3]).[82] The yields of B5 and B6 were 2% and 6%, respectively. In fact, Stoddart systematically investigated the effect of the amount of BBr3 and the reaction temperature on the deprotection reaction. They found that deprotection of the methoxy groups of DMpillar[5]arene with BBr3 occurred in a stepwise manner at low temperatures under kinetic control. When 4 equivalents of BBr3 were used and the reaction was carried out at –30 °C within 2 hours, followed by triflation, the trifunctional pillar[5]arenes B7 and B8 were obtained in yields of 20% and 7%, respectively.[82]
In addition to this Lewis acid mediated demethylation methodology, an oxidation followed by reduction strategy has also been developed.[25] Interestingly, this method can produce mono- and dihydroquinone-containing copillar[5]arenes, which is almost impossible by Lewis acid deprotection. In 2012, the Ogoshi[83] and Huang groups[84] independently reported the preparation of pillar[5]arenes containing one hydroquinone by oxidation of one pillar[5]arene subunit followed by reduction. Ogoshi and co-workers used 2 equivalents of the hypervalent iodine reagent PIFA to oxidize DMpillar[5]arene to afford copillar[5]arene B9, containing one benzoquinone unit in 26% isolated yield, along with B10 and B11 (Scheme [4]). The subsequent reduction of B9 by NaBH4 yielded bisphenol copillar[5]arene B12, which could be easily converted into a difunctionalized copillar[5]arene by etherification or esterification. A clickable copillar[5]arene B13 was thus obtained in 60% yield by reaction with propargyl bromide in the presence of NaH.
Following a similar oxidation/reduction sequence, Huang and co-workers employed one equivalent of (NH4)2[Ce(NO3)6] (CAN) to partially oxidize DMpillar[5]arene to give copillar[5]arene B9 in 30% isolated yield.[84] Subsequent reduction by Na2S2O4 quantitatively afforded the corresponding pillar[5]arene B12 (Scheme [4]).
Importantly, copillar[3+2]arenes could also be synthesized through this strategy. As shown in Scheme [4], copillar[3+2]arenes displaying two hydroquinones at the A,B- (B10) and A,C-positions (B11) were produced and isolated in 0.3% and 2.2% yields, respectively. Using CAN as the oxidizing agent, the yield of the copillar[5]arene B9 increased to 16%. However, the yield of the copillar[3+2]arene B11, with an A,C-dibenzoquinone, was less than 1%.[85] Meanwhile, Xue and co-workers[85] found that when DMpillar[4]arene[1]quinone B9 was utilized as the starting material the yield of the A,C type DMpillar[3]arene[2]quinone B11 could be increased to 42%. In contrast, by optimizing the amount of CAN, the reaction time and the reaction temperature, DMpillar[3]arene[2]quinone B11 could be obtained in 38% yield using DMpillar[5]arene as the starting material. Accordingly, by modifying the ratio of CAN, copillar[5]arenes containing tri- and tetra-benzoquinones were successfully prepared from DMpillar[5]arene.[86] A neat application of this ‘oxidation/reduction sequence strategy’ is the generation of complex copillar[5]arenes B15, B16 and B18 bearing three different types of aryl unit (Scheme [5]).[87] Furthermore, reduction of benzoquinones to hydroquinones and hydrolysis of methoxycarbonyl groups may provide a modular platform for their potential functionalization.






# 3.2.2
Co-oligomerization of Different Monomers
A co-oligomerization consists of generating a pillar[5]arene by mixing at least two distinct p-dialkoxybenzenes. In principle, the 1,4-dialkoxybenzene units can be symmetrical or they can bear 2 distinct alkyl groups. The latter strategy is interesting as it increases the complexity of the resulting macrocycle, but it generates de facto a more complex mixture of pillar[5]arenes, resulting in chromatographic separation challenges.


Co-oligomerization of two different 1,4-dialkoxybenzene monomers can yield mono-, di-, and tetra-functionalized copillar[4+1]arenes. Copillar[3+2]arenes are accessible using this strategy as well. Huang and co-workers first developed a co-cyclization methodology to prepare a copillar[5]arene using 1,4-dimethoxybenzene (DMB) as the key building block mixed with either 1,4-dibutoxybenzene (DBB) or 1,4-di(octyloxy)benzene (DOB).[23] When 4 equivalents of DMB, 1 equivalent of DBB, 5 equivalents of paraformaldehyde, and 5 equivalents of BF3·Et2O were stirred in 1,2-dichloroethane under a nitrogen atmosphere at room temperature for 4 hours, copillar[5]arene B19 was obtained in 16% yield (Scheme [6a]). However, after inverting the ratio of the two co-monomers, copillar[5]arene B23, containing 1 DMB and 4 DBB units, was obtained in only 9% yield. When DOB was used instead of DBB under the same reaction conditions, the copillar[5]arene B20 (containing 1 DOB and 4 DMB units) was generated in 27% yield. Furthermore, when the heterosubstituted monomer 1-methoxy-4-(octyloxy)benzene was co-oligomerized with DMB rather than DOB, the isolated yield of copillar[5]arene B21 dropped to 9% (Scheme [6a]). A similar yield of 10% of B22 was obtained when the non-symmetric monomer 1-(2-bromoethoxy)-4-methoxybenzene was co-cyclized with 5 equivalents of DMB, as observed by Stoddart and co-workers (Scheme [6b]).[47] These results show that co-oligomerization of different monomers is a practical method to prepare copillar[4+1]arenes, whilst the length of the aliphatic chains in the monomers does impact the yield.
To improve the selectivity and yields of copillar[5]arenes using a co-oligomerization strategy, Meier and co-workers[88] systematically investigated the relative ratio between the two monomers, and compared a variety of catalysts. They found that FeCl3 in CH2Cl2 as the solvent was an excellent system (Scheme [7a]). Using DMB and (6-bromohexyloxy)-4-methoxybenzene (2b) as the model monomer, the product distribution was first probed by adding 4, 8 and 16 equivalents of DMB.


If equally reactive, a 4:1 mixture of DMB and 2b should theoretically give the following product distribution: DMpillar[5]arene/B24/B25 = 45:5 × 44:10 × 43 from a statistical point of view.[88] This corresponds to a % distribution of 24% of DMpillar[5]arene, 30% of B24, and 15% of B25. The actual isolated yields were very close to this ratio, indicating that increasing the feed ratio of DMB should increase the yield of B24 and minimize the formation of by-products containing additional units of 2b. On increasing the feed ratio to 16 equivalents, the isolated yield of B24 was 85% (calculated based on the feed amount of 2b) (Scheme [7a]). Under these reaction conditions, a series of new copillar[5]arenes was synthesized in good isolated yields (Scheme [7b]). These investigations show that the feed ratio between two different monomers plays a crucial role in the formation of copillar[5]arenes. They also show that the type of catalysis (Lewis vs Brønsted) can also influence the outcome of these macrocyclizations. For instance, 10 equivalents of DMB were co-oligomerized with 1,4-bis(3-bromopropoxy)benzene to prepare a copillar[5]arene containing one 1,4-bis(3-bromopropoxy)benzene unit in the presence of BF3·Et2O, in a moderate 27% yield.[43] In addition to Lewis acids such as FeCl3 and BF3·Et2O, Brønsted acids that are commonly used in Friedel–Crafts chemistry have also been investigated to produce copillar[5]arenes.[89] TfOH was found to be an efficient catalyst that not only provided good yields for generating homopillar[5]arenes, but also copillar[5]arenes containing DMB and bromoalkyl-substituted 1,4-dialkoxybenzene units. When 5 equivalents of DMB were used, the yields of the corresponding copillar[5]arenes B22 and B32–B34 ranged from 9% to 21% (Scheme [8]). Inverting the relative ratio gave moderate yields (15% and 8%) of B35 and B36, respectively. Additionally, a ‘free-radical initiation and Friedel–Crafts alkylation process’ mechanism was proposed for the formation of pillar[5]arenes under the reaction condition.[89]
To date, a variety of copillar[4+1]arenes have been prepared with the co-oligomerization strategies mentioned above, and used for further applications.[25] Most of the known copillar[4+1]arenes prepared by co-oligomerization contain at least one DMB unit, whilst the other units are simple 1,4-dialkoxybenzene[23] [90] or bromoalkyl-substituted 1,4-dialkoxybenzenes,[43] [47] or mono or dimethoxycarbonyl methyl-substituted 1,4-dialkoxybenzenes.[91] [92] To the best of our knowledge, there is only one case of 1,4-mono- or dibenzyloxybenzene being used for a co-oligomerization to prepare copillar[4+1]arenes B37 and B38, which are ready for hydrogenolysis (Scheme [9]).[93]




As mentioned above, tuning the ratio between the two different monomers dramatically impacts the distribution of the formed copillar[5]arenes. The designed copillar[4+1]arenes have been generated in high yields by increasing the proportion of the monomer that contributes to four units in the product, thereby decreasing the formation of copillar[3+2]arene side products.[88] On the contrary, when the feed ratio of the two monomers is close, the trend is reversed. For instance, using 3 equivalents of DMB and 1 equivalent of 1,4-bis(4-bromobutoxy)benzene, the copillar[3+2]arenes B39 and B40 were both obtained in a reasonable isolated yields of 8%, especially when considering that the two repeating units can be connected in many distinct ways (Scheme [10]).


To improve the selectivity and yields of di- and tetrafunctionalized pillar[5]arenes, a step-growth cyclo-oligomerization strategy was developed by Ma.[94] In this method, dimers, trimers, and tetramers of 1,4-dialkoxybenzene were first synthesized and then co-oligomerized with another 1,4-dialkoxybenzene derivative to provide copillar[5]arenes B41–B43 (Scheme [11]). This multistep synthetic strategy significantly decreases the probability of forming constitutional isomers and other by-products.
In summary, a variety of copillar[5]arenes with different functional groups such as bromides, alkynes and carboxylic acids have been successfully developed based on the post-modification of preformed pillar[5]arenes and by co-oligomerization of different monomers. The introduction of different repeating units into pillar[5]arenes largely changes their physical properties, conformations, host–guest properties and further extends their application potential.[25]
#
# 3.3
Applications of Copillar[5]arenes
As host molecules, pillar[5]arenes can accommodate many kinds of guests, including neutral molecules that can be stabilized by the formation of multiple CH/π-interactions between C–H moieties and the π-electron-rich pillar[5]arene cavity.[27] Therefore, copillar[5]arenes containing long alkyl chains may self-assemble to form polymers by multiple self-inclusion phenomena, where the long alkyl chains act as guest molecules.[90] [95] [96] For instance, Wei and co-workers[97] found that copillar[5]arene B44, containing 1,4-bis(dodecyloxy)benzene, was able to form a supramolecular polymeric gel by a self-inclusion process in acetonitrile (Figure [5a]). Moreover, the supramolecular polymeric gel displayed reversible gel–sol phase transitions upon heating and cooling. These transparent films have potential applications in the field of anti-acidic rain materials.[97] Later, the same group discovered that copillar[5]arene B36 produces blue fluorescence because it easily forms [c2]daisy-chain dimers by self-assembly in solution.[98] This copillar[5]arene exhibited high selectivity and sensitivity towards iron and forms a Fe3+ complex. This complex was further utilized to sense F– and was shown to act as a fluorescence ‘on–off–on’ sensor (Figure [5b]).
3.3.1Monofunctionalization of Copillar[4+1]arenes




Copillar[5]arenes, with a controlled number and localization of phenolic groups, are important intermediates because their etherification with alkyl halides in the presence of appropriate bases can afford various functionalizing pathways. As detailed above, two main approaches have been developed to generate phenol groups, including selective deprotection or a redox sequence.[100] For example, Cao et al.[81] reported a copillar[5]arene B46 with one phosphoryl group, prepared by phosphorylation using a chlorophosphate followed by a deprotection (Scheme [12a]). The phosphorylated copillar[5]arene can form stable 1:1 host–guest complexes with alkanols in CDCl3, which may find potential application in their selective separation. Similarly, pillar[5]arene B47, with one propargyl moiety, was obtained by etherification of the same mono-hydroxylated pillar[5]arene with propargyl bromide. The mono-alkyne copillar[5]arene B47 is a useful key compound for the construction of an azobenzene-bridged pillar[5]arene dimer (Scheme [12b]).[101] Interestingly, this dimer can further be used for photoreversible switching between assembly and disassembly of a supramolecular polymer, the control of which by a photo-stimulus may be useful in a variety of applications (Scheme [12b]).


Co-pillar[5]arenes containing bromoalkyl-substituted units are conveniently produced by co-cyclization of one or two bromoalkyl-substituted 1,4-dialkoxybenzenes with the other monomer. The resulting primary bromide can be easily converted into an azide, an amine or a thiol, dramatically expanding the scope of the application of copillararenes.[102] For instance, once converted into azides, a Huisgen alkyne–azide 1,3-dipolar cycloaddition (CuAAC reaction) can be applied for structure diversification (Scheme [13a]).[47] [103] [104] Zhao and co-workers found that the functionalized pillar[5]arenes B51a–d could be assembled into thermo-responsive fluorescent vesicles that can potentially be used as thermo-responsive fluorescent sensors and drug delivery vehicles (Scheme [13b]).[105]
Copillar[5]arenes substituted with a single ester can be prepared either through etherification of the corresponding mono phenol B2 or by co-oligomerization of two different monomers.[106] The ester group can be hydrolyzed to a carboxylic acid and then coupled with various functional groups (Scheme [14]). Using this strategy, Ghosh et al.[91] synthesized the copillar[5]arene-rhodamine conjugate B54 as a selective sensor for Hg2+ ions. Han and co-workers[107] developed a copillar[5]arene B53b with two carboxylates that could serve as a host molecule for alkyldiamines and formed stable host–guest complexes (Scheme [14a]). The formation of the complexes is driven by the cooperativity of electrostatic interactions, multiple C–H…π interactions, and hydrogen bonds. This specific new recognition motif outlines the wide range of applications derived from this class of molecules in various fields, including supramolecular polymers, nanoelectronics, sensors, and drug delivery systems.
Recently, Meguellati and co-workers[92] synthesized the bidentate bispyridyl-hydrazone-functionalized copillar[5]arene B56, which can self-assemble through strong intermolecular hydrogen bonds (Scheme [14b]). This self-assembly generates size-controllable vesicles, with the synergistic interactions of intermolecular hydrogen bonding and internal amphiphilicity. These vesicles are responsive to pH, temperature and solvent. Notably, B56 can form a bidentate metal–ligand-coordinated complex with zinc trifluoromethanesulfonate resulting in a new rectangular cavity containing hexacoordinated zinc ions complexed between two adjacent B56 molecules. Such a system may be used for the controlled release of valuable compounds, in nanocatalysis, as artificial metalloenzymes, and as multitopic ligands for bivalent metals.
# 3.3.2
Multiple Functionalizations of Copillar[4+1]arenes
As mentioned above, pillararenes are interesting scaffolds for the preparation of heteromultivalent structures, which can be exploited to probe complex biological phenomena.[24] Heteromultivalency is met when at least two structurally distinct ligands are present on a central scaffold, preferably in a topologically controlled manner.[108] [109] [110] [111] Copillararenes are thus ideal tools for selectively generating heterovalent multimers in a controlled manner. Heteromultivalency can also be achieved by exploiting the cavity of the copillar to generate rotaxanes.[24]




To achieve this goal, our group developed a methodology to generate copillar[4+1]arenes[112] using the co-oligomerization protocols reported in the literature.[23] [113] 1,4-Bis(2-bromoethoxy)benzene (3b)[89,114] was selected as a key building block to co-oligomerize with a range of p-dialkoxybenzenes bearing different functional groups. The co-oligomerizations were realized using BF3·Et2O as the catalyst and dichloroethane (DCE) as the solvent. It was found that the efficiency of the copillar[4+1]arene formation was extremely sensitive to the structures of the two p-alkoxybenzenes.


The best building block for the co-oligomerization with 3b was bis-alkyne 3c, thus opening the possibility for generating clickable copillararenes. The co-oligomerization was extensively optimized (nature of the activator, solvent, temperature, relative proportions of the two hydroquinone units, etc.) to give a general protocol allowing the synthesis of copillars B57 and B58 in yields of 40% (Scheme [15]).


With copillar[4+1]arene B58 in hand, octamannosylated copillar[4+1]arene B59 could be efficiently assembled via a Cu-catalyzed Huisgen cycloaddition followed by an azidation. d-Mannose was selected because its multimers are competitors of infections by major bacterial and viral human pathogens.[115] [116] [117] [118] [119] [120] The versatility of this strategy was demonstrated by the synthesis of a family of mannosylated copillar[4+1]arenes functionalized with carbohydrates, fluorescent probes, an amino acid, or functional groups commonly used in chemical biology such as biotin, maleimides and boronic acids (Scheme [16]).
These results demonstrated that both copillar[5]arenes B57 and B58 are suitable as heteromultivalent scaffolds.
# 3.3.3
Further Functionalizations of Heteroglycoclusters
Moreover, we wished to demonstrate that copillararene B60c, bearing two Fmoc-protected amino acids and 8 peracetylated mannosides, could be further functionalized by exploiting an orthogonal deprotection and peptide coupling to yield B61 (Scheme [16]).[112] Such a structure bearing a cyclooctyne is interesting in chemical biology as many applications of cell engineering require copper-free reactions.[121] [122]
Interestingly, after the total deacetylation of B60f, the resulting deprotected fluorescent glycocluster displayed good water solubility, which is not always the case for typical pillararenes. This opens potential applications as fluorescence probes, for instance to follow interactions with bacteria or viruses during an infection process.


In addition, the same group[112] demonstrated that these advanced copillar[4+1]arenes maintain host–guest properties by synthesizing the fluorescent rotaxane C1 (Scheme [17]). Compound C1 features two distinct carbohydrates (l-fucose on the axle and d-glucose on the two rims of the pillararene), whilst the fluorescent character is provided by the dansyl groups selectively grafted thanks to the copillar structure.[112]
Such advanced copillararenes are now being assayed for diverse biological applications including bacterial biofilm eradication.[123] They are also being studied for applications in antivirulence,[124] [125] [126] as antibiofilm agents and for multivalent enzyme inhibition.
Finally, we wish to illustrate this section with the recently published study of Sue, Zhao and co-workers.[77] These authors pushed the limits of this field in their work describing the first methodology for the synthesis of rim-differentiated copillar[4+1]arenes B63x (Scheme [18]). These molecules were obtained in yields of around 10%, as expected considering the inherent synthetic methodology described above.[74] However, the presence of the five terminal alkynes on a single rim offers many additional perspectives through click functionalizations.


#
#
# 4
Concluding Remarks
In less than 15 years, pillararene chemistry has witnessed a major expansion, not only in terms of the development of specific synthetic methods but also in the broad area of applications, spanning from materials science to medicinal chemistry. Even more recently, copillararenes have been recognized as unique members of this growing family as the differentiation of at least one of the hydroquinone subunits of pillararenes dramatically enhances the structural diversity, and thus the areas of application of these molecules. From a purely synthetic point of view, many questions and challenges in copillararene chemistry are still to be addressed, especially regio- and stereoselectivity issues. This short review has mainly focused on copillar[4+1]arenes, but we can foresee that new and efficient methods will have to be developed for the synthesis of copillar[3+2]arenes. Furthermore, beyond pillar[5]arenes, many aspects of pillar[6]arene synthetic chemistry and their copillars remain to be explored.
#
#
Conflict of Interest
The authors declare no conflict of interest.
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Corresponding Author
Publication History
Received: 21 March 2022
Accepted after revision: 05 April 2022
Article published online:
30 May 2022
© 2022. Thieme. All rights reserved
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