Functionalized pillar arenes

We have introduced a nomenclature system for identifying the functionalizing position in pillar[n]arenes. The numbers and letters refer to the upper/lower rims and unit positions of the pillar[n]arenes, respectively. Mono-, di-, tetra-, penta- and per-functionalized pillar[5]arenes have been obtained to date. In the case of pillar[6]arenes, mono-, di- and per-functionalization have been achieved. Mono- and per-functionalized pillar[ ]arenes have only one constitutional isomer. Therefore, synthesis of mono- and per-functionalized pillar[ ]arenes is relatively easy. However, multi-functionalized pillar[n]arenes have many conformers. For example, di-functionalized pillar[5]arenes have five possible conformers (A1/B2, All Cl, A1/A2, Al/Bl and A1/C2). The number of possible conformers increased as the number of the functional groups increased the tri-functionalized pillar[5]arene has 10 constitutional isomers (Al/Bl/Cl, Al/Bl/Dl, A1/B1/C2, A1/B1/D2, A1/A2/B1, A1/A2/B2, A1/A2/C1, A1/A2/C2, A1/B2/C1 and A1/B2/D1). As the number of rings increased, the number of conformers also increased di-functionalized pillar[6]arenes have seven isomers (Al/Bl, Al/Cl, Al/Dl, A1/A2, A1/B2, A1/C2 and A1/D2), while di-functionalized pillar[5]arenes have five. Isolation of a particular constitutional isomer from a mixture is quite difficult, therefore position-selective functionalization based on the unique... 

Per-functionalized pillar[n]arenes have only one isomer, therefore their synthesis is relatively easy. One of the reliable routes for per-funetionalized pillar[ ]arenes is by using pre-formed reactive pillar[ ]arenes. Per-hydro ylated pillar[n]arenes having phenolic moieties at both rims are one of the useful key compounds for the synthesis of various functionalized pillar[ ]arene derivatives because phenolic moieties are highly reaetive. Removing the methoxy groups on the rim of pillar[5]arene (3.1) with Bfirg afforded a completely de-protected pillar[5]arene with 10 OH moieties (3.6) in quantitative yield (Scheme 3.1). ... 

The synthetic protocol for per-functionalized pillar[5]arene derivatives from per-hydroxylated pillar[5]arene can be applied to the synthesis of larger per-functionalized pillar[ ]arene derivatives. A per-hydro3tylated pillar[6]ar-ene with 12 phenolic moieties (3.7) was synthesized by Huang and Hou et al. (Scheme 3.3). 3.7 can be synthesized by de-protection of ethoty moieties (3.2) with BBts, which is the same method as used for the synthesis of per-hydrotylated pillar[5]arene. 

Fluorescence titrations (Fig. 13.12d,e) were subsequently carried out by adding small aliquots (5 jjlL, 17 mM, l lMeCN/H20) of various potential guests into a solution of pyrene-functionalized pillar-[5]arene(57.2 jxM, 1 1 MeCN/ H2O). The peak excitation X (355 nm) was used, and the fluorescence intensity was monitored at the peak mission X (395 nm). The association constant between the guests and pyrene-functionalized pillar-[5]arene was calculated using the software Dynafit [106], which is based on nonlinear least-sqnaies regression analysis. 

Compared with other typical host molecules, one of the important advantages of pillar[n]arene chemistry is the versatile functionality. A wide variety of multi-functionalized pillar[n]arene derivatives, which are difficult to obtain using other typical macrocyclic platforms, can be synthesized in moderate yields. To date, pillar[5]- and pillar[6]arenes, containing five and six repeat units, respectively, have mainly been used because they can be obtained in relatively high yields by a one-step reaction (details in Chapter 2). Pillar[5]- and pillar[6]arenes have 10 and 12 substituents, respectively. Figure 3.1 shows the assignment of positions in pillar[5]- and pillar[6]arenes. ... 

Scheme 3.2 shows per-functionalized pillar[5]arene derivatives prepared from per-hydro)ylated pillar[5]arene 3.6 as a starting compound. Applying an efficient organic reaction is required for the perfect introduction of functional groups at all 10 reaction sites. A straightforward and efficient functionalization process for per-hydroxylated pillar[5]arene is etherification, which has been used for functionalization of the lower rims of phenolic moieties in calix[ ]arene derivatives. Various functionalized pillar[5]arene derivatives can be obtained by etherification of per-hydroxylated pillar[5]-arene with an alkyl-halide in the presence of appropriate bases, such as NaH and K2CO3. Introduction of the substituents can change various physical... 

Scheme 3.2 Synthesis of per-functionalized pillar[5]arene derivatives from preformed per-hydro3q lated pillar[5]arene.

The introduction of substituents can change the conformational flexibility of pillar[n]arenes modification of the bullq substituents of the cyclohex-ylmethyl moieties by etherification (3.20) leads to inhibition of the rotation units, and enables the separation of pillar[5]arene enantiomers (see Chapter 4 for details). Various functional pillar[5]arenes can be produced from per-hydrojq lated pillar[5]arene 3.6 by modification of various functional groups. 

Scheme 3.3 Synthesis of per-functionalized pillar[n]arene homologs (nS6) from pre-formed per-hydro5g lated pillar[n]arenes.

We synthesized various functionalized pillar[5]arenes by the CuAAC reaction between decaall nes 3.21 and azides (Scheme 3.4). Reactions of the clickahle decaalkyne 3.21 with hoylazide, henzylazide, phenylazide and pyrenylazide afforded functionalized pillar[5]arenes with 10 hexyl (3.32), henzyl (3.33), phenyl" (3.34) and pyrenyl moieties (3.35), respectively. Zhao et al. reported hiocompatihle pillar[5]arenes with amphiphilic oligoethylene glycol chains (3.36 and 3.37) hy a CuAAC reaction between 3.21 and... 

Scheme 3.4 Synthesis of per-functionalized pillar[5]arenes from per-ethylated pillar[5]arene via CuAAC reaction.

Reaction of 3.40, 3.41, 3.43 or 3.51 with 1-methylimidazole, pyridine, amine " and tributylphosphine afforded cationic pillar[5]- and pil-lar[6]arenes (3.52-3.56). A pillar[5]arene with 10 ionic liquids (imidazolium cations 3.53) was produced in the liquid state at 25 °C by choosing an appropriate counter anion. A pillar[5]arene with 10 phosphonium cations (3.56) is amphiphilic and acts as a substrate-selective phase-transfer catalyst. Oxidation of linear alkane 1-hexene to 1-pentanal by KMn04 vwis >99%, whereas that of the branched alkene, 4-methyl-l-hexene, was only 31%, even under ideal conditions. An etherification reaction between an allqrl-halide and phenolic compounds is a good method to synthesize functionalized pillar[5]arene. Etherification of pillar[5]arene containing 10 bromide with a coumarin derivative with a phenolie moiety gave a pillar[5]arene eanying 10 coumarin moieties (3.57) 3.57 aeted as a fluorescence sensor for methyl parathion. Pillar[5]- and pillar[6]arenes with 10 and 12 bromide moieties should be good key compounds for the synthesis of various functionalized pillar[5]- and pillar[6]arenes. 

There are two different approaches to synthesizing mono-functionalized pillar[n]arenes co-cyclization of different monomers, and mono-deprotec-tion and functionalization of pre-formed pillar[n]arenes. Stoddart et al. reported formation of a pillar[5]arene with one bromide moiety (3.51) by eo-cyclization of dialko)ybenzene derivatives (Scheme 3.7). ... 

Scheme 3.6 Synthesis of per-functionalized pillar[5]- and pillar[6]arenes from pillar[5]- and pillar[6]arene with 10 and 12 bromides via etherification and cationation.

Wang and co-workers used the mono-bromide 3.58 as a key compound to construct a pillar[5]arene-based supramolecular assembly. The monobromide 3.58 was substituted with an amino group by Gabriel synthesis. A mono-ureidopyrimidinone-functionalized pillar[5]arene (3.65) was synthesized from the mono-amine 3.64. 3.65 formed a supramolecular dimer by a quadruple hydrogen bond between ureidopyrimidinone moieties, and addition of a bisparaquat derivative afforded supramolecular polymers at high concentration. 

Zhou et al. synthesized the mono-functionalized pillar[6]arene 3.72 by etherification between excess pillar[6]arene with 12 bromides (3.43) and a naphthalene derivative with one phenolic moiety. The other 11 bromides remained unreacted, therefore other functional groups could be installed. A cationic water-soluble pillar[5]arene (3.73) was synthesized with one naphthalene and nine trimethylammonium bromide moieties by a cationation reaction between the 11 bromides and trimethylamine (Scheme 3.9). 

Scheme 3.8 Synthesis of mono-functionalized pillar[n]arenes and pillar[5]arene dimer from pillar[5]arene with one phenolic moiety.

There is only one conformational isomer in the per- and mono-functionalized pillar[5]- and pillar[6]arenes. However, pillar[5]- and pillar[6]arenes with two functional groups afford various constitutional isomers di-func-tionalized pillar[5]- and pillar[6]arenes have five (A1/B2, Al/Cl, A1/A2, Al/Bl and A1/C2) and seven isomers (Al/Bl, Al/Cl, Al/Dl, A1/A2, A1/B2, A1/C2 and A1/D2), respectively. Therefore, new synthetic strategies are required for their synthesis. First, di-functionalized pillar[5]arene was obtained by chance. ... 

The reaction of 1,4-dimethoxybenzene and paraformaldehyde with AlBrs afforded multiple-deprotected pillar[5]arenes. The deprotection reaction took place concurrently with cyclization (Scheme 3.10). A regioselective di-protected pillar[5]arene at the A1/B2 positions (3.74) can be isolated by silica gel chromatography and washing with methanol. The other method for the synthesis of di-functionalized pillar[5]arenes is co-cyclization (Scheme 3.11). First, co-pillar[5]arenes were synthesized by Huang and... 

Synthesis of A1/A2 di-functionalized pillar[5]arenes by the co-tycliza-tion method. 

Wang and co-workers synthesized a reactive di-bromo-functionalized pillar[5]arene by co-cyclization of l,4-bis(2-bromoetho>y)benzene with DMB. The two bromide moieties on pillar[5]arene 3.78 were converted to amino moieties 3.79 by Gabriel synthesis. Using the diamine 3.79 as a key compound, di-ureidopyrimidinone (3.80) and di-urea (3.81) functionalized pillar[5]arene derivatives were prepared. 

Stoddart and co-workers synthesized the di-bromo-functionalized pillar[5]arene 3.82 by co-cyclization of l,4-bis(3-bromopropoxy)benzene with DMB. Elimination of bromide moieties afforded diallyl ether-substituted pillar[5]arene 3.83. De-protection of the allyl moiety afforded Al/A2-di-hydrojgrlated pillar[5]arene 3.84. Reaction of 3.84 with triflic anhydride gave a ditriflated pillar[5]arene (3.85). A ter-phenyl substituted pillar[5]arene (3.86) was prepared by Pd-catalyzed Suzuki coupling between ditriflated... 

The co-cyclization of different monomers represents a useful approach for the synthesis of functionalized pillar[5]arenes by a one-step reaction. However, this method cannot be applied for the synthesis of functionalized pillar[6]arenes because pillar[5]arenes are obtained as major products when dichloroethane is used as solvent. We found that chlorocyclohexane is a useful guest solvent for the synthesis of pillar[6]arenes (details in Chapter 2), therefore we synthesized a co-pillar[6]arene by co-cyclization of l,4-bis(methylcyclohe grl)benzene and l,4-bis(4-bromobut03gr)benzene. A co-pillar[6]arene (3.90) was obtained in a yield of 9% along with a homo-pillar[5]arene (3.20 yield 1%) and a homopillar[6]arene (3.91 yield 8%). 

The bromide moieties on 3.90 could be changed to clickable azide moieties, thus 3.90 was used as a key compound to synthesize A1/A2 di-functionalized pillar[6]arenes (Scheme 3.14). 

Another new route for the selective synthesis of di-functionalized pillar[5]arenes is oxidation and reduction of pillar[n]arene units (Scheme 3.15). Our group and Huang s group reported that the oxidation of one pillar[5]arene unit afforded pillar[5]arenes containing one benzo-quinone unit (3.92 and 3.93). Reduction of the benzoquinone unit yielded di-hydrojylated pillar[5]arenes at the A1/A2 positions (3.84 and 3.95). This method avoids the formation of many constitutional isomers and can be used for pillar[5]arenes with one benzoquinone and two hydro)q l groups at the A1/A2 positions. A clickable di-functionalized pillar[5]arene was prepared by modification of the alkyne moieties. The A1/A2 di-all e... 

Functionalized Pillar[5]arenes with More Than Three Different Substituents... 

Penta-functionalized pillar[5]arenes can be prepared from non-symmetrical monomers with reactive moieties (Scheme 3.19). Huang et al. synthesized a pillar[5]arene with five allq nes on the same rim (3.116). A CuAAC reaction between 3.116 and a naphthalene containing an azide... 

Based on the various organic synthetic methods, mono-, di-, tetra-, penta- and per-functionalized pillar[n]arenes have been obtained. The high solubility of pillar[n]arenes in different organic media enables their functionalization by various organic reactions. Although several methods of functionalization have been uncovered, new functionalization methods based on organic reactions should appear in the near future. A combination of different functionalization methods should lead to the synthesis of multi-functionalized pillar[n]arenes. In addition, their highly symmetrical structure makes characterization of multi-functionalized pillar[n]arenes easy, whereas characterization of multi-functionalized macrocycles based on the typical host molecules is quite difficult. Therefore, pillar[n]arenes are truly versatile macrocyclic compounds. Their versatile functionality is one of the... 

Scheme 3.19 S)nithesis of penta-functionalized pillar[5]arene from a pillar[5]arene with five ethynyl groups, at Al, Bl, Cl, D1 and El.

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