Trimeric and hexameric calixarene-based capsules

In this paper trimeric and hexameric capsules are presented. In the first section trimeric calixarene-based capsules are described, they are followed by trimeric cavitand-based capsules. In the second section hexameric resorcinarene-based capsules are characterized; moreover two examples of covalently bound hexameric cavitand-based capsules are shown.


Introduction
Calixarene-based capsules are a topic of numerous reports; so dimeric capsules [1][2][3][4][5] as well as species of higher multiplicity [6][7][8][9] are intensively studied due to their interesting properties and application possibilities.Calixarene-based capsules of higher multiplicity are mainly trimeric and hexameric species, albeit tetrameric and octameric compounds are also known. 10,11An attention is paid now to nanotubes, 12,13 this theme however is not described here.

Trimeric capsules
Trimeric capsules, i.e. trimers consisting of three calixarene or cavitand units are held together by weak noncovalent interactions.First, the examples of calixarene-based trimeric capsules will be presented, followed by examples of cavitand based trimeric capsules.
The introduced functionalities affect the thermodynamic stability of 5, and 6.For example, hydrogen bond donating or accepting groups interfere with the existing hydrogen bonding, and bulky groups cause a steric hindrance decreasing the thermodynamic stability of 5, and 6.It was observed that 5, and 6 containing n-alkyl groups are more stable than those bearing more polar aminoalkyl or pyridyl groups.The stability of 5, and 6 decreases in the order of alkyl groups present: 1a > 1b > 1c since their increased branching results in a higher steric hindrance.
It should be pointed out that the stability of 5, and 6 containing ureido groups is the highest as compared to those bearing n-alkyl, aminoalkyl and pyridyl functionalities due to the formation of extra hydrogen bonds of ureido groups with the triazine units.

Scheme 1
The self-assembly via hydrogen-bond formation is useful for preparation of liquid-crystalline materials. 33,34It was observed that calix [4]arene 7 and B or C self-assemble spontaneously upon mixing in apolar solvent to give the mesogenic trimeric capsules 7 3 •B 6 or 7 3 •C 6 which are thermodynamically stable.The trimeric capsule 7 3 • B 6 shows lower thermal stability than 7 3 • C 6 , since melamine forms weaker hydrogen bonds with barbiturates than with cyanurates.The melamine units of 7 are functionalized with octadecyl groups to promote the selforganization of the trimeric capsules into a liquid-crystalline phase.The long substituents of benzamide moieties of 7 prevent their interference with hydrogen bonding network which holds the double rosette together.
The trimeric capsules form columns, which assemble into columnar liquid-crystalline mesophases of a high degree of order and of a considerable thermal stability.It is noteworthy that the liquid-crystalline phase is observed for the trimeric capsule assemblies, even though none of the isolated building components is mesogenic.The driving force for the self-assembly of columns is the nanoscale segregation of the double rosette cores and the lipophilic alkyl chains.
It was found that the reaction of calixarenes 8-10 with C affords trimeric capsules 11 which may confine phenols 12, carboxylic acids 13 and carbohydrate derivative 14 serving as guests. 35rimeric capsules 11 are exo-receptors since their recognition sites are situated at the periphery, i.e. at the top and the bottom of the receptor; the encapsulation of six guest molecules affords inclusion complexes 15.The melamine units of trimeric capsules 11 bear ureido , amino and L-serine moieties to recognize phenols 12 a-c, carboxylic acids 13 a-c and carbohydrate derivative 14, respectively.The complexation was studied by 1 H NMR spectroscopy and ITC (isothermal titration calorimetry).
The complexation of calixarene 8 with p-nitrophenol 12a shows a 1:6 binding mode; single hydrogen bonding exists between all six ureido carbonyl groups of 8 and hydroxyl groups of 12a; with 12b and 12c however the 1:3 binding mode was observed: each guest molecule forms two hydrogen bonds with two urea moieties at the top and the bottom rosette of 11.
The complexation of calixarene 9 with carboxylic acids 13a-c shows the 1:6 binding mode; inclusion of these guests involves hydrogen bonding between amino groups of the receptor and carboxylic groups of the guests.The complexation of 10 with n-octylgalactopyranoside 14 involves the formation of hydrogen bonds between the serine hydroxyl groups of the receptor and hydroxyl groups of the guest 14.The reaction of calixarenes 1 and 16-18 with B yields trimeric capsules 19; their complexation with hydrogen bonded trimers of anthraquinone derivatives 20-25 serving as guests was investigated. 36The driving force for the encapsulation of guest trimers leading to inclusion complexes 26 is the π-π stacking between melamine units of the host and the central ring of anthraquinone derivatives.
Trimeric capsules 19 and hydrogen-bonded alizarin trimer 20 3 form the inclusion complexes in which alizarin trimer 20 3 is encapsulated between the two rosette layers.The complexation of trimers of 21 and of 22 occurs in a similar way.It was observed that the presence of the carbonyl groups in the central ring and the presence of at least one hydroxyl group in the anthraquinone molecule are necessary for complexation.For this reason anthracene 23 and anthraquinone 24 do not form complexes; in the case of anthracene 23 both carbonyl and hydroxyl groups are lacking, and in anthraquinone 24 the hydroxyl groups are lacking.It should be noted that derivative 25 cannot be encapsulated due to steric reasons.It was found that dimeric calixarene 27a, b consisting of two calix [4]arene units linked by the Z spacer reacts with B to give tetrarosette 28 formed from two double rosettes linked by three Z spacers. 37arbiturate-based tetrarosettes 27 3 • B 12 i.e. 28 are spontaneously formed in apolar solvents such as benzene, toluene or chloroform when 27 is mixed with twelve equivalents of B at room temperature.The driving force for this self-assembly is the formation of 72 hydrogen bonds, i.e. 18 hydrogen bonds for each rosette.The above self-assembly process results in the formation of tetrarosettes with high kinetic stability; the dissociation of tetrarosette requires the disruption of 24 hydrogen bonds.
Cyananurate based tetrarosettes 37 3 • C 12 have been obtained by two methods: by mixing 37 and C derivatives in toluene and heating to 100 °C for one week (direct method) or by treatment of 37 with B and subsequent exchange by C derivatives (exchange method).
The amplification of chirality of tetrarosettes was investigated under thermodynamically controlled conditions.In the study of double rosettes 38 it was established that an important factor for the amplification of chirality is the dissociation rate of calixarenes 1.A lower dissociation rate constant leads to higher amplification of chirality, i.e. a larger optical activity with lower amounts of chiral component.
Tetrarosettes consist of two double rosettes.The dissociation of one dimeric calixarene 27 from tetrarosette requires the disruption of 24 hydrogen bonds, i.e. the dissociation rate constant is lower as compared to a double rosette, in which dissociation of one calixarene 1 unit requires disruption of only 12 hydrogen bonds.Therefore a higher amplification of chirality occurs in the case of a tetrarosette.
The difference in free energy between the M and P diastereomers of the tetrarosettes introduced by a chiral center is higher than in the case of double rosettes.This difference results from the lower dissociation rate constant of the calixarene 27 units than in the case of calixarene 1 units.
The extent of the chiral amplification depends on the structure of the tetrarosette; when the bisureido spacer of tetrarosette 28a was replaced by the more rigid m-xylene spacer to give tetrarosette 28b the amplification of chirality considerably decreased due to steric hindrance resulting from the presence of the rigid spacer.It was established that the degree of chiral amplification of the tetrarosette is not influenced by the method of its formation (direct or exchange method).
Tetrarosette 28a• B 12 undergoes complexation with six molecules of alizarin 20 in the form of two trimers which are hydrogen bonded; they are intercalated inside both double rosettes to give inclusion complex 29. 39Upon encapsulation large conformational changes in the host structure occur.It should be pointed out that the intercalation is highly selective.

Scheme 4
][45] It was established that the self-assembly of rigid cavitands 30 and 31 with platinum complex 32 affords platinum coordinated trimeric capsules 33 and 34. 46These supramolecular platinum complexes were characterized by 1 H and 31 P NMR spectroscopy and electrospray ionization mass spectrometry.

Scheme 5
One should also mention cavitand-based polymetallic assemblies containing Zn(II), Cd(II), Cu(II), Au(II), Ni(II) and Pd(II) ions; in these compounds the cavitand structures are functionalized with dithiocarbamate units.In dependence on stereochemical coordination preference of metals, the trimeric or tetrameric capsules 35 or 36, respectively, are formed.In the case of zinc (II) and cadmium (II) the trimeric capsules 35a-f are obtained, while for copper (II), gold (II), nickel (II) and palladium (II) the tetrameric capsules are formed; 47 the formulas of Cu(II) tetrameric capsules 36a-c are shown.
Both types of capsules form strong inclusion complexes with fullerenes C 60 and C 70 ; the cadmium capsule has proven to be the most suitable receptor for fullerenes.The strong binding of the above capsules with fullerenes results from the interaction of fullerenes with sulfur atoms of multiple dithiocarbamate moieties of the host systems.

Hexameric capsules
The synthesis of large spheroid capsules able to entrap different guest molecules is an important topic in supramolecular chemistry. 26The methods of their construction mainly involve selfassembly via hydrogen bonds or metal coordination. 25The bowl-shaped resorcin [4]arene and pyrogallol [4]arene macrocycles form large hexameric capsules, i.e. hexamers, by hydrogen bonding.Substitution of hydrogen atoms for metal ions results in structural preservation of hexameric structure, while introducing inorganic functionality.
In the study of hexameric capsules their guest affinity, tautomeric equilibria and isotope effects 7,8,26 were examined.It should be pointed out that the investigation of dimeric cylindrical capsules 14 is more detailed than that of hexameric capsules of resorcinarenes and pyrogallolarenes.
9][50] It should be pointed out that pyrogallol [4]arenes contain four additional upper rim hydroxyl groups, as compared with resorcinarenes; this fact results in a larger number of ARKAT USA, Inc.
hydrogen-bonding interactions in formed hexamers and, as a consequence, the higher stability than in the case of resorcinarene-based hexameric capsules. 50,51esorcinarenes and pyrogallolarenes form hexameric capsules in the solid state and in solution via a network of hydrogen bonds.Usually water molecules are involved to complete the hydrogen bond network of resorcinarene-based hexameric capsules, 49 while assembly of pyrogallolarenes does not require water molecules.In hexameric capsules solvent molecules often serve as guests. 48,52irst the hexamers formed from resorcinarenes and pyrogallolarenes are described, they are followed by two examples of covalently bound hexamers obtained from cavitands.In the study of guests exchange it was established that capsules act as mechanical barriers between guest and the bulk solution; for formation of a suitable opening for guest release the rupture of multiple hydrogen bonds is necessary.
Resorcinarene 37 forms in the presence of trialkylammonium salts 38 in water-saturated CDCl 3 the hexameric capsule 37 6 incorporating one 38 + Br -molecule.The remaining space in the hexamer cavity is occupied by coencapsulated solvent molecules, their number decreasing with the cation size of 38 + Br -.
The guest exchange requires the dissociation of one resorcinarene molecule from the hexamer.
It was observed that 38a + Br -and 38b + Br -share the cavity with three chloroform molecules, however in the case of 38c + Br -and 38d + Br -only two CHCl 3 molecules are coencapsulated, while 38e + Br -and 38f + Br leave place merely for one CHCl 3 molecule.The stability of considered inclusion complexes decreases in the case of larger cations and is anion-dependent, for example the inclusion complex 37•38e + Br -is more stable than 37•38e + •Cl -. 53 In investigation of inclusion complexes of hexamer 37 6 with glutaric acid 39, with 1,2-ciscyclohexanediol 40 and with L-phenylalanine 41, the in-out guest exchange rate constants were determined by an exchange (EXSY) NMR spectroscopy 54 .The resorcinarene 37 and an appropriate guest, or more than one guest in wet solvents is all that is required for formation of the hexameric capsule.The proper filling of space is of importance; optimal guests fill about half the available cavity themselves or together with additional solvent molecules.The hexamer 37 6 may confine even three different guests.
Resorcinarenes 42 form hexamers 42 6 ⋅(H 2 O) 8 held together by an array of hydrogen bonds.It was found that the water molecules in 42 6 ⋅(H 2 O) 8 may be replaced by alcohols, such as (±) 2ethylhexanol (EH). 55esorcinarene 42a was crystallized from EH.It was observed that the crystals of 42a grown by evaporation from EH afford hexamer 42a 6 ⋅ (EH) 6 (H 2 O) 2 , in which three molecules of EH are included.The difference between 42a 6 ⋅(H 2 O) 8 and 42a 6 (EH) 6 (H 2 O) 2 is the fact that 42a 6 ⋅(H 2 O) 8 is chiral, whereas 42a 6 (EH) 6 (H 2 O) 2 is achiral.The replacement of some number x of the eight water molecules from 42b 6 ⋅(H 2 O) 8 by EH molecules affords 42b 6 ⋅ (EH) x ⋅ (H 2 O) 8-x along with x liberated water molecules.It should be pointed out that the all eight molecules of water cannot be completely expelled by EH from 42b 6 ⋅ (EH) x ⋅ (H 2 O) 8-x . 55t was observed that pyrogallolarene 43 undergoes a spontaneous self-assembly to give hexameric capsule 43 6 . 56For the solvent-free synthesis of 43 the dispersion of pyrrogallol and a catalytic amount of solid p-toluenesulfonic acid was treated with aldehyde and milled using a mortar and a pestle; this solvent-free procedure yields pyrogallol [4]arene 43.The self-assembly of 43 affords hexameric capsule 43 6 .
Pyrogallol [4]arene 44 forms the hexamer 44 6 of a large cavity which can serve as a nanoreactor; the behavior of solvent molecules within the cavity of 44 6 was investigated by different NMR techniques. 52t was found that 6-7 molecules of chloroform are enclosed in this hexamer.Using a mixture of benzene with chloroform as a solvent one could expect that at least some hexameric capsules 44 6 should contain only benzene or only chloroform, however it was not the case.The results of 1 H NMR spectroscopy have not indicated the presence of hexamer 44 6 enclosing only benzene, or only CHCl 3 , even in the presence of a large excess of benzene or CHCl 3 , respectively.It was shown that the benzene and chloroform co-encapsulation is preferred and that the larger molecular fraction of the so-called benzene / chloroform complex in 44 6 as compared with the bulk is indicated by a strong ASIS (aromatic solvent-induced shift) effect. 52esorcinarenes 45 and pyrogallolarene 46 form hexameric capsules.In the case of 45 the six resorcinarene units assemble with eight structural water molecules to give the near-spherical hexamer 45 6 , held by hydrogen bonding.In the case of pyrogallolarene 46, the formed hexamer 46 6 has more hydrogen bonds than 45 6 , therefore is more stable; it cannot assemble with water molecules. 57he anthracene derivative 47 was used as a fluorescent probe molecule for inclusion into hexamer 46 6 .It was observed that 47 crystallizes endo or exo to the 46 6 framework, the former mode being more frequent.In the case of endo-crystallization 47 is encapsulated in the hexamer; in the case of exo-crystallization the molecules of 47 intercalate between walls of neighboring hexameric capsules.Both crystallization modes result in highly different fluorescence emission, the fluorescence emission intensity of 47 in the case of endo-crystallisation being higher than for the free 47. 57 ARKAT USA, Inc. Formation of hexameric capsules from resorcinarenes 48, 49 and pyrogallolarene 50 has been investigated using MS methods.Cationic guests may template the capsule formation, as those 51-53 have been used. 58t was observed that the size, shape and symmetry of cationic guests serving as templates are very important in formation of hexameric capsules; the template properties of used cations decrease in the order 53>52>51 showing that 51 is too small for cavity of hexamers.In the case of 51 the dimeric capsule 51•50 2 and in the case of 52 the hexameric capsule 52•50 6 are formed.Modeling studies on the basis of X-ray crystallography for [53•50] 2+ have shown that 53 fits very well into the cavity of hexamer 50 6 .In this hexamer the periphery of a pyridine ring of 53 is ARKAT USA, Inc.
directed towards each of the six molecules of pyrogallolarene 50.The hexameric capsules formed from resorcinarenes 48, 49 and from pyrogallolarene 50 retain their structure even in the gas phase and do not rearrange during ionization indicating the stabilizing influence of suitable templating cationic guests. 58esorcinarenes and pyrogallol [4]arenes may form large spherical, metal coordinated hexamers in both solution and solid state.It should be pointed out that among metal coordinated capsules the dimeric capsules are more common than the larger ones.
It was found that the treatment of pyrogallolarene 54 with Cu(NO 3 ) The hexamer 55 is held together by combination of metal-ligand coordination and of hydrogen bonding; it may be viewed as an octahedron 58 in which eight faces are capped by 8 six-membered [Cu 3 O 3 ] arrays.The hexamer 55 preserves the structural framework of hydrogen bonded hexamer 57 and has similar dimensions.This structural preservation enables the interchangeability of a desired function; the hydrogen-bonded hexamers are preferred when reversible encapsulation is necessary, whereas metal coordinated ones are more rigid and stable.
It should be pointed out that 24 hydroxyl groups localized at the periphery of 55 can act as recognition sites.In the solid state, these periphery hydroxyl groups connect to adjacent hexameric capsules 55 via copper-hydroxyl coordination. 59t was found that treatment of pyrogallol [4]  O 3 ] arrays 61, situated on four faces of octahedron. 60he results of X-ray analysis show that 60 consists of 18 components: 6 pyrogallol The two next examples concern covalent capsules obtained by dynamic covalent chemistry.It is noteworthy that dynamic covalent chemistry is very convenient for syntheses of complex molecules.[61][62][63] In the first example the cavitand 62 derived from pyrogallolarene was a starting material.The benzylation of two adjacent hydroxyl groups of 62 leads to cavitand 63.The subsequent cyclization of 63 with bromochloromethane affords hexabenzylated trimer 64, which was debenzylated by hydrogenation to give hexahydroxyl trimer 65.The bridging of 65 with bromochloromethane in the presence of DMSO yields hexameric capsule incorporating seven DMSO molecules as guests, i.e. 66•(DMSO) 7 .64 It should be pointed out that this is a very large carceplex which is a covalent analogue of noncovalently bound pyrogallolarene hexamers.
The Template ratios for competing seven-molecule templates in the formation of 66⋅ (DMSO) x ⋅ G (7-x) for reactions in DMSO/G (G = DMF or DMA) were evaluated.The high selectivity of DMSO over DMF or DMA was found.For 66⋅ (DMSO) x ⋅ G (7-x) the templating ability for seven-molecule templates increases with the number of encapsulated DMSO molecules; carceplexes with four or more DMF or DMA molecules were not even observed.It should be pointed out that for such a large container, and for guests of similar shape and polarity, this selectivity is very high. 64n the second example the tetraformyl cavitand 67 was a starting material.It was observed that one-pot reactions of 67 with ethylene 1,2-diamine 68 lead to covalently bound capsules of a different shape, in dependence on the kind of solvent; in THF the tetramer 69, in CHCl 3 the hexamer 70 and in CH 2 Cl 2 the octamer 71 are formed 10,11 .Octamer 71 is a square antiprismatic capsule in which each cavitand occupies one of the eight corners 11

Scheme 9
It should be noted that linear oligomers or 2D sheets are not formed. 65,66Reduction of all imine bonds in 69-71 with NaBH 4 in the presence of trifluoroacetic acid yields covalently bound capsules 72-74, respectively, isolated as trifluoroacetate salts.

Conclusions
In this article selected examples of trimeric and hexameric calixarene-based capsules are presented.][69][70] The above review, albeit presenting only chosen examples of trimeric and hexameric capsules highlights to some extent their formation and properties which are promising for their applications.
arene 59 with Ga(NO 3 ) 3 •H 2 O in a mixture of acetone and water results in a self-assembly affording large metal-coordinated hexameric capsule 60, i.e.Ga 12 (H 2 O) 24 (C 40 H 42 O 12 ) 6 ⊂(acetone) 8 (H 2 O) 6 ] held together by four slightly curved [Ga 3 NMR data and MM2 calculations indicate that 66•(DMSO) 7 has a slightly flattened, non symmetric structure; it reversibly complexes water molecules to give 66•(DMSO) 7 • (H 2 O) x ; x is not known.The host may entrap larger guests (e.g.DMSO) permanently and smaller guests (e.g.H 2 O) temporarily.Carceplex 66 •( guest) 7 shows a permanent entrapment of the largest number of guests for such a container.The formation of this carceplex is driven by a seven-guest template effect.The high selectivity for statistically unfavored seven molecule templates over templates with other molecularities involves the binding of one guest by each of the six bowls; in the centre of the formed cavity is a place for the seventh guest molecule.