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DOI: 10.1002/ijch.201100056

Supramolecular Capsules Derived from Resorcin[4]arenesby H-Bonding and Metal Coordination: Synthesis,Characterization, and Single-Molecule Force SpectroscopyTobias Schrçder,[a] Satya Narayan Sahu,[a] Dario Anselmetti,[b] and Jochen Mattay*[a]

1. Introduction

1.1. General Remarks

In general, (supra)molecular capsules are accessible byforming covalent bonds between suitable monomericbuilding blocks or by self-assembly of correspondingmonomers fitted with receptor units that complementeach other. Whereas the other articles in this special issueshow impressive examples of both types, demonstratingthe high level of today�s organic synthesis (especially dy-namic covalent chemistry) and supramolecular chemistry,this article concentrates on a special type of monomericbuilding block, namely the resorcin[4]arene and its deriv-atives, and is restricted to capsules formed by H-bondingand metal coordination. Beside reviewing some selectedexamples from the literature, emphasis is laid on resultsfrom our own laboratory rather than to give a compre-hensive overview about the chemistry and physics of mo-lecular capsules derived from resorcin[4]arenes. Such acomprehensive review article is currently being pre-pared.[1]

1.2. The Monomeric Building Blocks: Resorcin[4]arenes

Calixarenes are synthetic macrocycles generally derivedfrom tert-butylphenols and formaldehyde or from resorci-nol and aldehydes.[2] They have goblet-like structures(Scheme 1) and therefore they provide a receptor cavityfor charged and neutral guest molecules.[3] Beside phenol-calix[n]arenes (with generally n=4, 6, 8) and resorci-n[4]arenes there are other macrocycles accessible derivedfor example, from pyrrole,[4] 2,6-dihydroxypyridine,[5] andeven higher benzoid arenes[6] to mention only a few.

All these macrocycles exist in various geometries; how-ever, the crown (C4v) and the boat (C2v) conformation areshown to be the most abundant ones, at least for resorci-n[4]arenes (Scheme 2). Both conformers are in a dynamicequilibrium that can be influenced by substitution patternand medium effects such as solvents.[7] In addition, thecrown-conformation can be fixed by forming cavitandsfollowing Cram�s procedure.[8] Due to their easy accessand their broad functionalization possibilities, we haveused calixarenes in many areas of supramolecular chemis-try such as host–guest complexes, sensors, self-assemblies,and mesoscopic systems, among others.[9–12]

2. Synthesis and Characterization ofSupramolecular Capsules Formed by H-Bonding

2.1. Selected Examples

Already in 1988, Aoyama et al. observed self-assembly ofresorcin[4]arenes to higher supramolecular aggregates bymeans of vapor pressure osmometry (VPO).[13] Only onedecade later, Atwood and our group unambiguously

[a] T. Schrçder, S. N. Sahu, J. MattayBielefeld University, Faculty of ChemistryP.O. Box 100131 , Bielefeld 33501, Germanyphone:+49 (0)521 106-2072fax:+49 (0)521 106-6146e-mail: [email protected]

[b] D. AnselmettiBielefeld University, Faculty of PhysicsP.O. Box 100131 , Bielefeld 33501, Germany

Abstract : Self-assembly by H-bonding and by metal-coordi-nation of functionalized calix[4]arenes and cavitands tolarge supramolecular capsules is described. In addition, anew method of analyzing supramolecular recognition pro-cesses at the single molecule level is discussed. By measur-ing interaction forces in a hydrogen-bonded assembly using

single-molecule force spectroscopy (SMFS), the dynamics ofthe self-assembly process can be evaluated. In the future,consequent application of this new technique will influencesupramolecular design principles and the use of non-cova-lent interactions as construction elements in the field ofnanotechnology.

Keywords: H-bonding · metal coordination · resorcin[4]arene · self-assembly · single-molecule force spectroscopy · supramolecular chemistry

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Review

proved the formation of hexameric self-assembled molec-ular capsules from resorcin[4]arenes and pyrogallo[4]ar-enes by X-ray crystallography (Scheme 3).[14,15] The fol-lowing years witnessed a tremendous activity by variousgroups resulting not only in a variety of other types ofhexameric capsules but also in a deeper understanding ofthe parameters controlling their formation in the solidstate, in solution, and in the gas phase as well. Contribu-tions from the laboratories of Atwood,[14,16] Rebek,[17] andCohen[18] were fundamental and opened a new path tolarge supramolecular capsules derived from resorcin[4]ar-enes and their derivatives (see also Section 2.2). The sta-bility of supramolecular binding motifs defines the degreeof reversibility during self-assembly and therefore theability for self-correction, ensures the integrity of thestructure, and controls the adaptability to environmental

changes.[19] Connecting building blocks via multiple hy-drogen bonds is one of the most frequently used strat-egies to obtain dynamic structures. The combination ofpredictable orientation and fast equilibration accounts forthe high appeal of employing hydrogen bonds in supra-molecular design principles.[20]

Several capsules based on hydrogen bond motifs havebeen synthesized, with dimeric systems composed of func-tionalized cavitands as one important subgroup.[21] Theuniform design defined by the cavitands makes thesestructures valuable objects for the study of differentbridging units. Atomic force microscopy–single-moleculeforce spectroscopy (AFM-SMFS) represents an outstand-ing technique providing quantitative data on the mechani-cal stability of interactions and mechanochemical effectsbeyond conventional ensemble approaches.[22–25] More-

Tobias Schrçder received his Diplomain Chemistry from Bielefeld Universityin 2006, under the supervision of Prof.Dr. Thomas Braun. In 2010, he receivedhis Ph.D. at Bielefeld University in thegroups of Prof. Dr. Jochen Mattay andProf. Dr. Dario Anselmetti. His re-search activity was concentrated on thesynthesis, structure and dynamic prop-erties of capsules derived from cavi-tands. Besides the synthesis of giantcoordination cages based on terpyridyl-substituted cavitands, he investigatedthe dynamics and stability of hydrogen-bonded supramolecular cap-sules by dynamic single-molecule force spectroscopy (SMFS) usingan atomic force microscope (AFM). In 2010 he joined Voco GmbH,Cuxhaven.

Satya Narayan Sahu earned his M.Sc.degree in Chemistry from Utkal Univer-sity, India, in 2001 and received hisM.Tech. degree in Modern Methods ofChemical Analysis in 2003 and Ph.D.degree in Organic Chemistry in 2009from Indian Institute of Technology,Delhi, India. After completion his Ph.D.he joined Sambalpur University, India,as a Lecturer in Chemistry, and thenmoved to Bielefeld University, Germa-ny, for post-doctoral work in the groupof Professor Jochen Mattay after receiv-ing the BOYSCAST fellowship (2009–2010) from the Department ofScience and Technology, Government of India. He is currently fo-cusing on the synthesis of resorcin[4]arene cavitand-based molecu-lar capsules/cages through covalent and non-covalent interactions.

Dario Anselmetti received his Ph.D. inExperimental Physics in 1990 from theUniversity of Basel, Switzerland, afterwhich he was a postdoctoral associateat the IBM Zurich Research Laboratoryin R�schlikon (1990–1991) and the In-stitute of Physics at the University ofBasel (1992–1994). He joined Ciba-Geigy as a research associate and proj-ect leader in 1994, then Novartis in1996 as a consequence of the companymerger. In 1998 he received the Novar-tis Leading Scientist Award and his ha-bilitation in Experimental Physics at the University of Basel. Now afull professor in the Physics Faculty of Bielefeld University, Ansel-metti has more than 20 years of experience in scanning probemethods, nanoscience and nanotechnology, single molecule bio-physics, optical tweezers, nanopores, biosensors and bioanalytics,as well as micro- and nanofluidics.

Jochen Mattay graduated from RWTHAachen University in 1978, then spentmore than one year as a NATO post-doctoral fellow at Columbia Universityworking on micellar and magnetic fieldeffects of photocleavage reactions inthe group of Nick Turro. Returning toAachen in 1980, he finished his Habili-tation in 1983 and was appointed lec-turer (Privatdozent) in the followingyear. Before joining the Department ofChemistry at Bielefeld University in1998, he held positions at the universi-ties of Aachen, M�nster , and Kiel. He also was Visiting Professorat Osaka University (1995) and the University of Berne (1996). Cur-rent research in his group revolves around various aspects of pho-tochemistry as well as supramolecular chemistry, including self-as-sembly of calixarenes to non-covalent capsules and synthesis ofnew organic electronic materials from 2-aminopyrimidines and sil-ver(I)salts, molecular recognition at single molecule level using MSand AFM techniques, chiral recognition, optical switches, and solar(green) photochemistry.

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over, detailed information about the energy landscape ofinteractions as well as quantitative kinetic and thermody-namic data can be obtained under solvent conditions in abroad affinity range, virtually solubility-independent.Therefore, single-molecule force spectroscopy is a uniquetool bridging the molecular and the macroscopic worldand is especially suited for the characterization of supra-molecular binding motifs in different dimensions to un-derstand interactions at the single-molecule level (formore details see Section 4).

The synthesis of hollow architectures based on cavi-tands started in 1985, when Cram et al. reported on the

inclusion of solvent molecules in a carcerand obtained bycovalent linkage of two cavitands.[8] Since then, molecularand supramolecular capsules have been prepared fromcavitands and calix[n]arenes due to two important proper-ties: the bowl-shaped form and the various functionaliza-tions which can be introduced at the upper rim of thecavitands or the wider rim of the calix[n]arenes(Scheme 4).

While the conformation of the methylene-bridged cavi-tands 1 is fixed (Scheme 4a), a number of more flexiblecavitands with other bridging units (BU) have been pre-pared (Scheme 4 b).[26] Depending on the substituent R’ atphenolic oxygen and the group (G) attached to the widerrim, the calix[n]arenes 2 can adopt different conforma-tions (Scheme 4 c, d).[27,28] Calix[n]arenes with more thanfour phenol units in the cyclophane basis are particularlyflexible.

Because cavitands and calix[n]arenes with various func-tional groups (G) can be synthesized, a range of reactionscan be applied to obtain substituted derivatives. Some ofthese molecules can be used as receptors for neutral mol-ecules and ions, for the synthesis of stationary phases forchromatography, and as catalysts for organic reac-tions.[28,29] In the following sections it will be shown thatcavitands and calix[n]arenes are valuable building blocksfor complex structures as supramolecular capsules due tothe unique combination of shape and functional groupsthat can be attached to the cyclophane basis.

Following their covalent analogues, hydrogen-bondedsupramolecular capsules have been synthesized from cavi-tands and calix[n]arenes.[21] The heterodimeric aggregate5 introduced by Kobayashi et al. , shown in Scheme 5, is astructurally well studied example for a hydrogen-bondedcomplex.[31] In solvents suitable as guest molecules, or inthe presence of added guests, cavitands with four carbox-ylic acid groups and cavitands with four pyridyl groups se-lectively form heterodimers stitched together by four hy-drogen bonds. In CDCl3 (which is an ill-fitting guest),from a mixture of selected arenes, 1,4-disubstituted ben-zenes were preferentially encapsulated (Scheme 5 d). Thisselectivity was attributed to specific host–guest interac-tions that stabilize the complex in addition to the hydro-gen-bonding.[31] One factor is the CH–halogen interac-tions between the inner protons of the methylene-bridges

Scheme 3. Hexameric capsules derived from a resorcin[4]arene(Atwood[14]) and a pyrogallo[4]arene (Mattay[15]).

Scheme 1. Calix[n]arenes (calix [lat.]: cup, goblet, calyx) derivedfrom tert.-butylphenol and resorcin[4]arenes derived from resorci-nol.

Scheme 2. General features of resorcin[4]arenes (a: axial, e: equa-torial).

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Supramolecular Capsules Derived from Resorcin[4]arenes by H-Bonding and Metal Coordination


Scheme 4. (a) Structure of a methylene-bridged cavitand 1 substituted with functional groups (G) at the upper rim. (b) General structureof cavitands with different bridging units (BU) and one example of an aryl-bridged cavitand.[30] (c) Structure of calix[n]arenes 2 with func-tional groups (G) at the wider rim. (d) Conformations of calix[4]arenes.

Scheme 5. (a) Association of cavitands to the heterodimeric capsule 5 in para-xylene. (b), (c) Molecular structure of 5 (with one moleculepara-xylene encapsulated) in the solid state as determined by X-ray diffraction analysis ((b): side view, (c): top view, alkyl chains omitted).(d) Preference of guest encapsulation of 1,4-distubstituted benzenes relative to 1,4-dibromobenzene determined by 1H NMR spectroscopy.




of the cavitand units and the halogen atom of an arylha-logenide guest. In the case of methoxy-substituted ben-zene guest molecules, the CH-p-interaction between thearomatic cavities of the cavitands and the polarized me-thoxy protons have a stabilizing effect. Independent ofthe functional groups, the filling of the void space insidethe capsule by a guest of optimal size and shape has animportant impact on capsule formation.

Dimeric hydrogen-bonded capsules have also been ob-tained from calix[4]arenes (Scheme 6). The tetra-(urea)calix[4]arene 6 exists as a monomeric species in the

cone conformation in polar solvents such as DMSO.[33] Inapolar solvents that are suited for encapsulation (such asbenzene and chloroform), the molecules form dimers 7that are held together by hydrogen bonds between theHN- and the O=C-functions of the urea groups.[33,34] Be-cause no additional molecules take part in the hydrogen-bonding network, the building blocks are called “self-complementary”.

2.2. The Resorcin[4]arene Case

Following the first reports on the crystal structure of hex-americ resorcin[4]arenes and the corresponding pyrogal-lol derivatives, the groups of Cohen,[35] Rebek,[36] andAtwood[37] studied self-assembly in solution in greatdetail by using NMR spectroscopy, including NOE anddiffusion coefficient determination. Very early on,Atwood[38] suggested the formation of the smaller, self-as-sembled resorcin[4]arene 8 c dimer, facilitated by hydro-gen-bond bridges involving eight 2-propanol molecules,which was characterized by X-ray diffraction analysis.More recently, Ugono and Holman[39] discovered an achi-ral hexameric capsule related to the chiral form reportedby Atwood. In contrast to the water-bridged chiral assem-bly, this capsule is held together by a hydrogen-bondingnetwork with six 2-ethylhexanol molecules (12) and, addi-tionally, two water molecules on the edges of the formedcube.

In 2008, the works of Holman, Aoyama, and Atwoodprompted us to report on the controlled molecular assem-bling processes of 1 : 1 complexes, dimers, and hexamersin apolar solvents by addition of selected alcohols.[40] Tovisualize such interactions, first we attempted to detectand characterize these species by mass spectrometrymethods such as MALDI-TOF, ESI, and CSI techniques.None showed evidence supporting the formation of ag-gregates that survived in the gas phase. Also, Williams[41]

reported that neither variable temperature 1H NMR norGPC measurements yielded coherent information con-cerning the aggregation of similar systems in solution.However, the diffusion NMR technique provided usefuldata concerning the solution states of aggregated species.Based on the diffusion coefficients it is possible to reachconclusions on the particle size in solution. The results ofour NMR experiments using a solution of undecylresorci-n[4]arene 8 a in dry CDCl3, to which alcohols 10–12 wereadded, are summarized in Scheme 7:

With 2,2,2-trifluoro-1-phenylethanol 10, the diffusioncoefficient of 0.42� 10�5 cm2 s�1 indicated monomeric spe-cies, in accordance with Cohen�s reports.[35] Consideringthe studies of Kobayashi,[32] we proposed a 1 : 1 complexa-tion of 2,2,2-trifluoro-1-phenylethanol in the cavity of re-sorcin[4]arene. The driving force for this complexation isapparently the p–p interaction between the aromatic resi-

Scheme 6. Association of the tetra(urea)calix[4]arene 6.

Scheme 7. Influence of alcohols 10–12 on the diffusion coeffi-cients of 8 a in CDCl3 at 298 K.




due of the alcohol and the cavity. Moreover, the aggrega-tion may be assisted by the hydrogen-bonding networkformed by the alcohol and two resorcinol units. In addi-tion, solvophobic forces may also play a minor role instrengthening the complexation.

For the addition of 2-butanol 11 we found a diffusioncoefficient of 0.32� 10�5 cm2 s�1, which is typical for adimer and which is in good agreement with the results ofAtwood in solid state.[35] This aggregate is formed by 24delocalized hydrogen bonds between two molecules of 8 aand eight molecules of 11 (Scheme 8).

Finally, for the addition of racemic 12 we determined adiffusion coefficient of 0.25 �105 cm2 s�1, which corre-sponds to the formation of a hexameric nano-capsule asalready reported earlier by Holman.[39] In contrast to thesolid state, in our experiments under absolutely dry con-ditions we assume the complete “substitution” of allwater molecules by racemic 2-ethylhexanol, resulting inthe hexameric complex 8 a6@128 in solution.

In summary, the origin of the puzzling aggregation be-havior of resorcin[4]arenes with various alcohols could beevaluated by revealing the dramatic influence of bridgingmolecules on the muticomponent aggregation in solutionunder fixed conditions (concentration, pH-dependence,etc.). Again, Cohen et al. recently studied the encapsula-tion of alcohols in more detail.[42] They showed on thebasis of diffusion NMR spectroscopy that, contrary tocommon belief, high-field chemical shifts of neutralguests, such as alcohols, in the presence of hexameric cap-sules do not necessarily imply guest encapsulation. Onlysome alcohols are indeed encapsulated, whereas othersbecome part of the hexameric structure of the capsules.

Note that, in case of the corresponding pyrogallo[4]ar-enes, additives like water or alcohols are not required toform hexameric cages.[15]

2.3. The Pyridine[4]arene Case

In 2001 we reported the first convenient synthesis of anew type of calixarene derived from 2,6-dihydroxypyri-dine.[43] Like resorcinol and a number of resorcinol deriv-atives, 2,6-dihydroxypyridine has been proven to formcyclic tetramers in moderate yields with a number of ali-phatic and two aromatic aldehydes in acidic media(Scheme 9). The problem of the formation of configura-

tional isomers can be reduced by increasing the reactiontemperature and time. With electron-rich aromatic alde-hydes, 2,6-dihydroxypyridine unexpectedly yields deep-colored acyclic quinoid systems. The octahydroxypyridi-ne[4]arenes have a high potential as receptors for molecu-lar recognition and self organization as shown later byourselves[44,45] and Cohen.[35h]

In the context of this article the self-assembling to mo-lecular capsules should receive special attention. Alreadyin the first paper we reported the formation of dimericcapsules proven by X-ray analysis (Scheme 9).[43] We alsoshowed that these dimers are stable even in the gasphase.[44] Later Evan-Salem and Cohen clearly showed bydiffusion NMR that C-tetra-n-undecyl-2,6,8,12,14,-18,20,24-octahydroxypyridine[4]arene (13, Scheme 9) self-assembles spontaneously into hexameric capsules in non-polar organic solvents, as do resorcin[4]arenes and pyro-gallol[4]arenes.[35h]

3. Synthesis and Characterization ofSupramolecular Capsules formed by MetalCoordination

3.1. Selected Examples

Several metallosupramolecular cages with different geo-metries have been synthesized from cavitands and calix[-n]arenes functionalized with metal-coordinating groups atthe upper rim.[46] The successful self-assembly of suchbuilding blocks is a complex reaction, that yields the mostthermodynamically stable product.[47] A reversible forma-tion of the coordinative bonds is necessary to allow

Scheme 8. Stick models of the 8 a@10 complex, the 8 a2@118

dimer, and the hexameric nano-capsule of 8 a6@(12)6@(H2O)2. Thealkyl chains are omitted for clarity. The hydrogen-bonding networkis visualized by the dotted lines.

Scheme 9. rccc-2, 8, 14, 20-tetra-n-undecyl-4, 6, 10, 12, 16, 18, 22,24-octahydroxypyridine[4]arene 13 with its self-assembled dimer(from X-ray analysis).




“error correction” by partial disassembly of less stable in-termediates to form the final assembly. On the otherhand, a stable connection of the cages� subunits has to berealized to ensure the integrity of the structure and allowthe characterization of the assembly in solution. The de-velopment of rigid ligands with a high preference to self-assemble to only one aggregate with defined geometry isof major importance for the synthesis of coordinationcages. The degree of preorganization of building blocksderived from cavitands and calix[n]arenes is controlled bythe shape and conformational freedom of the cavitand orcalix[n]arene framework and the flexibility of the attach-ment of the metal-coordinating group. To illustrate theimpact of the ligand properties on the geometry of theobtained structures, selected examples of coordinationcages based on cavitands are presented in this section.

The self-assembly of the tetra(cyano)cavitands 14 and15 with differing flexibility of the cavitand base was inves-tigated by Dalcanale et al. (Scheme 10).[48] Compared tothe methylene-bridged cavitand 15, the ethylene-bridgedcavitand 14 is conformationally less rigid. The higher flex-ibility of 14 accounts for its lower tendency to aggregateto discrete coordination cages. While 15 forms dimericcoordination cages in the presence of Pd(dppp)(CF3SO3)2,no successful capsule self-assembly was observed for theflexible cavitand 14.

The kind of attachment of the metal coordinatinggroups to the cavitand is an important structure-defining

parameter. Hong et al. studied the self-assembly of a cavi-tand 17 functionalized with pyridyl groups via flexibleether linkages (Scheme 11).[49] Due to the conformationalfreedom of the connection, intramolecular coordinationof the Pt2+ centers is observed in competition with inter-molecular complexation, leading to the supramolecularcapsule 18. While the capsule 18 and the half-capsule 19are in dynamic equilibrium in nitromethane, only the di-meric capsule is formed in chloroform/methanol solventmixtures.

To ensure the integrity of the assemblies in solution,stable connections between the building blocks of thecages are required. Scheme 12 shows an example of anaggregate that has been characterized in the solid state byX-ray diffraction analysis, where no evidence for intactcoordination cages in solution were obtained.[50] The as-sembly 21 contains six tetra(carboxyl)cavitands 20 thatare stitched together by Zn2+ ions coordinated to the car-boxylate groups. In the solid state, one-dimensional coor-dination polymers of the coordination cages 21 areformed by aggregation through linear m-hydroxy- or m-oxo-linkages. Attempts to provide evidence for discretehexameric species in solution by ESI-MS or NMR spec-troscopy have not been successful. The insufficient stabili-ty of the aggregates can be attributed to the weak con-nection of the cavitands via the carboxylate groups at theupper rim coordinated to zinc ions.

Scheme 10. (a) The ethylene-bridged cavitand 14 is not suited for capsule self-assembly with Pd(dppp)(CF3SO3)2. (b) Self-assembly of themethylene-bridged cavitand 15.




3.2. The Terpy-Resorcin[4]arene Building Block and itsMetallosupramolecular Cage

As shown above, cavitands and calix[n]arenes are valua-ble building blocks for coordination cages due to theirshape and the wide range of functional groups that canbe introduced at four positions of the macrocycles.Though several supramolecular capsules have been ob-tained from the much more flexible calix[4]arenes, the in-

creased preorganization of the cavitand basis can provideenhanced control of metal-directed self-assembly of thetetratopic ligands. To prevent intramolecular complexa-tion of metal ions and constrain the potential geometriesof the self-assembled structures, rigid attachment of themetal coordinating groups is of major importance.

Transition metal complexes of 2,2’ : 6’,2’’-terpyridine arehighly directional, connecting units ideally suited to

Scheme 11. Self-assembly of 17 and equilibrium between capsule 18 and interclipped bowl 19.

Scheme 12. Formation of the hexameric assembly 21 contained in the coordination polymer (not shown for clarity).




bridge the bowl-shaped building blocks (Scheme 13).[51,52]

The chelating terpyridine group coordinates via three ni-trogen atoms of the pyridyl rings and ensures a stableconnection to various metal ions in different oxidationstates. Because of the space requirements of the heteroar-omatic rings of this metal-coordinating group, the aggre-gation of the building blocks to large assemblies is likelyto be preferred compared towards dimeric structures,which are frequently obtained from sterically uncon-strained cavitands and for calix[4]arenes.[21]

With the synthesis of large supramolecular coordina-tion cages based on cavitands and calix[n]arenes, newhosts for the simultaneous encapsulation of several guestmolecules will be available. The application of bis-terpyri-dine complexes as bridging units in the synthesis of coor-dination cages may open the way to large, stable, andfunctional supramolecular assemblies.

For the synthesis of a cavitand functionalized with ter-pyridyl groups via rigid linkages, transition metal-cata-lyzed cross-coupling reactions are especially well suited.Starting with the boronic acid ester 23,[54] attachment ofthe terpyridyl groups to the cavitand was realized bySuzuki–Miyaura reaction with the tetraiodocavitand 22(Scheme 14).[55]

To increase the solubility of the aggregates formed,large lipophilic TFPB anions (TFPB= tetrakis-(3,5-bis-(trifluormethyl)-phenyl)-borate) were used instead of tri-flate anions.[56] The zinc salt [Zn(NCMe)6][TFPB]2 25 wasobtained by reaction of zinc bromide with Ag(TFBP) in

acetonitrile under exclusion of light. Addition of[D8]THF to a mixture of the cavitand 24 and the zinc salt25 gave the coordination cage 26 after keeping the reac-tion mixture at 60 8C for 1 h (Scheme 15).

The product, which was readily soluble in organic sol-vents including acetone, tetrahydrofurane, and methylenechloride, was characterized by ESI-MS, 1H-, and13C NMR spectroscopy, diffusion NMR spectroscopy,SAXS measurements, and elementary analysis.[55] In ESI-MS, multiply charged ions [26- n TFPB]n+ with n=7–11containing the intact coordination cage were observed ex-clusively. The isotope patterns prove the charge states ofthe ions and confirm the hexameric nature of the aggre-gate (Scheme 16).

Attempts to synthesize an analogous hexameric metal-losupramolecular cage from a terpyridyl-substituted cal-ix[n]arene failed so far.[61] Although the synthesis of theterpy-calixarene building block was successful, X-rayanalysis showed a cone conformation with intramolecularp-stacking of two terpyridyl units and already indicatedhigher flexibility of the macrocyclic unit. Consequently,the lower degree of preorganization of the calix[4]areneleads to a significantly different self-assembly in the pres-

Scheme 13. (a) Structure of 2,2’ : 6’,2’’-terpyridine and [Zn(tpy)2]2+ .(b) Molecular structure of [Zn(tpy)2]2 + as determined by X-ray dif-fraction analysis.[53]

Scheme 14. Preparation of a tetra-(4-(2,2’ : 6’,2’’-terpyridyl)-phenyl)-cavitand 24. Scheme 15. Synthesis of the hexameric assembly 26.




ence of Zn2+ ions with a variety of species formed as de-termined by ESI-MS and 1H NMR spectroscopy.

4. Studies on Complexation Dynamics by Single-Molecule Force Spectroscopy (SMFS)

4.1. Introduction to SMFS[62]

The atomic force microscope (AFM) is a versatile toolfor various imaging and manipulation applications at the(sub-)nm scale.[63,64] The basic setup consists of a smallforce sensor (cantilever) and a piezo scan tube on whichthe sample is placed to precisely control the relative posi-tion of the cantilever and the sample in horizontal andvertical direction (Scheme 17). The interaction betweenthe sharp tip of the cantilever (tip radius � 10 nm) andthe substrate is transduced to minimal deflections of theforce sensor. The deflection of the cantilever can typicallybe measured by the displacement of a laser beam whichis reflected from the back of the sensor and detected by aquadrant detector.[65] The feedback loop allows exact con-trol of the forces acting between tip and sample, which is

the precondition for topographic scans. In addition to theimaging mode, nano-scale objects can be precisely manip-ulated with the cantilever tip by applying very low forcesin the range of piconewtons (1 pN=10�12 N), which is themagnitude of weak intermolecular bonds.

To probe the interactions between a ligand and a re-ceptor molecule in an AFM-SMFS mechanochemistry ex-periment, the cantilever surface is functionalized with aligand via, for example, a flexible poly(ethylene glycol)linker (PEG linker), and is moved toward a substratewith the immobilized receptor (Scheme 18).[66] While the

cantilever tip is in contact with the substrate, the ligandcan access the receptors due to the flexible PEG linkerwhere a complex is formed. When the cantilever is with-drawn from the surface, the linker molecule is uncoiledand stretched due to the increasing force, acting on theligand–receptor complex. Once the externally appliedforce exceeds the mechanical stability of the complex, fi-nally, the molecular complex dissociates.

Since the deflection of the force sensor during this ex-periment is monitored, a detailed evaluation of the forcesrequired for the rupture of the ligand–receptor bond ispossible. In Scheme 18a, a typical force–distance curve isshown. While at first uncoiling of the PEG linker pro-ceeds without significant deflection of the cantilever,stretching of the chain-like polymer results in a non-linear force load acting on the complex. When theligand–receptor bond dissociates, the cantilever snapsScheme 17. Setup of an atomic force microscope (AFM).

Scheme 18. (a) Scheme of the single-molecule force spectroscopyexperiment and typical force–distance curve. (b) Histogram of thedissociation forces and Gaussian fit to the distribution.

Scheme 16. (a) Space-filling representation of the O-symmetricstationary point of the methyl derivative of 26 on the PM3 hyper-surface. (b) Representation of the energy minimized structure ofthe methyl derivative 26 containing seven TFPB anions obtainedfrom a force field calculation.




back to the zero-force position and a distinct force jump(dissociation force) is detected. Due to the stochasticnature of the thermally activated dissociation process,these approach–retract cycles have to be repeated manytimes where the measured dissociation forces are plottedin a force histogram (Scheme 18b). The distribution canbe fitted with a distribution function (e.g., Gaussian) toyield the most probable dissociation force (f*) at a givenloading rate.

A connection between the mechanical forces acting onthe complex and the dissociation rate constant in the ab-sence of an external force has been provided within theKramers–Bell–Evans model.[67,68] In general, the forma-tion of the complex AB from two components A and B isdescribed by the law of mass action.

kon0 Rate constant of association

koff0 Rate constant of dissociation

The equilibrium constant of association (Kass) is givenby Equation 1 and, under standard conditions, is relatedto the standard Gibbs free energy by Equation 2.

Kass ¼½AB�½A� � ½B� ¼

k0on

k0off

ð1Þ

DG0 ¼ R � T � lnðKassÞ ð2Þ

[X] Concentration of component X

T Temperature

R Universal gas constant

According to Arrhenius, the dissociation rate constantdepends on the activation energy (DG#) (Equation 3).

k0off ¼ C � e�

DG#

kB �T ð3Þ

kB Boltzmann constant

Now, in a single-molecule force spectroscopy experi-ment, a mechanical force is additionally acting on thecomplex, which leads to a thermally activated dissociationunder the externally applied force. Scheme 19 schemati-cally shows the influence of the force load on the poten-tial barriers. According to Bell and Evans, the externalforce f lowers the energy barrier to the unbound stateand therefore promotes the dissociation of the complex(Equation 4).

DG#ðfÞ ¼ DG# � f � xb ð4Þ

xb molecular reaction length (width of the binding poten-tial)

f force applied on the complex in direction of the reac-tion coordinate

with the implication, that the dissociation rate constantdepends on the force acting on the complex (Equation 5).

koffðfÞ ¼ k0off � e

f�xb

kB �T ð5Þ

While the cantilever is retracted from the substrate inthe SMFS experiment, the applied force increases withtip–substrate distance, until finally the bond dissociates.The time-dependent force is given by the product of thecantilever deflection and the effective spring constant c ofthe molecule (molecular elasticity), which comprises thespring constant of the cantilever and the elasticity of thepolymer linker used to tether the ligand to the cantilever(Equation 6). The product of effective spring constantand retract velocity vretract referred to as loading rate r is

fðtÞ ¼ c � vretract � t ¼ r � t ð6Þ

Based on this model, Bell and Evans derived an equa-tion that connects the most probable dissociation force f*determined in single-molecule force spectroscopy experi-ments with the loading rate r (Equation 7).

f* ¼ kB � Txb

� lnxb � r

k0off � kB � T

� �ð7Þ

According to this equation, the dissociation rate con-stant in the absence of external force can be determinedfrom single-molecule force spectroscopy experiments car-ried out at different retract velocities (DFS-SMFS, Dy-namic Force–Single-Molecule Force Spectroscopy). Byplotting the most probable dissociation forces vs. ln (r),

Scheme 19. Scheme of the energy barriers between bound andunbound state (a) in the absence or (b) in the presence of an ex-ternal force acting on the complex.




the molecular reaction length xb and the dissociation rateconstant in the absence of an external force koff

0 can bedetermined from the slope and the extrapolated regres-sion of the linear fit to zero force (f*=0). In the lastdecade, it has been shown that the dissociation rate con-stants estimated from single molecule experiments favor-ably compare with those measured from standard ensem-ble systems.

4.2. AFM-SMFS of a Hydrogen-Bonded Supramolecular DimericCapsule[69]

The selective functionalization of the substrate and thecantilever is crucial for successful SMFS experiments. Awell established method for the immobilization of cavi-tands on gold is the formation of self-assembled monolay-ers (SAMs) of thioether-footed cavitands.[70] The tetra-(pyridyl)cavitand 27 with four thioether moieties at thelower rim (Scheme 20) is suited for immobilization on agold substrate. To obtain adsorbates of high quality, theself-assembly process is carried out at elevated tempera-tures (60 8C).

For single-molecule force spectroscopy experiments,the tetra(carboxyl)cavitand should be immobilized via a

flexible PEG linker to the cantilever, to add steric free-dom to the system and allow complex formation to takeplace.[71] Scheme 21 shows a schematic representation ofthe attachment. A PEG linker with one carboxylic acidgroup can be coupled to the amino-functionalized cantile-ver by amidation. The second terminal group of the heter-obifunctional PEG should be attached via orthogonalcoupling reaction to a tetra(carboxyl)cavitand with oneappropriate reactive group at the lower rim. To preventinteraction with the tetra(carboxyl)cavitand, remainingfree amino groups at the surface have to be blocked. Al-though the sequence of the coupling steps is not predeter-mined, a short sequence of reliable reactions on the canti-lever surface is advantageous due to the high sensitivityof the cantilever towards mechanical damage. Therefore,the tetra(carboxyl)cavitand should be coupled to thePEG linker before the conjugate is attached to the canti-lever.

The details of this special immobilization strategy hasbeen described by Schrçder et al. by introducing a newtype of linker via “click chemistry” (see for example,28).[62,69] Scheme 22 shows just the final step of cantileverfunctionalization.

To get a first insight into the interactions between thecapsules� halves by force spectroscopy, initial experimentswere carried out using undiluted SAMs of the tetra-(pyridyl)cavitand 27 on a gold substrate. A schematic rep-resentation of the experiment is shown in Scheme 23. Thetetra(carboxyl)cavitands are depicted as red bowls, whilethe tetra(pyridyl)cavitands immobilized at the gold sub-strate are represented by the blue bowls. All measure-ments are carried out in para-xylene, which is encapsulat-ed in the assembly (yellow ball).

Because of the high concentration of the tetra-(pyridyl)cavitand at the substrate surface, multiple inter-actions due to simultaneous formation of several supra-molecular capsules were expected. This was actually ob-served, as reflected in a typical AFM force–distancecurve shown in Scheme 24. Several partially separateddissociation events are detected, which sum up to astrong interaction between cantilever tip and substrate.Scheme 20. Structure of the tetra(pyridyl)cavitand 27.

Scheme 21. Scheme of the functionalization of the cantilever.




For the quantitative evaluation of the bonding interac-tion in the supramolecular capsule system, single-mole-cule force spectroscopy experiments with fewer eventshave to be designed. Mixed SAMs containing alkylsul-fides without functional groups can be used to realize alower concentration at the substrate and reduce the bind-ing activity between tip and sample.[72,73] To prepare such

diluted SAMs on gold, the substrates were placed in a so-lution (1 mm) of the cavitand 27 and decyl sulfide in aratio of 1:100 at 60 8C for 10 h.[70] In subsequent forcespectroscopy experiments using the diluted SAM, a sig-nificant reduction of the binding activity was observed.While multiple rupture events were detected in all of the

Scheme 22. Functionalization of the cantilever (TBTU: 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate; DIPEA: N,N-diisopropylethylamine; DMSO: dimethyl sulfoxide)

Scheme 23. Scheme of the force spectroscopy experiments on anundiluted SAM of 27.

Scheme 24. Typical force–distance curve obtained in a force spec-troscopy experiment using an undiluted SAM of 27.




measurements on the undiluted SAM, the binding activitywas significantly reduced using the diluted SAM(Scheme 25). The typical force–distance curve shown inScheme 25 a contains only one distinct force jump, whichcan be associated to the dissociation of a supramolecularcapsule formed between a tetra(carboxyl)cavitand at-tached to the cantilever tip and a tetra(pyridyl)cavitandimmobilized on the gold substrate. The characteristicnon-linear force–distance curves could be assigned to theelastic stretching of the chain-like polymer and used todiscriminate the specific single-molecule dissociationevents from unspecific and multiple adhesion events. Fur-thermore, the dissociation events were observed well sep-arated from the surface (20�80 nm). This simplifies iden-tification and allows precise determination of the dissoci-ation force. Force–distance curves containing more thanone dissociation event were discarded and not included inthe quantitative data analysis.

Plotting the detected dissociation forces in a force his-togram, a narrow distribution of forces characteristic forsingle-molecule force spectroscopy experiments was ob-served. To verify the specificity of the interaction, a con-trol experiment was carried out (Scheme 26). Addition ofexcess of tetra(carboxyl)cavitand to the diluted SAM ofthe tetra(pyridyl)cavitand results in a strongly reducedbinding activity between tip and sample due to effectiveblockage of the capsule formation between cantilever-

bound tetra(carboxyl)cavitand and the tetra-(pyridyl)cavitand.

Further information about the mechanical stability ofthe supramolecular capsule was obtained from SMFS ex-periments carried out at different retract velocities.Single-molecule dissociation events were identified andthe most probable dissociation forces obtained by fittinga Gaussian distribution to the histograms. Starting at f*=(39.1�4.1) pN at a loading rate of r=200 pN s�1, themost probable dissociation rate increased to f*= (71�12) pN at a retract velocity of vr =12,600 pN s�1. To relatethe results to kinetic and thermodynamic properties ofthe system in p-xylene, the data were evaluated accordingto the theory of Bell and Evans.[67,68] By plotting the mostprobable dissociation force f* vs. ln (r), the dissociationrate constant koff

0 = (0.13�0.14) s�1 was obtained corre-sponding to an average bond lifetime of approximately t

�7 s (Scheme 27). The molecular reaction length was de-termined to be xb = (0.560�0.076) nm. Assuming a typicalfast association (kon =1·104

m�1 s�1), the equilibrium con-

stant of association can be estimated to be Ka =4.6·104

m�1, yielding DG0 =�27 kJ mol�1 [62] at T=293 K.

The mechanical stability of the heterodimeric capsuleanalyzed in this study can be compared with the data ob-tained for the tetra(urea)calix[4]arene oligomer reportedby Janshoff et al. in 2009.[25] The dissociation forces off*=30–100 pN at loading rates of r=60–30,000 pN s�1

Scheme 25. (a) Single-molecule dissociation event detected in a measurement on a diluted SAM of 27. (b) Force–distance curve containinga multiple adhesion event.

Scheme 26. (a) Histogram of the dissociation forces of single heterodimeric capsules and Gaussian fit to the distribution. (b) Strongly sup-pressed binding activity between tip and sample. Inset: Schematic representation of the competition experiment.




measured for the Janshoff system containing calix[4]arenecapsules connected via eight strong and eight weak hy-drogen bonds are in the same range as the dissociationforces of Kobayashi�s capsule studied here.[68] Our experi-mental setup seems to be better suited to determine themechanical stability and the dynamics of the dissociationprocess of the supramolecular capsule in a quantitativemanner, because the stretching experiments on the morecomplex Janshoff system might be influenced by forceconvolution effects. This might result from an insufficientdiscrimination from the force steps resulting from thecomplete unfolding of a sterically locked conformation of

the alkyl chains and might additionally be reduced be-cause several non-covalently bound segments are stretch-ed at the same time.[74]

4.3. Other Studies on the Dynamics of Capsule Formation

While several hydrogen-bonded supramolecular capsuleshave been synthesized, less is known about the self-as-sembly dynamics of these systems in solution. The kinet-ics of the hydrogen-bonded dimeric capsules based oncalix[4]arenes substituted with urea functions at the widerrim has been analyzed by NMR spectroscopy and FRETmeasurements. Special modifications had to be carriedout in order to evaluate the kinetics of these systems: ForNMR studies, the symmetry of the associate was reducedby introducing different substituents leading to separatesignals.[75] For FRET studies, the building blocks were la-beled at the narrow rim with fluorophores. Formation ofthe dimer was indicated by acceptor emission due toenergy transfer between donor (D) and acceptor (A),which was not detected for free labeled calix[4]arenes.[76]

The data obtained by these experiments range betweenkexchange =0.26 s�1 (NMR) and kdiss =10�3 �10�6 s�1

(FRET). The discrepancy in the dissociation rate con-stants obtained by these different techniques were ex-plained with differences in the structure of the buildingblocks and a concentration dependence of the rate con-stants.

A second type of dimeric capsule analyzed by FRETmeasurements is based on cavitands stitched together byeight hydrogen bonds (Scheme 28).[77] Attachment of flu-orescent dyes to the monomers allowed the observation

Scheme 28. Setup of the FRET experiment to determine the exchange rate of the subunits of a dimeric cavitand capsule 31. The encapsu-lated guest (G) has a strong influence on the stability of the capsule.

Scheme 27. Plot and fitting analysis of the most probable dissocia-tion forces against ln (r).




of dynamic processes. Upon mixing solutions of the cap-sules 29 and 30 composed of acceptor- (A) and donor-(D) labeled building blocks, acceptor emission was ob-served due to exchange of capsule subunits. While assem-bly of the capsule is known to occur very rapidly, the rateconstant for exchange of the subunits was determined tobe k=1.9·10�3 s�1 in toluene.

5. Summary

In this review article we have summarized our own resultsand selected reports from the literature on the synthesisand self-assembly dynamics of supramolecular capsulesbased on cavitands and calix[4]arenes. Large supramolec-ular capsules are accessible by H-bonding and by metal-directed self-assembly of functionalized cavitands. In ad-dition, a new method of analyzing supramolecular recog-nition processes at the single molecule level in mechano-chemical experiments has been discussed. By measuringinteraction forces in a hydrogen-bonded assembly usingsingle-molecule force spectroscopy, the dynamics of theself-assembly process can be evaluated. In the future, fur-ther application of this new technique will influencesupramolecular design principles and the use of non-cova-lent interactions as construction elements in the field ofnanochemistry.

Acknowledgments

Financial support by the Deutsche Forschungsgemein-schaft (SFB 613) is gratefully acknowledged.

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Received: May 28, 2011Accepted: July 7, 2011

Published online: August 9, 2011




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