Highly Strong and Tough Supramolecular Polymer Networks Enabled by Cryptand-Based Host-Guest Recognition.

Supramolecular polymer networks (SPNs) demonstrate great potential in the development of smart materials owing to their attractive dynamic properties. However, as they suffer from the inherent weak bonding of most noncovalent cross-links, it remains a significant challenge to construct SPNs with outstanding mechanical performance. Herein, we exploit the cryptand/paraquat host-guest recognition motifs as cross-links to prepare a class of highly strong and tough SPNs. Unlike those supramolecular cross-links with relatively weak binding abilities, the cryptand-based host-guest interactions have a high association constant and steady complexing structure, which effectively stabilizes the network and resists mechanical deformation under external force. Such favorable structural stability endows our SPNs with greatly enhanced mechanical performance, compared with the control-1 cross-linked by the weakly complexed crown ether/secondary ammonium salt motif (tensile strength: 21.1±0.5 vs 2.8±0.1 MPa; Young's modulus: 102.6±4.8 vs 2.1±0.3 MPa; toughness: 90.4±2.0 vs 10.8±0.6 MJ m-3 ). Moreover, our SPNs also retain abundant dynamic properties including good abilities in energy dissipation, reprocessability, and stimuli-responsiveness. These findings provide novel insights into the preparation of SPNs with enhanced mechanical properties, and promote the development of high-performance intelligent supramolecular materials.

Supramolecular Pseudorotaxane Polymers from Biscryptands and Bisparaquats.

Five new bis(dibenzo-30-crown-10-based cryptand)s were synthesized, two of which (16 and 17) had long (12-atom), flexible spacers that led to cooperative complexation of dibenzyl paraquat TFSI ( Kave = 4.36 × 105 M-1 for 17•2b). Self-assembly of 16 and 17 with bisparaquats with similar spacers (18, 21, and 23) led to high molecular weight supramolecular pseudorotaxane polymers in solution. Continuous, flexible fibers were drawn from concentrated solutions. 17 with C10-linked bisparaquat 23 in dichloromethane (DCM) produced a log-log viscosity vs concentration plot with a limiting slope of 3.55, confirming high molecular weight; at 37 mM, the degree of polymerization was estimated to be 126 and Mn = 407 kDa. These are the first truly polymeric pseudorotaxane-type AA/BB supramolecular polymers.

Viologen-Based Rotaxanes from Dibenzo-30-crown-10.

Three [2]rotaxanes (4, 7, and 12) and one [3]rotaxane (8) were synthesized based on the dibenzo-30-crown-10/viologen binding motif. To the best of our knowledge, these are the first rotaxanes formed from dibenzo-30-crown-10 and viologens. The rotaxanes were all characterized by 1H NMR, 13C NMR, and HRMS. An X-ray crystal structure of one of the [2]rotaxanes (7) was obtained. This work demonstrates for the first time that dibenzo-30-crown-10 does form pseudorotaxane complexes with viologens in solution.

Pseudocryptand Hosts for Paraquats and Diquats.

H-bonding interaction of acidic moieties (CH2OH, COOH) at the 5- and 5'-positions of bis(1,3-phenylene)-32-crown-10 (1) with di- or tritopic anions leads to enhanced formation of inclusion complexes with N,N'-dialkyl-4,4'-bipyridinium salts ("paraquats", 2); the enforced folding of the crown ethers into pseudocryptands thus leads to pseudo-pseudorotaxanes. Strikingly, in the presence of the most effective anion (trifluoroacetate, TFA), the apparent bimolecular association constants for crown-paraquat complexation increase by more than an order of magnitude and approach those for covalent cryptands derived from the crown ether. Even though they may form pseudocryptands, the picolinate, nicotinate, and isonicotinate diesters 6 of cis-(4,4')-bis(hydroxymethyl)dibenzo-30-crown-10 do not exhibit enhanced binding of either diquat or paraquat relative to the starting diol in contrast to the picolinate ester of isomeric 5,5'-bis(hydroxymethyl)bis(m-phenylene)-32-crown-10, which displayed a higher binding constant than the starting diol. The results for the analogous reverse esters 7 derived from cis-(4,4')-dicarboxydibenzo-30-crown-10 and pyridylmethanols reveal weaker complexes with diquat than the normal esters 6; however, surprisingly, two reverse esters 7 complex paraquat more strongly than isomers 6.

High-Yielding Syntheses of Crown Ether-Based Pyridyl Cryptands.

Pyridinium bis(trifluoromethylsulfonyl)imide (PyTFSI)-templated syntheses of 2,6-pyridyl cryptands of cis(4,4')-dibenzo-30-crown-10 (3a), the p-bromobenzyloxy derivative 3b, bis(m-phenylene)-32-crown-10 (5), cis(4,4')-dibenzo-27S-crown-9 (7), cis(4,4')-dibenzo-27L-crown-9 (9), and cis(4,4')-dibenzo-24-crown-8 (11) are reported. Here we provide a fast (12 h), high-yielding (89%, 74%, 80%, and 62% for 3a, 3b, 5, and 9, respectively) templation method without the use of a syringe pump. The yields for 7 (19%) and 11 (26%) were lower than with the previous pseudo-high-dilution method, indicating ineffective templation in these cases. Coupled with our previously developed templated syntheses of dibenzo crown ethers, this protocol makes powerful cryptand hosts readily available in gram quantities in good yields from methyl 4(or 3)-hydroxy-3(or 4)-benzyloxybenzoate.

The Long and the Short of It: Regiospecific Syntheses of Isomers of Dicarbomethoxydibenzo-27-crown-9 and Binding Abilities of Their Pyridyl Cryptands.

The two isomers 6 and 9 of cis(4,4'-)-dicarbomethoxydibenzo-27-crown-9 with tri- and tetra-(ethyleneoxy) linkages transposed were synthesized regiospecifically in high yields (94 and 92%, respectively) by the Wang-Pederson-Wessels (WPW) protocol and were converted via the corresponding diols 7 and 10 to the corresponding pyridyl cryptands 3 and 4 by reaction with pyridine-2,6-dicarbonyl chloride. As expected from Corey-Pauling-Koltun (CPK) models, the cryptand with the tri(ethyleneoxy) arm para to the ester linkages, "short-armed" cryptand 3, did display a higher binding constant (Ka = 2.4 × 105 M-1) with paraquats than the analogous dibenzo-30-crown-10-based cryptand previously studied; however, the effect was only twofold. Its binding to diquat was reduced by an order of magnitude (1.5 × 105 M-1), as expected on the basis of its narrower cavity. Also as expected, the cryptand with the tetra(ethyleneoxy) arm para to the ester linkages, "long-armed" cryptand 4, possessed diminished binding with both paraquats and diquat relative to the 30-crown-based analogue; in these systems, 2:1 H:G complexes were also detected by mass spectrometry. A crystal structure is reported for 3·DQ(PF6)2.

Stimuli-responsive host-guest systems based on the recognition of cryptands by organic guests.

CONSPECTUS: As the star compounds in host-guest chemistry, the syntheses of crown ethers proclaimed the birth of supramolecular chemistry. Crown ether-based host-guest systems have attracted great attention in self-assembly processes because of their good selectivity, high efficiency, and convenient responsiveness, enabling their facile application to the "bottom-up" approach for construction of functional molecular aggregates, such as artificial molecular machines, drug delivery materials, and supramolecular polymers. Cryptands, as preorganized derivatives of crown ethers, not only possess the above-mentioned properties but also have three-dimensional spatial structures and higher association constants compared with crown ethers. More importantly, the introduction of the additional arms makes cryptand-based host-guest systems responsive to more stimuli, which is crucial for the construction of adaptive or smart materials. In the past decade, we designed and synthesized crown ether-based cryptands as a new type of host for small organic guests with the purpose of greatly increasing the stabilities of the host-guest complexes and preparing mechanically interlocked structures and large supramolecular systems more efficiently while retaining or increasing their stimuli-responsiveness. Organic molecules such as paraquat derivatives and secondary ammonium salts have been widely used in the fabrication of functional supramolecular aggregates. Many host molecules including crown ethers, cyclodextrins, calixarenes, cucurbiturils, pillararenes, and cryptands have been used in the preparation of self-assembled structures with these guest molecules, but among them cryptands exhibit the best stabilities with paraquat derivatives in organic solvents due to their preorganization and additional and optimized binding sites. They enable the construction of sophisticated molecules or supramolecules in high yields, affording a very efficient way to fabricate stimuli-responsive functional supramolecular systems. This Account mainly focuses on the application of cryptands in the construction of mechanically interlocked molecules such as rotaxanes and catenanes, and stimuli-responsive host-guest systems such as molecular switches and supramolecular polymers due to their good host-guest properties. These cryptands are bicyclic derivatives of crown ethers, including dibenzo-24-crown-8, bis(m-phenylene)-26-crown-8, dibenzo-30-crown-10, and bis(m-phenylene)-32-crown-10. The length of the third arm has a very important influence on the binding strength of these cryptands with organic guests, because it affects not only the size fit between the host and the guest but also the distances and angles that govern the strengths of the noncovalent interactions between the host and the guest. For example, for bis(m-phenylene)-32-crown-10-based cryptands, a third arm of nine atoms is the best. The environmental responsiveness of these cryptand-based host-guest systems arises from either the crown ether units or the third arms. For example, a dibenzo-24-crown-8 unit introduces potassium cation responsiveness and an azobenzene group on the third arm imbues photoresponsiveness. We believe that studies on stimuli-responsive host-guest systems based on cryptands and organic guests will contribute significantly to future research on molecular devices, supramolecular polymers, and other functional supramolecular materials.

Supramolecular AA-BB-type linear polymers with relatively high molecular weights via the self-assembly of bis(m-phenylene)-32-crown-10 cryptands and a bisparaquat derivative.

Two novel bis(m-phenylene)-32-crown-10-based cryptands, one bearing covalent linkages and the other metal-complex linkages, were designed and prepared. By self-assembly of these biscryptands, which can be viewed as AA monomers, and a bisparaquat, which can be viewed as a BB monomer, AA-BB-type linear supramolecular polymers with relatively high molecular weights were successfully prepared.

Complexation equilibria involving salts in non-aqueous solvents: ion pairing and activity considerations.

Complexation of anions, cations and even ion pairs is now an active area of investigation in supramolecular chemistry; unfortunately it is an area fraught with complications when these processes are examined in low polarity organic media. Using a pseudorotaxane complex as an example, apparent K(a2) values (=[complex]/{[salt](o)-[complex]}{[host](o)-[complex]}) for pseudorotaxane formation from dibenzylammonium salts (2-X) and dibenzo-[24]crown-8 (1, DB24C8) in CDCl(3)/CD(3)CN 3:2 vary with concentration. This is attributable to the fact that the salt is ion paired, but the complex is not. We report an equilibrium model that explicitly includes ion pair dissociation and is based upon activities rather than molar concentrations for study of such processes in non-aqueous media. Proper analysis requires both a dissociation constant, K(ipd), for the salt and a binding constant for interaction of the free cation 2(+) with the host, K(a5); K(a5) for pseudorotaxane complexation is independent of the counterion (500 M(-1)), a result of the complex existing in solution as a free cation, but K(ipd) values for the salts vary by nearly two orders of magnitude from trifluoroacetate to tosylate to tetrafluoroborate to hexafluorophosphate anions. The activity coefficients depend on the nature of the predominant ions present, whether the pseudorotaxane or the ions from the salt, and also strongly on the molar concentrations; activity coefficients as low as 0.2 are observed, emphasizing the magnitude of their effect. Based on this type of analysis, a method for precise determination of relative binding constants, K(a5), for multiple hosts with a given guest is described. However, while the incorporation of activity coefficients is clearly necessary, it removes the ability to predict from the equilibrium constants the effects of concentration on the extent of binding, which can only be determined experimentally. This has serious implications for study of all such complexation processes in low polarity media.

Contrasting biscryptand/dimethyl paraquat [3]pseudorotaxanes: statistical vs. anticooperative complexation behavior.

Via the self-assembly of two bis(meta-phenylene)-32-crown-10-based cryptands, bearing covalent and metal complex (ferrocene) linkages, with dimethyl paraquat, novel [3]pseudorotaxanes were formed statistically and anticooperatively, respectively.

In vitro and in vivo studies of single-walled carbon nanohorns with encapsulated metallofullerenes and exohedrally functionalized quantum dots.

Single-walled carbon nanohorns (SWNHs) are new carbonaceous materials. In this paper, we report the first successful preparation of SWNHs encapsulating trimetallic nitride template endohedral metallofullerenes (TNT-EMFs). The resultant materials were functionalized by a high-speed vibration milling method and conjugated with CdSe/ZnS quantum dots (QDs). The successful encapsulation of TNT-EMFs and external functionalization with QDs provide a dual diagnostic platform for in vitro and in vivo biomedical applications of these new carbonaceous materials.

Encapsulation of a radiolabeled cluster inside a fullerene cage, (177)Lu(x)Lu((3-x))N@C(80): an interleukin-13-conjugated radiolabeled metallofullerene platform.

In this communication, we describe the successful encapsulation of (177)Lu into the endohedral metallofullerene (177)Lu(x)Lu(3-x)N@C(80) (x = 1-3) starting with (177)LuCl(3) in a modified quartz Kraschmer-Huffman electric generator. We demonstrate that the (177)Lu (beta-emitter) in this fullerene cage is not significantly released for a period of up to at least one-half-life (6.7 days). We also demonstrate that this agent can be conjugated with an interleukin-13 peptide that is designed to target an overexpressed receptor in glioblastoma multiforme tumors. This nanoparticle delivery platform provides flexibility for a wide range of radiotherapeutic and radiodiagnostic multimodal applications.

High relaxivity trimetallic nitride (Gd3N) metallofullerene MRI contrast agents with optimized functionality.

Water-soluble poly(ethylene glycol) (PEG) functionalized and hydroxylated endohedral trimetallic nitride metallofullerene derivatives, Gd(3)N@C(80)[DiPEG(OH)(x)], have been synthesized and characterized. The (1)H MRI relaxivities in aqueous solution were measured for the derivatives with four different molecular weights of PEG (350-5000 Da) at 0.35, 2.4, and 9.4 T. The 350/750 Da PEG derivatives have the highest relaxivities among the derivatives, 237/232 mM(-1) s(-1) for r(1) and 460/398 mM(-1) s(-1) for r(2) (79/77 mM(-1) s(-1) and 153/133 mM(-1) s(-1) based on Gd(3+) ion), respectively, at a clinical-range magnetic field of 2.4 T. These represent some of the highest relaxivities reported for commercial or investigational MRI contrast agents. Dynamic light scattering results confirm a larger average size for 350/750 Da PEGs derivatives (95/96 nm) relative to longer chain length derivatives, 5000 Da PEG derivatives (37 nm). Direct infusion of the optimized 350 Da PEG derivatives into live tumor-bearing rat brains demonstrated an initial uniform distribution, and hence, the potential for effective brachytherapy applications when the encapsulated Gd(3+) ions are replaced with radioactive (177)Lu.

Facile preparation of a new gadofullerene-based magnetic resonance imaging contrast agent with high 1H relaxivity.

A new magnetic resonance imaging (MRI) contrast agent based on the trimetallic nitride templated (TNT) metallofullerene Gd(3)N@C(80) was synthesized by a facile method in high yield. The observed longitudinal and transverse relaxivities r(1) and r(2) for water hydrogens in the presence of the water-soluble gadofullerene 2 Gd(3)N@C(80)(OH)(approximately 26)(CH(2)CH(2)COOM)(approximately 16) (M = Na or H) are 207 and 282 mM(-1) s(-1) (per C(80) cage) at 2.4 T, respectively; these values are 50 times larger than those of Gd(3+) poly(aminocarboxylate) complexes, such as commercial Omniscan and Magnevist. This high (1)H relaxivity for this new hydroxylated and carboxylated gadofullerene derivative provides high signal enhancement at significantly lower Gd concentration as demonstrated by in vitro and in vivo MRI studies. Dynamic light scattering data reveal a unimodal size distribution with an average hydrodynamic radius of ca. 78 nm in pure water (pH = 7), which is significantly different from other hydroxylated or carboxylated fullerene and metallofullerene derivatives reported to date. Agarose gel infusion results indicate that the gadofullerene 2 displayed diffusion properties different from those of commercial Omniscan and those of PEG5000 modified Gd(3)N@C(80). The reactive carboxyl functionality present on this highly efficient contrast agent may also serve as a precursor for biomarker tissue-targeting purposes.

Highly regioselective derivatization of trimetallic nitride templated endohedral metallofullerenes via a facile photochemical reaction.

Photochemically generated benzyl radicals react with Sc(3)N@C(80)-I(h) to produce a dibenzyl adduct [Sc(3)N@C(80)(CH(2)C(6)H(5))(2)] in 82% yield and high regioselectivity. The adduct's (1)H spectrum revealed high symmetry: only one AB pattern was observed for the methylene protons. The (13)C NMR spectrum suggested a C(2)-symmetrical structure. DFT calculations reveal that a 1,4-adduct is more favorable than a 1,2-adduct by >10 kcal/mol. The 1,4-structure on [566] ring junctions was unambiguously confirmed by X-ray crystallographic analysis. UV-vis spectra revealed that the removal of two p orbitals from the pi system of the cage together with the benzylic substituents change the electronic properties of the metallofullerene in a manner similar to those reported for disilirane and trifluoromethyl moieties. Under the same conditions from Lu(3)N@C(80)-I(h) we prepared (63% yield) Lu(3)N@C(80)(CH(2)C(6)H(5))(2), which demonstrated properties similar to the 1,4-dibenzyl adduct of Sc(3)N@C(80)-I(h).

High-yielding, regiospecific synthesis of cis(4,4')-di(carbomethoxybenzo)-30-crown-10, its conversion to a pyridyl cryptand and strong complexation of 2,2'- and 4,4'-bipyridinium derivatives.

A high yielding (93%), regiospecific synthesis of cis(4,4')-di(carbomethoxybenzo)-30-crown-10 (1c) is reported. The derived crown ether diol 1d was converted to pyridyl cryptand 12 in 44% yield by reaction with pyridine-2,6-dicarbonyl chloride. Binding of two different 4,4'-bipyridinium (paraquat) species (3) and 2,2'-bipyridinium (diquat) 4 by 12 was explored via (1)H NMR spectroscopy, NOE experiments, mass spectrometry, X-ray crystallographic analyses, and isothermal titration calorimetry. Cryptand 12 exhibits the highest association constant for diquat ever reported (Ka = 1.9 x 10(6) M(-1)) and very high association constants for paraquats (Ka > 10(5) M(-1)) in acetone at 22 degrees C. The binding constant of diquat 4 by cryptand 12 is nearly 6-times higher than any other reported host.

A new functional bis(m-phenylene)-32-crown-10-based cryptand host for paraquats.

The pseudorotaxane complex of the new hydroxymethyl cryptand 3 with N,N'-dimethyl-4,4'-bipyridinium bis(hexafluorophosphate), PQ(PF6)2, has an association constant of 2.0(+/-0.3) x 10(4) M(-1). In the crystal structure of 3 x PQ(PF6)2 one of the bonding elements appears to be an aromatic edge-to-face interaction of a paraquat beta-proton with the hydroquinone moiety; this is the first time this interaction has been reported between a cryptand and paraquat.

Manganese(III)-catalyzed free radical reactions on trimetallic nitride endohedral metallofullerenes.

The first reactions of trimetallic nitride templated endohedral metallofullerenes (TNT EMFs) with carbon radicals generated from diethyl malonate catalyzed by manganese(III) acetate are reported. Two methano monoadducts, Sc3N@C80-A and Sc3N@C80-B, were isolated and characterized. Sc3N@C80-A contains two ester moieties, whereas Sc3N@C80-B contains only one ester group and a hydrogen atom on the central carbon of the addend. NMR spectroscopy of the two monoadducts suggests that the addition occurs regioselectively at a 6,6-ring juncture on the surface of the icosahedrally (Ih) symmetric Sc3N@C80, forming the first 6,6-ring-bridged methano Ih Sc3N@C80 derivatives. The measured 1J(C,H) = 147 Hz for the methano carbon with its hydrogen in monoadduct Sc3N@C80-B nearly perfectly matches the data for pi-homoaromatic systems, indicating an open [6,6]-methano structure. Geometry optimization also found that the "closed" [6,6]-methano structures were energetically unstable and always led to the open forms. Thus, an "open" [6,6]-methanofulleride structure is proposed, which was induced by the norcaradiene rearrangement, resulting in the cleavage of the cyclopropane ring and the formation of energetically stable open cage fullerene derivatives. These are the first examples of thermodynamically stable adducts of the "open" type at the 6,6-ring juncture of Ih Sc3N@C80, differing greatly from the "closed" 5,6-ring juncture adducts reported previously. In addition, bis-, tri-, and up to octaadducts of Sc3N@C80 were detected by matrix-assisted laser desorption ionization time-of-flight mass spectrometry; this synthetic method was also applied to Lu3N@C80, producing adducts with up to 10 substituents on the carbon cage. These are the highest levels of substitution of TNT metallofullerenes reported so far.

Bis(meta-phenylene)-32-crown-10-based cryptand/diquat inclusion [2]complexes.

Bis(meta-phenylene)-32-crown-10-based cryptands have been proved to complex diquat much more strongly than bis(meta-phenylene)-32-crown-10 itself; in fact, one containing a pyridyl moiety has one of the highest Ka values yet reported.