DOI: 10.1002/chem.201500568
Concept
& Supramolecular Chemistry
How to Make Weak Noncovalent Interactions Stronger Jiang-Fei Xu, Linghui Chen, and Xi Zhang*[a]
Chem. Eur. J. 2015, 21, 11938 – 11946
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Concept fined self-assembled structures with high stability. In addition, classical and newly reported examples are combined to follow the traditional philosophy of research: novelty is always linked to the past. We hope this concept article offers guidance in the construction and fabrication of stable molecular assemblies and supramolecular materials.
Abstract: By employing noncovalent interactions, chemists have constructed a variety of molecular aggregates with well-defined structures and fascinating properties. In fabricating stable and large molecular assemblies, noncovalent interactions with high binding strength are needed. This Concept summarizes some strategies to modify and optimize the structures of building blocks for making weak noncovalent interactions stronger. The strategies include: 1) Preorganization of binding sites; 2) spatial confinement effects; 3) multivalent enhancement; 4) synergistic binding with multiple forces. Examples of the fabrication of supramolecular architectures by utilizing these strategies are presented and discussed. Guidance is offered in the construction and fabrication of stable molecular assemblies and supramolecular materials.
Preorganization of Binding Sites
Introduction The development of supramolecular chemistry, defined by Lehn as chemistry beyond the molecule, has offered great opportunities for chemists to design and study molecular aggregates with well-defined structures and functions.[1, 2] The formation of supramolecular systems is driven by noncovalent intermolecular forces, such as hydrogen bonding, p–p stacking, metal-ligand coordination, and electrostatic interactions. The dynamic nature of noncovalent interactions can endow supramolecular materials with fascinating new functions, such as responsiveness and adaptiveness, that are different from their covalent counterparts.[3] These attributes have motivated chemists to construct a variety of functional supramolecular systems, including supramolecular polymers, mechanically interlocked structures, chemosensors, supramolecular gels, drug carriers, and so on.[4–13] However, the binding strength of common noncovalent interactions is not strong enough to drive the formation of large and stable supramolecular assemblies. For example, in making supramolecular polymers with high molecular weight or fabricating stable molecular assemblies in general, we need to find out ways to make weak noncovalent interactions strong enough to meet the need.[14, 15] Herein, we summarize and discuss some strategies, generally for how to modify and optimize the structures of building blocks to make weak noncovalent interactions stronger. These strategies, which have been successfully applied in the design of highly interactive building blocks that further self-assemble into large supramolecular architectures, include: 1) Preorganization of binding sites; 2) spatial confinement effects; 3) multivalent enhancement; 4) synergistic binding with multiple forces. Some of them were inspired by nature, as we know that all of organisms in nature are highly complex and well-de[a] Dr. J.-F. Xu, L. Chen, Prof. X. Zhang The Key Lab of Organic Optoelectronics & Molecular Engineering Department of Chemistry Tsinghua University, Beijing 100084 (P. R. China) E-mail: [email protected] Chem. Eur. J. 2015, 21, 11938 – 11946
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In host–guest chemistry, a host is defined as an organic molecule or ion whose binding sites converge in the complex, whereas a guest is defined as any molecule or ion whose binding sites diverge in the complex.[16] The synthesis of crown ethers and studies of their host–guest complexations led to the birth of supramolecular chemistry. It has been widely accepted that preorganization is a central determinant of binding ability for crown ethers and their derivatives. The principle of preorganization was stated by Cram as “the more highly hosts and guests are organized for binding and low solvation prior to their complexation, the more stable will be their complexes.”[17] The effect of preorganization contributes to the enhanced binding ability of macrocyclic hosts over linear analogues, the so-called macrocyclic effect, and further improvements with cryptands are observed. Cryptands, as preorganized derivatives of crown ethers, greatly increase the stabilities of the host–guest complexes. Great attention has been attracted by cryptands due to their applications in efficient preparation of mechanically interlocked structures and supramolecular polymers in the past decades.[18, 19] The enhanced binding ability from crown ether to cryptand is clearly illustrated when paraquats are used as the guest molecules. As shown in Figure 1, bis(m-phenylene)-32-crown-10 (BMP32C10) is a bisarylene crown ether with 32 atoms. One of the most interesting properties of BMP32C10 derivatives is their complexation with paraquats, N,N’-dialkyl-4,4’-bipyridini-
Figure 1. Top; Chemical structures of paraquat derivative 1, BMP32C10 2, and BMP32C10-based cryptands 3 and 4. Bottom: X-ray structure of complex between 3 and 1. Reprinted with permission from ref. [20]. Copyright Ó 1999, American Chemical Society.
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Concept um salts, with association constants on the order of 102– 103 m¢1. Gibson and co-workers reported a BMP32C10-based cryptand 3 in 1999,[20] which exhibited a 100-fold increase in association constant (Ka) for paraquat derivative 1 relative to BMP32C10 2 (6.1 Õ 104 m¢1 vs 5.5 Õ 102 m¢1). The enhanced association was demonstrated to be purely due to preorganization; the enthalpy terms for complexation by the crown ether and the cryptand were exactly the same, but the entropic penalty with the cryptand was significantly reduced.[21] As expected, the cryptand underwent significantly less structural change in the complexation process. This result was consistent with the X-ray analysis that the crown ether BMP32C10 was not folded in the solid state, but the host–guest complexes based on BMP32C10 derivatives showed folded structures (“taco complexes”), in which the guest molecules were enveloped within the folded hosts. Further enhancement in binding ability of BMP32C10-based cryptands was achieved by optimization of the cryptand size and introduction of additional binding sites on the arms. The optimized cryptand 4 exhibited a very high association constant with paraquat, 5.0 Õ 106 m¢1, 9000 times greater than that of BMP32C10 2 (Figure 1).[21] The number of atoms in the third arm of cryptand 4 was 9, which was the adequate ring size for occupation by the guest. The pyridyl unit on the third arm introduced additional hydrogen bonding or electrostatic interactions between the pyridyl nitrogen atom and the b-pyridinium hydrogens of the paraquat guest. These factors, in cooperation with preorganization, resulted in the extremely high binding affinity of cryptand 4 and paraquat guests, the highest reported to date. The stronger host–guest interaction of BMP32C10-based cryptands and paraquats makes it possible to fabricate supramolecular polymers with high degrees of polymerization. As reported by Gibson and co-workers, two BMP32C10-based cryptands were linked by terephthalate or ferrocene esters to perform as homoditopic AA monomers 5 and 6, and a bisparaquat as a BB monomer 7 (Figure 2).[22] By self-assembly of equimolar of AA monomers and BB monomers in solution, linear
Figure 2. Schematic representation of the formation of supramolecular polymers by self-assembly of cryptand-based AA monomers with paraquatbased BB monomer. Adapted with permission from ref. [22]. Copyright Ó 2011, American Chemical Society. Chem. Eur. J. 2015, 21, 11938 – 11946
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supramolecular polymers with relatively high molecular weights were prepared. For example, the degree of polymerization was estimated to be 93 47 at monomer concentrations of 290 mm, indicating a number average molecular weight of 241 kDa. The supramolecular polymers were polymerized from homoditopic AA and BB monomers via heterodimerization in an alternating manner, and the high molecular weight resulted from the strong binding capability of the hosts and guests. Preorganization is a classical concept in host–guest chemistry and it has been proven to be an effective way to increase binding ability of crown ethers. However, it remains synthetically challenging to achieve this increased affinity for some structurally complex guests. If the fit is not perfect, then the lack of conformational flexibility could actually hamper binding. Thus, analysis of conformation of host–guest complexes based on X-ray structures should be carefully performed, so that structural parameters from the X-ray structures are helpful in providing some guidance on the design of preorganization.
Spatial Confinement Effects In confined spaces, interactions between guest molecules can be enhanced due to their close contact. Examples include the formation of stable charge-transfer complexes in the pores of zeolites[23] and stabilized hydrogen-bonded supramolecular polymers in the liquid crystalline state.[24] However, the aforementioned carriers are not able to act as a part of building blocks themselves in self-assembly processes in solution. With the aim to fabricate well-defined supramolecular structures conveniently, we focus on the enhanced intermolecular interactions in cavities provided by macrocyclic hosts. In such systems, the host molecules act as nano-carriers to stabilize and enhance interactions between guest molecules, and as building blocks to construct molecular assemblies simultaneously. Cucurbit[8]uril (CB[8]), as a member of CB[n] host family, has a hydrophobic cavity and two carbonyl-laced portals.[25] Owing to its relatively large cavity size, CB[8] exhibits unique host– guest properties, such as the ability to encapsulate two aromatic guests inside the cavity. Hence, the charge-transfer interactions, p–p interactions, and dimerization of radical cations between the two encapsulated guest molecules are dramatically enhanced by CB[8].[26, 27] The first host-enhanced chargetransfer interaction based on CB[8] was reported by Kim and co-workers in 2001.[28] The electron-deficient guest methyl viologen (MV) formed a 1:1 host–guest complex with CB[8] in water with a binding constant of 1.1 Õ 105 m¢1. Upon addition of one equivalent of an electron-rich guest, 2,6-dihydroxynaphthalene (HN) or 1,4-dihydroxybenzene (HB), to the binary complex, a stable 1:1:1 complex containing the electron donor–acceptor pair was formed instantaneously and quantitatively (Figure 3 a). Later, by altering the electron-rich guest molecules, the formation of a stable ternary host–guest complex consisting of an anthracene (An) derivative, MV, and CB[8], driven by host-enhanced charge-transfer interactions, was reported (Figure 3 b).[29] It was noted that the MV–CB[8] binary complex was
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Concept from the strong host-enhanced p–p interactions, supramolecular polymers in aqueous solutions at relatively low concentrations (ca. 1 mm) were successfully fabricated. Radicals are very unstable species because of the high reactivity of unpaired electrons. However, not only the stability, but also the stacking interactions of radicals can be promoted by host encapsulation.[33–35] Recently, Li and co-workers reported the formation of a two-dimensional supramolecular organic framework, driven by CB[8]-promoted dimerization of viologen radical cations.[36] The viologen radical cations tended to stack into radical dimers in aqueous solution. The apparent association constant for the dimerization was 3.5 Õ 103 m¢1. In the presence of CB[8], the association constant was significantly increased to 9.6 Õ 105 m¢1 (Figure 5). With the assistance of CB[8],
Figure 3. a) Formation of charge-transfer complexes in CB[8]. Reprinted with permission from ref. [26]. Copyright Ó 2007, the Royal Society of Chemistry. b) Complexation of the MV–CB[8] binary complex with An derivative.
found to bind with the An derivative in a 1:1 molar ratio with a high binding constant of 1.1 Õ 106 m¢1. p–p interactions are a kind of weak force that is difficult to employ in the construction of large supramolecular assemblies. It is also inconvenient to enhance p–p interactions by using large p-conjugated molecules that require time-consuming synthesis. Luckily, like host-enhanced charge-transfer interactions, p–p interactions between two p-conjugated guests encapsulated in CB[8] cavities can be markedly enhanced. We have reported that CB[8] can bind either anthracene derivatives or naphthalene derivatives with 1:2 stoichiometry in water (Figure 4).[30–32] In the presence of CB[8], the fluorescence
Figure 4. Enhanced p–p interactions in CB[8]. Inset: Fluorescence spectra of An derivative in the absence and in the presence of CB[8]. Adapted with permission from ref. [30]. Copyright Ó 2011, John Wiley & Sons, Inc.
spectra showed a strong emission band assigned to the excimer of anthracene or naphthalene, respectively, indicating strong p–p interactions between the guest molecules enhanced by CB[8]. The two-site binding constants were measured to be 1011–1012 m¢2 for the naphthalene/CB[8] system and 1.46 Õ 1012 m¢2 for the anthracene/CB[8] system. Benefiting Chem. Eur. J. 2015, 21, 11938 – 11946
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Figure 5. Promoted dimerization of viologen radical cations by CB[8] encapsulation.
a triangular building block containing three viologen radical cations assembled into two dimensional supramolecular organic frameworks in water, and the single-layer structure was maintained in the solid state, demonstrating their high stability. Host-enhanced noncovalent interactions are useful tools when macrocycles are involved in molecular assemblies. CB[8] is a good candidate for effecting environmentally friendly selfassembly and fabricating functional materials. However, the poor water solubility of CB[8] may limit its applications. Therefore, CB derivatives with good solubility are highly desirable. To construct new materials with new functions, it is necessary to expand the noncovalent interactions that could be enhanced by CB[8] and to develop novel supramolecular hosts that may enhance noncovalent interactions.
Multivalent Enhancement The binding strength of single set of noncovalent interactions is usually weak, in most cases being on the order of 10 kJ mol¢1. It is easily understood that a direct method to strengthen interactions is to increase the number of binding sites in the building blocks. This strategy is so straightforward that it has been widely applied in supramolecular chemistry.[37–39] It is also very important that when multiple binding sites are integrated within one molecule, the arrangement of the binding arrays should be carefully optimized.
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Concept Aromatic donor–acceptor interactions are too weak and nondirectional to drive highly ordered self-assembly. In addition to the well-studied host-enhanced charge-transfer interaction, the introduction of additional binding units and directing groups on the building blocks can significantly promote the binding strength. Molecular tweezers,[40] as noncyclic host molecules with open cavities capable of binding guest molecules, are a representative example. We have measured the binding strength of interactions between C60 and a porphyrin tweezer by AFM-based single-molecule force spectroscopy (SMFS; Figure 6).[41] Compared with the interaction between C60 and
Figure 6. Left: Interaction between C60 and a porphyrin tweezer. Right: Interaction between C60 and a single porphyrin. Reprinted with permission from ref. [41]. Copyright Ó 2009, American Chemical Society.
a single porphyrin (29 pN), SMFS revealed that the porphyrin tweezer can provide an enhanced binding interaction with C60, resulting in a more than twofold higher unbinding force (75 pN). Therefore, multivalent binding can lead to the enhanced effect such that one plus one is more than two. The development of molecular tweezers makes the fabrication of linear supramolecular polymers driven by strong aromatic donor–acceptor interactions feasible.[42] Recently, a molecular tweezer incorporating two pincer-like alkynylplatinum(II) terpyridine units connected by a rigid spacer was reported by Yam and co-workers.[43, 44] The predetermined distance between the two electron-deficient pincers efficiently facilitated the tweezer-type host binding with electron-rich arenes through enhanced charge-transfer interactions. By employing this tweezer–guest molecular recognition, Wang and co-workers very recently designed the heteroditopic AB-type monomers to construct supramolecular polymers.[45] The electron-rich planar guest pyrene, as the head, was linked with the molecular tweezer 8, as the tail, by long alkyl spacers to form the ABtype monomers 9 and 10 (Figure 7). The complementary heteroditopic monomer facilitated the formation of linear supramolecular polymers in head-to-tail fashion, and the flexible alkyl spacer was expected to decrease conformational entropy for the multiple binding processes. The binding constant Ka for the tweezer/pyrene recognition motif was 1.43 Õ 104 m¢1. The isodesmic model was chosen to theoretically calculate the average degree of polymerization, N, for the resulting supramolecular polymer. Using the Ka value in the equation[22, 48] N = (Ka [conc])1/2, N = 32, corresponding to the total molar mass of 6.97 Õ 104 g mol¢1 was calculated at the monomer concentration of 70 mm. The equation indicates that both the binding constant and the monomer concentration are important in formation of supramolecular polymers with high degrees of polymerization. Chem. Eur. J. 2015, 21, 11938 – 11946
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Figure 7. Schematic representation of the formation of supramolecular polymer driven by the interactions of molecular tweezer and pyrene. Adapted with permission from ref. [45]. Copyright Ó 2014, John Wiley & Sons, Inc.
For CB[8]-based supramolecular systems, due to their poor solubility in aqueous solutions, very high binding strength is highly desired for the formation of stable and large molecular assemblies in dilute solutions. To promote linear supramolecular polymerization, we designed a unique ABBA-type monomer, in which the host-enhanced charge-transfer interactions with double binding mode were successfully realized (Figure 8).[29] The ABBA type monomer was prepared with an anthracene–viologen–viologen–anthracene (DADV) structure. This design prevented the possibility of intramolecular complexation to form a 1:1 cyclic species and inhibited the formation of 2:2 cyclic dimers, two factors unfavorable for supramolecular polymerization. Therefore, when mixing DADV with CB[8] in a 1:2 molar ratio in water, linear supramolecular polymerization was highly favored, benefiting from the successful
Figure 8. Schematic representation of the formation of supramolecular polymer based on multiple host-enhanced charge-transfer interactions. Reprinted with permission from ref. [29]. Copyright Ó 2010, John Wiley & Sons, Inc.
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Concept combination of high binding strength and high orientation selectivity in ABBA-type building blocks. Another well-known means of combining multiple binding sites is the design of multiple hydrogen-bonding arrays. Both the binding strength and the directionality can be increased when multiple hydrogen bonds are arrayed in one unit.[46] The triple hydrogen-bonding interaction between diamidopyridine and uracil derivatives was utilized to drive the formation of a supramolecular polymer, as first reported by Lehn and coworkers in 1990.[47] The supramolecular polymer displayed crystallinity in the solid phase, in contrast to the behavior of each of the monomers. Later, a self-complementary quadruple hydrogen-bonding array, ureidopyrimidinone (UPy), was reported by Meijer and co-workers in 1997.[48] Due to its high dimerization constant (up to 6 Õ 107 m¢1 in chloroform) and directionality, the UPy unit has become one of the most used building blocks in supramolecular chemistry.[49, 50] The high dimerization constants of UPy derivatives are attributed to the self-complementary donor–donor–acceptor–acceptor (DDAA) array of the hydrogen-bonding sites. Further studies pointed out that the order of donors and acceptors in the multiple hydrogen-bonding arrays influenced the binding strength significantly.[51, 52] The UPy unit has two tautomers that are able to form selfcomplementary quadruple hydrogen-bonded dimers; the 4[1H]-pyrimidinone tautomer forms dimers via DDAA hydrogen-bonding arrays and the pyrimidin-4-ol tautomer forms the dimers via DADA arrays (Figure 9). On account of the addition-
Figure 9. Chemical structures of the keto (top) and enol (bottom) tautomers of UPy and their dimers. Adapted with permission from ref. [51]. Copyright Ó 1998, American Chemical Society.
al attractive secondary electrostatic interactions in DDAA dimers, the dimerization constant of DDAA arrays is significantly higher than that of DADA arrays (Kdim 6 Õ 107 m¢1 vs 9 Õ 105 m¢1). In consequence, the order of arrangement of the multiple hydrogen-bonding arrays should be carefully optimized in the design of such building blocks. It should be pointed out that the strength of hydrogen bonding is strongly solvent dependent. Taking the UPy dimers of DDAA arrays as an example, Kdim is 6 Õ 107 m¢1 in CHCl3, 1 Õ 107 m¢1 in chloroform saturated Chem. Eur. J. 2015, 21, 11938 – 11946
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with water (ca. 55 mm), and 6 Õ 108 m¢1 in toluene.[53] The dimerization is facilitated by the lower polarity of toluene. Kdim decreased significantly to 1.2 Õ 106 m¢1 in chloroform containing only 0.3 % v/v DMSO,[51] indicating the strong dependency on polarity of the solvent.
Synergistic Binding with Multiple Forces In many cases, a simple but effective way to enhance the binding affinity is to combine two or more sorts of driving forces together; thus they can drive the self-assembly synergistically. Coupling of interactions can lead to positive or negative cooperativity.[54] In this section we will focus on the coupling of different interactions in a positively cooperative manner, in which the coupled binding affinity is significantly larger than when these forces are used alone. To drive the self-assembly process by synergistic binding is a well-established strategy in nature. Many important biological processes and complex structures in living systems are driven and directed by a variety of noncovalent interactions synergistically. One of the well-known examples is the formation of the DNA double helix, which is directed by complementary pairing of nucleotides by hydrogen bonding, and stabilized by hydrophobic interactions between the covalently linked nucleotides perpendicular to the hydrogen bonds.[55, 56] Inspired by DNA, Yang and co-workers combined hydrogen bonding with hydrophobic interactions to drive the construction of stable aggregates in water.[57] They designed and synthesized three amphiphilic building blocks; compounds 11 and 12, containing one and two UPy hydrogen-bonding units per molecule, respectively, and compound 13, without any hydrogen-bonding units, as a control (Figure 10). The three amphiphiles self-assembled into micelle or vesicle structures in water, and the stability of the aggregates was represented by their low critical aggregation concentrations (CAC). It was found that despite the similar weight fraction of hydrophobic parts of compounds 11 and 13, the CAC of 11 (one UPy unit per molecule, 22 mm) was 5.5 times lower than that of 13 (no UPy units, 120 mm). Increasing the number of UPy units from one in 11 to two in 12 further lowered the CAC by a factor of 16 (from 22 to 1.4 mm). The change in CAC across the series 13 > 11 > 12 was consistent with the important contribution of hydrogen bonding to self-assembly of amphiphiles 11–13 in water. Simple modifications on crown ethers may combine some additional interactions, such as electrostatic interactions, with the original host–guest complexations.[58, 59] Supramolecular polymerization driven by a combination of electrostatic attraction and crown ether-based host–guest interaction in aqueous media was reported by Huang and co-workers[60] The neutral BMP32C10 derivative 14, containing two carboxylic acid groups on the crown ether, bound with a positively charged viologen derivative very weakly in aqueous solutions (Figure 11; Ka = 57 m¢1 by 1H NMR titration). However, when the neutral carboxylic groups were deprotonated to give anionic carboxylate groups, the crown ether 15 developed into a good host for binding cationic viologen salts. The introduction of
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Concept
Figure 10. Chemical structures, self-assemblies, and CACs of amphiphiles 11, 12, and 13 in water. Adapted with permission from ref. [57]. Copyright Ó 2014, American Chemical Society.
but < 10 m¢1 in 5 % DMSO in chloroform). The hydrogen-bonding patterns in dimers of 17 and in dimers of 18 were essentially identical but the lack of ionic interactions dramatically lowered the stability of the neutral form. It was further revealed that the hydrogen-bonding network, the electrostatic attraction, and also their mutual interactions were responsible for the high stability of dimers of the zwitterion.[63] Synergistic effects are remarkable when multiple binding sites in separate building blocks are spatially matched very well. Li and co-workers constructed highly stable supramolecular copolymers with high molecular weight that took advantage of the multivalency and cooperativity principles to achieve enhanced binding efficiency.[64] The hydrogen-bonded C6-symmetric zinc porphyrin hexamer 196, one of the monomers for the supramolecular copolymer, was self-assembled from the heterocyclic unit of 19 by
Figure 12. Chemical structures of dimers of the zwitterion 17 and its neutral analogue 18. Reprinted with permission from ref. [62]. Copyright Ó 2003, American Chemical Society.
Figure 11. Chemical structures of BMP32C10 derivatives 14 and 15, and the AB monomer 16.
electrostatic attraction significantly enhanced the host–guest complexation with the association constant of 1.7 Õ 103 m¢1, which was 30 times larger than the neutral crown ether analog. Thus, by utilizing the electrostatic attraction-enhanced crown ether-based molecular recognition, the heteroditopic AB monomer 16 self-assembled into a linear supramolecular polymer at high concentrations. Hydrogen-bonding interactions are commonly used to drive self-assembly in apolar solvents, because polar solvents, such as water and DMSO, compete strongly with hydrogen-bonding sites.[61] However, when combined with ion-pairing interactions, the hydrogen bonding may show considerable strength in polar solvents. A self-complementary zwitterion, successfully coupling multiple ion-pairing and hydrogen-bonding interactions, was reported by Schmuck and co-workers.[62] The watersoluble guanidiniocarbonyl pyrrole carboxylate zwitterion 17 formed extremely stable dimers in highly polar solvents. The association constant for the dimerization was up to 1010 m¢1 in DMSO and was still surprisingly high (170 m¢1) in water (Figure 12). In comparison, the neutral analogue of the zwitterion, amidopyridine pyrrole carboxylic acid 18, dimerized only in organic solvents of low polarity (Kdim > 104 m¢1 in chloroform Chem. Eur. J. 2015, 21, 11938 – 11946
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multiple hydrogen-bonding interactions in toluene (Figure 13). The hexamer then bound with the C3-symmetric hexadentate linker 20 by alternately forming three N¢Zn coordination bonds in an induced-fit manner to generate the layered supramolecular copolymer. Because of the highly spatially matched binding sites in the hydrogen-bonded pophyrin hexamer and the hexadentate linker, cooperative complexation between zinc porphyrin and pyridine units was observed. The apparent association constant for the complex of the zinc porphyrin in the hexamer 196 and the pyridine in the model compound tridentate linker 21 was determined to be 3.4 Õ 107 m¢1, which was 4.4 Õ 103 times higher than that of the complex of the free zinc porphyrin 22 and the pyridine of 21 (7.7 Õ 103 m¢1). Driven by the multivalent and cooperative complexation, a supramolecular copolymer was fabricated with average molecular weight higher than 4.2 Õ 106 g mol¢1. The key point for the strategy of multivalent enhancement and synergistic binding with multiple forces is to make multiple interactions that work together with positive cooperativity. We can learn a lot from nature. The strong binding of biotin to the streptavidin tetramer (Ka = 1013.4 m¢1) is about 1000 times stronger than the expected binding, based solely on the sum of the parts,[54] thus providing a clear example where binding affinity is a property of the whole system. In the design of building blocks, multiple binding units should be well organized and arranged. The preorganized and spatially matched structure will significantly reduce the entropic penalty during
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Concept played by strong intermolecular complexation. Although many supramolecular devices work well in solution, problems can arise when they are transferred onto solid surfaces. It is highly desirable to develop powerful technologies that can enhance the stability of supramolecular assemblies on surfaces and, in the meantime, order and mobility should be combined and balanced. Novel functional surfaces and thin-film materials are expected to be fabricated through new strategies.
Acknowledgements This work was financially supported by the National Natural Science Foundation of China (21434004, 91427301), the NSFC Innovation Group (21421064), and the National Basic Research Program of China (2013CB834502). We acknowledge Ms. Dan Yu (Rochester Institute of Technology) and Mr. Qiao Song (Tsinghua University) for artwork. Keywords: binding constants · host–guest systems · noncovalent interactions · self-assembly · supramolecular chemistry Figure 13. Schematic representation of the formation of an A6B-type supramolecular copolymer. Reprinted with permission from ref. [64]. Copyright Ó 2011, American Chemical Society.
the binding process, therefore making the combined interaction stronger.
Summary and Outlook In this concept article, we have summarized some established methods to construct stable supramolecular assemblies by increasing the strength of noncovalent interactions. Some general rules in the design of building blocks for enhanced binding ability are outlined as follows. 1) The best-fitted host conformation to recognize guest molecules is significant in host–guest complexation; 2) the rational arrangement of binding sites is essential in making multiple interactions synergistically; 3) a good (uncompetitive) solvent is very important in making complexation more favorable. Although considerable achievements have been made to attain very strong binding affinity in recent decades, it is still necessary to develop new strategies to enhance the binding strength to make self-assembly efficient and convenient. Furthermore, with the aim to build supramolecular architectures with desired topologies, especially in the case of sequencespecific assemblies, we also need to develop new strategies to control the directionality and selectivity of noncovalent interactions. Hierarchical assembly and integrative self-sorting may play important roles in future work to make self-assembly a powerful tool in creating new materials. Moreover, it is also very important to extend the applications of enhanced noncovalent interactions from bulk solution onto surfaces. Multifunctional interfaces and surfaces can be fabricated at liquid–solid interfaces, in which essential roles are Chem. Eur. J. 2015, 21, 11938 – 11946
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Received: February 10, 2015 Published online on June 26, 2015
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Concept
& Supramolecular Chemistry
How to Make Weak Noncovalent Interactions Stronger Jiang-Fei Xu, Linghui Chen, and Xi Zhang*[a]
Chem. Eur. J. 2015, 21, 11938 – 11946
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Concept fined self-assembled structures with high stability. In addition, classical and newly reported examples are combined to follow the traditional philosophy of research: novelty is always linked to the past. We hope this concept article offers guidance in the construction and fabrication of stable molecular assemblies and supramolecular materials.
Abstract: By employing noncovalent interactions, chemists have constructed a variety of molecular aggregates with well-defined structures and fascinating properties. In fabricating stable and large molecular assemblies, noncovalent interactions with high binding strength are needed. This Concept summarizes some strategies to modify and optimize the structures of building blocks for making weak noncovalent interactions stronger. The strategies include: 1) Preorganization of binding sites; 2) spatial confinement effects; 3) multivalent enhancement; 4) synergistic binding with multiple forces. Examples of the fabrication of supramolecular architectures by utilizing these strategies are presented and discussed. Guidance is offered in the construction and fabrication of stable molecular assemblies and supramolecular materials.
Preorganization of Binding Sites
Introduction The development of supramolecular chemistry, defined by Lehn as chemistry beyond the molecule, has offered great opportunities for chemists to design and study molecular aggregates with well-defined structures and functions.[1, 2] The formation of supramolecular systems is driven by noncovalent intermolecular forces, such as hydrogen bonding, p–p stacking, metal-ligand coordination, and electrostatic interactions. The dynamic nature of noncovalent interactions can endow supramolecular materials with fascinating new functions, such as responsiveness and adaptiveness, that are different from their covalent counterparts.[3] These attributes have motivated chemists to construct a variety of functional supramolecular systems, including supramolecular polymers, mechanically interlocked structures, chemosensors, supramolecular gels, drug carriers, and so on.[4–13] However, the binding strength of common noncovalent interactions is not strong enough to drive the formation of large and stable supramolecular assemblies. For example, in making supramolecular polymers with high molecular weight or fabricating stable molecular assemblies in general, we need to find out ways to make weak noncovalent interactions strong enough to meet the need.[14, 15] Herein, we summarize and discuss some strategies, generally for how to modify and optimize the structures of building blocks to make weak noncovalent interactions stronger. These strategies, which have been successfully applied in the design of highly interactive building blocks that further self-assemble into large supramolecular architectures, include: 1) Preorganization of binding sites; 2) spatial confinement effects; 3) multivalent enhancement; 4) synergistic binding with multiple forces. Some of them were inspired by nature, as we know that all of organisms in nature are highly complex and well-de[a] Dr. J.-F. Xu, L. Chen, Prof. X. Zhang The Key Lab of Organic Optoelectronics & Molecular Engineering Department of Chemistry Tsinghua University, Beijing 100084 (P. R. China) E-mail: [email protected] Chem. Eur. J. 2015, 21, 11938 – 11946
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In host–guest chemistry, a host is defined as an organic molecule or ion whose binding sites converge in the complex, whereas a guest is defined as any molecule or ion whose binding sites diverge in the complex.[16] The synthesis of crown ethers and studies of their host–guest complexations led to the birth of supramolecular chemistry. It has been widely accepted that preorganization is a central determinant of binding ability for crown ethers and their derivatives. The principle of preorganization was stated by Cram as “the more highly hosts and guests are organized for binding and low solvation prior to their complexation, the more stable will be their complexes.”[17] The effect of preorganization contributes to the enhanced binding ability of macrocyclic hosts over linear analogues, the so-called macrocyclic effect, and further improvements with cryptands are observed. Cryptands, as preorganized derivatives of crown ethers, greatly increase the stabilities of the host–guest complexes. Great attention has been attracted by cryptands due to their applications in efficient preparation of mechanically interlocked structures and supramolecular polymers in the past decades.[18, 19] The enhanced binding ability from crown ether to cryptand is clearly illustrated when paraquats are used as the guest molecules. As shown in Figure 1, bis(m-phenylene)-32-crown-10 (BMP32C10) is a bisarylene crown ether with 32 atoms. One of the most interesting properties of BMP32C10 derivatives is their complexation with paraquats, N,N’-dialkyl-4,4’-bipyridini-
Figure 1. Top; Chemical structures of paraquat derivative 1, BMP32C10 2, and BMP32C10-based cryptands 3 and 4. Bottom: X-ray structure of complex between 3 and 1. Reprinted with permission from ref. [20]. Copyright Ó 1999, American Chemical Society.
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Concept um salts, with association constants on the order of 102– 103 m¢1. Gibson and co-workers reported a BMP32C10-based cryptand 3 in 1999,[20] which exhibited a 100-fold increase in association constant (Ka) for paraquat derivative 1 relative to BMP32C10 2 (6.1 Õ 104 m¢1 vs 5.5 Õ 102 m¢1). The enhanced association was demonstrated to be purely due to preorganization; the enthalpy terms for complexation by the crown ether and the cryptand were exactly the same, but the entropic penalty with the cryptand was significantly reduced.[21] As expected, the cryptand underwent significantly less structural change in the complexation process. This result was consistent with the X-ray analysis that the crown ether BMP32C10 was not folded in the solid state, but the host–guest complexes based on BMP32C10 derivatives showed folded structures (“taco complexes”), in which the guest molecules were enveloped within the folded hosts. Further enhancement in binding ability of BMP32C10-based cryptands was achieved by optimization of the cryptand size and introduction of additional binding sites on the arms. The optimized cryptand 4 exhibited a very high association constant with paraquat, 5.0 Õ 106 m¢1, 9000 times greater than that of BMP32C10 2 (Figure 1).[21] The number of atoms in the third arm of cryptand 4 was 9, which was the adequate ring size for occupation by the guest. The pyridyl unit on the third arm introduced additional hydrogen bonding or electrostatic interactions between the pyridyl nitrogen atom and the b-pyridinium hydrogens of the paraquat guest. These factors, in cooperation with preorganization, resulted in the extremely high binding affinity of cryptand 4 and paraquat guests, the highest reported to date. The stronger host–guest interaction of BMP32C10-based cryptands and paraquats makes it possible to fabricate supramolecular polymers with high degrees of polymerization. As reported by Gibson and co-workers, two BMP32C10-based cryptands were linked by terephthalate or ferrocene esters to perform as homoditopic AA monomers 5 and 6, and a bisparaquat as a BB monomer 7 (Figure 2).[22] By self-assembly of equimolar of AA monomers and BB monomers in solution, linear
Figure 2. Schematic representation of the formation of supramolecular polymers by self-assembly of cryptand-based AA monomers with paraquatbased BB monomer. Adapted with permission from ref. [22]. Copyright Ó 2011, American Chemical Society. Chem. Eur. J. 2015, 21, 11938 – 11946
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supramolecular polymers with relatively high molecular weights were prepared. For example, the degree of polymerization was estimated to be 93 47 at monomer concentrations of 290 mm, indicating a number average molecular weight of 241 kDa. The supramolecular polymers were polymerized from homoditopic AA and BB monomers via heterodimerization in an alternating manner, and the high molecular weight resulted from the strong binding capability of the hosts and guests. Preorganization is a classical concept in host–guest chemistry and it has been proven to be an effective way to increase binding ability of crown ethers. However, it remains synthetically challenging to achieve this increased affinity for some structurally complex guests. If the fit is not perfect, then the lack of conformational flexibility could actually hamper binding. Thus, analysis of conformation of host–guest complexes based on X-ray structures should be carefully performed, so that structural parameters from the X-ray structures are helpful in providing some guidance on the design of preorganization.
Spatial Confinement Effects In confined spaces, interactions between guest molecules can be enhanced due to their close contact. Examples include the formation of stable charge-transfer complexes in the pores of zeolites[23] and stabilized hydrogen-bonded supramolecular polymers in the liquid crystalline state.[24] However, the aforementioned carriers are not able to act as a part of building blocks themselves in self-assembly processes in solution. With the aim to fabricate well-defined supramolecular structures conveniently, we focus on the enhanced intermolecular interactions in cavities provided by macrocyclic hosts. In such systems, the host molecules act as nano-carriers to stabilize and enhance interactions between guest molecules, and as building blocks to construct molecular assemblies simultaneously. Cucurbit[8]uril (CB[8]), as a member of CB[n] host family, has a hydrophobic cavity and two carbonyl-laced portals.[25] Owing to its relatively large cavity size, CB[8] exhibits unique host– guest properties, such as the ability to encapsulate two aromatic guests inside the cavity. Hence, the charge-transfer interactions, p–p interactions, and dimerization of radical cations between the two encapsulated guest molecules are dramatically enhanced by CB[8].[26, 27] The first host-enhanced chargetransfer interaction based on CB[8] was reported by Kim and co-workers in 2001.[28] The electron-deficient guest methyl viologen (MV) formed a 1:1 host–guest complex with CB[8] in water with a binding constant of 1.1 Õ 105 m¢1. Upon addition of one equivalent of an electron-rich guest, 2,6-dihydroxynaphthalene (HN) or 1,4-dihydroxybenzene (HB), to the binary complex, a stable 1:1:1 complex containing the electron donor–acceptor pair was formed instantaneously and quantitatively (Figure 3 a). Later, by altering the electron-rich guest molecules, the formation of a stable ternary host–guest complex consisting of an anthracene (An) derivative, MV, and CB[8], driven by host-enhanced charge-transfer interactions, was reported (Figure 3 b).[29] It was noted that the MV–CB[8] binary complex was
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Concept from the strong host-enhanced p–p interactions, supramolecular polymers in aqueous solutions at relatively low concentrations (ca. 1 mm) were successfully fabricated. Radicals are very unstable species because of the high reactivity of unpaired electrons. However, not only the stability, but also the stacking interactions of radicals can be promoted by host encapsulation.[33–35] Recently, Li and co-workers reported the formation of a two-dimensional supramolecular organic framework, driven by CB[8]-promoted dimerization of viologen radical cations.[36] The viologen radical cations tended to stack into radical dimers in aqueous solution. The apparent association constant for the dimerization was 3.5 Õ 103 m¢1. In the presence of CB[8], the association constant was significantly increased to 9.6 Õ 105 m¢1 (Figure 5). With the assistance of CB[8],
Figure 3. a) Formation of charge-transfer complexes in CB[8]. Reprinted with permission from ref. [26]. Copyright Ó 2007, the Royal Society of Chemistry. b) Complexation of the MV–CB[8] binary complex with An derivative.
found to bind with the An derivative in a 1:1 molar ratio with a high binding constant of 1.1 Õ 106 m¢1. p–p interactions are a kind of weak force that is difficult to employ in the construction of large supramolecular assemblies. It is also inconvenient to enhance p–p interactions by using large p-conjugated molecules that require time-consuming synthesis. Luckily, like host-enhanced charge-transfer interactions, p–p interactions between two p-conjugated guests encapsulated in CB[8] cavities can be markedly enhanced. We have reported that CB[8] can bind either anthracene derivatives or naphthalene derivatives with 1:2 stoichiometry in water (Figure 4).[30–32] In the presence of CB[8], the fluorescence
Figure 4. Enhanced p–p interactions in CB[8]. Inset: Fluorescence spectra of An derivative in the absence and in the presence of CB[8]. Adapted with permission from ref. [30]. Copyright Ó 2011, John Wiley & Sons, Inc.
spectra showed a strong emission band assigned to the excimer of anthracene or naphthalene, respectively, indicating strong p–p interactions between the guest molecules enhanced by CB[8]. The two-site binding constants were measured to be 1011–1012 m¢2 for the naphthalene/CB[8] system and 1.46 Õ 1012 m¢2 for the anthracene/CB[8] system. Benefiting Chem. Eur. J. 2015, 21, 11938 – 11946
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Figure 5. Promoted dimerization of viologen radical cations by CB[8] encapsulation.
a triangular building block containing three viologen radical cations assembled into two dimensional supramolecular organic frameworks in water, and the single-layer structure was maintained in the solid state, demonstrating their high stability. Host-enhanced noncovalent interactions are useful tools when macrocycles are involved in molecular assemblies. CB[8] is a good candidate for effecting environmentally friendly selfassembly and fabricating functional materials. However, the poor water solubility of CB[8] may limit its applications. Therefore, CB derivatives with good solubility are highly desirable. To construct new materials with new functions, it is necessary to expand the noncovalent interactions that could be enhanced by CB[8] and to develop novel supramolecular hosts that may enhance noncovalent interactions.
Multivalent Enhancement The binding strength of single set of noncovalent interactions is usually weak, in most cases being on the order of 10 kJ mol¢1. It is easily understood that a direct method to strengthen interactions is to increase the number of binding sites in the building blocks. This strategy is so straightforward that it has been widely applied in supramolecular chemistry.[37–39] It is also very important that when multiple binding sites are integrated within one molecule, the arrangement of the binding arrays should be carefully optimized.
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Concept Aromatic donor–acceptor interactions are too weak and nondirectional to drive highly ordered self-assembly. In addition to the well-studied host-enhanced charge-transfer interaction, the introduction of additional binding units and directing groups on the building blocks can significantly promote the binding strength. Molecular tweezers,[40] as noncyclic host molecules with open cavities capable of binding guest molecules, are a representative example. We have measured the binding strength of interactions between C60 and a porphyrin tweezer by AFM-based single-molecule force spectroscopy (SMFS; Figure 6).[41] Compared with the interaction between C60 and
Figure 6. Left: Interaction between C60 and a porphyrin tweezer. Right: Interaction between C60 and a single porphyrin. Reprinted with permission from ref. [41]. Copyright Ó 2009, American Chemical Society.
a single porphyrin (29 pN), SMFS revealed that the porphyrin tweezer can provide an enhanced binding interaction with C60, resulting in a more than twofold higher unbinding force (75 pN). Therefore, multivalent binding can lead to the enhanced effect such that one plus one is more than two. The development of molecular tweezers makes the fabrication of linear supramolecular polymers driven by strong aromatic donor–acceptor interactions feasible.[42] Recently, a molecular tweezer incorporating two pincer-like alkynylplatinum(II) terpyridine units connected by a rigid spacer was reported by Yam and co-workers.[43, 44] The predetermined distance between the two electron-deficient pincers efficiently facilitated the tweezer-type host binding with electron-rich arenes through enhanced charge-transfer interactions. By employing this tweezer–guest molecular recognition, Wang and co-workers very recently designed the heteroditopic AB-type monomers to construct supramolecular polymers.[45] The electron-rich planar guest pyrene, as the head, was linked with the molecular tweezer 8, as the tail, by long alkyl spacers to form the ABtype monomers 9 and 10 (Figure 7). The complementary heteroditopic monomer facilitated the formation of linear supramolecular polymers in head-to-tail fashion, and the flexible alkyl spacer was expected to decrease conformational entropy for the multiple binding processes. The binding constant Ka for the tweezer/pyrene recognition motif was 1.43 Õ 104 m¢1. The isodesmic model was chosen to theoretically calculate the average degree of polymerization, N, for the resulting supramolecular polymer. Using the Ka value in the equation[22, 48] N = (Ka [conc])1/2, N = 32, corresponding to the total molar mass of 6.97 Õ 104 g mol¢1 was calculated at the monomer concentration of 70 mm. The equation indicates that both the binding constant and the monomer concentration are important in formation of supramolecular polymers with high degrees of polymerization. Chem. Eur. J. 2015, 21, 11938 – 11946
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Figure 7. Schematic representation of the formation of supramolecular polymer driven by the interactions of molecular tweezer and pyrene. Adapted with permission from ref. [45]. Copyright Ó 2014, John Wiley & Sons, Inc.
For CB[8]-based supramolecular systems, due to their poor solubility in aqueous solutions, very high binding strength is highly desired for the formation of stable and large molecular assemblies in dilute solutions. To promote linear supramolecular polymerization, we designed a unique ABBA-type monomer, in which the host-enhanced charge-transfer interactions with double binding mode were successfully realized (Figure 8).[29] The ABBA type monomer was prepared with an anthracene–viologen–viologen–anthracene (DADV) structure. This design prevented the possibility of intramolecular complexation to form a 1:1 cyclic species and inhibited the formation of 2:2 cyclic dimers, two factors unfavorable for supramolecular polymerization. Therefore, when mixing DADV with CB[8] in a 1:2 molar ratio in water, linear supramolecular polymerization was highly favored, benefiting from the successful
Figure 8. Schematic representation of the formation of supramolecular polymer based on multiple host-enhanced charge-transfer interactions. Reprinted with permission from ref. [29]. Copyright Ó 2010, John Wiley & Sons, Inc.
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Concept combination of high binding strength and high orientation selectivity in ABBA-type building blocks. Another well-known means of combining multiple binding sites is the design of multiple hydrogen-bonding arrays. Both the binding strength and the directionality can be increased when multiple hydrogen bonds are arrayed in one unit.[46] The triple hydrogen-bonding interaction between diamidopyridine and uracil derivatives was utilized to drive the formation of a supramolecular polymer, as first reported by Lehn and coworkers in 1990.[47] The supramolecular polymer displayed crystallinity in the solid phase, in contrast to the behavior of each of the monomers. Later, a self-complementary quadruple hydrogen-bonding array, ureidopyrimidinone (UPy), was reported by Meijer and co-workers in 1997.[48] Due to its high dimerization constant (up to 6 Õ 107 m¢1 in chloroform) and directionality, the UPy unit has become one of the most used building blocks in supramolecular chemistry.[49, 50] The high dimerization constants of UPy derivatives are attributed to the self-complementary donor–donor–acceptor–acceptor (DDAA) array of the hydrogen-bonding sites. Further studies pointed out that the order of donors and acceptors in the multiple hydrogen-bonding arrays influenced the binding strength significantly.[51, 52] The UPy unit has two tautomers that are able to form selfcomplementary quadruple hydrogen-bonded dimers; the 4[1H]-pyrimidinone tautomer forms dimers via DDAA hydrogen-bonding arrays and the pyrimidin-4-ol tautomer forms the dimers via DADA arrays (Figure 9). On account of the addition-
Figure 9. Chemical structures of the keto (top) and enol (bottom) tautomers of UPy and their dimers. Adapted with permission from ref. [51]. Copyright Ó 1998, American Chemical Society.
al attractive secondary electrostatic interactions in DDAA dimers, the dimerization constant of DDAA arrays is significantly higher than that of DADA arrays (Kdim 6 Õ 107 m¢1 vs 9 Õ 105 m¢1). In consequence, the order of arrangement of the multiple hydrogen-bonding arrays should be carefully optimized in the design of such building blocks. It should be pointed out that the strength of hydrogen bonding is strongly solvent dependent. Taking the UPy dimers of DDAA arrays as an example, Kdim is 6 Õ 107 m¢1 in CHCl3, 1 Õ 107 m¢1 in chloroform saturated Chem. Eur. J. 2015, 21, 11938 – 11946
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with water (ca. 55 mm), and 6 Õ 108 m¢1 in toluene.[53] The dimerization is facilitated by the lower polarity of toluene. Kdim decreased significantly to 1.2 Õ 106 m¢1 in chloroform containing only 0.3 % v/v DMSO,[51] indicating the strong dependency on polarity of the solvent.
Synergistic Binding with Multiple Forces In many cases, a simple but effective way to enhance the binding affinity is to combine two or more sorts of driving forces together; thus they can drive the self-assembly synergistically. Coupling of interactions can lead to positive or negative cooperativity.[54] In this section we will focus on the coupling of different interactions in a positively cooperative manner, in which the coupled binding affinity is significantly larger than when these forces are used alone. To drive the self-assembly process by synergistic binding is a well-established strategy in nature. Many important biological processes and complex structures in living systems are driven and directed by a variety of noncovalent interactions synergistically. One of the well-known examples is the formation of the DNA double helix, which is directed by complementary pairing of nucleotides by hydrogen bonding, and stabilized by hydrophobic interactions between the covalently linked nucleotides perpendicular to the hydrogen bonds.[55, 56] Inspired by DNA, Yang and co-workers combined hydrogen bonding with hydrophobic interactions to drive the construction of stable aggregates in water.[57] They designed and synthesized three amphiphilic building blocks; compounds 11 and 12, containing one and two UPy hydrogen-bonding units per molecule, respectively, and compound 13, without any hydrogen-bonding units, as a control (Figure 10). The three amphiphiles self-assembled into micelle or vesicle structures in water, and the stability of the aggregates was represented by their low critical aggregation concentrations (CAC). It was found that despite the similar weight fraction of hydrophobic parts of compounds 11 and 13, the CAC of 11 (one UPy unit per molecule, 22 mm) was 5.5 times lower than that of 13 (no UPy units, 120 mm). Increasing the number of UPy units from one in 11 to two in 12 further lowered the CAC by a factor of 16 (from 22 to 1.4 mm). The change in CAC across the series 13 > 11 > 12 was consistent with the important contribution of hydrogen bonding to self-assembly of amphiphiles 11–13 in water. Simple modifications on crown ethers may combine some additional interactions, such as electrostatic interactions, with the original host–guest complexations.[58, 59] Supramolecular polymerization driven by a combination of electrostatic attraction and crown ether-based host–guest interaction in aqueous media was reported by Huang and co-workers[60] The neutral BMP32C10 derivative 14, containing two carboxylic acid groups on the crown ether, bound with a positively charged viologen derivative very weakly in aqueous solutions (Figure 11; Ka = 57 m¢1 by 1H NMR titration). However, when the neutral carboxylic groups were deprotonated to give anionic carboxylate groups, the crown ether 15 developed into a good host for binding cationic viologen salts. The introduction of
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Concept
Figure 10. Chemical structures, self-assemblies, and CACs of amphiphiles 11, 12, and 13 in water. Adapted with permission from ref. [57]. Copyright Ó 2014, American Chemical Society.
but < 10 m¢1 in 5 % DMSO in chloroform). The hydrogen-bonding patterns in dimers of 17 and in dimers of 18 were essentially identical but the lack of ionic interactions dramatically lowered the stability of the neutral form. It was further revealed that the hydrogen-bonding network, the electrostatic attraction, and also their mutual interactions were responsible for the high stability of dimers of the zwitterion.[63] Synergistic effects are remarkable when multiple binding sites in separate building blocks are spatially matched very well. Li and co-workers constructed highly stable supramolecular copolymers with high molecular weight that took advantage of the multivalency and cooperativity principles to achieve enhanced binding efficiency.[64] The hydrogen-bonded C6-symmetric zinc porphyrin hexamer 196, one of the monomers for the supramolecular copolymer, was self-assembled from the heterocyclic unit of 19 by
Figure 12. Chemical structures of dimers of the zwitterion 17 and its neutral analogue 18. Reprinted with permission from ref. [62]. Copyright Ó 2003, American Chemical Society.
Figure 11. Chemical structures of BMP32C10 derivatives 14 and 15, and the AB monomer 16.
electrostatic attraction significantly enhanced the host–guest complexation with the association constant of 1.7 Õ 103 m¢1, which was 30 times larger than the neutral crown ether analog. Thus, by utilizing the electrostatic attraction-enhanced crown ether-based molecular recognition, the heteroditopic AB monomer 16 self-assembled into a linear supramolecular polymer at high concentrations. Hydrogen-bonding interactions are commonly used to drive self-assembly in apolar solvents, because polar solvents, such as water and DMSO, compete strongly with hydrogen-bonding sites.[61] However, when combined with ion-pairing interactions, the hydrogen bonding may show considerable strength in polar solvents. A self-complementary zwitterion, successfully coupling multiple ion-pairing and hydrogen-bonding interactions, was reported by Schmuck and co-workers.[62] The watersoluble guanidiniocarbonyl pyrrole carboxylate zwitterion 17 formed extremely stable dimers in highly polar solvents. The association constant for the dimerization was up to 1010 m¢1 in DMSO and was still surprisingly high (170 m¢1) in water (Figure 12). In comparison, the neutral analogue of the zwitterion, amidopyridine pyrrole carboxylic acid 18, dimerized only in organic solvents of low polarity (Kdim > 104 m¢1 in chloroform Chem. Eur. J. 2015, 21, 11938 – 11946
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multiple hydrogen-bonding interactions in toluene (Figure 13). The hexamer then bound with the C3-symmetric hexadentate linker 20 by alternately forming three N¢Zn coordination bonds in an induced-fit manner to generate the layered supramolecular copolymer. Because of the highly spatially matched binding sites in the hydrogen-bonded pophyrin hexamer and the hexadentate linker, cooperative complexation between zinc porphyrin and pyridine units was observed. The apparent association constant for the complex of the zinc porphyrin in the hexamer 196 and the pyridine in the model compound tridentate linker 21 was determined to be 3.4 Õ 107 m¢1, which was 4.4 Õ 103 times higher than that of the complex of the free zinc porphyrin 22 and the pyridine of 21 (7.7 Õ 103 m¢1). Driven by the multivalent and cooperative complexation, a supramolecular copolymer was fabricated with average molecular weight higher than 4.2 Õ 106 g mol¢1. The key point for the strategy of multivalent enhancement and synergistic binding with multiple forces is to make multiple interactions that work together with positive cooperativity. We can learn a lot from nature. The strong binding of biotin to the streptavidin tetramer (Ka = 1013.4 m¢1) is about 1000 times stronger than the expected binding, based solely on the sum of the parts,[54] thus providing a clear example where binding affinity is a property of the whole system. In the design of building blocks, multiple binding units should be well organized and arranged. The preorganized and spatially matched structure will significantly reduce the entropic penalty during
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Concept played by strong intermolecular complexation. Although many supramolecular devices work well in solution, problems can arise when they are transferred onto solid surfaces. It is highly desirable to develop powerful technologies that can enhance the stability of supramolecular assemblies on surfaces and, in the meantime, order and mobility should be combined and balanced. Novel functional surfaces and thin-film materials are expected to be fabricated through new strategies.
Acknowledgements This work was financially supported by the National Natural Science Foundation of China (21434004, 91427301), the NSFC Innovation Group (21421064), and the National Basic Research Program of China (2013CB834502). We acknowledge Ms. Dan Yu (Rochester Institute of Technology) and Mr. Qiao Song (Tsinghua University) for artwork. Keywords: binding constants · host–guest systems · noncovalent interactions · self-assembly · supramolecular chemistry Figure 13. Schematic representation of the formation of an A6B-type supramolecular copolymer. Reprinted with permission from ref. [64]. Copyright Ó 2011, American Chemical Society.
the binding process, therefore making the combined interaction stronger.
Summary and Outlook In this concept article, we have summarized some established methods to construct stable supramolecular assemblies by increasing the strength of noncovalent interactions. Some general rules in the design of building blocks for enhanced binding ability are outlined as follows. 1) The best-fitted host conformation to recognize guest molecules is significant in host–guest complexation; 2) the rational arrangement of binding sites is essential in making multiple interactions synergistically; 3) a good (uncompetitive) solvent is very important in making complexation more favorable. Although considerable achievements have been made to attain very strong binding affinity in recent decades, it is still necessary to develop new strategies to enhance the binding strength to make self-assembly efficient and convenient. Furthermore, with the aim to build supramolecular architectures with desired topologies, especially in the case of sequencespecific assemblies, we also need to develop new strategies to control the directionality and selectivity of noncovalent interactions. Hierarchical assembly and integrative self-sorting may play important roles in future work to make self-assembly a powerful tool in creating new materials. Moreover, it is also very important to extend the applications of enhanced noncovalent interactions from bulk solution onto surfaces. Multifunctional interfaces and surfaces can be fabricated at liquid–solid interfaces, in which essential roles are Chem. Eur. J. 2015, 21, 11938 – 11946
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Received: February 10, 2015 Published online on June 26, 2015
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