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Catenanes from Catenanes: Quantitative Assessment of Cooperativity in Dynamic Combinatorial Catenation
Chemical Science
Abstract
A new azobenzene-based dithiol building block was developed which, upon oxidation, forms predominantly a [2]catenane consisting of two interlocked trimers. In the presence of cyclodextrin templates a series of [2] and [3]catenanes was formed instead. We developed a method that enabled estimating the equilibrium constants for catenation in all of these systems. The formation of the [3]catenanes is either cooperative or anticooperative, depending on the nature of the cyclodextrin. Using molecular dynamics simulations, we linked positive and negative cooperativity to, respectively, burying and exposure of hydrophobic surfaces upon catenation. Our results underline the importance of directly quantifying noncovalent interactions within catenanes, as the corresponding pseudo-rotaxane model systems were found to be poor predictors of binding interactions in the actual catenane.
... Wu et al. prepared a β-CD-based [2]catenane with a macrocyclic axile compound consisting of 4,4'-bipyridine and 1,6-dibromohexane ( Fig. 5b) [36]. Interestingly, this catenane worked as a chiral sensor by treatment with Cu(II) ions because the Fig. 4 Examples of CD-based catenanes [26,[29][30][31][32][33][34] Content courtesy of Springer Nature, terms of use apply. Rights reserved. ...
... Li et al. reported the formation of[2]catenane or[3]catenane consisting of di-thiolated azobenzene derivatives and β-CD or γ-CD(Fig. 4e)[33].As an example of a heterocatenane including two kinds of cyclic compounds, Ng et al. fabricated hetero[4]catenane ...
In recent years, a number of interlocked molecules such as rotaxanes, catenanes, polyrotaxanes, and polycatenanes have been actively synthesized. Cyclodextrins (CDs) are representative building blocks of these interlocked molecules; however, very few reports are available on CD-based catenanes and polycatenanes. In this review article, we provide an overview of CD-based interlocked molecules and introduce examples of CD-based catenanes and polycatenanes. Finally, the perspectives of research on CD-based catenanes and polycatenanes are discussed.
... However, they are always followed by a step-wise process of evaluating the synthetic receptors, practically which is time-consuming and sometimes even frustrating. Accordingly, researchers have developed a library-based strategy, DCC, to speed up the discovery processes for receptors [50][51][52][53][54]. In a dynamic combinatorial library (DCL), building blocks react with each Fig. 2 The mechanism of screening affinity strategy for exploring synthetic polymer nanoparticles with selective affinity. ...
... Inspired by enzymatic system, chemists have developed the field of supramolecular catalysis by utilizing noncovalent interactions to accelerate rate of reaction and/ or allow high selective reactions to occur [51,54]. Very recently, Leigh's laboratory has reported that knotting molecules can be used to reduce the degrees of freedom of flexible chains, showing thermo-dynamically inaccessible functional conformations. ...
The specific interactions responsible for molecular recognition play a crucial role in the fundamental functions of biological systems. Mimicking these interactions remains one of the overriding challenges for advances in both fundamental research in biochemistry and applications in material science. However, current molecular recognition systems based on host–guest supramolecular chemistry rely on familiar platforms (e.g., cyclodextrins, crown ethers, cucurbiturils, calixarenes, etc.) for orienting functionality. These platforms limit the opportunity for diversification of function, especially considering the vast demands in modern material science. Rational design of novel receptor-like systems for both biological and chemical recognition is important for the development of diverse functional materials. In this review, we focus on recent progress in chemically designed molecular recognition and their applications in material science. After a brief introduction to representative strategies, we describe selected advances in these emerging fields. The developed functional materials with dynamic properties including molecular assembly, enzyme-like and bio-recognition abilities are highlighted. We have also selected materials with dynamic properties in contract to traditional supramolecular host–guest systems. Finally, the current limitations and some future trends of these systems are discussed.
... In order to obtain host molecules containing purely organic elements (i.e., C, H, O and N) with decent yields without the need of tedious synthetic procedures, chemists also developed dynamic covalent approaches [33][34][35][36][37][38][39][40] relying on reversible organic reactions. For example, disulfide bond formation was employed by Otto et al. [41][42][43][44][45][46] to accomplish self-assembly in weakly basic aqueous media. Imine [47][48][49][50][51][52][53][54] formation, has been considered as one of more often used dynamic approaches, because its precursors, namely aldehydes and amines are relatively more synthetic accessible, compared to thiol derivatives in disulfide approaches. ...
A bowl-shaped molecule can be self-assembled by condensing a triscationic hexaaldehyde compound and three equiv. of a dihydrazide linkers in pure water. The molecular bowl is thus composed of a triscationic π-electron deficient platform, as well as a hexagonal rim that contains six acylhydrazone functions. When the counteranions are chloride, the solid-state structure reveals that this molecular bowl undergoes dimerization via N–H···Cl hydrogen bonds, forming a cage-like dimer with a huge inner cavity. This molecular bowl can employ its cavity to accommodate a hydrophobic guest, namely 1-adamantanecarboxylic acid in aqueous media.
... An interesting discovery of a dynamic [2]catenane disulfide system came courtesy of the Otto group. [71] They reported that a very simple azobenzene-based dithiol could give rise to duallevel catenation behavior. In the absence of additional compounds, the building block initially formed a trimeric macrocycle. ...
Mechanically interlocked molecules have found extensive applications in areas all across the physical sciences, from materials to catalysis and sensing. However, introducing mechanical bonds and entanglements at the molecular level is still a significant challenge due to the inherent restriction in entropy needed to preorganize strands before interlocking. Over the last decade, dynamic covalent chemistry has emerged as one of the most efficient methods of forming rotaxanes, catenanes and molecular knots. By using reversible bonds such as imines, disulfides and boronate esters, one can use the inherent error‐correction in these linkages to form interlocked architectures with high fidelity and often in excellent yields. This review reports on recent advances in the use of dynamic covalent chemistry to make mechanically interlocked molecules, systematically surveying clipping, capping and templating approaches with dynamic bonds. Furthermore, it is also discussed how dynamic bonds can be used to control motion, co‐conformational expression and catalytic activity in mechanically interlocked molecular machinery.
... Most of the work on DCLs made use of external templates. [23][24][25][26] Only more recently DCC has been used for exploring self-assembly processes, leading to foldamers, 27 interlocked structures, [28][29][30][31][32] surfactant assemblies, [33][34][35] or assembly-driven self-replication. [36][37][38][39] In most of these systems, a single product was obtained. ...
Self-assembly enables access to complex molecular architectures but is traditionally confined to structures that represent global minima on the Gibbs energy landscape. We now report that it is possible to access structures other than those with the lowest individual Gibbs energy, while remaining under thermodynamic control. We prepared dynamic combinatorial libraries from two building blocks possessing complementary binding motifs. Depending on the building block stoichiometry, one of three competing self-assembling macrocycles can be formed with remarkable selectivity. By mixing the same two building blocks, we could access a self-replicating octamer, self-assembling into fibers; a hexamer with a precise 4:2 building block stoichiometry, assembling into hexagonally packed fiber bundles; and a tetramer with 1:3 building block ratio affording a [c3]daisy chain pseudorotaxane. Thus, systems chemistry approaches can enhance the versatility of self-assembly by allowing to navigate complex Gibbs energy landscapes to access structures beyond those that are individually the most stable.
... [1][2][3] Two main strategies have been developed in parallel for their syntheses: metal-templated synthesis [4][5][6][7][8][9] and dynamic combinatorial chemistry (DCC). 3,[10][11][12][13][14][15][16] Aer the statistical catenation era (where the interlocked molecules were produced by statistical threading), Jean-Pierre Sauvage pioneered the metal-templated synthesis. 4 This approach takes advantage of the preorganisation of the ligands around transition metal cations followed by the catenation step (mechanical bond formation). ...
We report herein the first all-donor aromatic [2]catenane formed through dynamic combinatorial chemistry, using single component libraries. The building block is a benzo[1,2-b:4,5-b’]dithiophene derivative, a p-donor molecule, with cysteine appendages that allow for disulfide exchange. The hydrophobic effect plays an essential role in the formation of the all-donor [2]catenane. The design of the building block allows the formation of a quasi-fused pentacyclic core, which enhances the stacking interactions between the cores. The [2]catenane has chiro-optical and fluorescent properties, being also the first known DCC-disulphide-based interlocked molecule to be fluorescent.
... This can open the door for the development of other divergent reactions on racemic mixtures based on aqueous, metal-free chemistry. Figure 4 depicts the major species and equilibria involved in their assembly (a full depiction of the possible library members-up to tetramers-is presented in Supplementary Fig. 91) 23,24 . ...
Structurally Divergent Reactions on Racemic Mixtures are atypical processes in Nature. The few examples reported in the literature take place in organic solvents and are driven by the reagents’ interaction with bulky chiral catalysts. Herein, we describe a dynamic combinatorial approach to generate structural divergence from racemic building blocks. The divergence is due to a stereospecific electron-donor – electron-acceptor interaction of diastereomeric macrocycles, leading to structurally distinct pseudorotaxanes. The equilibrated dynamic combinatorial library contains, amongst various macrocycles, two different types of [2]catenanes that are non-isomeric. The formation of these [2]catenanes is due to a spontaneous stereo and structurally divergent assembly of the building blocks. Structurally divergent reactions on racemic mixtures, which produce distinct chemical species from an enantiomeric mixture, are extremely rare in the literature. Here, the authors are able to use a dynamic combinatorial approach to yield structurally divergent, non-isomeric [2]catenanes from an enantiomeric mixture.
... Macrocyclizing terephthaloyl chloride with a biphenylene unit bis-functionalized with flexible amine-terminated tetraethylene glycol linkers in the presence of heptakis (2,6- [64] as a 1:1 mixture of head-to-head/tail-to-tail and head-to-tail orientational isomers, respectively, which may be distinguished by their different timeaveraged (D2 and C2) symmetries. A group led by Otto [65] has also observed [3]catenane orientational isomers within a dynamic combinatorial library of catenated cyclodextrins. ...
Cyclodextrins (CDs) are cone-shaped molecular rings that have been widely employed in supramolecular/host–guest chemistry because of their low cost, high biocompatibility, stability, wide availability in multiple sizes, and their promiscuity for binding a range of molecular guests in water. Consequently, CD-based host–guest complexes are often employed as templates for the synthesis of mechanically bonded molecules (mechanomolecules) such as catenanes, rotaxanes, and polyrotaxanes in particular. The conical shape and cyclodirectionality of the CD “bead” gives rise to a symmetry-breaking effect when it is threaded onto a molecular “string”; even symmetrical guests are rendered asymmetric by the presence of an encircling CD host. This review focuses on the stereochemical implications of this symmetry-breaking effect in mechanomolecules, including orientational isomerism, mechanically planar chirality, and topological chirality, as well as how they support applications in regioselective and stereoselective chemical synthesis, the design of molecular machine prototypes, and the development of advanced materials.
... Previously, the largest number of cyclic components in a discrete catenane was reported for a [7]catenane [27][28][29][46][47][48] . Only a few [n]catenanes with n ≥ 5 have been reported 49 , with most studies reporting CyD-based catenanes bearing a maximum of two CyDs ([3]catenane) 36,50 . Importantly, we believe that higher-order polycatenanes exhibit novel properties distinct from [2]-and [3]catenanes and are thus well suited to the development of advanced supramolecular structures and materials, such as molecular machines, molecular actuators, molecular switches, biomaterials, and drug carriers. ...
Supermolecules such as rotaxanes and catenanes have recently attracted considerable attention due to their potential widespread applications in areas such as molecular machines and switches. Moreover, the development of polyrotaxanes and polycatenanes, comprising multiple cyclic compounds, has allowed the fabrication of structures with novel properties. Although rotaxanes and polyrotaxanes have been extensively prepared from cyclodextrins as building blocks, very few studies have considered the syntheses of cyclodextrin-based polycatenanes. Here we report the one-pot syntheses and isolation of cyclodextrin-based radial polycatenanes with large numbers of cyclic components (>10) attached to a poly(ethylene glycol)–poly(propylene glycol)–poly(ethylene glycol) copolymer core, with characterization performed using Raman spectroscopy, gel permeation chromatography, ¹H-NMR spectroscopy, and other techniques. Overall, the results presented herein may be used to develop advanced supramolecular structures and materials, such as molecular machines, molecular actuators, molecular switches, biomaterials, and drug carriers.
... Thereafter, only a few reports on CyD catenanes have been published. [45][46][47] Very few reports on CyD polycatenanes possessing a number of CyD molecules have been acknowledged. Okada and Harada 48) reported the formation of a CyD polycatenane through cyclization of 9-anthracene-capped α-CyD/polyethyl- ene glycol (PEG) polyrotaxane as the only example of CyD polycatenane. ...
Supramolecular chemistry is an extremely useful and important domain for understanding pharmaceutical sciences because various physiological reactions and drug activities are based on supramolecular chemistry. However, it is not a major domain in the pharmaceutical field. In this review, we propose a new concept in pharmaceutical sciences termed “supramolecular pharmaceutical sciences,” which combines pharmaceutical sciences and supramolecular chemistry. This concept could be useful for developing new ideas, methods, hypotheses, strategies, materials, and mechanisms in pharmaceutical sciences. Herein, we focus on cyclodextrin (CyD)-based supermolecules, because CyDs have been used not only as pharmaceutical excipients or active pharmaceutical ingredients but also as components of supermolecules.
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... In good agreement with our NMR spectroscopicr esults, the simulations show that dimer 1b-1b establishes multiple intramolecular hydrogen-bond interactions during most of the simulation time ( Figure 5b and the Supporting Information, Figure S20), whereas 1e-1e exhibits am uch lower number (Figure 5e and the Supporting Information,F igureS21). The distances between pairs of carbon atoms of the carboxylates (1b-1b)a nd pairs of carbons that hold the amino groups (1e-1e), which are separated by the same number of bonds, were used to comparet he distance between charged groups.T hese distances are, on average, about 1 shorter for 1b-1b than for 1e-1e (Figure 5a,d and the Supporting Information, Figures S20a nd S21), indicating that the carboxylates are generally closer than the ammonium groups.F urthermore, lookinga tt he variation of the areas of the exposed polar and hydrophobic surfaces of the two compounds [24] (Figure 5c,f and the Supporting Information, Figures S20 and S21), the area of the polar surface is similar but the area of the hydrophobic surface is substantially smaller for 1b-1b (500-650 2 )t han for 1e-1e (650-800 2 ). Thus, these results indicate that under the simulation conditions compound 1b-1b adopts more packed conformations, with less-exposed hydrophobic moieties, than that of 1e-1e. ...
Dynamic combinatorial libraries are powerful systems for studying adaptive behaviors and relationships, as models of more complex molecular networks. With this aim, we set up a chemically diverse dynamic library of pseudopeptidic macrocycles containing amino-acid side chains with differently charged residues (negative, positive, and neutral). The responsive ability of this complex library upon the increase of the ionic strength has been thoroughly studied. The families of the macrocyclic members concentrating charges of the same sign showed a large increase in its proportion as the ionic strength increases, whereas those with residues of opposite charges showed the reverse behavior. This observation suggested an electrostatic shielding effect of the salt within the library of macrocycles. The top-down deconvolution of the library allowed us to obtain the fundamental thermodynamic information connecting the library members (exchange equilibrium constants), as well as to parameterize the adaptation to the external stimulus. We also visualized the physicochemical driving forces for the process by structural analysis using NMR spectroscopy and molecular modeling. This knowledge permitted the full understanding of the whole dynamic library and also the de novo design of dynamic chemical systems with tailored co-adaptive relationships, containing competing or cooperating species. This study highlights the utility of dynamic combinatorial libraries in the emerging field of systems chemistry.
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Dynamics and stimuli-responsiveness of two hetero[4]rotaxanes containing interlocked cucurbit[6]uril and cyclodextrin (β-CD or γ-CD) were studied and reported. Due to the different relative strength of the various inter-component interactions involving the interlocked β-CD and γ-CD, different co-conformations, dynamic features and response to temperature and solvent polarity change, and the presence of base and external guest were revealed by NMR for the two homologous [4]rotaxanes.
From being an aesthetic molecular object to a building block for the construction of molecular machines, catenanes and related mechanically interlocked molecules (MIMs) continue to attract immense interest in many research areas. Catenane chemistry is closely tied to that of rotaxanes and knots, and involves concepts like mechanical bonds, chemical topology and co-conformation that are unique to these molecules. Yet, because of their different topological structures and mechanical bond properties, there are some fundamental differences between the chemistry of catenanes and that of rotaxanes and knots although the boundary is sometimes blurred. Clearly distinguishing these differences, in aspects of bonding, structure, synthesis and properties, between catenanes and other MIMs is therefore of fundamental importance to understand their chemistry and explore the new opportunities from mechanical bonds.
A mono-mercapto-functionalized pillar[5]arene and its dimer, capable of being reversiblly interconverted, were successfully synthesized. Fascinatingly, a faster reversible redox conversion involving dynamic disulfide bond was observed between their host-guest complexes...
Self‐assembly of host molecules in aqueous media via metal–ligand coordination is well developed. However, the preparation of purely covalent counterparts in water has remained a formidable task. An anionic tetrahedron cage was successfully self‐assembled in a [4+4] manner by condensing a trisamine and a trisformyl in water. Even although each individual imine bond is rather labile and apt to hydrolyze in water, the tetrahedron is remarkably stable or inert due to multivalence. The tetrahedral cages, as well as its neutral counterparts dissolved in organic solvent, have homochirality, namely that their four propeller‐shaped trisformyl residues adopt the same rotational conformation. The cage is able to take advantage of hydrophobic effect to accommodate a variety of guest molecules in water. When a chiral guest was recognized, the formation of one enantiomer of the cage became more favored relative to the other. As a consequence, the cage could be produced in an enantioselective manner. The tetrahedron is able to maintain its chirality after removal of the chiral guest—probably on account of the cooperative occurrence of intramolecular forces that restrict the intramolecular flipping of phenyl units in the cage framework.
A chiral, anionic tetrahedral cage was self-assembled in water by condensing an anionic trisbenzaldehyde and a trisamine in a [4+4] manner, enantioselectively, with the help of templating by a chiral guest. The tetrahedron is remarkably stable and can accommodate a variety of guest molecules when in water.
Abstract
Self-assembly of host molecules in aqueous media via metal–ligand coordination is well developed. However, the preparation of purely covalent counterparts in water has remained a formidable task. An anionic tetrahedron cage was successfully self-assembled in a [4+4] manner by condensing a trisamine and a trisformyl in water. Even although each individual imine bond is rather labile and apt to hydrolyze in water, the tetrahedron is remarkably stable or inert due to multivalence. The tetrahedral cages, as well as its neutral counterparts dissolved in organic solvent, have homochirality, namely that their four propeller-shaped trisformyl residues adopt the same rotational conformation. The cage is able to take advantage of hydrophobic effect to accommodate a variety of guest molecules in water. When a chiral guest was recognized, the formation of one enantiomer of the cage became more favored relative to the other. As a consequence, the cage could be produced in an enantioselective manner. The tetrahedron is able to maintain its chirality after removal of the chiral guest—probably on account of the cooperative occurrence of intramolecular forces that restrict the intramolecular flipping of phenyl units in the cage framework.
A pair of radial [4]catenane isomers interlocked with two CB[6]s and one β-CD is reported. Due to the different positions of the tightly bound CB[6]s, shuttling dynamics of the β-CD between the two biphenyl stations are different in the isomers.
Dynamic combinatorial chemistry was employed to explore an ideal carrier molecule for anti‐cancer drug delivery. Driven by thermodynamics, the carrier molecule was quantitatively yielded by its co‐self‐assembly with a template and a drug doxorubicin (DOX). The self‐assembled nanocarrier with a drug‐loading content of 40 % was stable yet pH‐ and redox‐ responsive and could enhance drug potency and eliminate DOX‐resistant cancer in vivo in 13 days.
Abstract
Molecular self‐assembly has been widely used to develop nanocarriers for drug delivery. However, most of them have unsatisfactory drug loading capacity (DLC) and the dilemma between stimuli‐responsiveness and stability, stagnating their translational process. Herein, we overcame these drawbacks using dynamic combinatorial chemistry. A carrier molecule was spontaneously and quantitatively synthesized, aided by co‐self‐assembly with a template molecule and an anti‐cancer drug doxorubicin (DOX) from a dynamic combinatorial library that was operated by disulfide exchange under thermodynamic control. The highly selective synthesis guaranteed a stable yet pH‐ and redox‐ responsive nanocarrier with a maximized DLC of 40.1 % and an enhanced drug potency to fight DOX resistance in vitro and in vivo. Our findings suggested that harnessing the interplay between synthesis and self‐assembly in complex chemical systems could yield functional nanomaterials for advanced applications.
Molecular self‐assembly has been widely used to develop nanocarriers for drug delivery. However, most of them have unsatisfactory drug loading capacity (DLC) and the dilemma between stimuli‐responsiveness and stability, stagnating their translational process. Herein, we overcame these drawbacks using dynamic combinatorial chemistry. A carrier molecule was spontaneously and quantitatively synthesized, aided by co‐self‐assembly with a template molecule and an anti‐cancer drug doxorubicin (DOX) from a dynamic combinatorial library that was operated by disulfide exchange under thermodynamic control. The highly selective synthesis guaranteed a stable yet pH‐ and redox‐ responsive nanocarrier with a maximized DLC of 40.1 % and an enhanced drug potency to fight DOX resistance in vitro and in vivo. Our findings suggested that harnessing the interplay between synthesis and self‐assembly in complex chemical systems could yield functional nanomaterials for advanced applications.
A pair of radial [5]catenanes with an isomeric cyclic –AABB– or –ABAB– type sequence of the interlocked β‐cyclodextrin (β‐CD) and cucurbit[6]uril (CB[6]) have been efficiently synthesized via CB[6]‐mediated azide‐alkyne cycloaddition of strategically designed building blocks. Due to a marked difference in the binding strength and interlocking sequence of the peripheral macrocycles, interesting sequence‐dependent properties characteristic to mechanically bonded macrocycles were realized. Variable 1 H NMR studies showed that the –ABAB– isomer has a more independent β‐CD dynamics whereas the β‐CD motions in the –AABB– isomer are coupled. Dynamics of the pH‐insensitive β‐CD can also be further modulated upon a base‐triggered mobilization of the CB[6]. Moreover, scission of the central ring in tandem MS experiment led to the dethreading of both β‐CD from the –AABB– isomer, but one β‐CD is mechanically protected from slippage by the strongly bound CB[6] in the –ABAB– isomer. These unique properties of the mechanical bond expressed in a sequence‐specific fashion and the transmission of the control on the macrocycle dynamics from one interlocked component to another highlight the potential of complex hetero[n]catenanes that combine the properties of different macrocycles in an inter‐dependent manner, which will be implicated in the design of advanced, multi‐component molecular machines.
A pair of radial [5]catenanes, with either an isomeric cyclic ‐AABB‐ or ‐ABAB‐ type sequence of the interlocked β‐cyclodextrin (β‐CD) and cucurbit[6]uril (CB[6]) units, has been efficiently synthesized. Because of a marked difference in the binding strength and interlocking sequence of the peripheral macrocycles, interesting sequence‐dependent properties, characteristic of mechanically bonded macrocycles, were realized. Variable‐temperature ¹H NMR studies showed that the ‐ABAB‐ isomer has a more independent β‐CD dynamic, whereas the β‐CD motions in the ‐AABB‐ isomer are coupled. Dynamics of the pH‐insensitive β‐CD can also be further modulated upon base‐triggered mobilization of the CB[6]. These unique properties of the mechanical bond expressed in a sequence‐specific fashion and the transmission of the control on the macrocycle dynamics from one interlocked component to another, highlight the potential of similar complex hetero[n]catenanes in the design of advanced, multicomponent molecular machines.
An extension of the Jacobson-Stockmayer (JS) theory is presented to include the reversible formation of [2]catenanes in a ring-chain system under thermodynamic control. The extended theory is based upon the molar catenation constant, measuring the ease of catenation of two ring oligomers, whose expression was obtained in a previous work. Two scenarios have been considered; that of “thick” (hydrocarbon-like) chains and that of “thin” (DNA-like) chains. In the case of “thick” chains, the formation of catenanes can be neglected, unless in the unlikely case of a very large value of the equilibrium constant for linear propagation (K 108 mol-1 L, or larger). For K tending to infinity, the system becomes a chain-free system where only ring-catenane equilibria occur. Under this condition, there is a critical concentration below which only rings are present at equilibrium and above which the ring fraction remains constant and the excess monomer is converted into catenanes only. In the case of “thin” chains, the formation of catenanes cannot be neglected even for values of K as low as 102 mol-1 L, thus justifying the use of the extended theory.
This chapter highlights the mechanically interlocked molecules (MIMs) to illuminate the diverse strategies, recognition chemistry, and reversible bonding motifs that have been invoked in order to create mechanical bonds. The synthesis of rotaxanes by slippage is unique among these approaches because it does not involve the making and breaking of any chemical bonds. Reversible covalent bonds have also enriched the field of mechanostereochemistry by allowing MIMs to be synthesized in up to near-quantitative yields from relatively simple and even commercially available building blocks. The chapter focuses on discrete mechanically interlocked assemblies, metallosupramolecular polymers based on the self-assembly of interpenetrated ligands and metals can also be assembled under thermodynamic control. Reversible condensation reactions, especially those involving the loss of water, such as the formation of imines, hydrazones, and boronic esters or boroxines, are powerful tools for establishing mechanical bonds in interpenetrated assemblies under thermodynamic control.
We demonstrate the preparation of surface-bound cucurbit[8]uril (CB[8]) catenanes on silica nanoparticles(NPs), where CB[8] was employed as a tethered supramolecular "handcuff" to selectively capture targetguest molecules. In this catenane, CB[8] was threaded onto a methyl viologen (MV2+) axle and immobilized onto silica NPs. The formation of CB[8] catenanes on NPs wereconfirmed by UV-vis titration experiments and lithographic characterization, demonstrating high density of CB[8] on the silica NPs surface, 0.56 nm-2 . This CB[8] catenane system exhibits specific molecular recognition towards certain aromatic molecules such as perylene bis(diimide), naphthol and aromatic amino acids, therefore, can act as a nanoscale molecular receptor for target guests. Furthermore, we also demonstrate its use as an efficient and recyclable nanoplatform for peptide separation. By embedding magnetic NPs inside silica NPs, separation could be achieved by simply applying an external magnetic field. Moreover, the peptides captured by the catenanes could be released by reversible single-electron reduction of MV2+. The entire process demonstrated high recoverability.
On the basis of many literature measurements, a critical overview is given on essential noncovalent interactions in synthetic supramolecular complexes, accompanied by analyses with selected proteins. The methods, which can be applied to derive binding increments for single noncovalent interactions, start with the evaluation of consistency and additivity with a sufficiently large number of different host–guest complexes by applying linear free energy relations. Other strategies involve the use of double mutant cycles, of molecular balances, of dynamic combinatorial libraries, and of crystal structures. Promises and limitations of these strategies are discussed. Most of the analyses stem from solution studies, but a few also from gas phase. The empirically derived interactions are then presented on the basis of selected complexes with respect to ion pairing, hydrogen bonding, electrostatic contributions, halogen bonding, π–π-stacking, dispersive forces, cation−π and anion−π interactions, and contributions from the hydrophobic effect. Cooperativity in host–guest complexes as well as in self-assembly, and entropy factors are briefly highlighted. Tables with typical values for single noncovalent free energies and polarity parameters are in the Supporting Information.
We report here a DCL study of a phenanthroline-based building block focusing on catenane formation with copper templates. Two [2]catenanes have been amplified by using Cu+ as a template from the DCLs that contain no interlocked compounds in the absence of copper. In addition, an unexpected Cu2+ template effect on the [2]catenane formation was discovered. The observed Cu2+ template effect was found to originate from the in situ reduction of the divalent metal to Cu+.
Rotacatenane is an interlocked compound composed of two mechanically interlocked macrocyclic components, i. e., a [2]catenane, and one axle component. In this paper we describe the selective synthesis of isomeric rotacatenanes. Two [2]rotaxanes with different phenanthroline moieties were synthesized by the oxidative coupling of alkyne with bulky blocking group, which proceeded in the cavity of the macrocyclic phenanthroline-Cu complex. The metal template method was used to install another cyclic component: the tetrahedral Cu(I) complex, which was composed of a [2]rotaxane and an acyclic phenanthroline derivative, was synthesized and the cyclization of the phenanthroline derivative gave the rotacatenane. The sequential isomers of rotacatenanes were distinguished by 1H and 13C NMR spectroscopy.
Application of nanoparticles in multivalent recognition of biomacromolecules or programmed self-assembly requires control over the relative placement of chemical groups on their surface. We have developed a method to direct functionalization of surfaces of aldehyde-equipped gold nanoparticles using a DNA template. An error-correction mechanism is built into the functionalization process thanks to the thermodynamic control enabled by the hydrazone exchange reaction. This reversible reaction can be conveniently switched off by removing the catalyst, preserving the functionalization.
Self-assembly of a specific member of a dynamic combinatorial library (DCL) may lead to self-replication of this molecule. However, if the concentration of the potential replicator in the DCL fails to exceed its critical aggregation concentration (CAC) self-replication will not occur. We now show how addition of a template can raise the concentration of a library member - template complex beyond its CAC, leading to the onset of self-replication. Once in existence, the replicator aggregates promote further replication also in the absence of the template that induced the initial emergence of the replicator.
We have developed a method for the localized functionalization of gold nanoparticles using imine-based dynamic combinatorial chemistry. By using DNA templates, amines were grafted on the aldehyde-functionalized nanoparticles only if and where the nanoparticles interacted with the template molecules. Functionalization of the nanoparticles was controlled solely by the DNA template; only amines capable of interacting with DNA were bound to the surface. Interestingly, even though our libraries contained only a handful of simple amines, the DNA sequence influenced their attachment to the surface. Our method opens up new opportunities for the synthesis of multivalent, nanoparticle-based receptors for biomacromolecules.
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Allosteric synthetic receptors are difficult to access by design. Herein we report a dynamic combinatorial strategy towards such systems based on the simultaneous use of two different templates. Through a process of simultaneous casting (the assembly of a library member around a template) and molding (the assembly of a library member inside the binding pocket of a template), a Russian-doll-like termolecular complex was obtained with remarkable selectivity. Analysis of the stepwise formation of the complex indicates that binding of the two partners by the central macrocycle exhibits significant positive cooperativity. Such allosteric systems represent hubs that may have considerable potential in systems chemistry.
Allosteric synthetic receptors are difficult to access by design. Herein we report a dynamic combinatorial strategy towards such systems based on the simultaneous use of two different templates. Through a process of simultaneous casting (the assembly of a library member around a template) and molding (the assembly of a library member inside the binding pocket of a template), a Russian-doll-like termolecular complex was obtained with remarkable selectivity. Analysis of the stepwise formation of the complex indicates that binding of the two partners by the central macrocycle exhibits significant positive cooperativity. Such allosteric systems represent hubs that may have considerable potential in systems chemistry.
New methodology for making novel materials is highly desirable. Here, an “ingredients” approach to functional self-assembled hydrogels was developed. By designing a building block to contain the right ingredients, a multi-responsive, self-assembled hydrogel was obtained through a process of template-induced self-synthesis in a dynamic combinatorial library. The system can be switched between gel and solution by light, redox reactions, pH, temperature, mechanical energy and sequestration or addition of MgII salt.
In this paper we show the possibility of using very mild stochastic damping to stabilize long time
step integrators for Newtonian molecular dynamics. More specifically, stable and accurate
integrations are obtained for damping coefficients that are only a few percent of the natural decay
rate of processes of interest, such as the velocity autocorrelation function. Two new multiple time
stepping integrators, Langevin Molly ~LM! and Bru¨nger–Brooks–Karplus–Molly ~BBK–M!, are
introduced in this paper. Both use the mollified impulse method for the Newtonian term. LM uses
a discretization of the Langevin equation that is exact for the constant force, and BBK–M uses the
popular Bru¨nger–Brooks–Karplus integrator ~BBK!. These integrators, along with an extrapolative
method called LN, are evaluated across a wide range of damping coefficient values. When large
damping coefficients are used, as one would for the implicit modeling of solvent molecules, the
method LN is superior, with LM closely following. However, with mild damping of 0.2 ps21
, LM
produces the best results, allowing long time steps of 14 fs in simulations containing explicitly
modeled flexible water. With BBK–M and the same damping coefficient, time steps of 12 fs are
possible for the same system. Similar results are obtained for a solvated protein–DNA simulation of
estrogen receptor ER with estrogen response element ERE. A parallel version of BBK–M runs
nearly three times faster than the Verlet-I/r-RESPA ~reversible reference system propagator
algorithm! when using the largest stable time step on each one, and it also parallelizes well. The
computation of diffusion coefficients for flexible water and ER/ERE shows that when mild damping
of up to 0.2 ps21 is used the dynamics are not significantly distorted.
This tutorial review outlines the different template strategies that chemists have employed to synthesise knotted molecular topologies. Metal ion coordination, hydrogen bonding and aromatic donor-acceptor interactions have all been used to direct the formation of well-defined crossing points for molecular strands. Advances in the methods used to covalently capture the interwoven structures are highlighted, including the active metal template strategy in which metal ions both organise crossing points and catalyse the bond forming reactions that close the loop to form the topologically complex product. Although most non-trivial knots prepared to date from small-molecule building blocks have been trefoil knots, the first pentafoil knot was recently synthesised. Possible future directions and strategies in this rapidly evolving area of chemistry are discussed.
Classical Monte Carlo simulations have been carried out for liquid water in the NPT ensemble at 25 °C and 1 atm using six of the simpler intermolecular potential functions for the water dimer: Bernal–Fowler (BF), SPC, ST2, TIPS2, TIP3P, and TIP4P. Comparisons are made with experimental thermodynamic and structural data including the recent neutron diffraction results of Thiessen and Narten. The computed densities and potential energies are in reasonable accord with experiment except for the original BF model, which yields an 18% overestimate of the density and poor structural results. The TIPS2 and TIP4P potentials yield oxygen–oxygen partial structure functions in good agreement with the neutron diffraction results. The accord with the experimental OH and HH partial structure functions is poorer; however, the computed results for these functions are similar for all the potential functions. Consequently, the discrepancy may be due to the correction terms needed in processing the neutron data or to an effect uniformly neglected in the computations. Comparisons are also made for self‐diffusion coefficients obtained from molecular dynamics simulations. Overall, the SPC, ST2, TIPS2, and TIP4P models give reasonable structural and thermodynamic descriptions of liquid water and they should be useful in simulations of aqueous solutions. The simplicity of the SPC, TIPS2, and TIP4P functions is also attractive from a computational standpoint.
In donor-acceptor mechanically interlocked molecules that exhibit bistability, the relative populations of the translational isomers--present, for example, in a bistable [2]rotaxane, as well as in a couple of bistable [2]catenanes of the donor-acceptor vintage--can be elucidated by slow scan rate cyclic voltammetry. The practice of transitioning from a fast scan rate regime to a slow one permits the measurement of an intermediate redox couple that is a function of the equilibrium that exists between the two translational isomers in the case of all three mechanically interlocked molecules investigated. These intermediate redox potentials can be used to calculate the ground-state distribution constants, K. Whereas, (i) in the case of the bistable [2]rotaxane, composed of a dumbbell component containing π-electron-rich tetrathiafulvalene and dioxynaphthalene recognition sites for the ring component (namely, a tetracationic cyclophane, containing two π-electron-deficient bipyridinium units), a value for K of 10 ± 2 is calculated, (ii) in the case of the two bistable [2]catenanes--one containing a crown ether with tetrathiafulvalene and dioxynaphthalene recognition sites for the tetracationic cyclophane, and the other, tetrathiafulvalene and butadiyne recognition sites--the values for K are orders (one and three, respectively) of magnitude greater. This observation, which has also been probed by theoretical calculations, supports the hypothesis that the extra stability of one translational isomer over the other is because of the influence of the enforced side-on donor-acceptor interactions brought about by both π-electron-rich recognition sites being part of a macrocyclic polyether.
The behaviour of aqueous dynamic combinatorial libraries (DCLs) containing either electron-rich donor building blocks based on dioxynaphthalene (DN), or electron-deficient acceptor building blocks based on naphthalenediimide (NDI) are described. The influence of concentration and ionic strength on library distribution and diversity, together with the responses to electronically-complementary templates have been explored in detail, establishing the principles to be employed in more complex libraries leading to a new generation of catenanes.
Deriving atomic charges and building a force field library for a new molecule are key steps when developing a force field required for conducting structural and energy-based analysis using molecular mechanics. Derivation of popular RESP charges for a set of residues is a complex and error prone procedure because it depends on numerous input parameters. To overcome these problems, the R.E.D. Tools (RESP and ESP charge Derive, ) have been developed to perform charge derivation in an automatic and straightforward way. The R.E.D. program handles chemical elements up to bromine in the periodic table. It interfaces different quantum mechanical programs employed for geometry optimization and computing molecular electrostatic potential(s), and performs charge fitting using the RESP program. By defining tight optimization criteria and by controlling the molecular orientation of each optimized geometry, charge values are reproduced at any computer platform with an accuracy of 0.0001 e. The charges can be fitted using multiple conformations, making them suitable for molecular dynamics simulations. R.E.D. allows also for defining charge constraints during multiple molecule charge fitting, which are used to derive charges for molecular fragments. Finally, R.E.D. incorporates charges into a force field library, readily usable in molecular dynamics computer packages. For complex cases, such as a set of homologous molecules belonging to a common family, an entire force field topology database is generated. Currently, the atomic charges and force field libraries have been developed for more than fifty model systems and stored in the RESP ESP charge DDataBase. Selected results related to non-polarizable charge models are presented and discussed.
Effective techniques for applying Dynamic Combinatorial Chemistry In a relatively short period, Dynamic Combinatorial Chemistry (DCC) has grown from proof-of-concept experiments in a few isolated labs to a broad conceptual framework with applications to an exceptional range of problems in molecular recognition, lead compound identification, catalyst design, nanotechnology, polymer science, and others. Bringing together a group of respected experts, this overview explains how chemists can apply DCC and fragment-based library methods to lead generation for drug discovery and molecular recognition in bioorganic chemistry and materials science. Chapters cover: Basic theory Approaches to binding in proteins and nucleic acids Molecular recognition Self-sorting Catalyst discovery Materials discovery Analytical chemistry challenges A comprehensive, single-source reference about DCC methods and applications including aspects of fragment-based drug discovery, this is a core reference that will spark the development of new solutions and strategies for chemists building structure libraries and designing compounds and materials.
In recent years, combinatorial chemistry has evolved as an attempt to significantly shorten the lead identification and lead optimization portions of drug development. Combinatorial chemistry has become a widely used tool for synthetic chemists looking to streamline lead identification and for those needing novel structures to drive a plethora of studies in chemistry, biology, materials science, and beyond. This article describes the characteristics and applications of combinatorial chemistry in the drug discovery process.
Making receptors to order: A small dynamic combinatorial library (DCL), formed from two dithiols in water, provides a continuous range of six receptors of different sizes. The majority of the 30 tested amines and ammonium ions amplified receptors from this library, thus spanning the complete receptor-size range and showing that this DCL provides a generic platform for the development of receptors for this important class of compounds.
Understanding hydrophobic interactions requires a molecular-level picture of how water molecules adjust to the introduction of a nonpolar solute. New insights into the latter process are derived from the observation that the Gibbs energies of solvation of the noble gases and linear alkanes by a wide range of solvents, including water, correlate well with linear combinations of internal pressure (Pi) and cohesive energy density (ced) of the solvent. Pi and ced are empirical solvent parameters that quantify two different aspects of solvent cohesion: the former reflects the cost of creating a cavity by a subtle rearrangement of solvent molecules, whereas the latter captures the cost of creating a cavity with complete disruption of solvent–solvent interactions. For the solvation of smaller solutes the internal pressure is the dominant parameter, while for larger solutes the ced becomes more important. The intriguing observation that the solubility of alkanes in water decreases with increasing chain length, whereas the solubility of noble gases increases with increasing size, can be understood by considering the different relative influences of the ced and Pi on the solvation processes of both classes of compounds. Also the solvation enthalpy, but not the entropy, correlates with linear combinations of solvent ced and Pi, albeit poorly, suggesting that the good correlations observed for the Gibbs energy are largely due to enthalpy, most likely that related to cavity formation.
[2]Rotaxanes consisting of butadiyne-linked porphyrin dimers threaded through a phenanthroline-containing macrocycle, can be synthesised by an active-metal template directed copper-mediated Glaser coupling, in yields of up to 61%, without requiring a large excess of the macrocycle. The crystal structure of one of these rotaxanes confirms that the macrocycle is clasped around the centre of the porphyrin dimer. A radial hexa-pyridyl template was used to convert the alkyne-terminated [2]rotaxane into a [4]catenane cyclic porphyrin hexamer in 62% yield, via palladium-catalysed Glaser coupling. The related [7]catenane porphyrin dodecamer complex was also isolated as a by-product of this cyclisation, in 6% yield. These results illustrate the scope of template-directed synthesis for creating complex interlocked structures directly from simple starting materials.
Insulated molecular wires (IMWs), in which the π-conjugated polymers are covered by a protective sheath, have attracted considerable attention because of their potential applicability in next-generation mono-molecular electronic devices. We have developed new methods of synthesizing IMWs involving the polymerization of permethylated cyclodextrin (PMCD)-based rotaxane monomers. The obtained IMWs are highly soluble in organic solvents and have a high covering ratio, rigidity, and photoluminescence efficiency; further, they show high charge mobility, even in the solid state. In this review, the synthetic methodologies and characteristic of IMWs are discussed.
Efficient templates play an important role in the construction of mechanically interlocked molecules such as catenanes and rotaxanes. This minireview presents a retrospective introduction on the traditional templates and highlights recent significant accomplishments in developing novel and efficient templates, especially active metal templates and radical templates, employed in the construction of rotaxanes and catenanes. The current status of this field is summarized and the scope and future prospects are also discussed in this minireview.
The synthesis of novel diastereomeric [2]-catenanes derived from β-cyclodextrin and an enantiomeric trianglamine is described using a [3+3] cyclocondensation reaction.
The Schotten-Baumann reaction between a diamine with a central bitolyl unit and terephthaloyl chloride in the presence of heptakis(2,6-di-0-methyl)-beta-cyclodextrin (Dm-beta-CD) in dilute solution affords the [2]catenanes 1 and 2 as well as two analogous [3]catenanes, in which two DM-beta-CD units are threaded on a tetrakislactam ring. In catenane 1 the bitolyl unit is found to be situated inside the cyclodextrin torus.
The term hydrophobic interactions denotes the tendency of relatively apolar molecules to stick together in aqueous solution. These interactions are of importance in many chemical disciplines, including the chemistry of in vivo processes. Enzyme-substrate interactions, the assembly of lipids in biomembranes, surfactant aggregation, and kinetic solvent effects in water-rich solutions are all predominantly governed by hydrophobic interactions. Despite extensive research efforts, the hydration of apolar molecules and the noncovalent interactions between these molecules in water are still poorly understood. In fact, the question as to what the driving force for hydrophobic intractions is shifts the study into a quest for a detailed understanding of the remarkable properties of liquid water. This review highlights some of the novel insights that have been obtained in the past decade. The emphasis is on both hydrophobic hydration and hydrophobic interactions since both phenomena are intimately connected. Several traditional views have been found to be deeply unsatisfactory, and courageous attempts have been made to conceptualize the driving force behind pairwise and bulk hydrophobic interactions. The review presents an admittedly personal selection of the recent experimental and theoretical developments, and when necessary, reference is made to relevant studies of earlier date.
Dynamic Combinatorial Chemistry (DCC) is a subset of combinatorial chemistry where the library members interconvert continuously by exchanging building blocks with each other. Dynamic combinatorial libraries (DCLs) are powerful tools for discovering the unexpected and have given rise to many fascinating molecules, ranging from interlocked structures to self-replicators. Furthermore, dynamic combinatorial molecular networks can produce emerging properties at systems level, which provide exciting new opportunities in systems chemistry. In this perspective article we will highlight some new methodologies in this field and analyze selected examples of DCLs that are under thermodynamic control, leading to synthetic receptors, catalytic systems and complex self-assembled supramolecular architectures. Also reviewed are extensions of the principles of DCC to systems that are not at equilibrium and may therefore harbor richer functional behavior. Examples include self-replication and molecular machines.
This review summarizes the different synthetic strategies based on chemical templation for the construction of threaded and interlocked molecules (rotaxanes, pseudorotaxanes and catenanes). The chemical templates or intermolecular interactions used to bring together in an organised fashion the different component parts of the threaded or interlocked structures can be divided into: anionic and cationic templates, hydrogen bonding interactions, π-stacking and charge-transfer interactions and hydrophobic interactions. Examples of the most common structures displaying these interactions will be discussed.
We report here the first dynamic combinatorial synthesis in water of an all-acceptor [2]catenane, and of different types of donor-acceptor [2] and [3]catenanes. We demonstrate that linking two electron-deficient motifs within one building block using a series of homologous alkyl chains provides efficient and selective access to a variety of catenanes, and offers an unprecedented opportunity to explore the parameters that govern their synthesis in water. In this series, the catenane assembly is controlled by a fine balance between kinetics and thermodynamics and subtle variations in the building block structure, such as the linker length and building block chirality; a remarkable and unexpected odd-even effect with respect to the number of atoms in the alkyl linker is reported.
This tutorial review summarizes the progress made towards mechanically interlocked daisy chains. Such materials can be seen as a further development in polymer science, where the conventional covalent interlinking bonds are replaced by supramolecular binding concepts. Materials in which the mechanical bond is an integral part of the polymeric backbone are expected to possess unique macroscopic properties and are therefore the synthetic aim in an ever growing research community. After introducing general considerations about daisy chains, the most common analytic methods to get insight into the aggregation behaviour of such self-complementary monomers are presented. Cyclodextrins/aromatic rods, crown ethers/cationic rods and pillararenes/alkyl chains are systems used to achieve daisy chain-like molecular arrays. By comparison of the reported systems, conclusions about an improved structural design are drawn.
Langkettige Dithiole unterschiedlicher Kettenlänge mit verschieden substituierten, mittelständigen aromatischen Ringen lassen sich zu makrocyclischen Disulfiden (Ringgliederzahl 18, 20, 24 und 28) mit Ansa-Struktur dehydrocyclisieren. Alle untersuchten Dithiole geben Einschlußverbindungen mit α- bzw. β- Cyclodextrin. Die Dehydrocyclisation nach Einschluß sollte zu einem neuartigen Verbindungstyp X bzw. XXIX führen, bei dem sich zwei Ringe wie Kettenglieder umfassen, ohne chemisch aneinander gebunden zu sein. Es wird gezeigt, daß die Cyclodextrin-Umhüllung auch in verdünnter wäßriger Lösung noch so stark ist, daß die Dithiol-Dehydrierung bei der gewählten Kettenlänge verhindert wird.
Statistical analysis of the solid-state structures available for the cyclodextrins and their inclusion compounds – 42 for α-CD (1), 48 for β-CD (2), and 8 for γ-CD (3) – revealed their mean molecular geometry parameters to be within normal ranges, such as the intersaccharidic bond angle (φ) and torsion angles Φ and Ψ, or the tilt angle (τ) signifying the inclination of the pyranoid 4C1 chairs toward the macroring perimeter. The mean 2–0…0–3' distances between adjacent glucose portions decrease in the order α-CD > β-CD > γ-CD from 3.05 to 2.84 Å, allowing more intense 2–0…H0–3' hydrogen bonding interactions. This reduces the overall flexibility of the macrocycles correspondingly. The intersaccharidic oxygens that without exception point toward the inside of the macrocycles, essentially lie in one plane, deviations from planarity being in the range of only 0.02–0.12 Å. The global molecular shape of 1–3 in their various hydrates and inclusion complexes is thus uniformly characterized by essentially unstrained, torus-shaped cones with a nearly unpuckered mean plane. These results justify considering the solid-state structures of α-, β- and γ-CD hydrates, crystallizing with 8–14 water molecules, as relevant “frozen molecular images” of their solution conformations. The solid-state data were used to compute the contact surfaces, cavity dimensions, and molecular lipophilicity patterns (MLPs) of 1–3. The MLPs, presented in color-coded form, provide a lucid picture of how these cyclodextrins are balanced with respect to their hydrophilic (blue) and hydrophobic (yellow) areas: the larger opening of the cone-shaped macrocycles carrying the 2-OH and 3-OH groups is intensely hydrophilic; the opposite, narrower opening, ringed by the CH2OH groups, is considerably less hydrophilic, and is partially permeated by hydrophobic areas, whereas the bulk of the intensely hydrophobic regions is concentrated on the inner region of the cavities. Thus, the complexation of suitable guest molecules by α, β-, and γ-cyclodextrin (1–3), which is governed by a variety of factors, can be rationalized with respect to the hydrophobic interactions on the basis of their MLP profiles. Application of these molecular modelling techniques to the one solid-state structure available for the nine-glucose unit δ-CD tetradecahydrate (4) suggests a less pronounced separation of hydrophilic and hydrophobic surface regions, obviously due to a bowl-shaped torus with irregular tilting of four of the nine glucopyranoses which gives rise to substantial puckering of the macrocycle.
Using dynamic combinatorial chemistry, mixtures of dipeptide monomers were combined to probe how the structural elements of a family of self-assembled [2]-catenanes affect their equilibrium stability versus competing non-catenated structures. Of particular interest were experiments to target the effects of CH-π interactions, inter-ring hydrogen bonds, and β-turn types on [2]-catenane energetics. The non-variant core of the [2]-catenane was shown only to adopt type II' and type VIII turns at the β-2 and β-4 positions, respectively. Monomers were designed to delineate how these factors contribute to [2]-catenane equilibrium speciation/stability. Dipeptide turn adaptation studies, including three-component dynamic self-assembly experiments, suggested that stability losses are localized to the mutated sites, and that the turn types for the core β-2 and β-4 positions, type II' and type VIII, respectively, cannot be modified. Mutagenesis studies on the core Aib residue involved in a seemingly key CH-π-CH sandwich reported on how CH-π interactions and inter-ring hydrogen bonds affect stability. The interacting methyl group of Aib could be replaced with a range of alkyl and aryl substituents with monotonic affects on stability, though polar heteroatoms were disproportionately destabilizing. The importance of a key cross-ring H-bond was also probed by examining an Aib for l-Pro variant. Inductive affects and the effect of CH donor multiplicity on the core proline-π interaction also demonstrated that electronegative substituents and the number of CH donors can enhance the effectiveness of a CH-π interaction. These data were interpreted using a cooperative binding model wherein multiple non-covalent interactions create a web of interdependent interactions. In some cases, changes to a component of the web lead to compensating effects in the linked interactions, while in others, the perturbations create a cascade of destabilizing interactions that lead to disproportionate losses in stability.
Under acidic conditions (50 equiv of TFA), combinations of hydrazide A-B monomers self-assemble into octameric [2]-catenanes with high selectivity for [1(3)2](2), where 1 is a D-Pro-X (X = Aib, Ac(4)c, Ac(6)c, L-4-Cl-PhGly)-derived monomer and 2 is an L-Pro'-L-arylGly (Pro' = Pro, trans-F-Pro, trans-HO-Pro, aryl = naphthyl, phenyl)-derived monomer. Five different combinations of monomers were studied by X-ray crystallography. In each case, the unique aryl glycine unit is located in the core of the structure where the aryl ring templates a CH-π-CH sandwich. Analysis of metrical parameters indicates that this core region is highly conserved, while the more peripheral zones are flexible. (1)H NMR spectroscopy indicate that the solid-state structures are largely retained in solution, though several non-C(2)-symmetric compounds have a net C(2)-symmetry that indicates accessible dynamic processes. Catenane dynamic processes were additionally probed through H/D exchange, with the core being inflexible relative to the peripheral structure. Mass spectrometry was utilized to identify the constitutional isomerism in the minor asymmetric [1(5)2(3)] catenanes.
This article is concerned with the incorporation of cooperative molecular recognition and metal ion coordination in the design of selective sensors that signal binding events through their optical properties. Sensors that rely on non-specific hydrophobic effects are first considered before looking at the use of specific, directed intermolecular interactions to achieve greater specificity and chiral discrimination. The natural development of the same design concepts to produce catalysts and actuating devices with similar discriminatory abilities is also discussed.
Linking in: Two-ring and three-ring catenane nanostructures that are made from sequences of DNA have been shown to undergo programmed and reversible reconfiguration across defined topologies by using strand displacement. The switchable nature of the configurations may enable a more flexible approach to the transport and delivery of molecular cargoes, or for the use of such structures as labels in an intracellular environment.
Dynamic combinatorial libraries (DCLs) are molecular networks in which the network members exchange building blocks. The resulting product distribution is initially under thermodynamic control. Addition of a guest or template molecule tends to shift the equilibrium towards compounds that are receptors for the guest. This Account gives an overview of our work in this area. We have demonstrated the template-induced amplification of synthetic receptors, which has given rise to several high-affinity binders for cationic and anionic guests in highly competitive aqueous solution. The dynamic combinatorial approach allows for the identification of new receptors unlikely to be obtained through rational design. Receptor discovery is possible and more efficient in larger libraries. The dynamic combinatorial approach has the attractive characteristic of revealing interesting structures, such as catenanes, even when they are not specifically targeted. Using a transition-state analogue as a guest we can identify receptors with catalytic activity. Although DCLs were initially used with the reductionistic view of identifying new synthetic receptors or catalysts, it is becoming increasingly apparent that DCLs are also of interest in their own right. We performed detailed computational studies of the effect of templates on the product distributions of DCLs using DCLSim software. Template effects can be rationalized by considering the entire network: the system tends to maximize global host-guest binding energy. A data-fitting analysis of the response of the global position of the DCLs to the addition of the template using DCLFit software allowed us to disentangle individual host-guest binding constants. This powerful procedure eliminates the need for isolation and purification of the various individual receptors. Furthermore, local network binding events tend to propagate through the entire network and may be harnessed for transmitting and processing of information. We demonstrated this possibility in silico through a simple dynamic molecular network that can perform AND logic with input and output in the form of molecules. Not only are dynamic molecular networks responsive to externally added templates, but they also adjust to internal template effects, giving rise to self-replication. Recently we have started to explore scenarios where library members recognize copies of themselves, resulting in a self-assembly process that drives the synthesis of the very molecules that self-assemble. We have developed a system that shows unprecedented mechanosensitive self-replication behavior: depending on whether the solution is shaken, stirred or not agitated, we have obtained a hexameric replicator, a heptameric replicator or no replication, respectively. We rationalize this behavior through a mechanism in which replication is promoted by mechanically-induced fragmentation of self-assembled replicator fibers. These results represent a new mode of self-replication in which mechanical energy liberates replicators from a self-inhibited state. These systems may also be viewed as self-synthesizing, self-assembling materials. These materials can be captured photochemically, converting a free-flowing fiber solution into a hydrogel through photo-induced homolytic disulfide exchange.
Three rings: The self-assembly of a water-soluble [3]catenane from a library composed of two linear building blocks, both terminated by cysteine components, is promoted either by a high salt concentration or by the presence of spermine. The spermine-templated synthesis of the [3]catenane shows that such structures can exhibit strong binding interactions with a biologically relevant target in water under near-physiological conditions.
Since its inception in the mid-1990s, dynamic combinatorial chemistry (DCC), the chemistry of complex systems under thermodynamic control, has proved valuable in identifying unexpected molecules with remarkable binding properties and in providing effective synthetic routes to complex species. Essentially, in this approach, one designs the experiment rather than the molecule. DCC has also provided us with insights into how some chemical systems respond to external stimuli. Using examples from the work of our laboratory and others, this Account shows how the concept of DCC, inspired by the evolution of living systems, has found an increasing range of applications in diverse areas and has evolved conceptually and experimentally.
Supramolecular chemistry aims at implementing highly complex chemical systems from molecular components held together by non-covalent intermolecular forces and effecting molecular recognition, catalysis and transport processes. A further step consists in the investigation of chemical systems undergoing self-organization, i.e. systems capable of spontaneously generating well-defined functional supramolecular architectures by self-assembly from their components, thus behaving as programmed chemical systems. Supramolecular chemistry is intrinsically a dynamic chemistry in view of the lability of the interactions connecting the molecular components of a supramolecular entity and the resulting ability of supramolecular species to exchange their constituents. The same holds for molecular chemistry when the molecular entity contains covalent bonds that may form and break reversibility, so as to allow a continuous change in constitution by reorganization and exchange of building blocks. These features define a Constitutional Dynamic Chemistry (CDC) on both the molecular and supramolecular levels.
CDC introduces a paradigm shift with respect to constitutionally static chemistry. The latter relies on design for the generation of a target entity, whereas CDC takes advantage of dynamic diversity to allow variation and selection. The implementation of selection in chemistry introduces a fundamental change in outlook. Whereas self-organization by design strives to achieve full control over the output molecular or supramolecular entity by explicit programming, self-organization with selection operates on dynamic constitutional diversity in response to either internal or external factors to achieve adaptation.
The merging of the features: -information and programmability, -dynamics and reversibility, -constitution and structural diversity, points to the emergence of adaptive and evolutive chemistry, towards a chemistry of complex matter.
Control of the self-assembly and disassembly at the molecular level has become a subject of increasing activity. The supramolecular assembly between a photoswitchable azobenzene-containing surfactant, AzoC10, and α-cyclodextrin that combines photochemistry and host-guest chemistry for a stimulus-responsive vesicle has been recently reported. To clarify the role of photoisomerization in the reversible assembly and disassembly, we present in this work atomistic molecular dynamics simulations of the host-guest complexation of AzoC10 with α-cyclodextrin. The results of simulation reveal that both cis- and trans-AzoC10 form the inclusion complexes with α-CD, but the binding modes are rather different. The azobenzene moiety of trans-AzoC10 is included at the center of the cavity of α-CD, whereas one of the phenyl rings of cis-AzoC10 is exposed to water and the other is included in the cavity of α-CD. The shuttling motion of α-CD over the long alkyl chain of cis-AzoC10 is observed in the simulations. The potentials of mean force calculated for AzoC10 to pass through the cavity of α-CD show that the host-guest assembly is basically downhill for trans-AzoC10, but an energy barrier has to be overcome for cis-AzoC10 to complex with α-CD.
We present an extension of the generalized amber force field to allow the modeling of azobenzenes by means of classical molecular mechanics. TD-DFT calculations were employed to derive different interaction models for 4-hydroxy-4'-methyl-azobenzene, including the ground (S(0)) and S(1) excited state. For both states, partial charges and the -N = N- torsion potentials were characterized. On this basis, we pave the way to large-scale model simulations involving azobenzene molecular switches. Using the example of an isolated molecule, the mechanics of cyclic switching processes are demonstrated by classical molecular dynamics simulations.
More than a quarter of a century after the first metal template synthesis of a [2]catenane in Strasbourg, there now exists a plethora of strategies available for the construction of mechanically bonded and entwined molecular level structures. Catenanes, rotaxanes, knots and Borromean rings have all been successfully accessed by methods in which metal ions play a pivotal role. Originally metal ions were used solely for their coordination chemistry; acting either to gather and position the building blocks such that subsequent reactions generated the interlocked products or by being an integral part of the rings or "stoppers" of the interlocked assembly. Recently the role of the metal has evolved to encompass catalysis: the metal ions not only organize the building blocks in an entwined or threaded arrangement but also actively promote the reaction that covalently captures the interlocked structure. This Review outlines the diverse strategies that currently exist for forming mechanically bonded molecular structures with metal ions and details the tactics that the chemist can utilize for creating cross-over points, maximizing the yield of interlocked over non-interlocked products, and the reactions-of-choice for the covalent capture of threaded and entwined intermediates.
A simple water-soluble naphthalenedithiol building block is converted quantitatively into a series of octameric [2]-catenanes, composed of two interlocked molecular squares. When this mixture is re-equilibrated in the presence of an adamantyl ammonium guest, the catenanes disassemble into their macrocyclic components that bind the guest with nanomolar affinity in water.
The role of covalent, coordinative, and supramolecular interactions utilized by chemists and biochemists, when they are assembling molecular knots and links, are presented. The Trefoil Knot comprises a simple overhand knot where the two ends have been connected and can exist in left-handed and right-handed forms. A molecular Trefoil Knot displays inherent topological chirality and any representation of its graph cannot be deformed in 3D space to its mirror image, and exists as two enantiomers. A significant increase in knot yields is achieved by replacing the polymethylene linker with a meta-phenylene bridge, a change of design that resulted in the quantitative assembly of the precursor double helical complex. Alkene metathesis is particularly suited to macrocyclizations involving Cu(I)-templated species as it is a thermodynamically controlled reaction. It also avoids the need for addition of destabilizing bases, such as NaH, which are required when alkylation is the final step in the reaction sequence.
Mixtures of dipeptide monomers create stereochemically and constitutionally complex dynamic libraries of potential receptors. When (−)-cytidine was utilized as guest an 84-membered cyclic host was amplified (70–175 fold) from a nearly undetectable initial concentration. Only the specified diastereomeric combination of the two chiral building blocks yielded a dynamic library from which the macrocyclic receptor could be amplified.
Chloride, you're nicked! A novel handcuff catenane was prepared by anion templation and π-π stacking interactions. In addition, the first crystal structure determination of such a catenane is reported (see picture).
We describe the use of dynamic combinatorial chemistry to discover a new series of linear hydrazone-based receptors that bind multiple dihydrogen phosphate ions. Through the use of a template-driven, selection-based approach to receptor synthesis, dynamic combinatorial chemistry allows for the identification of unexpected host structures and binding motifs. Notably, we observed the unprecedented selection of these linear receptors in preference to competing macrocyclic hosts. Furthermore, linear receptors containing up to nine building blocks and three different building blocks were amplified in the dynamic combinatorial library. The receptors were formed using a dihydrazide building block based on an amino acid-disubstituted ferrocene scaffold. A detailed study of the linear pentamer revealed that it forms a helical ditopic receptor that employs four acylhydrazone hydrogen-bond donor motifs to cooperatively bind two dihydrogen phosphate ions.
The discovery through dynamic combinatorial chemistry (DCC) of a new generation of donor-acceptor [2]catenanes highlights the power of DCC to access unprecedented structures. While conventional thinking has limited the scope of donor-acceptor catenanes to strictly alternating stacks of donor (D) and acceptor (A) aromatic units, DCC is demonstrated in this paper to give access to unusual DAAD, DADD, and ADAA stacks. Each of these catenanes has specific structural requirements, allowing control of their formation. On the basis of these results, and on the observation that the catenanes represent kinetic bottlenecks in the reaction pathway, we propose a mechanism that explains and predicts the structures formed. Furthermore, the spontaneous assembly of catenanes in aqueous dynamic systems gives a fundamental insight into the role played by hydrophobic effect and donor-acceptor interactions when building such complex architectures.
Combinatorial chemistry is a tool for selecting molecules with special properties. Dynamic combinatorial chemistry started off aiming to be just that. However, unlike ordinary combinatorial chemistry, the interconnectedness of dynamic libraries gives them an extra dimension. An understanding of these molecular networks at systems level is essential for their use as a selection tool and creates exciting new opportunities in systems chemistry. In this feature article we discuss selected examples and considerations related to the advanced exploitation of dynamic combinatorial libraries for their originally conceived purpose of identifying strong binding interactions. Also reviewed are examples illustrating a trend towards increasing complexity in terms of network behaviour and reversible chemistry. Finally, new applications of dynamic combinatorial chemistry in self-assembly, transport and self-replication are discussed.
A hexanuclear coordination cage can increase the size of its cavity from nearly zero to more than 500 Å(3), which allows the encapsulation of two coronene molecules.
Shine a light: A supramolecular hydrogel is formed by the glucan curdlan equipped with α-cyclodextrins (CD-CUR) and azobenzene-modified poly(acrylic acid)(pAC12Azo). The sol-gel transition and the morphology of the supramolecular hydrogel can be switched by photoirradiation at the appropriate wavelength, which controls the formation of an inclusion complex between the α-cyclodextrins and the azobenzene moieties (see picture).
Im Zeichen des Zwillings: Ein Donor-Akzeptor-[2]Catenan mit schaltbarer Konformation wurde aus einer dynamischen kombinatorischen Bibliothek erhalten. In einer der Konformationen wurde eine neuartige Anordnung der π-Einheiten beobachtet, die an das astrologische Zeichen für Zwillinge erinnert (rechts). Das Catenan kann durch thermische und chemische Stimuli oder durch Änderung der Hydrophobie seiner Umgebung zwischen der parallelen und der nichtparallelen Konformation geschaltet werden.
We synthesized various azobenzenes methylated at their ortho positions with respect to the azo bond for more effective photoregulation of DNA hybridization. Photoregulatory efficiency, evaluated from the change of T(m) (DeltaT(m)) induced by trans-cis isomerization, was significantly improved for all ortho-modified azobenzenes compared with non-modified azobenzene due to the more stabilized trans form and the more destabilized cis form. Among the synthesized azobenzenes, 4-carboxy-2',6'-dimethylazobenzene (2',6'-Me-Azo), in which two ortho positions of the distal benzene ring with respect to carboxyl group were methylated, exhibited the largest DeltaT(m), whereas the newly synthesized 2,6-Me-Azo (4-carboxy-2,6-dimethylazobenzene), which possesses two methyl groups on the two ortho positions of the other benzene ring, showed moderate improvement of DeltaT(m). Both NMR spectroscopic analysis and computer modeling revealed that the two methyl groups on 2',6'-Me-Azo were located near the imino protons of adjacent base pairs; these stabilized the DNA duplex by stacking interactions in the trans form and destabilized the DNA duplex by steric hindrance in the cis form. In addition, the thermal stability of cis-2',6'-Me-Azo was also greatly improved, but not that of cis-2,6-Me-Azo. Solvent effects on the half-life of the cis form demonstrated that cis-to-trans isomerization of all the modified azobenzenes proceeded through an inversion route. Improved thermal stability of 2',6'-Me-Azo but not 2,6-Me-Azo in the cis form was attributed to the retardation of the inversion process due to steric hindrance between lone pair electrons of the pi orbital of the nitrogen atom and the methyl group on the distal benzene ring.
The study of positive homotropic allosterism in supramolecular receptors is important for elucidating design strategies that can lead to increased sensitivity in various molecular recognition applications. In this work, the cooperative relationship between tetrathiafulvalene (TTF)-calix[4]pyrroles and several nitroaromatic guests is examined. The design and synthesis of new annulated TTF-calix[4]pyrrole receptors with the goal of rigidifying the system to accommodate better nitroaromatic guests is outlined. These new derivatives, which display significant improvement in terms of binding constants, also display a positive homotropic allosteric relationship, as borne out from the sigmoidal nature of the binding isotherms and analysis by using the Hill equation, Adair equation, and Scatchard plots. The host-guest complexes themselves have been characterized by single-crystal X-ray diffraction analyses and studied by means of UV-spectroscopic titrations. Investigations into the electronic nature of the receptors were made by using cyclic voltammetry; this revealed that the binding efficiency was not strictly related to the redox potential of the receptor. On the other hand, this work serves to illustrate how cooperative effects may be used to enhance the recognition ability of TTF-calix[4]pyrrole receptors. It has led to new allosteric systems that function as rudimentary colorimetric chemosensors for common nitroaromatic-based explosives, and which are effective even in the presence of potentially interfering anions.
Two donor-acceptor [2]catenanes have been synthesized and characterized from a single dynamic combinatorial library in water. One of these catenanes is different from earlier related interlocked molecules in that two donor units stack on each other in an unexpected order. Shifting the equilibrium by choosing the right conditions resulted in a significant increase in the yields of the individual catenanes.
Multicomponent chemical systems that exhibit a network of covalent and intermolecular interactions may produce interesting and often unexpected chemical or physical behavior. The formation of aggregates is a well-recognized example and presents a particular analytical challenge. We now report the development of a numerical fitting method capable of estimating equilibrium constants for the formation of aggregates from the product distribution of a dynamic combinatorial library containing self-recognizing library members.
The lamprey holds the clue to the link between supramolecular self-assembly and allosteric ligand binding. Chelate cooperativity in self-assembled structures results in denaturation behavior that is indistinguishable from allosteric ligand binding. The chelate effect is the most common origin of positive cooperativity, yet its significance has been widely overlooked.