Host-Guest Stimuli-Responsive Click Chemistry.

Click chemistry has reached its maturity as the weapon of choice for the irreversible ligation of molecular fragments, with over 20 years of research resulting in the development or improvement of highly efficient kinetically controlled conjugation reactions. Nevertheless, traditional click reactions can be disadvantageous not only in terms of efficiency (side products, slow kinetics, air/water tolerance, etc.), but also because they completely avoid the possibility to reversibly produce and control bound/unbound states. Recently, non-covalent click chemistry has appeared as a more efficient alternative, in particular by using host-guest self-assembled systems of high thermodynamic stability and kinetic lability. This review discusses the implementation of molecular switches in the development of such non-covalent ligation processes, resulting in what we have termed stimuli-responsive click chemistry, in which the bound/unbound constitutional states of the system can be favored by external stimulation, in particular using host-guest complexes. As we exemplify with handpicked selected examples, these supramolecular systems are well suited for the development of human-controlled molecular conjugation, by coupling thermodynamically regulated processes with appropriate temporally resolved extrinsic control mechanisms, thus mimicking nature and advancing our efforts to develop a more function-oriented chemical synthesis.

Aqueous Three-Component Self-Assembly of a Pseudo[1]rotaxane Using Hydrazone Bonds.

We present herein the synthesis of a new polycationic pseudo[1]rotaxane, self-assembled in excellent yield through hydrazone bonds in aqueous media of three different aldehyde and hydrazine building blocks. A thermodynamically controlled process has been studied sequentially by analyzing the [1 + 1] reaction of a bisaldehyde and a trishydrazine leading to the macrocyclic part of the system, the ability of this species to act as a molecular receptor, the conversion of a hydrazine-pending cyclophane into the pseudo[1]rotaxane and, lastly, the one-pot [1 + 1 + 1] condensation process. The latter was found to smoothly produce the target molecule through an integrative social self-sorting process, a species that was found to behave in water as a discrete self-inclusion complex below 2.5 mM concentration and to form supramolecular aggregates in the 2.5-70 mM range. Furthermore, we demonstrate how the abnormal kinetic stability of the hydrazone bonds on the macrocycle annulus can be advantageously used for the conversion of the obtained pseudo[1]rotaxane into other exo-functionalized macrocyclic species.

"Vermellogens" and the Development of CB[8]-Based Supramolecular Switches Using pH-Responsive and Non-Toxic Viologen Analogues.

We present herein the "vermellogens", a new class of pH-responsive viologen analogues, which replace the direct linking between para-substituted pyridinium moieties within those by a hydrazone functional group. A series of such compounds have been efficiently synthesized in aqueous media by hydrazone exchange reactions, displaying a marked pH-responsivity. Furthermore, the parent N,N'-dimethylated "vermellogen": the "red thread", an analogue of the herbicide paraquat and used herein as a representative model of the series, showed anion-recognition abilities, non-reversible electrochemical behavior, and non-toxicity of the modified bis-pyridinium core. The host-guest chemistry for the "red thread" with the CB[7,8] macrocyclic receptors has been extensively studied experimentally and by dispersion corrected density functional theory methods, showing a parallel behavior to that previously described for the herbicide but, crucially, swapping the well-known redox reactive capabilities of the viologen-based inclusion complexes by acid-base supramolecular responsiveness.

Amino Acid-Viologen Hybrids: Synthesis, Cucurbituril Host-Guest Chemistry, and Implementation on the Production of Peptides.

We present herein the development of a series of viologen-amino acid hybrids, obtained in good yields either by successive alkylations of 4,4'-bipyridine, or by Zincke reactions followed by a second alkylation step. The potential of the obtained amino acids has been exemplified, either as typical guests of the curcubituril family of hosts (particularly CB[7]/[8]) or as suitable building blocks for the solution/solid-phase synthesis of two model tripeptides with the viologen core inserted within their sequences.

Reversible Control of DNA Binding with Cucurbit[8]uril-Induced Supramolecular 4,4'-Bipyridinium-Peptide Dimers.

Many cellular processes in living organisms are regulated by complex regulatory networks, built from noncovalent interactions between relatively few proteins that perform their functions by switching between homo- and heterooligomeric assemblies or mono- and bivalent states. Herein, we demonstrate that the conjugation of a 4,4'-bipyridinium scaffold to the basic region of the GCN4 bZip transcription factor can be exploited to control the dimerization of the conjugate by formation of a supramolecular complex with cucurbit[8]uril. Importantly, this supramolecular complex is able to specifically recognize its target dsDNA, and this binding can be reversibly switched by the application of external stimuli.

Dissecting the "Blue Box": Self-Assembly Strategies for the Construction of Multipurpose Polycationic Cyclophanes.

Stoddart's "blue box" (B4+), is one of the most iconic molecules in the recent history of chemistry. This rectangular tetracationic cyclophane has not only the ability to complex a wide variety of aromatic guests in organic or aqueous media, but because of the presence of viologen units on its structure, it also behaves as a redox-based molecular switch. In turn, B4+-based host-guest complexes can translate this responsiveness from the molecular to the supramolecular level, resulting in host-controlled binding. This unique behavior has allowed the development of a wide variety of B4+-containing (supra)molecular switches and machines, which certainly have inspired a whole generation of supramolecular chemists. Nevertheless, issues, such as synthetic accessibility, structural diversity, or the implementation of new chemical properties (luminescence, pH- or photo-responsiveness, etc.), have restricted somehow the development of new practical applications in the ever-changing realm of modern host-guest chemistry.Based largely on our own research throughout the past decade, we will highlight in this account two different strategies for the self-assembly of new B4+ analogues: (1) Pd(II)/Pt(II) metal-directed self-assembly and (2) hydrazone-based dynamic covalent chemistry. In essence, the strategies are based on the substitution of inert C-C single bonds on the macrocycle by Pd/Pt-N or C═N bonds of modifiable lability. In the case of the metal-directed synthesis, the use of Pd(II) centers allows for the spontaneous self-assembly at r.t., either in organic or aqueous media, of N-alkyl-4,4'-bipyridinium-based ligands into the desired metallacycles. Conversely, more inert Pt(II) salts can be also implemented, rendering the synthesis of more kinetically stable analogues. Alternatively, wholly organic B4+ congeners can be produced in a modular fashion by using hydrazone-based dynamic covalent chemistry, allowing for the self-assembly in acidic water of macrocyclic pH-responsive molecular switches of adjustable kinetic stability.Owning pyridinium-based cavities of appropriate size, our B4+-inspired cyclophanes are able to complex aromatic substrates by a conjunction of the hydrophobic effect and π-π/C-H···π interactions. Consequently, we will discuss in detail the different host-guest complexes that can be achieved using our cyclophanes. Considering this knowledge, the implementation of our B4+-based macrocycles onto mechanically interlocked molecules and knots will be introduced, as well as the development of practical applications for the hosts in currently important research fields, such as the development of duplex and G4-DNA binders, supramolecular catalysis or the sequestration of relevant pollutants. Finally, self-assembled hosts offer the unique opportunity to include constitutional dynamism into host-guest chemistry, so examples of the development by our group of stimuli-responsive constitutionally dynamic libraries and self-sorted systems will be highlighted.

Cucurbiturils as Effectors on the Self-Assembly of Pd(II) and Pt(II) Metallacycles.

Four bidentate, dicationic ligands (L12+-L42+) were prepared and investigated as guests for binding by the cucurbit[7]uril (CB[7]) host and structural components for metal (Pd and Pt)-coordinated self-assembly into metallacycles. In aqueous solutions, all the ligands were found to form stable complexes of variable stoichiometries with CB[7], and only one (L22+) failed to self-assemble, induced by the presence of suitable Pd or Pt complexes, into metallacycles. Exposure of the Pd-based metallacycles to CB[7] led to their disassembly at room temperature, while the Pt-based metallacycles remained stable under these conditions. However, heating of the Pt metallacycles in the presence of CB[7] also led to their disassembly. This interplay between the interactions in aqueous media of the L12+, L32+, and L42+ ligands with the CB[7] host and Pd (or Pt) complexes suggests the possibility of using these or related systems for controlled drug delivery applications.

Controlled binding of organic guests by stimuli-responsive macrocycles.

Synthetic supramolecular chemistry pursues not only the construction of new matter, but also control over its inherently dynamic behaviour. In this context, classic host-guest chemistry, based on the development of a myriad of macrocyclic receptors with fine-tuned affinities and selectivities, has enormously contributed to the discovery of new chemical function under self-assembly conditions. In turn, the use of molecular switches as control units within host-guest assemblies opened the door for the regulation of their dynamic interactional behaviour, which can be translated into controlled aggregation. In this review, we will focus on different strategies developed for the regulated binding of organic molecules by switchable macrocyclic hosts. As we will see, an appropriate design using stimuli-responsive versions of well-known organic receptors allows the molecular switches implemented within their structures to transform their regulated behaviour from the molecular to the supramolecular level.

An electrochemically controlled supramolecular zip tie based on host-guest chemistry of CB[8].

Three molecular threads incorporating two viologen units attached by an oligo-ethylene glycol chain of variable length and an electron rich naphthalene moiety were prepared. The internal viologen unit is connected to the naphthalene by a rigid linker that prevents the simultaneous complexation of these systems. The axle with the shortest chain (14+) in the presence of CB[8] placed the chain inside the macrocycle in aqueous media. In contrast, the longer chains in 24+ and 34+ allow locating the terminal viologen and the electron rich unit inside the cavity. Upon reduction of the bipyridinium salts, the system behaves like a zip tie relaxing the chain as a consequence of the insertion of both radical cation moieties within the CB[8] and making these switches as potential components for molecular machinery.

Thinking Outside the "Blue Box": Induced Fit within a Unique Self-Assembled Polycationic Cyclophane.

We present herein the development of a new polycationic molecular receptor, inspired by the ubiquitous cyclobis(paraquat- p-phenylene)cyclophane ("blue box"). Our analogue, the "white box", has been easily self-assembled on a preparative scale in water, using a template-assisted process by acyl hydrazone bonding of complementary bis(pyridinium)xylylene tweezers, followed by kinetic trapping of the empty receptor. The obtained macrocycle was found to display a marked pH responsiveness in water, because of an abnormal acidity of the amide protons within its structure. Consequently, and because of the concurrence of rotational isomerism under acidic conditions (fixed at higher pH values), the compound was found to display a dual behavior as a conformationally locked/flexible molecular host, being able to recognize appropriate aromatic substrates, in a lock and key or induced fit fashion, by a conjunction of π-π, C-H···π, and, crucially, the hydrophobic effect.

Tuning of the Self-Threading of Ring-in-Ring Structures in Aqueous Media.

A series of aryl-extended N-monoalkyl-4,4'-bipyridinium salts L (aryl=1,4-phenyl, 4,4'-biphenyl, 2,6-naphthyl and 9,10-anthracenyl) have been implemented by PdII /PtII -directed self-assembly into constitutionally dynamic systems (CDSs). As a result, the intended processes produced not only (en)M2 L2 (en=ethylenediamine) metallacyclic species but also (en)M4 L4 ring-in-ring aggregates, in equilibrium with the former, as a consequence of the hydrophobic nature of the aryl rings within the 4,4'-bipyridinium scaffold. The key feature of the obtained dynamic systems is the possibility of modulating their response against external stimuli by modifying the hydrophobic character of the ligand. While the different dynamic libraries follow the same trends upon changes in concentration, temperature, polarity of the medium, or addition of an aromatic chemical effector, subtle changes in the ligand hydrophobic core results in a fine-tuning of the speciation when applying a certain degree of the different stimulus. The exception is the anthracene-containing derivative, which does not form inclusion complexes or self-threaded structures.

Terminal Carboxylate Effects on the Thermodynamics and Kinetics of Cucurbit[7]uril Binding to Guests Containing a Central Bis(Pyridinium)-Xylylene Site.

A series of bis(pyridinium)-xylylene derivatives bearing carboxylate terminal groups were investigated as guests for the cucurbit[7]uril host in aqueous solution. While the presence of the terminal carboxylates has a modest effect on the thermodynamic stability of the complexes, the kinetics of complex association/dissociation is strongly affected. The relative position ( meta, para) of the carboxylate group in relation to the pyridinium nitrogen also exerts a considerable effect on the binding kinetics.

Cucurbit[8]uril (CB[8])-Based Supramolecular Switches.

The use of cucurbit[8]uril as a molecular host has emerged in the chemical literature as a reliable strategy for the creation of dynamic chemical systems, owing to its ability to form homo- and heteroternary complexes in aqueous media with appropriate molecular switches as guests. In this manner, CB[8]-based supramolecular switches can be designed in a predictable and modular fashion, through the selection of appropriate guests able to condition the redox, photochemical, or pH-triggered behavior of tailored multicomponent systems. Furthermore, CB[8] allows the implementation of dual/triple and linear/orthogonal stimuli-dependent properties into these molecular devices by a careful selection of the guests. This versatility in their design gives these supramolecular switches great potential for the rational development of new materials, in which their function is not only determined by the custom-made stimuli-responsiveness, but also by the transient aggregation/disaggregation of homo- or heteromeric building blocks.

Subcellular Duplex DNA and G-Quadruplex Interaction Profiling of a Hexagonal PtII Metallacycle.

Metal-driven self-assembly afforded a multitude of fascinating supramolecular coordination complexes (SCCs) with applications as catalysts, host-guest, and stimuli-responsive systems. However, the interest in the biological applications of SCCs is only starting to emerge and thorough characterization of their behavior in biological milieus is still lacking. Herein, we report on the synthesis and detailed in-cell tracking of a Pt2 L2 metallacycle. We show that our hexagonal supramolecule accumulates in cancer cell nuclei, exerting a distinctive blue fluorescence staining of chromatin resistant to UV photobleaching selectively in nucleolar G4-rich regions. SCC co-localizes with epitopes of the quadruplex-specific antibody BG4 and replaces other well-known G4 stabilizers. Moreover, the photophysical changes accompanying the metallacycle binding to G4s in solution (fluorescence quenching, absorption enhancement) also take place intracellularly, allowing its subcellular interaction tracking.

Integrative Self-Sorting of Bipyridinium/Diazapyrenium-Based Ligands into Pseudo[1]rotaxanes.

We present here the design and synthesis of a series of multicomponent supramolecular architectures, structures formed by the PdII /PtII -directed integrative social self-sorting in aqueous media of pairs of complementary N-monoalkyl-4,4'-bipyridinium/2,7-diazapyrenium-based ligands. Out of the different potential outcomes of the processes, we have found out how the designed systems selectively enhance the production of pseudo[1]rotaxanes, hermaphroditic host-guest aggregates that maximize the strength of the occurring π-π, C-H⋅⋅⋅π, and hydrophobic interactions, as well as the number of those interactions per receptor. It is also demonstrated how both integrative social and narcissistic PdII -directed self-sorting can occur orthogonally and concomitantly for this type of ditopic ligands.

Synthesis of non-symmetric viologen-containing ditopic ligands and their Pd(ii)/Pt(ii)-directed self-assembly.

We present here an efficient method for the preparation of non-symmetric viologen-containing ditopic ligands, as well as the Pd(ii)/Pt(ii)-directed self-assembly of some of these into metallacyclic receptors. The designed synthetic route, that implies the sequential alkylation and the Zincke reaction of activated bipyridinium salts, allowed us to substantially improve the yield in the preparation of three previously reported ligands. The versatility and efficiency of the method have also been tested for the preparation of four new viologen-containing ligands with very different structural features. Furthermore, the self-assembly of the new ligands around Pd(ii) and Pt(ii) centers has been tested, yielding mononuclear rectangular-shaped metallacycles of different dimensions and electronic characteristics.

Self-assembly of Pd2L2 Metallacycles Owning Diversely Functionalized Racemic Ligands.

We present herein the efficient palladium(II)-directed self-assembly in water of a series of nine new diversely functionalized metallacycles, owning hydroxy/alkoxycarbonyl/azidoalkyl exo pendant groups attached to ditopic N-monoalkyl/aryl-4,4'-bipyridinium/2,7-diazapyrenium ligands. The highly convergent and versatile synthetic route for the ligands uses the Zincke reaction between (dinitrophenyl)bipyridinium/diazapyrenium salts and racemic amines as the key step. The stereochemical outcome of the self-assembly of the Pd2L2 species is discussed on the basis of density functional theory quantum-chemical calculations.

When self-assembly fails: stepwise metal-directed synthesis of [2]catenanes.

On the attempted synthesis of a series of homo- and heterotrimetallic [2]catenanes by the self-assembly of a 2-(pyridin-4-ylmethyl)-2,7-diazapyrenium ligand, (ethylenediamine)palladium(II) or platinum(II) nitrate, and a dioxoaryl bis(N-monoalkyl-4,4'-bipyridinium) salt as building blocks, both the one-pot direct self-assembly of the components and the so called "magic ring" approach fail to produce the expected trinuclear [2]catenanes under thermodynamically driven conditions. However, one of the target supramolecules is obtained by following a stepwise protocol, consisting of the threading of a dinuclear Pt(II) metallacycle and the dioxoaryl bis(N-monoalkyl-4,4'-bipyridinium) axle, followed by kinetically controlled Pt(II) -directed cyclization of the corresponding pseudorotaxane.

Complexation and Catenation in Aqueous Media Using a Self-Assembled Pd(II) Metallacyclic Receptor.

A M2L2 rectangular-shaped metallacycle, obtained by metal-directed self-assembly of a 2-(pyridin-4-ylmethyl)-2,7-diazapyrenium salt and [(en)Pd(NO3)2 (en=ethylenediamine), has been investigated as a molecular receptor for a wide range of aromatic substrates in water. Complexation and catenation of the receptor with selected mono- and polycyclic aromatic substrates produced 1:1 inclusion complexes and [2]catenanes in a highly efficient fashion, as determined by NMR and UV/Vis spectroscopic techniques, as well as single-crystal X-ray crystallography. Furthermore, the thermodynamic and kinetic features of the complexation processes have been analyzed for selected model guests.

Metallacycle-catalyzed SNAr reaction in water: supramolecular inhibition by means of host­guest complexation.

The performance of a Pt(II) diazapyrenium-based metallacycle as a reusable substoichiometric catalyst for the SNAr reaction between halodinitrobenzenes and sodium azide at rt in aqueous media is reported. The results suggest that the catalytic effect is promoted by the association of the azide to the diazapyrenium cationic subunits of the catalyst. The findings demonstrate that the formation of an inclusion complex between pyrene and the metallacycle has a regulatory effect over the system, resulting in allosteric-like inhibition of the SNAr reaction.