Metal-directed self-assembly of constitutionally dynamic systems: control of the nuclearity of Pd(II)/Pt(II) metallacycles.

Self-assembly with the square-planar Pd(II) or Pt(II) (en)M(ONO2)2 (en = ethylenediamine) complexes of ditopic ligands incorporating both N,N'-dialkyl-4,4'-bipyridinium and N-monoalkyl-4,4'-bipyridinium or N-monoalkyl-2,7-diazapyrenium moieties leads to constitutionally dynamic systems responsive to the concentration of the components. At low concentrations, the metallamacrocyclic mononuclear [ML]5+ species is formed. In contrast, when the concentration is increased, a defined dinuclear [M2L2]10+ structure appears as a second species in equilibrium, becoming the major one at high concentrations. Besides concentration changes, the addition of an aromatic guest also allows the control of the system speciation, shifting the outcome of the metal-directed self-assembly towards the mononuclear metallacycle. This dynamic behavior enables the control of the nuclearity of the metallacycles assembled by 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.

Adjusting the Dynamism of Covalent Imine Chemistry in the Aqueous Synthesis of Cucurbit[7]uril-based [2]Rotaxanes.

The self-assembly of [2]rotaxane has been achieved in aqueous media at pD 4 by the simultaneous threading into CB[7] of an appropriate axle ended with acyl hydrazine groups and its concurrent capping with two molecules of a triphenylphosphonium aldehyde as stoppers. The dynamism of the rotaxane has been demonstrated under acidic conditions and can be diminished by solvent swapping, pH modulation, or, surprisingly, the removal of the carbonyl groups on the axle.

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.

Amplification of a metallacyclic receptor out of a dynamic combinatorial library.

We present herein the Pt(ii)-directed self-assembly in water of a new conformationally flexible N-monoalkyl-4,4-bipyridinium-based ditopic ligand into a library of six different metallacyclic structures. This constitutionally dynamic library can be pushed to increase the production of one of the supramolecules in aqueous media, either by controlling the concentration of the building blocks or upon addition of an appropriate aromatic substrate.

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.

Stimuli-responsive metal-directed self-assembly of a ring-in-ring complex.

Concentration, temperature and/or solvent polarity control the speciation on the metal-directed self-assembly of a ditopic pyridyl ligand L with cis-protected Pd(ii) metal centers. This results into a controllable dynamic system, involving a [Pd2L2](6+) metallacycle and a [Pd4L4](12+) ring-in-ring complex.

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.

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.

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.

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.

Dimensional matching of polycyclic aromatics with rectangular metallacycles: insertion modes determined by [C-H···π] interactions.

A family of Pd(II)/Pt(II) dinuclear receptors, designed to give a smooth increase in their cavity lengths (from 7.46-13.78 Å), is presented. Their inclusion complexes with a representative set of polycyclic aromatic substrates (naphthalene, carbazol, pyrene, and benzo[a]pyrene), were characterized and studied in aqueous solution and the solid state. By taking into account the dimensions of both receptors and substrates, an excellent complementarity was found between the size of the receptors and their ability to complex a given substrate. Furthermore, this dimensional matching results in specific binding modes depending on the ability of the guest to establish stabilizing [C-H···π] interactions with the host.

DNA binding studies and cytotoxicity of a dinuclear PtII diazapyrenium-based metallo-supramolecular rectangular box.

The interaction with native DNA of a 2,7-diazapyrenium-based ligand 1 and its Pt(II) rectangular metallacycle 2 is explored through circular and linear dichroism and fluorescence spectroscopies. The metal-free ligand 1 binds through intercalation, with a binding constant of approximately 5×10(5) M(-1), whereas the metallacycle 2 binds and bends the DNA with a binding constant of 7×10(6) M(-1). PCR assays show that metallo-supramolecular box 2 interferes with DNA transactions in vitro whereas the intercalator 1 does not. The metallacycle is active against four human cancer cell lines, with IC(50) values ranging between 3.1 and 19.2 µM and shows similar levels of efficacy, but a different spectrum of activity, to cisplatin.

[2]Catenanes and inclusion complexes derived from self-assembled rectangular Pd(II) and Pt(II) metallocycles.

New inclusion complexes and [2]catenanes were self-assembled from a fluorescent diazapyrenium based ligand, a PdII or PtII complex, and cyclic or acyclic electron rich aromatic guests in aqueous and organic media. The molecular rectangles display a π-deficient cavity suitable to incorporate π-donor aromatic systems. The inclusion complexes between the metallocycles and phenylenic (2a,b) and naphthalenic (3a,b­5a,b) derivatives were studied by NMR, UV-vis and fluorescence spectroscopy. The crystal structure of (3b) ⊂ 1a·6PF(6) confirmed the insertion of the guest into the cavity of the metallocycle. Following the same self-assembly strategy, the use of polyethers 6,7 as π-donors resulted in the self-assembly of the [2]catenanes 1a(6,7)·6PF(6). Single-crystal X-ray analysis of 1a(7)·6PF6 revealed the [2]catenane structure being stabilized by π-stacking and [C­H···O] interactions.

Probing electrostatic potential by NMR with the use of a paramagnetic lanthanide(III) chelate.

The paramagnetic complex [Yb(DOTA)](-) forms ion pairs in aqueous solution with cationic species such as N-monoalkyl- and N,N'-dialkyl-4,4'-bipyridinium cations. The magnitude and sign of the induced (1)H NMR pseudocontact shift values can be correlated to the electrostatic potential calculated at the MPWLYP/6-311G** level.

Synthesis of platinum(II) metallocycles using microwave-assisted heating.

An efficient microwave-assisted self-assembly of dinuclear platinum metallocycles is reported. The reactions proceed to afford the products with high purity and yields within 3-4 h. We have used this methodology to synthesize a new 14.75 Å × 14.75 Å molecular square. The solid-state structure showed a perfect alignment of the squares along the c axis.

Complexation and extraction of PAHs to the aqueous phase with a dinuclear Pt(II) diazapyrenium-based metallacycle.

New palladium and platinum metallacycles have been synthesized by reaction between a 2,7-diazapyrenium-based ligand and Pd(II) and Pt(II) complexes. The inclusion complexes between the metallacycles and polycyclic aromatic hydrocarbons (PAHs) in CD(3)NO(2) and D(2)O were studied by NMR spectroscopy. The structures of the inclusion complexes of the Pt metallacycle as host with pyrene, phenanthrene, and triphenylene were confirmed by single crystal X-ray crystallography. The association constants between the Pt metallacycle and the selected PAHs were determined in CH(3)CN following the characteristic charge-transfer band displayed in their UV/Vis absorption spectrum. Although in aqueous solution all the complexes showed a 1:1 stoichiometry, in CH(3)CN the Job plot indicated a 2:1 stoichiometry for complexes with triphenylene and benzo[a]pyrene. The estimated association constants in water correlate with the hydrophobicity of the PAH, indicating that hydrophobic forces play an important role in the complexation process.

Dynamic formation of self-organized corner-connected square metallocycles by stoichiometric control.

Corner-connected molecular squares were self-assembled from a three-component system formed by a bidentate ligand and two palladium or platinum complexes. The system is dynamic and the constitution of the species in solution can be modulated under stoichiometric control.

Complexation of pyrene in aqueous solution with a self-assembled palladium metallocycle.

A bidentate ligand based on N-monoaryl 4,4'-bipyridinium undergoes self-assembly to dinuclear rectangular metallocycles upon coordination to palladium(II) and platinum(II) centers. These metallocycles form a very stable complex with pyrene in aqueous solution and in the solid state. A crystal structure of the pyrene inclusion complex is presented. The association constants between pyrene and metallocycle 3a in organic solvents and water (K(a) = 2.3 x 10(6)) were determined.