2022-2021 Publications

Biological substrate specificity ensures that organisms interact accurately with biomolecular receptors, crucial for key functions such as signaling and immunity. Nevertheless, this phenomenon is still poorly understood, with host–guest chemistry offering a suitable platform for studying simplified models. Herein, we report an in-depth study of the host–guest chemistry of alkyltriphenylphosphonium cations with cucurbit[8]uril (CB[8]), initiated by the serendipitous discovery of salt forming a tightly bound pseudoheteroternary 1:1 complex with CB[8]. A first generation of model substrates was designed to explore an unusual binding mode characterized by the simultaneous introduction of two distinct guest fragments within the host cavity. Structural features of the complexes were elucidated using ESI-MS and NMR 1D/2D techniques; thermodynamic properties were assessed by isothermal titration calorimetry, and kinetic parameters were derived from selective inversion–recovery NMR. Experimental results aligned well with electronic structure calculations, revealing a reproducible binding motif with submicromolar affinities. This peculiar complexation mode involves a synergistic effect caused by steric crowding around the P+ atom, facilitating the insertion of two aromatic units into CB[8] while hindering association with CB[7]. Based on these findings, a second generation of minimalistic substrates was developed, preserving the synergistic interaction mode and exhibiting specific binding to CB[8].

The ability to exploit an energy source to drive chemical reactions away from thermodynamic equilibrium is an essential feature of life and a grand challenge for the design of fuel-driven dynamic artificial nanosystems.
Here, we investigate the effect of light irradiation on the formation of supramolecular complexes composed of azobenzene-type guests and a cyclodextrin (CD) host in water. Whereas previous studies on these complexes have focused on equilibrium properties, our work explores far-from-equilibrium distributions obtained by light-driven association. We demonstrate that the relative abundance of the two CD orientational diastereomeric complexes can be inverted upon photoirradiation and showcase a ratcheted approach, employing biocompatible macrocycles and harnessing visible light, to the spontaneous formation of high-energy CD complexes with broad applicability in aqueous environments. We foresee opportunities for the development of active materials, the design of artificial metabolic networks, and the engineering of molecular machines operating under physiological conditions.

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.

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. The thermodynamically–controlled pro-cess has been studied sequentially by analyzing: the [1+1] reaction of a bisaldehyde and a trishydrazine leading to the macro-cyclic 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 annu-lus can be advantageously used for the conversion of the obtained pseudo[1]rotaxane into other exo-functionalized macrocy-clic species.

The self-assembly with 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

We present herein the “vermellogens”, a new class of pH-responsive viologen analogues, which replace the direct linking between para-substituted pyridinium moieties in 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. Fur-thermore, the parent N,N’-dimethylated “vermellogen”: the “red thread”, analogue of the herbicide paraquat and used herein as representative model of the series, showed as well 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] macrocy-clic receptors has been extensively studied experimentally and by dispersion corrected DFT 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.

The synthesis of new triphenylphosphonium-capped cucurbit[7]uril (CB[7]) and cucurbit[8]uril (CB[8])-based [2]rotaxanes was intended by a simultaneous threading-capping strategy. Whilst the use of CB[7] produced the designed [2]rotaxane, attempts to obtain the CB[8] analogue were unsuccessful, due to the unexpected strong interaction found between the host and the phosphonium caps leading to pseudo-heteroternary host-guest complexes. This unusual binding motif has been ex-tensively studied experimentally, with results in good agreement with those obtained by dispersion-corrected DFT methods.

We present herein the implementation of pH-responsiveness into a new polycationic macrobicyclic structure, namely what we have termed the “red cage”. The hydrolytically-stable cryptand-like compound has been prepared in a relatively high yield in aqueous media by a kinetically-controlled hydrazone-exchange reaction, promoted by the unusual high stability of the new hydrazone C[double bond, length as m-dash]N bonds formed. In organic media the macrobicycle was found not able to complex model aromatic substrates. In buffered aqueous solutions, as a comparison, the “red cage” was found able to recognize them, but the binding was observed to be more efficient in acidic form of the cyclophane compared with its conjugate base.

We present herein the development of a series of 5 viologen−amino acid hybrids, obtained in good yields either by 6 successive alkylations of 4,4′-bipyridine, or by Zincke reactions 7 followed by a second alkylation step. The potential of the obtained 8 amino acids has been exemplified, either as typical guests of the 9 curcubituril family of hosts (particularly CB[7]/[8]) or as suitable 10 building blocks for the solution/solid-phase synthesis of two model 11 tripeptides with the viologen core inserted within their sequences.

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.