Cortón, P.; Fernández-Labandeira, N.; Díaz-Abellás, M.; Peinador, C.; Pazos, E.; Blanco-Gómez, A.; García, M. D., Aqueous Three-component Self-assembly of a Pseudorotaxane using Hydrazone Bonds. J. Org. Chem. 2023, in press. DOI: 10.1021/acs.joc.3c00108
We present herein the synthesis of a new polycationic pseudorotaxane, 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 pseudorotaxane 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 pseudorotaxane into other exo-functionalized macrocy-clic species.
Neira, I.; Domarco , O.; Rama, T.; Blanco, V.; Peinador, C.; García, M. D.; Quintela, J.M., Metal-Directed Self-Assembly of Constitutionally Dynamic Systems: Control of the Nuclearity of Pd(II)/Pt(II) Metallacycles . Dalton Trans. 2023, 52, 90-96. DOI: 10.1039/D2DT02955C
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
Barravecchia, L.; Blanco-Gómez, A.; Neira, I.; Skackauskaite , R.; Vila, A.; Rey-Rico, A.; Peinador, C.; García, M. D., Vermellogens” and the development of CB-based Supramolecular Switches Using pH-responsive and Non-Toxic Viologen Analogues. J. Am. Chem. Soc. 2022, 144, 19127-19136. DOI: 10.1021/jacs.2c08575
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.
Neira, I.; Peinador, C.; García, M. D., CB and CB-based -(pseudo)rotaxanes with triphenylphosphonium-capped threads: Serendipitous discovery of a new high-affinity binding motif. Org. Lett. 2022,24, 4491-4495. DOI: 10.1021/acs.orglett.2c01028
The synthesis of new triphenylphosphonium-capped cucurbituril (CB) and cucurbituril (CB)-based rotaxanes was intended by a simultaneous threading-capping strategy. Whilst the use of CB produced the designed rotaxane, attempts to obtain the CB 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.
Cortón, P.; Wang, H.; Neira, I.; Blanco-Gómez, A.; Pazos, E.; Peinador, C.; Li, H.; García, M. D., “The red cage”: implementation of pH-responsiveness within a macrobicyclic pyridinium-based molecular host. Org. Chem. Front. 2022,9, 81-87. DOI: 10.1039/D1QO01331A
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.
Barravecchia, L; Neira, I; Pazos, E.; Peinador, C.; García, M. D., Amino Acid−Viologen Hybrids: Synthesis, Cucurbituril Host−Guest2 Chemistry, and Implementation on the Production of Peptides. J. Org. Chem. 2022, 87, 760-764. DOI: 10.1021/acs.joc.1c02040
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/) 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.
Novo, P.; García, M. D.; Peinador, C.; Pazos, E., Reversible Control of DNA Binding with Cucurbituril-Induced Supramolecular 4,4′-Bipyridinium-Peptide Dimers. Bioconjugate Chemistry 2021, 32, 507-511. DOI: 10.1021/acs.bioconjchem.1c00063
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 cucurbituril. 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.
Neira, I.; García, M. D.; Peinador, C.; Kaifer, A. E., Cucurbiturils as Effectors on the Self-Assembly of Pd(II) and Pt(II) Metallacycles. J. Org. Chem. 2021, 86, 14608-14616. DOI: 10.1021/acs.joc.1c01460
Four bidentate, dicationic ligands (L12+-L42+) were prepared and investigated as guests for binding by the cucurbituril (CB) 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, 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 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 also led to their disassembly. This interplay between the interactions in aqueous media of the L12+, L32+, and L42+ ligands with the CB host and Pd (or Pt) complexes suggests the possibility of using these or related systems for controlled drug delivery applications.