Dynamic Covalent Capsules based on Calix[4]pyrrole Scaffolds

In this thesis work we describe the self-assembly of [1+1] tetra-imine and [4+2] octa-imine capsular aggregates based on calix[4]pyrrole scaffolds. The [1+1] molecular containers were prepared by the condensation reaction of two tetra-α aryl-extended calix[4]pyrrole decorated with aldehyde and amino groups at the upper rims. The [4+2] analogues were obtained by the condensation of four copies of a di- aldehydephenyl linker with two copies of the tetra-α tetra-amino aryl-extended calix[4]pyrrole. We investigated the self-assembly processes of the polar poly-imine containers in the presence of di-topic pyridinyl-N-oxides as template. We also studied the emergence of the containers in pure chloroform and in 9:1 CDCl₃: CD₃CN solvent mixture.

The self-assembly of the capsules in the absence of a template, allowed the thermodynamic and kinetic characterization of a series of encapsulation complexes with pyridyl-N-oxide derivatives. ¹H NMR spectroscopy studies revealed that the inclusion complexes were mainly stabilized through the formation of an array of hydrogen bonding interactions between the oxygen atoms of the N-oxide groups and  the pyrrole NHs of the capsule’s calix[4]pyrrole hemispheres. We also determined the structures of several encapsulation complexes in the solid state using single-crystal X-ray diffraction. We observed that in addition to hydrogen bonding interactions CH-π and π-π interactions were also involved in the stabilization of the complexes.

The post-synthetic modification of the labile and conformationally rigid [4+2] octa-imine capsule produced the corresponding octa-amine derivative. The reduction of the imine groups was uneventful and the obtained octa-amine capsule displayed an increased conformational flexibility.

We performed binding studies of the capsules with a series of pyridyl-N-oxide guests (ditopic guest 4′,4′-bipyridine N,N’dioxide and several the monotopic N-oxide guests).

We concluded that only the more flexible amine capsule was able to adapt the dimensions of its cavity to those of the encapsulated di-topic pyridyl-N-oxide.

The kinetics of encapsulation of the guests turned out to be solvent dependent (CDCl₃ and CDCl₃:CD₃CN mixtures).The dimensions of the N-oxides also impacted on the encapsulation rate, thus providing some insights on the mechanisms that are operative.

We investigated the use of the [4+2] octa-imine and octa-amine capsules as supramolecular nanoreactors. We selected the Huisgen azide-alkyne 1,3-dipolar cycloaddition reaction between properly functionalized pyridine-N-oxides. We demonstrated that  the co-encapsulation of the pyridine-N-oxides in the capsule’s cavities produced a significant acceleration of the reaction rate compared to that in the bulk solution. Notably, the 1,4- regioisomer was exclusively produced in the reaction taking place inside the cavity of the containers.

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