Development of flexible cavitand receptors based on calix[5]arene. Rational design, synthesis and study of their properties
- Autores: Ruben Álvarez Yebra
- Directores de la Tesis: Agustí Lledó Ponsatí (dir. tes.)
- Lectura: En la Universitat de Girona ( España ) en 2023
- Idioma: inglés
- Tribunal Calificador de la Tesis: Xavier Ribas Salamaña (presid.), Jordi Solà i Oller (secret.), Elena Pazos Chantrero (voc.)
- Programa de doctorado: Programa de Doctorado en Química por la Universidad de Girona
- Materias:
- Enlaces
- Tesis en acceso abierto en: TDX
- Resumen
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Els cavitands són macromolècules amb una cavitat permanent on es poden allotjar molècules o ions més petits . La cavitat hidrofòbica d’aquests receptors permet la unió amb altres molècules a traves de forces no covalents, resultant en la formació de complexos hostatger hoste (host guest). Aquest és un comportament similar al dels enzims amb els seus substrats, i per aquesta raó els cavitands son considerats un bons candidats per a la mimesi biològica. Els cavitans més recurrents, i alhora més estudiats, són els derivats de resorcin[4]arè. Alguns d’aquests cavitands presenten la capacitat d’auto plegar se (self folding) gràcies a una xarxa d’enllaços d’hidrogen intramoleculars, i d’aquesta manera estabil itzar ne la conformació còncava. Havent demostrat ser útils en innumerables aplicacions i multitud d’àmbits com ara el reconeixement molecular o la catàlisi biomimètica, els cavitands derivats de resorcin[4]arè es presenten com la cúspide d’aquesta discipl ina. No obstant això, el nostre grup de recerca ha identificat algunes limitacions d’aquesta estructura. En primer lloc, els cavitands de resorcin[4]arè presenten un volum reduït, la qual cosa limita la varietat d'hostes a molècules petites de rellevància limitada. I en segon lloc, i més remarcable, tenen una alta rigidesa estructural, mancant los la capacitat d'adaptar se als hostes i, per tant, dificultant les aplicacions inspirades en els sistemes biològics. A causa d'aquests inconvenients, el nostre gru p de recerca ha concebut una nova família de cavitands basada en macrocicles de calix[5]arè amb cavitats expandides i flexibles. Aquest receptors presenten la propietat d'auto plegar se i un comportament d'encaix induït (induced fit) genuí. Es preveu que a questa nova aproximació permeti el desenvolupament d'aplicacions amb una varietat més diversa d'hostes i substrats significatius. Els objectius principals establerts en aquesta tesi van ser el desenvolupament d'una nova família de receptors d'auto plegables amb cavitats eixamplades i flexibles, conjuntament amb la consolidació dels fonaments que ens permetin diversificar l’estructura i accedir a una varietat de característiques diferents emprant la mateixa base de construcció.
- English
Cavitands are macromolecules with a permanent cavity where smaller molecules or ions can be accommodated. The hydrophobic cavity of these supramolecules allows the binding of other molecules though non-covalent interactions, resulting in host-guest complexation. This behavior is very similar to the one that enzymes have toward their substrates, and for this reason cavitands are considered good candidates for biological mimesis.
The most common and studied cavitands are the derivatives of resorcin[4]arene. Some of these cavitands present the ability to self-fold into a stabilized closed conformation that defines a deep cavity, through an intramolecular hydrogen bond network. Having proven useful in countless applications and a wide range of fields, such as molecular recognition or biomimetic and supramolecular catalysis, resorcin[4]arene cavitands have been presented as the pinnacle of this discipline. Nevertheless, our research group has identified some limitations of this scaffold. First, resorcin[4]arene cavitands have a reduced volume, limiting the variety of viable guests to small molecules or ions of lesser relevance. And second and most remarkable, these cavitands have high structural rigidity, lacking the ability to adapt to bound guests and hence hindering the applications inspired on biological systems. Due to these disadvantages, we have conceived a completely new family of cavitands based on calixarene macrocycles with expanded and flexible cavities, featuring self-¬folding properties and genuine induced fit behavior. This new approach promises to enable the development of applications with a more diverse and significant variety of guests and/or substrates.
The main goals set within the context of this thesis were the development of a novel self--folding family of receptors with expanded and flexible binding sites, and the consolidation of the basis for the diversification of the structure in order to access a variety of features and characteristics within the same scaffold.
As reported in Chapter 3, we succeeded in the synthesis of a new cavitand based on a flexible scaffold of calix[5]arene and bearing 1,8-amidonaphthol walls that define an enlarged cavity stabilized by intramolecular hydrogen bonds. This cavitand displays molecular recognition for polycyclic aromatic hydrocarbons, which are guest of interest for various reasons. The results obtained in Chapter 3 allowed us to further diversify the structure as reported in the following chapters. We found that 1,8-amidonaphthol walls are still somewhat rigid to properly wrap around bulky and non-planar guests. Chapter 4 describes the implementation of 2-(amidomethyl)phenol moieties instead. First, we report a highly flexible cavitand that lacks sufficient conformational stability in solution, even in the presence of suitable guests. Next, we described a modified structure with similar degrees of flexibility but more preorganized thanks to steric effects, incorporating as a panel de so-called Betti base, a chiral benzylic amine. This new chiral cavitand exhibits the highest enantioselectivity in the molecular recognition of chiral ammonium salts so far reported. The first chapters of the thesis evidence the delicate balance between the preorganization of the host (higher degree of rigidity) and the adaptability towards guests (higher degree of flexibility). This concept is further developed in Chapter 5, where we explored the modification of the cavitands lower rim to access spherical and more symmetrical cavities. We have managed to conformationally stabilize this receptor by means of auxiliary molecules that establish an intermolecular hydrogen bond network. This new spherical cavitand provides molecular recognition of fullerenes, due to the good geometric complementarity between host and guest. In Chapter 6 we describe the exploration of halogen bonds as surrogate stabilizing interactions instead of hydrogen bonds. Finally, Chapter 7 describes the development of water-soluble receptors employing ionic groups at the upper rim of the structure.
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