My MSc project aims at developing pH-responsive molecular tweezers for drug delivery applications. The project began with the synthesis of our 2nd generation tweezer, whose main objective was to improve our previous model, 1st generation tweezer, which contained a pH-responsive triad spacer and two naphthalene walls known to interact with hydrophobic drugs such as Mitoxantrone®. The naphthalene interaction sites were successfully modified to contain oligoethylene glycol chains to improve their water-solubility, in anticipation for more accurate measurements of pKa and binding constants in aqueous media. However, all attempts to convert such naphthalene derivatives into their corresponding boronic acid or ester through standard protocols (halogen-lithium exchange, palladium catalyzed borylation) failed. Without the required boronic acid/ester, the final Suzuki-Miyaura coupling with the di-bromo triad spacer was not achieved. Synthesis of the 3rd generation tweezer, which was modified to contain theophylline as the new interaction sites, was then attempted. The half-tweezer was successfully synthesized via copper (II) catalyzed coupling of theophylline with the 5-bromo-4-methoxyphenyl boronic acid. However, all attempts to convert it into the required boronic acid/ ester for the final Suzuki- Miyaura coupling reaction with 2,6-dibromopyridine failed. We then focused our attention on the conversion of the triad spacer into its corresponding diboronic acid. The synthesis of the triad diboronic acid was a success, however, the final copper (II) catalyzed reaction with theophylline to form the tweezer only yielded the mono-coupled product. Lastly, our 4th generation tweezer was engineered to avoid the synthetic difficulties encountered in the boronic acid/ ester synthesis stage. Using the commercially available 5-formyl-2-methoxyphenylboronic acid and o-phenylenediamine, we successfully synthesized a benzimidazole-derived “half tweezer” through ring condensation reaction. Alkylation of this half-tweezer was also successfully achieved, although purification of the alkylated product was not optimized. Using this crude product, we carried out the final tweezer reaction via Suzuki- Miyaura coupling with 2,6-dibromopyridine under microwave irradiation. 1H NMR results show formation of new species that is believed to be the 4th generation tweezer (although the presence of impurities made integration of the signals unreliable). Much work is needed in the purification of the alkylated half tweezer boronic acid in order to avoid complicated mixtures in the final tweezer reaction. / Thesis (Master, Chemistry) -- Queen's University, 2011-10-06 00:29:04.248

Motivé par leur implication dans le centre réactionnel de l’appareil photosynthétique, puis plus tard, par les défis de la catalyse par transfert multi–électronique, des exemples d'édifices composés de deux porphyrines maintenues face–à–face apparaissent dans les années 70. Les premiers exemples font appel à l’utilisation d’espaceurs rigides qui maintiennent les porphyrines selon une géométrie bien définie permettant d’établir des relations précises entre la structure et les propriétés de ces dérivés. Ce projet de recherche a consisté à synthétiser une « nouvelle génération » de systèmes Pacman, plus flexibles et présentant deux types de conformations : une ouverte et une fermée. En ce sens, ces dérivés peuvent être décrits comme des pinces moléculaires. Le passage d’une conformation à l’autre serait contrôlé par la coordination d’un cation métallique au sein d’un espaceur–ligand. La conformation du système ne dépendrait alors plus de l’espaceur mais serait imposée par la géométrie de coordination du métal. Outre le contrôle conformationnel en fonction de la nature du cation métallique, l’avantage de cette approche est de pouvoir moduler, ou réguler dans le cas d’une coordination réversible, les propriétés physico–chimiques du système par simples interactions de type hôte/invité. Alors que les porphyrines sont supposées se comporter indépendamment dans la forme ouverte, la fermeture de la pince devrait se traduire par un rapprochement des macrocycles selon une disposition cofaciale impliquant des interactions entre les porphyrines. Ainsi, une modification des propriétés physico–chimiques de l’espèce et de son activité est attendue de par la communication électronique et/ou la coopérativité intermétallique établie. Nous nous sommes attachés également à présenter les études physico–chimiques entreprises sur certains systèmes bi– et trimétalliques afin de valider ces différents concepts. / Motivated by their involvement in the reaction center of the photosynthetic apparatus, and later, by the challenges of the multi–electron transfer catalysis, some examples of porphyrin dimer maintained in a face–to–face arrangement, appeared in the seventies. The first examples consisted in rigid spacers, which maintain the porphyrins in a well–defined geometry in order to establish a precise relationship between the structure and the properties of these derivatives. This research project consists in the synthesis of a “new generation” of Pacman systems, more flexible and presenting two types of conformations: one open, the other closed. In this way, these derivatives can be described as molecular tweezers. The way to go from one conformation to the other would be controlled by the coordination of a metal cation within a spacer–ligand. Thus, the conformation of the system will not depend on the spacer (like in the previous Pacman systems) but would be determined by the metal coordination geometry. In addition to the conformational control as a function of the nature of the metal cation, the advantage of this appraoch is to modulate, or regulate in the case of a reversible coordination, the physico–chemical properties of the system by simple host/guest interactions. Although the porphyrins are supposed to act independantly in the open form, the closure of the tweezer would bring the macrocycles closer according to a cofacial arrangement involving interporphyrinic interactions. Thus, a modification of the physico–chemical properties and the activity of the species is expected by the electronic communication between both macrocycles and/or the established bimetallic cooperativity. In order to validate these concepts, physico–chemical studies performed on some bis– and tris–metal systems are described.