Exploiting crystal engineering of boron: novel applications in pharmaceutics, separation science and photochemistry

Gonzalo Campillo-Alvarado

doi:10.17077/etd.005731

Organoboron compounds have been a powerful and long-standing auxiliary class of molecules for organic synthetic transformations. A testament of the synthetic value of this class of molecules is the development of C–C bonds through the Suzuki-Miyaura coupling (or Suzuki coupling) through metal catalyzed cross-coupling reactions with boronic acid derivatives (i.e., 2010 Nobel Prize in Chemistry). However, the potential of supramolecular chemistry of organoboron compounds has remained largely uninvestigated. My dissertation focuses on incorporating supramolecular chemistry of boron into modern applications of crystal engineering, with emphasis on the development of solid functional materials. Specifically, we have found novel applications of hydrogen bonding, B←N coordination and π∙∙∙π interactions in a series organoboron compounds (i.e., benzoxaboroles, boronic acids, boronic esters, boroxines). Explorations into supramolecular interactions of benzoxaboroles have allowed us to generate novel solid forms of blockbuster boron-containing active pharmaceutical ingredients (APIs) Crisaborole (Eucrisa®) and Tavaborole (Kerydin®). Chapter 2 describes our results involving polymorph screening and characterization of the boron-containing APIs. In addition, hydrogen-bonded cocrystals were generated by employing pyridyl-containing coformers. Our studies constitute the first examples of multicomponent crystals of boron-containing APIs as well as the first report on polymorphism of Crisaborole. Cocrystallization with bipyridines was also used to generate a series of cocrystals of the anti-HIV API Emtricitabine (Emtriva®). The hydrogen bonding capacity of boronic acids, and B←N coordination of boronic esters and boroxines were exploited in Chapter 3 for the generation of photoactive solids. Specifically, our work introduces the ability of organoboron molecules to organize pyridyl-containing olefins into a suitable geometry for [2 + 2]-photodimerizations. Boronic acids act as linear templates with two hydrogen bond donors that preorganize 1,2-bis(4-pyridyl)ethylene (bpe) into a photoactive solid. The generation of rctt-tetrakis(2-pyridyl)cyclobutane (tpcb) is carried out stereoselectively and in near quantitative yield. Remarkably, boronic acids facilitate supramolecular catalysis in the solid state (i.e., use of substoichiometric amounts of boronic acids) through mechanochemistry. Likewise, B←N coordination of boronic esters and boroxines also enabled the formation of photoactive solids, representing the first examples of B←N coordination promoting [2 + 2]-photodimerizations. In the case of photoreactions involving B←N coordination to boronic esters, the reaction proceeds as a rare case of a single-crystal-to-single-crystal transformation, allowing us to provide a unique mechanistic insight of the photoreaction process in the solid-state. Photoactive solids involving halophenols as templates for bpe were also developed using an emerging crystal engineering strategy involving large supramolecular synthons (Long Range Synthon Aufbau Modules, LSAMs). Our observations derived from B←N coordination were also used to develop boron hosts that are able to separate complex mixtures of solvents by fractional crystallization (Chapter 4). Specifically, boron tweezers and bis-tweezers were able to separate equimolar mixtures of xylene isomers and thiophene from benzene, respectively. Two of the studied host-guest systems exhibit conductivity as determined by atomic force microscopy (AFM). Lastly, we report the observation of a new type of molecular machine that consists in collective motions facilitated by a dynamic boron-based host. The motion in the boron-based molecular machine facilitates crystal-to-crystal desolvation in a close-packed organic crystal without affecting the crystallinity of the sample. The work in this dissertation provides examples of the colossal potential of supramolecular chemistry of organoboron molecules for the design of functional materials.

Exploiting crystal engineering of boron: novel applications in pharmaceutics, separation science and photochemistry

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