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The need for chemoselective bond formation within complex biological systems has driven much research in chemical biology and chemical medicine and has allowed control over the structure and biological properties of a range of chemical entities. Reactions that are highly biocompatible, selective and occur at low concentration are classified as being bioorthogonal. Although bioorthogonal reactions have been successfully applied to bioconjugation and imaging in living systems, only a few examples exist of bioorthogonal reactions being utilised for the activation of prodrugs. The tetrazine mediated inverse electron demand Diels-Alder reaction is characterized by excellent reaction rates and high biocompatibility in both in vitro and in vivo applications. To date, this chemistry has found only limited application in prodrug activation or drug release strategies. Herein, a series of tetrazine-trigger systems are reported in which an active drug is liberated from its inactive form upon triggering with tetrazine. It is shown that the release of encapsulated and conjugated drugs from polymeric nanoparticles can be triggered by tetrazines providing an on-demand release within biological systems. In a totally new approach that fully complies with the principle of bioorthogonality by avoiding the generation of any by-products, tetrazine was utilised as a prodrug scaffold leading to symbiotic and traceless dyadic prodrug activation. The simultaneous formation of two active drugs (here the anticancer drug camptothecin and a known micro RNA inhibitor) was confirmed and validated within a biological environment. The use of tetrazines as a trigger to activate or release an active drug will open new directions in the field of chemical biology/medicine.

The concept of gating was introduced into host-guest chemistry by our group in the 1990s, as a result of computational studies on Cram's hemicarcerands. Since that time, a variety of gated host systems have been developed by our group and others. The gated hemicarcerands presented in this dissertation are examples of hosts with controllable gates that function upon external stimuli, which we refer to as redox reaction gated hemicarcerands and photochemically gated hemicarcerands. In both cases, a chemically modifiable moiety was installed on the host molecule so that it undergoes chemical change in response to external stimuli. In particular, we took advantage of disulfide-dithiol interchange (redox reaction control) and anthracene dimerization (photochemical control) to achieve gating in these hemicarcerands. Molecular mechanics computations were employed to understand the experimental observations during the complexation and decomplexation processes.The second part of this dissertation focuses on understanding Diels-Alder reactivities of a wide range of organic molecules with the tools of computational chemistry. Among these extensively studied molecules, tetrazine is the most outstanding one, in the sense that its cycloaddition reactions with strained alkenes are extremely rapid, with second order rate constants up to 2000 M-1s-1. Such reactions take place at a decent rate even at micromolar concentration, suggesting their application in live cell imaging. The emerging use of tetrazines as labeling reagents has added an extra dimension to bioorthogonal cycloadditions. Our computational studies have provided a thorough understanding of the cycloaddition reactivities and a guideline for developing new reagents.

Tetrazines are aromatic compounds that consist of a six membered ring containing four nitrogens. They are not as much explored as light emitting materials as compared to other common organic compounds. Still they are likely to be important for as substrates for HEDM (High Energy Density Materials), sensors (for anions), important chromophoric materials (absorption and emission wavelengths in distinct regions), fluorescent probes (gives color to an organic compound) and possible day to day standard and useful organic molecular reference in photo physical studies. Much research still needs to be done on tetrazines in order to understand comparisons with the benzene ring with regard to reactivity, electron affinity, and photooptical properties as well as reaction mechanisms, as well as different types of reactions.A series of tetrazine derivatives with varying substitution patterns were successfully synthesized, characterized and preliminary photochemical studies were performed using them. Special quantitative 13C NMR techniques were employed in characterizing these compounds. Their emission wavelengths were found to be independent of the excitation wavelength. Longer singlet excited state life times of monosubstituted tetrazines were obtained which may be due to the formation of an intramolecular charge transfer state. A study of solvent effect based on polarity on these life times would be interesting to characterize the nature and stability of the formed charge transfer state.