Orthogonal Chemistries in the Directed Assembly of Complex Molecular Architectures

Abstract

Chemical orthogonality is the ability of one or more reactions to efficiently proceed in the presence of other reactive functional groups. The concept of including orthogonal reactions to fabricate molecular structures has been applied to natural and synthetic polymers and often used as a tool to increase the level of chemical complexity. Nucleic acids (e.g., DNA and RNA), for instance, are polymers that serve as ubiquitous information-bearing species throughout biology, present the most versatile class of materials for producing diverse, specific nanostructures to date owing to their predictable, information-directed self-assembly. The information borne by nucleic acids is encoded in the sequences of orthogonal nucleobases affixed to a single (deoxy)ribophosphate strand. Thus, through careful consideration of their residue sequence, nucleic acids can be designed to predictably self-assemble via the hydrogen bond-based hybridization of complementary strands into arbitrary, although thermally and mechanically fragile, structures with nanometer precision. This dissertation investigated the use of orthogonal chemistries to fabricate and functionalize different molecular architectures to overcome some of the stability issues of nucleic acid-based structures. First, we explored the formation of cyclic peptoids through the archtypical “click” reaction, a copper (I) catalyzed alkyne-azide cycloaddition reaction between terminal alkyne/azide residues. These cyclic peptoids were post-synthetically conjugated to a maleimide group through the specific spacing of furan groups on the initial oligomers that were designed to undergo a Diels-Alder reaction. This simple example of utilizing orthogonal chemistries to fabricate and decorate cyclic structures highlights the versatility of peptoids in forming more complex molecules. The subsequent chapters in this dissertation explored the information-directed hybridization of oligomeric sequences, analogous to nucleic acid assemblies; however, instead of the hydrogen bonding observed between complementary nucleic acid strands, we employed transient or ‘dynamic’ covalent bonds to produce more stable and robust structures. We fabricated molecular ladders from oligopeptoids by controlling the equilibrium of three different dynamic covalent chemistries. First, a thermally-reversible reaction between a furan and maleimide mimicked the melting and annealing process of nucleic acids to form a likewise double-stranded structure as confirmed by mass spectrometry. We then explored a pH-mediated reaction forming molecular ladders with boronate ester rungs from oligomeric strands comprised of boronic acid and catechol functional groups. In addition to double-stranded structures, we introduced a method assembling “molecular grids” from precursor peptoid oligomers as a preliminary effort towards the formation of cross-linked nanosheets and ribbons. The boronate ester chemistry was ultimately combined with the final dynamic covalent chemistry of an amine and aldehyde to form Schiff base imines; we were able to confirm the formation of molecular ladders and grids bearing rungs of both boronate ester and imines in an aqueous solution by utilizing mass spectrometry. This effectively created an information system encoded in base-4 that was able to mimic the assembly process and reaction conditions for nucleic acid hybridization. The described work expands upon the foundational principles for a method that will enable a route to the facile fabrication of complex and robust assembled structures through orthogonal chemistries.