Title: Modular Assembly of Hierarchically Structured Polymers
Description: The synthesis of macromolecules with complex yet highly controlled molecular architectures has attracted significant attention in the past few decades due to the growing demand for specialty polymers that possess novel properties. Despite recent efforts, current synthetic routes lack the ability to control several important architectural variables while maintaining low polydispersity index. This dissertation explores a new synthetic scheme for the modular assembly of hierarchically structured polymers (MAHP) that allows virtually any complex polymer to be assembled from a few basic molecular building blocks using a single common coupling chemistry. Complex polymer structures can be assembled from a molecular toolkit consisting of (1) copper-catalyzed azide-alkyne cycloaddition (CuAAC), (2) linear heterobifunctional macromonomers, (3) a branching heterotrifunctional molecule, (4) a protection/deprotection strategy, (5) “click” functional solid substrates, and (6) functional and responsive polymers.

This work addresses the different challenges that emerged during the development of this synthetic scheme, and presents strategies to overcome those challenges. Chapter 3 investigates the alkyne-alkyne (i.e. Glaser) coupling side reactions associated with the atom transfer radical polymerization (ATRP) synthesis of alkyne-functional macromonomers, as well as with the CuAAC reaction of alkyne functional building blocks. In typical ATRP synthesis of unprotected alkyne functional polymers, Glaser coupling reactions can significantly compromise the polymer functionality and undermine the success of subsequent click reactions in which the polymers are used. Two strategies are reported that effectively eliminate these coupling reactions: (1) maintaining low temperature post-ATRP upon exposure to air, followed by immediate removal of copper catalyst; and (2) adding excess reducing agents post-ATRP, which prevents the oxidation of Cu(I) catalyst required by the Glaser coupling mechanism. Post-ATRP Glaser coupling was also influenced by the ATRP synthesis ligand used.

The order of ligand activity for catalyzing Glaser coupling was: linear bidentate > tridentate > tetradentate. Glaser coupling can also occur for alkynes held under CuAAC reaction conditions but again can be eliminated by adding appropriate reducing agents. With the strategy presented in Chapter 3, alkyne-terminated polymers of high-functionality were produced without the need for alkyne protecting groups. These “click” functional building blocks were employed to investigate the overall efficiency of the CuAAC “click” coupling reactions between alkyne- and azide-terminated macromonomers as discussed in Chapter 4. Quantitative convolution modeling of the entire molecular weight distribution post-CuAAC indicates a CuAAC efficiency of about 94% and an azide substitution efficiency of >99%. However, incomplete functionality of the azide-terminated macromonomer (~92%) proves to be the largest factor compromising the overall efficacy of the coupling reactions, and is attributed primarily to the loss of bromine functionality during synthesis by ATRP.

To address this issue, we discuss in Chapter 6 the development of a new set of molecular building blocks consisting of alkyne functional substrates and heterobifunctional degradable linkers that allow the growth and subsequent detachment of polymers from the solid substrate. Complex polymeric structures are created by progressive cycles of CuAAC and deprotection reactions that add building blocks to the growing polymer chain ends. We demonstrate that these building blocks were completely stable under both CuAAC and deprotection reaction conditions. Since the desired product is covalently bound to the solid surface, the unreacted monomers/macromonomers and by-products (i.e. non-functional building blocks) can be easily separated from the product via removal of the polymer-tethered solid substrate in one step. Chapter 5 discusses how MAHP was employed to prepare a variety of hierarchically structured polymers and copolymers with controlled branching architectures. α-azido,ω-TIPS-alkyne-heterobifunctional and heterotrifunctional building blocks were first prepared via ATRP and organic synthesis.

Preliminary NMR and SEC studies demonstrated that these building blocks all satisfied the criteria necessary for MAHP: (1) the TIPS protecting group is stable during ATRP and CuAAC, (2) the “click” functionality is completely regenerated during the deprotection step, and (3) the CuAAC reaction of branching macromonomers is quantitative (>94%). To demonstrate the concept, poly(n-butyl acrylate)-b-dipolystyrene-b-dipoly(tert-butyl acrylate) penta-block branching copolymacromer was prepared via MAHP and quantitively characterized with SEC and NMR. In Chapter 7, we introduce a new family of molecular building blocks consisting of temperature-responsive and acid-degradable polyacetals with main-chain “click” functionalities. These water-soluble polyacetal polymers respond not only to pH, degrading under acidic conditions, but also to temperature. The polymers exhibit an exquisite lower critical solution temperature (LCST) behavior that can be precisely tuned within a range of 7-84°C by controlling the hydrophobic/hydrophilic balance of the monomers.

The polyacetals were relatively stable at neutral pH but degraded rapidly under acidic conditions. Internal alkyne and alkene functionalities were incorporated into the backbones of these polymers, enabling attachment of small molecules (i.e. therapeutic agents) onto the backbones. Finally, to broaden the scope of potential molecules for conjugation with the internal functional sites of the polymer, an α-azido,ω-vinyl ether heterobifunctional molecular linker was prepared. The linker can be conjugated with virtually any hydroxyl molecule, providing the molecule with an azide moiety that enables the subsequent click reaction with the internal alkyne of the polyacetal.