Chapter 1
Synthetic Methods Toward Single-Chain Polymer Nanoparticles

Ozcan Altintas1, Tobias S. Fischer2 and Christopher Barner-Kowollik2,3

1University of Minnesota, Department of Chemistry, 207 Pleasant St SE, Minneapolis, MN, 55455-0431, USA

2Institut für Technische Chemie und Polymerchemie Karlsruhe Institute of Technology (KIT), Preparative Macromolecular Chemistry, Engesserstraße 18, 76128 Karlsruhe, Germany

3Queensland University of Technology (QUT), School of Chemistry, Physics and Mechanical Engineering, 2 George Street, QLD 4000, Brisbane, Australia

1.1 Introduction

Natural macromolecules such as enzymes effectively function due to a precise as well as dynamic three-dimensional (3D) architecture. One of the most important driving forces for synthetic macromolecular design is the emulation of natural processes and the design of chemical reaction sequences that are inspired by nature [1-3]. Nature's degree of controlling the synthesis remains unreached by synthetic chemists. Nevertheless, well-defined compact 3D synthetic functional structures can be prepared, reducing the conformational freedom of single polymer chains by connecting pendant subunits at predefined positions [4-6].

Scientists have been interested in intramolecular cross-linking reactions since the mid-twentieth century where cross-linking processes have been investigated between variable molecules at very low concentrations of polymers in solution [7-9]. Reversible deactivation radical polymerization (RDRP) techniques such as atom transfer radical polymerization (ATRP) [10, 11], reversible addition-fragmentation chain transfer (RAFT) polymerization [12, 13], and nitroxide-mediated polymerization (NMP) [14] are employed to synthesize well-defined polymers by controlling the dispersity, molecular weight, and architecture of the macromolecules. In addition, exploiting the combination of RDRP techniques with modular and orthogonal ligation protocols [15-17], the intramolecular cross-linking of a single polymer chain leading to single-chain nanoparticles (SCNPs), has rapidly emerged as an alternative approach to generate well-defined compact 3D synthetic functional structures with diameters of below 20 nm [18-27]. Supramolecular chemistry affords a high degree of control over naturally occurring molecules and macromolecules [28]. Typically, the formed natural biopolymers and their structure are controlled by reversible self-folding processes induced by supramolecular interactions [29]. Hydrogen bonds, van der Waals interactions, and electrostatic or hydrophobic interactions force biomolecules such as proteins into their 3D folded analog. Folding of proteins, for instance, leads to complex secondary, tertiary, and quaternary structures, which determine their properties and functions [30].

Single-chain folding of synthetic macromolecules has been a fast moving and innovative field in macromolecular chemistry, constituting a promising pathway toward artificial, adaptative, and smart single-chain polymer nanodevices. The folding and unfolding of well-defined single linear polymer chains has been studied by means of single-chain technology [23] through intramolecular bonds from the viewpoint of synthetic macromolecular chemistry [25]. Generally, SCNPs can be generated by two approaches [26]. In one approach, individual - and often mutually orthogonal - recognition motifs are attached to preselected and defined points along the polymer chain, leading to well-defined SCNPs, a process that has been termed "selective-point folding". A second pathway to form SCNPs is the so-called "repeat-unit approach." For repeat-unit folding, block copolymers with specific complementary yet statistically scattered motifs along the polymer backbone are designed. The resulting structures are less defined due to a chaotic and statistical collapse compared with selective-point folding. Single-chain folding technology makes intensive use of supramolecular non-covalent interactions to generate SCNPs. We here focus on the application of irreversible bonds, non-covalent bonds, and dynamic covalent bonds to fold one single polymer chain into a SCNP. The current understanding of how to synthesize well-defined precursor polymers as well as the corresponding SCNPs will be discussed in detail. Our exploration into SCNP synthetic technology commences with a foray into the simplest of all folding systems, that is, rings. Throughout the current chapter, we do not attempt to provide a complete review of the field but will rather focus on critically selected examples.

1.2 Single-Chain Rings via Irreversible and Reversible Bonds

In nature, ring formation is employed to equip polypeptides with specific properties, such as improved stability against enzymatic degradation. In recent years, polymers possessing various topologies have been prepared via advanced modular ligation reactions. Cyclic polymers with an endless molecular topology have gained interest from polymer and material scientists due to their unique physical properties [31, 32]. Cyclic polymers have significantly different characteristics with regard to intrinsic viscosity, glass transition temperature, and order-disorder transition compared with their linear counterparts [33]. A wide variety of cyclization methods has been reported. We submit that the provision of cyclic polymer systems is a key step preceding the preparation of single-chain polymeric nanoparticles. There exist important similarities between the preparation of cyclic polymers and single-chain polymeric nanoparticles in terms of reaction conditions as well as characterization methods. However, the cyclic polymer field is immense, and therefore, we highlight here selected examples only, where the same or similar chemistries were used for the preparation of the SCNPs.

Grayson and coworkers first reported the preparation of single-chain rings based on the combination of ATRP and the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction coupling azide and alkyne-functional end groups (Figure 1.1) [34]. A linear poly(styrene) (PS) precursor was prepared via the ATRP technique, using propargyl 2-bromoisobutyrate as the initiator. Subsequent azidation of the end group was carried out. The cyclization reaction was successfully conducted on a-alkyne- and ?-azide-functionalized linear polymers using a syringe pump system, allowing for very low concentrations (<0.01 mM). The single-chain folding was followed by size-exclusion chromatography (SEC), 1H nuclear magnetic resonance (NMR) spectrometry, and Fourier transform infrared (FT-IR) analysis. The CuAAC reaction has received substantial attention in the field of cyclic polymers [35, 36] due to its often quantitative yields, mild reaction condition, tolerance to a wide range of functional groups, and harmony with the RDRP techniques for the preparation of various cyclic topologies [37, 38].

Figure 1.1 Synthetic route for the preparation of well-defined cyclic polystyrene via the combination of ATRP and CuAAC reaction. (i) NaN3, DMF, room temperature (r.t.). (ii) CuBr/Bipy, in degassed DMF, 120 °C.

(Laurent and Grayson 2006 [34]. Reproduced with permission of the American Chemical Society.)

As an alternative to CuAAC processes, Diels-Alder (DA) cycloadditions involve the reaction of a conjugated diene (4p) with a dieneophile (2p) to yield a 6-membered ring, where the [4 + 2] denotes the number of p-electrons that are taking part in the cycloaddition process. Especially light-triggered DA reactions ensure near quantitative coupling within short reaction times at ambient temperature without a catalyst and are a highly promising avenue for the preparation of cyclic polymers and SCNPs alike. Barner-Kowollik and coworkers introduced a facile method for the preparation of macrocyclic aliphatic polyesters based on the catalyst-free and ambient-temperature intramolecular DA coupling of highly functional photosensitive a-o-methylbenzaldehyde and ?-acrylate polyester chains (Figure 1.2) [39, 40]. Polycaprolactone (PCL) and polylactide (PLA) were synthesized via ring-opening polymerization (ROP) using 2-((11-hydroxyundecyl)oxy)-6-methyl-benzaldehyde as an initiator in the presence of triazabicyclodecene (TBD) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) functioning as organocatalysts. The hydroxyl functionality of the linear polymers was reacted with acryloyl chloride to afford a terminal dienophile group. The completion of the end-group transformation was confirmed by 1H NMR and electrospray ionization mass spectrometry (ESI-MS), and the subsequent DA reactions were performed by irradiation of the linear precursor solutions in acetonitrile at ambient temperature at concentrations of 25 mg L-1 for 12 h under ultraviolet (UV) light (?max = 320 nm). The cyclic products were collected by evaporation of the solvent without the need for additional purification steps and confirmed by SEC, 1H NMR, and ESI-MS. In the same context, Zhang and coworkers developed a method for the formation of various types of cyclic homopolymers and block polymers by a combination of RAFT polymerization and a light-induced DA click reaction [41], based on synthetic technology we introduced (light-induced hetero-DA chemistry) [42]. In following work by the same research group, an efficient and practical way was investigated to produce cyclic polystyrenes on a large scale by the combination of continuous flow techniques and UV-induced DA reactions [43]. In an alternative light-triggered approach,...