Chapter 1
A Supramolecular Approach to Macromolecular Self-Assembly: Cyclodextrin Host/Guest Complexes

Bernhard V. K. J. Schmidt and Christopher Barner-Kowollik

Materials Research Laboratory, University of California, Santa Barbara, USA

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

Institut für Biologische Grenzflächen, Karlsruhe Institut of Technology (KIT), Eggenstein-Leopoldshafen, Germany

1.1 Introduction

Macromolecular self-assembly is one of the key research areas in contemporary polymer science. Because complex macromolecular architectures have a significant effect on self-assembly behavior, tremendous effort has been made in the synthesis of well-defined complex macromolecular architectures [1]. The versatility of polymeric materials, such as indicated by polymer functionality, polymer composition, and polymer topology, enables the formation of materials for a broad range of applications, including hybrid materials [2], biomedical materials [3], drug/gene delivery [4], supersoft elastomers [5], and microelectronic materials [6]. In order to obtain well-defined structures, synthetic techniques are required that can provide precise control over the material properties of these structures. Among the polymerization techniques that have proved to be powerful tools for the synthesis of well-defined polymers are reversible-deactivation radical polymerization approaches, such as nitroxide-mediated radical polymerization (NMP) [7], atom transfer radical polymerization (ATRP) [8], and reversible addition-fragmentation chain transfer (RAFT) polymerization [9]. Especially their convenient handling and tolerance toward functional groups have led to a plethora of novel materials with precision-designed properties. Furthermore, the introduction of modular ligation chemistry has provided the opportunity to synthesize complex building blocks and architectures in a precise and efficient manner and again with high functional group tolerance [10]. Several modular ligation reactions are widely utilized in that regard, such as copper(I)-catalyzed azide-alkyne cycloaddition (CuAAc) [11], Diels-Alder reactions [12], and thiol-ene reactions [13]. Thus perfectly suited tools for the formation of materials for macromolecular self-assembly are currently available [14].

The introduction of the concept of supramolecular chemistry has influenced the entire field of chemistry significantly. Especially polymer science and the formation of complex macromolecular architectures have benefited from supramolecular chemistry [15]. New types of macromolecular architectures based on supramolecular bonds are now continually being investigated and higher level complex self-assemblies of macromolecules governed by supramolecular interactions have been formed. Several types of supramolecular interactions are used in polymer science such as hydrogen bonding [16], metal complexes [17], and inclusion complexes [18]. One of the frequently employed supramolecular motifs is cyclodextrin (CD), which forms inclusion complexes with hydrophobic guest molecules in aqueous solution. This property has been exploited readily in polymer chemistry and materials science for various applications, such as drug delivery [19], nanostructures [18b,20], supramolecular polymers [21], self-healing materials [22], amphiphiles [23], hydrogels [24], bioactive materials [25], or in polymerization reactions [26].

The incorporation of CD-based supramolecular chemistry has proved to be an elegant way for the formation of complex macromolecular architectures [14c,24a]. Reversible-deactivation radical polymerization and modular ligation techniques have emerged as effective tools for the synthesis of CD and guest functionalized building blocks. Taking the overall goal of macromolecular self-assembly into account, these building blocks can be considered as the primary structure specifying which blocks are guest and which are host functionalized. The formation of the direct supramolecular host/guest complexes can be considered the secondary structure leading to complex macromolecular architectures. The next level is the assembly of the supramolecularly formed macromolecules into higher aggregates/self-assemblies-the tertiary structure. Thus several levels of molecular complexity are available via the combination of CD host/guest chemistry and polymeric building blocks (Figure 1.1) [18a].

Figure 1.1 Overview over the different levels of complexity enabled via the combination of CD host/guest chemistry and macromolecular structures.

An interesting feature of polymer architectures governed by supramolecular interactions is modularity. The formation of a variety of architectures can be achieved by a small number of initial building blocks much like modularity in modular ligation chemistry. Thus structure-property relationships are accessible via a small amount of reactions compared to traditional material formation. Furthermore, the dynamic nature of the supramolecular bonds affords the opportunity to study systems in the bound as well as the unbound state or to dynamically change the properties of the materials via external stimuli or addition of materials with competing supramolecular interactions. Especially in the case of CD host/guest chemistry, a broad range of stimuli-responsive host/guest pairs is available. Combined with stimuli-responsive polymers an extraordinary amount of combinations, and thus materials with unique properties, is accessible.

1.2 Synthetic Approaches to Host/Guest Functionalized Building Blocks

1.2.1 CD Functionalization

CDs are oligosaccharides and thus contain a significant number of hydroxyl groups that can be utilized for functionalization. Hence selectivity of CD functionalization reactions is a major issue. The primary hydroxyls at C-6 are more reactive due to less steric hindrance, while the secondary hydroxyls at C-2 or C-3 are less reactive. The difference in reactivity gives the opportunity to obtain selectivity with regard to the addressed face of the CD and can be tuned with reaction conditions [27]. The selectivity toward the number of functionalized hydroxyl function remains much more challenging, yet the optimization of reaction conditions has led to several effective protocols to yield-mostly-mono functionalized CDs.

Mono tosyl CDs are the most utilized building blocks because they are readily converted into a variety of useful reactants (Figure 1.2). Several methods have been described for the synthesis of mono tosylated CDs at C-6. The most convenient route for a-CD and ß-CD utilizes tosylchloride in aqueous NaOH [28], while another convenient method toward mono tosyl ß-CD makes use of 1-(p-toluenesulfonyl)imidazole instead of tosylchloride [29]. For ?-CD, a synthesis with triisopropylphenylsulfonyl chloride has been reported in order to form a ?-CD derivative with single leaving group [30]. Furthermore, all CD mono tosylates are available via tosylation in pyridine as well [31]. Starting from mono tosylated CD or CDs with similar leaving groups, several useful building blocks are accessible. A nucleophilic substitution with sodium azide leads to the corresponding azides that are suitable for click reactions [31], namely CuAAc. After methyl ether protection, the mono tosylates can be converted into mono alkynes via sodium propargylate, which is the complementary building block for CuAAc in addition to the well-known CD azides [32]. The azides can be further converted to amines via reduction, for example, via hydrogenolysis [31b,33] or Staudinger reduction [31a]. Another possibility to obtain mono amine functionalized CD is the substitution of the mono tosylate with an excess of a suitable diamine [34]. A thiol functionalization is amenable via substitution with thiourea and subsequent hydrolysis [35], which opens up access to thiol-ene click chemistry [36]. Less frequently utilized are C-2 or C-3 substituted CD derivatives, which is most likely due to the inconvenient and tedious synthesis of pure mono functionalized derivatives. Nevertheless, several reports on the synthesis exist [10]. Having several hydroxyl groups, CDs are, in principle, targets for esterification or etherification reactions as well, yet the selectivity in ester/ether functionalization reactions is usually low. Either full conversions of the hydroxyl groups are desired or-in the case of lower targeted substitution grades-complicated purification methods are required in order to obtain pure products. Nevertheless, the broad range of different mono functionalizations of CDs allows for the incorporation into polymers either pre- or post-polymerization. Several examples for CD functionalized polymerization mediators-the pre-polymerization incorporation-are described in the literature, for example, for NMP [37], ATRP [38], and RAFT [39]. Furthermore, post-polymerization conjugations are described as well, for example, after ATRP [38a] or RAFT polymerization [40].

Figure 1.2 Synthesis of various mono functionalized CD derivatives [14c].

Reprinted from [14c]. Copyright 2014, with permission from Elsevier.

1.2.2 Suitable Guest Groups

Besides functionalization with CDs, guest moieties have to be incorporated in order to form supramolecular host/guest complexes. The common guest groups do not possess a similar multifunctionality as CDs, which makes the pre- or post-polymerization functionalization straightforward. Common...