Macromolecular Self-Assembly

List of Contributors

Jancy Nixon Abraham, University of Geneva, Sciences II, Department of inorganic and analytical chemistry, quai Ernest Ansermet 30, 1211, Geneva 4, Switzerland

Christopher Barner-Kowollik, Preparative Macromolecular Chemistry, Institut für Technische Chemie und Polymerchemie, Karlsruhe Institute of Technology (KIT), Engesserstr. 18, 76128 Karlsruhe, Germany and Institut für Biologische Grenzflächen, Karlsruhe Institut of Technology (KIT), Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany

Laurent Billon, Institut des Sciences Analytiqueset de Physico-Chimie pour l'Environnement et les MatériauxIPREM, CNRS - UMR 5254, Université de Pau & Pays de l'Adour, 64053 Pau, France

Olga Borisova, Department of Polymer Science, Moscow State University, Leninskie Gory, Moscow 119191, Russia

Oleg Borisov, Institut des Sciences Analytiqueset de Physico-Chimie pour l'Environnement et les MatériauxIPREM, CNRS - UMR 5254, Université de Pau & Pays de l'Adour, 64053 Pau, France

Munish Chanana, ETH Zürich, Institute of Building Materials, Stefano-Franscini-Platz 3, 8093 Zürich, Switzerland, University of Bayreuth, Physical Chemistry II, Universitätsstrasse 30, 95440 Bayreuth, Germany

Franck D'Agosto, Université de Lyon, Univ. Lyon 1, CPE Lyon, CNRS UMR 5265, Laboratoire de Chimie, Catalyse, Polymères et Procédés (C2P2), LCPP group, 69616 Villeurbanne, France

Elise Deniau-Lejeune, Institut des Sciences Analytiqueset de Physico-Chimie pour l'Environnement et les MatériauxIPREM, CNRS - UMR 5254, Université de Pau & Pays de l'Adour, 64053 Pau, France

Andreas Fery, Leibniz-Institut für Polymerforschung Dresden e.V., Institute of Physical Chemistry and Polymer Physics, Technische Universität Dresden, Physical Chemistry of Polymeric Materials and Cluster of Excellence Centre for Advancing Electronics Dresden (cfaed), Hohe Strasse 6, 01069 Dresden, Germany, University of Bayreuth, Physical Chemistry II, Universitätsstrasse 30, 95440 Bayreuth, Germany

Sergey K. Filippov, Institute of Macromolecular Chemistry AS CR, Prague, Czech Republic

Martin Hrubý, Institute of Macromolecular Chemistry AS CR, Prague, Czech Republic

Matthias Karg, Heinrich Heine University Düsseldorf, Physical Chemistry I, Universitätsstrasse 1, 40225 Düsseldorf, Germany, University of Bayreuth, Physical Chemistry I, Universitätsstrasse 30, 95440 Bayreuth, Germany

Dawid Kedracki, University of Geneva, Sciences II, Department of inorganic and analytical chemistry, quai Ernest Ansermet 30, 1211, Geneva 4, Switzerland

Christian Kuttner, Leibniz-Institut für Polymerforschung Dresden e.V., Institute of Physical Chemistry and Polymer Physics, Technische Universität Dresden, Cluster of Excellence Centre for Advancing Electronics Dresden (cfaed), Hohe Strasse 6, 01069 Dresden, Germany, University of Bayreuth, Physical Chemistry II, Universitätsstrasse 30, 95440 Bayreuth, Germany

Muriel Lansalot, Université de Lyon, Univ. Lyon 1, CPE Lyon, CNRS UMR 5265, Laboratoire de Chimie, Catalyse, Polymères et Procédés (C2P2), LCPP group, 69616 Villeurbanne, France

Corinne Nardin, University of Geneva, Sciences II, Department of inorganic and analytical chemistry, quai Ernest Ansermet 30, 1211, Geneva 4, Switzerland

Dmitry V. Pergushov, Department of Chemistry, M.V. Lomonosov Moscow State University Leninskie Gory 1/3, 119991 Moscow, Russia

Olga Philippova, Physics Department, Moscow State University, 119991 Moscow, Russia

Felix A. Plamper, Institute of Physical Chemistry II, RWTH Aachen University Landoltweg 2, 52056 Aachen, Germany

Enora Prado, University of Geneva, Sciences II, Department of inorganic and analytical chemistry, quai Ernest Ansermet 30, 1211, Geneva 4, Switzerland

Jutta Rieger, UPMC Univ. Paris 6, Sorbonne Universités and CNRS, Laboratoire de Chimie des Polymères, UMR 7610, 3 rue Galilée, 94200 Ivry, France

Bernhard V. K. J. Schmidt, Materials Research Laboratory, University of California, Santa Barbara, CA, 93106, USA

Petr Štěpánek, Institute of Macromolecular Chemistry AS CR, Prague, Czech Republic

Preface

Macromolecular self-assembly is a generic term utilized to describe spontaneous associations of individual macromolecular species, as either identical or complementary building blocks, giving rise to a zoo of supramolecular structures. In contrast to macroscopic phase separation in polymer solution, the self-assembly process is always a result of subtle balance between attractive (i.e., driving assembly) and repulsive intermolecular forces. The latter serve as a limiting or stopping mechanism and ensure formation of supramolecular structures with well-defined shapes and sizes. In particular, self-assembly of the amphiphilic block-copolymers in aqueous environment is driven by hydrophobic attraction and counterbalanced by electrostatic repulsion or steric hindrance from ionic or non-ionic hydrophilic blocks, respectively.

The morphology of the self-assembled structures is controlled by intramolecular solvophilic/solvophobic balance, which is determined primarily by the lengths of soluble and insoluble blocks, but can be affected also by environmental conditions. As an example, spherical micelles formed in selective solvent by diblock copolymers with one soluble and another insoluble block comprise typically of the order of 10²–10³ individual copolymer chains and have dimensions on the order of 10¹–10² nm. Copolymers with longer insoluble block associate into cylindrical wormlike micelles that may reach micrometer length or bi-layer vesicles (polymersomes) with a size of 10²–10³ nm.

The electrostatic attraction between oppositely charged ionic macromolecules (polyelectrolytes) provides an alternative (with respect to hydrophobic attraction) mechanism for building up supramolecular assemblies in aqueous media. The association of oppositely charged polyelectrolytes in solutions or at charged interfaces leads, respectively, to interpolyelectrolyte complexes or polyelectrolyte multi-layers. There is an evidence of a formation of soluble interpolyelectrolyte complexes involving oppositely charged macro-ions of different topologies (e.g., linear and branched polyelectrolytes). Co-micellization of a pair of oppositely charged bis-hydrophhilic block polyelectrolytes leads to formation of micelles with complex coacervate cores and uniformly mixed or phase-separated coronae. The latter exemplify asymmetric patchy nanoparticles capable to undergo a secondary assembly process.

At the same time, the spectrum of possible assembled structures can be enriched dramatically because of enormous diversity of macromolecular architectures—from simple diblock to multiblock copolymers, comprising of multiple blocks of different chemical nature, from linear to branched macromolecules where different topology (miktoarm stars, graft copolymers, etc.). Furthermore, (bio)nanocolloids, such as globular proteins, can be involved as elementary building blocks in the co-assembly process. This diversity of architectures of building blocks enables going beyond conventional morphologies of self-assembled aggregates and thus fabricating multicompartment, patchy, asymmetric nanoparticles, nanoworms, or nanodisks, that can serve as building blocks for more complex hierarchically assembled structures.

The hierarchical or multi-scale assembly concept assumes that in the first step individual macromolecules assemble into nanoparticles, which can undergo another assembly process into structures that in turn may serve as building blocks for larger supramolecular objects with highly complex internal organization. The success in multi-scale assembly depends crucially on proper encoding of specific properties into primary chemical sequence of the elementary building blocks and precise control and directing of the assembly on each stage. Ultimately, structures as complex as those manufactured by nature can be built up from rationally designed and properly combined macromolecular building blocks by multi-step hierarchical assembly.

In many cases the block copolymer aggregates behave as frozen supramolecular structures. Indeed, micellization and formation of mesophases by block copolymers in selective solvents resembles corresponding phenomena in solutions of low-molecular-weight amphiphilies (surfactants). However, the polymeric nature of the assembling species slows down dramatically the dynamics of the assembly process and the exchange rate between associated into superstructures species and individual free macromolecules (unimers) in solution. Thus special efforts are required to make the supermolecular structures capable of dynamic response to varied environmental conditions.

In the block copolymer self-assembly, the combination of monomer units with different properties within single functional blocks enables fine-tuning of the strength of intermolecular interactions and achieving perfect control over the thermodynamics and kinetics of the assembly process. An important effort was made and a significant progress was achieved in creating smart self-assembled polymer nanostructures, so called because they respond by variation in size, shape, and aggregation state to specific variation in environmental conditions (temperature, pH and ionic strength of the solution, light, etc.). This can be achieved by involving monomers with stimuli-responsive properties (e.g., pH-, themoresponsive) as constituents of the copolymer building blocks.

Moreover, in interpolyelectrolyte complexes or polyelectrolyte multi-layers, the strength of attractive electrostatic interactions can be efficiently tuned by the pH or ionic strength of the solution. Hence electrostatically assembled structures inherently exhibit pronounced stimuli-responsive features. Furthermore, the enormous diversity of possible combinations of co-assembling components, including oppositely charged ionic polymers, nucleic acids and proteins, metal/ligand complexes and inorganic nanoparticles, makes electrostatically driven assembly a very promising approach for design of novel smart functional materials.

Macromolecular self-assembly is a domain of fundamental research and, at the same time, a versatile tool in soft nanotechnology, based on the bottom-up approach, that is exploited to rationally build up structures of almost arbitrary complexity and functionality by directing the assembly routes. This strategy enables one to reach precision and complexity unattainable by top-down methods. Smart nanocontainers, colloidal nanoreactors, molecular templates for nanoelectronic devices are just a few examples of prospective applications.

A completely new and easily scaled up, at the industrial level, approach toward creating polymer nanostructures of various and well-defined morphologies assumes the assembly of amphiphilic block copolymers that occurs simultaneously with their controlled radical polymerization in aqueous medium (so-called polymerization-induced assembly).

Macromolecular assembly at interfaces is considered to be a versatile method of fabrication of ultra-thin coatings with improved (adhesive, tribological, optical, biointeractive, etc.) properties and a controllable nanopatterned structure.

In nanomedicine, self-assembled polymeric nanostructures, specifically diblock copolymer micelles are extensively explored too. A combination of proper micellar size that ensures efficient accumulation and retention in tumor tissues with high stability and the potential for controlled release of cargo through stimuli-triggered dissociation make block copolymer micelles very promising candidates for being exploited as delivery systems for drugs or radionuclides in anticancer therapy and diagnostics.

Biomedical applications give also a strong impulse to study assemblies of biohybrid macromolecules that consists of synthetic (typically hydrophobic) polymer blocks linked to blocks of biological origin (peptides, sugars, oligo- or polynucleotides, polysaccharides). Similar to the synthetic block copolymer, the biohybrid macromolecules demonstrate ability to form micellar-like aggregates, vesicles, or more complex supramolecular architectures in aqueous media. Amphiphilic block polypeptides have demonstrated the ability of stimuli-responsive assembly due to a tuneable hydrophilic/hydrophobic nature of the peptide blocks. The ability of biopolymer blocks to form intra- and intermolecular secondary structure and to take part in (bio)specific interactions opens up a fascinating perspective for the design of novel diagnostic systems or smart vectors that can deliver drugs or biologically active molecules on the basis of supramolecular assemblies of biohybrid macromolecules.

Hence macromolecular assembly is an important field where macromolecular chemistry merges with nanoscience and nanotechnology. Though many excellent books and reviews in this field have been recently published, we consider our present book as a relevant update with its focus on emergent developments in this domain.

Laurent Billon and Oleg Borisov

April 2016

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 α-CD and β-CD utilizes tosylchloride in aqueous NaOH [28], while another convenient method toward mono tosyl β-CD makes use of 1-(p-toluenesulfonyl)imidazole instead of tosylchloride [29]. For γ-CD, a synthesis with triisopropylphenylsulfonyl chloride has been reported in order to form a γ-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 routes include esterification, amide formation, or several types of modular ligation reaction.

One of the most interesting features of CD complexes is their response to external stimuli, that is, the complex dissociates and/or associates reversibly due to external stimuli. The stimuli response that all guests share is temperature, namely at higher temperatures the complexes dissociate due to the usually negative association enthalpy (Figure 1.3a) [41]. A further frequently utilized stimulus is redox response based on the ferrocene/CD pair. Oxidation of ferrocene to ferrocenium leads to an increase in size that ultimately leads to complex dissociation, since the ferrocenium cation does not fit into the β-CD cavity (Figure 1.3b) [42]. Furthermore, after reduction, complexation is observed again, which can be followed via cyclovoltammetry [43]. Complexation of phenolphthalein derivatives with β-CD leads to a color change at basic pH from pink to colorless (Figure 1.3c). The lactone ring of phenophthalein forms again at higher pH due to association with β-CD, which forces the molecule into the sterically more compact structure [44]. Very recently, Harada et al. showed metal–ion responsive complexation based on bipyridine ligands and iron (II) or copper (II) ions (Figure 1.3d). While bipyridines are complexed with β-CD in metal-ion free solutions, bipyridine/metal ion complex formation leads to an increase in size of the guest moieties and thus to decomplexation of the CD/bipyridine complex [45]. Recently, pH responsive complexes were introduced. For example, the benzimidazole/β-CD pair shows complexation/decomplexation depending on the apparent pH (Figure 1.3e) [46]. A further development of benzimidazole pH response is protonation in CO2 enriched aqueous solution. The increased size of the protonated benzimidazole molecule leads to decomplexation, yielding a CO2 responsive host/guest complex [47]. Dansyl groups show pH responsive complexation with β-CD as well; namely at pH below 4 the complexation is not favored [48]. A very beneficial stimulus is light as it can be controlled spatially and temporarily in a precise way. Common light responsive guest groups that lead to decomplexation upon light irradiation are azobenzenes or stilbenes. UV irradiation induces an isomerization from the thermodynamically more stable trans conformation to the cis conformation that exhibits lower complexation constants due to steric hindrance (Figure 1.3f). The situation can be reversed via irradiation with visible light, where a re-isomerization takes place and the complexes can form again. A rather biochemical stimulus is enzymatic degradation of CDs that leads to disassembly of the complexes as well, yet in an irreversible fashion [49].

Figure 1.3 Stimuli-responsive host/guest complexation based on β-CD: (a) Thermoresponsive adamantyl complex, (b) redox-responsive ferrocene complex, (c) color changing phenolphthalein complex, (d) metal–ion-responsive bipyridine complex, (e) pH-responsive benzimidazole or dansyl complexes, and (f) light-responsive azobenzene or stilbene complexes.

1.3 Supramolecular CD Self-Assemblies

After successful formation of building blocks, as described above, supramolecular interactions can be utilized to connect different building blocks in order to obtain complex architectures. Taking the manifold types of guest molecules with their various types of stimuli-responsive complexation into account, a broad range of material properties is accessible. Furthermore, the utilization of different polymer types leads to arguably unlimited possible combinations and more stimuli responses, when stimuli-responsive polymers are incorporated. In the following, several types of CD self-assemblies are presented, such as block copolymers, star polymers, and polymer brushes, leading to single macromolecules connected in a supramolecular way (Figure 1.4). CD complexes have been employed to obtain materials with special polymer functionality, polymer composition, and polymer topology. Polymer functionalities can be obtained via reversible-deactivation radical polymerization of CD and guest functionalized mediators or via modular ligation techniques. Various polymer compositions are available via CD and guest units between blocks in order to obtain supramolecular block copolymers. Complex topologies can be formed via more complex building blocks, such as multi-guest and/or CD functional building species. Complex macromolecular architectures governed by CD complexes can be constructed step by step: the polymer functionality gives rise to more complex compositions or topologies—from the primary structure to the secondary structure.

Figure 1.4 Overview of complex macromolecular architectures formed via CD host/guest complexes.

1.3.1 Linear Polymers

Linear block copolymers are a frequently studied class of CD-based macromolecular architectures. The formation of AB block copolymers is straightforward as only two homo polymers with guest and CD end-group, respectively, are needed. Higher block copolymers are accessible via the introduction of double functionalized middle blocks. The borderline case for higher block copolymers would be supramolecular polymers that are formed from multi-host/guest functionalized building blocks in a supramolecular step growth polymerization mechanism. The degree of polymerization is directly correlated with the number of host–guest complexes formed. This type of linear polymer is based on a step growth reaction approach. Guest and host moieties are combined in an AB- or AA/BB-type fashion to obtain supramolecular polymers.

As described in Section 1.2.3, stimuli-responsive complexation is well known with CDs, and in the following several examples of block copolymers with stimuli-responsive linkage are described. Furthermore, the respective blocks allow the incorporation of additional stimuli response, and in combination, a broad range of multi-stimuli-responsive materials is accessible, giving the opportunity to tailor the polymeric material with regard to application.

1.3.1.1 Diblock Copolymers

The first example of CD-based block copolymers was described in 2008 by Zhang et al. (refer to Figure 1.5a) [39b]. A CD functionalized poly(4-vinylpyridine) (P4VP) and an adamantyl functionalized poly(N-isopropylacrylamide) (PNIPAM) block were synthesized via RAFT polymerization. The block copolymer was formed via supramolecular host/guest complexation and proved to be pH- and thermoresponsive, which was utilized for stimulus-induced micellization that was investigated via dynamic light scattering (DLS), static light scattering (SLS), fluorescence measurements, and transmission electron microscopy (TEM). The most frequently utilized guest moiety is adamantyl, yet it only provides a temperature responsive connection [40b]. Other examples of diblock copolymers based on CD/adamantyl complexation include poly(2-methyl oxazoline)-b-PNIPAM [38b], poly(N,N-dimethylaminoethyl methacrylate)-b-PNIPAM (PDMAEMA-b-PNIPAM) [38a], and poly(methyl methacrylate)-b-poly(hydroxyethyl acrylate) (PMMA-b-PHEA) [36]. A voltage/redox responsive block copolymer was presented by Yin et al., where a ferrocene functionalized poly(ethylene glycol) (PEG) was connected to a β-CD functionalized poly(styrene) (PS) [51]. Vesicles were formed that were prone to disruption by an application of external current and small molecule release was probed. More recently, Yuan et al. presented a block copolymer of poly(lactic acid) (PLA) and PEG [52]. A pH sensitive block copolymer amphiphile was formed by He et al. [46]. Benzimidazole functionalized poly(ϵ-caprolactone) (PCL) was connected to β-CD functionalized Dextran and utilized as biodegradable drug delivery vehicle upon micelle formation in neutral aqueous solution. Drug release of Doxorubicin was studied and was supported by the difference of intra and extra cellular pH. A CO2 responsive AB block copolymer was described by Zhao et al. (refer to Figure 1.8a) [47]. A β-CD functionalized Dextran was coupled to a benzimidazole functionalized poly(l-valine) in dimethylsulfoxide. Addition of water led to the formation of nanostructures depending on the degree of polymerization (DP) of the poly(l-valine) block. Vesicles were obtained for similar DP of dextran and poly(l-valine), while fiber-like structures were obtained for higher DPs of poly(l-valine). A photoresponsive block copolymer was described by Yuan et al. (refer to Figure 1.6b) [53]. The supramolecular block copolymer was based on PCL-b-poly(acrylic acid) (PCL-b-PAA) with azobenzene and α-CD end-groups, respectively. In aqueous solution nanotubes were formed that were disassembled upon UV irradiation. Furthermore, Rhodamine B was released from the nano tubes via light irradiation.

Figure 1.5 (a) Formation of a supramolecular double stimuli responsive diblock copolymer based on P4VP and PNIPAM [39b] (Reproduced from [38b] with permission of The Royal Society of Chemistry), (b) formation of an ABA triblock copolymer with temperature- and light-responsive block junctions [40b] (Adapted with permission from [39b]. Copyright 2013 American Chemical Society), and (c) formation of an AB monomer (α-CD-adamantyl/β-CD-cinnamoyl) based supramolecular alternating α-CD/β-CD copolymer [50] (Adapted with permission from [49]. Copyright 2013 American Chemical Society).

1.3.1.2 Higher Order Block Copolymers

While diblock copolymers are described frequently, multi-block copolymers are underrepresented so far. Our team prepared an ABA triblock copolymer based on β-CD featuring thermoresponsive and light responsive connections, namely adamantyl or azobenzene guests (refer to Figure 1.5b) [40b]. Poly(N,N-dimethylacrylamide) (PDMA) and poly(N,N-diethylacrylamide) (PDEA) middle blocks were connected with biocompatible poly(N-2-hydroxypropyl methacrylamide) (PHPMA) outer blocks. The block formation and dissociation upon external stimuli was investigated via DLS and nuclear Overhauser enhancement spectroscopy (NOESY). Furthermore, the temperature-induced aggregation due to thermoresponsive PDEA blocks was studied via temperature sequenced DLS and turbidimetry showing a two-stage aggregation. Another example of supramolecular ABA block copolymers was described by Zhang et al. [54]. PS with an adamantyl group on one end and an azobenzene group on the other end were complexed with β-CD functionalized PEG. Vesicles were formed in aqueous solution, characterized via TEM and DLS. The response of the vesicles to photo irradiation was probed as well, indicating a change in morphology toward micelles. A pH/CO2 responsive ABC block copolymer was described by Yuan et al. [55]. RAFT-derived PNIPAM was subjected to aminolysis in order to obtain thiol functionalized PNIPAM. Furthermore, methacrylate and adamantyl functional hetero telechelic PCL and β-CD end-functionalized PDMAEMA were connected in one pot via a combination of a thiol-ene reaction and supramolecular complexation. Vesicles with variable size, depending on CO2 or N2 stimulation, were obtained via the pH responsive PDMAEMA. Furthermore, these vesicles could be transformed into micelles via heating due to the collapse of the PNIPAM block.

1.3.1.3 Supramolecular Step Growth Polymers

An alternative to linear polymers based on supramolecular CD interactions is based on a step polymerization analogue [21a,56]. Host and/or guest functionalized small molecules are joined, leading to a polymer formed by multiple host/guest complexes. Either an AB or an AA/BB approach is utilized to form such polymers. Harada et al. utilized an α-CD functionalized with a cinnamoyl group as an AB monomer to form supramolecular polymers in the fashion of a daisy chain [57]. An AA/BB approach was undertaken by the same group [58]. A double adamantyl functionalized molecule was complexed with a β-CD dimer. Depending on the rigidity of the spacer between the adamantyl moieties, cycles, or linear polymers were obtained. The combination of different CDs was probed by Harada et al. as well, utilizing the strong complexations between the pairs of α-CD/cinnamoyl and β-CD/adamantyl, such as the combination of an α-CD/adamantyl and a β-CD/cinnamoyl based linker (refer to Figure 1.5c) [50]. Ritter et al. presented a linear supramolecular polymer based on a PDMS backbone and β-CD/adamantyl or ferrocene complexation that showed redox response [59]. A ternary supramolecular polymer was described by Liu et al. A naphthol functionalized β-CD was combined with an adamantyl-viologen dilinker and cucurbit[8]uril [60]. The β-CD complexes with the adamantyl moiety, while the cucurbit[8]uril complexes with the viologen and naphthol units. Thus a supramolecular polymer is formed via the utilization of two host/guest complex systems. A similar approach was performed by Zhang et al. [61]. Metal-complexes were utilized in the formation of supramolecular polymers as well: Tian et al. utilized a pyridine functionalized β-CD and a double azobenzene end-functionalized linker molecule [62]. The azobenzene functionalized linker was complexed by two pyridine containing β-CD units. Addition of a Pd (II) ethylenediamine salt led to polymer formation as the β-CD units were linked via metal-complex formation of two pyridines and a Pd (II) complex. The formation of the poly(pseudorotaxane) was evidenced by atomic-force microscopy (AFM) and NOESY. Zhang et al. presented a tripeptide (Phe-Gly-Gly) functionalized with an azobenzene that was complexed with cucurbit[8]uril in the ratio 2:1, which led to dimerization via complexation of two phenylalanine units [61]. The exposed azobenzenes were complexed with a β-CD dilinker, ultimately forming a supramolecular polymer. A difunctional β-CD molecule and a cationic difunctional ferrocene molecule were utilized in an AA/BB fashion to obtain redox responsive supramolecular polymers that show interesting gene vector abilities [63]. Tian et al. reported a photoresponsive supramolecular polymer based on γ-CD [64]. Two coumarin units were connected by a viologen unit. After addition of γ-CD in water, a ternary complex of two coumarin units originating