Single-Chain Nanoparticles as Catalytic Nanoreactors - Journal of the

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Single-Chain Nanoparticles as Catalytic Nanoreactors Hannah Rothfuss, Nicolai D. Knöfel, Peter W Roesky, and Christopher Barner-Kowollik J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b02135 • Publication Date (Web): 09 Apr 2018 Downloaded from http://pubs.acs.org on April 9, 2018

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Single-Chain Nanoparticles as Catalytic Nanoreactors Hannah Rothfuss‡,1,2 Nicolai D. Knöfel‡,3 Peter W. Roesky,3* Christopher Barner-Kowollik1,2* 1

School of Chemistry, Physics and Mechanical Engineering, Queensland University of Technology (QUT), 2 George Street, QLD 4000, Brisbane, Australia. 2 Macromolecular Architectures, Institut für Technische Chemie und Polymerchemie, Karlsruhe Institut of Technology (KIT), Engesserstr. 18, 761331 Karlsruhe, Germany. 3 Institut für Anorganische Chemie, Karlsruhe Institute of Technology (KIT), Engesserstr. 15, 76131 Karlsruhe, Germany. ABSTRACT: The need for efficient, tailor-made catalysts has inspired chemists to fuse the design principles of natural enzymes with synthetic macromolecular architectures. A highly interesting pathway mimics a metallo-enzyme’s tertiary structure via the target placement of metal-ions in a tailor-made polymeric framework, resulting in catalytically active single-chain nanoparticles. Initial studies reveal unusual and promising effects, regarding both new catalyst characteristics and a high impact on product formation. These multifunctional nanoreactors, constructed from simple folded polymer chains, will lead to advanced bio-inspired catalytic systems. As found in enzymes, their impact lies specifically within the defined construction of a polymeric pocket around the catalytic active cores for substrate recognition.

Introduction Chemical catalytic systems, both for industrial and laboratory use, are of fundamental importance in our everyday life. Catalysts not only activate inert starting materials, yet ease reaction conditions and improve product selectivity.1 However, there is an on-going need to further develop and improve catalytic systems, since contemporary catalysts often display considerable disadvantages. Homogeneous catalysts, in particular, while generally exhibiting higher catalytic activity than comparable heterogeneous systems, are more difficult to isolate, thus often remaining in the final product.2 As a result, many chemical reactions are in need of tailor-made catalysts to allow the selective synthesis of desired substrates. Indeed, in nature such a remarkable system already exists: the enzyme.3 Natural enzymes are sophisticated and specialized architectures, unrivalled in their efficacy to synthesize molecules in biological environments. The high efficiency of enzymes is based on an exquisitely developed reversible synergism of well-organized molecular entities. Driven by a finely selected sequence of building blocks, the macromolecular chains arrange reversibly into secondary and tertiary structures, adjustable to variable conditions. In engineering technology, the detailed observation and understanding of nature’s structural designs has often been an inspiration for exciting new concepts and innovative ideas. Perhaps most notably is the biomimicry of the lotus leaf, leading to the creation of ultrahydrophobic coatings and materials. 4 Just as engineers have successfully started incorporating biomimetic designs into the macroscale, chemists too have attempted to include those principles to today’s catalytic designs. Over the last few decades, chemists have endeavored to emulate and learn from these fascinating biological catalysts. Among other approaches, important steps towards alternative catalytic systems on a molecular basis have been made implementing nature’s building blocks into metal-organic and macromolecular chemistry.5 Here, the variety of building blocks (i.e. monomers) is almost unlimited and enables the versatile adjustment of the

molecular environment to specific reaction conditions. Investigating nature’s complex processes on a molecular level and applying these insights to new catalytic developments combines the best of both worlds. In other words, does the imitation of nature’s catalytic systems effectively help to develop advanced catalysts for our purposes? Metal-Complexed SCNPs The artificial synthesis of enhanced catalytic architectures, such as enzyme mimics, is a pioneering and challenging topic requiring a detailed understanding of natural processes on a molecular level. Interestingly, natural enzymes are complex 3D structures of polypeptide chains, in which intramolecular folding and interaction play an essential role. Due to a predetermined reversible folding mechanism, the polypeptide chains form a tailor-made pocket which serves as a catalytic cavity.6 The unique interplay between framework and catalytic core allows merely suitable substrates to enter the cavity and be transformed efficiently, resulting in substrate-, regio- and stereo-selectivity at mild reaction conditions.5 The performance of enzymes can be readily influenced by environmental cues, including pH or temperature.7 Natural enzymes and their modifications have – accessible via biotechnological processes – to some extent found use in industrial processes such as biocatalysis.8 On the laboratory scale, first approaches towards polymerbased enzyme mimics have been made, based on structures such as foldamers or dendrimers.9-12 These strategies arrange molecular building blocks into spherical macromolecules, entailing catalytic entities either at the end of the branches or in their center as a catalytic core. Typical for the latter are metal-nanoparticles, embedded into a dendrimer template.13 An alternative promising and newly emerging method mimics an enzyme’s folded tertiary structure utilizing single-chain technology. Here, specifically designed nanostructures consist of folded functional polymer chains.14-18 Under highly diluted conditions, the

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Figure 1. (A) The introduction of well-chosen ligand functionalities – capable of metal-complexation – in the polymer chain allows singlechain folding and catalytic functionalization in one step. (B) Nanoparticle formation via an external trigger and subsequent metal loading of a pre-folded scaffold.

chains form – via an external trigger – intramolecular linkages and collapse into compact single-chain nanoparticles (SCNPs). The degree of SCNP complexity and functionality is regulated by the constituting monomers, the type of linkage – covalent, non-covalent or supramolecular – and the additional side group functionalities. Post collapse, the nanoparticles usually exhibit diameters between 3 to 30 nm, within the range of an enzyme’s size. Whereas single chain nanoparticles can be collapsed by a variety of folding mechanisms, we herein highlight the incorporation of metal-ions into SCNP structures. This fusion, inspired by biological metallo-enzymes, enables the creation of an enclosed polymeric pocket, entailing metal-ions as catalytic active elements. Similar to some approaches from bioinorganic chemistry,19 SCNPs do not directly copy the catalytically active center of an enzyme, yet rather take advantage of their structural (biomimetic) or functional designs (bioinspired).20 Specifically, artificial catalysts and metal-complexes, not or rarely used by nature, are incorporated into an enzyme-like matrix, allowing an unprecedented flexibility in catalyst design. This fundamentally new approach simultaneously combines the process of metal-incorporation with the collapse of the chain. Here, the externally introduced metal-ions do not only impart the desired catalytic function to the polymeric architecture, yet additionally operate as structure forming elements (Figure 1 A). However, from a synthetic point of view, this approach is challenging, since metal precursors are required, which feature readily replaceable leaving groups or free coordination sites to allow the folding process. Yet, by judiciously choosing the reaction conditions, the ligand moieties of the chain can directly form polymeric pockets around the inserted metal-ions. Alternatively, the folding process does not necessarily need to be induced via an external metal precursor to construct an enzyme mimetic catalytic SCNP framework. Nanostructured systems have been developed, in which the initial

formation of a polymeric scaffold proceeds via covalent or hydrogen bond formation. In a subsequent step, metal-ions are placed target-oriented into the pre-folded nanostructure, complexed by additional preserved side-groups of the polymer chain (Figure 1 B). Alternative methodologies introduce organo-catalytic moieties into the polymeric nanostructure, thus creating active, yet metal-free SCNP systems. Structurally similar to natural enzymes – a polymeric chain surrounding catalytic active centers – the hybrid SCNP systems must exhibit unique catalytic properties. However, metal-containing bioinspired SCNPs targeted at catalytic purposes are in their infancy and only a few examples have been reported to date.21 The current perspective will provide an overview of catalytic performances with a particular emphasis on the comparison between SCNP systems and molecular organometallic catalysts. Critically, we will explore which conceptual and synthetic barriers need to be overcome to enable the field of SCNP chemistry to deliver on its foreshadowed advantages and catalytic promises. SCNPs as Catalytic Devices From a physical point of view, the replacement of molecular ligands in an organometallic catalyst by a space demanding polymer chain should have significant effects. A decrease of catalytic efficacy may occur if the catalytic pockets, e.g. the chain loops around the metal-ions, are too dense. Due to shielding, the starting material may be prevented from diffusing to the active catalytic centers, resulting in a decline in activity. The diffusional limitations were recognized by the group of Pomposo, who documented a considerable decrease in catalytic activity when applying acrylate-based organocatalytic SCNPs in a reduction of α-diketones.22 Thus, it is necessary for the polymeric support to allow the diffusion of both starting material and products freely in and out of the SCNP nanoreactor. On the other 2


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Figure 2. Conceptual differences between molecular catalysts and catalytically active SCNPs: (A) Significant impact on the product ratio in a cross-coupling reaction when a molecular catalyst [Rh(cod)Cl] 2 is substituted by Rh(I)-SCNPs.23 (B) Unique substrate specificity in an oxidative coupling of terminal acetylenes when applying Cu(II)-SCNPs instead of CuCl2 as a catalyst.26

hand, a purposeful shielding of the catalytic pocket can be desirable, allowing merely selective substrates into the cavity, thus increasing the selectivity and specificity of the reaction. The selectivity can be amplified to a point where individually designed pockets are created, which are only accessible for the target substrates, as occurring in natural analogs. The above noted selective product formation was, for instance, observed and thoroughly investigated by Lemcoff’s team, who directly compared molecular and SCNP catalyst systems. In a first step, metal-SCNPs were synthesized by collapsing diene-functionalized polymer chains into catalytic nanoparticles via the incorporation of Ir(I)- or Rh(I)-ions.23 In a subsequent cross-coupling reaction, the analogous molecular catalyst [Rh(cod)Cl]2 was replaced by Rh(I)-SCNPs. The homo to hetero-product ratio changed significantly depending on which

catalytic system was applied (Figure 2 A). Remarkably, the polymer surrounding the Rh(I)-ions had a direct influence on the catalytic selectivity. Often problematic for molecular metal-catalysts is the reduction or even the loss of their catalytic activity due to aggregation, inhibition by the solvent, lability of metal-ligand bonds or undesired oxidation.24 In addition, the molecular catalysts in conventional reactions systems are widely distributed, which can lead to long reaction times. These critical issues can be addressed by embedding molecular complexes into a protecting polymer framework. The targeted placement of functional binding units along the polymer chain enables high local concentrations of catalytically active species, inducing positive localization effects.25 Together with the concurrent suppression of aggregation, SCNP systems can have an increased catalytic activity. To illustrate this point, Pomposo and colleagues reported

Figure 3. Tailoring of SCNP characteristics by selective reaction conditions. (A) The formation of 2:1 complexes between phosphine units in the polymer chain and an externally added platinum(II) salt results in single-chain nanoparticles. (B) Pt(II)-SCNPs – employed in the amination of allyl alcohol – change their solubility behavior and therefore catalytic activity due to the polarity of the solvent, thus combining both homogeneous and heterogeneous properties and enabling catalyst recyclability. 28 3



the benefit of lower catalyst concentrations employing homogeneous Cu(II)-SCNPs instead of CuCl2 as catalyst. The nanoparticles exhibited an unprecedented substrate specificity in an oxidative coupling of terminal acetylenes (Figure 2 B). 26 Besides the local concentration of metal-ions in a frame work, an advantage is a possible stabilization of uncommon oxidation states by the polymeric matrix. Such effects are already observed in natural enzymes, e.g. the Ni(III) fixation in superoxide dismutase.27 The stabilization of such highly reactive species offers new and pioneering catalytic properties. Polymer chains entail the advantage of being readily adjustable in terms of their solubility, size or stability – achievable by varying the monomer type, their composition or chain length. Thus, the synergism of polymer chains with metal-ions allows adjusting their applicational scope to nearly any required chemical reaction and condition. Continued investigations of new synthetic procedures focus on the solubility behavior of polymeric material to – on demand – homogenize or heterogenize SCNPs within their reaction media. In contrast to homogeneous catalysts, anchored on classical polymer supports, SCNPs are well soluble in organic solvents and aqueous media depending on their composition. Thus, a change of the solvent polarity can either lead to their dissolution or precipitation, which in turn allows isolation and reusability, as recently demonstrated by the Barner-Kowollik and Roesky teams (Figure 3).28 The synthesis of Pt(II)-SCNPs via phosphine functionalized polymer chains allowed their application as homogeneous catalysts in an amination of allyl alcohol. When changing the polarity of the solvent, the Pt(II)-SCNPs was successfully isolated from the reaction mixture and reused in a further catalytic cycle. The solubility behavior of SCNPs was illustrated from a different point of view by Zimmerman and colleagues. In their study, they combined hydrophilic monomers with Cu(II)-ions, resulting in water-soluble SCNPs, sufficiently small to enable their entry into cells. The low concentration of copper in the SCNPs allowed catalytic activity – alkyne-azide click-reactions via Cu(I) species – in the cells without cytotoxicity, foreshadowing possible applications of metal-SCNPs in nanomedicine.29

Importantly, the use of a macromolecular chain enables the introduction of additional functionalized side-groups, which can be essential to stabilize or support the catalytically active center. An elegant system was described by Meijer and colleagues, who based their catalytic SCNP structure on a carefully designed helical terpolymer.30 The SCNPs contained, next to the structure forming elements, either an organo-catalytic monomer (L-proline) or an additional side-group as complexing ligand for ruthenium-ions. Both SCNP systems showed catalytic activity. The Ru(II)-SCNPs quantitatively catalyzed a hydrogen transfer from sodium formate to cyclohexanone resulting in cyclohexanol, whereas the activity of the L-proline SCNPs was assessed in an aldol reaction between cyclohexanone and p-nitrobenzaldehyd (Figure 4 A). Impressively, further studies suggested that it was essential for the organocatalytic L-proline functionalized system to be in its folded conformation, thus shielded by the hydrophobic pocket of benzene-1,3,5-tricarboxamide units around them.31 In contrast, the ruthenium-containing SCNPs were not affected by any additional side-groups of the polymer chain.32 These socalled secondary coordination site effects were also observed in further metal-SCNP systems. He and colleagues reported the influence of additionally introduced hydroxyl groups in a Nithiolate SCNP system. Although not critical for the general catalytic activity, they are considered to increase both the catalytic efficiency and selectivity regarding the photocatalytic activity of a CO2 reduction, due to their role as weak Brønsted acids (Figure 4 B).33 In a direct comparison, 1 g of Ni-foldamers led to a CO formation rate of close to 2 mmol·h-1. In comparison, the enzyme carbon monoxide dehydrogenase (CODH) on TiO2 or on CdS quantum dots yields lower reduction rates of 250 µmol·h-1 and 60 µmol·h-1 per 1 g, respectively. In addition, the Ni-foldamers were employed at higher temperatures than the natural catalyst carbon monoxide dehydrogenase, due to the encapsulation of the metal-ions into the polymer framework, resulting in even higher formation rates of close to 240 mmol·h-1 (at 80 °C).

Figure 4. (A) The influence of a second coordination site regarding catalytic applications is illustrated by a helical terpolymer entailing organo-catalytic L-proline moieties: The aldol reaction of cyclohexanone and p-nitrobenzaldehyd can only be catalyzed if the polymer is in a folded conformation, thereby forming hydrophobic pockets around the catalytic L-proline centers.31 (B) Simplified formation of a NiSCNP cavity, exhibiting a higher temperature stability and catalytic activity due to secondary coordination effects, as a consequence of additional functional hydroxyl units in the surrounding polymer system.33 4


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Journal of the American Chemical Society folding processes, enabling the assembly of equally tailored catalytic cavities. However, to date the synthesis of sequence-defined polymers is challenged by scale up. Thus, it appears that sequence-controlled polymers – essentially multi-segment block copolymers – are an attractive alternative to control the placement of variable polymer segments. Here, the folding functionalities and catalytically active centers can be placed within the polymer chains at defined positions, albeit at the expense of monodispersity.39,40 For the synthetic chemist, it is essential to both evidence the formation of the targeted folded structure as well as the prediction of the required geometry as a function of the catalytic task.41,42 First promising steps have been made, for example using high resolution mass spectrometry for SCNP imaging or employing all-atomistic molecular dynamic simulations for SCNP design.43,44 As noted, the ring or loop size around the active center is important for catalytic purposes, yet it is also prerequisite for the folding into a nanoparticle. An important factor thereby is the limitation for both a minimum and a maximum ring size. For example, the minimum size, amongst other factors, is highly dependent on the persistence length of the polymer backbone and the coordination polyhedron formed around the metal center. The maximum ring size, on the other hand, is determined by diffusion limitations during the reaction. 45,46

Vision The development of catalytically active SCNPs is one – yet critical – step towards advanced enzyme-mimetic systems. Based on promising initial results, SCNP applications in homogeneous catalysis are highly attractive. However, synthetic and analytical challenges, such as the use of – ultimately – precision polymer chain and the exact positioning of metal-complexes are key challenges. To overcome them, a joint effort of polymer and inorganic chemists, working in close collaboration with theoretical chemists, is essential to effect a powerful catalytic process. Although most of the applied polymers for SCNP formation are synthesized via reversible deactivation radical polymerization,34-36 the individual chains within the ensemble still vary significantly in composition and length. Thus, the placement of functional groups – including those that induce the folding process – is mostly statistical. Consequently, every polymer chain within the collective is diverse and therefore each SCNP is folded slightly differently, unlike enzymes, which exhibit no dispersity of identically arranged chains. Clearly, the field of sequence-defined polymers,37,38 where every monomer unit is placed at a predefined position within a monodisperse chain, can play a critical role in SCNP precision

Figure 5. (A) SCNP technology envisions the controlled folding process of sequence defined polymers. Specifically placed functional units allow the orthogonal implementation of different metal-ions – catalytic active cores – into the same polymer chain. Expected are subsequently catalyzed cascade reactions of the advanced monodisperse SCNPs or independent reactions catalyzed with the same catalytic system. (B) Visualization of reversible folded SCNPs which – on demand – can switch their catalytic activity on and off by outer field control, e.g. different wavelengths. 5



ACKNOWLEDGMENT

These aspects critically dictate the most effective placement of functional and catalytically active units along the polymer chain. Regarding the examples discussed herein, the placement of functional units can be optimized to a point at which specified pockets are formed around the metal-ions. As in natural enzymes, the control of the entities in the catalytic center and the subsequent core-substrate interaction within the polymeric catalytic pocket is the ultimate aim. Within the realm of SCNP synthesis, to date, a very large amount of solvent is required during the folding step to ensure unimolecular chain collapse. Thus, only milligram amounts are accessible. However, their widespread application as catalysts is drastically limited if no avenues are found to effectively scale up their production. We submit that looped flow processes – both in their photochemical and thermal variants – will play a critical role in producing precision catalytic SCNPs on a large scale.47 Other approaches investigate pre-folded systems to adjust the internal structure before folding into a more compact geometry. The physical vicinity of functional groups thereby allows higher concentrations during the folding step. 48 Synthetically more challenging, yet opening SCNP chemistry to an entirely new terrain, is the introduction of orthogonal linker moieties to selectively coordinate metal ions, resulting in heterometallic SCNPs. Due to cooperative effects,49 enhanced catalytic reactions are feasible, e.g. cascade or multi-step reactions, utilizing exclusively a single catalyst (Figure 5 A). Along with the development of extended, metal-specific ligand moieties, investigations head for dynamic SCNP systems, which can switch their catalytic activity on and off by outer field control. Necessary are orthogonally and reversibly functioning linker units that bond and de-bond on demand, e.g. via different colors of light.50 Initial promising steps in the area of dynamically responsive SCNPs have been made by our team, indicating that the geometry of SCNPs can be reversibly altered (Figure 5 B). Thus, the targeted manipulation of the catalytic activity via conformational adaptable pockets, regulated by light, seems conceivable.51,52 Clearly, reaching the above noted demands on SCNP system is an enormous challenge. However, the attraction of basing enzyme mimicry on readily accessible synthetic polymers is a highly appealing proposition, which is at the verge of emerging into fully-fledged research field. The attraction includes the ability to precision tailor SCNP systems for each catalytic task, fusing high catalyst stability, selectivity and reusability with dynamic properties that will allow the remote activation and deactivation of catalytic ability. We suggest that synthetic polymer based SCNPs hold the potential of fulfilling these characteristics. At stake is nothing less than the design and implementation of the next generation of catalytic materials.

C. B.-K. and P. W. R. acknowledge support from the SFB 1176, Project A2, funded by the German Research Council (DFG). H. R.´s and N. K.´s PhD studies are additionally funded by the Fonds der Chemischen Industrie (FCI). C.B.-K. acknowledges support from the Australian Research Council in the context of a Laureate Fellowship as well as by the Queensland University of Technology (QUT). C.B.-K. additionally acknowledges continued support by the Helmholtz association via the STN and BIFTM programs.

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AUTHOR INFORMATION Corresponding Author *C.B-K., Email: [email protected]; [email protected] *P. W. R, Email: [email protected]. Author Contributions All authors have given approval to the final version of the manuscript. ‡These authors contributed equally. 6


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