Jean-François Lutz

Sequence-Controlled Polymers

Background During the last few decades, progress has been made in manipulating the architecture of synthetic polymer materials. However, the primary structure—that is, the sequential arrangement of monomer units in a polymer chain—is generally poorly controlled in synthetic macromolecules. Common synthetic polymers are usually homopolymers, made of the same monomer unit, or copolymers with simple chain microstructures, such as random or block copolymers. These polymers are used in many areas but do not have the structural and functional complexity of sequence-defined biopolymers, such as nucleic acids or proteins. Indeed, monomer sequence regulation plays a key role in biology and is a prerequisite for crucial features of life, such as heredity, self-replication, complex self-assembly, and molecular recognition. In this context, developing synthetic polymers containing controlled monomer sequences is an important area for research. Precise molecular encoding of synthetic polymer chains. In most synthetic copolymers, monomer units (represented here as colored square boxes A, B, C, and D) are distributed randomly along the polymer chains (left). In sequence-controlled polymers, they are arranged in a specific order in all of the chains (right). Monomer sequence regularity strongly influences the molecular, supramolecular, andmacroscopic properties of polymer materials. Advances Various synthetic methods for controlling monomer sequences in polymers have been identified, and two major trends in the field of sequence-controlled polymers have emerged. Some approaches use biological concepts that have been optimized by nature for sequence regulation. For instance, DNA templates, enzymes, or even living organisms can be used to prepare sequence-defined polymers. These natural mechanisms can be adapted to tolerate nonnatural monomers. The other trend is the preparation of sequence-controlled polymers by synthetic chemistry. In the most popular approach, monomer units are attached one by one to a support, which is an efficient method but demanding in practice. Recently, some strategies have been proposed for controlling sequences in chain-growth and step-growth polymerizations. These mechanisms usually allow fast and large-scale synthesis of polymers. Specific kinetics and particular catalytic or template conditions allow sequence regulation in these processes. Outlook The possibility of controlling monomer sequences in synthetic macromolecules has many scientific and technological implications. Information can be controlled at the molecular level in synthetic polymer chains. This opens up interesting perspectives for the field of data storage. In addition, having power over monomer sequences could mean structural control of the resulting polymer, as it strongly influences macromolecular folding and self-assembly. For instance, functional synthetic assemblies that mimic the properties of globular proteins, such as enzymes and transporters, can be foreseen. Moreover, monomer sequence control influences some macroscopic properties. For example, bulk properties such as conductivity, rigidity, elasticity, or biodegradability can be finely tuned in sequence-controlled polymers. The behavior of polymers in solution, particularly in water, is also strongly dependent on monomer sequences. Thus, sequence regulation may enable a more effective control of structure-property relations in tomorrow’s polymer materials. Controlled Polymers Nature has achieved exquisite sequence control in the synthesis of polymers like DNA. In contrast, synthetic polymers rarely have the same fidelity in their chemistry or uniformity in chain-length distribution, especially when more than one monomer is involved. Lutz et al. (1238149) review the progress that has been made in making sequence-controlled polymers of increasing length and complexity. These developments have come from both advances in synthetic chemistry methods and the exploitation of biological machinery. Sequence-controlled polymers are macromolecules in which monomer units of different chemical nature are arranged in an ordered fashion. The most prominent examples are biological and have been studied and used primarily by molecular biologists and biochemists. However, recent progress in protein- and DNA-based nanotechnologies has shown the relevance of sequence-controlled polymers to nonbiological applications, including data storage, nanoelectronics, and catalysis. In addition, synthetic polymer chemistry has provided interesting routes for preparing nonnatural sequence-controlled polymers. Although these synthetic macromolecules do not yet compare in functional scope with their natural counterparts, they open up opportunities for controlling the structure, self-assembly, and macroscopic properties of polymer materials.

Copper-free azide-alkyne cycloadditions: new insights and perspectives.

The “click” concept, proposed by Sharpless, Kolb, and Finn in 2001, is undeniably one of the most noticeable synthetic trends in this new century. The catchy term “click” refers to energetically favored, specific, and versatile chemical transformations, which lead to a single reaction product. In other words, the essence of “click” chemistry is simplicity and efficiency. This tantalizing concept seems to answer perfectly the needs of modern scientists working in areas of research as diverse as molecular biology, drug-design, biotechnology, macromolecular chemistry, or materials science. It is indeed noteworthy that over recent years, complicated reactions requiring either complex apparatus, harsh experimental conditions, or high-purification techniques, have been less frequently studied than in the last century and gradually replaced by simpler tools. In this context, the straightforward “click” reactions have become tremendously popular in both academic and industrial research. Reactions of the “click” type are rather rare. Yet, the last few years saw the emergence of a rudimentary “click” toolbox, which includes, for example Diels–Alder cycloadditions, thiol–ene additions, oxime formation, and coppercatalyzed Huisgen azide–alkyne cycloadditions (CuAAC). However, in recent literature, the term “click chemistry” has been used almost exclusively to denote the latter reactions. The synthesis of 1,2,3-triazoles by 1,3-dipolar cycloaddition of azides and alkynes was discovered by Arthur Michael at the end of the 19th century and significantly developed by Rolf Huisgen in the 1960s. In the absence of a transition-metal catalyst, these reactions are not regioselective, relatively slow, and require high temperatures to reach acceptable yields (Scheme 1A). In early 2002, Meldal and co-workers reported that the use of catalytic amounts of copper(I), which can bind to terminal alkynes, leads to fast, highly efficient, and regioselective azide–alkyne cycloadditions at room temperature in organic medium (Scheme 1B). Shortly after, Sharpless and Fokin demonstrated that CuAAC can be successfully performed in polar media, such as tert-butyl alcohol, ethanol or pure water. These two important breakthroughs led to a remarkable renaissance of Huisgen cycloadditions in synthetic chemistry. Hence, research on CuAAC has increased exponentially in the last few years in organic synthesis, inorganic chemistry, polymer chemistry, and biochemistry. Numerous authors collectively demonstrated that CuAAC is a true example of efficient and versatile “click” chemistry. In particular, azide–alkyne cycloadditions have been shown to be highly relevant for biological applications. Indeed, such reactions can be performed under experimental conditions, which are compatible with biological environments (e.g. aqueous medium and body temperature). Moreover, azide and alkyne functions are, respectively, absent or relatively rare in the biological world. Thus, azide–alkyne chemistry constitutes a very interesting chemoselective platform for the functionalization or ligation of biological systems. For instance, CuAAC has been recently investigated for designing a wide range of biomaterials, such as stationary phases for bioseparation, site-specific modified proteins or viruses, drugor genedelivery carriers, protein or oligonucleotide microarrays, and functionalized cell surfaces. Scheme 1. Different types of azide–alkyne cycloaddition: A) standard thermal cycloaddition, B) copper(I)-catalyzed cycloaddition, 9,11] C) strain-promoted and fluorine-activated cycloaddition.

Sequence-controlled polymerizations: the next Holy Grail in polymer science?

The aim of this short perspective article is to sensitize polymer chemists to the importance of controlling comonomer sequences. During the last twenty years, our scientific community has made impressive progress in controlling the architecture of synthetic macromolecules (i.e. chain length, shape and composition). In comparison, our tools for controlling polymer microstructures (i.e. sequences and tacticity) are still very rudimentary. However, as learned from Nature, sequence-controlled polymers are most likely the key toward functional sub-nanometric materials.

Controlled folding of synthetic polymer chains through the formation of positionable covalent bridges

Covalent bridges play a crucial role in the folding process of sequence-defined biopolymers. This feature, however, has not been recreated in synthetic polymers because, apart from some simple regular arrangements (such as block co-polymers), these macromolecules generally do not exhibit a controlled primary structure—that is, it is difficult to predetermine precisely the sequence of their monomers. Herein, we introduce a versatile strategy for preparing foldable linear polymer chains. Well-defined polymers were synthesized by the atom transfer radical polymerization of styrene. The controlled addition of discrete amounts of protected maleimide at precise times during the synthesis enabled the formation of polystyrene chains that contained positionable reactive alkyne functions. Intramolecular reactions between these functions subsequently led to the formation of different types of covalently folded polymer chains. For example, tadpole (P-shaped), pseudocyclic (Q-shaped), bicyclic (8-shaped) and knotted (α-shaped) macromolecular origamis were prepared in a relatively straightforward manner. Synthetic polymers are typically difficult to fold into particular origamis because the monomers can usually not be precisely organized along their backbones. Reactive alkyne groups have now been placed at specific locations in linear polystyrene chains, enabling those to be folded into predetermined shapes through intramolecular covalent bonding.

Ultra-precise insertion of functional monomers in chain-growth polymerizations

Chain-growth polymerizations are popular methods because they allow synthesis of high-molecular weight polymers in high yields and in short times. However, copolymers prepared by such processes generally exhibit uncontrolled monomer sequences. The controlled radical copolymerization of styrene with N-substituted maleimides is an interesting exception allowing preparation of controlled primary structures. However, because of the statistical nature of chain-growth mechanisms, sequence deviations are still present in these copolymers. Here we describe a specific range of experimental conditions that allows ultra-precise incorporation of a single N-substituted maleimide unit in a polystyrene chain. This occurs in a given kinetic regime where the styrene/N-substituted maleimide comonomer ratio is very low. This situation usually only arises in the later stages of a chain-growth polymerization. Nevertheless, we show that it is possible to restore these particular kinetic conditions multiple times during a single polymerization by using successive feeds of donor and acceptor comonomers.

Design and synthesis of digitally encoded polymers that can be decoded and erased

Biopolymers such as DNA store information in their chains using controlled sequences of monomers. Here we describe a non-natural information-containing macromolecule that can store and retrieve digital information. Monodisperse sequence-encoded poly(alkoxyamine amide)s were synthesized using an iterative strategy employing two chemoselective steps: the reaction of a primary amine with an acid anhydride and the radical coupling of a carbon-centred radical with a nitroxide. A binary code was implemented in the polymer chains using three monomers: one nitroxide spacer and two interchangeable anhydrides defined as 0-bit and 1-bit. This methodology allows encryption of any desired sequence in the chains. Moreover, the formed sequences are easy to decode using tandem mass spectrometry. Indeed, these polymers follow predictable fragmentation pathways that can be easily deciphered. Moreover, poly(alkoxyamine amide)s are thermolabile. Thus, the digital information encrypted in the chains can be erased by heating the polymers in the solid state or in solution.

Polymer chemistry: A controlled sequence of events

Yttrium-based catalysts can be used to stitch together two different lactone monomers in an alternating fashion to produce polyesters with well-defined primary structures. The ability to control the sequence of building blocks in polymers with increasing levels of precision offers new opportunities for tailoring the properties of designer synthetic macromolecules.

Tailored Polymer Microstructures Prepared by Atom Transfer Radical Copolymerization of Styrene and N-substituted Maleimides

In the present Feature Article, a kinetic strategy for controlling the microstructure of synthetic polymer chains prepared via a radical chain-growth polymerization process is presented. This approach was recently developed in our laboratory and relies on the controlled kinetic addition of ultrareactive N-substituted maleimides during the atom transfer radical polymerization of styrene. This method is experimentally straightforward and can be applied to a broad library of functional N-substituted maleimides. Thus, this platform allows synthesis of unprecedented polymer materials such as 1D macromolecular arrays. The basic kinetic requirements, the experimental conditions, and the synthetic scope of this approach are discussed in details herein.

Kinetic modeling of the chain-end functionality in atom transfer radical polymerization†

The evolution of chain-end functionality of polymers synthesized by atom transfer radical polymerization (ATRP) was modeled. By comparing various kinetic models, the effect of specific side reactions was estimated. The slow elimination of hydrobromic acid from the polymer end-groups as well as the thermal self-initiation of the monomer may affect the chain-end functionality. Although the polymerization possesses several characters of a living process (i.e. linear increase of molecular weight versus conversion, low polydispersity index), the final polymer may have a limited functionality. However, polymers with enhanced functionality can be prepared through adjusting certain experimental parameters such as conversion of the monomer or initial concentration of the reactants.

PEG-based thermogels: Applicability in physiological media

Novel biocompatible thermogels have been synthesized and characterized. The hydrogelators were synthesized by atom transfer radical copolymerization of 2-(2-methoxyethoxy)ethyl methacrylate (MEO(2)MA) and oligo(ethylene glycol) methyl ether methacrylate (OEGMA(475), M(n)=475 g mol(-1) or OEGMA(300), M(n)=300 g mol(-1)) in the presence of a 4-arm star poly(ethylene glycol) (PEG) macroinitiator. The formed macromolecules possess a permanently hydrophilic PEG core and thermoresponsive P(MEO(2)MA-co-OEGMA) outer-blocks. These star-block architectures exhibit an inverse thermogelation behavior in aqueous medium. Typically, above their lower critical solution temperature (LCST), the thermoresponsive P(MEO(2)MA-co-OEGMA) precipitate, thus forming physical crosslinks, which are stabilized in water by hydrophilic PEG bridges. This thermo-induced sol-gel transition can be adjusted within a near-physiological range of temperature by simply varying the composition of the thermoresponsive segments. Moreover, these novel hydrogelators formed free-standing gels in various buffer solutions (e.g., PBS, Tris, MOPS, bicine and HEPES) and in cell culture media. In saline solutions, a weak salting-out effect was observed. However, other components of physiological media (e.g., buffering agents, amino acids, vitamins, proteins) did not hinder the thermogelation process. Hence, these novel thermogels appear as highly attractive candidates for applications in biosciences.