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The storage of information in synthetic (macro)molecules provides an attractive alternative for current archival storage media, and the advancements made within this area have prompted the investigation of such molecules for numerous other applications (e.g., anti-counterfeiting tags, steganography). While different strategies have been described for storing information at the molecular level, this Perspective aims to provide a critical overview of the most prominent approaches that can be utilized for retrieving the encoded information. The major part will focus on the sequence determination of synthetic macromolecules, wherein information is stored by the precise arrangement of constituting monomers, with an emphasis on chemically aided strategies, (tandem) mass spectrometry, and nanopore sensing. In addition, recent progress in utilizing (mixtures of) small molecules for information storage will be discussed. Finally, the closing remarks aim to highlight which strategy we believe is the most suitable for a series of specific applications, and will also touch upon the future research avenues that can be pursued for reading (macro)molecular information.

The synthesis of sequence-defined, discrete star-shaped macromolecules is a major challenge due to the lack of straightforward and versatile approaches. Here, a robust strategy is proposed that allows not only the preparation of sequence-defined mikto-arm star-shaped macromolecules but also the synthesis of a series of unprecedented discrete, multifunctional complex architectures with molar masses above 11 kDa. The iterative approach reported makes use of readily available building blocks and results in asymmetrically branched macromolecules with high purity and yields, which is showcased with monodisperse mikto-arm three-, four-, and five-arm star-shaped structures that were all characterized via LC-MS, MALDI-ToF, and NMR. This effective strategy drastically improves upon synthetic abilities of polymer chemists by enabling simultaneously sequence definition, precision insertion of branching points, as well as the orthogonal end-group functionalization of complex polymeric architectures. The presented approach, which can be translated to different platforms such as peptides and peptoids, is therefore particularly interesting in biomedical applications for which multiple different functional moieties on a single discrete macromolecule are needed.

A monodisperse soluble support is used as an effective tool for the large-scale, liquid-phase synthesis of sequence-defined macromolecules. This uniform support allows for direct characterisation and leads to a single peak in mass spectrometry.

Antibody-recruiting molecules represent a novel class of therapeutic agents that mediate the recruitment of endogenous antibodies to target cells, leading to their elimination by the immune system. Compared to single-ligand...

Polyampholytes, widely investigated for their distinct properties, are typically prepared via conventional polymerisation techniques. This results in an ensemble of polymer chains with variation in molecular parameters such as length, ratio of charged groups and monomer order, which could influence their behaviour. Here, uniform oligoampholytes with precisely positioned negatively charged carboxylate and positively charged ammonium side-chains were synthesised using an iterative solid-phase synthesis strategy based on thiolactone chemistry. The amine side-chains were initially introduced via an acrylate, resulting in an amino-functionalised β-thioester that was shown to be susceptible to transesterification and hydrolysis, even under ambient conditions. While increasing the spacer length between the β-thioester and amine functionality could slow down this undesired side-reaction, it could not be completely suppressed. On the other hand, a tertiary amine-bearing vinyl sulfonamide proved to be a viable, hydrolytically stable alternative to introduce this moiety. The resulting uniform oligoampholytes are soluble in water and show UCST-type thermoresponsive behaviour in 85 vol% isopropanol/water mixtures.

Sequence-encoded oligo(thioether urethane)s with two different coding monomers per backbone unit were prepared via a solid phase, two-step iterative protocol based on thiolactone chemistry. The first step of the synthetic cycle consists of the thiolactone ring opening with a primary amine, whereby the in situ released thiol is immediately reacted with an epoxide. In the second step, the thiolactone group is reinstalled to initiate the next cycle. This strategy allows to introduce two different coding monomers per synthetic cycle, rendering the resulting macromolecules especially attractive in the area of (macro)molecular data storage because of their increased data storage capacity. Subsequently, the efficiency of the herein reported synthesis route and the applicability of the dual-encoded sequence-defined macromolecules as a potential data storage platform have been demonstrated by unraveling the exact monomer order using tandem mass spectrometry techniques.

In contrast to biomacromolecules, synthetic polymers generally lack a defined monomer sequence, therefore one of the challenges of polymer chemists these days is gaining more control over the primary structure of synthetic polymers and oligomers. In this work, stereocontrolled sequence-defined oligomers were synthesised using a thiolactone-based platform. Step-wise elongation of the oligomer occurs via ring-opening of the thiolactone, resulting in the formation of stereocenters along the backbone. These initial studies indicate remarkable differences in the strength of non-covalent interactions in isotactic and atactic oligomers. Different side-chain moieties were introduced using alkyl halide building blocks and the synthetic protocol was succesfully optimised and automated. Furthermore, the possible post-synthesis modification of the oligomers was demonstrated using 'click' chemistry.

In the last decade, the field of sequence‐defined polymers and related ultraprecise, monodisperse synthetic macromolecules has grown exponentially. In the early stage, mainly articles or reviews dedicated to the development of synthetic routes toward their preparation have been published. Nowadays, those synthetic methodologies, combined with the elucidation of the structure–property relationships, allow envisioning many promising applications. Consequently, in the past 3 years, application‐oriented papers based on discrete synthetic macromolecules emerged. Hence, material science applications such as macromolecular data storage and encryption, self‐assembly of discrete structures and foldamers have been the object of many fascinating studies. Moreover, in the area of life sciences, such structures have also been the focus of numerous research studies. Here, it is aimed to highlight these recent applications and to give the reader a critical overview of the future trends in this area of research., A comprehensive overview of the applications of discrete synthetic macromolecules in biology and materials science is presented. Topics as diverse as macromolecular data storage, self‐assembly, foldamers, catalysis, lectin‐binding, and antimicrobial properties are presented. Additionally, features such as the influence of sequence regulation on the physical properties of such uniform macromolecules are elaborated and future trends in the field are provided.

Dynamic sequence‐defined oligomers carrying a chemically written pin code are obtained through a strategy combining multicomponent reactions with the thermoreversible addition of 1,2,4‐triazoline‐3,5‐diones (TADs) to indole substrates. The precision oligomers are specifically designed to be encrypted upon heating as a result of the random reshuffling of the TAD‐indole covalent bonds within the backbone, thereby resulting in the scrambling of the encoded information. The encrypted pin code can eventually be decrypted following a second heating step that enables the macromolecular pin code to be deciphered using 1D electrospray ionization‐mass spectrometry (ESI‐MS). The herein introduced concept of encryption/decryption represents a key advancement compared with current strategies that typically use uncontrolled degradation to erase and tandem mass spectrometry (MS/MS) to analyze, decipher, and read‐out chemically encrypted information. Additionally, the synthesized macromolecules are coated onto a high‐value polymer material, which demonstrates their potential application as coded product tags for anti‐counterfeiting purposes., Macromolecular pin codes are obtained through the combination of the dynamic Alder‐ene reaction of 1,2,4‐triazoline‐3,5‐dione (TAD) molecules with indole substrates and the Passerini three‐component reaction for the synthesis of tailor‐made, sequence‐defined macromolecules. The thermoreversible nature of the TAD‐indole reaction enables the encryption and decryption of the code and the read‐out is performed using electrospray ionization‐MS and liquid chromatography‐MS.

Multivalent glycomaterials show high affinity toward lectins but are often nonselective as they lack the precise 3-D presentation found in native glycans. Here, thiolactone chemistry is exploited to enable the synthesis of glycopolymers with both a primary binding (galactose) and a variable secondary binding unit in close proximity to each other on the linker. These polymers are used to target the Cholera toxin B subunit, CTxB, inspired by its native branched glycan target, GM-1. The secondary, nonbinding unit was shown to dramatically modulate affinity and selectivity toward the Cholera toxin. These increasingly complex glycopolymers, assembled using accessible chemistry, can help breach the synthetic/biological divide to obtain future glycomimetics.

Poly(ethylene glycol) (PEG) is one of the most used polymers in medical and biological applications. Its non-toxicity, non-immunogenicity, biocompatibility and solubility in a wide range of solvents offer various possibilities of utilization and explain the amount of studies dealing with this polymer. More recently, non-linear PEG-based monomers attracted much interest due to their thermal behavior. The present review aims at presenting many PEG-based thermoresponsive systems from structural and synthesis point of view and at highlighting all their fascinating properties from their behavior in solution, the fine-tuning of the transition temperature until the formation of smart materials.

Future advancement of coatings relies on new synthetic building blocks and methods that enable added functionality, while minimising the environmental impact and cost. This review highlights the use of thiol–ene chemistry for surface modification and coatings, a topic of increasing interest in academic and industrial context since the beginning of this century. This chemistry platform has the advantages of rapid and uniform cross-linking, delayed gelation, reduced shrinkage, and insensitivity to oxygen. Recently, it resulted in significant advances in UV-cured coatings, including pigmented acrylate coatings and waterborne polyurethane dispersions. Moreover, biobased coatings were developed via thiol–ene coupling of unsaturated moieties in vegetable oils with multifunctional thiols, resulting in tunable properties. The homogeneous thiol–ene network formation has also been employed in hybrid coatings, yielding synergistic effects of the inorganic components within the thiol–ene matrix. Moreover, the UV-triggered thiol–ene reaction is fast and efficient, which is useful for surface modification with spatial and temporal control. In general, this review will critically describe how thiol–ene chemistry became a powerful tool for the sustainable development of functional coating materials and surfaces with a variety of building blocks.

A wide set of norbornene-derived polymers with a diversity in backbone and side chain structures has been prepared based on norbornene building blocks that also include a thiolactone group. For this purpose, two thiolactone monomers with differently substituted norbornene moieties were synthesized and their reactivity compared using three different polymerization strategies. First, their potential for amine-thiol-ene polymerization was evaluated using different amines, solvents and initiator concentrations in order to screen their influence on the molecular weight and glass transition temperature. Free radical (co-)polymerization and ring-opening metathesis polymerization were also applied and the obtained polymers were submitted to post-polymerization modification. The results showed that only the monomer 5-norbornenemethyl thiolactone carbamate results in polymer formation under the tested conditions. The obtained compounds were characterized by SEC, TGA, DSC and NMR.

Polyampholytes with precisely alternating cationic and anionic functional groups were prepared using sustainable thiolactone building blocks in a simple one-pot procedure at room temperature and in water. Ring opening of the N-maleamic acidfunctionalized homocysteine thiolactone monomer enabled the introduction of different functional groups into the polymer chain, which contributed to both ionic and hydrogen bonding interactions. The resulting polyampholytes exhibited various isoelectric points while maintaining high solubility in water under different pH and ionic strengths, which expands their potential applications. Finally, it is shown that the upper critical solution temperature (UCST) of these alternating polyampholytes in water/ethanol (30/70% vol) solutions can be tuned as a function of the content of ionic and hydroxyl groups.

Despite the huge efforts made in the last half century to develop new controlled polymerization techniques, synthetic polymers are without exception composed of macromolecules with a molecular weight distribution. Several studies dealt with relationship between polymer molecular weight, structure or architecture and properties, but only recently, researchers are trying to develop tools for creating fully monodisperse macromolecules or even sequence-defined ones. Dispersity was shown to lead to a misinterpretation of the data as highlighted by recent studies. In the present paper, the synthesis of poly(ethylene imine)s derivatives (PEId) with well-defined structure, precisely controlled molecular weight and subsequent PEGylation is reported. The strategy can be further used in order to prepare long polymer chain with not only controlled molecular weight but also different monomer sequences.

Fundamental polymer science is undergoing a profound transformation. As a result of recent progress in macromolecular chemistry and physics, synthetic polymer chains are becoming much more than just the modest building blocks of traditional 'plastics'. Promising options for controlling the primary and secondary structures of synthetic polymers have been proposed and, therefore, similarly to biopolymers, synthetic macromolecules may now be exploited as discrete objects with carefully engineered structures and functions. Although it is not possible today to reach the high level of complexity found in biomaterials, these new chemical possibilities open interesting avenues for applications in microelectronics, photovoltaics, catalysis and biotechnology. Here, we describe in detail these recent advances in macromolecular science and emphasize the possible emergence of technologies based on single-chain devices.

An automated, iterative protocol for the synthesis of multifunctional, sequence-defined oligo-urethane-amides using thiolactone chemistry is reported. Here, sequenced functionalization of the backbone is easily introduced using commercially available primary amines. The chemistry is carried out on solid phase using different supports for better optimization of the synthetic protocol and in order to demonstrate the versatility of the approach. This technique is very effective for iterative synthesis and solid-phase chemistry and enables the exploration of full automation of this approach using a robotic peptide synthesizer. As a result, this automated protocol allows for the synthesis of a sequence-defined nonamer of high purity.

A novel class of β-cyclodextrins (β-CDs) bearing alkyl chains on the secondary face and poly(ethylene oxide) chains on the primary face was synthesized. Their interactions with two water-soluble derivatives of triphenylphosphane were investigated by 31P{1H} and 1H NMR. Their behaviour in rhodium-catalysed biphasic hydroformylation of 1-decene was evaluated and the best result was obtained with a β-CD bearing methyl groups on the secondary face and poly(ethylene oxide) chains on the primary face. This CD appeared to be more efficient than randomly methylated β-CD which is currently one of the best mass transfer additives for hydroformylation.

The purpose of this highlight is to define the emerging field of bioactive surfaces. In recent years, various types of synthetic materials capable of “communicating” with biological objects such as nucleic acids, proteins, polysaccharides, viruses, bacteria or living cells have been described in the literature. This novel area of research certainly goes beyond the traditional field of smart materials and includes different types of sophisticated interactions with biological entities, such as reversible adhesion, conformational control, biologically-triggered release and selective permeation. These novel materials may be 2D planar surfaces as well as colloidal objects or 3D scaffolds. Overall, they show great promise for numerous applications in biosciences and biotechnology. For instance, practical applications of bioactive surfaces in the fields of bioseparation, cell engineering, biochips and stem-cell differentiation are briefly discussed herein.

Previous works on the polymerization of 1,3-pentadiene initiated by aluminium trichloride in non polar solvent at room temperature in the presence of bulky electron donor (ED) as tri-p-tolylamine have highlighted a stabilization of the polymerizing actives centres by ED, which allowed a reduction of some side reactions and the formation of more precisely defined polypentadienes than ever by cationic polymerization in non polar medium. The aim of this research was to investigate the role of bulky EDs such as tri-p-tolylamine and similar compounds in polar medium in order to obtain if possible a complete control of the polymerization of isoprene and 1,3-pentadiene. The beneficial effect of tri-p-tolylamine was shown in the case of isoprene polymerization at room temperature, with an important reduction of the cross-linked fraction for long reaction times and strong reduction of termination reactions. At −30 °C in the presence of tri-p-tolylamine, polypentadienes more controlled than in non polar solvent could be obtained, with a nearly complete elimination of the cross-linked fraction, while keeping the microstructure approximately constant.

Summary Different alkyl sulfides (dimethylsulfide, ditertiobutylsulfide and diphenylsulfide) were investigated in the polymerization of 1,3-pentadiene initiated by aluminum trichloride in polar solvent in order to control the polymerization and to study the interaction between the electron donor and the active species. Thus, it was found that dimethylsulfide totally inhibited the polymerization, while thanks to its steric hindrance the polymerization occurred in the presence of ditertiobutylsulfide. However, for this electron donor, a transfer activity was evidenced at room temperature and at O'C, which contributes to prevent the control of the polymerization. Diphenylsulfide stabilizes a little the active centers with nearly no transfer reaction. However in the studied experimental conditions, the stabilization was not sufficient to obtain a living polymerization.

International audience

Copolymers containing water-soluble poly(ethylene glycol) (PEG) side chains and precisely controlled functional microstructures were synthesized by sequence-controlled copolymerization of donor and acceptor comonomers, that is, styrene derivatives and N-substituted maleimides. Two routes were compared for the preparation of these structures: a) the direct use of a PEG-styrene macromonomer as a donor comonomer, and b) the use of an alkyne-functionalized styrenic comonomer, which was PEGylated by copper-catalyzed alkyne-azide cycloaddition after polymerization. The latter method was found to be the most versatile and enabled the synthesis of high-precision copolymers. For example, PEGylated copolymers containing precisely positioned fluorescent (e.g. pyrene), switchable (e.g. azobenzene), and reactive functionalities (e.g. an activated ester) were prepared.

Thiolactone chemistry is a powerful tool for the design of complex multifunctional architectures. In this study, this versatile click-inspired synthetic strategy is conducted to prepare multifunctional dendrimer-like structures. For this purpose, a thiolactone bearing an isocyanate function, prepared in multigram scale, is utilized for multiple step functionalization starting from a 4-arm star-shaped poly(ethylene glycol). Amine-thiol-acrylate conjugation is carried out in order to form the aforementioned structures. The efficient aminolysis of the thiolactone ring and the reaction of the generated thiol with the double bond of an acrylate derivative are completed in a one-pot procedure. The choice of the amine and/or acrylate derivatives can allow the introduction of different functional groups for each new generation, potentially leading to multivalent dendrimer-like structures. (Figure presented.).

The present trend article analyzes recent progress in synthetic polymer chemistry. In particular, it emphasizes the importance of microstructural parameters such as stereoregularity and monomer sequences in polymer design allowing the preparation of highly complex ordered structures. This message is illustrated herein by examples from our laboratory and recent literature. Microstructures with different levels of complexity are presented and discussed. For instance, simple strategies such as random copolymerization of functional monomers are still relevant in current polymer chemistry. More complex microstructures such as gradient, periodic, or regulated sequence patterns are also examined.

International audience; Star polymers based on β-cyclodextrin were synthesized by a “click-chemistry” process and characterized by NMR, SEC and BLM. The resulting triazole functional groups create, at a specific pH range, electrostatic hindrance between pores inserted in lipid bilayers, preventing their aggregation, allowing formation of well-defined isolated unitary pores and mimicking biological natural channels.

International audience; Anionic polymerization initiated by cyclodextrins suffers from a poor solubility of those derivatives in standard polymerization solvents. The possibility to perform ethylene oxide polymerization initiated by monofunctional initiators (allyl alcohol, 2-methoxyethanol) by living ring opening polymerization in DMF, a good solvent for any CD derivative, was demonstrated by SEC, 1H and 13C NMR analyses. The study was extended to the use of native CD as initiator, leading to the synthesis of ill-defined structures, explained by the reactivity scale of the various hydroxyl functions. Two selectively modified CD derivatives are then used to synthesize a new family of star-shaped poly(ethylene oxide) polymers with CD core, having 14 or 21 arms. The polymerization was found to be living and DOSY experiments confirmed the well-defined structures for the synthesized star-polymers.

Well-defined cleavable or non-cleavable soluble polystyrene supports were prepared by atom transfer radical polymerization and utilized for the iterative synthesis of functional hexapeptides. This approach allowed rapid and efficient liquid phase synthesis of peptide–polymer conjugates.

Homopolymers of N-acryloyl glycinamide were prepared by reversible addition-fragmentation chain transfer polymerization in water. The formed macromolecules exhibit strong polymer-polymer interactions in aqueous milieu and therefore form thermoreversible physical hydrogels in pure water, physiological buffer or cell medium.

The control over comonomer sequences is barely studied in macromolecular science nowadays. This is an astonishing situation, taking into account that sequence-defined polymers such as nucleic acids and proteins are key components of the living world. In fact, fascinating biological machines such as enzymes, transport proteins, cytochromes or sensory receptors would certainly not exist if evolution had not favored chemical pathways for controlling chirality and sequences. Thus, it seems obvious that synthetic polymers with controlled monomer sequences have an enormous role to play in the materials science of the next centuries. The goal of this tutorial review is to shed light on this highly important but embryonic field of research. Both biological and synthetic mechanisms for controlling sequences in polymerization processes are critically discussed herein. This state-of-the-art overview may serve as a source of inspiration for the development of new generations of synthetic macromolecules.

Stimuli-responsive macromolecules (i.e., pH-, thermo-, photo-, chemo-, and bioresponsive polymers) have gained exponential importance in materials science, nanotechnology, and biotechnology during the last two decades. This chapter describes the usefulness of this class of polymer for preparing smart surfaces (e.g., modified planar surfaces, particles surfaces, and surfaces of three-dimensional scaffolds). Some efficient pathways for connecting these macromolecules to inorganic, polymer, or biological substrates are described. In addition, some emerging bioapplications of smart polymer surfaces (e.g., antifouling surfaces, cell engineering, protein chromatography, tissue engineering, biochips, and bioassays) are critically discussed.

Monodisperse sequence-defined oligomers have been synthesized in solution in the absence of protecting groups. These structures have been prepared stepwise using two consecutive chemoselective reactions: 1,3-dipolar cycloaddition of terminal alkynes and azides and amidification of carboxylic acids with primary amines. These oligomers were efficiently constructed on either a conventional solid support (commercial Wang resin) or tailor-made soluble polystyrene supports synthesized by atom-transfer radical polymerization. The latter approach was found to be very versatile. Indeed, well-defined soluble macromolecular supports allowed not only the synthesis and cleavage of defined oligomers (i.e., sacrificial support) but also the preparation of noncleavable block Copolymers containing sequence-defined segments.

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.

Natural β-cyclodextrin (cyclomaltoheptaose) was treated with sodium hydride and allyl bromide to form the per- O -allyl-β-cyclodextrin. 9-BBN, sodium hydroxide and hydrogen peroxide were then added to form, after adequate treatments, the desired per- O -(3-hydroxy)propyl-β-cyclodextrin in yields close to 65%. This modified cyclodextrin, which bears only primary hydroxyl groups, can be used as a macro-initiator of the anionic polymerisation of ethylene oxide to form star-shaped polymers. The presence of only primary hydroxyl groups allows us to expect identical initiation kinetics for all the hydroxyl groups of the modified glucopyranosyl units.

The synthesis of per-2,3-di-O-heptyl-β and γ-cyclodextrins, a new kind of amphiphilic cyclodextrins bearing long and stable hydrophobic chains is described. The products are obtained in a three-step synthesis from natural cyclodextrins in good yield. tert-Butyldimethylsilyl protection of the primary hydroxyl group was found to be stable under the basic conditions required for the nucleophilic substitution of the bromine derivatives. The structure of the new amphiphilic molecules was proved by NMR spectroscopy and mass spectrometry (ESI-MS or MALDI-TOF-MS).

The control over comonomer sequences is barely studied in macromolecular science nowadays. This is an astonishing situation, taking into account that sequence-defined polymers such as nucleic acids and proteins are key components of the living world. In fact, fascinating biological machines such as enzymes, transport proteins, cytochromes or sensory receptors would certainly not exist if evolution had not favored chemical pathways for controlling chirality and sequences. Thus, it seems obvious that synthetic polymers with controlled monomer sequences have an enormous role to play in the materials science of the next centuries. The goal of this tutorial review is to shed light on this highly important but embryonic field of research. Both biological and synthetic mechanisms for controlling sequences in polymerization processes are critically discussed herein. This state-of-the-art overview may serve as a source of inspiration for the development of new generations of synthetic macromolecules.