Applications of discrete synthetic macromolecules in life and materials science : recent and future trends

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

Stereocontrolled, multi-functional sequence-defined oligomers through automated synthesis

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 occursviaring-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

Reading Information Stored in Synthetic Macromolecules

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

Sequence-defined oligoampholytes using hydrolytically stable vinyl sulfonamides : design and UCST behaviour

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 beta-thioester that was shown to be susceptible to transesterification and hydrolysis, even under ambient conditions. While increasing the spacer length between the beta-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

Uniform soluble support for the large-scale synthesis of sequence-defined macromolecules

Herein, a monodisperse soluble support is explored and used as an effective tool for the large-scale, liquid-phase synthesis of sequence-defined macromolecules. This support, based on a benzyl derivative with three long hydrophobic alkyl chains, combines the advantages of solid-phase and soluble support- based synthesis by allowing a straightforward workup after each coupling step and a direct characterisation of the intermediates, without prior cleavage from the support. While the soluble support is used for the multi-gram synthesis of thiolactone-based sequence-defined macromolecules, it can be applied for numerous other synthetic strategies too. Additionally, as it is uniform, it leads to a single peak in mass spectrometry and thus not to a molecular weight distribution as typically observed for standard polymeric soluble supports, thus facilitating the characterisation. To demonstrate the potential for the synthesis of sequence-defined macromolecules on a scale that is sufficient for their introduction in bulk material synthesis, a hexamer is prepared on a 14 g scale. Furthermore, two different cleavable linkers have been attached to the uniform soluble support, hence emphasizing the versatility of this strategy

Sequence-Encoded Macromolecules with Increased Data Storage Capacity through a Thiol-Epoxy Reaction

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

Using nickel to fold discrete synthetic macromolecules into single-chain nanoparticles

Macromolecules found in Nature display a precise control over the primary as well as higher ordered architectures. To mimic the folding found in Nature, we herein demonstrate the design and characterization of single-chain nanoparticles that are formed by the folding of sequence-defined macromolecules with metal ions. The study showcases the influence of the loop size of such precision macromolecules on their relative hydrodynamic radius. The sequence-defined structures are fabricated using thiolactone chemistry, where two picolyl moieties are installed forming a valuable ligand system for subsequent metal complexation. Next, metal ions such as Ni(ii) and Cu(ii) ions are introduced to fold the unimers into sequence-defined single-chain nanoparticles (SD-SCNPs). After proving the successful complexation using a trimer, a systematic study is conducted altering the distance between the respective ligands by incorporating variable numbers of non-functionalized spacer units. Finally, the loop size formation of the SD-SCNPs is evidenced by DOSY measurements. The result indicates that the positioning of the ligands plays a crucial role on the compaction process and, more specifically, on the final size of the SD-SCNP. In addition, molecular dynamics (MD) simulations show the effects of the sequence and Ni(ii) complexation on the structure and compaction of the SD-SCNPs, and highlight the differences of the nanoparticles' shape when varying the number of spacer units. Finally, the system is further expanded to a dodecamer and even a heptadecamer with drastically decreased hydrodynamic radii after compaction

Using nickel to fold discrete synthetic macromolecules into single-chain nanoparticles

Macromolecules found in Nature display a precise control over the primary as well as higher ordered architectures. To mimic the folding found in Nature, we herein demonstrate the design and characterization of single-chain nanoparticles that are formed by the folding of sequence-defined macromolecules with metal ions. The study showcases the influence of the loop size of such precision macromolecules on their relative hydrodynamic radius. The sequence-defined structures are fabricated using thiolactone chemistry, where two picolyl moieties are installed forming a valuable ligand system for subsequent metal complexation. Next, metal ions such as Ni(ii) and Cu(ii) ions are introduced to fold the unimers into sequence-defined single-chain nanoparticles (SD-SCNPs). After proving the successful complexation using a trimer, a systematic study is conducted altering the distance between the respective ligands by incorporating variable numbers of non-functionalized spacer units. Finally, the loop size formation of the SD-SCNPs is evidenced by DOSY measurements. The result indicates that the positioning of the ligands plays a crucial role on the compaction process and, more specifically, on the final size of the SD-SCNP. In addition, molecular dynamics (MD) simulations show the effects of the sequence and Ni(ii) complexation on the structure and compaction of the SD-SCNPs, and highlight the differences of the nanoparticles' shape when varying the number of spacer units. Finally, the system is further expanded to a dodecamer and even a heptadecamer with drastically decreased hydrodynamic radii after compaction