An Update on Isocyanide-Based Multicomponent Reactions in Polymer Science
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Developments and progress in polymer science are often inspired by organic chemistry. In recent years, multicomponent reactions—especially the Passerini and Ugi reactions—have become very important tools for macromolecular design, mainly due to their modular character. In this review, the versatility of the Passerini and Ugi reactions in polymer science is highlighted by discussing recent examples of their use for monomer synthesis, as polymerization techniques, and for postpolymerization modification, as well as their suitability for architecture control, sequence control, and sequence definition.
KeywordsPasserini Ugi Multicomponent reaction Polymer chemistry Macromolecule Polymerization
Driven by the quest towards new functional materials, multicomponent reactions were introduced into polymer science in 2011 by Meier and coworkers . In addition to their advantages of high efficiency and high atom economy, they enable straightforward access to products with broad structural diversity by varying the components of the respective reactions. Thus, due to the possibility to build new libraries of monomers and polymers with various functionalities, multicomponent reactions have recently emerged as a new tool in polymer science. Their versatility and modular character make them a powerful tool for macromolecular design. Among the few reviews dedicated to this topic, Meier and coworkers reviewed the use of the Passerini and Ugi reactions in polymer science in 2015 [11, 12, 13, 14]. The review presented herein constitutes an update, collection, and discussion on recent progress on this topic, against the context of previously published works. Use of the Passerini and Ugi reactions for monomer synthesis, for polymerization, and for postpolymerization modification, as well as their suitability for architecture control, sequence control, and sequence definition are described.
2 Monomer Synthesis
Roth, Lowe, and coworkers used the previously described thiol-reactive Passerini-derived monomers in RAFT dispersion polymerization to prepare reactive nanoparticles . More precisely, the thiol-reactive Passerini-derived monomers were introduced into the nanoparticle core by polymerization-induced self-assembly during RAFT polymerization. Indeed, copolymerization of 2-(dimethylamino)ethyl methacrylate with 5 % of Passerini-derived comonomer (three different ones were investigated) yielded macro chain-transfer agents (macro-CTAs) with degree of polymerization of around 35 and dispersity lower than 1.16. Subsequently, the macro-CTAs were used for ethanolic RAFT dispersion polymerization of 3-phenylpropyl methacrylate according to an already reported method by Lowe et al. . The polymerization produced several common morphologies, depending on the degree of polymerization. Lower degree of polymerization (around 48) yielded a purely spherical nanoparticle phase, higher degree of polymerization (around 95) yielded worm-shaped nanoparticles, while in between these two regions (at around 87), a mixture of both phases was obtained. The most inhomogeneous species were obtained at the highest degree of polymerization of around 131, yielding another mixed phase with worms and vesicles. All three applied Passerini-derived comonomers gave similar results. Subsequently, the surface of the obtained nanoparticles was modified by reacting the Passerini-derived pentafluorophenyl moiety with functional thiols such as 2-mercaptoethanol, 1-thio-β-d-glucose tetraacetate, captopril, thiophenol, and cysteamine hydrochloride. In most cases, except for cysteamine hydrochloride, which resulted in amide formation, quantitative formation of the desired thioethers was observed. The morphology of the spherical nanoparticles remained the same, but the worm-shaped nanoparticles changed into a mixed phase consisting of spheres and worms. This possibility of postpolymerization modification of polymeric nanoparticles enables synthesis of a library of novel functional nanoobjects.
3 Passerini Polymerization
Meier and coworkers polymerized carboxylic diacids (AA-type monomers) and dialdehydes (BB-type monomers), obtained respectively by self-metathesis of 10-undecenal and 10-undecenoic acid, with various isocyanides to yield α-amide substituted polyesters with molar mass up to 56,000 g/mol . Li and colleagues reported on Passerini polymerization of a carboxylic diacid and a diisocyanide (adipic acid and 1,6-diisocyanohexane) with different aldehydes on the one hand, and of a dialdehyde and a diisocyanide (adipaldehyde and 1,6-diisocyanohexane) with various carboxylic acids on the other hand [33, 34]. Poly(ester amide)s with molar mass up to 15,000 g/mol and polyamides with ester side chains with molar mass up to 16,600 g/mol were produced, respectively. The two groups also contributed to the development of Passerini polymerization employing AB-type monomers containing an aldehyde and a carboxylic acid moiety. Polymerization of 4-oxobutyric acid with different isocyanides resulted in amide substituted polyesters with moderate molar mass up to 8800 g/mol. These polymers proved to be degradable under acidic and neutral conditions, selectively forming a γ-butyrolactone derivative degradation product . Another AB-type monomer, synthesized in one step by thiol–ene addition reaction of 10-undecenal with mercaptopropionic acid, was polymerized with five different isocyanides. Amide substituted polyesters with molar mass up to 34,600 g/mol were obtained in high yields .
4 Ugi Polymerization
A similar polymerization approach has been reported using the Ugi reaction. In recent years, diversely substituted polyamides have been produced by this polycondensation process. Using this versatile methodology, the possibility to combine different mono- and bifunctional components of different nature enables tuning of the macromolecular structure of the obtained polymers.
5 Architecture Control
Synthesis of well-defined polymer architectures is a topic of great interest. Multicomponent reactions have been found to be a powerful tool for synthesis of such architectures, due to their modular nature, efficiency, and relatively simple reaction conditions.
In 2012, Rudick and coworkers described, for the first time, convergent synthesis of dendrimers using P-3CR . They synthesized second-generation dendrons with an alcohol end group at the center, which was used as a platform for synthesis of the three Passerini precursors (aldehyde, carboxylic acid, and isocyanide). The three resulting dendrons were then coupled into one dendrimer via P-3CR. However, this approach suffered from long reaction time and from the lack of reactivity of the dendrons. To solve these issues, the authors further investigated this reaction by introducing an unbranched linker to increase the distance between the reactive groups and the branching point, thus decreasing the steric interactions between the reagents . As expected, use of dendrons with poly(alkyl ether) spacers resulted in very short reaction time in the P-3CR. However, the authors demonstrated that the reason for the observed increased reactivity does not lie in the decrease of the steric hindrance but in an unexpected electronic effect. Indeed, the increase of the aldehyde electrophilicity through the presence of strong electron-withdrawing substituents was revealed to be the key factor in the accelerating effect. Under these conditions, the reaction time could be reduced from 65 or 72 h for unactivated components to 24 h when employing the activated aldehyde (for the second-generation dendrons). Moreover, the authors showed that the reaction time of the P-3CR increased with increasing generation.
Synthesis of copolymers with defined architecture is also an important field in macromolecular engineering. For this purpose, both the P-3CR and U-4CR have already been investigated. This section presents an update on use of the P-3CR to control the molar mass and architecture of the polymers; all the U-4CR studies have already been discussed previously . Li and coworkers produced graft copolymers by preparing a polyamide backbone with pending hydroxyl groups or atom-transfer radical polymerization (ATRP) initiators by P-3CR . Subsequent ring-opening polymerization of ε-caprolactone or ATRP of methyl methacrylate and N-isopropylacrylamide led to copolymers. The authors also reported on functionalization of poly(ethylene glycol) (PEG) with an ATRP initiator and an alkynyl group by P-3CR as precursors for miktoarm terpolymers .
6 Sequence-Defined Macromolecules
The properties of polymeric materials are directly linked to their molecular structure. Thus, high degree of control over the molecular composition of a polymer can enable adjustment of its properties and functions. To date, synthesis of artificial sequence-defined polymers is considered a major challenge in polymer chemistry. Sequence-defined macromolecules are monodisperse macromolecules which incorporate a variety of different monomers located in exactly defined positions within the polymer chain, whereas sequence control describes a polymer structure with a fixed monomer pattern but displaying dispersity [52, 53, 54]. Sequence-defined macromolecules could exhibit a wide array of properties, i.e., self-assembly, enzyme-mimetic catalytic activity, molecular recognition, or self-replication, offering numerous possible applications, for instance in data storage, cell signaling, biocatalysis, and ultimately living matter [55, 56, 57]. Multicomponent reactions (MCRs) can contribute to a great extent to preparation of sequence-controlled and sequence-defined macromolecules.
7 Postpolymerization Modifications
The term “postpolymerization modification” describes all chemical transformations that are performed on the polymer. Grafting-from approaches and modifications of side chains, end groups, or the polymer backbone are common reactions used to introduce new functionalities or tune the final material properties. Multicomponent reactions proved to be suitable postpolymerization modification tools, providing high coupling efficiencies while simultaneously introducing additional functionalities.
Modification of polymers bearing pending carboxylic acid groups by U-4CR was also explored for synthesis of glycopolymers with well-defined sugar units in the side chains by Chen and coworkers (Scheme 23b) . For this purpose, a poly(methacrylic acid) (PMMA) polymer was prepared via RAFT polymerization. Subsequently, the carboxylic groups of the PMMA were reacted in a U-4CR employing acetone, glucosamine or mannosamine hydrochloride (introducing a first sugar moiety), and propargyl isocyanoacetamide (introducing an alkynyl group). Then, the terminal alkyne groups reacted with azides bearing sugar moieties in a copper-catalyzed azide–alkyne cycloaddition reaction. The final homoglycopolymers (with two similar sugar units) and heteroglycopolymers (with two different sugar units) were further studied with respect to their aggregation behavior in aqueous medium (glycoassembly), their interactions with proteins, and bacterial adhesion.
Passerini and Ugi reactions are ideal versatile tools for polymer science. Benefiting from their modular character, easy reaction setup, and high tolerance towards functional groups, they have been implemented for synthesis of functional monomers and as polymerization and postmodification techniques. Polymers with polyester and/or polyamide backbones can be produced effectively. Functional polymers, sequence-defined polymers, and polymers with well-defined architecture have also been prepared using this approach. As described herein, this methodology has already attracted attention in the biomedical field, but can also be investigated for information storage. The possibility to combine multicomponent reactions with other polymerization techniques or orthogonal reactions opens the door to synthesis of a multitude of novel complex functional materials.
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