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An Update on Isocyanide-Based Multicomponent Reactions in Polymer Science

  • Audrey Llevot
  • Andreas C. Boukis
  • Stefan Oelmann
  • Katharina Wetzel
  • Michael A. R. Meier
Review
Part of the following topical collections:
  1. Polymer Synthesis Based on Triple-bond Building Blocks

Abstract

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.

Keywords

Passerini Ugi Multicomponent reaction Polymer chemistry Macromolecule Polymerization 

1 Introduction

Multicomponent reactions (MCRs) are highly efficient reactions that combine three or more starting components to form a single product in a one-pot procedure under mild conditions [1, 2]. Since the pioneering work of Strecker in 1850, a multitude of MCRs have been described and can be divided into three classes: isocyanide-based reactions, non-isocyanide-based reactions, and metal-catalyzed reactions [3, 4]. Amongst the above-mentioned reactions, the Passerini three-component reaction (P-3CR) and Ugi four-component reaction (U-4CR), which are both isocyanide-based reactions traditionally employed in combinatorial or medicinal chemistry, are among the most well established [5, 6, 7]. The P-3CR, discovered by Mario Passerini in 1921, involves reaction of a carboxylic acid, a ketone or aldehyde, and an isocyanide to form an α-acyloxycarboxamide (Scheme 1) [7]. The commonly accepted mechanism starts with activation of the oxo-compound by formation of a loose hydrogen adduct with the carboxylic acid. Then, the lone pair of the nucleophilic carbon of the isocyanide attacks the carbonyl group of the adduct, while simultaneously acting as an electrophile that reacts with the carboxylic acid moiety in a so-called α-addition. The resulting intermediate rearranges via intramolecular acyl transfer to generate the α-acyloxycarboxamide.
Scheme 1

Overall reaction and mechanism of the P-3CR involving a carboxylic acid, aldehyde, and isocyanide

The U-4CR, discovered by Ivar Karl Ugi in 1959, involves reaction of a carboxylic acid, a ketone or aldehyde, an isocyanide, and a primary amine as fourth component to generate an α-aminoacylamide with release of water (Scheme 2) [8]. The commonly accepted mechanism is initiated by formation of a Schiff base from the aldehyde and amine, which is subsequently protonated by the carboxylic acid to form the iminium ion. Then, the lone pair of the nucleophilic carbon of the isocyanide attacks the electrophilic center of the iminium, while concertedly acting as electrophile and reacting with the carboxylic acid (α-addition). Subsequent intramolecular Mumm rearrangement finally leads to the α-aminoacylamide [9]. The introduction of a fourth component into the U-4CR increases the structural diversity and thermal stability (due to the creation of two amide bonds instead of one ester and one amide bond) of the final products in comparison with the P-3CR.
Scheme 2

Overall reaction and mechanism of the U-4CR involving a carboxylic acid, aldehyde, isocyanide, and amine

Driven by the quest towards new functional materials, multicomponent reactions were introduced into polymer science in 2011 by Meier and coworkers [10]. 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

MCRs were described for the first time in the field of polymer science for monomer synthesis [15]. Indeed, due to their modular nature and simple reaction procedures, MCRs proved to be valuable tools for synthesis of a broad variety of monomers with different functional groups. In this context, novel functionalized hemilactides, α,ω-dienes, and vinyl monomers were synthesized by P-3CR or U-4CR and polymerized by ring-opening polymerization (ROP), acyclic diene metathesis (ADMET), and radical polymerization, respectively [10, 15, 16, 17, 18, 19]. Thus, a library of (meth)acrylate monomers has been synthesized by reaction of (meth)acrylic acid with different isocyanides and aldehydes or ketones. Similarly, styrenic monomers were produced by reaction of 3-vinylbenzaldehyde with various isocyanides and carboxylic acids [18, 19]. This strategy was, for instance, investigated by Roth and colleagues, who applied the P-3CR for synthesis of a series of 15 different (meth)acrylic and styrenic monomers in high to quantitative isolated yields (Scheme 3) [19].
Scheme 3

Synthesis of (meth)acrylate monomers by P-3CR of (meth)acrylic acid with different isocyanides and aldehydes or ketones (a) and of styrenic monomers by P-3CR of 3-vinylbenzaldehyde with tert-butyl isocyanide and carboxylic acids (b)

The vinyl products proved to be suitable monomers for production of homo- and copolymers by reversible addition–fragmentation chain-transfer (RAFT) polymerization [19]. Controlled polymerization was observed, conversions up to 95 % were reached, and polymers with dispersity between 1.05 and 1.29 were obtained. The comonomer composition of the copolymers was similar to the comonomer feed ratio. Additionally, the (co)polymers showed very good solubility in most common organic solvents, including ethanol and methanol, unlike many other polystyrene and poly(meth)acrylate derivatives. Advantageously, use of differently functionalized components led to monomers bearing functional groups suitable for postpolymerization modification, such as a furan moiety, a double bond, a silyl-protected triple bond, as well as a perfluorinated aromatic side group. As an example of postpolymerization modification, homopolymers carrying acetate-protected hydroxyl groups were deprotected and afterwards partially modified with methyl red dye (Scheme 4a). The same group also reported synthesis of a series of thiol-reactive (meth)acrylate monomers by P-3CR, and their subsequent RAFT (co)polymerization and quantitative postpolymerization modification with various thiols (Scheme 4b) [20]. For monomer synthesis, methacrylic acid, pentafluorobenzaldehyde, and various isocyanides reacted in quantitative yields. Homopolymers as well as copolymers with dispersity lower than 1.23 were synthesized [20]. Postpolymerization modification of the pentafluorophenyl-functionalized polymers was performed in presence of base [triethylamine or 1,8-diazabicyclo(5,4,0)undec-7-en (DBU)] to achieve a selective para-fluoro substitution reaction with thiols, such as various alkanethiols, a thiolated glucose derivative, mercaptopropionic acid, l-cysteine, and the drug captopril. In these reactions, no side reaction was observed and quantitative substitution was achieved in 3 min. These postpolymerization modifications enable tuning of the aqueous thermal response of the polymers. Indeed, the cloud point of an unmodified polymer of 68.9 °C was shifted to 70.1 °C after thiol-para-fluoro substitution with thiophenol and to 64.1 °C after reaction with a sugar derivative. Furthermore, a “doubly reactive” copolymer was synthesized by copolymerization of a thiol-reactive pentafluorophenyl acrylate monomer (previously synthesized in a P-3CR) and an active ester comonomer, which can undergo acyl-substitution reactions. The latter functional group was first reacted with isopropylamine to N-isopropylacrylamide. Subsequently, the thio-reactive groups were reacted with thiophenol. This modification demonstrates the selective reactivity of the two different side groups and, thus, the orthogonality of the modification reactions.
Scheme 4

Postpolymerization modifications of polymers prepared from monomers synthesized by P-3CR: a acetate-deprotection of hydroxyl groups and esterification with methyl red dye, and b thiol-para-fluoro substitution of pentafluorophenyl-functionalized polymers

Roth, Lowe, and coworkers used the previously described thiol-reactive Passerini-derived monomers in RAFT dispersion polymerization to prepare reactive nanoparticles [21]. 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. [22]. 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.

In 2016, Meier and coworkers reported on synthesis of an aldehyde from renewable resources and its further derivatization into an acrylate monomer by P-3CR (Scheme 5). The resulting product was polymerized by free radical polymerization. The aldehyde was prepared from limonene, a natural terpene, employing sustainable procedures, i.e., regioselective catalytic acetoxylation and subsequent catalytic isomerization. First, the acetoxylated limonene derivative was synthesized using a palladium-catalyzed C–H activation process in presence of para-benzoquinone (BQ) as reoxidation agent in acetic acid with the aim of selectively functionalizing the exocyclic double bond [23]. The (E)-allylic acetate of limonene was obtained in yield of 52 % (the functionalization of the endocyclic double bond could not be avoided completely, thus two byproducts were obtained in enantiomeric mixtures) [24]. Subsequently, the product was quantitatively saponified to the corresponding allylic alcohol by treating with triazabicyclodecene (TBD) as catalyst in excess of methanol. Next, isomerization into the corresponding aldehyde was performed using hydrogen-preactivated palladium hydroxide on carbon as catalyst [25]. The aldehyde compound was then reacted with acrylic acid and various isocyanides in a P-3CR to obtain several acrylate monomers. Five different isocyanides with different apolar aliphatic and aromatic moieties were used, yielding products in yield of up to 78 %. In a free radical polymerization, polyacrylates with molar mass up to 30,000 g/mol were produced. The glass-transition temperature was easily tuned (from 86 to 143 °C) by varying the isocyanide component, offering access to polymers with tailorable properties.
Scheme 5

Sustainable synthesis of an aldehyde from limonene (a), subsequent synthesis of various acrylate monomers by P-3CR with acrylic acid and different isocyanides, and further polymerization (b)

The U-4CR was also used to synthesize vinyl monomers by Meier and coworkers, enabling synthesis of differently functionalized acrylamide monomers bearing three different chemical moieties [26]. Due to the modular character of the U-4CR, the properties of the monomers and thus of the respective polymers could be adjusted. The U-4CR was performed with acrylic acid and various aldehydes (or ketones), amines, and isocyanides to study the reactivity of different starting materials (Scheme 6). All the reactions were carried out at room temperature for 24 h. First, the amine component was varied. Aliphatic, aromatic, and functional group containing amines were reacted with iso-butyraldehyde and tert-butyl isocyanide. Most of the products were obtained in yield between 74 and 91 %, excepted for the aniline- and ethanolamine-derived products, which were obtained in moderate yield of 53 and 39 %, respectively. Aldehyde components with blocked α-position are preferred for the U-4CR to avoid undesired aldol reaction, as observed for heptaldehyde. The highest yields were achieved with benzaldehyde and iso-butyraldehyde. The reaction proved to be highly tolerant towards all types of isocyanide components, as aliphatic, aromatic, and functionalized isocyanides were incorporated into the product in good yield between 73 and 89 %. In this study, 14 different monomers were synthesized and polymerized by free radical polymerization [18]. In most cases, polymers with high molar mass (around 50,000 g/mol with dispersity around 2) were obtained in yield of around 80 %. The polymer synthesized from the formaldehyde-derived monomer achieved molar mass of 270,000 g/mol with dispersity of 3.05. The monomers bearing aromatic moieties such as benzylamine, aniline, and benzaldehyde did not polymerize. This can be explained based on either steric reasons, because of bulky and stiff side chains, or electronic effects. All polymers showed glass-transition temperature from 41 to 68 °C, depending on the nature of the side chains. Since polyacrylamides are suitable polymers for biomedical applications and the Ugi-derived monomers exhibit similar structures, their biological compatibility was tested [27, 28, 29, 30]. The modified Japanese Industrial Standard Z 2801:2000 protocol was applied to evaluate the biocompatibility of the polymers [31, 32]. All tested acrylamides indicated good tolerance towards several bacterial strains (Gram-negative Escherichia coli and Pseudomonas fluorescens and Gram-positive Bacillus subtilis), but the results only gave an indication regarding biocompatibility, and further evaluation would be necessary before biomedical application [26].
Scheme 6

U-4CR of acrylic acid with various amines, aldehydes, and isocyanides, yielding a library of acrylamide monomers

3 Passerini Polymerization

The Passerini-3CR was investigated as a direct polymerization method for the first time by Meier and coworkers [10]. This addition polymerization, which occurs via a classic step-growth polymerization mechanism, involves use of bifunctional components (AA + BB-type monomers or AB-type monomers). By varying the combination of the components, polymers with different structures, i.e., amide and ester moieties in the main and/or side chains, can be produced (Scheme 7).
Scheme 7

Synthesis of polymers with different structures via P-3CR using two bifunctional (AA-type and BB-type) and one monofunctional monomer:  carboxylic diacid + dialdehyde (a) [10], carboxylic diacid + diisocyanide (b) [33], and dialdehyde + diisocyanide (c) [34], and using an AB-type monomer and a monofunctional isocyanide (d) [35] and (e) [36]

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 [10]. 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 [35]. 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 [36].

Recently, Li and coworkers described synthesis of several functional poly(caprolactone)s by Passerini polymerization of 6-oxohexanoic acid with five different isocyanides (Scheme 8) [37]. The obtained functional poly(caprolactone)s bear tunable amide-linked side groups at ε-position. The AB-monomer was synthesized in a one-step procedure by oxidation of 2-hydroxycyclohexanone dimer with sodium periodate. Subsequent polymerization with various isocyanides (tert-butyl isocyanide, 2,6-dimethylphenyl isocyanide, 2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}ethyl isocyanide, 5-isocyanopent-1-ene, and 5-isocyanopent-1-yne) led to polymers with molar mass up to 30,000 g/mol and narrow dispersity of around 1.5, in good to excellent yield. Furthermore, the copolymerization using a mixture of two isocyanides (tert-butyl isocyanide and, 2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}ethyl isocyanide) in different molar ratios was also successful. Moreover, postpolymerization modification was demonstrated by performing a thiol–ene addition reaction with a thiol-glucose on the homopolymer bearing the pending alkenyl groups (with full conversion being observed). All reported polymers were amorphous, exhibiting variable glass-transition temperature from −31 to 116 °C, with decomposition onset temperature of around 300 °C. The degradation of the water-soluble polymers, bearing the oligo ethylene glycol side chains, was investigated under neutral, acidic, and basic conditions. Although the polymer was stable in water for up to 15 days, it degraded quickly under acidic and basic conditions (showing complete hydrolysis in 24 and 6 h, respectively). The cytotoxicity of two polymers was studied to test their compatibility for biomedical applications. The tested polymers did not exhibit toxicity to LO2 cells, indicating good biocompatibility.
Scheme 8

Synthesis of functional poly(caprolactone)s by Passerini polymerization of 6-oxohexanoic with five different isocyanides

Finally, reduction-sensitive amphiphilic copolymers finding applications in the biomedical field were synthesized by Passerini polymerization by Xie and coworkers [38]. The polymers were prepared by polymerization of 1,6-diisocyanohexane, 3,3′-dithiodipropionic acid, and 4-(methoxytriethyleneoxy)-carboxybenzaldehyde (Scheme 9). Using these components, hydrophilic ethylene glycol oligomers were introduced into the side chains and disulfide bonds into the hydrophobic polymeric backbone. The polymerization was performed at room temperature for 4 days, yielding a polymer with dispersity of 1.69 and molar mass of 1400 g/mol. The amphiphilic character of the polymer was exploited to prepare micelles by self-assembly. To demonstrate micelle formation, a Nile Red-probe-based fluorescence technique was applied. Formation of micelles with critical micellar concentration (CMC) of 0.0121 mg/mL was observed. Average diameter of 119.5 nm and polydispersity index (PDI) of 0.179 were measured by dynamic light scattering (DLS). Under reductive conditions, breakage of the disulfide bonds was confirmed by DLS by the presence of microaggregates in solution, due to disassembly of the micelles and rearrangement of the hydrophobic fragments. Finally, these new nanoparticles were tested as smart nanocarriers for drug delivery. For this purpose, curcumin, an effective anticancer agent that is normally limited by its low solubility in water and its fast degradation at physiological pH, was loaded into the micelles. The micelles showed good loading efficiency and fast intracellular curcumin release, if pretreated with glutathione as reducing agent. Additionally, in vitro 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays showed that the micelles were biocompatible. In conclusion, this study indicated the suitability of polymeric micelles prepared by Passerini polymerization for drug delivery in cancer therapy.
Scheme 9

Synthesis of amphiphilic polymers by P-3CR of 1,6-diisocyanohexane, 3,3′-dithiodipropionic acid, and 4-(methoxytriethyleneoxy)-carboxybenzaldehyde

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.

Meier and coworkers investigated the optimal polymerization conditions for the combination of two bifunctional and two monofunctional components. This approach enables six possible combinations to generate diversely substituted polyamides via the U-4CR (diisocyanide + dialdehyde, diamine + diisocyanide, dialdehyde + diamine, diamine + carboxylic diacid, dialdehyde + carboxylic diacid, and diisocyanide + carboxylic diacid) (Scheme 10) [39]. The design of the side groups, as well as the repeating units, could be tuned by variation of the starting components. The reaction conditions were optimized to obtain polymers with high molar mass. All reactions were performed at room temperature for at least 36 h without catalyst. Although U-4CRs are usually carried out in methanol, use of different mixtures of tetrahydrofuran (THF)/methanol was required to prevent precipitation of the polymers during reaction. The concentration also played an important role in this process. Indeed, high dilution led to ring formation, whereas high concentration favored polymer formation, as expected for step-growth polymerization. However, too high concentration resulted in high viscosity of the reaction mixture, decreasing the molar mass of the polymer. Considering all these parameters, Meier and coworkers investigated the best THF/methanol mixture and the optimal concentration for each of the mentioned combinations. After optimization, polymers with molar mass above 10,000 g/mol were obtained after precipitation for all six combinations. Depending on their structure, the polymers showed glass-transition temperature from 1 to 65 °C. Furthermore, the mild conditions and tolerance of the U-4CR towards many functional groups enabled the reaction with an alkyne-containing component. The resulting polyamide, bearing terminal alkynes in its side chains, offered the opportunity for postpolymerization modification. The successful coupling via azide–alkyne cycloaddition demonstrated the possibility of efficient grafting-onto reactions.
Scheme 10

Six possible combinations to generate diversely substituted polyamides via the U-4CR using two bifunctional and two monofunctional monomers: diisocyanide + dialdehyde (a), dialdehyde + diamine (b), dialdehyde + carboxylic diacid (c), diamine + diisocyanide (d), diamine + carboxylic diacid (e), and diisocyanide + carboxylic diacid (f)

In addition, Meier and coworkers reported incorporation of carbon dioxide into polymers via Ugi five-component condensation (U-5CC) [40]. This reaction is a modified version of the U-4CR, with the use of an alcohol (mostly methanol), a primary amine, an oxo-component (ketone or aldehyde), an isocyanide, and carbon dioxide. The U-5CC was employed as a direct polymerization method with two bifunctional components (1,12-diaminododecane and 1,6-diisocyanohexane), an aldehyde, methanol, and carbon dioxide to produce polyamides containing methyl carbamate side chains (Scheme 11). These could then be further converted into the corresponding polyhydantoins using aqueous potassium hydroxide solution. Decrease of the glass-transition temperature from 37 to 0 °C was observed upon formation of the polyhydantoin. The molar mass of the synthesized polymers reached 20,000 g/mol. Thus, the U-5CC is a novel route to synthesize polyurethanes, polycarbonates, and polyhydantoins in a straightforward as well as catalyst-free way, avoiding handling of toxic isocyanate or phosgene, commonly used in such synthesis.
Scheme 11

Polymerization of 1,12-diaminododecane, carbon dioxide, 1,6-diisocyanohexane, and methanol via Ugi-5CC and subsequent treatment with potassium hydroxide yielding the corresponding polyhydantoin

Luxenhofer and coworkers also investigated the six above-mentioned possible combinations of components of the U-4CR for synthesis of polymers bearing aromatic moieties in the backbone and side chain (Scheme 12) [41]. After screening the reaction conditions, most of the combinations led to formation of oligomers. However, polymers with higher molar mass (between 28,000 and 44,000 g/mol) could be prepared for the diisocyanide + dialdehyde combination by reacting benzoic acid, hexadecan-1-amine, terephthalaldehyde, and 1,6-diisocyanohexane for 5 days at room temperature, using N-methyl-2-pyrrolidone (NMP) as solvent under argon atmosphere (Scheme 12). For the described combination, the polymer backbone is formed before the Mumm rearrangement starts, whereas for all other combinations the polymer backbone is formed during the Mumm rearrangement, which might be an explanation for the better polymerization results.
Scheme 12

Polymerization of benzoic acid, hexadecan-1-amine, terephthalaldehyde, and 1,6-diisocyanohexane via U-4CR

Despite its bifunctionality, levulinic acid has to be modified chemically before its polymerization. The only example of its direct polymerization was reported by Becer and coworkers, who used it in the U-4CR for synthesis of polyamides (Scheme 13) [42]. Bearing carboxylic acid and ketone moieties in its structure, levulinic acid acts as an AB-type monomer in an U-4CR. Two equivalents of levulinic acid were reacted with one equivalent of diisocyanide and one equivalent of diamine in a microwave reactor at 100 °C in methanol for 30 min. 1,6-Diisocyanocyclohexane was chosen as the diisocyanide, and varying diamines were tested. Use of ethylenediamine led to polymers with molar mass of 8000 g/mol, and use of longer-chain diamines, such as hexamethylenediamine or 1,12-diaminododecane, yielded polymers with molar mass up to 12,000 g/mol. A secondary amine (spermine) could also be used as a building block in the modified U-4CR. The polymerization with a triamine [tris(2-aminoethyl)amine] resulted in a crosslinked spongy material, and use of an aromatic diamine (p-phenylenediamine) mainly yielded oligomers or macrocycles. Depending on the length of the amine employed, the levulinic acid derived polymers exhibited Tg from 52 to 120 °C.
Scheme 13

Polymerization of levulinic acid, 1,6-diisocyclohexane, and various diamines via U-4CR

Using a similar strategy, Tao, Wang, and coworker evaluated for the first time the use of natural amino acids in the U-4CR for synthesis of structurally diverse polypeptoids [43]. Amino acids, containing both carboxylic acid and amino groups in their structure, are prominent candidates for use as AB-type monomers for U-4CR (Scheme 14). The combination with additional aldehydes and isocyanides results in polypeptoid structures with polyamide and substitution on the amide nitrogen. Although polymerization of α-amino acids, such as glycine or alanine, was unsuccessful due to formation of a six-membered ring as intermediate, lysine, which contains two amino groups including an ε-amino group at greater “distance” to the α-carboxyl group, enabled the polymerization. After protection of the α-amino group with tert-butyloxycarbonyl (Boc) protecting group, the AB-type monomer reacted with benzaldehyde and tert-butyl isocyanide at room temperature for 96 h in methanol. Subsequently, the Boc protecting groups were cleaved to obtain the deprotected polypeptoids, reaching molar mass up to 11,000 g/mol. The obtained polymer displayed amphiphilic character and can therefore be self-assembled into nanoparticles in an aqueous environment for investigation as a carrier for drug delivery. In this context, the polymer proved to be biocompatible and to exhibit antibacterial properties. Using similar procedures, l-glutamic acid methyl ester and Nα-Boc-l-ornithine reacted with benzaldehyde and tert-butyl isocyanide to yield poly(γ-peptoid)s and poly(δ-peptoid)s. Additionally, this strategy provided the opportunity to introduce functional groups into polypeptoids, such as alkenes or fluorescent moieties, by variation of the aldehyde structure.
Scheme 14

Polymerization of amino acids with benzaldehyde and tert-butyl isocyanide via U-4CR

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.

For instance, dendrimers are an important class of highly defined macromolecules, benefiting from their monodispersity and high functionality. Their synthesis can be performed by two main approaches: the divergent and convergent pathway. Divergent synthesis of dendrimers consists in using a multifunctional core, in which each functional group reacts with one novel unit. The added groups display new functionalities available for further addition of a new unit. This sequence is repeated until the dendrimer reaches the desired size. Several studies have employed the P-3CR or the U-4CR for synthesis of dendrimers using a divergent approach [44, 45, 46]. These works have already been discussed elsewhere [13]. In convergent synthesis, different precursors (dendrons), often built from small molecules, react to form the core of the dendrimer. This section focuses on recent updates reporting use of multicomponent reactions for convergent synthesis of dendrimers (Scheme 15).
Scheme 15

Convergent synthesis of dendrimers using P-3CR

In 2012, Rudick and coworkers described, for the first time, convergent synthesis of dendrimers using P-3CR [47]. 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 [48]. 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 [13]. 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 [49]. 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 [50].

Recently, a new versatile approach to control the polymer molar mass and architecture in a straightforward fashion was investigated by the group of Meier [51]. Indeed, an irreversible and selective chain-transfer agent (ICTA) was introduced into the Passerini polymerization of an AB-type monomer (combination of aldehyde and carboxylic acid) and an excess of different isocyanides (Scheme 16). Thereby, the molar mass of the polymers could be predicted based on the ICTA-to-monomer ratio, analogously to the initiator-to-monomer ratio in a living controlled polymerization technique. Monocarboxylic acids were employed as ICTA to react irreversibly with the aldehyde of the AB-type monomer and the isocyanides, until the monomers were completely consumed. Thus, α-amide substituted polyesters with controlled molar mass and high chain end fidelity were prepared. Further reaction of such homopolymers (acting as macro-ICTA) in a second Passerini polymerization with the AB-type monomer and another isocyanide enabled synthesis of block copolymers. Additionally, star-shaped polymers were prepared by Passerini polymerization using a trifunctional core unit as ICTA. These star-shaped polymers could also serve as macro-ICTAs in a second Passerini polymerization for the design of star-shaped block copolymers. This versatile strategy can be exploited to design a wide variety of polymers with controlled architecture.
Scheme 16

Synthesis of polymers with controlled architecture: block copolymers (a), star-shaped polymers (b)

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.

In 2015, Hong et al. used the P-3CR in combination with the three-component amine–thiol–ene conjugation reaction in a one-pot procedure for synthesis of sequence-controlled polymers (Scheme 17) [58]. The P-3CR was conducted utilizing methacrylic acid, adipaldehyde, and 2-isocyanobutanoate, affording a symmetric AA-type monomer containing a reactive double bond at each end. Subsequently, a monofunctional amine and a bifunctional thiolactone (BB-type monomer) were added to the reaction system in one pot. Hence, the amine–thiol–ene conjugation reaction enabled step-growth polymerization. The polymer exhibited molar mass of 13,700 g/mol with dispersity of 3.1. To investigate the possibility of postpolymerization modifications, P-3CR was performed with the same components, but the amine–thiol–ene reaction was carried out with a diamine in combination with a monofunctional thiolactone equipped with a terminal double bond. After polymerization and precipitation, a polymer with molar mass of 49,800 g/mol and dispersity of 2.03 was obtained. The thereby introduced double bond could be further used for postpolymerization functionalization in a thiol–ene addition with benzyl mercaptan.
Scheme 17

Synthesis of novel polymers via tandem multicomponent reactions: P-3CR in combination with the three-component amine–thiol–ene conjugation reaction in a one-pot procedure and postpolymerization modification by thiol–ene reaction

Multicomponent reactions have also been exploited for synthesis of sequence-defined polymers, since introduction of different defined side chains into the polymer structure is straightforward using MCRs, especially using so-called iterative approaches in which one monomer unit is installed after another. This approach requires the implementation of either an activation step (Scheme 18a) or a protection group (Scheme 18b). For instance, a bifunctional monomer with functional groups A and B can be linked with a third component carrying functional group C. By variation of the third component (different Rx), sequence definition is achieved, while the degree of polymerization/molar mass is controlled by the total number of iterative reaction steps. In conclusion, the multicomponent reaction A + B + C uses the two functional groups A and B for chain growth, while C introduces sequence definition. However, if a multicomponent reaction with more than three components is used, more side chains can be installed within the same reaction step and more complex architectures accessed.
Scheme 18

Iterative multicomponent strategies for preparation of sequence-defined macromolecules. a Activation-based approach: the growing chain is equipped with an orthogonal functional group, which can react with a substrate carrying functional group B, and the sequence-defined side chain is installed in the multicomponent step involving functional group C. b Protection group-based approach: a bifunctional monomer (black ball) reacts with a starting unit/propagating chain. In order to propagate, functional group B needs to be deprotected. Sequence definition is achieved via installation of a defined side chain (Rx, introduced via an additional component)

In 2014, Meier and coworkers introduced an approach towards sequence-defined macromolecules based on iterative P-3CR and subsequent thiol–ene additions (Scheme 19) [59]. In this activation-based strategy, variation of the isocyanide components introduces a defined side chain to the sequence-defined macromolecule. The carboxylic acid (B) and aldehyde (A) components are used for chain growth. 10-Undecenal was chosen as the aldehyde component because it carries a terminal double bond (for orthogonal reactions) and is commercially available. Subsequently, the terminal double bond reacted in a thiol–ene addition with 3-mercaptopropionic acid. In the course of the thiol–ene reaction, the terminus of the chain is equipped with a carboxylic acid (B) (activation for the next Passerini step). After the next P-3CR with 10-undecenal and another isocyanide, the iteration of one cycle is completed. As starting molecule, stearic acid was chosen. A sequence-defined tetramer with 3.5 repeating units and four different side chains was obtained in overall yield of 26 % (120 mg) after seven steps and purification via column chromatography (after Passerini steps) and recrystallization (after thiol–ene additions). In an alternative approach, a soluble poly(ethylene glycol) equipped with a carboxylic acid functional group was used as starting molecule, which enabled simple precipitation of the crude reaction mixtures in cold diethyl ether for purification. A polymer with five sequence-defined repeat units was obtained in 34 % yield after nine reaction steps [59].
Scheme 19

Structure of sequence-defined macromolecules synthesized by iterative activation approach: P-3CR and subsequent thiol–ene additions

In another work, Meier and coworkers published a similar strategy using the U-4CR [60]. With the introduction of an amine as fourth component, the U-4CR led to installation of a second side chain within the same reaction step. Hence, in every repeat unit, dual side chain control was achieved and the Ugi products exhibited two amide bonds, which are chemically more stable compared with the ester–amide backbone formed in the previously described Passerini approach. The U-4CRs were conducted with stearic acid as starting point, tert-butyl isocyanide, 10-undecenal in combination with varying amine components. After each U-4CR, the terminal double bond of the 10-undecenal side chain was reacted with 3-mercaptopropionic acid in a thiol–ene addition to install another carboxylic acid moiety into the macromolecule. With this protocol in hand, a sequence-defined tetramer with 3.5 repeat units and four sequence-defined side chains (derived from the corresponding amine component) was obtained in overall yield of 15 %. In a second approach, both the amine and the isocyanide components were varied in each U-4CR. In this fashion, a sequence-defined pentamer with 4.5 repeat units equipped with ten individually selectable side chains was synthesized in nine steps in overall yield of 15 % (Scheme 20). The yields of the U-4CR are often lower than the yields of the P-3CR, which is also observed for small molecules and can therefore not be directly linked to the polymer approach [60].
Scheme 20

Structure of sequence-defined macromolecules synthesized by iterative activation approach: U-4CR and subsequent thiol–ene additions

The aforementioned coupling/deprotection approach (Scheme 18b) was explored by Meier and coworkers in 2016 [61]. In this investigation, a monoprotected AB-monomer (benzyl-protected carboxylic acid–isocyanide monomer) was synthesized in three steps starting from 11-aminoundecanoic acid in overall yield of 63 %. The AB-monomer was employed in P-3CR for chain elongations, whereas the aldehyde component introduced the sequence-defined side chains into the macromolecule (Scheme 21). The reaction products after each P-3CR were equipped with a terminal benzyl ester, which was subsequently deprotected by hydrogenolysis with hydrogen gas and a heterogeneous palladium catalyst to obtain a free carboxylic acid for further P-3CR. This strategy provides higher overall yields than the activation approaches. The products after the P-3CR were purified via column chromatography, while the products of the hydrogenolysis were simply isolated by filtering off the heterogeneous catalyst. A sequence-defined decamer with ten different side chains was synthesized in 19 steps in overall yield of 44 % (2.40 g). In the last sequence, an unsaturated aliphatic side chain was introduced, which allowed a subsequent self-metathesis reaction. After self-metathesis, a sequence-defined symmetric icosamer was obtained [61].
Scheme 21

Structure of sequence-defined macromolecules synthesized by iterative protection/deprotection approach: P-3CR and subsequent deprotection by hydrogenolysis

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.

Meier and coworkers used the P-3CR and U-4CR for preparation of α,ω-diene monomers employing a 2-(2,2-dimethoxyethyl)phenyl isocyanide, which can be converted into an indole substituted active amide, thus enabling postpolymerization modifications (Scheme 22). These monomers were polymerized by ADMET polymerization [16]. The resulting polymers obtained with molar mass of around 20,000 g/mol were hydrogenated and their side chains converted to the indole amide upon treatment in mild acidic conditions. The active indol amides were cleaved through elimination of indole after addition of different nucleophiles. Depending on the nature of the nucleophile, carboxylic acids (by hydrolysis in THF/water 10:1), esters (by alcoholysis in THF/MeOH 8:5), secondary and tertiary amides (by aminolysis in xylene via TBD catalysis), and thioesters (by reaction with thiols) were obtained as side groups. Moreover, polymers bearing the pending carboxylic acid groups were used in further multicomponent grafting reactions (P-3CR and U-4CR); For instance, a U-4CR employing undec-10-enyl amine, undec-10-enyl isocyanide, and undec-10-enyl aldehyde resulted in attachment of three double bonds to each repeating unit of the polymer chain (assuming full conversion). These postpolymerization-modified polymers could potentially be used for synthesis of dendronized polymers via either thiol–ene addition or olefin cross-metathesis.
Scheme 22

Synthesis of α,ω-diene monomers employing 2-(2,2-dimethoxyethyl)phenyl isocyanide by P-3CR, ADMET polymerization, and conversion into indole substituted active amides, with postpolymerization modifications

In another study, Meier, Hoogenboom, et al. postmodified poly(2-oxazoline)s by P-3CR and U-4CR to tune their lower critical solution temperature (LCST) in water (Scheme 23a) [62]. Poly(2-oxazoline) random copolymers were prepared by living cationic ring-opening polymerization of two different 2-oxazoline monomers including one monomer bearing a methyl ester group (copolymer of 2-ethyl-2-oxazoline and 2-methyl butyrate-2-oxazoline). After the polymerization, the pending methyl esters were saponified into carboxylic acids to enable subsequent multicomponent reactions. Two or more functionalities were introduced into the polymer side chains via either P-3CR or U-4CR. By variation of the starting components, the glass-transition temperature of the copolymers could be tuned from 50 to 99 °C and the cloud temperature in water from 24 to 91 °C.
Scheme 23

Postmodification of poly(2-oxazoline)s by P-3CR and U-4CR (a), synthesis of well-defined glycopolymers by postmodification of poly(methacrylic acid) by U-4CR and click reaction (b)

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) [63]. 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.

Tao et al. employed the U-4CR for preparation of middle-functional block copolymers under mild conditions [64]. In this example, the multicomponent postpolymerization modification consists in a coupling reaction between two different polymers and a functionalized third component, resulting in middle-functional block copolymers or miktoarm copolymers (Scheme 24). The coupling reaction between the polymer chain ends was, in some cases, limited by the steric hindrance of the polymer chain. As a result, further purification to remove unreacted polymers was required. A benzaldehyde-terminated poly(methyl methacrylate) [Mn(NMR) = 8800 g/mol] and a phenylamine-terminated methoxypolyethylene glycol [Mn(NMR) = 5000 g/mol] were prepared by ATRP, and coupled via reaction with cyclohexyl isocyanide and different carboxylic acids to obtain various block copolymers. Mid-reactive block and miktoarm copolymers were prepared by employing a carboxylic acid bearing additionally another functional group (i.e., vinyl group or chain-transfer agent, respectively). The mid-reactive block copolymers bearing the vinyl group were used in postpolymerization modification to attach another molecule (i.e., captopril). After successful introduction of the chain-transfer agent in the middle of the copolymer, miktoarm polymers could be prepared via subsequent RAFT polymerization of N-isopropylacrylamide.
Scheme 24

Postpolymerization modification by U-4CR yielding middle-functional block copolymers and miktoarm copolymers

In another work, the same group synthesized fluorescent protein-reactive polymers via a one-pot combination of U-4CR and RAFT polymerization (Scheme 25) [65]. The polymer–protein conjugates were prepared by utilizing multifunctional chain-transfer agents containing protein-reactive groups, fluorescent groups, and trithiocarbonates for the RAFT process. The protein-reactive and fluorescent chain-transfer agent was generated in situ via the U-4CR of a difunctional compound containing benzaldehyde and trithiolcarbonate, a pyridine disulfide containing carboxylic acid (protein-reactive group), a fluorescent aniline derivative, and cyclohexyl isocyanide. This in situ synthesis simultaneously enabled RAFT polymerization of N-(2-hydroxypropyl)methacrylamides in methanol. After mixing with selected proteins, the polymers were conjugated to the protein surface (postpolymerization modification). Dithiopyridine (reacting with thiol groups of, e.g., cysteine) and biotin (for avidin conjugation) were tested separately as protein-reactive groups. In both cases, a high degree of functionalization and fluorescent properties of the resulting polymer–protein conjugates were observed.
Scheme 25

Synthesis of fluorescent protein-reactive polymers via a one-pot combination of Ugi-4CR and RAFT polymerization

8 Conclusions

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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Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  1. 1.Laboratory of Applied Chemistry, Institute of Organic Chemistry (IOC), Materialwissenschaftliches Zentrum MZEKarlsruhe Institute of Technology (KIT)KarlsruheGermany

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