Materials Functionalization with Multicomponent Reactions: State of

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Review

Materials Functionalization with Multicomponent Reactions: State of the Art Ronak Afshari, and Ahmad Shaabani ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.8b00072 • Publication Date (Web): 14 Aug 2018 Downloaded from http://pubs.acs.org on August 16, 2018

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ACS Combinatorial Science

Materials Functionalization with Multicomponent Reactions: State of the Art

Ronak Afshari and Ahmad Shaabani* Faculty of Chemistry, Shahid Beheshti University, G. C., P. O. Box 19396-4716, Tehran, Iran

∗ Corresponding author. Tel.: +982129902800; e-mail: [email protected]

Abstract The emergence of neoteric synthetic routes for materials functionalization is an interesting phenomenon in materials chemistry. In particular, the union of materials chemistry with multicomponent reactions (MCRs) opens a new avenue leading to the realm of highly innovative functionalized architectures with unique features. MCRs have recently been recognized as considerable part of the synthetic chemist’s toolbox due to their great efficiency, inherent molecular diversity, atom and pot economy along with operational simplicity. Also, MCRs can improve E-factor and mass intensity as important green chemistry metrics. By rationally tuning the materials as well as the MCRs, wide ranges of functionalized materials can be produced with tailorable properties that can play important roles in the plethora of applications. To date, there has not reported any exclusive review of a materials functionalization with MCRs. This critical review highlights the state-of-the-art on the one-pot functionalization of carbonaceous and siliceous materials, polysaccharides, proteins, enzymes, synthetic polymers, etc. via diverse kind of MCRs like Ugi, Passerini, Petasis, Khabachnik-Fields, Biginelli and MALI reactions through covalent or noncovalent manners. Besides the complementary discussion of synthetic routes, superior properties and detailed applicability of each functionalized material in modern technologies are discussed. Our outlook also emphasizes future strategies for this unprecedented area and their use as materials for industrial implementation. With no doubt, MCRs-functionalization of materials bridges the gap between materials science domain and applied chemistry.

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Table of Contents Introduction................................................................................................................................................... 3 Scope of the review .................................................................................................................................................. 5 Covalent functionalization through multicomponent reactions .................................................................... 7 Carbonaceous materials ............................................................................................................................................ 7 Graphene oxide ..................................................................................................................................................... 8 Carbon nanotubes ...............................................................................................................................................10 Fullerene .............................................................................................................................................................12 Natural polymers ....................................................................................................................................................13 Polysaccharides ..................................................................................................................................................14 Proteins ...............................................................................................................................................................34 Siliceous materials ..................................................................................................................................................35 Synthetic polymers .................................................................................................................................................37 Polyamide ...........................................................................................................................................................37 Polyester .............................................................................................................................................................40 Polyacrylamide ...................................................................................................................................................41 Polyvinyl alcohol ................................................................................................................................................42 Miscellaneous .....................................................................................................................................................42 Magnetic nanoparticle ............................................................................................................................................44 Noncovalent functionalization through multicomponent reaction.............................................................. 45 Summary and outlook ................................................................................................................................. 48 List of acronyms and abbreviations ............................................................................................................ 50 Conflicts of interest ..................................................................................................................................... 53 Acknowledgments ...................................................................................................................................... 53 References................................................................................................................................................... 53


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Introduction In the history of science, most of the novel innovations, important progress and neoteric gateways have been made from the solidarity of interdisciplinary sciences. For instance, the 20th century saw the integration of physics and chemistry, with chemical properties explained as the result of the electronic structure of the atom. Meanwhile, the interdisciplinary sciences make it possible to creating something new by thinking across boundaries, combine the efficient and applicable features of diverse sciences and facilitate the simultaneous utilization.1 In this context, one of the emerging interdisciplinary fields is the coupling of materials science with chemical transformations for the synthesis of tailor-made functionalized materials. Surface functionalization/modification is the act of modifying the surface of materials by bringing physical, chemical or biological characteristics different from the ones originally found on the surface of a material.2 Functionalization processes introduce desired groups on the surface of materials, based on the chemical reactions which later can participate in the other organic reactions to construct applicable surface-functionalized materials.3 The modification can be done by distinct methods for altering the origin characteristics of the surface, such as roughness, hydrophilicity, surface charge, surface energy, biocompatibility and reactivity.4 Multicomponent reactions as diversity-oriented syntheses are superior synthetic procedures which provide highly valuable scaffolds with a minimum number of synthetic steps. In the MCRs, three or more starting materials are combined in a one-pot vessel and caused to the production of skeletal diverse compounds. Among the various synthetic routes, performing MCRs is ideal for the environmentally friendly synthesis of libraries of medicinal molecules with high atom-economy and also MCRs can improve E-factor and mass intensity as important green chemistry metrics.5 One-pot multicomponent strategies express the pursuit of chemists to construct complicated scaffolds through minimum synthesis and purification steps. Many basic MCRs are name reactions, for example, Ugi,6 Passerini,7 Strecker,8 Hantzsch,9 Biginelli,10 or one of their many variations. Thanks to the massive versatile products, MCRs have been widely recognized in organic and medicinal chemistry,11 and have been applied in drug discovery12 and for the synthesis of natural product,13 peptidomimetic14 and macrocyclic compounds.15 Although most of the mentioned MCRs date back more than half a century or even century, still looking at this “old” MCRs from new perspectives bring novel breakthroughs in the hot research fields. Consistent with this point of view, the first utilization of Passerini reaction for polymer synthesis by Meier et al. in 2011,16 helped to open up a new window in the field of polymer syntheses. A high number of articles and books bear witness to the growth and development of MCRs as new synthetic tools for polymer chemists.17



Interestingly, in recent years, the union of materials chemistry with multicomponent approaches has accelerated the preparation of neoteric functional materials. As the familiar adage says “it takes two to tango”, this partnership and combination caused to the great symphony of high-performance constructions that are able to serve as novel materials in modern technologies. Since, amine, carboxylic, or carbonyl groups that are main components of MCRs are present in the structure of most of the materials like natural and synthetic polymers, carbonaceous and siliceous materials or can easily be introduced on their surfaces; therefore they can participate in MCRs for the synthesis of highly applicable functionalized materials. What causes the MCRs in the spotlight as unparalleled strategies for materials functionalization is their “power of one-pot” which is the dream of many researchers.18 This power induces many advantages to the strategies of materials functionalization via MCRs which major ones can be highlighted. First, operational simplicity; MCRs-functionalization are straightforward procedures that do not have the necessity to isolate or purify any intermediates and the reaction can take place in one vessel instead of complex equipment. Substrates diversity; wide ranges of materials and substrates can be used in this convergent one-pot manner. Finally and in particular, pot, atom and step economic feature which caused a considerable decrease in the number of functionalization steps.19 Subsequently, all of these advantages lead to adequate aspects of green chemistry; reduced cost, low waste and pollutant productions.20 Another interesting peculiarity of these procedures is the ability to produce, as a whole or in part, highly stable, soluble, biocompatible and environmentally-benign materials by attachment of hydrophilic, pseudo-peptide scaffolds caused from MCR functionalization, which is often an important challenge for chemists working in the area of materials functionalization. The exciting journey of material functionalization with MCRs began in the early 1970s when Axen and co-workers represented the immobilization of biologically active substances to diverse kind of isonitrile containing natural polymers via the isocyanide-based Ugi four-component reaction (Ugi-4CR).21 In the years thereafter, the Ugi-4CR approach was developed for enzyme immobilization on the surface of different polymeric supports such as polysaccharides, polyacrylamide, polyester and polyamides.22 In 1991, König and Ugi have shown that alginic acid, anionic polysaccharide, can be a part of the famous Ugi-4CR;23 the reaction which had already been discovered by Ugi in 1959.6 From that time onward and until recently, few amounts of works was done in this field. The renaissance of materials functionalization/modification with MCRs as state-of-the-art occurred with the beginning of the 20th century but the intensive researches are related to 2013 till now.


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Scope of the review

This comprehensive review represents the first work covering all of the methods of one-pot materials functionalization via MCRs including their classification. The complementary discussion of both synthesis and application aspects of functionalized materials is presented. Notably, this review represents all of the works that have been utilized a kind of amine, carboxyl, carbonyl or isonitrile functionalized materials as a part of the MCRs with the aim of functionalization for construction of tailor-made architectures. Since the MCRs not only have the ability to functionalize materials but also can conjugate biomolecules and enzymes with different materials; therefore, these procedures were embedded in every discussed material as immobilization processes. We critically evaluated the MCRs-functionalized materials based on the two synthetic routes; covalent and non-covalent functionalization through the different MCRs (Scheme 1). As can be shown in Scheme 1, the functionalization modes through Ugi-4CR represent a significant part of the review, which due to the prominent and outstanding features of this isocyanide-based multicomponent reaction (I-MCR), its valuable pseudo-peptide products along with wide ranges of commercially available substrates.24 Carbonecous Materials Natural Polymers

Ugi

Silicious Materials Synthetic Polymers Magnetic Particles

Passerini

Natural Polymers Carbonecous Materials

Passerini-type

Covalent

Silicious Materials

Petasis-Ugi

Natural Polymers

Khabachnik-Fields MALI

Synthetic Polymers

Natural Polymers

Materials functionalization

Carbonecous Materials

Miscellaneous

with MCRs

Natural Polymers Synthetic Polymers

Non-covalent

Ugi

Carbonecous Material

Biginelli


MALI


Scheme 1. General classification of covalent and non-covalent functionalized materials based on MCRs and material types



In addition, the superior properties and detailed applicability of each functionalized material are extensively discussed in the following parts. This stupendous growth of MCRs for materials functionalization caused to highly innovative materials which have been utilized in almost every area of applicable materials and industry such as medicinal applications and drug delivery, enzyme immobilization, electrodes, biosensor, water treatment, emulsifiers, catalyst, biodiesel, affinity chromatography, food packaging, etc. This says that there is clearly much work to still be done on these “old horizon” reactions for developing the properties of functionalized materials, thereby opening new avenues of interdisciplinary research (Scheme 2).

Scheme 2. Applications of MCR-functionalized materials in various fields of modern technology Although the utilization of MCRs as a “click” reactions for polymer synthesis has become a mainstream topic of some excellent reviews,25 and very recently the utilization of MCRs for the synthesis of aggregation-induced emission (AIE) active polymers have been reported,26 but there is no review article devoted to the materials functionalization/modification through MCRs approach so far in the literature. Therefore, the present review is elaborated the state-of-the-art MCR synthetic strategies for materials functionalization and divided into three main sections. First, covalent functionalization of materials through MCR approach and their applications is described which divided into five parts; carbonaceous materials, natural polymers, siliceous materials, synthetic polymers and magnetic nanoparticle. Then, non-covalent functionalization is detailed. Finally, concluding remarks and outlook are examined through reflection on current research progresses. 6 ACS Paragon Plus Environment

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Covalent functionalization through multicomponent reactions Carbonaceous materials

Graphene, carbon nanotubes (CNTs) and fullerene (C60) are going to revolutionize the 21st century because they are fascinating materials with many potential applications that stem from their remarkable and unusual electronic, mechanical and optical properties.27 Graphene is a two-dimensional material, basically, a single layer of graphite, with carbon atoms arranged in a hexagonal, honeycomb lattice, while, CNTs are hollow, cylindrical structures, essentially a sheet of graphene rolled into a cylinder.28 Fullerene, a third form of carbon, is similar in structure to graphite, which is composed of stacked graphene sheets of linked hexagonal rings.29 Since the first discovery of these materials, they have been able to encompass a wide spectrum of scientific papers and open the door to many industries. Despite the great application potentials, they have two major problems; low dispersity, high toxicity. In order to conquer these disadvantages, a dominant focus of researchers has been concentrated on the development of new synthetic routes for their functionalization and modification.30 Notably, functionalization and dispersion of carbonaceous materials are of crucial importance for their future bioapplications. As a consequence of their significant applications and along with a growing demand for functional materials, pseudo-peptide functionalized carbonaceous materials with readily carboxamide groups which synthesized via Ugi-4CR received increasing attention nowadays. Ugi-4CR, without doubt, is one of the famous and most commonly used I-MCRs. In 1959, Ugi reported for the first time this four-component reaction, in which a carboxylic acid 1, an amine 2, a carbonyl compound 3, and an isocyanide 4 are reacting to result in pseudo-peptide scaffolds 5 with water as the only byproduct (Scheme 3).6 Recently, this reaction have been frequently used for the synthesis of medicinal compounds31 and polymer synthesis.32

Scheme 3. Ugi four-component reaction



Graphene oxide

In 2016, Rezaei and co-workers reported the first covalent functionalization of graphene with the Ugi4CR approach. In this work, the carboxylated-graphene oxide (GO-COOH) 6, benzylamine 7 or 1-(3aminopropyl)-3-methylimidazolium chloride (IL-NH2) 8 as an amine source, formaldehydes 9 or p-chloro benzaldehyde 10 and cyclohexyl isocyanide 11 came together in a single reaction vessel and generated the hydrophobic- 12, hydrophilic- 13 or amphiphilic 14 multi-functionalized graphene composites in mild conditions (Scheme 4). Henceforth, they proved the high competency of Ugi-4CR for covalent immobilization of Bacillus thermocatenulatus lipase (BTL), as an amine moiety, on graphene surface with high bio-catalytic activity for hydrolysis of short- and long-chain triacylglycerols.33

Scheme 4. Representation of Ugi-functionalized GO to afford hydrophobic (a), hydrophilic (b), and amphiphilic (c) multi-functionalized graphene composites Enzymes are green superior biological catalysts with the high chemo-, stereo- and regioselective ability.34 However, they showed some drawbacks in their native forms such as low stability in reaction conditions, 8 ACS Paragon Plus Environment

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contamination in products, denaturation and difficulties in recovery and reuse.35 Therefore, designing novel methods for fixation of enzyme on the supports that can improve the activity of the enzymes in harsh reaction conditions such as extreme pH, high temperature or in the presence of organic solvents is in the spotlight nowadays. Taking advantages of Ugi-4CR for enzyme immobilization on graphene surfaces, in 2016, the Rhizomucor miehei lipase (RML) was immobilized on GO-COOH sheets with the maximum loading capacity of 530 mg and high thermal and co-solvent stability in comparison with the soluble enzyme.36 In a follow-up investigation, this efficient method was developed for the synthesis of a novel nonviral graphene-based gene carrier for high efficient plasmid DNA (pDNA) transfection into mammalian cells by Rezaei group.37 In this procedure, a new complex of GO-COOH with ethidium bromide (EtBr), most commonly used fluorescent dye for detecting nucleic acids after electrophoresis, was designed and their application as nanovector for efficient gene delivery into the AGS cells was investigated. As shown in Scheme 5, EtBr 15, cyclohexyl isocyanide 11, formaldehyde 9 and GO-COOH 6 were participated in Ugi-4CR to construct EtBr-functionalized graphene oxide nanocomposite (GO-f-EtBr) 16 under extremely mild conditions (25 °C, water). Then, the complexation capability of GO-f-EtBr with pDNA was assessed by the ability of nanovector for DNA extraction from the solution and the results revealed that synthesized nanocarrier had a high DNA-loading capacity, good stability in physiological media and excellent biocompatibility in comparison with GO-COOH sheets.

Scheme 5. Carboxamide-functionalized GO through Ugi-4CR for gene carrier Following the previous approach, Adibi-Motlagh et al. reported the straightforward route for the covalent immobilization of the cell-adhesion peptide onto the graphene surface based on the Ugi-4CR. The peptide-graphene biomaterial showed excellent biocompatibility. In addition, the peptide-functionalized 9 ACS Paragon Plus Environment


graphene accelerated the proliferation of human mesenchymal stem cells at a better rate regarding the tissue plate.38 Very recently, Shaabani and Afshari evaluated the efficiency of MCRs for ligand production on the surface of graphene sheets with the ability to immobilized metal nanoparticles for organic transformations as a pioneer report in this field. They described the utilization of Ugi-4CR as a tailored multicomponent ligation approach towards the synthesis of carboxamide-ligands chemically grafted on the surface of graphene nanosheets (carboxamide-f-GO) 17, caused to the novel nanocatalyst with high affinity to complex with copper nanoparticles 18.39 Aniline 19 and 2-hydroxy-4-methylbenzaldehyde 20 were used for better construction of ligands. The catalytic activity of nanocatalyst was investigated in Ullmann cross-coupling reaction for direct access to corresponding N-aryl amines in a deep eutectic solvent (DES) as a green and recyclable media. (Scheme 6)

Scheme 6. Synthesis of Cu NP-carboxamide-f-GO@Fe3O4 nanocatalyst via Ugi-4CR strategy for C-N cross-coupling reaction Carbon nanotubes

Based on our knowledge, the first report on the multicomponent functionalization of multi-wall carbon nanotubes (MWCNTs) is the paper by Tahermansouri and co-worker in 2014. They reported the facile one-pot three-component procedure for the synthesis of highly dispersed MWCNT. In this work, by the reaction of MWCNT-COOH 21 with thionyl chloride 22, acyl-chloride MWCNTs (MWCNT-COCl) 23 were prepared and then reacted with isatoic anhydride 24 and benzylamine 7 for producing 2-amino-Nbenzylbenzamide functionalized nanotubes 25. Afterward, by addition of POCl3 to a reaction vessel, 310 ACS Paragon Plus Environment

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benzylquinazolin-4(3H)-one functionalized MWCNT 26 were synthesized (Scheme 7).40 The functionalized MWCNTs showed photo-electronic properties, which was due to the existence of strong fluorescence quenching for organic moieties bonded to the MWCNT scaffold. The toxicity of the nanotubes was evaluated with human gastric (MKN-45) and breast cancer cells (MCF7) and the results

demonstrated that functionalized MWCNTs are a powerful agent for MKN-45 (45-70% toxicity), as compared with MCF7 (39-51% toxicity), which kills cancer cells. Scheme 7. Three-component reaction for the introduction of 2-amino-N-benzylbenzamide moieties on MWCNTs and their transformation to quinazoline derivatives In 2017, Shaabani and co-worker reported a direct synthesis of novel carboxamide-functionalized MWCNTs (carboxamide-f-MWCNTs) as a nanovector through a covalent functionalization via Ugi-4CR approach.41 The expedient approach was commenced through the reaction of carboxylated MWCNT as an acid component in Ugi-4CR. By this functionalization in a single step, the peptidomimetic coated MWCNT nanohybrids were able to serve as promising biocompatible nanocarriers with excellent pH dependent sustainability which prolonged the drug release profile and prevented premature release of Folic acid (FA). Furthermore, the synthesized nanobiohybrid exhibited a high and long-term dispersity and stability in water in comparison with pure MWCNT. In addition, biocompatibility and cytotoxicity of carboxamide-f-MWCNTs were examined and no obvious adverse effects on the viability of NIH-3T3 fibroblast cells were observed. In another example, prompted by the promising enzyme-immobilization efficiency of Ugi-4CR, Mohammadi et al. described an effective way for immobilization of RML enzyme 27 on the surface of the MWCNTs. This immobilization route was performed in mild conditions; at room temperature, in water and a very short reaction time (15-30 min) which maximized the survival rate of particularly 11 ACS Paragon Plus Environment


unstable proteins, without a significant decrease in specific activity of the enzyme (Scheme 8). The authors claimed that this approach approved the loading capacity of enzyme to 680 mg compared to previously reported methods.36

Scheme 8. A one-pot immobilization of RML enzyme on carbonaceous nanomaterials by using the Ugi4CR Fullerene

In 2018, Westermann and co-workers profited from superior features of Ugi and Passerini reaction for diversity-oriented decoration and ligation of fullerenes.42 Passerini three-component reaction (Passerini3CR), is the first multicomponent reaction based on isocyanides serendipitously discovered by Mario Passerini in 1921, which reported that isocyanides 4 react with carboxylic acids 1 and carbonyl compounds 3 in one-step manner to provide α-acyloxycarboxamides 28 (Scheme 9).7

Scheme 9. Passerini three-component reaction


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For this purpose, the fullereno-carboxylic acids 29 were reacted with variation of the aldehyde and isocyanide components through Passerini-3CR pathway for the construction of α-acyloxycarboxamidefunctionalized-fullerene 30 (Scheme 10-a) along with diverse amines for Ugi-4CR pathway to prepare carboxamide-functionalized fullerenes 31 (Scheme 10-b). The procedure was employed for the ligation of oligopeptides and polyethyleneglycol chains (PEG) to C60, as well as for the construction of bisantennary and PEG-tethered dimeric fullerenes and the fluorescently labeled fullerene derivative. Notably, the quantum yields for the formation of cytotoxic singlet oxygen (1O2) was remarkable for some derivatives which confirmed the potential of these compounds for photodynamic therapy.

Scheme 10. Diversity driven decoration and ligation of fullerene by Passerini-3CR and Ugi-4CR Natural polymers

From the beginning of the earth, nature was using natural polymers to make life possible. These polymers are abundant components present in biological extracellular matrices and the famous one is cellulose.43 The natural polymers are often water-based and can be extracted from diverse natural sources.44 There are three main types; first, polynucleotides, which are chains of nucleotides, like DNA and RNA, second, polyamides, which are chains of proteins for example enzymes, silk and collagen and third, polysaccharides, chains of sugars.45 Since most of the natural polymers have different functional groups on their backbones or can easily be introduced, they can be great candidates for participation in MCRs. Therefore, it is reasonable to say that natural polymers are one of the first materials that functionalized with MCR approach. As pioneering works in the early 1970s, Axen et al., described an efficient method toward the immobilization of diverse kind of enzymes, nucleotides and peptides on the surface of the 13 ACS Paragon Plus Environment


different polysaccharides, like cellulose, dextran, agarose, and proteins such as keratin and wool.21 In the following, functionalization and modification of diverse kind of polysaccharides and protein through MCRs were summarized in detail. Polysaccharides

Polysaccharides, polymeric carbohydrate structures, have been harbingers of an exciting new field in the realms of “green chemistry”. The future of these sustainable biopolymers not only depends on their availability and multi-functional structures caused to many chemical modifications overcoming knowledge barriers in developing biocompatible functionalized materials but also on conveniently addressing the environmental concerns, especially when large-scale material is involved in the industry. The typical examples of polysaccharides are cellulose, chitin and chitosan, alginate, agarose, pectin, and little-known polysaccharides like hyaluronan, pullulan and scleroglucan.46 In the late 1970s, the participation of diverse polysaccharides in Ugi-4CR as a support for enzyme immobilization was developed. The method was based on a two-step procedure involving (a) ionization of the hydroxyl groups on the polymer by treatment with a strong base (t-butoxide) in a polar aprotic solvent (DMSO) and (b) introduction of isocyanide side chains by nucleophilic attack of polymeric alkoxide ions on a lowmolecular-weight isocyanide, e.g. 1-tosyl-3-isocyanopropane. Then, the side chains containing –NC functional groups generated peptide bonds in four-component reactions, with the trypsin, a serine protease found in the digestive system of many vertebrates, where it hydrolyzes proteins47 and urease enzymes.48 Although the enzyme activities were low in some cases, these reports opened a new gateway for the development of polysaccharides functionalization with MCRs. One of the best features of these biopolymers is their ability to crosslinked to form a biodegradable hydrogels which gained widespread attention in various fields such as drug delivery,49 prosthetic materials,50 contact lenses51 and emulsifiers.52 Therefore, they can be great candidates for participation in MCRs for the synthesis of crosslinked hydrogels when one of the components is a bifunctional linker. The pioneering and revolutionary work on the crosslinking of the biopolymers with MCRs was carried out by Van Leusen and Ugi, in 1991. They utilized alginate, anionic polysaccharide distributed widely in the cell walls of brown algae,53 as an acid part and di-functional amine as an amine moiety/crosslinking agent in famous Ugi reaction for the production of a novel gel for capturing enzymes such as “acidic phosphatase” (AP) and L-( + )-lactate dehydrogenase (LDH) (Scheme 11).23


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Scheme 11. Alginate crosslinking with Ugi-4CR approach for capturing LDH enzyme Going ahead, Crescenzi et al. attempted to tap the substantial diversity potentials of Ugi and Passerini reaction through exploiting a wide spectrum of functional polysaccharides as an acid, aldehyde or amine segments in these approaches. The authors profited from superior features of Passerini and Ugi reaction to devised simple procedures for performing novel chemical hydrogels from different types of polysaccharides in HCl diluted water with a pH of about 3.5-4 (Table 1).54 As illustrated in Table 1-entry 3,4/Passerini section, partially oxidized scleroglucan (POS) and pullulan (POP) was also used as an acid and aldehyde moieties that present in the polysaccharide chain, simultaneously, without the need of bifunctional linker and a gel was obtained by adding only the isocyanide. Notably, the polysaccharides were partially oxidized by a selective TEMPO-mediated oxidation of primary alcohols.55 In the case of the chitosan as an amine source in dilute acetic acid, an intensely yellow gel was performed after addition of glutaraldehyde and cyclohexyl isocyanide due to the formation of imine, before the Ugi-4CR could take place (Table 1-entry 3/Ugi section). Despite different substrates examination, the synthesis of stable and swellable gel from pure chitosan was unsuccessful caused to utilization of more soluble derivative of chitosan, 1-(deoxylactit-1-yl)chitosan (Table 1-entry 4/Ugi section). It was observed that the properties of the hydrogels like swelling, transparency and stability tuned by changing the substrates and their relative proportions. Table 1. Passerini and Ugi reactions for polysaccharides functionalization Passerini reaction components Entry

Acid

Aldehyde

Ugi reaction components Isocyanide

Acid


Aldehyde

Amine


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1

CMC

glutaraldehyde

cyclohexyl

CMC

glutaraldehyde

ammonium chloride

2

hyaluronic acid

glutaraldehyde

cyclohexyl

CMC

formaldehyde

1,5diaminopentane

3

POS

POS

cyclohexyl

acetic acid

glutaraldehyde

chitosan

4

POP

POP

cyclohexyl

Ltartaric acid

formaldehyde

1-(deoxylactit-1yl)chitosan

One year later, in 2000, they extended this methodology to the other polysaccharides like alginate, carboxymethyl dextran (CMD), carboxymethyl scleroglucan (CMS), C6-oxidized scleroglucan (OxS) and carboxymethyl scleroglucans (CMS) and studied the behavior and solid-state NMR characterization of crosslinked polysaccharides.56 Hydrogels prepared via the Passerini-3CR were transparent, alkali labile materials whereas the transparency of the Ugi gels depending on the polysaccharide, the cross-linker, and the degree of cross-linking. Moreover, Ugi hydrogels were stable for several months at a pH ranging from 1.3 to 11 and up to temperatures over 90 °C. Ultimately, solid-state NMR analysis of several gels confirmed the structure of the expected cross-links with efficiency for the reactions of about 80%. Recently, the same approach was used for functionalization of the other carboxymethyl-polysaccharides like carboxymethyl ethers of xylan (CMX), and pullulan (CMP) besides cellulose.57 The reactions were carried out using 2-methoxyethylamine and propargylamine, paraformaldehyde and benzaldehyde as well as tert-butyl isocyanide at room temperature in acidic aqueous medium after 20 h. The results confirmed that the polysaccharide derivatives synthesized through the reaction of CMX, CMP and CMC with paraformaldehyde, 2-methoxyethylamine, and tert-butyl isocyanide were soluble in water and organic solvents including DMSO, DMA and DMF. In an interesting work in 2018, Rivera and co-workers benefited from the important potential of MCRs for protein-polysaccharide conjugation in the field of antibacterial glycoconjugate vaccines.58 They investigated the utilization of the Ugi-4CR for bioconjugation of functionalized capsular polysaccharides (CPs) of Streptococcus pneumoniae and Salmonella enterica serovar Typhi to carrier proteins such as diphtheria and tetanus toxoids (DT and TT, respectively) in the presence of acetone and tert-butyl isocyanide. In continuation, they accomplished a neoteric synthetic route for the simultaneous 16 ACS Paragon Plus Environment

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conjugation of two different polysaccharides to a protein in a single step. In this regard, the TEMPOoxidized CPs as the carboxylic acid component, periodate-oxidized CPs as the aldehyde component, and TT as the amino component were reacted with tert-butyl isocyanide in PBS (pH 7.4) at room temperature led to multivalent unimolecular glycoconjugate that contained two different polysaccharide antigens attached into a carrier protein. The Ugi-derived glycoconjugates showed great antigenicity and elicited good titers of functional specific antibodies which confirmed the potential of the multicomponent bioconjugation approach for the development of multivalent vaccine candidates. Cellulose

In spite of high abundance of cellulose, polysaccharide consisting of a linear chain of several hundred to many thousands of β(1→4) linked D-glucose units, on Earth,59 pure cellulose has not reached its potential applications in chemical industries due to the lack of insolubility in common organic solvents and especially in water owing to the strong intramolecular hydrogen bonding.60 Thus, dissolution and modification of pure cellulose have become a mainstream topic.61 In this regard, Mironov and co-workers executed the synthesis of cross-linked sub-micron microgels from various types of pure cellulose including Avicel, wood cellulose, cotton linters and filter paper.62 In the first step cellulose microgels prepared through the sol-gel transition in the cellulose 32 NaOH/urea solutions. Then, low substituted CMCs 33 synthesized via addition of sodium monochloroacetate 34 to 4 wt% cellulose solutions, followed by dilution with aqueous solution of NaOH under intensive stirring which caused to the formation of microgel particles with average diameters in the range of 150–250 nm after 4 h of storage at room temperature. Eventually, a different type of amines 2 and 1,4-bis(3-isocyanopropyl)piperazine 35 as a basic isocyanide added to form a cross-linked sub-micron microgels 36 (Scheme 12). The authors could not obtain appropriate cross-linked microgels from cotton linter and filter paper that are high molecular weight cellulose derivatives. Moreover, synthesized microgels formed stable oil-in-water emulsions at low concentrations (circa 2 g/l) over a broad pH range (3–11) known as Pickering emulsifier.



Scheme 12. CMC crosslinking through Ugi-4CR for production of sub-micron microgels62 Following the same approaches and in an interesting effort for advance cellulose dissolution and modification with MCRs, Meier and co-workers reported the dissolution and activation of filter paper cellulose 32, for the subsequent derivatization with succinic anhydride 37 in a CO2 based switchable solvent. The obvious distinction between this method and the previous reports in the field of functionalization/modification of cellulose with MCRs is the utilization of cellulose succinates 38 instead of the CMC as an acid part. Furthermore, the carboxylic acid moieties introduced by the succinylation, was participated in Passerini-3CR and Ugi-4CR as cellulose modification versatile tools (Scheme 13).63 The Ugi and Passerini products 39-40, were soluble in common organic solvents including THF, CHCl3, DCM, MeOH as well as DMSO and DMF. Also, the thermal test possessed high thermal stability close to the native cellulose.


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Scheme 13. Dissolution and functionalization of cellulose (filter paper) with succinic anhydride followed by modification via Passerini-3CR (right) and Ugi-4CR (left). Very recently, Stenzel and co-workers demonstrated an efficient surface modification approach for chemical tethering of the temperature responsive polymers onto cellulose nanofibers under mild condition.64 They benefited from the advantages of Passerini-3CR to modify TEMPO-oxidized cellulose nanofibers (TOCNs) with thermoresponsive poly(N-isopropylacrylamide) (pNIPAm). For this purpose, a TEMPO-oxidized cellulose nanofiber bearing carboxylic acid moieties (TOCN-COOH) 41, a pNIPAm with aldehyde end-functionality (pNIPAm-COH) 42, which obtained via Reversible AdditionFragmentation Chain-Transfer (RAFT) polymerization technique, and a cyclohexyl isocyanide 11, were reacted in aqueous condition at ambient temperature resulting in 36% of grafting efficiency within 30 min (Scheme 14). Additionally, the chemical coupling was evidenced by improved aqueous dispersibility and turbidity studies.



Scheme 14. Synthesis of polymer-grafted cellulose fibrils (pNIPAm-g-TOCNs) via Passerini 3-CR To expand the repertoire of applicable solid phases for recognition of biologically active molecules, cellulosic filter-paper disks were chemically modified through isonitrile moieties by Goldstein group for immobilization of avidin, tetrameric biotin-binding protein, in the presence of the acetaldehyde and trishydroxymethylaminomethane through Ugi-4CR in buffer (pH 7.4) at 4 oC overnight.65 Then, quantitative assay of unknown d-biotin solutions was carried out over a wide range of temperatures (0-35°C) and pH values (4-11). Going ahead, Garcia and co-workers explored the efficiency of Ugi-4CR for the synthesis of thermostable trypsin-O-CMC neoglycoenzymes in the presence of formaldehyde and tert-butyl isocyanide in sodium phosphate buffer, pH 5.0, for 12 h at 4 oC.66 The analytical characterization revealed the stabilization against thermal treatment and autolytic degradation. Chitosan

Chitosan is one of the most plentiful polysaccharides prepared from N-deacetylation of chitin and composed of randomly distributed β-(1→4)-linked D-glucosamine (deacetylated unit) and N-acetyl-Dglucosamine (acetylated unit) that has been attracted significant interest in biomedical and bio-imaging fields owing to well-known low toxicity, favorable biocompatibility and biodegradability.67 Nevertheless, its biomedical applications are limited due to the low solubility in aqueous medium. To overcome this low-solubility, Mironov et al. explored the use of Ugi-4CR for the synthesis of highly soluble chitosan derivatives as a coating agent for the construction of modified liposomes for drug delivery application.68 In this procedure, pelargonic acid or lauric acid as an acid containing nonpolar tails for stabilizing of liposome suspension were mixed with formaldehyde and 2-methoxyethyl isocyanide and added to the solution of chitosan in a 0.01 M HCl and stirred for 4 h at room temperature. The Ugi-modified chitosan exhibited high effectiveness for stabilization of liposomes with a positive surface charge, while chitosan, which is soluble in acidic water, cannot be used for coating of positively charged liposomes owing to 20 ACS Paragon Plus Environment

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ionic repulsion between the positively charged surface of the chitosan and phosphatidylcholine. In addition, the result proved its great pharmaceutical carrier efficiency for mucoadhesive medicine trough stability, the ability for loading and affinity to mucous membrane. In an interesting work, the luminescent chitosan nanoparticles with AIE feature were synthesized through a one-pot mercaptoacetic acid locking imine three-component reaction (MALI-3CR). Since its birth in 1947, this three-component reaction has been used for the synthesis of 4-thiazolidinones 43 scaffolds through the covalent bonding of amine 2 and aldehyde 3 substrates together like a lock via mercaptoacetic acid 44 (Scheme 15).69 The addition of mercaptoacetic acid to an imine bond also considered as a clickable MCR for polymer synthesis, since this catalyst-free reaction can occur smoothly under benign conditions in a short time with water as the only byproduct.70

Scheme 15. MALI three-component reaction Based on the above principles, and due to the impressive developments for fabrication of AIE nanoparticles since its first discovering in 2001,71 Wan et al. explored the use of mercaptoacetic acid as the lock to form covalent linkage between the amino groups of water-soluble chitosan (WS-Chitosan) 45, synthesized via depolymerization of insoluble chitosan using H2O2 as oxidant, and aldehyde groups of 9,10-bis(aldehydephenl)anthracene (An-CHO) AIE dye 46 under mild reaction conditions (Scheme 16).72 Since the AIE dyes have the ability to emit strong fluorescence in aggregated state while nonfluorescence or weak fluorescence in dispersed state,73 consequently, the obtained amphiphilic luminescent chitosan nanocomposite 47 self-assembled into ultra-bright yellow nanoparticles in aqueous solution because of hydrophobic AIE dyes as core while hydrophilic chitosan as shell and exhibited excellent biocompatibility, water dispersibility and photostability, making them ideal candidates for biological imaging especially for a long time tracing.



Scheme 16. Synthetic procedure for the preparation of AIE active luminescent chitosan nanoparticles via MALI-3CR In an effort to advance the diversity of MCRs for materials functionalization, Airoldi and co-workers reported the utilization of dithiocarbamate MCRs for modification of chitosan.74 The design of novel synthetic routes for dithiocarbamate preparation has unleashed many opportunities in organic chemistry and polymer synthesis.75 In this reaction, an amine 2, carbon disulfide 48 and a Michael acceptor moieties such as alkenes 49 were reacted through simple Michael’s reaction, in a three-component manner to generate dithiocarbamate derivatives 50 (Scheme 17).76


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Scheme 17. Dithiocarbamate three-component reaction They chemically modified chitosan with carbon disulfide 48 and acrylamide 51 through dithiocarbamate3CR which caused to two pendant chains of dithiocarbamate that bonded directly to the amino nitrogen atom of the biopolymer 52, and applied for lead, copper and cadmium removal (Scheme 18). Interestingly, the TGA results revealed that the synthesized product is more stable than the pure chitosan. The maximum capacities of 2.24; 1.14 and 0.84 mmol g−1 for divalent lead, copper and cadmium from aqueous solution were observed. The highest sorption capacity for lead confirmed the soft lead/soft sulfur interactions. H3COCHN

H3COCHN

OH O O HO

HO O

O

48

OH

n

NH2

2 CS2

Water

2

O 60

OH O

oC

O HO

m

HO

S S

O

OH

n

N

O O

O

m

S 52

S

H2N 51 O

Dithiocarbamate 3-CR

O NH2

H2N

Scheme 18. Modification of chitosan through dithiocarbamate-3CR for toxic cation remediation Glucan

In an interesting work in 2016, Wei et al., applied a one-pot procedure for the preparation of amphiphilic AIE active fluorescent organic nanoparticles (FONs) 53 through the reaction of hydrophobic 4-(1,2,2triphenylvinyl) benzaldehyde (TPE-CHO) AIE dye 54, 3-aminobenzeneboronic acids (ABBA) 55 and hydrophilic glucan 56, a polysaccharide of D-glucose monomers linked by glycosidic bonds,77 in room temperature using ABBA as the linkage for conjugation of TPE-CHO with glucan via formation of Schiff base and phenyl borate which can response to pH and glucose (Scheme 19).78 The hydrophobic AIE dye was encapsulated in the core of FONs, which result in strong fluorescence emission for the AIE properties of TPE-CHO. However, the hydrophilic glucan was coated on the surface of hydrophobic core, which led to water dispersibility of functionalized glucan. In addition, functionalized composite showed strong luminescent intensity, good biocompatibility and self-assembly appropriate for fabrication of multifunctional biomaterials.



Scheme 19. Preparation of AIE-active glucan-based polymers Starch

One of the other polysaccharides that have been used for the construction of AIE-active luminescentbased nanoprobes is starch. Starch 57 is a polysaccharide consisting of a large number of glucose units joined by glycosidic bonds which produced by most green plants as energy storage.79 In 2016, luminescent starch-based polymers with AIE characteristic was synthesized by Wei et al. same as their previous procedure for glucan functionalization, through the reaction of the TPE-CHO with carboxyl methyl starch sodium (CMS) and ABBA in DMSO at room temperature.80 The Schiff base and phenyl borate dynamic bonds can respond to both pH and glucose that are useful for fabrication of responsive drug delivery carriers. The dual responsive AIE-active glycosylated bioprobes with intense blue fluorescence, excellent water dispersibility and extremely low cytotoxicity showed great internalization to HepG2 human liver cancer cells, implied their further potential for bioimaging applications. Very recently, the same group executed the synthesis of starch-dopamine conjugates fluorescent organic nanoparticles 58.81 They introduced aldehyde groups onto starch through oxidized by NaIO4. Then, dopamine 59 was linked with the oxidized starch 60 using MALI-3CR in DMSO. Finally, polyethyleneimine (PEI) was added to react with starch-dopamine conjugates 61 and self-polymerized which caused to obvious green-yellow fluorescence under the ultraviolet lamp (Scheme 20). Due to the great properties of starch-based FONs, Wei group suggested this functionalized polysaccharides as novel potentially fluorescence probes and carriers for delivering of biologically active components.


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Scheme 20. Schematic procedure for the synthesis of starch-based FONs through MALI-3CR81 Alginate

The first utilization of alginate, comprising of ᵦ-D-mannuronic acid (M block) and (1→4)-linked α-L guluronic acid (G block) units arranged in an irregular pattern of GG, MG and MM blocks,82 as an acid part in Ugi-4CR by Ugi,23 have opened a new vision to polysaccharides functionalization and their synthesized hydrogels behaviors. Continuously and on similar lines, Nystrom and co-workers explored turbidity, structural, and rheological features of alginate hydrogels, synthesized via the Ugi-4CR. Sodium alginate, formaldehyde, 1,5-diaminopentane (DAP) or n-octylamine and cyclohexyl isocyanide participated in these reactions for gel formation. By investigating the impacts of different parameters such as reaction temperature, presence of the surfactant and polymer and cross-linker concentrations in details, they showed that the properties of the Ugi-functionalized hydrogels, such as structure, transparency, gel point, and viscoelasticity were tuned by changing these parameters.83 In the same line, the effects of pH on dynamics and rheology of aqueous alginate during gelation via the Ugi reaction were described by the same group.84 They also investigated the interactions between alginate derivative hydrophobically modified by Ugi-4CR and sodium dodecyl sulfate (SDS), using the alginate/SDS system as a reference.85 In 2016, Feng et al. applied the same protocol for the synthesis of amphiphilic Ugi-functionalized alginate. Similar to Nystrom’s procedure, they synthesized self-aggregated semi-spherical shape Ugifunctionalized alginate micelles with the average size of 162.3 nm that prepared through the hydrophobic interaction among the octyl and cyclohexyl groups.86 Very recently, they reported the preparation of ecofriendly O/W Pickering emulsions formed with silica nanoparticles adsorbed with amphiphilic Ugifunctionalized alginate derivatives. The rheological behaviors of the emulsions were studied and results showed that Ugi-functionalized alginates with high molecular weight led to more rigid structures that can



be justified by the formation of silica particle strong network attributed to the entanglement and bridging of Ugi-functionalized alginates.87 In its pursuit, Camacho et al. uncovered an efficient synthetic route towards the construction of alginate modified-gold electrode as a support for immobilizing the horseradish peroxidase (HRP) 62 enzyme via Ugi-4CR.88 In this procedure, the sodium alginate 63 used as coating material for the gold electrode was produced by activation with NaIO4, for introducing aldehyde moieties into the polymeric backbone. Then, the cysteamine 64 was attached to oxidized polysaccharide through a reductive alkylation reaction in the presence of NaBH4. Henceforth, the surface of the gold electrode was covered with cysteamine functionalized alginate 65 through covalent attachment of the free thiol groups to the Au surface. In the final step, the modification of alginate coated-Au electrode as support for immobilizing the enzyme was occurred by Ugi-4CR (Scheme 21). The enzyme-modified Au electrode 66 was further used for the construction of a biosensor and exhibited good sensitivity and fast electroanalytical response toward H2O2. In addition, the analytical device retained full activity after 1 month of storage at 4 °C.


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Scheme 21. Preparation of alginate-coated Au electrode for HRP immobilization through Ugi-4CR as an amperometric enzyme biosensor for hydrogen peroxide Pectin

Pectin is an anionic hetero-polysaccharide consists of (1→4) linked α-D-galacturonyl units occasionally interrupted by (1→2) linked α-L-rhamnopyranosyl residues which contained in the primary cell walls of 27 ACS Paragon Plus Environment


terrestrial plants and widely used as a gelling agent and emulsifiers.89 In an effort to develop environmentally benign hydrogels, in 2006, Nystrom and co-workers employed Ugi-4CR for gelation of semidilute solutions of pectin with the participation of formaldehyde, DAP and cyclohexyl isocyanide.90 Hereafter, rheological, turbidimetric and structural features of the systems during the gelation were investigated in details. The rheological results featured that increasing polymer and cross-linker concentrations promote faster gelation and give rise to stronger gels. Additionally, the gels were strengthened in the post-gel region; therefore the turbidities for most gelling systems were virtually constant with the prolonging reaction time. Another successful strategy was implemented by Mironov et al. for the synthesis of tailor-made polyampholyte microgels from colloidal salts of pectinic acid as pH-responsive emulsifiers.91 As shown in Scheme 22, initially the salt was performed by mixing pectinic acids 67 and benzylamine 7 in water. Thus, the 1,4-bis(3-isocyanopropyl)piperazine 35 and formaldehyde 9 were added to the colloidal suspension of pectinic acid salt. By increasing the degree of crosslinking, polyampholyte microgels 68 were obtained which protonated in acidic medium or deprotonated in basic medium. In continuation, by using different amine choices like furfurylamine, 4-picolylamine, and 3- (diethylamino)propylamine as well as water-soluble 4-fluorobenzylamine, they obtained different properties of particle size and surface, since decrease of the particle diameter occurred with increase of the amine solubility. Eventually, polyampholyte microgels as an effective pH-responsive Pickering emulsifier were identified, whereof at low concentrations (pH=2–3) formed stable oil-in-water emulsions and with raising the solution pH to 10 immediate demulsification happened.


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Scheme 22. pH-responsive emulsifier synthesis through Ugi-4CR functionalization of pectin (a), toluene-in-water emulsion of cross-linked microgel (b), at pH=8.5 (left tube) and pH=2 (right tube)91 Hyaluronan

Hyaluronan or hyaluronic acid (HA) is a linear polysaccharide with anionic, nonsulfated repeats of Dglucuronic acid and N-acetyl-D-glucosamine distributed widely throughout connective, epithelial, and neural tissues.92 Crescenzi and co-workers reported the Ugi-functionalization of partially deacylated hyaluronic acid (deHA) in continuation of their investigation on distinct polysaccharides functionalization with Ugi-4CR and Passerini-3CR. deHA chains are well suited for chemical gel formation by means of Ugi-4CR processes since they exhibit an appropriate degree of polymerization and due to the presence of both carboxylate and primary amino groups along the backbone. Chemical gels prepared with different degrees of cross-linking by means of Ugi-4CR involving aqueous deHA, formaldehyde, and cyclohexyl isocyanide.93 In continuation, structural elucidation and cross-linking degrees were obtained by NMR studies.94 Moreover, the same group described a hyaluronan networking via Ugi-4CR using deHA 69 and



lysine 70 as a cross-linking agent caused to Ugi-functionalized HA hydrogels 71 with suitable physical characteristic and good swelling properties (Scheme 23).95

Scheme 23. Hyaluronan networking via Ugi-4CR using lysine as cross-linker Agarose (SepharoseTM)

The pioneering works on the enzyme immobilization on the surface of sepharose, a tradename for a crosslinked beaded-form of agarose, a polysaccharide material extracted from seaweed,96 was carried out by Axen and co-worker.97 In short, they treated amine derivatives of sepharose with pepsin enzyme, cyclohexyl isocyanide and acetaldehyde by Ugi-4CR to generate water-insoluble pepsin composite with the ability to digest hemoglobin and bovine serum albumin. The fixed enzyme showed great activity after one month of storage. This method was further modified by the same group to improve the scope of enzyme input in the similar approach.21b, 98 Of late, there has been resurgence of interest in the construction of fully-synthetic low-molecular weight affinity ligands from small-molecule screening methodologies instead of biological ligands that suffered from instability, high production costs and low reusability.99 In a very interesting work in 2009, Lowe et al. profited from the outstanding features of MCRs; being “one-pot” and high-structural variations due their inherent combinatorial nature, to combining with chromatographic solid supports for rational design of spectrum of beneficial affinity ligands-modified sepharose supports via Ugi-4CR that are suitable for the purification of immunoglobulins and their fragments by affinity chromatography.100 By choosing different types of amine and carboxylic acids, the library of synthetic ligands were synthesized on the surface of the aldehyde-functionalized sepharose supports. Then, the synthetic ligands screened 30 ACS Paragon Plus Environment

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chromatographically against whole human immunoglobulin G (IgG) and its fragments (Fc and Fab) to yield a Fab-specific superior ligand based on its efficiency to bind Fab differentially over Fc. The adequate chosen ligand prepared through reaction of aldehyde-functionalized sepharose, 1-amino-2naphtol, glutaric acid and isopropyl isocyanide in MeOH at 50 °C. Accordingly, preparative chromatography of IgG from human serum showed 100% adsorption of IgG from the 20 mg/ml crude stock and subsequently elution with a purity of 81.0%, in addition with high purity Fab and IgG isolation from both yeast and E. coli host cell proteins (Scheme 24).

Scheme 24. Synthetic ligand-immobilized sepharose via Ugi-4CR for immunoglobulins purification by affinity chromatography In the years that thereafter, this Ugi-modification approach opens a new window to the combinatorial synthesis of pseudo-biospecific ligands modified sepharose-supports for purification of diverse kinds of proteins, caused to several reports based on the same methodology.101 The synthetic ligands have been employed efficiently for mimic Protein G for the purification of mammalian immunoglobulins 72,

102

mimicking the third domain of Protein G (domain III) and isolate highly pure IgG and Fab fragments from mammalian and yeast cell extracts 73,103 purification of recombinant human erythropoietin (rHuEPO) 74,104 interacting with glycan moieties on glycoproteins 75,105 purification of green fluorescent 31 ACS Paragon Plus Environment


protein (GFP) or GFP fusion proteins 76,106 and expression and purification of fusion proteins through “tag–receptor” affinity pair 77.107 (Scheme 25)

Scheme 25. Synthesis of different affinity ligands with Ugi-4CR for protein purification Furthermore, to expand the repertoire of novel affinity ligands, one-pot two-step Petasis-Ugi reaction was designed by Batalha and Roque.108 The Petasis reaction, also referred to the boronic acid Mannich reaction, is a MCR that enables the preparation of amines and their derivatives such as α-amino acids which discovered by Nicos Petasis in 1993.109 The reaction proceeds via an imine with the organic ligand of the boronic acid 78 acting as the nucleophile, similar to the role of the enolizable ketone component in the original Mannich reaction.110 The Petasis-3CR of produces α-amino acid scaffolds with free carboxylic acid 79, which can be further accompanied as a component in other MCRs, such as the Ugi reaction. (Scheme 26)


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Scheme 26. Petasis three-component reaction In this work, the combination of Petasis-3CR with Ugi-4CR caused to molecular diverse high-throughput solid-phase platforms for the enrichment of phosphorylated peptides due to the incorporation of a higher number of functional groups compared to the individual Ugi and Petasis reactions. First of all, the feasibility of modification of cross-linked sepharose with the Petasis-Ugi reaction was assessed with both boronic acid- and amine-functionalized sepharose beads and the amine-functionalized sepharose 80 was chosen as a substrate. Then, the Petasis-3CR was carried out using phenylboronic acid 81 and glyoxylic acid 82 subsequently the resultant Petasis-functionalized sepharose containing carboxylic acid 83 was mixed with different kinds of aldehydes 3, amines 2 and isopropyl isocyanide 84 in MeOH at 60 °C (Scheme 27). A library of 84 synthetic ligands was synthesized and finally, three lead ligands identified due to their superior performance in terms of binding capacity and selectivity towards the phosphorylated moiety on peptides.



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Scheme 27. Petasis-Ugi reaction using amine-functionalized sepharose as a solid support for the enrichment of phosphorylated peptides by affinity chromatography Proteins

Proteins are the other type of natural polymers which constitutes in almost all the living organisms and consisting of one or more long chains of amino acid residues. This polymer consists of amide groups present in the backbone chain of human body.111 The presence of amide segments makes these amidecontaining polymers unusual characteristic due to the high hydrogen bonding efficiency.112 Some important examples of proteins that have been utilized in MCRs are enzymes, collagen, keratin and wool. As described previously, the conjugation of enzymes on the surface of the materials with MCR approaches were mentioned in detail in every discussed material as immobilization processes. Collagen

Collagen is a natural polymer which holds our skin, tendons, muscles, and bones together, makes up about a quarter of the body's total protein.113 In 1992, Vrbova and Marek used collagen as a natural support for construction of an enzyme electrode for

D-galactose

determination by fixation with

immobilized galactose oxidase or co-immobilized galactose oxidase and catalase to a Clark-type oxygen sensor using the Ugi-4CR strategy.114 In this procedure the collagen was hydrolyzed by hydrochloric acid. Then, glucose oxidase and catalase solution were applied to the hydrolyzed surface, following the 34 ACS Paragon Plus Environment

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addition of glutaraldehyde solution and cyclohexyl isocyanide and incubation for 2-8 days at 4 °C. Then, the enzyme-immobilized collagen membrane was fixed on the tip of a Clark-type oxygen sensor. The prepared biosensor was used for the determination of D-galactose content in samples of blood plasma and serum of patients with suspected galactosemia. Keratin and wool

Axen et al. reported the covalent fixation of chymotrypsin on the surface of the keratin and wool, fibrous structural proteins, by utilization of Ugi approach.21a In the mentioned procedure, 50 mg of keratin or wool suspended in 2 ml distilled water by addition of enzyme. Then, 3-dimethylaminopropyl isocyanide, acetaldehyde and acetate were added and the mixture was stirred for 6 h in the pH of 6.5. Notably, chymotrypsin was attached to keratin and wool with retention of activity. Siliceous materials

Siliceous materials, inorganic polymers composed of silanol groups, have extensively been used as a support for the immobilization of enzymes which leads to neoteric and applicable biocatalysts or biosensors.115 In 2015, Mohammadi et al. introduced the Ugi-4CR as a novel covalent RML immobilization strategy on aldehyde-functionalized silica supports.116 Silica gel with moderate surface areas of 500 m2 g-1 and mesoporous silica nanoparticles (SBA-15) with surface area of 952 m2 g-1 and pore sizes of 10.2 nm were first functionalized with 3-glycidoxypropyltrimethoxysilane to produce epoxy functionalized silica and SBA-15. In order to accomplish Ugi-4CR, further modification was performed by oxidation of epoxy groups using NaIO4 solution to produce aldehyde groups on the surfaces of silica. In addition, the enzyme has amino and carboxylic acid functionality simultaneously and acts as twofunctional part of this four-component approach. The reaction was carried out by the addition of isocyanide in water (pH 7) at 25 °C, in which rapid immobilization of 10 and 60 mg of RML on 1 g of aldehyde functionalized silica and SBA-15 after 10 and 30 minutes was achieved, respectively. The results showed obvious improvement in loading capacity, specific activity, thermal stability and cosolvent stability of the Ugi-functionalized supports in the presence of three polar organic solvents (1propanol, 2-propanol and dioxane) in comparison with soluble enzyme. Finally, the applications of Ugifunctionalized silica supports were investigated for transesterification of colza oil with methanol to produce fatty acid methyl esters. For silica-RML, the yield of conversion of 43% was obtained after 72 h, while the biodiesel production in presence of 40% of tert-butanol increases to 75% in the same condition. In the case of SBA-RML, the conversion yield is about 28% in the solvent-free system but the presence of 40% of tert-butanol (v/v) in the reaction had a substantial effect on biodiesel production and caused to 99% yield after 72 h of incubation. 35 ACS Paragon Plus Environment


In the next year, Mohammadi and co-workers have made further innovation to this approach. They used an old trick for immobilization of biomolecules on epoxy-functionalized silica supports via a one-pot three-component reaction.117 Formerly, Kern and co-worker promoted the classical Passerini reaction with a utilization of epoxide or aziridine group 85 instead of aldehyde moiety. They showed that the ring opening of the epoxide or aziridine leads to a low energy cation, conducted to simple and atom-efficient three-component reaction which proceeds under mild conditions (Scheme 28).118

Scheme 28. Passerini-type three-component reaction with utilization of epoxide or aziridine instead of aldehyde In view of the above mechanism, the three-component reaction on the surface of epoxy-functionalized silica supports (silica gel and SBA-15) 86 were carried out in the presence of enzymes (Lipase B from Candida antarctica (CALB) 87 or RML) which supplies carboxylic acid groups and isocyanide 4 as a third component in water at 25 °C. The results represented very rapid immobilization of 10 and 40 mg of RML on 1 gr of the supports shortly after 30 minutes of incubation (Scheme 29). It should be noted that investigation on mechanism of immobilization revealed that the amino groups of the enzyme surface are not involved in the immobilization process. Afterward, the efficiencies of enzyme immobilized silica supports which synthesized through isocyanide-based three-component reaction were examined in enantioselective esterification of (R, S)-ibuprofen 88 with 1-propanol at three temperatures (0 °C, 25°C and 30 °C) in anhydrous isooctane, with the best result of an enantiomeric excess (ee) of 92% and Evalue of 29.9 for 5 mg of silica-epoxy-RML.


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Scheme 29. Covalent immobilization of CALB on epoxy-functionalized siliceous supports for kinetic resolution of rac-ibuprofen

In 2018, the same group was developed the Ugi-4CR approach for RML immobilization by utilization of amine-functionalized silica and SBA-15.119 The results exhibited rapid immobilization of 150 and 200 mg of RML on 1 g of silica-NH2 and SBA-NH2, respectively, which caused to 95–100% of immobilization yield. Finally, the enantioselectivity of the biocatalyst in kinetic resolution of racemic ibuprofen was investigated and the results revealed that silica-RML showed the best selectivity with 92.2% ee and Evalue of 33.9. Synthetic polymers

Different types of human-made polymers have participated in MCRs with the plethora of applications. In this section, we want to highlight neoteric applications of MCR-functionalized synthetic polymers with probably high potential for industrial applications. Polyamide

Nylon net

In 1974, Goldstein and co-workers represented the functionalization of nylon-6 with an Ugi-4CR approach for immobilization of trypsin.120 The procedure is based on the partial hydrolysis of nylon to increase the functionality of the polyamide backbone and resealing of the newly formed -COOH ••• NH2pairs. Then, 1,6-diisocyanohexane and acetaldehyde were added as the other components of Ugi-4CR caused to a derivatized nylon with isocyanide functional groups, polyisonitrile nylon (PIN-nylon). In the next step and for the examination of the generality of Ugi-4CR, the coupling of trypsin through either their amino or carboxyl groups to the surface of PIN-nylon was accomplished in an aqueous medium at neutral pH in the presence of acetaldehyde. Based on the same approach, the immobilization of the other



protease enzymes like papain, pepsin and chymotrypsin on Ugi-functionalized nylon were also reported.120 Interestingly the Ugi-4CR approach were utilized for covalent conjugation of different materials such as linear water-soluble polysaccharides, linear polyacrylamides, polyacrylic acid, polyvinylamine and polyvinylalcohol on the surface of nylon structures for modification of the surface properties of support materials.121 In 1990, Vrbova and Marek executed the co-immobilization of glucose oxidase and catalase on the surface of the net nylon with Ugi-4CR approach for the preparation of D-glucose biosensor.122 The reaction proceeded with partially hydrolyzed of nylon net 89 with a 3969 cm-1 mesh 2 and thickness of 100 µm by hydrochloric acid. Then, glucose oxidase and catalase solution 90 was applied to the hydrolyzed surface, with the final addition of glutaraldehyde solution 91 and cyclohexyl isocyanide 11 and incubation for 2-8 days at 4 °C, prepared enzyme-immobilized nylon membrane 92 (Scheme 30). Ultimately, by fixing the enzyme-immobilized nylon membrane on the tip of a Clark-type oxygen sensor the enzyme electrodes for the determination of D-glucose were prepared. This method had some advantages such as stronger bonding of two or four substituted amides and long-term stability of the biosensor compared to classical method of immobilization with condensation through glutaraldehyde alone. In 1992, they also enhanced their procedure parameters and used the prepared biosensor for the determination of

D-galactose

amount in blood plasma and serum of patients with suspected

galactosemia.114

Scheme 30. Co-immobilization of glucose oxidase and catalase on the nylon net through Ugi-4CR Polyamide and ionomer film

In a distinct work, Ugi-4CR efficiency for simultaneous immobilization of enzymes has come to aid the development of antimicrobial packaging materials that are applicable in food processing for prolongation of shelf-life of non-sterile, chilled or minimally processed foods.123 In this procedure, glucose oxidase and


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lysozyme were immobilized by the Ugi-4CR with glutaraldehyde and cyclohexyl isocyanide on polyamide and ionomer films commonly used polymers for food packaging, hydrolyzed by hydrochloric acid. This functionalization led to the stronger bonding of the enzyme, in contrast to the direct covalent bond formed by the reaction of amino groups with glutaraldehyde alone, although immobilization of lysozyme was unsuitable due to substantial loss of enzyme activity. Immobilized glucose oxidase showed higher storage and thermal stability and it was less sensitive to pH changes than free enzyme. Additionally, immobilized glucose oxidase on polyamide film retained more than 90% of its initial specific activity for 40 days of storage, whereas the activity of ionomer film was higher than 90% only for 20 days. The immobilized glucose oxidase on both films was nearly inactive (≤5%) after 250 days of storage. Importantly, the functionalized packaging materials exhibited sufficient activity to inhibit the growth of selected bacteria on the agar plates which makes them great candidates for industrial food packaging alternatives. Reverse osmosis membrane

The miracle of inherent “one-pot” diverse-substrate characteristic of MCRs comes to the aid of Pan and co-workers to facilitate the simultaneous antifouling and antibacterial functionalization of reverse osmosis (RO) membranes, which have the ability to reject colloidal or dissolved matter from an aqueous solution, and produce pure water, however, often limited by membrane fouling, which includes organic, inorganic and microbial pollution.124 This harmful fouling is mainly attributed to the surface hydrophilicity, charge and roughness of the membrane. Since the commercial RO membranes, contain carboxylic acid moieties on their surfaces they were served as an acid source in Ugi reaction. Methoxy poly(ethylene glycol) aldehyde (MPEG-CHO), with a high hydrophilic characteristic, was selected as an aldehyde part to either remove the organic and inorganic fouling. The amine scaffold, with the ability to harness the reproduction of the bacteria, was an amino-terminated antibacterial agent, tris(2-aminoethyl)amine (TAEA) or sulfamethoxazole (SMZ). The reaction was conducted in methanol with the immersing of RO membrane 93 samples in the presence of MPEG-CHO 94, TAEA 95 and methyl isocyanoacetate 96 under the nitrogen atmosphere at 25 °C for production of antifouling and antibacterial functionalized RO membrane 97 (Scheme 31). The results depicted that a high reactant concentration led to better antifouling performance but lower membrane flux, therefore, the reaction conditions of 10 mmol L-1 for each component and 12 h reaction time were optimized to prepare the functionalized membranes. The surface roughness decreased, surface charge showed weakened negative charges and hydrophilicity improved upon Ugi-4CR modification. The obtained membranes showed lower flux attenuation ratios and higher flux recovery ratios than the original membrane in both cases when fouled by protein or inorganic salt. In



addition, they represented prevalent antibacterial activity, which indicated by a 98.6% bacterial inhibition rate even for a 24 h culture.

Scheme 31. Simultaneous antifouling and antibacterial functionalization of RO membranes with Ugi4CR Polyester

Chemically modified polyesters which have isonitrile functional groups, 98 can be used as supports for enzyme immobilization through MCR approach. As an example, isocyanide functional groups were introduced on the surface of poly(ethy1ene terephthalate), Dacron 99, through Passerini-3CR, and then the trypsin or urease enzymes were covalently attached to the surface of Passerini-functionalized polyesters containing isocyanide scaffolds by the utilization of Ugi-4CR method in an aqueous buffer at neutral pH in the presence of acetaldehyde 100 and excess acetate 101, as described by Goldstein et al. (Scheme 32).125


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Scheme 32. Synthesis of the isocyanide derivatives of polyesters by Passerini-3CR and their subsequent enzyme functionalization through Ugi-4CR Polyacrylamide

To check the reactivity of the functionalized polyacrylamides as a missing part of MCR, Axen and coworker reported an efficient procedure for the synthesis of Ugi-functionalized polyacrylamide structures.21b In this procedure, a series of acetal- or aldehyde-substituted polyacrylamide carriers were used for the immobilization of chymotrypsin through Ugi-4CR. Moreover, Goldstein and co-worker investigated the versatility of isocyanide derivatives of polyacrylamide as an isocyanide segment in Ugi-4CR. The isocyanide derivatives were synthesized by a two-step procedure: a) N-hydroxymethylation of amide groups on the polymer by treatment with formaldehyde, and b) attachment of isonitrile side chains by a displacement reaction involving 1tosyloxy-3-isocyanopropane and alkoxide ions generated on methylolated polyacrylamide by treatment 41 ACS Paragon Plus Environment


with a strong base in a polar aprotic solvent. Then, the modified polyacrylamide beads participated in Ugi-4CR for immobilization of enzymes and two amino acids, tyrosine and methionine in aqueous buffers at neutral pH.126 Trypsin-polyacrylamide acting on N-benzoyl-L-arginine ethylester exhibited nonlinear Michaelis Menten kinetics and distorted pH activity profiles.127 Polyvinyl alcohol

Pendant side chains containing isonitrile functional groups were introduced onto the backbone of watersoluble polyvinyl alcohols structures by dissolution of the polymer in DMSO following by ionization of polymer hydroxyl groups with tert-butoxide and finally, reaction with 1-tosyloxy-3-isocyanopropane. Subsequently, the isocyano-polyvinyl alcohols participated in Ugi-4CR for immobilization of glycyl-Lleucine amide and trypsin enzymes with 98 µmol/g bound proteins and 80 % active proteins.121 Miscellaneous

In an early report of enzyme immobilization, Marek and co-workers enhanced the catalytic activity of glucose oxidase by binding it on the surface of the modified glycidyl methacrylate polymers through Ugi4CR approach.128 For this purpose, the glycoenzyme was reacted with periodate to prepare aldehyde groups in the glycosidic part and then participated in Ugi-4CR with amino-functionalized glycidyl methacrylate polymers, excess acetic acid and cyclohexyl isocyanide. Notably, the Ugi product showed higher activity than those products which prepared by the direct binding between the aldehyde groups and the amino groups of the polymeric carrier. In 2014, Monteiro et al. reported an efficient method for multi-functionalization of worm/rod polymeric micelles based on the multicomponent ring opening of thiolactones.129 In this procedure, the βthiolactone-functionalized worm/rods 102, diblock copolymers of pNIPAm and polystyrene (pSTY) at a weight fraction of 10 wt%, which produced through the temperature-directed morphology transformation method were opened by allylamine 103, and the resultant free thiol groups were subsequently reacted with dipyridyl disulfide 104 to form pyridyl disulfide groups, resulting in a bifunctional (alkene/ pyridine disulfide) worm/rod micelles 105 in a one-pot three-component manner (Scheme 33).


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N

S

O

S

N

O NH

NH

N

H2N 103

S

Buffer 8.0, 4 oC S

S HN S

N

O

S HN S

O NH

NH

104

102

105 = Worm/rod micelles (pNIPAm-co-pSTY)

Scheme 33. One-pot double modification of nanoworm/rods through three-component thiolactone ringopening In 2015, Theato and co-workers attempted to prepare novel polymers containing α-amino phosphonate through another important multicomponent reaction; Kabachnik–Fields three-component reaction (KF3CR). This reaction generates α-amino phosphonates 106, which are structural analogues to α-amino acids from oxo compounds 3, an amine 2 and a phosphite 107 (Scheme 34).130

Scheme 34. Kabachnik-Fields three-component reaction They utilized an organic-inorganic hybrid copolymer poly(methylsilsesquioxane)-co-poly(4-vinyl benzaldehyde) 108 which prepared through RAFT polymerization for coating of the silicon wafers or copper plates 109 that further participated in KF-3CR as an oxo component along with p-anisidine 110 and diisopropyl phosphonate 111 in 1,4-dioxane at 80 °C for 4 h. Then the synthesized α-amino phosphonates 112 were hydrolyzed to zwitterionic α-aminophosphonic acids 113 in the presence of trimethylsilyl bromide (TMSBr) (Scheme 35). Later, the same group explored the antifouling property of the α-aminophosphonic acids covered silicone surfaces. The results revealed the obvious antifouling ability of zwitterionic polymer covered surfaces against the adhesion of proteins and bacteria.131



Scheme 35. Modification of silicon wafers or copper plates via Kabachnik-Fields-3CR In an interesting study in 2018, Lowe and co-workers described the preliminary procedure for the design and development of the holographic sensor modified with Ugi-ligands for cocaine detection using a smartphone-based instrument.132 A library of ligands was designed based on the protein–cocaine interactions, particularly those of human carboxylesterase-1 and catalytic monoclonal antibody GNL7A1. The final chosen ligand was synthesized through Ugi-4CR of γ-aminobutyric acid, β-alanine and cyclohexyl isocyanide under the surface of the hybrid hydrogel of poly (2-hydroxyethyl methacrylate–coethylene dimethacrylate-co-methacrolein) as the carbonyl source in MeOH. The results confirmed the efficiency of this platform for the detection of cocaine at the same range of value in presumptive assays of the drug, with appropriate sensitivity. Magnetic nanoparticle

In following approaches for designing robust and efficient functionalized solid supports for affinity chromatography, in 2017 Roque et al. published the in situ synthesis of Ugi-based ligands on magnetic beads first the time and their application for the magnetic recovery of the cognate proteins.133 In this regard, dextran-coated magnetic particles were synthesized by the co-precipitation method. The magnetic particles were then aminated by suspending in a solution containing (3-aminopropyl)trithoxysilane, acetic 44 ACS Paragon Plus Environment

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acid and ethanol/water and incubated for 1 h at 70 °C with constant shaking. The aminated dextran-coated magnetic particles were resuspended in glutaric dialdehyde in a basic environment (1M NaOH). Then different ligands, which were tested previously,106a, 107a were anchored on the surface through Ugi-4CR. The applicability of these novel Ugi-based affinity ligands for the purification of GFP and tagged proteins was examined by magnetic fishing.

Noncovalent functionalization through multicomponent reaction Noncovalent functionalization is a strategic way to construct highly dispersed and applicable materials. As already mentioned, despite the substantial features of pristine carbon nanotubes, they are hydrophobic in nature, therefore they cannot be dissolved in general solvents and this poor solubility hampers their real applications in pharmaceutical and industries. Thus, it would be the urgent task to design the neoteric noncovalent functionalization strategies for the synthesis of highly dispersed CNTs. To make CNTs soluble in common solvents, and thereby avoid stacking and agglomeration, noncovalent functionalization with different organic compounds and polymers by π-π interactions is an attractive synthetic route because it offers the possibility of attaching desired functional groups to the surface of CNTs without disturbing the electronic network.134 Recently, the happy marriage of MCRs and polymer chemistry for noncovalent functionalization of CNTs has accelerated the preparation of highly dispersed CNT-polymer composites. In this context, the one-pot synthesis of CNT-(co)polymer through noncovalent functionalization was first developed by Tao et al. with the vision of combining the MCRs and material chemistry through “grafting to” approaches. In 2014, they reported a new one-pot hexa-component system for simple polymer-conjugation on CNT through the Ugi reaction to efficiently collaborate with π-π stacking and RAFT polymerization.135 As illustrated in Scheme 36, 1-pyrenecarboxaldehyde 114 was used for π-π stacking with MWCNT 115 and as the aldehyde source of Ugi reaction; a trithiocarbonate 116 (for RAFT polymerization) containing a carboxylic group was selected as the carboxylic source; aniline 19 and cyclohexyl isocyanide 11 acted as the amine and the isocyanide moieties, respectively. Then they were mixed with 2,2'azobis(2methylpropionitrile) (AIBN, initiator for RAFT) and NIPAAm 117 (monomer for RAFT) in a methanol at 65 °C. In the following investigation, the reaction was operated under the same conditions only using aniline terminated methoxypolyethylene glycol (mPEG-NH2Mn ~ 5150) instead of aniline as the amine moiety. Also, the CNT hydrogel was prepared through the supramolecular interaction between MWCNT-copolymer and α-cyclodextrin (α-CD) suggesting the PEG on MWCNT surface is the critical



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gelator to create that supramolecular hydrogel. The results showed that synthesized CNT-(co)polymers showed good dispersity in both organic and aqueous solvents.

stacking 114 CHO NC

11

115

19 S 117

O HN

S

S

MeOH, 65 oC

Ugi

NH2 O H OH N O 116

CNT-co-polymer

=H or PEG RAFT

Scheme 36. Noncovalent modification of MWCNT through the one-pot strategy combining Ugi-4CR, π-

π stacking and RAFT polymerization In continuation, in 2015, Tao et al. made further differences to this approach. Based on that result, they synthesized another soluble CNT-polymer composite by the combination of noncovalent π-π stacking and the Biginelli reaction, a famous three-component reaction.136 The Biginelli reaction, involves the one-pot condensation of an aldehyde 3, a β-ketoester 118, and urea 119 under strongly acidic conditions for the preparation of dihydropyrimidione 120, which was first reported by Biginelli in 1893 (Scheme 37).137


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Scheme 37. Biginelli three-component reaction Tao and his group was chosen the formylpyrene 114 as a sticking agent on MWCNT surface also aldehyde moiety for participating in the Biginelli-3CR and the 1,3-dione terminated mPEG and pNIPAm 121 as a ketoester part in acetic acid as a solvent and in the presence of magnesium chloride and p-toluene sulfonic acid (p-TSA) as the catalyst (Scheme 38). The MWCNT-polymer composites 122 showed well dispersity in common organic and aqueous solvents and inherited the properties of polymers such as forming supramolecular hydrogel with α-CD.

ck sta

g in

gin Bi i el l

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Scheme 38. Surface modification of MWCNT through the combining Biginelli-3CR and π-π stacking To further explore the scope and generality of this approach, they introduced another three-component reaction for noncovalent functionalization of MWCNT; MALI reaction.138 As shown in Scheme 39, 1aminopyrene 123 was selected as the bridge to stack on MWCNT surface while taking part in the MALI reaction as the amine source and aldehyde terminated mPEG and poly(methylmethacrylate) (PMMA) 124 47 ACS Paragon Plus Environment


as an aldehyde part. The reaction was carried out in acetic acid at 25 °C for 5h. The obvious solubility improvement of MWCNT with mPEG-1900 was observed, the composite dispersed in solvents and trace sediment was found after two weeks. The MWCNT–mPEG 125 dissolved so well in solvents with no obvious precipitation even after one month.

Scheme 39. Noncovalent modification of MWCNT surface through the MALI-3CR and π-π stacking

Summary and outlook The present review provides insight into the comprehensive strategies of materials functionalization with the various MCRs for preparing functionalized materials of industrial interest. The functionalization modes classified according to the materials used and MCRs as such have been categorized into two synthetic routes; covalent and non-covalent functionalization through MCRs. Covalent functionalization of materials via MCRs are more interesting as they provide a strong real bond between the surface and the organic scaffolds. In this regard, diverse kinds of amine, carboxyl, carbonyl and isonitrile functionalized materials were employed as one part of the MCR for construction of tailor-made materials. Functionalization of materials with aldehyde groups and further participation in MCRs is more challenging but has been accomplished on the surface of some polysaccharides and silica nanoparticles in four-step procedures. In the case of rational design of novel ligands for affinity chromatography or catalyst, MCRs allow for a great diversity by incorporating three or more reactants, each of which can be varied systematically to produce a huge variety of subtle changes to the final ligand structure.


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Many of the mentioned materials such as carbonaceous materials and polysaccharides suffer from their low solubility or even non-biocompatibility. It is imperative that these synthetic issues are addressed in many MCR-functionalized cases so that materials can gain the highly promised application potential. More importantly, the ability of MCR to create crosslinked biocompatible polysaccharide-based hydrogels under mild pH and temperature conditions makes these functionalized-materials particularly attractive for biomedical applications including drug delivery and biosensors. The important distinction between the Ugi-4CR and Passerini-3CR for functionalization/modification of polysaccharides comes from this fact that the ester linkage, produced from Passerini-3CR, can be easily hydrolyzed at only slightly alkaline pH, whereas the amide linkages between the polysaccharide chains of Ugi-functionalized polysaccharides is stable at alkaline conditions.83a Thanks to the high molecular diversity and one-pot characteristic of MCRs, simultaneous attachment of two or more materials, enzymes and biomolecules also antifouling and antibacterial agents on the solid support is possible. Since, the previous membrane modifications approaches for reducing the fouling mainly caused to a single functional group attached to the surface which can only eliminate one type of pollution or needed the long-term multi-step reactions for preparing the RO membrane with both antifouling and antibacterial characteristic, MCRs can be great alternatives for membrane functionalization from a status of being one-pot high-diverse functionalization procedure. Non-covalent approaches that have been synthesized on the surface of MWCNTs till now were combined with polymer synthesis for construction of innovative and applied polymeric materials. These procedures maintain the basic structure of CNTs and retain their unique properties such as electro-conductivity and thermal stability. The MCRs also make it possible to develop branched, cyclized, and 3D polymeric materials with unique physical and structural properties. However, despite tremendous advances of MCR-functionalized materials and their widespread applications in recent years, some aspects require further research and it is firmly believed that the application of MCRs for materials functionalization will continue to grow steadily. For instance, the major challenge for the near future is the development of improved sequential or tandem MCRs for superior materials functionalization. In addition, combining new materials with MCRs can address the lack of designed ligand containing catalysts for metal immobilization for organic transformations. This protocol can also be easily used to conjugate any other useful biomolecules with an amine or carboxylic groups, such as nucleic acids and antibodies on the surface of the highly stable materials for medicinal applications. Last but not least, many other less-known MCRs with useful products can also be applied to 49 ACS Paragon Plus Environment


this functionalization. While in one case described here, the concept of the union of MCRs was used for the functionalization of high-performance agarose-functionalized affinity solid-supports with sequential Petasis-Ugi reaction, it seems that there is still room for investigation of the union of MCRs in these approaches. The MCR functionalized materials have shown widespread applications in many interdisciplinary fields and they have to an extent already become commercially available. Therefore it is predictable that more and more MCRs-functionalized materials have continued to emerge and set the new point for more imaginative technologies and equipment in many industrial applications over the coming years with the intensive collaboration of chemists and material scientists. We believe that this study will be interesting for scientists from the different field of materials, chemistry and polymer for design and development of novel materials, combinatorial chemistry, drug carriers, catalytic and analytical systems, polymer synthesis and water treatment; also, it will be interesting for scientists from pharmaceutical and medicinal chemistry, dentistry and bio-imaging.

List of acronyms and abbreviations MCRs

Multicomponent reaction

4CR

Four-component reaction

3CR

Three-component reaction

I-MCR

Isocyanide-based multicomponent reaction

AIE

Aggregation-induced emission

CNTs

Carbon nanotubes

GO-COOH

Carboxylated-graphene oxide

BTL

Bacillus thermocatenulatus lipase

RML

Rhizomucor miehei lipase

pDNA

Plasmid DNA

EtBr

Ethidium bromide

AGS cells

Human gastric adenocarcinoma cells

GO-f-EtBr

EtBr-functionalized graphene oxide nanocomposite

Carboxamide-f-GO

Carboxamide functionalized graphene oxide

DES

Deep eutectic solvent

MWCNTs

Multi-wall carbon nanotubes


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MWCNT-COCl

Acyl-chloride multi-wall carbon nanotubes

MKN-45 cells

Human gastric cells

MCF7 cells

Breast cancer cells

Carboxamide-f-MWCNTs Carboxamide functionalized multi-wall carbon nanotubes FA

Folic acid

NIH-3T3 cells

Human fibroblast cells

PEG

Polyethyleneglycol

AP

Acidic phosphatase

LDH

L-( + )-lactate dehydrogenase

POS

Partially oxidized scleroglucan

POP

Partially oxidized pullulan

CMC

Carboxymethyl cellulose

CMD

Carboxymethyl dextran

CMS

Carboxymethyl scleroglucan

OxS

C6-oxidized scleroglucan

CMS

Carboxymethyl scleroglucans

CMX

Carboxymethyl xylan

CMP

Carboxymethyl pullulan

NaOH

Sodium hydroxide

THF

Tetrahydrofuran

DCM

Dichloromethane

MeOH

Methanol

DMSO

Dimethyl sulfoxide

DMF

N,N-dimethylformamide

DMA

N,N-dimethylacetamide

HCl

Hydrochloric acid

CHCl3

Chloroform

CH3CN

Acetonitrile

AcOH

Acetic acid 51 ACS Paragon Plus Environment


PBS

Phosphate buffer saline

CPs

Capsular polysaccharides

DT

Diphtheria

TT

Tetanus toxoids

pNIPAm

Poly(N-isopropylacrylamide)

TOCNs

TEMPO-oxidized cellulose nanofibers

RAFT

Reversible Addition-Fragmentation Chain-Transfer polymerization

MALI

Mercaptoacetic acid locking imine

WS-Chitosan

Water-soluble chitosan

H2O2

Hydrogen peroxide

An-CHO

9,10-Bis(aldehydephenl)anthracene

TPE-CHO

4-(1,2,2-triphenylvinyl) benzaldehyde

CMS

Carboxyl methyl starch

DAP

1,5-Diaminopentane

SDS

Sodium dodecyl sulfate

HRP

Horseradish peroxidase

NaIO4

Sodium periodate

NaBH4

Sodium borohydride

HA

Hyaluronic acid

deHA

Deacylated hyaloronic acid

IgG

Human immunoglobulin G

Fc

Fragment crystallizable region of antibody

Fab

Fragment antigen-binding region of antibody

rHuEPO

Recombinant human erythropoietin

GFP

Green fluorescent protein

SBA-15

Mesoporous silica nanoparticles

CALB

Candida antarctica lipase

MPEG-CHO

Methoxy poly(ethylene glycol) aldehyde

TAEA

Tris(2-aminoethyl)amine 52 ACS Paragon Plus Environment

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SMZ

Sulfamethoxazole

AIBN

2,2'-azobis(2 methylpropionitrile)

pSTY

Polystyrene

NIPAAm

N-isopropylacrylamide

mPEG

Methoxypolyethylene glycol

α-CD

α-Cyclodextrin

p-TSA

p-Toluene sulfonic acid

PMMA

Poly(methylmethacrylate)

Conflicts of interest There are no conflicts of interest to declare.

Acknowledgments We gratefully acknowledge financial support from the Iran National Science Foundation (INSF) and the Research Council of Shahid Beheshti University.

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The union of materials chemistry with multicomponent reactions (MCRs) opens a new avenue leading to the realm of highly innovative functionalized architectures with unique features which have found wide applications in different fields of modern technologies such as medicinal applications and drug delivery, enzyme immobilization, electrodes, biosensors, biodiesel, water treatments, emulsifiers, catalysts, affinity chromatography and food packaging. 162x55mm (72 x 72 DPI)

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