Passerini Three-component Reaction Research Articles

Sustainable Functionalization of 2,3-Dialdehyde Cellulose via the Passerini Three-Component Reaction

Cellulose-based materials have gained more and more interest due to the increasing dependency of mankind on petroleum-based resources, especially during the last few decades. In this work, we report a mild and efficient method to modify 2,3-dialdehyde cellulose (DAC) via the Passerini three-component reaction (P-3CR) in an aqueous medium. Microcrystalline cellulose (MCC) was first oxidized to DAC and further reacted with different renewable carboxylic acids and commercially available isocyanides to obtain molecularly diverse modifications of cellulose with a degree of substitution (DS) ranging from 0.62 to 0.94. Confirmation of the structure of the obtained product was achieved via IR as well as 1H and 13C NMR. Differential scanning calorimetry (DSC) revealed glass transition temperatures (Tg) between 121 and 166 °C, depending on the chosen components for the P-3CR. Thus, we show a novel way to homogeneously modify DAC, which was so far mostly achieved by imine formation.

Catalyst-free synthesis of borodepsipeptides using isocyano arylboronate under aqueous condition

Herein, the synthesis of borodepsipeptides utilizing boron-containing isocyanides is described. The target compounds were synthesized via Passerini three-component reaction (P-3CR), in which H2O was utilized as the solvent. Further, unlike conventional P-3CR, where Lewis acid catalysts are often required, the reported method requires no catalyst and proceeds in room temperature. A variety of aldehydes and acids were used as the building blocks to generate the desired products.

The Passerini three-component reaction of aldehyde end-functionalized polymers via RAFT polymerization using chain transfer agents featuring aldehyde

In this study, a novel pyrazole–carbodithioate-based chain transfer agent (CTA) featuring an aldehyde group (CTA-CHO) was designed and synthesized for RAFT polymerization. The obtained CTA-CHO was employed for the RAFT polymerization of styrene to afford well-defined polystyrenes bearing an aldehyde at their chain ends with low Ð values (~1.1). In addition, the reactivity of the aldehyde moiety at the end of the chain was precisely evaluated, while the Passerini three-component reaction was successfully performed on the aldehyde group. In this study, a novel pyrazole–carbodithioate-based chain transfer agent (CTA) featuring an aldehyde group (CTA-CHO) was designed and synthesized. The newly synthesized CTA-CHO was used for the RAFT polymerization of styrene to afford well-defined polystyrenes end-functionalized with an aldehyde unit (PSt-end-CHO). The obtained PSt-end-CHOs feature low Ð values (~1.1), suggesting a living nature of the polymerization. Furthermore, the Passerini three-component reaction was successfully performed on the PSt-end-CHOs.

Dual sequence definition increases the data storage capacity of sequence-defined macromolecules

Sequence-defined macromolecules offer applications in the field of data storage. Challenges include synthesising precise and pure sequences, reading stored information and increasing data storage capacity. Herein, the synthesis of dual sequence-defined oligomers and their application for data storage is demonstrated. While applying the well-established Passerini three-component reaction, the degree of definition of the prepared monodisperse macromolecules is improved compared to previous reports by utilising nine specifically designed isocyanide monomers to introduce backbone definition. The monomers are combined with various aldehyde components to synthesise dual-sequence defined oligomers. Thus, the side chains and the backbones of these macromolecules can be varied independently, exhibiting increased molecular diversity and hence data storage capacity per repeat unit. In case of a dual sequence-defined pentamer, 33 bits are achieved in a single molecule. The oligomers are obtained in multigram scale and excellent purity. Sequential read-out by tandem ESI-MS/MS verifies the high data storage capacity of the prepared oligomers per repeat unit in comparison to other sequence defined macromolecules.

Multifunctionalization of cellulose microfibrils through a cascade pathway entailing the sustainable Passerini multi-component reaction

Through a cascade of chemical derivatizations involving the green Passerini three-component reaction (P-3CR), we describe herein the multifunctionnalization of cellulose microfibrils (MFC) previously subjected to a periodate oxidation step.

On-Resin Passerini Reaction toward C-Terminal Photocaged Peptides.

An on-resin, three-component Passerini reaction was developed to synthesize C-terminal photocaged peptides. Highly compatible with conventional Fmoc SPPS, this reaction produces peptides with a C-terminal o-amido-6-nitroveratryl (αANV) ester in one pot with conserved chirality. Under physiological conditions, the C-terminal αANV ester rapidly photolyzed to revert to carboxylate, offering a convenient method for optical control of cellular signals by modulating the C-terminal carboxylate.

Sustainable Modification of Carboxymethyl Cellulose by Passerini Three-Component Reaction and Subsequent Adsorption onto Cellulosic Substrates

The present work describes the chemical modification of carboxymethyl cellulose (CMC), a widely diffused commercial cellulose ether, by means of the Passerini three-component reaction (P-3CR). The reaction, performed in homogeneous aqueous medium, was proven to be effective at combining the carboxyl groups of CMC with different aldehydes and isocyanides, leading to the formation of a wide library of Passerini-modified CMC derivatives, in a simple and environmentally friendly one-pot process. The derivatized CMC products were thoroughly characterized to confirm the modification and determine the degrees of substitution (DS). The impact of experimental parameters (i.e., reaction T, time and pH, amount of employed reagents) and structure of the reactants (different aldehydes and isocyanides) on the reaction outcome was also discussed to explore the potential of this original approach for polysaccharide modification. Finally, the adsorption ability of selected CMC samples onto a model cellulosic surface was characterized by means of quartz crystal microbalance with energy dissipation monitoring (QCM-D). The analysis confirmed the successful adsorption of the Passerini-modified CMC derivatives and highlighted a positive effect of the derivatization on the amount of adsorbed polymer. Not only does the developed strategy appear as a mild and sustainable route for CMC functionalization, but also the promising adsorption ability of the functionalized derivatives opens the path toward the straightforward modification of surface properties of cellulosic substrates.

Synthesis of novel α-acyloxyamides using choline chloride-based deep eutectic solvent

The Passerini three-component reaction between acenaphthylene-1,2-dione, alkyl isocyanides, and carboxylic acids, leading to the formation of α-acyloxyamides in common organic solvents (CH2Cl2, MeOH) and choline chloride-based deep eutectic solvent, is described. The reaction in the latter solvent proceeded faster compared to common organic solvents. The structure of a typical product was confirmed by X-ray crystallography.

Enhancing Antioxidant Effect against Peroxyl Radical-Induced Oxidation of DNA: Linking with Ferrocene Moiety!

As a major member in the family of reactive oxygen species, peroxyl radical is able to abstract hydrogen atom from 4-position of ribose, leading to the collapse of DNA strand. Thus, inhibiting oxidative stress with exogenous antioxidants acts as a promising strategy to protect the integrity of DNA structure and is thereby suggested to be a pathway against developments of related diseases. Ferrocene as an organometallic scaffold is widely applied in the design of organometallic drugs, and redox of Fe(II)/Fe(III) in ferrocene offers advantage for providing electron to radicals. Presented herein are our ongoing studies on ferrocene-appended antioxidants, including McMurry reaction applied to construct ferrocifen; Aldol condensation used to prepare ferrocenyl curcumin; Povarov reaction employed to prepare ferrocenyl quinoline; Biginelli reaction used to construct ferrocenyl dihydropyrimidine; Groebke reaction used to synthesize ferrocenyl imidazo[1,2-a]pyridine; and Passerini three-component reaction as well as Ugi four-component reaction applied to synthesize α-acyloxycarboxamide and bisamide, respectively. It is found that ferrocene moiety is able to enhance antioxidative effect of the aforementioned scaffolds even without the aid of phenolic hydroxyl group. The role of ferrocene in enhancing antioxidative effect can be attributable to trapping radicals, decreasing oxidative potential, and increasing the affinity toward DNA strand. Therefore, ferrocene is worthy to be taken into consideration in the design of drugs in relation to DNA oxidation.

Functional Poly(ester–amide)s with Tertiary Ester Linkages via the Passerini Multicomponent Polymerization of a Dicarboxylic Acid and a Diisocyanide with Different Electron-Deficient Ketones

We describe a straightforward synthetic strategy for a new family of functional poly(ester–amide)s (PEAs) with tertiary ester linkages via the Passerini multicomponent polymerization (Passerini-MCP) of a diacid (A2), 1,6-diisocyanohexane (B2), and four kinds of electron-deficient ketones. First, Passerini three-component reactions (Passerni-3CR) of hexanoic acid and tert-butyl isocyanide with nine kinds of ketones were investigated to evaluate the reactivities of these ketones toward Passerni-3CR. Four electron-deficient ketones, 1,1,1-trifluoroacetone (1), 1,1,1-trifluoroacetophenone (2), ethyl pyruvate (3), and 2,3-butanedione (4), were found to be excellent oxo-compounds for this Passerini-3CR. Then, the Passerini-MCP of A2 and B2 with 1, 2, 3, and 4 in CH2Cl2 was performed to generate polymers P1–P4 with tertiary ester linkages and different electron-withdrawing substituents. Polymer P5 was also prepared by the Passerini-MCP of A2 and B2 with phenylacetaldehyde (5) for comparison. Size exclusion chrom...

An Unprecedented Retro-Mumm Rearrangement Revealed by ESI-MS/MS, IRMPD Spectroscopy, and DFT Calculations.

Brønsted acids and protic solvents mediate acyl transfer, known as the Mumm rearrangement, from imidates to the corresponding acylamides. This represents a key step in several reactions, for example, the Ugi four-component reaction (U-4CR) and Passerini three-component reaction (P-3CR). Herein, an unprecedented break of the non-reversibility of the Mumm rearrangement is reported. A combination of electrospray tandem mass spectrometry (ESI-MS/MS), infrared multiphoton dissociation (IRMPD) ion spectroscopy and theoretical calculations demonstrates the occurrence of the retro-Mumm rearrangement of protonated isopeptides in the gas phase. In the gas phase, the extra proton acquired during ESI promotes the backward isomerisation reaction in a catalytic fashion.

Covalent Tethering of Temperature Responsive pNIPAm onto TEMPO-Oxidized Cellulose Nanofibrils via Three-Component Passerini Reaction.

A critical challenge in the application of functional cellulose fibrils is to perform efficient surface modification without disrupting the original properties. Three-component Passerini reaction (Passerini 3-CR) is regarded as an effective functionalization approach which can be carried out under mild and fast reaction condition. In this study, we investigated the application of Passerini 3-CR for the synthesis of thermoresponsive cellulose fibrils by covalently tethering poly(N-isopropylacrylamide) in aqueous condition at ambient temperature. The three components, a TEMPO-oxidized cellulose nanofiber bearing carboxylic acid moieties (TOCN-COOH), a functionalized polymer with aldehyde group (pNIPAm-COH) and a cyclohexyl isocyanide, were reacted in one pot resulting in 36% of grafting efficiency within 30 min. The chemical coupling was evidenced by improved aqueous dispersibility, which was further confirmed by FT-IR, TGA, UV-vis, and turbidity study. It was observed that the grafting efficiency is strongly dependent on the chain length of the polymer. Furthermore, AFM and X-ray diffraction measurements affirmed the suitability of the proposed method for chemical modification of cellulose nanofibers without significantly compromising the original morphology and structural integrity.

A Combined Photochemical and Multicomponent Reaction Approach to Precision Oligomers.

We introduce the convergent synthesis of linear monodisperse sequence-defined oligomers through a unique approach, combining the Passerini three-component reaction (P-3CR) and a Diels-Alder (DA) reaction based on photocaged dienes. A set of oligomers is prepared resting on a Passerini linker unit carrying an isocyano group for chain extension by P-3CR and a maleimide moiety for photoenol conjugation enabling a modular approach for chain growth. Monodisperse oligomers are accessible in a stepwise fashion by switching between both reaction types. Employing sebacic acid as a core unit allows the synthesis of a library of symmetric sequence-defined oligomers. The oligomers consist of alternating P-3CR and photoblocks with molecular weights up to 3532.16 g mol-1 , demonstrating the successful switching from P-3CR to photoenol conjugation. In-depth characterization was carried out including size-exclusion chromatography (SEC), high-resolution electrospray ionization mass spectrometry (ESI-MS) and NMR spectroscopy, evidencing the monodisperse nature of the precision oligomers.

Combining Two Methods of Sequence Definition in a Convergent Approach: Scalable Synthesis of Highly Defined and Multifunctionalized Macromolecules.

The straightforward convergent synthesis of sequence-defined and multifunctionalized macromolecules is described herein. The first combination of two efficient approaches for the synthesis of sequence-defined macromolecules is reported: thiolactone chemistry and the Passerini three-component reaction (P-3CR). The thiolactone moiety was used as protecting group for the thiol, allowing the synthesis of a library of sequence-defined α,ω-functionalized building blocks. These building blocks were subsequently efficiently coupled to oligomers with carboxylic acid functionalities in a P-3CR. Thus, larger oligomers with molecular weights of up to 4629.73 g mol-1 were obtained in gram quantities in a convergent approach along with the introduction of independently selectable side chains (up to 15), thus clearly demonstrating the high versatility and the efficiency of the reported approach.

High-throughput polymer screening in microreactors: boosting the Passerini three component reaction

The Passerini three-component reaction (Passerini-3CR) has been studied via on-line microreactor/electrospray ionisation mass spectrometry (MRT/ESI-MS) reaction monitoring to demonstrate the high-throughput screening potential of microreactors for macromolecular design.

Self-Assembly of Amphiphilic Drug-Dye Conjugates into Nanoparticles for Imaging and Chemotherapy.

An amphiphilic drug-dye conjugate (PTX-Pt-BDP) was designed and synthesized with a platinum compound as the hydrophilic head. The precursor of PTX-Pt-BDP was obtained under mild conditions by means of a three-component Passerini reaction. PTX-Pt-BDP could self-assemble into nanoparticles (PTX-Pt-BDP NPs) in aqueous solution via a nanoprecipitation method. The obtained nanoparticles exhibited favorable structural stability in both water and physiological environment. PTX-Pt-BDP NPs could be endocytosed by cancer cells as revealed by confocal laser scanning microscopy and exert potent cytotoxicity. This work highlights the potential of nanomedicines from amphiphilic drug-dye conjugates for cancer cell imaging and chemotherapy.

Synthesis of polyacrylates from limonene by catalytic oxidation and multi-component reaction

A new strategy to obtain polyacrylates from limonene via regioselective catalytic acetoxylation, catalytic isomerization and subsequent Passerini three-component reaction (P-3CR) is described. The acetoxylated limonene derivative, selectively functionalized at the exocyclic double bond, was synthesized by a palladium-catalyzed C-H activation process in the presence of para-benzoquinone (BQ) as reoxidation agent and acetic acid in dimethyl sulfoxide. The obtained product was further saponified and subsequently isomerized under mild conditions into the corresponding aldehyde using a hydrogen-activated palladium catalyst. The resulting aldehyde, acrylic acid and various isocyanides were then used in the Passerini three-component reaction (P-3CR) in order to obtain several acrylate monomers in a straightforward and atom economic process. In subsequent free radical polymerizations using AIBN as thermal initiator, polyacrylates with molecular weights (Mn) up to 30kDa were obtained and carefully characterized by SEC, NMR and DSC analysis.

Passerini three-component cascade reactions in deep eutectic solvent: an environmentally benign and rapid system for the synthesis of α-acyloxyamides

A greener synthesis of α-acyloxyamides was achieved by one-pot three component cascade Passerini reactions in a deep eutectic solvent (DES). Reactions proceeded rapidly and afforded the corresponding α-acyloxyamides by a variety of aldehydes, acids and isocyanides in excellent yields. The DES has the advantages of easy workup, high yield, and an environmentally benign and, moreover, shortened time as the greatest exclusivity of this system compared with previously reported methods. Passerini three-component cascade reaction in a deep eutectic solvent: an environmentally benign and rapid system for the synthesis of α-acyloxyamides.

A Scalable and High-Yield Strategy for the Synthesis of Sequence-Defined Macromolecules.

The efficient synthesis of a sequence-defined decamer, its characterization, and its straightforward dimerization through self-metathesis are described. For this purpose, a monoprotected AB monomer was designed and used to synthesize a decamer bearing ten different and selectable side chains by iterative Passerini three-component reaction (P-3CR) and subsequent deprotection. The highly efficient procedure provided excellent yields and allows for the multigram-scale synthesis of such perfectly defined macromolecules. An olefin was introduced at the end of the synthesis, allowing the self-metathesis reaction of the resulting decamer to provide a sequence-defined 20-mer with a molecular weight of 7046.40 g mol(-1). The obtained oligomers were carefully characterized by NMR and IR spectroscopy, GPC and GPC coupled to ESI-MS, and mass spectrometry (FAB and orbitrap ESI-MS).

A novel and green synthesis of indolone-N-amino acid derivatives via the Passerini three-component reactions in water

Abstract A green Passerini three-component reaction of 2-(4-oxo-4,5,6,7-tetrahydro-1 H -indol-1-yl)acetic acid with alkyl or aryl isocyanides and aldehydes was reported under aqueous conditions at 35 °C for 1 h, and 21 indolone- N -amino acid derivatives were prepared in high yields of 42%–99%. Their structures were characterized by IR, ESI–MS, NMR and elemental analysis, and the possible mechanisms have been also proposed. The highly efficient and eco-friendly method provides a facile access to a library of indolone- N -amino acid derivatives for future research on bioactivity screening.