Atom Transfer Radical Reactions Research Articles

Sustainable methods for producing food-derived bioactive compounds

Background: Pursuing alternative starting materials has gained significant importance in the food and drug industries, driven by the global shift towards sustainable and renewable resources. Terpenes, naturally occurring hydrocarbons derived from plants, present a promising solution due to their abundant availability and range of physiological activities, including antioxidant, anti-inflammatory, antimicrobial, and anticancer properties. Objective: This study aims to develop a waste-free synthesis methodology for functionalizing limonene and myrcene, two notable terpenes, through Atom Transfer Radical Reactions (ATRR). The objective is to achieve high yields and purities while enhancing the therapeutic potential of these compounds and adhering to green chemistry principles. Methods: A catalytic complex of Cu(I)Br and dimethyl sulfoxide (DMSO) was used to facilitate the coupling of limonene and myrcene with various trichloroacetic acid derivatives. Reactions were performed at 80°C for 90 minutes, and products were purified by column chromatography. The synthesized compounds were characterized using Gas Chromatography-Mass Spectrometry (GC-MS) and Nuclear Magnetic Resonance (NMR). Microbiological analyses were conducted using the disk-diffusion method, and statistical analyses were performed to assess the reliability of the experiments. Results: The ATRR methodology enabled the efficient functionalization of limonene and myrcene, achieving high yields and purities. The best yield for limonene was 70%, and for myrcene, 82%, both using trichloroacetonitrile. The Cu(I) catalytic system showed dualistic biological effects, with 3% concentration exhibiting strong bactericidal and fungicidal activity, while 0.03% promoted growth. These results demonstrate the potential of the methodology and the catalytic system for bioactive compound synthesis and agricultural applications. Conclusion: This study demonstrates the viability of ATRR for efficiently functionalizing limonene and myrcene, achieving high yields and purities. The synthesized compounds show promise for pharmaceutical development. The dual antibacterial and antifungal activities of the Cu(I) catalytic system also suggest potential applications in wastewater reutilization. Future work should explore the biological effects and environmental impact of this process. Keywords: Terpenes, ATR reactions, Green Chemistry, Bioactive compounds, Therapeutic potential.

Reactivity Prediction of Cu-Catalyzed Halogen Atom Transfer Reactions Using Data-Driven Techniques.

In catalysis, linear free energy relationships (LFERs) are commonly used to identify reaction descriptors that enable the prediction of outcomes and the design of more effective catalysts. Herein, LFERs are established for the reductive cleavage of the C(sp3)-X bond in alkyl halides (RX) by Cu complexes. This reaction represents the activation step in atom transfer radical polymerization and atom transfer radical addition/cyclization. The values of the activation rate constant, kact, for 107 Cu complex/RX couples in 5 different solvents spanning over 13 orders of magnitude were effectively interpolated by the equation: log kact = sC(I + C + S), where I, C, and S are, respectively, the initiator, catalyst, and solvent parameters, and sC is the catalyst-specific sensitivity parameter. Furthermore, each of these parameters was correlated to relevant descriptors, which included the bond dissociation free energy of RX and its Tolman cone angle θ, the electron affinity of X, the radical stabilization energy, the standard reduction potential of the Cu complex, the polarizability parameter π* of the solvent, and the distortion energy of the complex in its transition state. This set of descriptors establishes the fundamental properties of Cu complexes and RX that determine their reactivity and that need to be considered when designing novel systems for atom transfer radical reactions. Finally, a multivariate linear regression (MLR) approach was adopted to develop an objective model that surpassed the predictive capability of the LFER equation. Thus, the MLR model was employed to predict kact values for >2000 Cu complex/RX pairs.

Cu- or Fe-catalyzed Atom-Transfer Radical Reactions in Cyclizations

Abstract Herein, we report an efficient method using transition metal catalysts for controlling atom-transfer radical cyclization elimination (ATRCE) and atom-transfer radical cyclization (ATRC) in the reaction of α-bromocarbonyls possessing a styrene moiety. An iron salt efficiently catalyzed the ATRCE to produce cyclic compounds possessing a C-C double bond. On the other hand, the copper catalyst produced halogenated cyclic compounds.

Radical Reactions in Alkaloid Synthesis: A Perspective from Carbon Radical Precursors

The usefulness of radical reactions in alkaloid synthesis is reviewed from the perspective of the functional groups embedded in the molecular structure of synthetic intermediates, that act as precursors of carbon‐centered radicals in the construction of new C–C bonds. The functional groups featured are alkenes, alkynes, halides (alkyl, vinyl, aryl), xanthates, sulfides, selenides, aldehydes, ketones, carboxylic acid derivatives (selenoesters, haloacetamides), β‐dicarbonyl compounds, and α‐heterosubstituted nitrogen‐compounds. The use of nitrogen‐centered radicals for C–N bond formation is also covered. Among the variety of radical processes applied, the most predominant are the hydride reductive method (Sn, Si), atom transfer radical reactions (Cu, Ru, B), and single‐electron transfer radical reactions promoted by Sm, Ni, Fe, Mn, Ti, and Ag. This review showcases the role radical reactions have played in the recent development of new strategies in alkaloid synthesis, as well as the implementation of new radical procedures in demanding substrates.

Photo-Induced Atom-Transfer Radical Reactions Using Charge-Transfer Complex between Iodine and Tertiary Amine.

In the presence of charge-transfer complexes between iodine and tertiary amines, the aqueous-medium atom-transfer radical reactions proceeded under visible light irradiation without the typical photocatalysts.

A highly efficient Cu catalyst system for the radical reactions of α-bromocarbonyls.

In this communication, we established highly efficient Cu-catalyzed ARGET-ATRS (atom-transfer radical substitution) of alpha-bromocarbonyls with styrenes to produce tert-alkylated styrenes. The maximum TON was up to 12 000. Hünig's base was very important to regenerate active CuI. Moreover, a Cu-catalyzed C-C cleavage reaction via SH2' and intermolecular C-H cyclization of α-bromoimide was found.

In Situ Catalyst Modification in Atom Transfer Radical Reactions with Ruthenium Benzylidene Complexes.

Ruthenium benzylidene complexes are well-known as olefin metathesis catalysts. Several reports have demonstrated the ability of these catalysts to also facilitate atom transfer radical (ATR) reactions, such as atom transfer radical addition (ATRA) and atom transfer radical polymerization (ATRP). However, while the mechanism of olefin metathesis with ruthenium benzylidenes has been well-studied, the mechanism by which ruthenium benzylidenes promote ATR reactions remains unknown. To probe this question, we have analyzed seven different ruthenium benzylidene complexes for ATR reactivity. Kinetic studies by (1)H NMR revealed that ruthenium benzylidene complexes are rapidly converted into new ATRA-active, metathesis-inactive species under typical ATRA conditions. When ruthenium benzylidene complexes were activated prior to substrate addition, the resulting activated species exhibited enhanced kinetic reactivity in ATRA with no significant difference in overall product yield compared to the original complexes. Even at low temperature, where the original intact complexes did not catalyze the reaction, preactivated catalysts successfully reacted. Only the ruthenium benzylidene complexes that could be rapidly transformed into ATRA-active species could successfully catalyze ATRP, whereas other complexes preferred redox-initiated free radical polymerization. Kinetic measurements along with additional mechanistic and computational studies show that a metathesis-inactive ruthenium species, generated in situ from the ruthenium benzylidene complexes, is the active catalyst in ATR reactions. Based on data from (1) H, (13)C, and (31)P NMR spectroscopy and X-ray crystallography, we suspect that this ATRA-active species is a RuxCly(PCy3)z complex.

ChemInform Abstract: Recent Developments in Copper‐Catalyzed Radical Alkylations of Electron‐Rich π‐Systems

AbstractReview: [41 refs.

Recent developments in copper-catalyzed radical alkylations of electron-rich π-systems.

Recently, a number of papers have emerged demonstrating copper-catalyzed alkylation reactions of electron-rich small molecules. The processes are generally thought to be related to long established atom-transfer radical reactions. However, unlike classical reactions, these new transformations lead to simple alkylation products. This short review will highlight recent advances in alkylations of nitronate anions, alkenes and alkynes, as well as discuss current mechanistic understanding of these novel reactions.

Direct Photoinduced Electron Transfer from Excited State of Rhodamine B for Carbon-Radical Generation

The photoinduced electron transfer (PIET) from the excited singlet state (<i>S</i> ₁) of rhodamine B to <i>i</i>-C₃F₇I smoothly proceeded in the presence of water. This process was supported by the fluorescence quenching of rhodamine B with addition of <i>i</i>-C₃F₇I in ethanol. The present method was applied to the atom-transfer radical reaction involving the cyclization step.

Reductive Bromine Atom-Transfer Reaction

Atom-transfer radical (ATR) reactions of alkenes with R-X usually give products having new C-C and C-X bonds at the adjacent carbons. However, when the reaction was carried out under irradiation using a low-pressure Hg lamp, addition/reduction products were obtained in good yield. Hydrogen bromide, formed by H-abstraction of a bromine radical from alkenes, is likely to play a key role in the reductive ATR reaction.

Organic–inorganic hybrid diblock copolymer composed of poly (ε‐caprolactone) and poly(MA POSS): Synthesis and its nanocomposites with epoxy resin

AbstractOrganic–inorganic hybrid diblock copolymers composed of poly(ε‐caprolactone) and poly(MA POSS) [PCL‐b‐P(MA POSS)] were synthesized via reversible addition‐fragmentation chain transfer polymerization of 3‐methacryloxypropylheptaphenyl polyhedral oligomeric silsesquioxane (MA POSS) with dithiobenzoate‐terminated poly(ε‐caprolactone) as the macromolecular chain transfer agent. The dithiobenzoate‐terminated poly(ε‐caprolactone) (PCL‐CTA) was synthesized via the atom transfer radical reaction of 2‐bromopropionyl‐terminated PCL with bis(thiobenzoyl)disulfide in the presence of the complex of copper (I) bromide with N,N,N′,N″,N″‐pentamethyldiethylenetriamine. The results of molecular weights and polydispersity indicate that the polymerizations were in a controlled fashion. The organic–inorganic diblock copolymer was incorporated into epoxy to afford the organic–inorganic nanocomposites. The nanostructures of the organic–inorganic composites were investigated by means of transmission electron microscopy and dynamic mechanical thermal analysis. Thermogravimetric analysis shows that the organic–inorganic nanocomposites displayed the increased yields of degradation residues compared to the control epoxy. In the organic–inorganic nanocomposites, the inorganic block [viz., P(MA POSS)] had a tendency to enrich at the surface of the materials and the dewettability of surface for the organic–inorganic nanocomposites were improved in terms of the measurement of surface contact angles. © 2013 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2013

Resorcinol-functionalized carbon nanoparticles with a stick-out nanostructure for stable hydrogen bonding with polyester microfibers

We report new functionalized carbon nanoparticles (CNPs) featuring a stick-out nanostructure that delivers strong hydrogen bonding with polar groups in polymer chains. To make the stick-out nanostructures with hydroxyl groups, bromoresorcinols were used to react with the double bonds of CNPs by atom transfer radical reaction (ATRR). The resorcinol-bound CNPs (CNP-RCs) were characterized by solid-state proton nuclear magnetic spectroscopy and Raman spectroscopy. CNP-RCs were extremely well dispersed and stable (>6 months) compared to the original CNPs which precipitated in less than 60 h. High resolution transmission electron microscopy measurements disclosed that the characteristic particle shape and fine nanostructure of the original CNPs were almost unchanged during the ATRR process. We found that the surface of poly(ethylene terephthalate) (PET) microfibers was almost fully covered with the CNP-RC material by employing a double soaking process at 130 °C. The resulting CNP-RC-bound PET microfibers in fabrics exhibited excellent washing and rubbing resistance and outstanding deodorizing properties against ammonia gas. Hence, the present stick-out nanostructured CNP-RCs are expected to be a breakthrough in widening the application of carbon nanoparticles in terms of environmentally friendly processes using water and product-level stability.

Microwave-assisted atom transfer radical addition of polychlorinated compounds to olefins without addition of metal catalysts

A new operationally simple and robust protocol for the metal-free atom transfer radical reaction (ATRA) has been developed. Polychlorinated compounds were effectively reacted with unactivated terminal olefins to generate 1,3-dichlorinated adducts under microwave irradiation in the presence of silicon carbide (SiC) as a heating element. The present microwave-assisted ATRA proceeds under essentially neutral conditions; thus, polar functionalities are well tolerated. In addition, an oxygen or a nitrogen unit was introduced to the internal side of the carbon chain via nucleophilic cyclization of the 1,3-dichlorinated adducts, and single-step formation of the six-membered carbocycle was realized through cyclization of the intermediate radical. The present methodology provides an expeditious way to prepare synthetically useful molecules from simple and unactivated terminal olefins.

Attachment of carbonyl functionalities onto olefins via copper-promoted radical reaction of dichloromethylcyanides

Chemo- and regioselective protocols for attachment of various carbonyl functionalities onto unactivated olefins have been developed. Atom transfer radical reactions of Cl3CCN, Cl2C(R)CN, and Cl2C(CN)2 were all promoted efficiently by a catalytic amount of CuCl and 1,1′-bis(diphenylphosphino)ferrocene to introduce chloromethylcyanide and chloride units to the C–C double bonds. Conversion of the chloromethylcyanide to the carbonyl functionalities (e.g., aldehydes, ketones and esters), and subsequent double bond reconstruction through elimination of HCl resulted in selective formation of the carbonyl-conjugated E-olefins.

Retracing the evolution of monometallic ruthenium–arene catalysts for C–C bond formation

Preformed or in situ generated monometallic ruthenium-arene complexes with the generic formula RuX(2)(arene)(L) (L = phosphine or N-heterocyclic carbene) are versatile and efficient catalyst precursors for olefin metathesis and atom transfer radical reactions. Their synthesis is usually accomplished using simple and straightforward experimental procedures starting from the [RuCl(2)(p-cymene)](2) dimer. This article retraces their evolution over the past 20 years and highlights similarities and differences with the parallel development of well-defined RuX(2)(=CHR)(L(1))(L(2)) ruthenium-alkylidene catalysts.

ChemInform Abstract: Atom Transfer Radical Reactions as a Tool for Olefin Functionalization — On the Way to Practical Applications

AbstractReview: ca. 100 refs.

Atom Transfer Radical Reactions as a Tool for Olefin Functionalization – On the Way to Practical Applications

AbstractTransition‐metal‐catalyzed atom transfer radical reactions of halogenated compounds with olefins constitute a versatile tool in organic synthesis within the area of C–C bond forming transformations. The inter‐ or intramolecular versions, atom transfer radical addition (ATRA) or cyclization (ATRC), respectively, lead to the atom‐economic, useful synthesis of compounds that can be further functionalized. This contribution summarizes the recent developments in this area in terms of catalyst design as well as the applicability of this methodology in sequential, domino, or tandem reactions.

Synthetically useful carbon–carbon and carbon–sulphur bond construction mediated by carbon- and sulphur-centred radicals in water and aqueous media

This account is focused on carbon–carbon, and carbon–sulphur bond-forming reactions through the use of carbon- and sulphur-centred radicals in water, respectively. It intends to show the scope and applications of these types of radicals with a synthetic goal, thus helping the radical synthetic chemist to grasp the fundamental aspects of the syntheses of a wide array of organic compounds through radical methods in environmentally friendly media. This account excludes the syntheses of organic substrates with the aid of organometallic/metal-centred radicals such as other Group IV-radicals and transition-metal radicals, and the important class of radical reductions currently accomplished in water using different metallic reducing species. The array of substrates synthesized through the present method encompasses intermolecular and intramolecular radical carbon–carbon bond formation reactions in water, and radical carbon–sulphur bond formation reactions. Among the radical carbon–carbon bond formation reactions, special attention is devoted to atom-transfer radical reactions, radical addition reactions to olefins, radical addition to carbon–nitrogen double bonds, the carboaminohydroxylation of alkenes, and the analogues of Knovonoegel reactions, the synthesis of functionalized enol ethers, thr carboazidation and azidation, and ynol formation, and radical cyclization reactions in water.

Tandem catalysis of ring-closing metathesis/atom transfer radical reactions with homobimetallic ruthenium–arene complexes

The tandem catalysis of ring-closing metathesis/atom transfer radical reactions was investigated with the homobimetallic ruthenium–indenylidene complex [(p-cymene)Ru(μ-Cl)3RuCl(3-phenyl-1-indenylidene)(PCy3)] (1) to generate active species in situ. The two catalytic processes were first carried out independently in a case study before the whole sequence was optimized and applied to the synthesis of several polyhalogenated bicyclic γ-lactams and lactones from α,ω-diene substrates bearing trihaloacetamide or trichloroacetate functionalities. The individual steps were carefully monitored by 1H and 31P NMR spectroscopies in order to understand the intimate details of the catalytic cycles. Polyhalogenated substrates and the ethylene released upon metathesis induced the clean transformation of catalyst precursor 1 into the Ru(II)–Ru(III) mixed-valence compound [(p-cymene)Ru(μ-Cl)3RuCl2(PCy3)], which was found to be an efficient promoter for atom transfer radical reactions under the adopted experimental conditions.