Radical Equivalents Research Articles

Acetal Radicals: Synthetic Access and Applications

AbstractAldehydes and ketones are two of the most versatile functional groups in organic synthesis, and the development of new reagents and protocols to install them are always warranted. Recently, the reemergence of radical chemistry has provided new opportunities to introduce these important carbonyl motifs. As such, acetal radicals can be employed as synthetic radical equivalents for acyl radicals that can also circumvent known stability challenges. This review aims to summarize the advancements and known uses of acetal radicals, as well as explore acetal radical formation and synthetic applications.

A photocatalytic traceless C–N bond formation/cleavage strategy enabling the use of (α-chiral) alkyl aldehydes as deoxygenative (chiral) alkyl radical equivalents

α-Chiral alkyl aldehydes were used as deoxygenative chiral alkyl radical equivalents for the first time in 4-CzIPN-catalyzed deoxygenative alkylation/cyclization of 2-biphenylisonitriles with alkyl aldehydes under photocatalytic conditions.

Erratum for the Research Article: "Ketones and Aldehydes as Alkyl Radical Equivalents for C-H Functionalization of Heteroarenes" by Dong et al.

Erratum for the Research Article: "Ketones and Aldehydes as Alkyl Radical Equivalents for C-H Functionalization of Heteroarenes" by Dong et al.

Deoxygenative Functionalizations of Aldehydes, Ketones and Carboxylic Acids.

The simple and efficient conversion of carbonyl compounds into functionalized alkanes via deoxygenation is highly enabling in chemical synthesis. This Review covers the recent methodology development in carbonyl and carboxyl deoxygenative functionalizations, highlighting some representative and significant contributions in this field. These advances are categorized based on the reactivity patterns of some oxygenated feedstock compounds, including aldehydes, ketones and carboxylic acids. Four types of reactive intermediates arising from aldehydes and ketones during the deoxygenation, namely, bis-electrophiles, carbenoids, bis-nucleophiles and alkyl radical equivalents, are presented, while the carboxylic acids mainly behave as tris-electrophiles when deoxygenated. In each subcategory, selected examples are organized according to the type of bond formation and discussed from a generalized mechanistic perspective.

Deoxygenative Functionalizations of Aldehydes, Ketones and Carboxylic Acids

AbstractThe simple and efficient conversion of carbonyl compounds into functionalized alkanes via deoxygenation is highly enabling in chemical synthesis. This Review covers the recent methodology development in carbonyl and carboxyl deoxygenative functionalizations, highlighting some representative and significant contributions in this field. These advances are categorized based on the reactivity patterns of some oxygenated feedstock compounds, including aldehydes, ketones and carboxylic acids. Four types of reactive intermediates arising from aldehydes and ketones during the deoxygenation, namely, bis‐electrophiles, carbenoids, bis‐nucleophiles and alkyl radical equivalents, are presented, while the carboxylic acids mainly behave as tris‐electrophiles when deoxygenated. In each subcategory, selected examples are organized according to the type of bond formation and discussed from a generalized mechanistic perspective.

Photocatalytic acyl azolium-promoted alkoxycarbonylation of trifluoroborates

Despite recent advancements in the selective generation and coupling of organic radical species, the alkoxycarbonyl radical remains underexplored relative to other carbon-containing radical species. Drawing inspiration from new strategies for generating acyl radical equivalents utilizing dual N-heterocyclic carbene catalysis and photocatalysis, we have prepared dimethylimidazolium esters that can function as an alkoxycarbonyl radical surrogate under photocatalytic conditions. We demonstrate the synthetic utility of these azolium-based partners through the preparation of esters arising from the coupling of this radical surrogate with an oxidatively generated alkyl radical.

Temperature-Dependent Effects of Alkyl Substitution on Diarylamine Antioxidant Reactivity.

Alkylated diphenylamines are among the most efficacious radical-trapping antioxidants (RTAs) for applications at elevated temperatures since they are able to trap multiple radical equivalents due to catalytic cycles involving persistent diphenylnitroxide and diphenylaminyl radical intermediates. We have previously shown that some heterocyclic diarylamine RTAs possess markedly greater efficacy than typical alkylated diphenylamines, and herein, report on our efforts to identify optimal alkyl substitution of the scaffold, which we had found to be the ideal compromise between reactivity and stability. Interestingly, the structure-activity relationships differ dramatically with temperature: para-alkyl substitution slightly increased reactivity and stoichiometry at 37 and 100 °C due to more favorable (stereo)electronic effects and corresponding diarylaminyl/diarylnitroxide formation, while ortho-alkyl substitution slightly decreased both reactivity and stoichiometry. No such trends were evident at 160 °C; instead, the compounds were segregated into two groups based on the presence/absence of benzylic C-H bonds. Electron spin resonance spectroscopy indicates that increased efficacy was associated with lesser diarylnitroxide formation, and deuterium-labeling suggests that this is due to abstraction of the benzylic H atom, precluding nitroxide formation. Computations predict that this reaction path is competitive with established fates of the diarylaminyl radical, thereby minimizing the formation of off-cycle products and leading to significant gains in high-temperature RTA efficacy.

Tertiary Amines Acting as Alkyl Radical Equivalents Enabled by a P/N Heteroleptic Cu(I) Photosensitizer

An unprecedented exploration of tertiary amines as alkyl radical equivalents for cross-coupling with aromatic alkynes to access allylarenes has been achieved by a P/N heteroleptic Cu(I)-based photosensitizer under photoredox catalysis conditions. Mechanistic studies reveal that the reaction might undergo radical addition of in situ-generated α-amino radical intermediates to alkynes followed by 1,5-hydrogen transfer, C-N bond cleavage, and concomitant isomerization of the resulting allyl radical species.

One More Assertion to Fermat’s Last Theorem

Around 1637, Fermat wrote his Last Theorem in the margin of his copy “It is impossible to separate a cube into two cubes, or a fourth power into two fourth powers, or in general, any power higher than the second, into two like powers”. With n, x, y, z ∈ N (meaning that n, x, y, z are all positive numbers) and n > 2, the equation xn + yn = zn has no solutions. In this paper, I try to prove Fermat’s statement by reverse order, which means no two cubes forms cube, no two fourth power forms a fourth power, or in general no two like powers forms a single like power greater than the two. I used roots, powers and radicals to assert Fermat’s last theorem. Also I tried to generalize Fermat’s conjecture for negative integers, with the help of radical equivalents of Pythagorean triplets and Euler’s disproven conjecture.

Ketones and aldehydes as alkyl radical equivalents for C─H functionalization of heteroarenes.

The polar nature of the C═O bond commonly allows it to undergo direct attack by nucleophiles at the electrophilic carbon atom in which ketones and aldehydes act as alkyl carbocation equivalents. In contrast, transformations in which ketones and aldehydes act as alkyl radical equivalents (generated in carbonyl carbon) are unknown. Here, we describe a new catalytic activation mode that combines proton-coupled electron transfer (PCET) with spin-center shift (SCS) and enables C─H alkylation of heteroarenes using ketones and aldehydes as alkyl radical equivalents. This transformation proceeded via reductive PCET activation of the ketones and aldehydes to form α-oxy radicals, addition of the radicals to the N-heteroarenes to form C─C bonds, and SCS to cleave the C─O bonds of the resulting alcohols. This mild protocol represents a general use of abundant, commercially available, ketones and aldehydes as latent alkyl radical equivalents.

Ketones and Aldehydes as Alkyl Radical Equivalents for Direct C-H Alkylation of Heteroarenes

Ketones and Aldehydes as Alkyl Radical Equivalents for Direct C-H Alkylation of Heteroarenes

Visible-Light Photoredox-Catalyzed Hydroalkoxymethylation of Activated Alkenes Using α-Silyl Ethers as Alkoxymethyl Radical Equivalents.

A new neutral silicon-based traceless activation group (TAG) for visible-light photoredox-catalyzed hydroalkoxymethylation of alkenes is presented. This reaction involves in-situ-generated alkoxymethyl radical via single electron oxidation (SET) of α-TMS-substituted ethers, followed by subsequent conjugate addition to activated alkenes. Various functional groups were tolerated both under mild metal and metal-free conditions to provide good to excellent yields. Furthermore, the addition products were transformed to valuable synthetic building blocks, such as carboxylic acids, γ-butyrolactones, and complex aryl alkyl ethers.

Antioxidant activity of fraxetin and its regeneration in aqueous media. A density functional theory study

Fraxetin is an excellent and versatile antioxidant in aqueous media. In addition it regenerates, scavenging two radical equivalents per cycle.

Theoretical study on the peroxyl radicals scavenging activity of esculetin and its regeneration in aqueous solution

The study of the ˙OOH, ˙OOCH3 and ˙OOCHCH2 radicals scavenging processes by esculetin (ES) was carried out in aqueous and lipid media, using the density functional theory. Three reaction mechanisms were considered: single electron transfer (SET), hydrogen transfer (HT) and radical adduct formation (RAF). Rate constants and branching ratios for the different paths are reported. It was found that in lipid media the main mechanism of reaction is HT, while in aqueous solution it depends on the predominant acid-base form of esculetin. HT was found to be the main mechanism involved in the free radical scavenging activity of neutral esculetin (H2ES), while for anionic esculetin (HES(-)) the relative importance of the different mechanisms changes with the reacting radical. Based on the calculated rate constants, it is proposed that esculetin has moderate peroxyl scavenging activity in lipid media while in aqueous solution, at physiological pH, it is excellent for that purpose. In addition, the possible regeneration of ES, after scavenging the first radical, was investigated in aqueous solution, at physiological pH. It was found that regeneration is very likely to occur, which suggests that this compound has the ability to scavenge several radical equivalents (two per cycle), under such conditions.

Piceatannol, a better peroxyl radical scavenger than resveratrol

The peroxyl radical scavenging activity of piceatannol has been studied in aqueous and lipid solutions, using the density functional theory, and compared to that of its structural analogue resveratrol. The following mechanisms of reaction have been considered: hydrogen transfer (HT), single electron transfer (SET) and radical adduct formation (RAF). Piceatannol was found to be a better peroxyl scavenger than resveratrol, regardless of the polarity of the environment. In aqueous solution, at physiological pH, its higher activity is directly related to its acidity. The further reactions of the phenoxyl radical products (yielded by the reactions of ˙OOH with piceatannol and resveratrol) with the superoxide radical anion have also been investigated. It was found that in the aqueous phase, at physiological pH, resveratrol and piceatannol can be efficiently regenerated after scavenging two free radicals (˙OOH and ˙O2−). This suggests that these compounds have the ability of scavenging more than 2 radical equivalents, under such conditions.

On the free radical scavenging mechanism of protocatechuic acid, regeneration of the catechol group in aqueous solution

The free radical scavenging activity of protocatechuic acid has been studied in aqueous and lipid solutions, using the density functional theory. It was found to be a moderately good protector in non-polar environments (lipid), while in aqueous solution it is predicted to be an excellent peroxyl radical scavenger. In such media, the pH has an important role in the free radical scavenging activity of protocatechuic acid. At physiological pH, after the first peroxyl radical is scavenged, and in the presence of a good electron-donor species, such as the superoxide radical anion, the latter is consumed and protocatechuic acid is regenerated. This means that, under such conditions, it has the ability of scavenging several radical equivalents, two per cycle. An equivalent cyclic process can be assumed as possible also for other scavengers with the catechol moiety. If this assumption is confirmed, the role of compounds with a catechol moiety as free radical scavengers might be even more important that what has been assumed so far.

ChemInform Abstract: Electron Transfer Reduction of Carboxylic Acids Using SmI2—H2O—Et3N.

AbstractThe reagent can be used as 6:18:18, 6:36:36 or 6:48:48 mixture.

Electron Transfer Reduction of Carboxylic Acids Using SmI2–H2O–Et3N

The first general method for efficient electron transfer reduction of carboxylic acids has been developed. The protocol using SmI(2)-H(2)O-Et(3)N allows for reduction of a variety of carboxylic acids in excellent yields and provides an attractive alternative to processes mediated by reactive alkali metals, lithium aluminum hydride, and boron hydrides. Of broader significance, the method allows acyl radical equivalents to be generated from carboxylic acids under mild reaction conditions.

ChemInform Abstract: Facile Reduction of Dithiocarbonates Derived from Secondary Alcohols with n-Bu3SnH-Et3B and Synthesis of 2-Furanthiones and 2-Furanones by Intramolecular Addition of Alkoxythiocarbonyl Free Radicals to Acetylenic Linkages.

The reduction of dithiocarbonates or thiocarbonates by n-Bu3SnH–Et3B easily gives the corresponding hydrocarbons. The intermediate alkoxythiocarbonyl radical equivalents are trapped by properly located carbon–carbon multiple bonds. The dithiocarbonates derived from either homopropargylic or homoallylic alcohols produce tetrahydrofuranones upon treatment with n-Bu3SnH–Et3B. Application of this new method to the conversion of carbonyl compounds into olefins is also described.

Stereocontrol in radical Mannich equivalents for aminosugar synthesis: haloacetal and 2-(phenylthio)vinyl tethered radical additions to α-hydroxyhydrazones

Studies of stereocontrol in two types of radical equivalents of Mannich addition reactions offer new insights for application to aminosugar synthesis. In the first method, haloacetal addition (Ueno–Stork reaction) is extended to dihydroxyhydrazones, leading to an adduct with the unexpected 3- epi- l-daunosamine configuration. A neighboring α-benzyloxy substituent causes a dramatic reversal of stereocontrol compared with hydrazones where this substituent is absent; vicinal dipole repulsion is proposed to account for the diastereoselectivity. In the second method, radical addition–cyclization with thiophenol and treatment with fluoride leads to diastereoselective group transfer from a silicon-tethered ethynyl group to the C N bond of hydrazones, affording anti-hydrazino alcohols with a trans-2-(phenylthio)vinyl substituent. The one-pot process occurs under neutral, tin-free radical conditions, and offers stereocontrol which is complementary to the haloacetal method. Synthetic utility of the radical Mannich concept is demonstrated in a brief asymmetric synthesis of N-trifluoroacetyl- l-daunosamine from achiral precursors.