Noncovalent Immobilization of Molecular Electrocatalysts for Chemical Synthesis: Efficient Electrochemical Alcohol Oxidation with a Pyrene–TEMPO Conjugate

Electrocatalytic methods for organic synthesis could offer sustainable alternatives to traditional redox reactions, but strategies are needed to enhance the performance of molecular catalysts designed for this purpose. The synthesis of a pyrene‐tethered TEMPO derivative (TEMPO=2,2,6,6‐tetramethylpiperidinyl‐N ‐oxyl) is described, which undergoes facile in situ noncovalent immobilization onto a carbon cloth electrode. Cyclic voltammetry and controlled potential electrolysis studies demonstrate that the immobilized catalyst exhibits much higher activity relative to 4‐acetamido–TEMPO, an electronically similar homogeneous catalyst. In preparative electrolysis experiments with a series of alcohol substrates and the immobilized catalyst, turnover numbers and frequencies approach 2 000 and 4 000 h⁻¹, respectively. The synthetic utility of the method is further demonstrated in the oxidation of a sterically hindered hydroxymethylpyrimidine precursor to the blockbuster drug, rosuvastatin.     

Simultaneous evaluation of one‐electron reducing systems and radical reactions in cells by nitroxyl biradical as probe

In the present study, a novel probe for the simultaneous evaluation of one‐electron reducing systems (electron transport chain) and one‐electron oxidizing systems (free radical reactions) in cells by electron chemical detection was developed. Six‐membered cyclic nitroxyl radicals (2,2,6,6‐tetramethylpiperidine‐1‐oxyl; TEMPO series) are sensitive to one‐electron redox systems, generating the hydroxylamine form [TEMPO(H)] via one‐electron reduction, and the secondary amine form [TEMPO(N)] via one‐electron oxidation in the presence of thiols. In contrast, the sensitivities of five‐membered cyclic nitroxyl radicals (2,2,5,5‐tetramethylpyrrolidine‐1‐oxyl; PROXYL series) to the one‐electron redox systems are comparatively low. The electron chemical detector can detect 2,2,6,6‐tetramethylpiperidine‐1‐oxyl (TEMPO), TEMPO(H) and PROXYL but not TEMPO(N). Therefore, nitroxyl biradical, TEMPO‐PROXYL, as a probe for the evaluation of one‐electron redox systems was employed. TEMPO‐PROXYL was synthesized by the conjunction of 4‐amino‐TEMPO with 3‐carboxyl‐PROXYL via the conventional dicyclohexyl carbodiimide reaction. TEMPO‐PROXYL, TEMPO(H)‐PROXYL and TEMPO(N)‐PROXYL were simultaneously quantified by HPLC with Coularray detection. Calibration curves for the quantification of TEMPO‐PROXYL, TEMPO(H)‐PROXYL and TEMPO(N)‐PROXYL were linear in the range from 80 nm to 80 μm , and the lowest quantification limit of each molecule was estimated to be <80 nm . The relative standard deviations at 0.8 and 80 μm were within 10% (n = 5). Copyright © 2015 John Wiley & Sons, Ltd.     

Metal‐Free 2,2,6,6‐Tetramethylpiperidin‐1‐yloxy Radical (TEMPO) Catalyzed Aerobic Oxidation of Hydroxylamines and Alkoxyamines to Oximes and Oxime Ethers

TEMPO‐Mediated oxidation of hydroxylamines (=hydroxyamines) and alkoxyamines to the corresponding oxime derivatives is reported (TEMPO=2,2,6,6‐tetramethylpiperidin‐1‐yloxy radical; Scheme 2). These environmentally benign oxidations proceed in good to excellent yields (Table 1). For alkoxyamines, oxidation to the corresponding oxime ethers can be performed by using dioxygen as a terminal oxidant in the presence of 5–10 mol‐% of TEMPO or 4‐substituted derivatives thereof as a catalyst (Scheme 3 and Table 2). Importantly, benzyl bromides can directly be transformed to oxime ethers via in situ alkoxyamine formation by a nucleophilic substitution followed by TEMPO‐mediated oxidation (Scheme 4 and Table 3).     

Selective Alcohol Oxidation by a Copper TEMPO Catalyst: Mechanistic Insights by Simultaneously Coupled Operando EPR/UV‐Vis/ATR‐IR Spectroscopy

The first coupled operando EPR/UV‐Vis/ATR‐IR spectroscopy setup for mechanistic studies of gas‐liquid phase reactions is presented and exemplarily applied to the well‐known copper/TEMPO‐catalyzed (TEMPO=(2,2,6,6‐tetramethylpiperidin‐1‐yl)oxyl) oxidation of benzyl alcohol. In contrast to previous proposals, no direct redox reaction between TEMPO and Cu^I/Cu^II has been detected. Instead, the role of TEMPO is postulated to be the stabilization of a (bpy)(NMI)Cu^II‐O₂^??‐TEMPO (bpy=2,2′‐bipyridine, NMI=N‐methylimidazole) intermediate formed by electron transfer from Cu^I to molecular O₂.     

Integrating TEMPO and Its Analogues with Visible‐Light Photocatalysis

Visible light has risen to become a very important facilitator for selective radical reactions enabled by well‐cognized photocatalysts. The renaissance of visible‐light photocatalysis on this matter partly relies on integrating it with other fields of catalysis. In parallel, 2,2,6,6‐tetramethylpiperidin N‐oxide (TEMPO), a quintessential persistent radical, has a wide range of uses owing to its exceptional redox behavior, which gives rise to its latest prominence in catalysis. Therefore, integrating the catalysis of TEMPO with photocatalysis to perform visible‐light‐induced selective reactions becomes a very convenient marriage of merits. In this context, the integration of different types of photocatalysts, including metal complexes, metal‐free organic dyes, and semiconductors, with TEMPO for outstanding organic transformations will be summarized. To expand further the catalytic repertoire, the integration of TEMPOH analogues such as NHPI (N‐hydroxyphthalimide) and NHS (N‐hydroxysuccinimide) with photocatalysis will also be discussed. Hopefully, these advances will pave the way for more breakthroughs by integrating TEMPO and its analogues with photocatalysis to lead to a valuable blueprint for visible‐light‐induced selective organic transformations.     

Mechanistic – Kinetic Scheme of Oxidation/Reduction of TEMPO Involving Hydrogen Bonded Dimer. RDE Probe for Availability of Protons in Reaction Environment

Mechanistic – kinetic studies on the electrochemical oxidation/reduction process of radical TEMPO (2,2,6,6‐tetramethylpiperidine‐1‐oxyl) under ionic strength (0.1 M, 1.0 M) and pH (0, 7) of aqueous perchlorate electrolyte (NaClO₄‐HClO₄) have been undertaken. Analytical and/or digital simulation methods for voltammetry at stationary (CV) and rotating electrode (RDE) have allowed one to determine numerical values of twelve parameters characterizing two electrode reactions (oxidation and reduction of the radical) and three chemical reactions (protonation, disproportionation, dimerization involving the radical and/or electrogenerated species). A potential window of the measurements was 0.6 V and it corresponded to that where the oxidation wave of TEMPO in neutral aqueous solution is situated. To account for the observed pH effect, the hydrogen bonded dimer resulting from the radical reactant and the protonation product of its reduction has been postulated to form in solution near the electrode surface. The RDE voltammetric discernables of the TEMPO process (i.e., absolute RDE wave current, zero RDE current potential, oxidation and reduction limiting RDE currents) can be considered good candidates for a use to follow acidity of complex reactive media.     

Electrochemical Intramolecular Aminooxygenation of Unactivated Alkenes

An electrochemical approach to the intramolecular aminooxygenation of unactivated alkenes has been developed. This process is based on the addition of nitrogen‐centered radicals, generated through electrochemical oxidation, to alkenes followed by trapping of the cyclized radical intermediate with 2,2,6,6‐tetramethylpiperidine‐N‐oxyl radical (TEMPO). Difunctionalization of a variety of alkenes with easily available carbamates/amides and TEMPO affords aminooxygenation products in high yields and with excellent trans selectivity for cyclic systems (d.r. up to>20:1). The approach provides a much‐needed complementary route to existing cis‐selective methods.     

Noncovalent Immobilization of Molecular Electrocatalysts for Chemical Synthesis: Efficient Electrochemical Alcohol Oxidation with a Pyrene–TEMPO Conjugate

Electrocatalytic methods for organic synthesis could offer sustainable alternatives to traditional redox reactions, but strategies are needed to enhance the performance of molecular catalysts designed for this purpose. The synthesis of a pyrene-tethered TEMPO derivative (TEMPO=2,2,6,6-tetramethylpiperidinyl-N-oxyl) is described, which undergoes facile in situ noncovalent immobilization onto a carbon cloth electrode. Cyclic voltammetry and controlled potential electrolysis studies demonstrate that the immobilized catalyst exhibits much higher activity relative to 4-acetamido–TEMPO, an electronically similar homogeneous catalyst. In preparative electrolysis experiments with a series of alcohol substrates and the immobilized catalyst, turnover numbers and frequencies approach 2 000 and 4 000 h⁻¹, respectively. The synthetic utility of the method is further demonstrated in the oxidation of a sterically hindered hydroxymethylpyrimidine precursor to the blockbuster drug, rosuvastatin.     

A TEMPO‐Free Copper‐Catalyzed Aerobic Oxidation of Alcohols

The copper‐catalyzed aerobic oxidation of primary and secondary alcohols without an external N‐oxide co‐oxidant is described. The catalyst system is composed of a Cu/diamine complex inspired by the enzyme tyrosinase, along with dimethylaminopyridine (DMAP) or N‐methylimidazole (NMI). The Cu catalyst system works without 2,2,6,6‐tetramethyl‐l‐piperidinoxyl (TEMPO) at ambient pressure and temperature, and displays activity for un‐activated secondary alcohols, which remain a challenging substrate for catalytic aerobic systems. Our work underscores the importance of finding alternative mechanistic pathways for alcohol oxidation, which complement Cu/TEMPO systems, and demonstrate, in this case, a preference for the oxidation of activated secondary over primary alcohols.     

A versatile approach for the preparation of end‐functional polymers and block copolymers by stable radical exchange reactions

A versatile strategy for the preparation of end‐functional polymers and block copolymers by radical exchange reactions is described. For this purpose, first polystyrene with 2,2,6,6‐tetramethylpiperidine‐1‐oxyl end group (PS‐TEMPO) is prepared by nitroxide‐mediated radical polymerization (NMRP). In the subsequent step, these polymers are heated to 130 °C in the presence of independently prepared TEMPO derivatives bearing hydroxyl, azide and carboxylic acid functionalities, and polymers such as poly(ethylene glycol) (TEMPO‐PEG) and poly(ε‐caprolactone) (TEMPO‐PCL). Due to the simultaneous radical generation and reversible termination of the polymer radical, TEMPO moiety on polystyrene is replaced to form the corresponding end‐functional polymers and block copolymers. The intermediates and final polymers are characterized by ¹H NMR, UV, IR, and GPC measurements. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019 , 57, 2387–2395     

Decomposition of model alkoxyamines in simple and polymerizing systems. I. 2,2,6,6‐tetramethylpiperidinyl‐ N‐oxyl‐based compounds

The thermal decomposition of five alkoxyamines labeled TEMPO–R, where TEMPO was 2,2,6,6‐tetramethylpiperidinyl‐N‐oxyl and R was cumyl (Cum), 2‐tert‐butoxy‐carbonyl‐2‐propyl (PEst), phenylethyl (PhEt), 1‐tert‐butoxy‐carbonylethyl (EEst), or 1‐methoxycarbonyl‐3‐methyl‐3‐phenylbutyl (Acrylate‐Cum), was studied with ¹H NMR in the absence and presence of styrene and methyl methacrylate. The major products were alkenes and the hydroxylamine 1‐hydroxy‐2,2,6,6‐tetramethyl‐ piperidine (TEMPOH), and in monomer‐containing solutions, unimeric and polymeric alkoxyamines and alkenes were also found. Furthermore, the reactions between TEMPO and the radicals EEst and PEst were studied with chemically induced dynamic nuclear polarization. In comparison with coupling, TEMPO reacted with the radicals Cum, PEst, PhEt, and EEst and their unimeric styrene adducts by disproportionation to alkenes and TEMPOH only to a minor extent (0.6–3%) but with the radical adducts to methyl methacrylate to a considerable degree (≥20%). Parallel to the radical cleavage, TEMPO–EEst (but not the other alkoxyamines or TEMPO–Acrylate‐Cum) underwent substantial nonradical decay. The consequences for TEMPO‐mediated living radical polymerizations are discussed. © 2001 John Wiley & Sons, Inc. J Polym Sci Part A: Polym Chem 39: 3604–3621, 2001     

DAIB/TEMPO mediated synthesis of anomeric lactones from anomeric hydroxides

Anomeric sugar lactones are important intermediates for the synthesis of C-glycosides, carbasugars and iminosugars. Herein we present a facile synthesis of anomeric sugar lactones via the DAIB/TEMPO oxidation of anomeric hydroxides. The reactions are very efficient providing the lactones in 2–4 h in almost quantitative yields. The reaction conditions tolerate several common protecting groups used in carbohydrate synthesis. The advantages of the present methodology over previously reported non-metal based methods have also been demonstrated through head to head comparisons. Finally, we have applied the reaction for the sequential conversion of anomeric thioglycosides to the lactones through sequential reactions with NBS followed by the oxidation with DAIB/TEMPO.     

离子液体-水介质中离子液体负载TEMPO催化选择氧化合成脂肪醇羟基芳香醛和酮

由于脂肪醇羟基和苄醇羟基具有相同的氧化反应活性,所以当分子内同时含有脂肪醇羟基和苄醇羟基时,很难选择氧化苄醇羟基合成含脂肪醇羟基的芳香醛或酮。本文报道了在离子液体-水介质中,NCS/NaBr/IL-TEMPO（离子液体负载TEMPO）催化氧化合成含有脂肪醇羟基的芳香醛、酮的方法,反应条件温和,选择性好,收率高,且离子液体和催化剂可以循环使用。     

Electrocatalytic Oxidation of Carbohydrates Mediated by Nitroxyl Radical‐modified Electrodes in Aqueous Solution

The electrocatalytic activity of a 2,2,6,6‐tetramethylpipridine‐N‐oxyl (TEMPO)‐modified electrode toward the oxidation of carbohydrates in phosphate buffer solution was investigated under neutral aqueous solution conditions at 25 °C. The modified electrode was prepared on the surface of a glassy carbon electrode by the electrochemical polymerization of a TEMPO precursor containing a pyrrole side chain. Cyclic voltammetric studies showed that the anodic peak current increased with the concentration of carbohydrates in a dose‐dependent manner.     

Synthesis of poly(chloromethylstyrene‐b‐styrene) block copolymers by controlled free‐radical polymerization

The controlled free‐radical polymerization of styrene and chloromethylstyrene monomers in the presence of 2,2,6,6‐tetramethyl‐1‐piperidinyloxyl (TEMPO) has been studied with the aim of synthesizing block copolymers with well‐defined structures. First, TEMPO‐capped poly(chloromethylstyrene) was prepared. Among several initiating systems [self‐initiation, dicumyl peroxide, and 2,2′‐azobis(isobutyronitrile)], the last offered the best compromise for obtaining a good control of the polymerization and a fast polymerization rate. The rate of the TEMPO‐mediated polymerization of chloromethylstyrene was independent of the initial concentration of TEMPO but unexpectedly higher than the rate of the thermal self‐initiated polymerization of chloromethylstyrene. Transfer reactions to the chloromethyl groups were thought to play an important role in the polymerization kinetics and the polydispersity index of the resulting poly(chloromethylstyrene). Second, this first block was used as a macroinitiator in the polymerization of styrene to obtain the desired poly(chloromethylstyrene‐b‐styrene) block copolymer. The kinetic modeling of the block copolymerization was in good agreement with experimental data. The block copolymers obtained in this work exhibited a low polydispersity index (weight‐average molecular weight/number‐average molecular weight < 1.5) and could be chemically modified with nucleophilic substitution reactions on the benzylic site, opening the way to a great variety of architectures. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 3845–3854, 2000     

Metal‐Free Oxidation of Primary Amines to Nitriles through Coupled Catalytic Cycles

Synergism among several intertwined catalytic cycles allows for selective, room temperature oxidation of primary amines to the corresponding nitriles in 85–98 % isolated yield. This metal‐free, scalable, operationally simple method employs a catalytic quantity of 4‐acetamido‐TEMPO (ACT; TEMPO=2,2,6,6‐tetramethylpiperidine N‐oxide) radical and the inexpensive, environmentally benign triple salt oxone as the terminal oxidant under mild conditions. Simple filtration of the reaction mixture through silica gel affords pure nitrile products.     

3‐miktoarm star terpolymers using triple click reactions: Diels–Alder,copper‐catalyzed azide‐alkyne cycloaddition,and nitroxide radical coupling reactions

Well‐defined linear furan‐protected maleimide‐terminated poly(ethylene glycol) (PEG‐MI), tetramethylpiperidine‐1‐oxyl‐terminated poly(ε‐caprolactone) (PCL‐TEMPO), and azide‐terminated polystyrene (PS‐N₃) or ‐poly(N‐butyl oxanorbornene imide) (PONB‐N₃) were ligated to an orthogonally functionalized core ( 1 ) in a two‐step reaction mode through triple click reactions. In a first step, Diels–Alder click reaction of PEG‐MI with 1 was performed in toluene at 110 °C for 24 h to afford α‐alkyne‐α‐bromide‐terminated PEG (PEG‐alkyne/Br). As a second step, this precursor was subsequently ligated with the PCL‐TEMPO and PS‐N₃ or PONB‐N₃ in N,N‐dimethylformamide at room temperature for 12 h catalyzed by Cu(0)/Cu(I) through copper‐catalyzed azide‐alkyne cycloaddition and nitroxide radical coupling click reactions, yield resulting ABC miktoarm star polymers in a one‐pot mode. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

4‐OH‐TEMPO/TCQ/TBN/HCl: A Metal‐Free Catalytic System for Aerobic Oxidation of Alcohols under Mild Conditions

A green and economical catalyst system, 4‐OH‐TEMPO/TCQ/TBN/HCl, for the aerobic oxidation of a broad range of primary and secondary alcohols to the corresponding carbonyl compounds has been developed. These reactions proceed without transition‐metals under mild conditions with excellent yields.     

Catalytic Activity Dependency on Catalyst Components in Aerobic Copper–TEMPO Oxidation

The influence of catalyst components in the copper–TEMPO (2,2,6,6‐tetramethylpiperidine N‐oxide) catalysed aerobic oxidation of alcohols was investigated. The type and amount of base greatly influences reactivity. The bipyridyl ligand concentration had no major influence on catalysis, but excessive amounts led to a decrease in activity for longer reaction times. The kinetic dependency for TEMPO was found to be 1.15, and for copper 2.25, which is an indication of a binuclear catalytic system. Optimised conditions with various allylic and aliphatic alcohols give good to excellent rapid oxidations.     

Rapid additive‐free TEMPO‐mediated stable free radical polymerizations of styrene

The stable free radical polymerization (SFRP) of styrene, initiated with benzoyl peroxide in the presence of TEMPO, under bulk conditions, is demonstrated to proceed rapidly without the need for any rate enhancing additives such as camphorsulfonic acid, 2‐fluoro‐1‐methyl pyridinium p‐toluenesulfonate, or acetic anhydride. Monomer conversions as high as 70% can be achieved in 5 h or less while maintaining polydispersity indexes of 1.15. These results stand in stark contrast to earlier reactions that required 70 h to achieve similar conversions. This study demonstrates that the single largest factor governing the rates of polymerization is the molar concentration of excess TEMPO remaining in solution after initiation. A reduction in the TEMPO to BPO ratio is required when large amounts of BPO are used to target low molecular weight polystyrenes. However, when a lower molar amount of BPO is used to obtain high molecular weight polystyrenes, a higher TEMPO to BPO ratio is required. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 5487–5493, 2007