Redox-Neutral TEMPO Catalysis: Direct Radical (Hetero)Aryl C−H Di- and Trifluoromethoxylation

Applications of TEMPO^. catalysis for the development of redox-neutral transformations are rare. Reported here is the first TEMPO^.-catalyzed, redox-neutral C−H di- and trifluoromethoxylation of (hetero)arenes. The reaction exhibits a broad substrate scope, has high functional-group tolerance, and can be employed for the late-stage functionalization of complex druglike molecules. Kinetic measurements, isolation and resubjection of catalytic intermediates, UV/Vis studies, and DFT calculations support the proposed oxidative TEMPO^./TEMPO⁺ redox catalytic cycle. Mechanistic studies also suggest that Li₂CO₃ plays an important role in preventing catalyst deactivation. These findings will provide new insights into the design and development of novel reactions through redox-neutral TEMPO^. catalysis.     

Decomposition of sodium hypochlorite in an aqueous solution in the presence of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) nitroxyl radical as a catalyst

Nitroxyl radical TEMPO is found to catalyze the decomposition of sodium hypochlorite in an aqueous-alkali medium. The mechanism of NaOCl decomposition to form ClO· radical is proposed which involves protonated TEMPO, oxoammonium salt TEMPO⁺, and hydroxyl radical.     

Evaluation of three applications of a semi-automated most-probable-number method for the assessment of microbiological parameters in dairy products

Several rapid and automated microbiological methods have been introduced by food control laboratories because they allow microbiological quality (e.g. contamination with spoilage microorganisms and/or pathogens) of products to be checked or hygiene monitoring undertaken during production. This study evaluated three applications of the TEMPO^® system; an automated method based on the most-probable-number technique, performed in parallel with the relevant ISO standard method for comparison. Escherichia coli certified reference material and soft cheese samples contaminated artificially with E. coli were used throughout the study. Performance characteristics including precision, bias and limit of detection of E. coli (EC), coliforms (TC) and viable aerobic mesophilic microflora (TVC) were determined with particular attention given to low-level contamination, which typically occur in manufacturing and retail as well as storage and consumption at home. TEMPO^® EC was more precise than TEMPO^® TC whilst TEMPO^® TVC showed the most variation. Moreover, higher numbers of E. coli were obtained with TEMPO^® EC than TEMPO^® TC. Reliability of the system depended on the specificity of detection of the targeted group of microorganisms as well on the method. Although, methods like TEMPO^® offer convenience, they often lack the necessary clarity in terms of operational details, measurement principles and data processing necessary for reliable routine use. Installation of an ‘expert modus’ to facilitate access to original data would significantly increase commercial confidence in the application and use of these systems.     

OH-Induced shift from carbon to oxygen acidity in the side-chain deprotonation of 2-, 3- and 4-methoxybenzyl alcohol radical cations in aqueous solution: results from pulse radiolysis and DFT calculations

DFT calculations have been carried out for 2-, 3- and 4-methoxybenzyl alcohol radical cations (1⁺, 3⁺ and 4⁺, respectively) and the α-methyl derivatives 2⁺ and 5⁺ using the UB3LYP/6-31G(d) method. The theoretical results have been compared with the experimental rate constants for deprotonation of 1⁺-5⁺ under acidic and basic conditions. In acidic solution, the decay of 1⁺-5⁺ proceeds by cleavage of the C-H bond, while in the presence of ⁻OH all the radical cations undergo deprotonation from the α-OH group. This pH-dependent change in mechanism has been interpreted qualitatively in terms of simple frontier molecular orbital theory. The ⁻OH induced α-O-H deprotonation is consistent with a charge controlled reaction, whereas the C-H deprotonation, observed when the base is H₂O, appears to be affected by frontier orbital interactions.     

DFT studies of unique stereoelectronic effects of substituents on divergent reaction pathways of methylenecyclobutanone radical cations

The results of DFT investigation suggest that C2–C3 bond cleavage of the 2,2-dianisyl-3,3-dimethyl-4-methylenecyclobutanone radical cation (2b⁺) is preferred from both a thermodynamic and a kinetic perspective while C1–C2 bond cleavage is both thermodynamically and kinetically favored in the parent methylenecyclobutanone radical cation (MCB⁺) and the 2,2-diphenyl- and 2,2-dianisyl-4-isopropylidenecyclobutanone radical cations (1a-b⁺). The DFT calculations also suggest that a bonding character exists in C2–C3 bond of the 2,2-diphenyl-3,3-dimethyl-4-methylenecyclobutanone radical cation (2a⁺) but not in that of 2b⁺. Consequently, the unique reactivity of 2b⁺ can be accounted for by the existence of the steric hindrance between methyl and anisyl substituents, which favors C2–C3 bond cleavage, and the absence of C2–C3 bonding character. Those results support that the previous experimental results of photoinduced electron-transfer reactions of 1 and 2. The combined factors comprise stereoelectronic substituent effects that lead to a drastic change in the reaction pathways followed by 2b⁺ relative to that of other methylenecyclobutanone-type radical cations.     

Formation of π-excimer or π-exciplex in electrogenerated chemiluminescence involving perylene molecule revealed using a dual-electrolysis stopped-flow method

Electrogenerated chemiluminescence (ECL) reactions involving the perylene cation radical (PE⁺) and perylene anion radical (PE⁻) in acetonitrile have been observed using a dual-electrolysis stopped-flow method. In this method, ECL emission from the systems composed of different kinds of ion radicals can be easily observed by mixing both the electrolyzed solutions directly. Therefore, the ECL spectra were observed systematically in the reactions of PE⁺ and PE⁻ with different ion radicals. Consequently, emission definitely from the singlet state of PE was observed in the reactions between PE⁺ and the 9,10-diphenylanthracene anion radical (DPA⁻), PE⁻ and DPA⁺, and PE⁻ and the thianthrene cation radical (TH⁺). In contrast, emission at long wavelength was obtained in the reaction between PE⁺ and the pyrene anion radical (PY⁻) as well as the reaction between PE⁺ and PE⁻. From this result, for the molecular interactions involving PE and PY, the presence of the π complexing interaction to form the π-excimer and the π-exciplex was strongly suggested in the ECL-emitting reactions. The present approach was thus found to be effective to reveal the molecular aspects of the excited states formed in solution.     

The role of oxygen acidity on the side-chain fragmentation of ring methoxylated benzocycloalkenol radical cations

The reactivity of 2,2-dimethyl-5-methoxyindan-1-ol (1) and 2,2-dimethyl-6-methoxytetral-1-ol (2) radical cations has been studied both in acidic and basic solution. At pH≤4 both 1⁺ and 2⁺ undergo C_αH deprotonation as the exclusive reaction with k=4.6×10⁴ and 3.2×10⁴ s⁻¹, respectively. In basic solution 1⁺ and 2⁺ behave as oxygen acids undergoing ⁻OH-induced αOH deprotonation in a diffusion controlled process (k_−OH≈10¹⁰ M⁻¹ s⁻¹). An intermediate alkoxyl radical is formed which undergoes a 1,2-hydrogen atom shift in competition with CC β-scission (with 1⁺) or as the exclusive pathway (with 2⁺). A behavior which is interpreted in terms of the greater ease of ring-opening of a five membered ring as compared to a six-membered one.     

Synthesis and chemical oxidation of 3-ferrocenylpyrrole and ferrocenyl-substituted triazoles: Iron versus ligand based oxidation

Copper catalyzed [3+2] cycloaddition reactions between ethynylferrocene and benzylazides yields 1-benzyl-4-ferrocenyl-1,2,3-triazoles (2–5). Reaction between phenylacetylene and azidoferrocene yields 1-ferrocenyl-4-phenyl-1,2,3-triazole (6). Anodic electrochemistry of 2–6 suggests reversible oxidation at potentials more positive than ferrocene. Chemical oxidation of 2 and 3-ferrocenylpyrrole (1) with dichlorodicyanoquinone (DDQ) yields the salts [2⁺] [DDQ⁻] and [1⁺] [DDQ⁻], respectively. ⁵⁷Fe Mössbauer spectroscopy reveals the presence of low-spin Fe^II in [1⁺][DDQ⁻] while Fe^II is oxidized to low-spin Fe^III in [2⁺][DDQ⁻]. Magnetization measurements indicate that [1⁺][DDQ⁻] is paramagnetic and cannot be viewed as a simple neutral charge transfer complex reminiscent of the mixed stack diamagnetic [ferrocene]⁰[TCNE]⁰.     

Specific Cα-C Bond Cleavage of β-Carbon-Centered Radical Peptides Produced by Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry

Radical-driven dissociation (RDD) of hydrogen-deficient peptide ions [M???H?+?H]^·+ has been examined using matrix-assisted laser dissociation/ionization in-source decay mass spectrometry (MALDI-ISD MS) with the hydrogen-abstracting matrices 4-nitro-1-naphthol (4,1-NNL) and 5-nitrosalicylic acid (5-NSA). The preferential fragment ions observed in the ISD spectra include N-terminal [a]?+?ions and C-terminal [x]⁺, [y?+?2]⁺, and [w]⁺ ions which imply that β-carbon (Cβ)-centered radical peptide ions [M???Hβ?+?H]^·+ are predominantly produced in MALDI conditions. RDD reactions from the peptide ions [M???Hβ?+?H]^·+ successfully explains the fact that both [a]⁺ and [x]⁺ ions arising from cleavage at the Cα-C bond of the backbone of Gly-Xxx residues are missing from the ISD spectra. Furthermore, the formation of [a]⁺ ions originating from the cleavage of Cα-C bond of deuterated Ala(d3)-Xxx residues indicates that the [a]⁺ ions are produced from the peptide ions [M???Hβ?+?H]^·+ generated by deuteron-abstraction from Ala(d3) residues. It is suggested that from the standpoint of hydrogen abstraction via direct interactions between the nitro group of matrix and hydrogen of peptides, the generation of the peptide radical ions [M???Hβ?+?H]^·+ is more favorable than that of the α-carbon (Cα)-centered radical ions [M???Hα?+?H]^·+ and the amide nitrogen-centered radical ions [M???H_N?+?H]^·+, while ab initio calculations indicate that the formation of [M???Hα?+?H]^·+ is energetically most favorable.

Open image in new window

Graphical Abstract ?

     

Electron delocalization in vinyl ruthenium substituted cyclophanes: Assessment of the through-space and the through-bond pathways

Pseudo-para[2.2]paracyclophane- and [2.1]orthocyclophane-bridged diruthenium complexes 2 and 3 with two interlinked electroactive styryl ruthenium moieties have been prepared and investigated. Both complexes undergo two reversible consecutive one-electron oxidation processes which are separated by 270 or 105 mV. Stepwise electrolysis of the neutral complexes to first the mixed-valent radical cations and then the dioxidized dications under IR monitoring reveal incremental shifts of the charge-sensitive Ru(CO) bands and allow for an assignment of their radical cations as moderately or very weakly coupled mixed-valent systems of class II according to Robin and Day. Ground-state delocalization in the mixed-valent forms of these complexes as based on the CO band shifts is considerably larger for the “closed” paracyclophane as for the “half-open” orthocyclophane. Experimental findings are backed by the calculated IR band patterns and spin density distributions for radical cations of slightly simplified model complexes 2^Me+ and 3^Me+ with the PⁱPr₃ ligands replaced by PMe₃. Radical cations 2⁺ and 3⁺ feature a characteristic NIR band that is neither present in their neutral or fully oxidized forms nor in the radical cation of the monoruthenium [2.2]paracyclophane complex 1 with just one vinyl ruthenium moiety. These bands are thus assigned as intervalence charge-transfer (IVCT) transitions. Our results indicate that, for the radical cations, electronic coupling “through-space” via the stacked styrene decks is significantly more efficient than the “through-bond” pathway.     

Spectroscopic and DFT evidence for a nonclassical radical cation derived from 7-benzhydrylidenenorbornene

Nanosecond time-resolved UV/vis absorption spectroscopy on laser flash photolysis was conducted for photoinduced electron-transfer reactions of 7-benzhydrylidenenorbornene (1) and 7-benzhydrylidenenorbornane (5). The differences in the observed absorption bands and the structures of 1⁺ and 5⁺ were evaluated successfully using calculations based on (time dependent) density functional theory, confirming the nonclassical nature of 1⁺.     

Intramolecular nucleophilic capture of radical cations by tethered hydroxy functions

A range of systems bearing hydroxy functions tethered to the molecular framework gives rise to a family of interesting radical cations, 5⁺-11⁺, upon electron transfer to photo-excited cyanoaromatics. Geraniol (5), nerol (6), citronellol (7), chrysanthemol (8), homochrysanthemol (9), trans-1-o-hydroxyphenyl-2-phenylcyclopropane (10), and endo-5-hydroxymethylnorbornene (11), generate a series of mono-, bi-, or tricyclic ethers via a series of four- to seven-membered transition states. Two of the radical cations, 5⁺ and 6⁺, undergo tandem cyclizations where 1,5- and/or 1,6-C-C cyclizations precede nucleophilic capture.     

Matrix isolation and DFT calculations of the TMM radical cation generated via the single electron oxidation of a methylenecyclopropane

A γ-irradiation of 2,2-diphenyl-1-methylenecyclopropane (3) in a degassed n-butyl chloride glassy matrix at 77 K produced an intense UV/vis absorption band with λ_ab at 432 nm. This result and calculations based on density functional theory for its radical cation 3⁺ and the corresponding trimethylenemethane radical cation (2⁺) strongly suggest that a single electron oxidation of 3 followed by ready ring opening affords 2⁺, whose molecular geometry is largely twisted (θ = 44.0°), and the positive charge and spin are localized mainly in the diphenyl methyl and allyl moieties, respectively.     

Highly Efficient Supramolecular Catalysis by Endowing the Reaction Intermediate with Adaptive Reactivity

A new strategy of highly efficient supramolecular catalysis is developed by endowing the reaction intermediate with adaptive reactivity. The supramolecular catalyst, prepared by host–guest complexation between 2,2,6,6‐tetramethylpiperidin‐1‐oxyl (TEMPO) and cucurbit[7]uril (CB[7]), was used for biphasic oxidation of alcohols. Cationic TEMPO⁺, the key intermediate, was stabilized by the electrostatic effect of CB[7] in aqueous phase, thus promoting the formation of TEMPO⁺ and inhibiting side reactions. Moreover, through the migration into the organic phase, TEMPO⁺ was separated from CB[7] and recovered the high reactivity to drive a fast oxidation of substrates. The adaptive reactivity of TEMPO⁺ induced an integral optimization of the catalytic cycle and greatly improved the conversion of the reaction. This work highlights the unique advantages of dynamic noncovalent interactions on modulating the activity of reaction intermediates, which may open new horizons for supramolecular catalysis.     

Electrochemical oxidation of xanthosine

The electrochemical oxidation of xanthosine in aqueous solution at pH 2.0 at the pyrolytic graphite electrode has been studied. The primary electrochemical oxidation reaction is an irreversible 1 e⁻, 1 H⁺ reaction giving the C(8) free radical. In order to account for the ultimate products formed, the latter primary radical reacts with xanthosine to give at least one N free radical and with water to give an 8-hydroxylated free radical. The C(8) and N radicals couple to give a xanthosylxanthosine dimer which rapidly loses one ribosyl residue to give a xanthosylxanthine dimer. The 8-hydroxylated radical reacts with the C(8) and N radicals to give two isomeric hydroxylated xanthosylxanthosines. The 8-hydroxylated radical can also undergo further electrochemical oxidation (1 e⁻, 1 H⁺) to 9-β-D-ribofuranosyluric acid which is immediately oxidized (2 e⁻, 2 H⁺) to a very reactive quinonoid. Attack by water on the quinonoid gives two isomeric tertiary alcohol intermediates which have been isolated and characterized by their UV and mass spectra and by their reaction with water to give a diol. The latter diol decomposes to 5-hydroxyhydantoin-5-carboxamide-3-riboside.     

Electrochemical nitration of naphthalene in the presence of nitrite ion in aqueous non-ionic surfactant solutions

The nitration of naphthalene (NapH) at a Pt electrode in aqueous NaNO₂ solutions both in the absence and presence of a non-ionic surfactant, Brij®35 (polyoxyethylene (23) dodecanol), has been studied. The electrochemical behaviour of the reactants NapH and NaNO₂ and a mixture of the two was investigated by cyclic voltammetry (CV) to determine the optimal electrolysis conditions. The peak current of NapH decreases with increasing NaNO₂ concentration, indicating that the oxidation product of the NO₂⁻ ion interacts with the NapH radical cation (NapH⁺). Controlled potential electrolysis (CPE) was carried out and the products were analysed by HPLC. The main products detected in the micellar medium were 1-nitronaphthalene, 2-nitronaphthalene, 1,2-naphthoquinone, and 1,4-naphthoquinone. In the absence of Brij 35, the naphthoquinones were produced but no nitration products were obtained. In both cases, unknown products are inferred by mass balance, which are believed to be derived from the oxidation of 1,1′-binaphthyl (BinapH) formed by NapH⁺ coupling in both micellar and aqueous media. A mechanism of nitration by the attack of NO₂ to NapH⁺ is proposed. The higher selectivity for formation of 2-nitronaphthalene in comparison to non-aqueous homogeneous media is attributed to the effect of the micellar microenvironment.     

Aromatization of cyclohexadienes by TEMPO electro-mediated oxidation: Kinetic and structural aspects

Cyclohexadienes are easily converted into the corresponding aromatics in excellent yield (>90%) in the presence of 2,2,6,6-tetramethyl-1-oxopiperidinium ion (TEMPO⁺). The TEMPO radical was used in catalytic amount and was electrochemically regenerated in the presence of 2,6-lutidine as a base in hydro-organic medium (AcCN/H₂O 95/5). This work has been focused on the kinetic aspects. We have demonstrated that the reactivity of different cyclohexadienes is strongly dependent on the configuration of the double bonds and on the nature of the substituents. Competition between allylic functionalization and aromatization has been observed during the oxidation of 1,2-dihydro-4-phenylnaphthalene.