N-Oxyls

One obvious way in which to attach a nitroxide group to B12 is to simple alkylate Cob(I)aiamin with a suitable nitroxide derivative. This would result in having the nitroxide covalently bound to the corrinoid at the upper axial coordination position of the cobalt. Such a procedure is outlined in Fig. 19. In this reaction 4-bromoacetamido 2,2,6,6-tetra-methylpiperidine-N-oxyl is used to alkylate Cob(I)alamin. This results in a Co(III)-nitroxalkylcobalamin. The corresponding cobinamide can then be produced by hydrolyzing the ribose-phosphate linkage (119). 

Fig. 19. Alkylation of Bias with 4 bromoacetamido 2,2,6,6-tetramethylpiperidine-N-oxyl to give nitroxalkylcobalamin, and (after hydrolysis) the corresponding cobinamide...

Another chemically more interesting spin labeled B12 derivative involves coordinate attachment of the nitroxyl function to the cobalt atom of a cobinamide. Fig. 22 shows a reaction in which an alkyl cobin-amide is mixed with 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl. The nitroxide displaces water from the 6th coordination position very slowly and therefore this reaction is usually allowed to proceed for a few days with a large excess of nitroxide. From the properties of the coordinated nitroxide derivative discussed below, it is certain that the cobalt is coordinated by the N—O functional group. An analogous compound to that shown in Fig. 22 can be made with a similar nitroxide in which the 4-hydroxyl-group is missing. In this case the N—O-function is the only basic site on the molecule and therefore must be the position of attachment to the cobalt 119). 

The u.v.-visible spectrum of the 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl-methyl-cobinamide is very similar to methyl-cobin-amide itself and as a result this technique cannot be used to rigorously identify the spin labeled derivative. The spin labeled compound does show a spectral change with pH between pH 7.0 and pH 2.0 which methyl-cobinamide does not exhibit. Despite the similarities between methyl-cobinamide and nitroxylmethylcobinamide, the circular dichroism spectrum of the two derivatives are quite different. Fig. 23 shows the marked difference in C. D. spectra of 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl, methylcobinamide, and a methylcobinamide solution containing an equimolar amount of uncoordinated nitroxide. 

Fig. 23. C. D. Spectra of 4-hydroxy-2,2,6,6-piperidine-N-oxyl-methyl-cobinamide (—) and methyl-cobinamide plus free nitroxide (---—) at 3 x 10 5 M in ethanol...

Fig. 25. Electron spin resonance spectra of 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl aquocobinamide before and after treatment with CN (a) spectrum of aquo derivative, (b) Expanded view of center line before addition of CN-. (c) Spectrum of liberated nitroxide. (d) Expanded view of centerline after CN- treatment showing additional proton hyperfine...

The most extensive and informative enzyme work with B12 spin labels has been carried out on the enzyme ethanolamine ammonia-lyase 123). This work has employed six-coordinate 4-hydroxy-2,2,6,6-tetra-methylpiperidine-N-oxyl-5 -deoxyadenosylcobinamide. Ethanolamine ammonia lyase uses 5 -deoxyadenosylcobalamin as cofactor. Spin labeled 5 -deoxyadenosylcobinamide was used in order to determine the nature of the first step in the mechanism of action of ethanolamine ammonia lyase by determining the manner in which the Co—C bond is broken. Spin labeled 5 -deoxyadenosylcobinamide was synthesized by taking reduced diaquocobinamide and reacting it with an excess of 5 -tosyl-adenosine to give 5 -deoxyadenosylcobinamide. This was stirred for three days with a 20 fold excess of 4-hydroxy-2,2,6,6-tetramethylpiperidine... 

M. x 108M 1s 1 at 25°C, but may be appreciably lower in the solid state. In comparison k2 for oxygen competition for the alkyl radical is 2 x 109M-1s 1. Thus for air-saturated PPH ([02] 8 x 10-1,M)reaction7 will be protection against xenon irradiation was improved as compared to the parent piperidine by about 25, but the nitroxide itself was reduced to the 1 x 10 M level within the first lOOh and persisted at this level until brittle failure (7,) In contrast the parent amine is completely destroyed in the first lOOh of xenon exposure. 

This approach was followed by Yushmanov for the localization of papaverine in ionic micelles.42 Another interesting application was reported by Chien43 who measured 19F NMR relaxation times of trifluor-omethyl labelled atrazine induced by paramagnetic probes gadolinium ethylenediamine tetraacetic acid and 2,2,6,6-tertramethyl-piperidine-N-oxyl. The results showed that atrazine solubilized by humic micelles occupied a hydrophobic domain accessible only to neutral hydrophobic molecules. 

Tab. 2 N-Oxyl derivatives used for electrooxidation of alcohols as mediators...

In a related study the adduct of hexafluoroacetylacetonate copper(II) (d ) with the free radical base 2,2,6,6-tetramethylp5nidine-N-oxyl,... 

We wish to report here on a new and highly efficient catalyst composition for the aerobic oxidation of alcohols to carbonyl derivatives (Scheme 1). The catalyst system is based on 2,2,6,6-tetramethylpiperidine N-oxyl (TEMPO), Mg(N03)2 (MNT) and N-Bromosuccinimide (NBS), utilizes ecologically friendly solvents and does not require any transition metal co-catalyst. It has been shown, that the described process represents a highly effective catalytic oxidation protocol that can easily and safely be scaled up and transferred to technical scale. 

A new reagent, AMiydroxyphthalimide combined with Co(acac)n (n = 2,3), transforms alkylbenzenes to ketones, whereas methylbenzenes give the corresponding carboxylic acids.1121 Phthalimide N-oxyl was found to be the key intermediate. Novel oxoperoxo Mo(VI) complexes mediate the cost-effective and environmentally benign oxidation of methylbenzenes to carboxylic acids.1384 Similar green oxidation of p-xylene to terephthalic acid was reported by using a Ru-substituted heteropolyanion.1385... 

Tandem lesion, where C(8) of G is bound to the methyl group of T Triace loneamine-N-oxyl... 

The incorporation of TEMPO alkoxy amine at the end of a PE chain has been achieved [99]. The dialkylmagnesium compound in ethylene polymerization was adopted as a chain transfer agent, as mentioned above. It was also reported that PE-TEMPO and terminally N-(2-mcthyl-2-propyl)-N-(l-diethylphosphono-2,2-dimethylpropyl)-N-oxyl PE were synthesized by the reaction with di-polyethylene magnesium produced in ethylene polymerization. They were used for CRP of n-butyl acrylate, leading to PE-h-PnBA. 

Recently, N-hydroxyphthalimide (NHPI) catalysis has been applied to a variety of aerobic oxidations of organic compounds [12], We have reported how NHPI, in the presence of Co(II) salts, is able to generate the phthalimido N-oxyl (PINO) radical, which rapidly abstracts hydrogen from aromatic and aliphatic aldehydes, in a free-radical chain mechanism under aerobic conditions (Scheme 14.2) [13]. The role of oxygen is to oxidize Co(II) to Co(III), which is also involved in the oxidation of the intermediate (Equation 14.8). 

The radical C-H transformation of ethers is generally initiated by a-hydrogen abstraction with highly reactive radicals generated from such initiators as peroxides [3a, g], photo-activated carbonyl compounds [3b—d], metallic reagents [3i, j], and redox systems [3f, h[. Various combinations of ethers, radical initiators, and radical acceptors (e.g. carbon-carbon multiple bonds) may be used as the reaction components [6], Several notable means of direct C-C bond formation via the radical a-C-H transformation of ethers involve the use of triflon derivatives [7], the phthalimide-N-oxyl (PINO) radical [8], 2-chloroethylsulfonyl oxime ethers [9], and N-acyl aldohydrazones [10],... 

The mechanism of the aerobic oxidation of alcohols depends on the particular catalyst used. Two general mechanisms can be considered (1) the direct oxygenation of alcohols by 02 through a free-radical chain process initiated by the catalyst, and (2) the direct oxidation of the alcohol by the catalyst, which is then regenerated by 02. Both mechanisms are well illustrated [6] by the aerobic oxidations catalyzed by the persistent tetramethylpiperidine-N-oxyl (TEMPO) radical 1 and the nonpersis-tent phthalimide-N-oxyl (PINO) radical 2. 

Because C-H bonds are usually less reactive towards dioxirane oxidation than heteroatoms and C-C multiple bonds, it is instructive to give a few general guidelines on the compatibility of functional groups within the substrate to be submitted to oxidative C-H insertion Substances with low-valent heteroatoms (N, P, S, Se, I, etc.), C-C multiple bonds, and C=X groups (where X is a N or S heteroatom) are normally not suitable for C-H insertions, because these functionalities react preferably. Even heteroarenes are more susceptible to dioxirane oxidation than C-H bonds, whereas electron-rich and polycyclic arenes are only moderately tolerant, but electron-poor arenes usually resist oxidation by dioxiranes. N-oxides and N-oxyl radicals are not compatible because they catalyze the decomposition of the dioxirane. Oxygen insertion into Si-H bonds by dioxirane is more facile than into C-H bonds and, therefore, silanes are not compatible. Substance classes normally resistant towards dioxirane oxidation include the carboxylic acids and their derivatives (anhydrides, esters, amides, and nitriles), sulfonic acids and their de-... 

Figure 9 Time-dependent PEDRI images of a living mouse with an intravenous infusion of 2,2,5,5-tetramethyl-3-carboxylpyrrolidine-N-oxyl (PCA) radical. (A) The posterior slice (a-e) no ESR irradiation, (f-j) 12 W of ESR irradiation and (k-o) the subtraction of ESR on and off images. (B) The anterior slice (a -e ) no ESR irradiation, (f -j ) 12 W of ESR irradiation and (k -o ) the subtraction of ESR on and off images. The posterior images show that PCA is initially distributed in the heart, lungs, kidneys and major vessels, while the anterior images show that PCA is collected in the bladder over time. Adapted with permission from Ref. [160].

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