Oxidation hypochlorite-TEMPO

TEMPO (2,2,6,6-tetramethylpiperidinyl-1-oxy) is a stable free radical that catalyzes many types of oxidations. For example, a catalytic amount of TEMPO added to a hypochlorite oxidation of an alcohol increases the rate by enabling lower-energy reaction mechanisms involving reversible oxidation of the N—0 bond. 

Newer methods of alcohol oxidation (Swem, Dess-Martin) are introduced as environmentally preferable to the older chromium methods, including a description of a general, unifying mechanism of alcohol oxidation to aldehydes and ketones. TEMPO is shown as an oxidation catalyst to enhance hypochlorite oxidation. 

For the sake of completeness we also note that oxygen transfer processes can be mediated by organic catalysts which can be categorized on the same basis as metal catalysts. For example, ketones catalyze a variety of oxidations with mono-peroxysulfate (KHS05) [14]. The active oxidant is the corresponding dkmrane and, hence, the reaction can be construed as involving a peroxometal pathway. Similarly, TEMPO-catalyzed oxidations of alcohols with hypochlorite [15, 16] involve an oxoammonium salt as the active oxidant, i.e. an oxometal pathway. 

There are various alternatives for reoxidizing the hydroxylamine back to TEMPO to complete the catalytic cycle. It can be oxidized by dioxygen, laccase or the oxoammonium cation. The active oxidant is the same as that in the TEMPO catalyzed oxidations of alcohols with hypochlorite (or other single oxygen donors), a method which is widely used in the oxidation of a broad range of alcohols using low catalyst loadings (1 mol % or less) (59). 

Figure 5.2 TEMPO-catalyzed oxidation of alcohols using hypochlorite as the oxidant...

The first oxidation of primary alcohols was described by Golubev et al. in 1965 [332], Oxoanunonium salt as the oxidant was separately synthesized from 4-hydroxy-TEMPO with elemental chlorine. Later, Semmelhack et al. generated the oxoanunonium cation in situ by electrochemical oxidation [328]. In 1987, Anelli and coworkers used 4-methoxy-TEMPO as catalyst in combination with sodium hypochlorite at O C under shghtly basic conditions [333-335]. Thus, it was possible to regenerate the oxoanunonium cation from the nitroxyl radical continuously. The TEMPO/hypochlorite protocol (Anelli-Montanari process. Scheme 7.83) has been widely applied in organic synthesis. 

Fig. 6. Specific oxidation of the 6-hydroxyl of starch usiag bromide—hypochlorite and tetramethylpiperidine oxide (TEMPO).

Oxidations Using Oxoammonium Ions. Another oxidation procedure uses an oxoammonium ion, usually derived from the stable nitroxide tetramethylpiperidine nitroxide, TEMPO, as the active reagent.31 It is regenerated in a catalytic cycle using hypochlorite ion32 or NCS33 as the stoichiometric oxidant. These reactions involve an intermediate adduct of the alcohol and the oxoammonium ion. 

Another interesting class of five-membered aromatic heterocycles has recently been published by Tron et al. [54]. These compounds have biological activity in the nM range. An example of the formation of these furazan (1,2,5-oxadiazole) derivatives is shown in Scheme 9. The diol 50 was oxidized to the diketone 51 using TEMPO and sodium hypochlorite. Transformation to the bisoxime 52 was performed in an excess of hydroxylamine hydrochloride and pyridine at high temperature for several days. Basic dehydration of 52 formed two products (53a and b). A Mitsunobu reaction was then employed using toluene as solvent to form compound 53b in 24% yield. 

Oxidation of primary alcohols by hypochlorite moderated by TEMPO... 

The reported procedure for the selective oxidation of natural glycosides is mild, convenient and easily reproducible. The biotransformations are performed in mildly acidic water solutions therefore, this method is complementary to other chemical approaches for the in situ regeneration of the oxidized form of TEMPO, such as sodium hypochlorite, that require alkaline pH. 

A convenient procedure for the oxidation of primary and secondary alcohols was reported by Anelli and co-workers (8,9). The oxidation was carried out in CH2CI2 with an aqueous buffer at pH 8.5-9.5 utilizing 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO, 1) as the catalyst and KBr as a co-catalyst. The terminal oxidant in this system was NaOCl. The major disadvantage of using sodium hypochlorite or any other hypohalite as a stoichiometric oxidant is that for each mole of alcohol oxidized during the reaction one mole of halogenated salt is formed. Furthermore,... 

Apart from sodium hypochlorite, a number of alternative secondary oxidants for TEMPO-mediated alcohol oxidations can be employed. These include cerium (IV) ammonium nitrate (CAN),24 trichloroisocyanuric acid (TCCA),25 oxone ,26 MCPBA,2,3,7 PhI(OAc)2,27 W-chlorosuccinimide,28 sodium bromite,29 electrooxidation,8,21 H5IO626 and a polymer-attached diacetoxybromide (I) complex.30... 

The very common TEMPO-mediated Anelli s protocol for the oxidation of alcohols, involving a biphasic CH2Cl2-water mixture containing catalytic TEMPO, or an analogue thereof, and sodium hypochlorite as a secondary oxidant, shows a great selectivity for the oxidation of primary alcohols in the presence of secondary ones9 and has found some use in Synthetic Organic Chemistry.10... 

Immobilized TEMPO has been used for the one-pot oxidation of alcohols to carboxylic acids as well.26 For this purpose TEMPO resin 1 was combined with two ion-exchange resins loaded with chlorite anions and hydrogen phosphate in the presence of catalytic amounts of potassium bromide and sodium hypochlorite in solution. The reaction required work-up for the removal of salts, but tolerated several protecting schemes and afforded pure products in good to excellent yields. The reaction is initiated by catalytic TEMPO oxidation of alcohols to aldehydes driven by dissolved hypochlorite followed by oxidation to the carboxylic acids effected by chlorite. 

The oxidation of alcohols to carbonyl compounds with the stable nitroxyl radical TEMPO (86) as catalyst is a well-known preparative method [134, 135]. Hypochlorite or peracetic acid is usually used as the final oxidizing agent and ca. 1 mol% of catalyst 86 is used. In 1996 Rychnovsky et al. reported the synthesis of the chiral, binaphthyl-derived TEMPO analog 87 [136], Results obtained by use of 0.5-1 mol% of catalyst 87 [136] are listed in Table 10.12. In these oxidation reactions 0.6-0.7 equiv. sodium hypochlorite were used as the final oxidizing agent (plus... 

The chiral TEMPO-derivative 87 has been shown to be an active catalyst for the oxidative kinetic resolution of 1-phenylethanol and derivatives. Catalyst loadings are in a practically very useful range (0.5-1 mol%) and hypochlorite is an attractive oxidant. Clearly, a more readily accessible catalyst would be desirable. In this respect, the Shi ketone 88 is advantageous. It must, however, be used in large excess and... 

The 2,2,6,6-tetramethylpiperidinoxyl (TEMPO) radical was first prepared in 1960 by Lebedev and Kazarnovskii by oxidation of its piperidine precursor. TEMPO is a highly persistent radical, resistant to air and moisture, which is stabilized primarily by the steric hindrance of the NO-bond. Paramagnetic TEMPO radicals can be used as powerful spin probes for investigating the structure and dynamics of biopolymers such as proteins, DNA, and synthetic polymers by ESR spectroscopy [7]. A versatile redox chemistry has been reported for TEMPO radicals. The radical species can be transformed by two-electron reduction into the respective hydroxyl-amine or by two-electron oxidation into the oxoammonium salt [8]. One-electron oxidations involving oxoammonium salts have also been postulated [9]. The TEMPO radical is usually employed under phase-transfer conditions with, e.g., sodium hypochlorite as activating oxidant in the aqueous phase. In oxidations of primary alcohols carboxylic acids are often formed by over-oxidation, in addition to the de-... 

The nitroxyl radical TEMPO (18a) is an active catalyst for the selective oxidation of alcohols, with hypochlorite as the oxidant. The actual oxidizing species is the oxoaminium ion (18b), which in the alcohol oxidation (I in the structure) is reduced to the hydroxylamine (18c). A catalytic amount of bromide is used to generate BrO , which is capable of reoxidizing the hydroxylamine or the aminoxyl radical (18a) to the oxoaminium stage (408). 

The TEMPO - sodium hypochlorite - sodium bromide system has been applied to starch ether derivatives, particularly hydroxyethyl starch, which has a primary hydroxyl group on the hydroxyethyl ether group that can also be oxidized to a carboxyl group and carboxymethyl starch. The apparent goal was improved sequestering agents via higher carboxyl content and the proper multidentate conformations... 

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