Oxoammonium ions

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. 

The A-oxoammonium ion is theoretically expected to react with an amine, eliminating a proton and forming the hydroxylamine while the amine is converted to imines and/or nitriles (Scheme 4). These were indeed observed by Semmelhack and Schmid (equation 28)". ... 

Besides this hydrogen atom transfer (HAT) route, the aminoxyl radical may also take part in oxidation procedures where, through a preliminary monoelectronic step, it is converted into an oxoammonium ion (R2N=0+), or variations of this route. Examples of... 

Persistent or moderately stable aminoxyl radicals (1, in Scheme 6) lend themselves to one-electron oxidation to yield an oxoammonium ion (4) at a redox potential that depends on the structure of the hydroxylamine precursor Calculation methods have... 

SCHEME 6. Oxidation of an alcohol by the oxoammonium ion 4 derived from an aminoxyl radical 1... 

This 1 —> 4 redox event has importance both in reactivity studies and in synthetic procedures because, for example, the oxoammonium ion 4 brings about the oxidation of primary or secondary alcohols into carbonyl compounds (Scheme 6). The chemistry of ion 4 represents the other main issue of the present review. Table 3 collects redox data for the R2N=0+/R2N0 one-electron reduction, which can be reversible or irreversible ( ° or ifP data, respectively) because ion 4 may present either moderate or low stability... 

As anticipated in Section II.B (Scheme 6), monoelectronic oxidation of R2N—O may afford a stable oxoammonium ion (R2N=0+), the case of TEMPO being exemplary. 

Although this point has been known for many years " , and despite the important synthetic applications of TEMPO-oxoammonium that will be summarized later, the nature of the involved reactive species and the ensuing mechanism of oxidation are still a matter of debate, and this is why the term oxoammonium ion is put within quotation marks in the title of the present section. The reactivity subtleties will be summarized here. 

The basic features are delineated in a fundamental review , where the alleged R2N=0+ species is reported to be generated in situ by a suitable primary oxidant from precursor R2N—O (i.e. TEMPO). The substrate to be oxidized, e.g. an alcohol, attacks the oxoammonium ion as a nucleophile (Scheme 15) , giving an adduct that, by a-elimination, yields the carbonyl end product, while the primary oxidant regenerates the reactive R2N=0+ ion from the reduced R2NO—H (viz. TEMPOH) in a catalytic cycle. 

SCHEME 15. Ionic mechanism of oxidation of alcohols by TEMPO-oxoammonium ion. Redrawn from Reference 63 by permission of The Royal Society of Chemistry on behalf of the Centre National de la Recherche Scientifique... 

However, the rationalization of this matter is made more complex by the possible equilibration among various forms deriving from catalyst TEMPO. For example, and depending on the pH of the reaction, either disproportionation of TEMPO or of TEMPOH (viz. R2NO—H) can occur (Scheme 16) , making it difficult to evaluate the extent of participation of the alleged oxoammonium ion in some cases. 

Operation of the latter mechanism has also been invoked for the oxidation of X-substituted benzyl alcohols with TEMPO and the enzyme laccase becanse the redox potential of the enzyme (0.78 is adeqnate for the oxidation of TEMPO to oxoammonium ion (0.8 Strangely enough, no linear correlation of the log A x/ h ratios... 

As opposed to such a consistent body of evidence in favour of the H-abstraction route with aminoxyl radical intermediates, the reactivity features of the oxoammonium ion , as a derivative of the aminoxyl radical (TEMPO), are somewhat baffling (Section III.E). In spite of the many studies from the literature, a lack of uniformity emerges whenever the Hammett and KIE parameters are investigated and compared. The possible interplay of different mechanistic routes has been suggested, and more experimental work is needed before satisfactory conclusions can be drawn. Certainly, this does not undermine the synthetic value of the procedure, as we will see below, even though care must be exerted when comparing results obtained by the use of different primary oxidants. 

Only a few examples will be summarized in Table 13 it is apt to remind the reader that a variety of primary oxidants have been used in the literature in order to produce the alleged oxoammonium ion (see Section in.E), and this might lie at the basis of some of the contrasting results experienced. 

SCHEME 18. Organic transformations accessible to the oxoammonium-ion system. Reprinted with permission from Reference 171. Copyright (2001) American Chemical Society... 

As anticipated, Sheldon and coworkers attempted to revise the Cu/TEMPO system, and suggested that a piperidinyloxycopper(II) adduct, rather than the oxoammonium ion, is instead formed as an intermediate species that adduct would be responsible for turning the alcohol into the carbonyl product. Sheldon and coworkers proposed the radical mechanism outlined in Scheme 17, and supported it with a Hammett p value of —0.16 (vs. a) and with a KIE of 5.4 . They also suggested that steric hindrance arising from interaction of secondary alcohols with the active-TEiMPO species, whatever it can be, are possibly responsible for the lower, or lack of, reactivity displayed by these substrates . Accordingly, a novel TEMPO-like system has been recently developed in order to specifically bypass this steric interference , as we are going to see below. 

Other organic mediators act as hydride atom-abstracting agents. This is true, for example, with 2,2-dichloro-5,6-dicyano-p-benzoquinone (DDQ) and the oxoammonium ion which is anodically accessible from 2,2,6,6-tetramethylpiperidyl oxide (TEMPO). DDQ has been electrochemically regenerated either externally or internally The in situ electrochemical oxidation, of TEMPO to the active oxoammonium ion is performed in lutidine-containing acetonitrile. Thus, primary alcohols can be oxidized to the aldehydes, while secondary ones are stable Primary amines are transformed to nitriles. If water is present, the amines are cleaved via the Schiff bases to the corresponding carbonyl compounds... 

It should be noted that the related imine-oxaziridine couple E-F finds application in asymmetric sulfoxidation, which is discussed in Section 10.3. Similarly, chiral oxoammonium ions G enable catalytic stereoselective oxidation of alcohols and thus, e.g., kinetic resolution of racemates. Processes of this type are discussed in Section 10.4. Whereas perhydrates, e.g. of fluorinated ketones, have several applications in oxidation catalysis [5], e.g. for the preparation of epoxides from olefins, it seems that no application of chiral perhydrates in asymmetric synthesis has yet been found. Metal-free oxidation catalysis - achiral or chiral - has, nevertheless, become a very potent method in organic synthesis, and the field is developing rapidly [6]. 

The use of oxoammonium ions such as those derived from TEMPO in combination with inexpensive, safe, and easy-to-handle terminal oxidants in the conversion of alcohols into aldehydes, ketones, and carboxylic acids is a significant example of how it is possible to develop safer and greener chemistry, by avoiding the use of environmentally-unfriendly or toxic metals. However, separation of the products from TEMPO can be problematic, especially when the reactions are run on... 

Alternatively TEMPO can be reoxidized by metal salts or enzyme. In one approach a heteropolyacid, which is a known redox catalyst, was able to generate oxoammonium ions in situ with 2 atm of molecular oxygen at 100 °C [223]. In the other approach, a combination of manganese and cobalt (5 mol%) was able to generate oxoammonium ions under acidic conditions at 40 °C [224]. Results for both methods are compared in Table 4.9. Although these conditions are still open to improvement both processes use molecular oxygen as the ultimate oxidant, are chlorine free and therefore valuable examples of progress in this area. Alternative Ru and Cu/TEMPO systems, where the mechanism is me-... 

Primary alcohol groups can be exclusively oxidized to aldehyde groups with pyridinium dichromate [149,150] and to carboxyl groups with the 2,2,6,6-tetramethyl-1-piperidine oxoammonium ion (TEMPO) [151]. The aldehydes can then be reduced to primary alcohols by reaction with NaB H4 [150,152], giving radiolabeled H-starch and the carboxyl group can be inverted by the action of Azotobacter vinlandii poly- 8-D-marmuronic acid C-5-epimerase to give L-iduronic acid [153]. 

In their oxidation mechanism, NCS and NaBr lead to the formation of hypobro-mons acid, which oxidizes the nitroxyl radical to the N-oxoammonium ion. For efficient oxidations, the presence of both nitroxyl radical and halide ion is required. 

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