TEMPO system, alcohol

FIGURE 4. Hammett plot for the oxidation of 4-X-substituted benzyl alcohols with the laccase/ TEMPO system, in competition experiments vs. benzyl alcohol. Reprinted with permission from Reference 156. Copyright (2004) John Wiley Sons Limited... 

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. 

Although, in separate experiments, secondary alcohols are oxidized faster than primary ones, in competition experiments the ruthenium/TEMPO system displayed a preference for primary over secondary alcohols. This can be explained by assuming that initial complex formation between the alcohol and the ruthenium precedes rate-limiting hydrogen transfer and determines substrate specificity, i.e. complex formation with a primary alcohol is favoured over a secondary one. 

In addition to primary and secondary aliphatic alcohols (entries 2-7), benzylic alcohols were also efficiently oxidised (entries 9 and 10), complete conversion being observed within 30 minutes. In competition experiments, the catalyst showed a marked preference for primary alcohols (entries 8 and 11). This is analogous to the already reported homogeneous3 and heterogeneous13 TEMPO systems. A stereogenic centre at the a-position is not affected during oxidation as shown by the selective oxidation of (S)-2-methylbutan-l-ol to (S)-2-methylbutanal (entry 12).20... 

Recently, an alternative to the catalytic system described above was reported [204]. The new catalytic procedure for the selective aerobic oxidation of primary alcohols to aldehydes was based on a CunBr2(Bpy)-TEMPO system (Bpy=2,2 -bipyridine). The reactions were carried out under air at room temperature and were catalyzed by a [copper11 (bipyridine ligand)] complex and TEMPO and base (KOtBu) as co-catalysts (Fig. 4.70). 

Fig. 4.69 Fluorous CuBr2-bipy-TEMPO system for alcohol oxidation.

Another option is the use of both solid-supported versions of the catalyst and the co-oxidant. The Toy group in Hong-Kong has developed a multipolymer system for the TEMPO-catalyzed alcohol oxidation in which both the pre-catalyst and the co-oxidant are attached to a polymer. As it was clearly impossible to use two insoluble supported reagents, the idea was to use an insoluble polymer in conjunction with a soluble one. An insoluble polymer-supported diacetoxyiodosobenzene (PSDIB), an analog of 10, and a soluble polymer-supported TEMPO were used,... 

The Cu/TEMPO catalyst system has been the subject of considerable mechanistic investigation. Initial reports of the Cu/TEMPO catalyst drew mechanistic analogies to the enzyme galactose oxidase, in which a coordinated tyrosyl radical ligand mediates H-atom abstraction from a Cu-bound alkoxide (Figure 6.7) [26]. Early mechanistic studies [27] showed that kinetic isotope effect (KIE) values with Cu/TEMPO catalysts and galactose oxidase are similar and led to the proposal that Cu/TEMPO-mediated alcohol oxidation proceeds via intramolecular abstraction of an H atom by and of a / -coordinated TEMPO. 

A similar oxidative protocol has been used for the oxidation of (fluoroalkyl)alkanols, Rf(CH2) CH20H, to the respective aldehydes [146], in the one-pot selective oxidation/olefination of primary alcohols using the PhI(OAc)2-TEMPO system and stabilized phosphorus ylides [147] and in the chemo-enzymatic oxidation-hydrocyanation of 7,8-unsaturated alcohols [148]. Other [bis(acyloxy)iodo]arenes can be used instead of PhI(OAc)2 in the TEMPO-catalyzed oxidations, in particular the recyclable monomeric and the polymer-supported hypervalent iodine reagents (Chapter 5). Further modifications of this method include the use of polymer-supported TEMPO [151], fluorous-tagged TEMPO [152,153], ion-supported TEMPO [154] and TEMPO immobilized on silica [148],... 

Based on the ability of the PhI(OAc)2-TEMPO system to selectively oxidize primary alcohols to the corresponding aldehydes in the presence of secondary alcohols, Forsyth and coworkers have developed the selective oxidative conversion of various highly functionalized l°,2°-l,5-diols into the corresponding 8-lactones [155]. A representative example, showing the conversion of substrate 127 into the 8-lactone... 

An efficient and mild procedure has been described for the oxidation of different types of alcohols to carbonyl compounds using TEMPO as the catalyst and (dichloroiodo)benzene as a stoichiometric oxidant at 50 °C in chloroform solution in the presence of pyridine [157]. Under these conditions, 1,2-diols are oxidized to p-hydroxyketones or p-diketones depending upon the amount of PhICh used. Interestingly, a competitive study has shown that this system preferentially oxidizes aliphatic secondary alcohols over aliphatic primary alcohols [157], while the PhI(OAc)2-TEMPO system selectively converts primary alcohols into the corresponding aldehydes in the presence of secondary alcohols. 

Hammett correlations, and kinetic isotope eflFect studies showed a similar pattern to those with the Ru/TEMPO system, that is, that they are inconsistent with a mechanism involving an oxoammonium species as the active oxidant. Hence, we propose the mechanism shown in Figure 5.21 for Cu/TEMPO-catalyzed aerobic oxidation of alcohols. 

In addition, many variations of the Cu/Tempo system have been published. In a first example, Knochel et al. [114] showed that CuBr.Me2S with perfiuoroalkyl-substituted bipyridine as the ligand was capable of oxidizing a large variety of primary and secondary alcohols in a fiuorous biphasic system of chlorobenzene and perfluorooctane (see Eq. (5.14)). In the second example Ansari and Gree [115] showed that the combination of CuCl and TEM PO can be used as a catalyst in 1 -butyl-3-methylimidazolium hexafluorophosphate, an ionic liquid, as the solvent. However,... 

Historically, Pt, Pd, Ru, Ir, and Rh complexes were among the most effective catalysts for alcohol oxidation. The series was expanded to 3d metals, e.g., and Cu/TEMPO systems (TEMPO = 2,2,6,6-... 

In contrast to the Cu/TEMPO combination, Fe(III)/TEMPO systems readily catalyze the aerobic oxidation of secondary alcohols and do not usually require any base or less stericaUy hindered ligands. The best activity was observed with weakly coordinating solvents (e.g., dichloroethane) unlike Cu/TEMPO systems, which normally are more active in acetonitrile. The performance and substrate scope (primary and secondary aUyHc, benzylic, or inactivated aliphatic alcohols) of Fe—TEMPO catalyst systems is improved by the presence of NaCl. ... 

SemmeUiack et al. [104] reported that the combination of CuCl and 4-hydroxy TEMPO catalyzes the aerobic oxidation of alcohols. However, the scope was limited to active benzyhc and allylic alcohols and activities were low (10 mol% of catalyst was needed for smooth reaction). They proposed that the copper catalyzes the reoxidation of TEMPO to the oxoammonium cation. Based on our results with the Ru/TEMPO system we doubted the validity of this mechanism. Hence, we subjected the Cu/ TEMPO to the same mechanistic studies described above for the Ru/TEMPO system [105]. The results of stoichiometric experiments under anaerobic conditions, Hammett correlations and kinetic isotope effect studies showed a similar pattern to those with the Ru/TEMPO system, i.e., they are inconsistent with a mechanism involving an oxoammonium species as the active oxidant. Hence, we propose the mechanism shown in Scheme 4.18 for Cu /TEM PO-catalyzed aerobic oxidation of alcohols. 

A new interesting branch of the modern antioxidant chemistry deals with the cyclic mechanisms involving acid catalysis. The first inhibiting system of this type was discovered in 1988 [44]. It consisted of an alcohol (primary or secondary), a stable nitroxyl radical TEMPO, and... 

In other cases, organic modification of the sol gel cages markedly protects the entrapped molecular dopant from degradation by external reactants, as shown for instance by the entrapment of the radical 2,2,6,6-tetramethylpiperidine-l-oxyl (TEMPO). This is a highly active catalyst which in the NaOCl oxidation of alcohols to carbonyls in a CH2CI2-H20 biphasic system becomes highly stabilized upon sol gel entrapment in an ORMOSIL matrix it progressively loses it activity when entrapped at the external surface of commercial silica.25... 

Figure 5.14 Sol-gel immobilized TEMPO is an off-the-shelf alcohol oxidation catalyst. In a biphasic reaction system and in organic solvent it yields carbonyls in water it yields carboxylates.

A double mediatory system consisting of modified TEMPO and halide ion or metal ion was also exploited for the oxidation of alcohols [53-55]. A number of carbohydrates have been chemoselectively oxidized at the primary hydroxyl group to uronic acids [56]. 

Some successful attempts to immobilize catalysts for the oxidation of alcohols to carbonyl compounds involve the attachment of TEMPO-derivatives to a solid phase. Bolm et al. were the first to immobilize l-hydroxy-2,2,6,6-tetramethylpiperi-dine to modified silica gel (SG-TMP-OH) (11) and applied in the oxidation of multifunctional alcohols [68]. Other groups further investigated the use of polymer-supported TEMPO [69]. This system allowed the oxidation of alcohols to aldehydes and ketones, respectively, using bleach to regenerate the immobilized ni-troxyl radical (Scheme 4.6). 

TEMPO has been structurally modified to bring about new selectivities. Highly efficient anionic water-soluble TEME<), oil-in-water nanoemulsion containing TEME for oxidation of alcohols and a waste-free system were developed. Especially, the sterically less crowded azabicyclo-Af-oxyls oxidized /-menthol to Z-menthone with much higher efficiencies than TEME O (equation 23). ... 

NaClO, or else in the two-phase system but with a quaternary ammonium (viz. AUquat) ion as a phase-transfer catalyst, overoxidation to the corresponding carboxylic acid is obtained (entry 4). Therefore, by proper choice of the experimental conditions, a synthetically useful distinction in products formation can be made for the oxidation of primary alcohols, even though we are far from a satisfactory understanding of the reason behind this different behaviour. In fact TEMPO, as a well-known inhibitor of free-radical processes is allegedly responsible for the lack of overoxidation of an aldehyde to carboxylic acid (entry 3) this notwithstanding, TEMPO is also present under those conditions where the overoxidation does occur (eutry 4). Moreover, a commou teuet is that the formation of the hydrated form of an aldehyde (in water solution) prevents further oxidation to the carboxylic acid however, both entries 3 and 4 refer to water-organic solutions, and their... 

The system RuCl3(PPh3)3/TEMPO/O3(10 atm air)/CgH3Cl (TEMPO=2,2, 6,6 -tetramethyl-piperidine-iV-oxyl radical. Fig. 1.40) oxidised primary alcohols to aldehydes and secondary alcohols to ketones. Hammett correlation studies and primary... 

The application of ionic liquids as a reaction medium for the copper-catalyzed aerobic oxidation of primary alcohols was reported recently by various groups, in attempts to recycle the relatively expensive oxidant TEMPO [150,151]. A TEMPO/CuCl-based system was employed using [bmim]PF6 (bmim = l-butyl-3-methylimodazolium) as the ionic liquid. At 65 °C a variety of allylic, benzylic, aliphatic primary and secondary alcohols were converted to the respective aldehydes or ketones, with good selectiv-ities [150]. A three-component catalytic system comprised of Cu(C104)2, dimethylaminopyridine (DMAP) and acetamido-TEMPO in the ionic liquid [bmpy]Pp6 (bmpy = l-butyl-4-methylpyridinium) was also applied for the oxidation of benzylic and allylic alcohols as well as selected primary alcohols. Possible recycling of the catalyst system for up to five runs was demonstrated, albeit with significant loss of activity and yields. No reactivity was observed with 1-phenylethanol and cyclohexanol [151]. 

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