TEMPO reactions

Oxidation of Alcohols. The oxidation of primary, benzylic, and allylic alcohols to aldehydes can be selectively achieved when the alcohol is treated with NCS catalyzed by TEMPO. Reaction conditions are mild and do not chlorinate olefins or allylic... 

A combination of RuQaCPhjP) and the stable nitroxyl radical, 2, 6,6-tetramethylpiperidine-N-oxyl (TEMPO) is a remarkably effective catalyst for the aerobic oxidation of a variety of primary and secondary alcohols, giving the corresponding aldehydes and ketones, respectively, in >99% selectivity. The best results were obtained using lm% of RuCl2(Ph3P)3 and 3m% of TEMPO (Reaction 4). 

Oxidation of Alcohols. The oxidation of primary, benzylic, and allylic alcohols to aldehydes can be selectively achieved when the alcohol is treated with NCS catalyzed by TEMPO. Reaction conditions are mild and do not chlorinate olefins or allylic positions. The reaction is run under t)q)ical phase-transfer conditions using a dichloromethane-water mixture and TBACl as the phase-transfer agent. The aqueous layer for the biphasic reaction is buffered at pH 8.6 with NaHC03-K2C03. Primary alcohols were... 

Most radicals are transient species. They (e.%. 1-10) decay by self-reaction with rates at or close to the diffusion-controlled limit (Section 1.4). This situation also pertains in conventional radical polymerization. Certain radicals, however, have thermodynamic stability, kinetic stability (persistence) or both that is conferred by appropriate substitution. Some well-known examples of stable radicals are diphenylpicrylhydrazyl (DPPH), nitroxides such as 2,2,6,6-tetramethylpiperidin-A -oxyl (TEMPO), triphenylniethyl radical (13) and galvinoxyl (14). Some examples of carbon-centered radicals which are persistent but which do not have intrinsic thermodynamic stability are shown in Section 1.4.3.2. These radicals (DPPH, TEMPO, 13, 14) are comparatively stable in isolation as solids or in solution and either do not react or react very slowly with compounds usually thought of as substrates for radical reactions. They may, nonetheless, react with less stable radicals at close to diffusion controlled rates. In polymer synthesis these species find use as inhibitors (to stabilize monomers against polymerization or to quench radical reactions - Section 5,3.1) and as reversible termination agents (in living radical polymerization - Section 9.3). 

The identification of both phenylethyl and 1-phenyl-1,2,3,4-lelrahydronaphthalenyl end groups in polymerizations of styrene retarded by FeCl3/DMP provides the most compelling evidence for the Mayo mechanism.316 The 1-phenyl-1.2,3,4-tetrahydronaphthalenvl end group is also seen amongst other products in the TEMPO mediated polymerization of styrene,317318 However, the mechanism of formation of radicals 96 in this case involves reaction of the nitroxide with the Diels-AIder dimer (Scheme 3.63). The mechanism of nitroxide mediated polymerization is discussed further in Section 9.3.6. 

The reaction between nitroxides and carbon-centered radicals occurs at near (but not at) diffusion controlled rates. Rate constants and Arrhenius parameters for coupling of nitroxides and various carbon-centered radicals have been determined.508 311 The rate constants (20 °C) for the reaction of TEMPO with primary, secondary and tertiary alkyl and benzyl radicals are 1.2, 1.0, 0.8 and 0.5x109 M 1 s 1 respectively. The corresponding rate constants for reaction of 115 are slightly higher. If due allowance is made for the afore-mentioned sensitivity to radical structure510 and some dependence on reaction conditions,511 the reaction can be applied as a clock reaction to estimate rate constants for reactions between carbon-centered radicals and monomers504 506"07312 or other substrates.20... 

ATRP catalysts may be used to generate radicals and thus alkoxyamines can be produced from alkyl halides in high yield (Scheme 9.21).174 The alkoxyaminc 102 was obtained in 92% yield 174 whereas reaction of TEMPO with PMMA under ATRP conditions is reported to provide a macromonomer (Section 9.7.2.1). 

Of the major methods for living radical polymerization, NMP appears the most successful for polymerization of the diene monomers. There are a number of reports on the use of NMP of diene monomers (B, I) with TEMPO,188,1103 861 4, cw and other nitroxides.127 High reaction temperatures (120-135 °C) were employed in all cases. The ratio of 1,2- 1,4-cis 1,4-trans structures obtained is similar to that observed in conventional radical polymerization (Section 4.3.2). 

NMP in miniemulsion has been more successful. In miniemulsion polymerization nuclealion lakes place directly in the monomer droplets that become the polymer particles. Particle sizes are small (<100 nm). Most w ork has used TEMPO and high reaction temperatures (120-140 °C) with S or BA as monomer. 

Developments in the synthesis and characterization of stable silylenes (RiSi ) open a new route for the generation of silyl radicals. For example, dialkylsilylene 2 is monomeric and stable at 0 °C, whereas N-heterocyclic silylene 3 is stable at room temperature under anaerobic conditions. The reactions of silylene 3 with a variety of free radicals have been studied by product characterization, EPR spectroscopy, and DFT calculations (Reaction 3). EPR studies have shown the formation of several radical adducts 4, which represent a new type of neutral silyl radicals stabilized by delocalization. The products obtained by addition of 2,2,6,6-tetramethyl-l-piperidinyloxy (TEMPO) to silylenes 2 and 3 has been studied in some detail. ... 

Another methodology is the deoxygenation of nitroxides by (TMSlsSiH, shown in Reaction (22). Indeed, the reaction of this silane with TEMPO, in the presence of thermal or photochemical radical initiators, afforded the corresponding amine in quantitative yield, together with the siloxane (TMS)2Si (H)OTMS. 

Sheldon et al. have combined a KR catalyzed by CALB with a racemization catalyzed by a Ru(II) complex in combination with TEMPO (2,2,6,6-tetramethylpi-peridine 1-oxyl free radical) [28]. They proposed that racemization involved initial ruthenium-catalyzed oxidation of the alcohol to the corresponding ketone, with TEMPO acting as a stoichiometric oxidant. The ketone was then reduced to racemic alcohol by ruthenium hydrides, which were proposed to be formed under the reaction conditions. Under these conditions, they obtained 76% yield of enantiopure 1-phenylethanol acetate at 70° after 48 hours. 

Complications of hydroquinone therapy include acute and chronic reactions. Common acute reactions are irritant and allergic contact dermatitis, and post-inflammatory hyperpigmentation. Lesional and perilesional hypopig-mentation may occur. This is usually a tempo-... 

The chemical reactivity of the organoruthenium and -osmium porphyrin complexes varies considerably, with some complexes (M(Por)R2, M(Por)R and Os(OEP)(NO)R) at least moderately air stable, while most are light sensitive and Stability is improved by handling them in the dark. Chemical transformations directly involving the methyl group have been observed for Ru(TTP) NO)Me, which inserts SO2 to form Ru(TTP)(N0) 0S(0)Me and Ru(OEP)Me which undergoes H- atom abstraction reactions with the radical trap TEMPO in benzene solution to yield Ru(OEP)(CO)(TEMPO). Isotope labeling studies indicate that the carbonyl carbon atom is derived from the methyl carbon atom. "" Reaction of... 

Although these reactions are formulated as ionic reactions via 947 and 949, because of the apparent partial formation of polymers and inhibition of the fluoride-catalyzed reaction of pyridine N-oxide 860 with aUyl 82 or benzyltrimethylsilane 83 by sulfur or galvinoxyl yet not by Tempo, a radical mechanism caimot be excluded [61, 62]. The closely related additions of allyltrimethylsilane 82 (cf. Section 7.3) to nitrones 976 are catalyzed by TMSOTf 20 to give, via 977, either o-unsatu-rated hydroxylamines 978 or isoxazoHdines 979 (cf also the additions of 965 to 962a and 969 in schemes 7.20 and 7.21). 

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. 

A number of modifications were made to meet scale-up requirements. In the preparation of the common intermediate, LiBH4 was used in place of LiAlH4 in Step A-2 and a TEMPO-NaOCl oxidation was used in place of Swern oxidation in Step A-3. Some reactions presented difficulty in the scale-up. For example, the boron enolate aldolization in Step B-l gave about 50% yield on the 20- to 25-kg scale as opposed to greater than 75% on a 50-g scale. The amide formation in Step B-3 was modified to eliminate the use of trimethylaluminum, and the common intermediate 17 could be prepared on a 30-kg scale using this modified sequence. The synthesis of the C(l)-C(6) segment V was done by Steps C-l to C-5 in 66% yield on the scale of several kg. 

The Ir11 dimer [Ir(oep)]2 (oep = octaethylporphyrin) has been prepared in low yield by photolysis of (oep)IrCH3 in C6D6.473 This preparation has been improved by Chan et al.474, as shown in Reaction Scheme 24, where TEMPO = 2,2,6,6-tetramethyl-l-piperidinyloxy, free radical. The dimer undergoes several organometallic reactions, including oxidative addition of alkyl C 11 bonds and alkene insertions.475... 

In an anionic/radical domino process an interim single-electron transfer (SET) from the intermediate of the first anionic reaction must occur. Thus, a radical is generated which can enter into subsequent reactions. Although a SET corresponds to a formal change of the oxidation state, the transformations will be treated as typical radical reactions. To date, only a few true anionic/radical domino transformations have been reported in the literature. However, some interesting examples of related one-pot procedures have been established where formation of the radical occurs after the anionic step by addition of TEMPO or Bu3SnH. A reason for the latter approach are the problems associated with the switch between anionic and radical reaction patterns, which often do not permit the presence of a radical generator until the initial anionic reaction step is finished. 

Jahn combined the formation of the enolate 2-713 resulting from an intermolecu-lar Michael addition of 2-711 and 2-712 with a radical reaction (Scheme 2.157) [363]. The enolate 2-713 did not undergo any further transformations due to the lack of appropriate functionalities. However, after formation of a radical using a mixture of ferrocenium hexafluorophosphate (2-714) and TEMPO, a new reaction channel was opened which afforded the highly substituted cyclopentene 2-715a diastereoselec-tively. 

Moreover, by using only TEMPO without addition of 2-714 the Michael adduct 2-713 is transformed into the isopropenylcyclopentane 2-715b as the major product. The process can also be extended by another radical reaction step [364]. 

The same group recently disclosed a related free radical process, namely an efficient one-pot sequence comprising a homolytic aromatic substitution followed by an ionic Homer-Wadsworth-Emmons olefination, for the production of a small library of a,/3-unsaturated oxindoles (Scheme 6.164) [311]. Suitable TEMPO-derived alkoxy-amine precursors were exposed to microwave irradiation in N,N-dimethylformam-ide for 2 min to generate an oxindole intermediate via a radical reaction pathway (intramolecular homolytic aromatic substitution). After the addition of potassium tert-butoxide base (1.2 equivalents) and a suitable aromatic aldehyde (10-20 equivalents), the mixture was further exposed to microwave irradiation at 180 °C for 6 min to provide the a,jS-unsaturated oxindoles in moderate to high overall yields. A number of related oxindoles were also prepared via the same one-pot radical/ionic pathway (Scheme 6.164). 

The cross-disproportionation of nitroxyl and hydroperoxyl radicals is an exothermic reaction. For example, the enthalpies of disproportionation of TEMPO radical with H02, Me2C(0H)02, and cydo-C(,Y 10(OH)O2 radicals are equal to 109, —92, and 82 kJ mol-1, respectively. The Ee0 value for the abstraction of an H atom from the O—H bond in ROOH by a nitroxyl radical is 45.6 kJ mol 1 and AHe min = —58 kJ mol-1. Since AHe < AHe min, (see Chapter 6), the activation energy of such exothermic reactions for these reactions is low (E 0.5RT), and the rate constant correspondingly is high [31 34]. Therefore, in the systems in which hydroperoxyl, hydroxyperoxyl, and aminoperoxyl radicals participate in chain propagation, the cyclic chain termination mechanism should be realized. 

Such reactions are exothermic. For example, the TEMPO radical abstracts an H atom from the (3-C—H bond of cumylperoxyl and cyclohexylperoxyl radicals with enthalpies equal to —42 and — 32 kJ mol-1, respectively. However, such reactions should occur with relatively high activation energy as it is seen from the data calculated by the IPM method [31]. 

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