Nitroxides, disproportionation

Georges et al showed that addition of camphorsulfonic acid significantly increases the rate of TEMPO mediated styrene polymerization. However, the mechanism of action was not unequivocally elucidated.One possible explanation is the reduction of the TEMPO concentration through its reaction with acid. It is well known that nitroxides disproportionate under acidic conditions into hydroxylamine 4 and oxoammonium salt 16 (Scheme 4.9). The mechanism of this reaction was recently investigated. ... 

Some limitations of the method arise due to side reactions involving the nitroxide. However, such problems can usually be avoided by the correct choice of nitroxide and reaction conditions. Nitroxides, while stable in the presence of most monomers, may act as oxidants or rcductants under suitable reaction conditions.516 The induced decomposition of certain initiators (e.g. diacyl peroxides) can be a problem (Scheme 3.94).166 177 There is some evidence that nitroxides may disproportionate with alkoxy radicals bearing a-hydrogens,123 Side reactions with thiols have also been identified.4 18... 

A wide range of nitroxidcs and derived alkoxyamincs has now been explored for application in NMP. Experimental work and theoretical studies have been carried out to establish structure-property correlations and provide further understanding of the kinetics and mechanism. Important parameters are the value of the activation-deactivation equilibrium constant K and the values of kaa and (Scheme 9.17), the combination disproportionation ratio for the reaction of the nilroxide with Ihe propagating radical (Section 9.3.6.3) and the intrinsic stability of the nitroxide and the alkoxyamine under the polymerization conditions (Section 9.3.6.4). The values of K, k3Cl and ktieact are influenced by several factors.11-1 "7-"9 ... 

While nitroxides give overwhelmingly combination in their reaction with carbon-centered radicals, the amount of disproportionation is finite (Scheme 9.24). Disproportionation cannot always be rigorously distinguished from elimination and it is possible that both reactions occur. The combinatiomdisproportionation ratio (or extent of elimination) depends on the nitroxide and radical structure and within a scries of structurally related systems appears to increase as... 

The thermal decomposition of the phenylelhyl alkoxyamine with TEMPO and the fraction of living ends in TEMPO-mediated S polymerization has been studied by Priddy and coworkers.143 179 They concluded that to achieve >90% living ends conversions and/or nitroxide concentrations should be chosen to give V/ less than 10000.143 However, disproportionation or elimination is most important during polymerizations of methacrylates and accounts for NMP being less successful with... 

A side reaction in NMP is loss of nilroxide functionality by thermal elimination. This may occur by disproportionation of the propagating radical with nitroxide or direct elimination of hydroxy lam ine as discussed in Section 9.3.6.3. In the case of methacrylate polymerization this leaves an unsaturated end group.1" The chemistry has also been used to prepare macromonomers from PMMA prepared by ATRP (Section 9.7.2.1),... 

Addition of TEMPO post-polymerization to a methacrylate polymerization provides an unsaturated chain end (Scheme 9.52)i07 sw presumably by disproportionation of the PMMA propagating radical with the nitroxide. For polymers based on monosubstituted monomers (PS,1 0" PBA59,[Pg.534]

Since no relatively stable free radical is present (such as 26 in 14-17), most of the product arises from dimerization and disproportionation. The addition of a small amount of nitrobenzene increases the yield of arylation product because the nitrobenzene is converted to diphenyl nitroxide, which abstracts the hydrogen from 1 and reduces the extent of side reactions. ... 

The presence of /3-hydrogen in the nitroxide radical may lead to disproportionation reactions. In spin-trapping experiments, N-t-butyl-a-phenyl nitrone yields rather unstable spin adducts. This type of radical can be stabilized by coordination to Nin. The Ni11 complex with N-oxy-A-r-butyl-(2-pyridyl)phenylmethanamine (923) reveals a distorted octahedral geometry with antiferromagnetic interactions between the unpaired electrons of the metal ion and the radical spins.00... 

Matyjaszewki et al. [229,236] pointed out the importance of the bimolecular exchange reaction (Eq. 19) to control the molecular weight and its distribution. Simulation revealed a decrease in the Mw/Mn values during polymerization, but the contribution in the actual polymerization is still ambiguous [237-240]. Reports have also addressed the importance of the decomposition of the alkoxyamine such as the disproportionation of the propagating radical and the nitroxide for the control of the polymerization [229,236,241 ]. 

The stability of nitroxides will be well known to readers acquainted with the spin-labelling technique (Berliner, 1976), but it must be recognized that nitroxides employed as spin labels or spin probes are almost invariably di-t-alkyl nitroxides. Diaryl and many aryl t-alkyl nitroxides are also sufficiently persistent to be isolated, and it has recently been shown that several acyl t-alkyl nitroxides can also be obtained pure (Perkins and Ward, 1973 Alewood et al., 1978). However, other nitroxides are less persistent. Monosubstituted nitroxides, RN(H)Q-, rapidly disproportionate to nitroso-... 

Further possibilities for nonenzymatic nitrone formation include the disproportionation of nitroxides in cases where the nitroxyl functionality is attached to an a-carbon bearing at least one hydrogen142 (equation 14), or the rearrangement of certain N-hydroxy compounds to the thermodynamically more stable tautomeric forms, as has been observed for the formation of a-aminonitrone from N--hydroxy-7V-methylbenzamidine50 (equation 15). 

Since the nitroxide and the carbon-centered radical diffuse away from each other, termination by combination or disproportionation of two carbon-centered radicals cannot be excluded. This will lead to the formation of dead polymer chains and an excess of free nitroxide. The build-up of free nitroxide is referred to as the Persistent Radical Effect [207] and slows down the polymerization, since it will favor trapping (radical-radical coupling) over propagation. Besides termination, other side reactions play an important role in nitroxide-mediated CRP. One of the important side reactions is the decomposition of dormant chains [208], yielding polymer chains with an unsaturated end-group and a hydroxyamine, TH (Scheme 3, reaction 6). Another side reaction is thermal self-initiation [209], which is observed in styrene polymerizations at high temperatures. Here two styrene monomers can form a dimer, which, after reaction with another styrene monomer, results in the formation of two radicals (Scheme 3, reaction 7). This additional radical flux can compensate for the loss of radicals due to irreversible termination and allows the poly-... 

Attention was paid to the reactivity of PP with aliphatic nitroso compounds too [235]. It was postulated that the stabilizing effect was based on formation of a PP bound nitroxide and its disproportionation into the respective derivatives of hydroxylamine and nitrone. 

Theoretical work has also been devoted to examine the influence of reactions that interrupt the often repeated cycles of radical formation (activation) and cross-termination to dormant species (deactivation). For the nitroxide- and the cobalt-mediated systems, such reactions are the formation of R(—H) and YH by a usual radical disproportionation, which competes with the coupling of R and Y or by a direct fragmentation of R—Y to the hydroxylamine or a hydridocobalt complex and the alkene.22-33a-35-47-51 57 Even rather small fractions of these processes limit the maximum conversion and stop the polymerization prematurely in nearly indistinguishable ways, because they lead to an exponential decay of the dormant species. Before the end of conversion this does not affect the linear dependence of An on conversion and causes only minor increases of the polydispersity.57 To some extent the deteriorating effect of these reactions can be compensated by the rate enhancement through an additional initiation.50... 

Reactions that convert the alkoxyamines to hy-droxylamines and alkenes can strongly limit the monomer conversion. These are either usual radical disproportionations between the nitroxide and the propagating radicals or concerted alkoxyamine decays. Both pathways lead to an exponential decrease of the concentration of the dormant chains with rate constant kdec = f)kd, where fn is the fraction of the side reaction concurring with radical coupling of alkoxyamine decay.57 kdec can be measured from the decay of the dormant alkoxyamine chains under nonscavenging conditions, and its relation with kd provides fn. From data of Fukuda et al. one can deduce fn = 0.4% for a TEMPO-polystyryl compound and fn = 1.1% for a di-tert-butylnitroxide-poly-terf-butylacrylate macroinitiator both at 120 °C.53,55 Similar small values of fn hold for TEMPO-cumyl (Scheme 10),22 TEMPO-1-phenylethyl,112 and a better mimetic compound for TEMPO-polystyryl.113 In these cases, fn probably represents the usual radical disproportionation. A much larger fn 25% holds for TEMPO—... 

The irreversible decay of the dormant alkoxamine chains stops the monomer conversion rather abruptly at the time t = H( nk. For methyl methacrylate polymerizations this stop has been observed, and it has been demonstrated that it is caused by a considerable fraction of cross-disproportionation between the nitroxide and the propagating radicals.51,97112 Unfortunately, the factors governing disproportion-ation-to-combination ratios in radical—radical reactions are not well understood up to now, but stereo-electronic effects are certainly very important.112 Hence, one cannot yet predict a nitroxide structure that will allow living methacrylate polymerizations up to large conversions. 

The presence of the nitroxide radical was confirmed through EPR and XH NMR spectroscopic methods. The copolymer GPC trace (Mn=33,100, Mw/Mn=1.37) was symmetrical with no evidence of unreacted macroinitiator or homopolymer of St resulting from either thermal initiation or from disproportionation of the pSt from the TEMPO chain end [231]. The kinetic results showed a first-order relationship between monomer conversion and time and the molecular weights increased linearly with conversion, indicating the polymerization proceeded with minimal termination or chain transfer reactions. The presence of the pEAD block produces an amphiphilic copolymer with a biodegradable block that may be useful for biomedical applications. 

Mechanistic data obtained with the diarylnitroxide 56 have also mostly been extrapolated for nitroxides derived from heterocyclic amines DHQ, DHI, PT and HAS. The relative participation of the relevant nitroxides in the three principal pathways (Scheme 7), i.e. scavenging of R and ROO and disproportionation, has been determined by the chemical structure of the particular nitroxide and its stability reflected in the tendency to react in mesomeric forms. The adjacent aromatic moiety enhances participation of the mesomeric structures. The stability of the nitroxides diminishes in the series from HAS to DHQ or DHI and DPA and is the lowest in the PD series [4], As a consequence, the nitroxides derived from PD exist only in the form of bisnitrones (81 in Scheme 9). The ROO scavenging ability is involved only in the aromatic (DPA, PNA) and heterocyclic (DHQ, DHI) amines and cannot be included in the reactivity of HAS derived nitroxides. On the contrary, the most efficient R scavenging is in the HAS series. 

Transformation products of 16b contribute to some extent to the antioxidant effect. The dimer 103 is a weak AO in squalene [106] and in fish oil [98], The nitroxide 108 stabilizes fish oil, if present at a relatively high concentration (0.1%) [105], Its effect is not significant at lower concentrations. QI 105 was a weak retarder in oxidized fish oil [98] and decane [103]. It may be anticipated that other QI arising from 16 contribute similarly to the stabilization effect. A transient formation of the respective hydroxylamines is theoretically possible after hydrogen abstraction from a donor by 108 according to Eq. (8) or after thermolysis of the respective O-alkylhydroxylamine (an analogy to the process shown in Scheme 7). Their contribution to the stabilization effect is certainly not important, as revealed by a model study with NOH derived from 16b. It is very unstable and disproportionates to the parent 16b and nitroxide 108 [5,101]. 

Nitroxides derived from amines having one hydrogen atom on a-carbon atom to nitrogen oxidize with ROO to nitrones [111] and/or disproportionate easily into the respective hydroxylamine and nitrone [112]. The cis and trans nitroxides derived from 18 differ in their disproportionation rates. The disproportionation proceeds via an intermediately formed dimer ... 

Decahydroquinoxaline 19 (R = benzyl) is another excellent LS and AO for PP [39], The photostabilizing effect is lower than that of HAS [113], most probably due to the presence of the a-CH bond to the amino group enabling formation of mesomeric structures of the derived aminyl. The respective nitroxide may disproportionate similarly as shown with 18 in Eq. (13). A stable nitroxide 113 was prepared from 19 and perbenzoic acid [39]. It is not clear if 113 may also form with ROO ... 

Scheme 14. pH-dependent disproportionation of nitroxides to oxoammonium salts and hydroxylamines... 

Treatment of nitroxides with strong acids such as toluenesulfonic acid or perchloric acid facilitates disproportionation to form one oxoammonium salt in situ for every two equivalents of starting nitroxide. Under strongly acidic conditions, secondary alcohols are efficiently oxidized to ketones, whereas primary alcohols are much slower to react [33]. The reaction mechanism [31] is most likely that shown in Scheme 15. A kinetic isotope effect [kn/ku = 3.1) supports deprotonation of the alpha hydrogen as the rate limiting step [34]. The use of an additional oxidant such as bleach (NaOCl) or hypobromous acid (HOBr) or hypochlorous acid (HOCl) generated in situ from bromide or chloride ion [35] can facilitate the reaction by rapidly reforming the oxoammonium species under the reaction conditions. This allows the nitroxide to be utilized in catalytic amounts. Recently, Bobbitt [36] has... 

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