Rate-determining oxidative cyclization

In order to illustrate the application of LSV in mechanistic analysis we can look at the redox behavior of the formazan-tetrazolium salt system which we studied some years ago [17], 1,3,5-Triphenyl formazane was oxidized at controlled potential in CH3CN-Et4NC104 solution to 2,3,5-triphenyl tetrazolium perchlorate which was then isolated in quantitative yield. Coulometry showed that the overall electrode reaction was a two-electron oxidation. It has been shown that the rate of variation of Ep with log v was 30 mV per decade of sweep rate and that there was no variation of the peak potential with the concentration of 1,3,5-triphenylformazan. According to Saveant s diagnostic criteria (Table 1), four mechanistic schemes were possible e-C-e-p-p, e-C-d-p-p, e-c-P-e-p and e-c-P-d-p. If cyclization is the rate-determining step, then the resulting e-C-e-p-p and e-C-d-p-p mechanisms would not imply variation of Ep with the concentration of base. However, we have observed the 35 mV shift of Ep cathodically in the presence of 4-cyanopyridine as a b e. These observations ruled out the first two mechanisms. The remaining possibilities were then e-c-P-e and e-c-P-d, as shown in Scheme 3. 

Our final conclusion was therefore that the mechanism of intramolecular oxidative cyclization of 1,3,5-triphenylformazan to 2,3,5-triphenyltetrazolium perchlorate involves cyclization of the initial radical cation and deprotonation as the rate-determining step, following the mechanistic scheme e-c-P-e. 

Oxidation of enaminone 1 is initiated by electron loss from the dimethylamino moiety leading to radical cation, RH". The following chemical reaction would be an intramolecular cyclization through addition of a hydroxy group on the radical cation site yielding a cyclic radical cation, cRH ". This step is most likely the rate-determining step. The cyclic radical cation then dimerizes... 

The reaction was carried out in CH3CN-Et4NC104 with addition of pyridine as base, using controlled potential electrolysis and a divided cell. The yield of (33) varied greatly, depending on the method of electrolysis. Oxidation of 32 in the presence of pyridine gave 33 in 60-85% yield, whereas the electrolysis without pyridine lowered the yield to 10-20%, and products of hydrolysis, because of accumulation of the acid in the anodic compartment, were identified. The mechanism of the reaction proposed on the basis of electroanalytical results involves the cyclization of the radical-cation or its deprotonation as the rate-determining step.78... 

The reaction of iV-(2,4-dinitrophenyl)amino acids with base in aqueous dioxane has been shown to give benzimidazole iV-oxides (7). The rate-determining step is likely to be formation of an iV-alkylidene-2-nitrosoaniline intermediate (6), which is followed by rapid cyclization and decarboxylation.19 The loss of carbon dioxide from perbenzoate anions has been investigated by mass spectrometry and electronic structure calculations. The results, including isotopic labelling experiments, support a mechanism involving initial intramolecular nucleophilic attack at either the ortho- or ipso-ring positions. They also indicate that epoxides may be intermediates en route to the phenoxide products.20 There has also been a theoretical study of the formation of trichlorinated dibenzo-/ -dioxins by reaction of 2,4,5-trichlorophenolate ions with 2,4-dichlorophenol.21... 

Experimental and computational studies of the pericyclic Meisenheimer rearrangement and a competitive rearrangement of A-propargyl morphol i nc N-oxide revealed a novel inverse secondary kinetic isotope effect (kn/kD 0.8) for the rate-determining cyclization step, probably occurring because of a C(sp) to C(sp2) change in hybridization at the reaction center (Scheme 3).5... 

There are four steps in these reactions as exemplified in the oxidative addition of acetic acid (1) to an alkene and the oxidative cyclization of 7b (Scheme 2). The first, rate-determining step is the slow reaction of acetic acid 1 or y9-keto ester 7b with Mn(OAc)3 to give Mn(III) enolates 2 and 8b, respectively [12, 13]. The rate of proton loss is proportional to the acidity of the hydrogen. Acetic acid, pK = 25,... 

The mechanism takes a different course with more acidic compounds such as )5-keto ester 7a (p/fa = 10). Mn(IlI) enolate 8a forms rapidly and reversibly. The rate-determining step is cyclization of the double bond to the Mn(lll) enolate of 8a with loss of Mn(ll) to give cyclohexanealkyl radical 11a, without the intermediacy of acyclic radical 9a, which is oxidized by Cu(OAc)2 to generate 71% of 12a. Similar mechanisms are operable with very acidic 1,3-diketones Mn(acac)j is stable and isolable. 

The SET mechanism was also proposed for some oxidations involving X -iodanes. In particular, mechanistic studies involving isotope labeling, kinetic studies, cyclic voltammetry measurements and NMR spectroscopic analysis confirm that SET is a rate-determining step in the IBX-promoted oxidative cyclization of unsaturated anilides in THE-DMSO solutions [216], The analogous mechanism was proposed for the oxidation of alkylbenzenes at the benzylic position under similar conditions [217]. 

It is not clear why the Mn(in)-mediated electrochemical cyclization of 20 and 22 was completely unsuccessful. It should be noted that the rate determining step in the cyclization of a-unsubstituted P-keto esters is the addition of the alkene to the Mn(ni) enolate with loss of Mn(II) while the rate determining step in the oxidation of a-alkyl substituted P-keto esters is the formation of the Mn(III) enolate, which rapidly loses Mn(II) to form the free a-keto radical (57, 40). Mn(III)-mediated electrochemical oxidation was somewhat successful for a-alkyl substituted P-keto esters, but failed for a-unsubstituted P-keto esters. 

It has been found that this oxidative cyclization does not exhibit kinetic isotope effect ( h/ d = 10), thus indicating that the cleavage of the p-C-H bond in the amidine adduct is not involved into the rate-determining step. Although the exact mechanistic details are not clear yet, it is assumed that the I species are initially coordinated with the amidine nitrogen atom, followed by ring closure and elimination of iodobenzene and acetic acid from the azoline intermediate 66 (Scheme 42). It is worth mentioning that the reaction proceeds under mild conditions and is free from acid or metal catalyst. 

The isotope effect was also studied in the palladium-catalyzed cyclization of substrates 15 to form oxindoles 16 via C—H bond functionalization (Scheme 11.5) [34]. Whereas, no kinetic isotope effect was observed in the competitive reaction of 15a and 15a-d5, an intramolecular primary isotope effect of 4 was found in the cyclization of the ortho-monodeuterated substrate 15a-di. The absence of any inter-molecular isotope effects suggests that the first step, the oxidative addition, is both slow and rate-determining overall. Although different mechanistic scenarios were considered, the significant intramolecular isotope effect shows that the palladation... 

Considering the kinetic data, the rate-determining step of the IBX-mediated cyclization of anilides 1 is the SET process (first step of the reaction). The variations of the measured oxidation potentials with the reaction rates are in good agreement with the initial SET proposed by the mechanism. 

The rates of formation of some phenazines by cyclization of di- and monoimines of JV-(2-aminophenyl)-l,4-benzoquinone have been determined spectrophotometrically. The reaction of 2-aminoindamines (quinoneimines) is a similar example (see Hotiben-Weyl, Vol. 7/3 b, p 330). The oxidation of benzene-1,2,4-lriamine (16) takes place through a series of intermediates, c.g. initial oxidation of 2-amino-l, 4-quinonediiminc (17) is followed by its condensation with beiizene-1,2,4-triamine (16) which leads to the formation of the indamine derivative 18 which, on further oxidation, undergoes cyclization to the amino-substituted phenazine. Different isomers of phenazinetriamines 19 can thus be formed. 

This presents an interesting analytical quandary. Epoxides are major products of lipid oxidation and derive from LO cyclization as well as LOO additions (see Section 3.2.2). Consequently, it may be difficult to determine the mechanism that is operative in a given reaction system, and indeed, both may contribute. For example, Hendry (283) reacted a series of ROO with their parent compounds at 60°C and found 40% of the products were epoxides. Rate constants of k = 20 to 1130 M sec were calculated assuming the reactions were aU additions, but at the elevated temperature of the study, hydrogen abstraction to form the hydroperoxides, followed by homolytic scission to alkoxyl radicals, could also have contributed to the yields. 

---