Dimethylaniline, demethylation

One of numerous examples of LOX-catalyzed cooxidation reactions is the oxidation and demethylation of amino derivatives of aromatic compounds. Oxidation of such compounds as 4-aminobiphenyl, a component of tobacco smoke, phenothiazine tranquillizers, and others is supposed to be the origin of their damaging effects including reproductive toxicity. Thus, LOX-catalyzed cooxidation of phenothiazine derivatives with hydrogen peroxide resulted in the formation of cation radicals [40]. Soybean LOX and human term placenta LOX catalyzed the free radical-mediated cooxidation of 4-aminobiphenyl to toxic intermediates [41]. It has been suggested that demethylation of aminopyrine by soybean LOX is mediated by the cation radicals and neutral radicals [42]. Similarly, soybean and human term placenta LOXs catalyzed N-demethylation of phenothiazines [43] and derivatives of A,A-dimethylaniline [44] and the formation of glutathione conjugate from ethacrynic acid and p-aminophenol [45,46],... 

Galliani G, Nali M, Rindone B, et al. The rate of N-demethylation of N, N-dimethylanilines and N-methylanilines by rat-liver microsomes is related to their first ionization potential, their lipophilicity and to a steric bulk factor. Xenobiotica 1986 16(6) 511—517. 

An oxometalloporphyrin is probably the actual oxidizing agent the threo erythro ratio (35 65) of the diastereomeric sulphoxides obtained from racemic sulphides is close to that obtained for the corresponding oxidation using cytochrome P450 oxidase and differs from that (58 42) obtained by the oxidation using periodate in the absence of the porphyrin [27]. The cytochrome-induced demethylation of N,N-dimethylaniline can also be mimicked with periodate and the metalloporphyrin. 

Demethylation ROOH + R1R2NCH3 ROH + R1R2NH + HCHO N,N-Dimethylaniline, ROOH HRP... 

To discern the ion-radical nature of reactions, the so-called intramolecular and intermolecular proton/deuterium isotope effects may be of use. Baciocchi et al. (2005) revealed ion-radical mechanism for A-demethylation of A,A-dimethylanilines, (CH3)2NAr, by phthalimide-A-oxyl radical (Scheme 4.14). In this reaction, ( e/ D)intra values were derived for reactivity of (CD3)(CH3)NAr, whereas ( H/ D)inter was referred for the reactivity of (CD3)2NAr. The values of (A e/ D)intra were found to be always different and higher than These results, although are incompat-... 

For example, PINO (i.e. >N—O"), generated from HPI by oxidation with Pb(OAc)4 (cf. Scheme 7) or by laser flash photolysis of (t-BuO)2 (cf. Scheme 5) at 266 nm, has been investigated in the oxidative A-demethylation of 4-X-substimted-Af,Af-dimethylanilines (X-DMAs) (Scheme 11). ... 

Nanbo, A. and Nanbo, T. (2002) Mechanistic study on N-demethylation catalyzed with P450 by quantitative structure activity relationship using electronic properties of 4-substituted N,N-dimethylaniline. Quant. Struct.-Act. Relat. 21,613-616. 

As early as 1938, Shorygin and Topchiyev [10] nitrated dimethylaniline with a solution of nitrogen dioxide in chloroform, but they were only able to obtain 4-nitro-dimethylaniline with a small amount of 3-nitiodimethylaniline. No demethylation of the N-dimethylamino group occurred. 

Dehydrogenation A-Demethylation Hydroxylation Epoxidation Sulfoxidation Oxidations Acetaminophen, benzidine, DES, epinephrine Dimethylaniline, benzphetamine, aminocarb Benzo[a]pyrene, 2-aminofluorene, phenylbutazone 7,8-Dihydrobenzo[a]pyrene Methylphenylsulfide FANFT, ANFT, bilirubin Esterases and Amidases Paraoxon, dimethoate, phenyl acetate Epoxide Hydrolase Benzo(a)pyrene epoxide, styrene oxide DDT-Dehydrochlorinase p,p- DDT Glutathione Reductase Disulfiram... 

Ozonation of 2-Carboxy-4-nitro-N,N-dimethylaniline (I). The amine (2.10 grams, 10 mmoles) was dissolved in the appropriate solvents (200 ml methanol, ethyl acetate, or methylene chloride) and ozonized at 0°C with equimolar amounts of ozone quantitative absorption occurred. Near the end of the ozonation time, a precipitate formed. In ozonations in methanol this substance was identical with lactone III mp 176°-177°C, prepared according to Villiger (10). In the other solvents the insoluble product was the demethylated starting material, mp 265°-268°C (dec.) reported mp 263°-264°C (11). The mother liquor was evaporated, and the two compounds were separated by fractional crystallization. The results are shown in Table I. 

Figure 9.3 Age-related changes in N-demethylation and N-oxidation of N,N-dimethylaniline in microsomes from rabbit liver. (From Devereux, T.R. and Fouts, J.R., Chem.-Biol. Interactions, 8, 91, 1974. With permission.)...

Demethylation of N,N-dimethylanilines is a reaction known to involve the intermediate formation of a radical cation, as has been demonstrated by anodic and chemical oxidation. Monodemethylation of N,N-dimethylaniline (without a substituent in the 4-position) has been observed by Penton and Zollinger but only in dry acetonitrile and in strict absence of bases (moisture ). In the opinion of the present authors Colonna s experiments with 1 -methyl-3-methylthio-2-phenylindole 139, X=SCHj) provide a better evidence for radical intermediates than the demethylation of N,N-dimethyl-4-acetylaniline, since that demethylation may also be a hetero-lytic process. 

Anhydrous Fe Cl3 catalyzes the stereospecific epoxidation of norbomene, the demethylation of A, A-dimethylaniline, and the oxidative cleavage of PhCMe(OH)CMe(OH)Ph (and other a-diols) by hydrogen peroxide (Table 11 and Scheme 4). For each class of substrate, the products parallel those that result from their enzymatic oxidation by cytochrome P-450. The close congruence of the prodncts indicates that the reactive oxygen in the Fe Cl3/HOOH model system and in the active form of cytochrome P-450 is essentially the same, with strong electrophilic oxene character (stabilized singlet atomic oxygen). 

Recent studies by Baciocchi et al. on kinetic deuterium isotope effect profiles and substituent effects in the oxidizing N-demethylation of iV,JV-dimethylanilines catalyzed by tetrakis (pentafluorophenyl)porphyrin also supports the electron-transfer mechanism and exclude the hydrogen-atom transfer mechanism in such processes [218]. 

To distinguish between paths A and B in Scheme 2, Dinnocenzo and coworkers [78-80] determined intramolecular isotope effects for deprotonation from the radical cations (path A) and for hydrogen-atom abstraction from a series of substituted 7V,A-dimethylanilines (path B) these were compared with isotope effects for N-demethylation of the same series of 7V,7V-dimethylanilines. The deprotonation iso-tope-effect profile for the radical cations of A, iV-dimethylanilines were determined by monitoring electron-transfer reactions from A, A -dimethylanilines to [Fe(phen)3] ... 

The rate of initial electron transfer from A,7V-dimethylaniline to [Fe(phen)3] + is diffusion-limited. This is followed by the rate-determining proton transfer from the radical cation to pyridine to give the deprotonated a-amino radical which is rapidly oxidized by a second equivalent of [Fe(phen)3] + to yield the product iminium ion. Kinetic isotope effects [kii/kjf) for the proton transfer were determined from the J3/tfo ratios of the products derived from p-substituted A-methyl-A-trideuteromethylanilines. The k /kx) value first increases and then decreases with increasing pAa of p-substituted A,A-dimethylaniline. Such a bell-shaped isotope effect profile is typical of proton-transfer reactions [82, 85]. The maximum kn/fco value is determined as 8.8 which is much larger than the corresponding value for the demethylation of the same substrate by cytochrome P-450 (2.6) [79]. 

P-450 amine dealkylation mechanisms. Because kn/ko values for A -demethylation of / -substituted A, A -dimethylanilines by cytochrome P-450 are nearly identical with those for the hydrogen abstraction reactions of t-BuO , it was proposed that P-450 reacted by a direct hydrogen-atom-abstraction mechanism (B) rather than a sequential electron-proton-electron-transfer mechanism (A) [78, 80]. Identical relationships between A h/ d values for reactions of t-BuO and P-450 has been expanded for other substrates including />-xylene, toluene, benzyl alcohol, and tertiary trialkylamine [78]. It has thus been suggested that all these P-450 reactions proceed by a common hydrogen-atom transfer mechanism [78]. 

For a synthetic P-450 model system, however, an opposite eonclusion was drawn from similar analysis of kinetic isotope effects for AT-demethylation of / -substituted iV,7V -dimethylanilines by PhIO, catalyzed by iron /Me5o-tetrakis(2,3,4,5,6-penta-fluorophenyl)porphyrin chloride, (TPFPP)FeCl [89]. Intramolecular /ch/Zcd values obtained from the d /do ratios of the products derived from 4-X-7V-methyl-A-tri-deuteromethylanilines [2.0 (X = NO2), 2.0 (X = CN), 2.6 (X = Br), 3.1 (X = H), 3.2 (X = Me), and 3.3 (X = OMe)], decreased regularly on going from electron-donating to electron-withdrawing substituents. Such a trend is the complete oppo-... 

To clarify the mechanism of reaction of P-450, it is crucial to characterize the reactive intermediates in the rate-determining step. Definitive evidence for an electron-transfer mechanism (C in Scheme 2) for the 7V-demethylation of N,N-dimethylanilines has been obtained by direct observation of the reduction of the high-valent species responsible for P-450 catalysis [96]. For peroxidase, an oxoferryl porphyrin 7r-radical cation, compound I ([(P)Fe =0] "), has been well characterized as the species equivalent to the proposed active intermediate of P-450 [97-103]. Compound I of horseradish peroxidase (HRP) can be readily generated by chemical oxidation of HRP [100-103]. The involvement of the electron-transfer process of compound I in the oxidation of several amines catalyzed by HRP was... 

M. F. Powell, E. F. Pai, T. C. Bruice, Study of (tetraphenylporphinato)manganese(III)-catalyzed epoxidation and demethylation using p-cyano-N,N-dimethylaniline N-oxide as oxygen donor in a homogeneous system. Kinetics, radiochemical ligation studies, and reaction mechanism for a model of cytochrome P-450, ]. Am. Cliem. Soc. 106 (1984) 3277. 

Several studies have used NMR spectroscopy to determine the number and identity of drug metabolites in bile. These include the use of NMR spectroscopy to study doxifluridine catabolites in human bile, and C NMR spectroscopy of perfluorinated fatty acids in rat bile and NMR for monitoring the formation of formaldehyde from demethylation of antipyrine. NMR spectroscopy of rat bile has been used to monitor the excretion of paracetamol metabolites. A combination of H and H- - C 2D NMR methods has allowed identification of 4-cyano-A,N-dimethylaniline, cefoperazone and benzyl chloride in rat bile. ... 

With regard to reproduction, demethylchlordimeform was more active than chlordimeform in decreasing fecundity and egg hatch in spider mites 4-chloro-2-methylaniline also possessed some activity against egg hatch only, while the formanilide was inactive ( 9). Thus it seemed that with chlordimeform the demethyl metabolite played a major role in its effects on spider mite reproduction. However, the results with amitraz and U-44193 were more difficult to interpret. Their common metabolites, BTS-27271, 2,4-dimethylformanilide, and 2,4-dimethylaniline all significantly decreased fecundity and egg hatch, yet U-44193 was one of the most active inhibitors of these processes in mites, and amitraz had no significant effect. Examination of metabolism data (28) revealed that in twospotted spider mites exposed to U-44193 or amitraz, levels of parent compounds were low (<1.0%), but levels of BTS-27271 were several fold higher in mites exposed to... 

Photo-induced demethylation of 4-nitro-iV,A-dimethylaniline,to give 4-nitro-N-methylaniline, has been observed upon excitation in the presence of an external acceptor in benzene or the methoxide ion in methanol. A quantum chemical study of the photodissociation of the alkyl C-N bond in AT-substituted anilines, PhNH-R (R = Me, PhCH2, Ph2CH, Ph3C), has also been carried out. " ... 

Under conditions of the Hofmann degradation (heating an aqueous solution of the hydroxide until the water is evaporated and decomposition occurs), trimethylphenylammonium hydroxide (5) demethylates exclusively to give N,N-dimethylaniline and methanol 27>. 

Single electron transfer-initiated N-demethylation of N-methylated alkaloids and N,N -dimethylanilines " has been described, and a photoremovable a-methylphenacylamido protecting... 

A particular case of metal-free bisacylation is reported concerning the reaction of para-substituted N,N-dimethylanilines with oxalyl chloride promoted by l,4-diazabicyclo(2.2.2)octane (DABCO) for the production of compounds 51 (Scheme 2.23). i The reaction requires anearly stoichiometric mixtureof oxalyl chloride, DABCO, andN,N-dimethylaniline, and proceeds through ortho-C-acylation followed by N-acylation-mono-demethylation. The base presumably takes part in the initial production of the oxalyl chloride acylium salt as well as in the demethylation step. 

Introduction of more than two nitro groups into jV,A-dimethylaniline is no longer a smooth reaction demethylation and JV-nitration lead eventually to iV-methyl-2,4,6,Af-tetranitroaniline which is used as an explosive under the name Tetryl . 

Peifluoroalkylation. By using CuiO as the catalyst, anilines undergo per-fluoroalkylation with RT in DMSO at 130°. The perfluoroalkyl groups enter at ortho- and para-positions that are open. (V,(V-Dimethylaniline suffers demethylation in the process. 

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