Benzhydrols, oxidation

Alkali metal benzhydrolate oxidizes in toluene [111] and benzene [112] as well as in f-butanol [113] with autocatalysis that is produced by the K02 formed in the oxidation [113]. The induction period disappears when K02 is added to a solution of potassium benzhydrolate. The kinetics of oxidation of sodium benzhydrolate was studied by Pereshein et al. [111]. The maximum oxidation rate appears to be approximately proportional to [RONa] [02]/[ROH],the activation energy being 12 kcal mole-1. The inhibiting action of alcohol (benzhydrol and t-butanol) on the oxidation of metal benzhydrolates was noted by Russell et al. [110], No deuterium exchange was observed during the oxidation of potassium benzhydrolate in t-butanol. Thus no dianions are produced from benzhydrolate ion by the equilibrium reaction... 

Diphenylmethane Base Method. In this method, the central carbon atom is derived from formaldehyde, which condenses with two moles of an arylamine to give a substituted diphenylmethane derivative. The methane base is oxidized with lead dioxide or manganese dioxide to the benzhydrol derivative. The reactive hydrols condense fairly easily with arylamines, sulfonated arylamines, and sulfonated naphthalenes. The resulting leuco base is oxidized in the presence of acid (Fig. 4). 

A mixture of 26 g (0.1 mol) of 0 -(4-pyridyl)-benzhydrol, 1.5 g of platinum oxide, and 250 ml of glacial acetic acid is shaken at 50°-60°C under hydrogen at a pressure of 40-50 Ib/in. The hydrogenation is complete in 2 to 3 hours. The solution is filtered and the filtrate evap-rated under reduced pressure. The residue is dissolved in a mixture of equal parts of methanol and butanone and 0.1 mol of concentrated hydrochloric acid is added. The mixture is cooled and filtered to give about 30 g of 0 -(4-piperldyl)-benzhydrol hydrochloride, MP 283°-285°C, as a white, crystalline substance. 

Decomposition Pyrolysis occurs at 170°C after prolonged periods yielding CO, COz, benzophenone, and benzhydrol appreciable hydrolysis in acidic or basic solutions occurs yielding 3-quinuclidinol and benzilic acid BZ is oxidized by hypochlorite at a pH of 1-13. 

From these data, it can be estimated that chlorphenoxamine (11.24, R = 4-C1, R = Me) should hydrolyze ca. 17 times faster than diphenhydramine. This decreased stability appears sufficient to drive formation of detectable amounts of the benzhydrol metabolite (11.25, R = 4-C1, R = Me) in the stomach of patients dosed with chlorphenoxamine. Indeed, ether bond cleavage to form this and derived metabolites was a major pathway in humans [49], Whether the reaction was entirely nonenzymatic or resulted in part from oxidative O-dealkylation (Chapt. 7 in [50]) remains unknown. 

N-Hydroxyphthalimide A-Hydroxyphth-alimide (NHPI) was shown to be a mediator for the electrochemical oxidation of (1) to (2) (Eq. 6) [57, 58], although the yields of (2) were not always satisfactory. A large deuterium isotope effect ( h/ d = 10.6) was observed in the oxidation of benzhydrol [59]. Recently, tetrafluoro-NHPI was found to be efficient for the oxidation of borneol [60]. 

There is ample evidence in the literature for conversion of reactive hydrocarbons to carbonyl compounds by autoxidation. In coals, the final products of autoxidation under the conditions used in the present study could be a mixture of carbonyl and carboxylic acid surface groups. Under mild oxidation conditions, a different set of functional groups such as ethers as proposed by Liotta et al. or epoxides as suggested in Scheme V could be formed. There are numerous examples of alkoxy radicals rearranging to epoxides . Choi and Stock have shown that ethers can be produced from benzhydrol structures, which are invoked as intermediates in Scheme IV. At higher temperatures, the epoxides and ethers are unstable and may rearrange to carbonyl compounds. 

Some lactol-to-lactone oxidations were effected by TPAP/NMO/PMS/CH Clj [498, 499], or TPAP/NMO/PMS/CH3CN [159]. The system RUCI3 or RuO / Na(Br03)/aq. M Na3(C03) generates [RuO ]" in aqueous solution and oxidised secondary alcohols to ketones in high yield (Table 2.2) [213]. Kinetics of the oxidation of benzhydrol and 9-fluorenol by TPAP/NMO/CH3CN/30°C were measured. 

RuCl2(picphen)]Cl (picphen=few(picolinaldehyde)-(9-phenylenedi-imine) is made by condensation of picolinaldehyde and o-phenylenediamine) and the resulting Schiff base then treated with RuClj in ethanol. Kinetics were followed of the oxidation of secondary alcohols (benzhydrol, 1-phenylethanol and a-tetralol) to the corresponding ketones by [RuCl2(picphen)] "/NMO or Tl(OAc)3/water/30°C. The intermediacy of a Ru(V) oxo species was suggested [800]. 

Oxidation of diphenylmethane in basic solutions involves a process where rate is limited by and equal to the rate of ionization of diphenylmethane. The diphenylmethide ion is trapped by oxygen more readily than it is protonated in dimethyl sulfoxide-text-butyl alcohol (4 to 1) solutions. Fluorene oxidizes by a process involving rapid and reversible ionization in text-butyl alcohol solutions. However, in the presence of m-trifluoromethylnitrobenzene, which readily accepts one electron from the carbanion, the rate of oxygen absorption can approach the rate of ionization. 9-Fluorenol oxidizes in basic solution by a process that appears to involve dianion or carbanion formation. Benzhydrol under similar conditions oxidizes to benzophenone by a process not involving carbanion or dianion formation. 

The present work demonstrates that the oxidation of diphenylmeth-ane in basic solution follows a pattern similar to triphenylmethane and not to fluorene. At high concentrations of good electron acceptors it is possible to realize a situation wherein the rate of oxidation of fluorene is limited by and equal to the rate of ionization. The oxidations of benzhydrol and 9-fluorenol in basic solution are considered the difference in acidity of the methine hydrogens has a pronounced effect on the course of these oxidations. 

If the oxidation of diphenylmethane in DMSO (80% )-tert-butyl alcohol (20% ) is interrupted after the absorption of one mole of oxygen per mole of diphenylmethane, one obtains an 86% yield of benzhydrol, 10% yield of unreacted diphenylmethane, and a few percent of the benzophenone-DMSO adduct. The over-all course of the reaction fol-... 

When the oxidation of a,a-dideuteriodiphenylmethane was interrupted after the absorption of 1.0 equivalent of oxygen, the product was found to be only benzhydrol and a trace of diphenylmethane (by GLPC). Mass spectroscopic analysis of the benzhydrol indicated 98.5% mono-deuterated material. 

Oxidation of Benzhydrol in Basic Solution. Reaction of benzhydrol with oxygen in basic solution results in the formation of benzophenone, or in DMSO solutions the benzophenone—DMSO adduct. Table VIII summarizes data on the oxidation of benzhydrol in three solvents and in the presence of various concentrations of potassium ferf-butoxide. The rates are the maximum oxidation rates, often observed after an inductive period (Figure 3). 

Table VIII. Oxidation of Benzhydrol in Basic Solutions at 27 = = 2°C.

Figure 3. Oxidation of 0.1M benzhydrol in tert-butyl alcohol containing 0.4 potassium tert-butoxide...

Ferric chloride (0.002M) reduced the rate of oxidation of benzhydrol (0.15M) in the presence of 0.39M potassium ferf-butoxide in tert-butyl alcohol to a rate of 0.001 mole of oxygen per mole of benzhydrol per minute, while arsenic trioxide (0.01M) reduced the rate of oxidation of 0.12M benzhydrol and 0.36M potassium ferf-butoxide to 0.0001 mole of oxygen per mole of benzhydrol per minute for a 4-hour period, after which the oxidation occurred at the uninhibited rate (Figure 3). Table IX summarizes some observed stoichiometries in the oxidation of benzhydrol. 

The stoichiometry of the oxidation appears to require the formation of potassium superoxide as one of the oxidation products, particularly at long reaction periods and high base concentrations. An oxidation of 3.00 mmoles of benzhydrol (0.12M) in the presence of 9.9 mmoles of potassium terf-butoxide (0.37M) in DMSO (80% )-ter -butyl alcohol (20%) absorbed 4.95 mmoles of oxygen in 27.7 minutes at 25°C. and yielded 2.2 mmoles of the benzophenone-DMSO adduct and 0.8 mmole of benzophenone. A precipitate formed (0.307 gram) which analyzed (23) as 103% (4.25 mmoles) potassium superoxide (K02). 

To ascertain the possibility of the intervention of benzophenone ketyl, (C6H5)2CO ", in the oxidation of benzhydrol, the oxidation of... 

The data apparently require a free radical chain mechanism for the oxidation of benzhydrol. Potassium superoxide filtered from a completed oxidation completely removed the induction period for a fresh oxidation. Thus, potassium superoxide must either serve as an initiation of oxidation... 

The oxidation of xanthenol and fluorenol showed a number of differences from the oxidation of benzhydrol. No induction period was observed (Figure 5). The rate was enhanced by ferric ion, and the stoichiometry was altered to 0.5 mole of oxygen per mole of fluorenol (Figure 5), apparently because of Reaction 25. 

Treatment of diphenylmethane in basic solution with a trace of oxygen in DMSO solutions fails to produce significant amounts of a paramagnetic product detectable by ESR spectroscopy. On the other hand, treatment of benzhydrol with traces of oxygen in basic solution can produce significant amounts of the ketyl. Pyridylthiazolylcarbinols are readily converted to the ketyls by base in alcoholic solution. (24). In pure DMSO significant amounts of the ketyl are formed whereas in tert-butyl alcohol or DMSO (80% )-tert-butyl alcohol (20% ) only traces of the ketyl can be detected. These results are consistent with the formation of the ketyl under oxidative conditions by Reaction 31. Only under the most basic conditions (pure DMSO) is the dianion formed by... 

The oxidation of benzhydrol and 9-fluorenol in basic solution again shows a difference in regard to mechanism that can be primarily attributed to a difference in acidity as carbon acids. In tert-butyl alcohol benzhydrol enters into an oxidation scheme as the mono (oxy) anion. The data strongly suggest a free radical chain. Under these conditions the more acidic fluorenol or xanthenol oxidizes via carbanions or dianions. These oxidations can be catalyzed to occur via a free radical chain process by one-electron acceptors, such as nitrobenzene, and a free radical chain process may well be involved in the absence of the catalyst. 

The product of the absorption of 3 mmoles of oxygen by a solution of 3 mmoles of diphenylmethane and 15 mmoles of potassium tert-butoxide in 20 ml. of DMSO (80% )-terf-butyl alcohol (20%) was poured into water. Upon standing, colorless crystals of benzhydrol (m.p. 64°C.) formed which could be recovered in 75% yield by filtration. Complete oxidation of the diphenylmethane gave an oxidate which after... 

Oxidation of Potassium Peroxide. Determination of Potassium Superoxide. Potassium peroxide was prepared by the addition of a tert-butyl alcohol solution of 90% hydrogen peroxide to potassium tert-butoxide in DMSO or tert-butyl alcohol. Oxygen absorption was followed in the standard manner (20). Analysis of solid precipitates for potassium superoxide followed exactly the method of Seyb and Kleinberg (23). Potassium superoxide formed in the oxidation of benzhydrol was determined in a 15-ml. aliquot of the oxidation solution. To this aliquot 10 ml. of diethyl phthlate was added to prevent freezing of the solution. The mixture was cooled to 0°C., and 10 ml. of acetic acid-diethyl phthlate (4 to 1) added over a period of 30 minutes with stirring. The volume of the evolved oxygen was measured. 

Alcohols such as methanol, 2-propanol, and benzhydrol are cleanly oxidized to the corresponding carbonyl compounds upon photoexcitation with Na3PWi2O40 in water or with (n-P NfoPW C in CH3CN (406). The quantum yields appear to be governed by the oxidation potential of the alcohol, the availability of a-hydrogens, and the tightness of complexation with the photocatalyst The reactivity order is primary alcohol > secondary alcohol > tertiary alcohol. 

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