Acetone reaction with hydroxylamine

In current industrial practice gas chromatographic analysis (glc) is used for quahty control. The impurities, mainly a small amount of water (by Kad-Fischer) and some organic trace constituents (by glc), are deterrnined quantitatively, and the balance to 100% is taken as the acetone content. Compliance to specified ranges of individual impurities can also be assured by this analysis. The gas chromatographic method is accurately correlated to any other tests specified for the assay of acetone in the product. Contract specification tests are performed on product to be shipped. Typical wet methods for the deterrnination of acetone are acidimetry (49), titration of the Hberated hydrochloric acid after treating the acetone with hydroxylamine hydrochloride and iodimetry (50), titrating the excess of iodine after treating the acetone with iodine and base (iodoform reaction). 

When acetone is treated with hydroxylamine in aqueous solution near neutral pH, the carbonyl UV absorption intensity decreases very rapidly this fast spectral change is followed by a much slower absorption increase that is due to the appearance of the oxime product. This suggests that, at such pH values, the initial addition is very rapid and the second step, dehydration of the carbinolamine, is the rds. Figure 5-12 is a plot of the apparent first-order rate constant against pH for this reaction. As the pH is decreased from neutrality, the rate increases, indicating that the rds... 

Unsubstituted quinazoline 3-oxide was prepared in an attempt to react quinazoline with hydroxylamine. This reaction gave a product of variable composition, but when an acetone solution was heated in a sealed tube it gave quinazoline 3-oxide. The oxide is more conveniently prepared, in excellent yield, from o-aminobenzaldehyde oxime and ethyl orthoformate. This method appears to be of general use and has been used for the preparation of 4-methylquinazoline... 

Isoniazide, the hydrazide of pyridine-4-carboxylic acid, is still, well over half a century after its discovery, one of the mainstays for the treatment of tuberculosis. Widespread use led to the serendipitous discovery of its antidepressant activity. This latter activity is retained when pyridine is replaced by isoxazole. The requisite ester (45-4) is obtained in a single step by condensation of the diketo ester (45-1), obtained by aldol condensation of acetone with diethyl oxalate, with hydroxylamine. One explanation of the outcome of the reaction assumes the hrst step to consist of conjugate addition-elimination of hydroxylamine to the enolized diketone to afford (45-2) an intermediate probably in equilibrium with the enol form (45-3). An ester-amide interchange of the product with hydrazine then affords the corresponding hydrazide (45-5) reductive alkylation with benzaldehyde completes the synthesis of isocarboxazid (45-6) [47]. 

Addition of primary amines to carbonyl groups has been the subject of extensive study, notably by Jencks and co-workers.91 The most striking feature of these reactions is the characteristic maximum in the graph of reaction rate as a function of pH.92 Figure 8.10 illustrates the observations for the reaction of hydroxylamine with acetone. It is also found that the sensitivity of rate to acid catalysis,93 and to substituent effects,94 is different on either side of the maximum in the pH-rate curve. These phenomena may be understood in terms of the two-step nature of the reaction. In acetal formation, we saw in Section 8.3 that the second step is rate-limiting in the overall process, and it is relatively easy to study the two steps separately here, the rates of the two steps are much more closely balanced, so that one or the other is rate-determining depending on the pH. 

Methanolysis of die sulfonates (175)141 and the reaction of the sulfonate ester (102) with hydroxylamine (103)88 were looked at earlier. Yoh and co-workers have looked at die reactions of (Z)-phenylediyl (X)-benzenesulfonates with (Y)-pyridines in acetonidile under pressure and die structure-reactivity relationships established show that as die pressure is increased die mechanism moves from a dissociative 5n2 to early-type concerted 5k2.276 In otiier sdtdies also under pressure the same group found that a mechanistic change from associative, k 2 to late-type 5n2 occurs as the pressure is increased in die reaction of (Z)-phenacyl (X)-benzenesvdfonates with (Y)-pyridines in acetone.277... 

Flammable by chemical reaction. A powerful oxidizer. Explosive reaction with hydrazine. Reacts violently or ignites with H2SO4 + acetone, hydroxylamine, ethylene glycol (above 100°C). Forms pyrotechnic mixtures with boron + silicon, iron (ignites at 1090°C), tungsten (ignites at 1700°C). Reacts with sulfuric acid to form the strong oxidant chromic acid. Used in... 

This is an interesting exercise, but we should not become excessively concerned with formal schemes for the identification of the rds. We want to know the rds because it is a piece of information about the reaction mechanism. If we have already acquired so much information about the system that we can construct a reaction coordinate diagram displaying all intermediates and transition states, we probably have no need to specify the rds. As an example of the experimental detection of the rds we will describe Jencks study of the reaction of hydroxylamine with acetone. The overall reaction is... 

Figure 5-12. pH-rate profile for the reaction of hydroxylamine with acetone in water at 25°C. Dashed fine rate of acid-catalyzed dehydration step solid line observed rate. 

Derivation Reaction of hydroxylamine in water solution with acetone, followed by ether extraction. 

A plot of the observed rate constant for the reaction of acetone with hydroxylamine as a function of the pH of the reaction mixture is shown in Figure 18.2. This type of plot is called a pH-rate profile. The pH-rate profile in the figure is a bell-shaped curve with the maximum rate occurring at about pH 4.5, 1.5 pH units below the pA a of hydroxylamine = 6.0). As the acidity increases below pH 4.5, the rate of the reaction decreases because more and more of the amine becomes protonated. As a result, less and less of the amine is present in the nucleophilic nonprotonated form. As the acidity decreases above pH 4.5, the rate decreases because less and less of the tetrahedral intermediate is present in the reactive protonated form. 

Dependence of the rate of the reaction of acetone with hydroxylamine on the pH of the reaction mixture. 

The direct observation of this reaction is difficult because of the small equilibrium constant for imine formation. This type of reaction is therefore commonly studied by trapping the imine as it is formed with hydroxylamine, which reacts rapidly to form an oxime. Because the equilibrium constant for formation of the imine between methyl amine and acetone is so small, the equilibrium is established very rapidly. (The observed rate constant for a reaction proceeding to an equilibrium position is larger than the first-order rate constant for the forward reaction [7].) Thus the addition of methylamine and acetone to an aqueous solution results in the establishment of an equilibrium concentration of imine (and iminium ion) in several seconds. In several studies described below wherein reactions subsequent to imine formation occur, it is common to find a presumption of rapid imine equilibria prior to the slower o-proton abstraction or decarboxylation events that occur subsequently. 

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