Acetal, 17-21, formation acetophenone

Kinetic data on acetal formation and cleavage in alcohols are scarce although kinetic and thermodynamic data in the same experimental conditions are of great interest (Davis et al., 1975). It should be noted that under these conditions inequality (53) is inverted and that, therefore, the rate-limiting step corresponds to water addition to an alkoxycarbenium ion (Step 3) or hemiacetal cleavage (Step 4). Recent data by El-Alaoui (1979) on forward and reverse rates are in agreement with those expected the acetal formation rate is independent of water concentration for a series of substituted acetophenones. 

Experiments on the bromination of equilibrated ketone-acetal systems in methanol were also recently performed for substituted acetophenones (El-Alaoui, 1979 Toullec and El-Alaoui, 1979). Lyonium catalytic constants fit (57), but for most of the substituents the (fcA)m term is negligible and cannot be obtained with accuracy. However, the relative partial rates for the bromination of equilibrated ketone-acetal systems can be estimated. For a given water concentration, it was observed that the enol path is more important for 3-nitroacetophenone than for 4-methoxyacetophenone. In fact, the smaller the proportion of free ketone at equilibrium, the more the enol path is followed. From these results, it can be seen that the enol-ether path is predominant even if the acetal form is of minor importance. The proportions of the two competing routes must only depend on (i) the relative stabilities of the hydroxy-and alkyoxycarbenium ions, (ii) the relative reactivities of these two ions yielding enol and enol ether, respectively, and (iii) the ratio of alcohol and water concentrations which determines the relative concentrations of the ions at equilibrium. Since acetal formation is a dead-end in the mechanism, the amount of acetal has no bearing on the relative rates. Bromination, isotope exchange or another reaction can occur via the enol ether even in secondary and tertiary alcohols, i.e. when the acetal is not stable at all because of steric hindrance. 

An improved route to the potent antidepressant Oxaflozane (376) that avoids the use of Grignard reagents has been described.It relies upon hemi-acetal formation of a substituted acetophenone. The overall yield of 34% was quite acceptable. 

Aldehydes and ketones may frequently be identified by their semicarbazones, obtained by direct condensation with semicarbazide (or amino-urea), NH,NHCONH a compound which is a monacidic base and usually available as its monohydrochloride, NHjCONHNH, HCl. Semicarbazones are particularly useful for identification of con jounds (such as acetophenone) of which the oxime is too soluble to be readily isolated and the phenylhydrazone is unstable moreover, the high nitrogen content of semicarbazones enables very small quantities to be accurately analysed and so identified. The general conditions for the formation of semicarbazones are very similar to those for oximes and phenylhydrazones (pp. 93, 229) the free base must of course be liberated from its salts by the addition of sodium acetate. 

Kinetic data exist for all these oxidants and some are given in Table 12. The important features are (i) Ce(IV) perchlorate forms 1 1 complexes with ketones with spectroscopically determined formation constants in good agreement with kinetic values (ii) only Co(III) fails to give an appreciable primary kinetic isotope effect (Ir(IV) has yet to be examined in this respect) (/ ) the acidity dependence for Co(III) oxidation is characteristic of the oxidant and iv) in some cases [Co(III) Ce(IV) perchlorate , Mn(III) sulphate ] the rate of disappearance of ketone considerably exceeds the corresponding rate of enolisation however, with Mn(ril) pyrophosphate and Ir(IV) the rates of the two processes are identical and with Ce(IV) sulphate and V(V) the rate of enolisation of ketone exceeds its rate of oxidation. (The opposite has been stated for Ce(IV) sulphate , but this was based on an erroneous value for k(enolisation) for cyclohexanone The oxidation of acetophenone by Mn(III) acetate in acetic acid is a crucial step in the Mn(II)-catalysed autoxidation of this substrate. The rate of autoxidation equals that of enolisation, determined by isotopic exchange , under these conditions, and evidently Mn(III) attacks the enolic form. 

In a more recent study, Westman and Lundin have described solid-phase syntheses of aminopropenones and aminopropenoates en route to heterocycles [32], Two different three-step methods for the preparation of these heterocycles were developed. The first method involved the formation of the respective ester from N-pro-tected glycine derivatives and Merrifield resin (Scheme 7.12 a), while the second method involved the use of aqueous methylamine solution for functionalization of the solid support (Scheme 7.12 b). The desired heterocycles were obtained by treatment of the generated polymer-bound benzylamine with the requisite acetophenones under similar conditions to those shown in Scheme 7.12 a, utilizing 5 equivalents of N,N-dimethylformamide diethyl acetal (DMFDEA) as reagent. The final... 

C-Glycosyl compounds are important molecular targets as they occur in Nature and have interesting biological properties (for reviews on C-glycosylation, see [72-75]). Chain extensions of aldonolactones have been employed to create C-C bond formation at the anomeric center. Claisen-type reactions of aldono-1,4-lactones (e.g., 9, 55) with acetone or acetophenone (Scheme 17) generate hemi-acetals of type 56a-c [76]. Similarly, lactone 55b reacts with CHsCN/NaH to give hemiacetal 57. 

Examples are the formation of diacetone alcohol from acetone [reaction type (A)] catalysed by barium or strontium hydroxide at 20—30°C [368] or by anion exchange resin at 12.5—37.5°C [387], condensation of benzaldehyde with acetophenone [type (C)] catalysed by anion exchangers at 25—-45°C [370] and condensation of furfural with nitromethane [type (D)] over the same type of catalyst [384]. The vapour phase self-condensation of acetaldehyde over sodium carbonate or acetate at 50°C [388], however, was found to be first order with respect to the reactant. 

N, N-Dimethylformamide diethyl acetal (DMFDEA) is a interesting reagent, since it can be used to form alkylaminopropenones or alkylaminopropenoates when reacted with compounds having activated methylene groups such as (3-ketoesters, acetophenone and N-acylglycine. These alkylaminopropenones or alkylaminopropenoates can subsequently be reacted with dinucleophiles to form a variety of heterocycles. Westman and co-workers32 have used DMFDEA for the synthesis of propenoates and propenones, which were used directly without intermediate purification for the formation of a number of heterocycles in a combinatorial fashion. Some examples are outlined in Scheme 5.16. The reactions were performed in a two-step one-pot procedure, which in this case were more suitable for combinatorial synthesis. 

Low Molecular Weight Acids. The method devised for analyzing free fatty acids will resolve Ci to CB acids as shown in Figure 1, except for formic and propionic acids which are poorly resolved under the conditions used. Propionic acid, however, has been shown to be absent in all mixtures of oxidation products, and thus it presents no problem in this study. Acetophenone, shown in the chromatogram, was a convenient and reliable internal standard for this technique. Detection by thermal conductivity was selected because the flame ionization detector is insensitive to formic acid and, as noted, the high volatility of methyl formate and acetate precludes their quantitative determination by reasonably simple esterification procedures. 

An unsuccessful attempt has been made to determine the separate electronic and steric effects of alkyl groups on the acidities of hydrocarbons, acetophenone derivatives, and acetone derivatives CH3COCHR1R2 (at either site) by multivariational analyses of experimental and theoretical acidities for each set.15 A thermodynamic cycle has been used to estimate the aqueous phase p/C, = 22.7 1.0 for the methyl group of acetic acid and p/C, = 3.3 1.0 for the corresponding enol.16 Equilibrium acidities have been determined for several nitroaryl substituted nitroalkanes and cyanomethanes, 2,4,6-TNT, and 9-cyanofluorene17 in acetonitrile the influence of common cation BH+ on the electronic spectra of the anions obtained in the presence of strong guanidine bases (B) has been attributed to formation of two types of ion pair.18... 

Acylation of ketones with esters requires the presence of a strong base under anhydrous conditions. Ketones where only one unique mesomeric carbanion is formed (e.g. symmetrical ketones or alkyl aryl ketones) yield a single regio-isomer. The reaction is illustrated by the formation of benzoylacetone from acetophenone and ethyl acetate (Expt 5.103), and may be outlined mechanistically as follows ... 

As mentioned in last section, ammonia is not suitable for the nitrogen source in the TCRT due to competitive ammonolysis. In order to avoid this undesired reaction, less nucleophilic ammonium acetate is employed instead of ammonia. When a methanol solution of nitropyrimidinone 3 is heated with acetophenone 22g and ammonium acetate, the formation of yellow precipitates is observed during the reaction. 4-Phenylpyrimidine 26g is isolated from the reaction mixture in a considerably improved 49% yield under quite milder conditions compared with the TCRT using ammonia (Scheme 13) [44,47]. 

During the first 2h of reaction, a decrease in AcOH conversion (from 48 to 43 %) for benzene acetylation at 523 K with an increase in selectivity to the monoacetylated product (from 80 to 90%) can be observed. The only problem involves the low catalyst activity 1.5 mmolh 1g 1 of acetophenone, which corresponds to a TOF value of 2.2 h-1. This means that less than 0.2 g of this acetylated arene can be produced per hour and per gram of catalyst under the operating conditions (i.e. 10 times less than in the liquid phase acetylation of anisole with AA). The kinetic study of the reaction shows an increase in the selectivity with the substrate/acetic acid ratio, but no increase in yield, an increase in acetic acid conversion with the reaction temperature with a significant decrease in selectivity due to a greater formation of diacetylated products.[62,63] HFAU and RE-FAU zeolites do... 

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