Acetal hydrolysis stepwise

Cyclopropylidene-l,3-dioxanes or -1,3-dioxolanes are ketene acetals and examples of bis-donor-substituted methylenecyclopropanes which undergo facile cycloaddition with electron-deficient alkenes 12. Thus, spiro[2.3]pentanone acetals 13 were obtained after reaction in an aromatic solvent either at room temperature or 40 C. Upon subsequent aqueous workup, hydrolytic cleavage of a C-C bond of the cyclobutane ring took place rather than the expected acetal hydrolysis (Table 7). This cycloaddition was found to proceed in a stepwise fashion as reaction of the dimethyl ( )-but-2-enedioate gave a cisj tram mixture of cycloadducts on further heating, this ratio changed. 

Two-dimensional potential energy diagrams can be used to evaluate structural effects on the reactivity of carbonyl compounds and the tetrahedral intermediates. These reactions involve the formation or breaking of two separate bonds. This is the case in the first stage of acetal hydrolysis, which involves both a proton transfer and breaking of a C—O bond. The overall reaction might take place in several ways, but there are two stepwise mechanistic extremes. 

Fig. 7.3. Representation of mechanism for the first stage of acetal hydrolysis (a) stepwise mechanism with initial C—O bond breaking (b) concerted mechanism with C—O bond breaking leading O—H bond formation (c) concerted mechanism with proton transfer leading C—O bond breaking and (d) stepwise mechanism with initial proton transfer.

Problem 17.8 asked you to write details of the mechanism describing formation of benzaldehyde diethyl acetal from benzaldehyde and ethanol. Write a stepwise mechanism for the acid hydrolysis of this acetal. 

Another important site of structural variation in cephalosporins is C(3) (Table 5.4.J). Electron-withdrawing substituents at C(3) such as a Cl-atom or a MeO group increase base-catalyzed hydrolysis of cephalosporins by both resonance and inductive effects [92], For cephalosporins carrying 3-methylene-linked substituents with leaving group ability (e.g., acetate, thiol, or pyridine), it has been postulated that a concerted expulsion of the substituent facilitates the nucleophilic attack on the /3-lactam carbonyl group [104][105]. However, there are also arguments for a stepwise process in which the ex-... 

The reduced basicity of phenothiazine nitrogen requires that even acylation proceed via the anion. The amide (34-2) from the methyl thioether (34-1) can be prepared, for example, by sequential reaction with sodium amide and acetic anhydride. Oxidation of that intermediate with peracid proceeds preferentially on the more electron-rich alkyl thioether to give the sulfone this affords the phenothiazine (34-3) on hydrolysis of the amide. Complex side chains are most conveniently incorporated in a stepwise fashion. The first step in the present sequence involves reaction of (34-3) as its anion with l-bromo-3-chloropropane to give (34-4). The use of that halide with alkylate piperidine-4-carboxamide (34-5) affords the antipsychotic agent metopimazine (34-6) [35]. 

Thus Rogovin and Shlakhover [81] performed a stepwise nitration applying mixed acids composed of nitric acid, acetic anhydride and acetic add. Nitrating mixtures of this composition do not bring about degradation, hydrolysis or oxidation of nitrocellulose during the nitration (see p. 344). Each additional nitration causes an increase of viscosity. The results are collected in Table 52. 

Scheme 11.1 Stepwise acid-catalysis mechanism for the hydrolysis of acetals (a) and the concerted alternative (b).

The detection of intermediates depends upon the relative values of the rate constants for their formation and decay (see Chapter 4). An example is the imidazole-catalysed hydrolysis of aryl acetates where the concentration of acetylimidazole builds up and decays subsequently by hydrolysis. A stepwise process is manifestly obvious if, during a kinetic study, an intermediate species is observed to accumulate and then decay to give products (Fig. 11.6A)[12,13]. The nature of the measuring device is not relevant to the argument but is likely to be spectroscopic (see Chapters 2 and 9). The direct observation of an intermediate depends on a build-up of its concentration to a measurable level and this requires that the decay to the product is relatively slow. The simplest possible case of a stepwise process is shown in Scheme 11.15 and this also happens to be one of the most generally applicable mechanisms (see Chapter 4). 

The cyclohexene 121, which was readily accessible from the Diels-Alder reaction of methyl hexa-3,5-dienoate and 3,4-methylenedioxy-(3-nitrostyrene (108), served as the starting point for another formal total synthesis of ( )-lycorine (1) (Scheme 11) (113). In the event dissolving metal reduction of 121 with zinc followed by reduction of the intermediate cyclic hydroxamic acid with lithium diethoxyaluminum hydride provided the secondary amine 122. Transformation of 122 to the tetracyclic lactam 123 was achieved by sequential treatment with ethyl chloroformate and Bischler-Napieralski cyclization of the resulting carbamate with phosphorus oxychloride. Since attempts to effect cleanly the direct allylic oxidation of 123 to provide an intermediate suitable for subsequent elaboration to ( )-lycorine (1) were unsuccessful, a stepwise protocol was devised. Namely, addition of phenylselenyl bromide to 123 in acetic acid followed by hydrolysis of the intermediate acetates gave a mixture of two hydroxy se-lenides. Oxidative elimination of phenylselenous acid from the minor product afforded the allylic alcohol 124, whereas the major hydroxy selenide was resistant to oxidation and elimination. When 124 was treated with a small amount of acetic anhydride and sulfuric acid in acetic acid, the main product was the rearranged acetate 67, which had been previously converted to ( )-lycorine (108). 

Acrolein and condensable by-products, mainly acrylic acid plus some acetic acid and acetaldehyde, are separated from nitrogen and carbon oxides in a water absorber. However in most industrial plants the product is not isolated for sale, but instead the acrolein-rich effluent is transferred to a second-stage reactor for oxidation to acrylic acid. In fact the volume of acrylic acid production ca. 4.2 Mt/a worldwide) is an order of magnitude larger than that of commercial acrolein. The propylene oxidation has supplanted earlier acrylic acid processes based on other feedstocks, such as the Reppe synthesis from acetylene, the ketene process from acetic acid and formaldehyde, or the hydrolysis of acrylonitrile or of ethylene cyanohydrin (from ethylene oxide). In addition to the (preferred) stepwise process, via acrolein (Equation 30), a... 

Although known for almost forty years, and in spite of a total synthesis of its racemate, the stereochemistry of doisynolic acid has remained in doubt. This problem has now been settled by a stepwise chemical conversion (Scheme 23) of 14)5-oestrone methyl ether (339), prepared from natural oestrone (114a), into c/s-doisynolic acid methyl ether (342). Osmium tetroxide oxidation of the enol acetate corresponding to (339) provided 16a-hydroxy-14)S-oestrone methyl ether. Subsequent periodic acid oxidation afforded the lactol (340), which upon treatment with diazomethane gave the aldehydo-ester (341). Electrochemical reduction of the aldehyde (341) afforded a methyl ester which by alkaline hydrolysis provided (-f )-ds-doisynolic acid 3-methyl ether (342), thus defining its complete stereochemistry. ... 

Enantioselective hydrogenation of imines in aqueous systems generated much research interest, partly because of the practical value of the product amines, partly due to the unusual kinetic observations. Imines, such as N-benzylacetophenone-imine, are relatively stable to hydrolysis, and could be reduced either in a water/ ethyl acetate two-phase solvent mixture [93, 130, 131], or in a benzene-AOT-water reverse micellar solution (AOT = bis(2-ethylhexyl)sulfosuccinate). With catalysts, prepared from [Rh(cod)Cl]2 and the products of the stepwise sulfonation of... 

M. L. Bender (Illinois Institute of Technology, Chicago, III.) We have found that imidazole, a constituent of chymotrypsin catalyzes the hydrolysis of p-nitrophenyl acetate at 25° and pH 7. The reaction occurs in a stepwise manner, as does the enzymatic reaction, with the intermediate formation of acetylimidazole, which is subsequently hydrolyzed by water. While a serine hydroxyl of chymotrypsin, as proposed by Dr. Gutfreund (Lecture 29), could be converted to acetylserine, there is no obvious way in which it could hydrolyze, whereas this possibility occurs straightforwardly with the imidazole-catalyzed sequence. 

Figure 2.4 Stepwise and combinational strategies for modulating the enantioselectivity of a /tara-nitrobenzyl esterase cloned from Bacillus amylolique-faciens (BAE) in the hydrolysis of l-(3, 4 -methylenedioxyphenyl)ethyl acetate. ...

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