Mechanism acid catalyzed hydrolysis

The mechanism for acid-catalyzed hydrolysis of amides involves attack by water on the protonated amide. An inqjortant feature of the chemistry of amides is that the most basic site in an amide is the carbonyl oxygen. Very little of the N-protonated form is present. The major factor that contributes to the stability of the O-protonated form is the... 

Two mechanisms for acid-catalyzed hydrolysis can be imagined depending on the initial site of protonation. One mechanism begins widi protonation at X this makes X a better leaving group. The alternative is protonation of the carbonyl oxygen. 

TMS ethers can be removed by treatment with fluoride ion as well as by acid-catalyzed hydrolysis. Propose a mechanism for the reaction of cyclohexyl TMS ether with LiF. Fluorotrimethylsilane is a product. 

Acid-catalyzed hydrolysis of a nitrile to give a carboxylic acid occurs by initial protonation of the nitrogen atom, followed by nucleophilic addition of water. Review the mechanism of base-catalyzed nitrile hydrolysis in Section 20.7, and then write all the steps involved in the acicl-catalyzed reaction, using curved arrows to represent electron flow in each step. 

The spontaneous polymerization of furan adsorbed on carbon black with or without SnCl4 vapours35 has been explained by a similar cationic mechanism. Also, the polymerization of gaseous furan on liquid acidic surfaces35 has the same origin, but in these systems the polymers suffer an acid-catalyzed hydrolysis of their tetrahydrofuran rings which produces a considerable proportion of hydroxyl and carbonyl groups. 

Taft, following Ingold," assumed that for the hydrolysis of carboxylic esters, steric, and resonance effects will be the same whether the hydrolysis is catalyzed by acid or base (see the discussion of ester-hydrolysis mechanisms. Reaction 10-10). Rate differences would therefore be caused only by the field effects of R and R in RCOOR. This is presumably a good system to use for this purpose because the transition state for acid-catalyzed hydrolysis (7) has a greater positive charge (and is hence destabilized by —I and stabilized by +1 substituents) than the starting ester. 

The intermediates 74 and 76 can now lose OR to give the acid (not shown in the equations given), or they can lose OH to regenerate the carboxylic ester. If 74 goes back to ester, the ester will still be labeled, but if 76 reverts to ester, the 0 will be lost. A test of the two possible mechanisms is to stop the reaction before completion and to analyze the recovered ester for 0. This is just what was done by Bender, who found that in alkaline hydrolysis of methyl, ethyl, and isopropyl benzoates, the esters had lost 0. A similar experiment carried out for acid-Catalyzed hydrolysis of ethyl benzoate showed that here too the ester lost However, alkaline hydrolysis of substimted benzyl benzoates showed no loss. This result does not necessarily mean that no tetrahedral intermediate is involved in this case. If 74 and 76 do not revert to ester, but go entirely to acid, no loss will be found even with a tetrahedral intermediate. In the case of benzyl benzoates this may very well be happening, because formation of the acid relieves steric strain. Another possibility is that 74 loses OR before it can become protonated to 75. Even the experiments that do show loss do not prove the existence of the tetrahedral intermediate, since it is possible that is lost by some independent process not leading to ester hydrolysis. To deal with this possibility. Bender and Heck measured the rate of loss in the hydrolysis of ethyl trifluorothioloacetate- 0 ... 

The acid-catalyzed hydrolysis of enol esters (RCOOCR =CR) can take place either by the normal Aac2 mechanism or by a mechanism involving initial protonation on the double-bond carbon, similar to the mechanism for the hydrolysis of enol ethers given in 10-6, ° depending on reaction conditions. In either case, the products are the carboxylic acid RCOOH and the aldehyde or ketone R2" CHCOR. ... 

Further evidence for this mechanism is that a small but detectable amount of 0 exchange (see p. 425) has been found in the acid-catalyzed hydrolysis of benz-amide. (The exchange has also been detected for the base-catalyzed... 

Treatment of suitably protected 2-triflates 220 and 222 of methyl ) -d-talopyranoside with Et4NF (MeCN, 50°, 30-50 min) gave, respectively, the 2-fluoro-y -D-galactopyranoside 221 (50%) and the unsaturated product 223 (74%). The mechanism was discussed. Acid-catalyzed hydrolysis of 221 (5... 

Oae found that for both base- and acid-catalyzed hydrolysis of phenyl benzenesul-fonate, there was no incorporation of 0 from solvent into the sulfonate ester after partial hydrolysis. This was interpreted as ruling out a stepwise mechanism, but in fact it could be stepwise with slow pseudorotation. In fact this nonexchange can be explained by Westheimer s rules for pseudorotation, assuming the same rules apply to pentacoordinate sulfur. For the acid-catalyzed reaction, the likely intermediate would be 8 for which pseudorotation would be disfavored because it would put a carbon at an apical position. Further protonation to the cationic intermediate is unlikely even in lOM HCl (the medium for Oae s experiments) because of the high acidity of this species a Branch and Calvin calculation (See Appendix), supplemented by allowance for the effect of the phenyl groups (taken as the difference in between sulfuric acid and benzenesulfonic acid ), leads to a pA, of -7 for the first pisTa of this cation about -2 for the second p/sTa. and about 3 for the third Thus, protonation by aqueous HCl to give the neutral intermediate is likely but further protonation to give cation 9 would be very unlikely. 

The carbonyl group can be deprotected by acid-catalyzed hydrolysis by the general mechanism for acetal hydrolysis (see Part A, Section 7.1). A number of Lewis acids have also been used to remove acetal protective groups. Hydrolysis is promoted by LiBF4 in acetonitrile.249 Bismuth triflate promotes hydrolysis of dimethoxy, diethoxy, and dioxolane acetals.250 The dimethyl and diethyl acetals are cleaved by 0.1-1.0 mol % of catalyst in aqueous THF at room temperature, whereas dioxolanes require reflux. Bismuth nitrate also catalyzes acetal hydrolysis.251... 

By employing anionic techniques, alkyl methacrylate containing block copolymer systems have been synthesized with controlled compositions, predictable molecular weights and narrow molecular weight distributions. Subsequent hydrolysis of the ester functionality to the metal carboxylate or carboxylic acid can be achieved either by potassium superoxide or the acid catalyzed hydrolysis of t-butyl methacrylate blocks. The presence of acid and ion groups has a profound effect on the solution and bulk mechanical behavior of the derived systems. The synthesis and characterization of various substituted styrene and all-acrylic block copolymer precursors with alkyl methacrylates will be discussed. 

Such a difference in partial double-bond character has implications for the mechanism, and, hence, the reaction rate, of acid-catalyzed hydrolysis (Fig. 6.15). In delocalized peptide bonds (Fig. 6.15,a), protonation involves the carbonyl O-atom with its partial negative charge. In non-delocalized peptide bonds (Fig. 6.15,b), protonation involves the N-atom, which is rendered more basic by the lack of delocalization [73],... 

Fig. 6.15. Simplified mechanisms of the acid-catalyzed hydrolysis of a) delocalized peptide bonds and b) non-delocalized peptide bonds...

The term acid catalysis is often taken to mean proton catalysis ( specific acid catalysis ) in contrast to general acid catalysis. In this sense, acid-catalyzed hydrolysis begins with protonation of the carbonyl O-atom, which renders the carbonyl C-atom more susceptible to nucleophilic attack. The reaction continues as depicted in Fig. 7. l.a (Pathway a) with hydration of the car-bonium ion to form a tetrahedral intermediate. This is followed by acyl cleavage (heterolytic cleavage of the acyl-0 bond). Pathway b presents an mechanism that can be observed in the presence of concentrated inorganic acids, but which appears irrelevant to hydrolysis under physiological conditions. The same is true for another mechanism of alkyl cleavage not shown in Fig. 7.Fa. All mechanisms of proton-catalyzed ester hydrolysis are reversible. 

The resonance mechanism shown in Fig. 8.15 accounts for the greater stability of dihydropyridine pro-prodrugs vs. their pyridinium metabolites in base-catalyzed and enzymatic reactions of hydrolysis, but it also suggests a decreased stability of the former in acid-catalyzed hydrolysis. Indeed, the carbonyl O-atom is deduced from Fig. 8.15 to be more nucleophilic in dihydropyridine (A) than in pyridinium derivatives (B). The stability of dihydropyridine pro-prodrugs under the acidic conditions of the stomach and small intestine should, therefore, be examined further. 

Scheme 11.—Mechanisms for the Acid-catalyzed Hydrolysis of Cellulose.

The mechanism of the acid-catalyzed hydrolysis of cellulose is based on that normally expected for an acetal (see Scheme 11). This involves formation of a conjugate acid by protonation of either of the acetal oxygen atoms at C-1, and formation of a carbonium ion, followed by stabilization of the product by heterolysis of a participating water molecule. The car-... 

Nucleophilic cleavage, acid catalyzed hydrolysis, and oxidation of aldicarb in dilute solution were achieved in batch and/or column experiments using macroporous reactive ion exchange resins. As in solution, nucleophilic cleavage proceeds faster than acid catalyzed hydrolysis. The basis for pursuing study of the latter mechanism is discussed. 

The implications of the above observations may be important, especially if similar trends are observed in pyranose anomers. For example, with respect to the mechanism of acid-catalyzed hydrolysis of pyranosides, endocyclic C-0 bond cleavage (preceeded by 05 protonation) may be assisted in P-anomers in which the Cl-01 bond is equatorial, since the 04-Cl bond may already be extended in these anomers. By a similar argument, exocyclic C-0 scission (preceeded by 01 protonation) may be assisted in the hydrolysis of a-pyranosides in which the Cl-01 is axial and extended, thus resembling the transition state. Post and Karplus have recently suggested that enzyme-catalyzed glycoside hydrolysis of P-pyranosides may indeed take place by ring oxygen protonation, followed by endocyclic C-0 bond scission. 

Anchimeric assistance may also explain slight changes in mechanism resulting from the presence of a neighboring group. One likely case is the acid-catalyzed hydrolysis of phenylglycosides. Raftery s group" found that the secondary kinetic isotope effect (/tr/ d) was 1.13 for acid hydrolysis of phenyl-4-0-(2-acetamido-2-deoxy-j8-D-glu-... 

Acid-catalyzed hydrolysis of Reissert compounds results in an aldehyde, a formal reduction product of the acyl halide utilized in the Reissert compound formation (11). The mechanism of the reaction according to McEwen and Cobb (3), is shown in Scheme 2. 

There are an extremely large number of reactions of 2-oxetanones with nucleophilic reagents, and space will allow inclusion of only representative examples. /3-Lactones show the interesting Bal.2 mechanism for base-catalyzed hydrolysis and the Aal2 mechanism for acid-catalyzed hydrolysis, according to data on kinetics and optical rotation studies of optically active lactones. The mechanistic interpretations are complicated, however, by the possibilities for subsequent elimination and addition reactions to occur, so that both of the two sites for nucleophilic attack on the 0-lactone skeleton, C-2 and C-4, may become involved. In fact 0-lactones are unusually insensitive to base, as well as acid, catalysis, the slow reaction with neutral water predominating between pH 1 and 9 (74JCS(P2)377). 

The mechanism for esterification given in Problem 16.16 is reversible, the reverse being the mechanism for acid-catalyzed hydrolysis of esters. As an example of the principle of microscopic reversibility, the forward and reverse mechanisms proceed through the same intermediates and transition states. 

We conclude that the neutral substrate enters 1 to form a host-guest complex, leading to the observed substrate saturation. The encapsulated substrate then undergoes encapsulation-driven protonation, presumably by deprotonation of water, followed by acid-catalyzed hydrolysis inside 1, during which two equivalents of the corresponding alcohol are released. Finally, the protonated formate ester is ejected from 1 and further hydrolyzed by base in solution. The reaction mechanism (Scheme 7.7) shows direct parallels to enzymes that obey Michaelis-Menten kinetics due to the initial pre-equilibrium followed by a first-order rate-limiting step. 

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