Carbonyl groups, hydrolysis

The nitroso compound is unstable because it can tautomerize with the transfer of a proton from carbon to the oxygen of the nitroso group. This process is exactly like enolization but uses an N=0 instead of a C-O group. It gives a more familiar functional group from Chapter 14, the oxime, as the stable enol . The second structure shows how the oxime s O-H can form an intramolecular hydrogen bond with the ketone carbonyl group. Hydrolysis of the oxime reveals the second ketone. 

The mechanism, as discussed above, can be thougjrt of as involving rapid nucleophilic attack by the Grignard reagent at the carbon of the carbonyl group. Hydrolysis of the resulting alkoxide ion intermediate with dilute acid yields the desired alcohol. The reaction sequence is outlined here ... 

Experimentally it is found that metal ions do not hydrolyze simple esters unless there is a second coordination site in the molecule in addition to the carbonyl group. Hydrolysis of the usual types of ester is not catalyzed by metal ions, but hydrolysis of amino acid esters is subject to catalysis. 

Hammen equation A correlation between the structure and reactivity in the side chain derivatives of aromatic compounds. Its derivation follows from many comparisons between rate constants for various reactions and the equilibrium constants for other reactions, or other functions of molecules which can be measured (e g. the i.r. carbonyl group stretching frequency). For example the dissociation constants of a series of para substituted (O2N —, MeO —, Cl —, etc.) benzoic acids correlate with the rate constant k for the alkaline hydrolysis of para substituted benzyl chlorides. If log Kq is plotted against log k, the data fall on a straight line. Similar results are obtained for meta substituted derivatives but not for orthosubstituted derivatives. 

By the ketonic hydrolysis of substituted acetoacetic esters this is brought about by the action of dilute alkali in the cold, followed by acidification and boiling. The free substituted acetoacetic acid is produced, which readily undergoes decarboxylation (since it has a carboxyl and a carbonyl group on the same carbon atom) to give a ketone, for example ... 

With concentrated alkali, fission occurs at the position adjacent to the carbonyl group to give acetic acid and a mono-substituted acetic acid the process is termed acid hydrolysis. 

Perhaps the most extensively studied catalytic reaction in acpreous solutions is the metal-ion catalysed hydrolysis of carboxylate esters, phosphate esters , phosphate diesters, amides and nittiles". Inspired by hydrolytic metalloenzymes, a multitude of different metal-ion complexes have been prepared and analysed with respect to their hydrolytic activity. Unfortunately, the exact mechanism by which these complexes operate is not completely clarified. The most important role of the catalyst is coordination of a hydroxide ion that is acting as a nucleophile. The extent of activation of tire substrate througji coordination to the Lewis-acidic metal centre is still unclear and probably varies from one substrate to another. For monodentate substrates this interaction is not very efficient. Only a few quantitative studies have been published. Chan et al. reported an equilibrium constant for coordination of the amide carbonyl group of... 

The mechanisms of all the reactions cited m Table 20 1 are similar to the mecha nism of hydrolysis of an acyl chlonde outlined m Figure 20 2 They differ with respect to the nucleophile that attacks the carbonyl group... 

In the first stage of the hydrolysis mechanism water undergoes nucleophilic addi tion to the carbonyl group to form a tetrahedral intermediate This stage of the process IS analogous to the hydration of aldehydes and ketones discussed m Section 17 6... 

Nucleophilic acyl substitutions at the ester carbonyl group are summarized m Table 20 5 on page 849 Esters are less reactive than acyl chlorides and acid anhydrides Nude ophilic acyl substitution m esters especially ester hydrolysis has been extensively mves tigated from a mechanistic perspective Indeed much of what we know concerning the general topic of nucleophilic acyl substitution comes from studies carried out on esters The following sections describe those mechanistic studies... 

Once It was established that hydroxide ion attacks the carbonyl group in basic ester hydrolysis the next question to be addressed concerned whether the reaction is concerted or involves a tetrahedral intermediate In a concerted reaction the bond to the leaving group breaks at the same time that hydroxide ion attacks the carbonyl... 

FIGURE 27 19 Proposed mechanism of hydrolysis of a peptide catalyzed by carboxypeptidase A The peptide is bound at the active site by an ionic bond between its C terminal ammo acid and the positively charged side chain of arginine 145 Coordination of Zn to oxygen makes the carbon of the carbonyl group more positive and increases the rate of nucleophilic attack by water... 

Hydantoins can react with electrophiles at both nitrogen atoms and at C-5. The electrophilic carbonyl groups can be attacked by nucleophiles, leading to hydrolysis of the ring or to partial or total reduction of the carbonyl system. Other reactions are possible, including photochemical cleavage of the ring. 

Penicillins are also degraded by aqueous acids via initial reaction of the sidechain carbonyl group with the P-lactam. PeniciEenic acids (33) are obtained when hydrolysis is carried out at pH 4, penillic acids (34) at pH 2. 

Chemical Properties. Neopentanoic acid [75-98-9] undergoes reactions typical of carboxyUc acids. Reactions often proceed less readily than with straight-chain acids because of the steric hindrance around the carbonyl group. However, this steric hindrance at the a-carbon results ia derivatives that are typically more resistant to hydrolysis and oxidation. 

It is generally beheved that selectivity of hydrolytic enzymes strongly depends on the proximity of the chiral center to the reacting carbonyl group, and only a few examples of successful resolutions exist for compounds that have the chiral center removed by more than three bonds. A noticeable exception to this rule is the enantioselective hydrolysis by Pseudomonasfluorescens Hpase (PEL) of racemic dithioacetal (5) that has a prochiral center four bonds away from the reactive carboxylate (24). The monoester (6) is obtained in 89% yield and 98% ee. 

A carbonyl group can be protected as a sulfur derivative—for example, a dithio acetal or ketal, 1,3-dithiane, or 1,3-dithiolane—by reaction of the carbonyl compound in the presence of an acid catalyst with a thiol or dithiol. The derivatives are in general cleaved by reaction with Hg(II) salts or oxidation acidic hydrolysis is unsatisfactory. The acyclic derivatives are formed and hydrolyzed much more readily than their cyclic counterparts. Representative examples of formation and cleavage are shown below. 

Acyclic monothio acetals and ketals can be prepared directly from a carbonyl compound or by transketalization, a reaction that does not involve a free carbonyl group, from a 1,3-dithiane or 1,3-dithiolane. They are cleaved by acidic hydrolysis or Hg(II) salts. 

NaN02, 1 N HCl, CH3OH, H2O, 0°, 3 h, 76% yield. In the last step of a synthesis of erythronolide A, acid-catalyzed hydrolysis of an acetonide failed because the carbonyl-containing precursor was unstable to acidic hydrolysis (3% MeOH, HCl, 0°, 30 min, conditions developed for the synthesis of erythronolide B). Consequently the carbonyl group was protected... 

In general, imines are too reactive to be used to protect carbonyl groups. In a synthesis of juncusol, however, a bromo- and an iodocyclohexylimine of two identical aromatic aldehydes were coupled by an Ullman coupling reaction modi-fied by Ziegler. The imines were cleaved by acidic hydrolysis (aq. oxalic acid, THF, 20°, 1 h, 95% yield). Imines of aromatic aldehydes have also been prepared... 

Cellobiose was prepared first by Skraup and Konig by the saponification of the octaacetate with alcoholic potassium hydroxide, and the method was improved by Pringsheim and Merkatz.3 Aqueous barium hydroxide also has been employed for the purpose, and methyl alcoholic ammonia has been used extensively for the hydrolysis of carbohydrate acetates. The method of catalytic hydrolysis with a small quantity of sodium methylate was introduced by Zemplen,i who considered the action to be due to the addition of the reagent to the ester-carbonyl groups of the sugar acetate and the decomposition of the addition compound by reaction with alcohol. The present procedure, reported by Zemplen, Gerecs, and Hadacsy, is a considerable improvement over the original method (see Note 2). 

Three-dimensional potential energy diagrams of the type discussed in connection with the variable E2 transition state theory for elimination reactions can be used to consider structural effects on the reactivity of carbonyl compounds and the tetrahedral intermediates involved in carbonyl-group reactions. Many of 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. There are two mechanistic extremes ... 

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