Tetrahedral intermediate acid anhydrides

Step 2 Structurally O acylisoureas resemble carboxylic acid anhydrides and are powerful acylatmg agents In the reaction s second stage the amine adds to the carbonyl group of the O acylisourea to give a tetrahedral intermediate... 

FIGURE 20.3 An acid catalyzes the hydrolysis of a carboxylic acid anhydride by increasing the rate of the first stage of the mechanism. The faster the tetrahedral intermediate is formed, the faster the rate of hydrolysis. 

The characteristic reaction of acyl chlorides, acid anhydrides, esters, and amides is nucleophilic acyl substitution. Addition of a nucleophilic reagent Nu—H to the carbonyl group leads to a tetrahedral intermediate that dissociates to give the product of substitution ... 

However, detection of the tetrahedral intermediate in the addition of a nucleophile to an ester, acid halide, amide or anhydride must be adduced from kinetic evidence, in particular the evidence of oxygen exchange in such an intermediate. Such tracer work has established the presence of symmetrical addition compounds in the hydrolysis of esters23, amides and acid chlorides24. Since the attempts to detect such intermediates have played a considerable part in the development of hydrolysis studies, it is worthwhile considering this point in some detail. 

Two further properties which must be intimately related with the problems of the tetrahedral intermediate are the solvent isotope effect and the entropy of activation for the hydrolysis of RCOX. Table 2 lists the values of entropies of activation for the neutral hydrolyses of esters, anhydrides, and acid chlorides. Values of —30 to — 40 eu are common to the hydrolyses of esters and anhydrides, but for acid halides the value is down to---10 eu. The only slight... 

SAMPLE SOLUTION (a) The reaction given is the acid-catalyzed esterification of methanol by benzoic anhydride. The tetrahedral intermediate is formed by addition of a molecule of methanol to one of the carbonyl groups of the anhydride. This reaction is analogous to the acid-catalyzed formation of a hemiacetal by reaction of methanol with an aldehyde or ketone. 

The kinetics of the hydrolysis of acetic anhydride in dilute hydrochloric acid, Scheme 1.9, may be described by a single pseudo-first-order rate constant, k, and the investigation by calorimetry combined with IR spectroscopy, as we shall see in Chapter 8, provides a clear distinction between the heat change due to mixing of the acetic anhydride into the aqueous solution and that due to the subsequent hydrolysis. This model of the reaction is sufficient for devising a safe and efficient large-scale process. We know from other evidence, of course, that the reaction at the molecular level is not a single-step process - it involves tetrahedral intermediates - but this does not detract from the validity or usefulness of the model for technical purposes. 

In the formation of anhydrides A and C one equivalent of HC1 is released. It attacks the activated carboxylic carbon atom of these anhydrides in an SN reaction. The carboxylic acid chloride is formed via the tetrahedral intermediates B or D, respec-... 

Propose a mechanism for the reaction of benzoic acid with oxalyl chloride. This mechanism begins like the thionyl chloride reaction, to give a reactive mixed anhydride. Nucleophilic acyl substitution by chloride ion gives a tetrahedral intermediate that eliminates a leaving group, which then fragments into carbon dioxide, carbon monoxide, and chloride ion. 

Acid chlorides are the most reactive acid derivatives, so they are easily converted to any of the other acid derivatives. Acid chlorides are often used to synthesize anhydrides, esters, and amides. Acid chlorides react with carboxylic acids (or their carboxylate salts) to form anhydrides. Either oxygen atom of the acid can attack the strongly electrophilic carbonyl group of the acid chloride to form a tetrahedral intermediate. Loss of chloride ion and a proton gives the anhydride. 

Once the tetrahedral intermediate has been formed by addition of the nucleophile to a carbonyl, the second carboxyl group acts as a good leaving group, favouring the collapse of the intermediate and the formation of the product. Acid anhydrides are therefore widely used in making the esters of alcohols. 

Similar experiments have indicated the reversible formation of tetrahedral intermediates in hydrolysis of other esters, amides, anhydrides, and acid chlorides, and are the basis of the general mechanism we have shown for nucleophilic acyl substitution. 

AnoAer procedure which was thought to pass through a mixed phosphoms anhydride was the acylation of Grignard reagents with an adduct formed between lithium carboxylates and triphenylphosphine dichloride (Scheme 26). The betaine (70) was the proposed tetrahedral intermediate however, since no evidence is provided, the reaction may have also proceeded by way of the acid chloride. Surprisingly, good yields of ketone are preserved even in the presence of excess nucleophile and no tertiary alcohol formation was observed. Triethylamine can be used for prior deprotonation of the carboxylic acid how-... 

In the first step the base (usually an alkoxide, LDA, or NaH) deprotonates the a-proton of the ester to generate an ester enolate that will serve as the nucleophile in the reaction. Next, the enolate attacks the carbonyl group of the other ester (or acyl halide or anhydride) to form a tetrahedral intermediate, which breaks down in the third step by ejecting a leaving group (alkoxide or halide). Since it is adjacent to two carbonyls, the a-proton in the product p-keto ester is more acidic than in the precursor ester. Linder the basic reaction conditions this proton is removed to give rise to a resonance stabilized anion, which is much less reactive than the ester enolate generated in the first step. Therefore, the p-keto ester product does not react further. 

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