Carboxylic acid amides tetrahedral intermediates

Mechanistically amide hydrolysis is similar to the hydrolysis of other carboxylic acid derivatives The mechanism of the hydrolysis m acid is presented m Figure 20 7 It proceeds m two stages a tetrahedral intermediate is formed m the first stage and disso ciates m the second... 

In base the tetrahedral intermediate is formed m a manner analogous to that pro posed for ester saponification Steps 1 and 2 m Figure 20 8 show the formation of the tetrahedral intermediate m the basic hydrolysis of amides In step 3 the basic ammo group of the tetrahedral intermediate abstracts a proton from water and m step 4 the derived ammonium ion dissociates Conversion of the carboxylic acid to its corresponding carboxylate anion m step 5 completes the process and renders the overall reaction irreversible... 

There are large differences in reactivity among the various carboxylic acid derivatives, such as amides, esters, and acyl chlorides. One important factor is the resonance stabilization provided by the heteroatom. This decreases in the order N > O > Cl. Electron donation reduces the electrophilicity of the carbonyl group, and the corresponding stabilization is lost in the tetrahedral intermediate. 

Following formation of the amide intermediate, a second nucleophilic addition of hydroxide ion to the amide carbonyl group then yields a tetrahedral alkoxide ion, which expels amide ion, NHZ-, as leaving group and gives the car-boxylate ion, thereby driving the reaction toward products. Subsequent acidification in a separate step yields the carboxylic acid. We ll look at this process in more detail in Section 21.7. 

In these reactions (12-41-12-44), a carbonyl group is attacked by a hydroxide ion (or amide ion) giving an intermediate that undergoes cleavage to a carboxylic acid (or an amide). With respect to the leaving group, this is nucleophilic substitution at a carbonyl group and the mechanism is the tetrahedral one discussed in Chapter 10. 

Conversions of carboxylic acids to ketones are typically performed in stepwise fashion6 via intermediates such as acid chlorides,7 anhydrides,8 thioesters,9 or N-alkoxy amides,10 or by the direct reaction of carboxylic adds with lithium reagents.11 In this latter method trimethylsifyl chloride has been shown to be an effective reagent for trapping the tetrahedral alkoxide intermediates and for quenching excess organolithium reagent. 

Before discussmg the mechanism of cleavage of carboxylic acid esters and amides by hydrolases, some chemical principles are worth recalling. The chemical hydrolysis of carboxylic acid derivatives can be catalyzed by acid or base, and, in both cases, the mechanisms involve addition-elimination via a tetrahedral intermediate. A general scheme of ester and amide hydrolysis is presented in Fig. 3. / the chemical mechanisms of ester hydrolysis will be... 

In HO -catalyzed hydrolysis (specific base catalyzed hydrolysis), the tetrahedral intermediate is formed by the addition of a nucleophilic HO ion (Fig. 3.1, Pathway b). This reaction is irreversible for both esters and amides, since the carboxylate ion formed is deprotonated in basic solution and, hence, is not receptive to attack by the nucleophilic alcohol, phenol, or amine. The reactivity of the carboxylic acid derivative toward a particular nucleophile depends on a) the relative electron-donating or -withdrawing power of the substituents on the carbonyl group, and b) the relative ability of the -OR or -NR R" moiety to act as a leaving group. Thus, electronegative substituents accelerate hydrolysis, and esters are more readily hydrolyzed than amides. 

As we have indicated in Section 23-12, amide hydrolysis can be an important route to amines. Hydrolysis under acidic conditions requires strong acids such as sulfuric or hydrochloric, and temperatures of about 100° for several hours. The mechanism involves protonation of the amide on oxygen followed by attack of water on the carbonyl carbon. The tetrahedral intermediate formed dissociates ultimately to the carboxylic acid and the ammonium salt ... 

Another strategy for catalyzing the hydrolysis of an ester or an amide is to replace water by a stronger nucleophilic group that is part of the enzyme s active site. The HOCH2— group of a serine residue is often used in this way. In such cases, the reaction of the serine with the substrate splits the overall reaction into a two-step process. Instead of immediately yielding the free carboxylic acid, the breakdown of the initial tetrahedral intermediate yields an intermediate ester that is attached covalently to the enzyme. 

Theoretical studies have been reported for the neutral29 and alkaline30,31 hydrolysis of formamide. A theoretical study of the acid hydrolysis of iV-formylaziridine concluded that both N- and O-protonated pathways compete.32 In an historical overview of tetrahedral intermediates in the reactions of carboxylic acid derivatives with nucleophiles, several citations of amide reactions are included.33... 

Aspartic proteases are characterized by their ability to cleave peptidic substrates with the aid of two catalytically active aspartic acid residues [19]. A water molecule is activated by one Asp and attacks the scissile amide carbonyl. The other Asp donates a proton to the amide nitrogen, creating a hydrogen-bond stabilized tetrahedral intermediate, which subsequently collapses into the carboxylic acid and amine cleavage products [20,21],... 

Carboxylic amides, carboxylic esters, and carboxylic acids react with acid-stable heteroatom nucleophiles in a neutral solution much more slowly via the mechanism of Figure 6.2 than in an acidic solution via the mechanism of Figure 6.5. In an acidic solution, their car-boxonium ion derivatives, which result from the reversible protonation of the carboxyl oxygen, act as precursors of the tetrahedral intermediate. According to the discussion earlier in... 

The Weinreb amide syntheses in Figure 6.50 proceeding via the stable tetrahedral intermediates B and F are chemoselective SN reactions at the carboxyl carbon atom of carbon acid derivatives that are based on strategy 1 of the chemistry of carboxylic acid derivatives outlined in Figure 6.41. Strategy 2 of the chemistry of carboxylic acid derivatives in Figure 6.41 also has a counterpart in carbon acid derivatives, as is demonstrated by a chemoselective acylation of an organolithium compound with chloroformic acid methyl ester in this chapter s final example ... 

A complementary access to alkoxy- and aminocarbene complexes ( Semmelhack-Hegedus route ) involves the addition of the pentacarbonylchromate dianion 18 (obtained from the reduction of hexacarbonylchromium with C8K) to carboxylic acid chlorides and amides [27] (Scheme 10). While alkylation of acyl chromate 19 leads to alkoxycarbene complexes 12, addition of chromate dianion 18 to carboxylic amides generates the tetrahedral intermediates 20, which are deoxygenated by trimethylsilyl chloride to give amino carbene complexes 14. 

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. 

The basic hydrolysis mechanism (shown next for a primary amide) is similar to that for hydrolysis of an ester. Hydroxide attacks the carbonyl to give a tetrahedral intermediate. Expulsion of an amide ion gives a carboxylic acid, which is quickly deproto-nated to give the salt of the acid and ammonia. 

For alkyl amines, a direct correlation between the steric bulk at the a-carbon and the yield of the reaction was found amines attached to a secondary carbon gave higher yields than amines connected to a tertiary carbon, while amines connected to a quaternary carbon led only to the formation of an amide-carboxylic acid intermediate, rather than the corresponding imide. In the case of amino acids whose ot-carbons are tertiary, a lower temperature was surprisingly required for high NMI selectivity in the first step (40 °C instead of 75 °C). This was explained by the presence of the COOR group, which assists in the collapse of the tetrahedral intermediate precursor to the imide formation. The amino acid derived NMIs were obtained as a mixture of open and closed forms due to the addition of triethylamine in the reaction. At high temperatures this promotes the formation of... 

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