Amide Hydrolysis in Basic Solution

Step 1 Nucleophilic addition of hydroxide ion to the carbonyl group 

Step 2 Proton transfer to anionic form of tetrahedral intermediate 

Step 3 Protonation of amino nitrogen of tetrahedral intermediate 

Step 4 Dissociation of A -protonated form of tetrahedral intermediate 

On the basis of the general mechanism for basic hydrolysis shown in Mechanism 19.7, 

Step 2 Proton transfer to the anionic form of the tetrahedral intermediate HQ pr- HQ Q-H 

Chapter 19 Carboxylic Acid Derivatives Nucleophilic Acyl Substitution 

On the basis of the general mechanism for basic hydrolysis shown in Mechanism 19.5, write an analc ous sequence for the hydrolysis of A/,A/-dimethylformamide, HCN(CH3)2. 

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FIGURE 20 8 The mecha nism of amide hydrolysis in basic solution... 

Fluorophenyl esters react with amine-containing molecules at slightly alkaline pH values to give the same amide bond linkages as NHS esters (Reaction 15). However, in most cases, the fluorophenyl ester compound will display better stability toward hydrolysis in aqueous solution. It has been reported that a TFP ester has over twice the half-life in basic pH buffers (pH 8) than a corresponding NHS ester on the same compound (Molecular Probes). 

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. 

Copper(JI) has been found to inhibit the hydrolysis of glycylglycine in basic solution (pH> 11).127 Conley and Martin128 have also found that, at pH values in excess of 11, copper(II) inhibits the hydrolysis of glycinamide due to amide hydrogen ionization. Similar results were obtained with picolinamide, and a bis-picolinamide complex of nickel(II) containing deprotonated amide groups was isolated.128... 

Amino acid esters, amides, and peptides can be hydrolyzed in basic solution, and metal ions (Cu(II), Co(II), Ni(II), Mn(II), Ca(II), and Mg(II), and others) speed these reactions. The uncertain mechanism is either through bidentate coordination of the a-amino group and the carbonyl, or only through the amine. The rates of these reactions often exhibit complicated temperature dependence and deduction of the mechanism is difficult. Co(III) complexes promote similar reactions. When four of the six octahedral positions are occupied by amine ligands, and two cis positions are available for ligand substitution, these hydrolysis reactions can be examined in detail. These compounds generally catalyze the hydrolysis of N-terminal amino acids from peptides the amino acid that is removed remains bound to the metal. The reactions apparently proceed by coordination of the free amine to cobalt, followed either by coordination of the carbonyl to cobalt and snbseqnent reaction with OFI or H2O (path 1 in Figure 12.16) or reaction of the carbonyl... 

The first four steps of the mechanism for hydrolysis of nitriles in basic solution are given in Mechanism 19.8. These steps convert the nitrile to an amide, which then proceeds to the hydrolysis products according to the mechanism of amide hydrolysis in Mechanism 19.7 (page 846). 

Esters are less reactive than acid chlorides and anhydrides in addition reactions, but more reactive than amides. Esters can be converted into their parent carboxylic acids under either basic or acidic aqueous conditions in a process called, logically enough, ester hydrolysis. In base, the mechanism is the familiar addition-elimination one (Fig. 18.31). Hydroxide ion attacks the carbonyl group to form a tetrahedral intermediate. Loss of alkoxide then gives the acid, which is rapidly deproto-nated to the carboxylate anion in basic solution. Notice that this reaction, saponification (p. 862), is not catalytic. The hydroxide ion used up in the reaction is not regenerated at the end. To get the carboxylic acid itself, a final acidification step is necessary. 

If only one mole of acetic anhydride is available, we need to consider which is the best available nucleophile, and an amino group beats hydroxy, because nitrogen is less electronegative and more willing to share its electrons. In considering the hydrolysis, the ester is more electrophilic than the amide, so more easily attacked. Also, particularly in basic solution, the [NHJ is a very poor leaving group. 

The difficulty of hydrolyzing amides in basic solution allows for some selectivity in the hydrolysis of nitriles (Figure 15.19). In neutral or weakly basic solutions, the amide is isolated, but under more forcing, and acidic, conditions, the carboxylic acid is obtained (Figure 15.20). Some examples of nitrile hydrolysis in synthesis are shown in Figure 15.21. In the first example, both the ester and the nitrile are hydrolyzed. In the second example, the reaction can be stopped at the amide stage. 

The hydrolytic stability of water soluble poly[N-(4-sulfo-phenyDdimethacrylamide] (PSPDM) was studied at 90 C in aqueous solutions at pH 7, pH 1.2 (0.1M HC1), and pH 12.3 (0.1M NaOH). PSPDM, which possesses predominantly 5-mem-bered ring imides, was prepared by the cyclopolymerization and subsequent sulfonation of N-phenyldimethacrylamide. No detectable PSPDM imide hydrolysis occurred after 30 days at pH 7 or pH 1.2. Under basic conditions, however, complete hydrolysis to amic acid occurred after one day. The resulting Nsubstituted amide was extremely stable to further basic hydrolysis. 

Acrylamide polymers in aqueous solution undergo thermal hydrolysis and cyclic imide formation. Acrylate, acrylamide and cyclic imide functional groups were detected when a poly(acrylamide) is heated at 150°C in water. The formation of intramolecular imide has been reported in literature. Moradi-Araghi, Hsieh and Westerman reported the formation of cyclic imide in acid, neutral and slightly basic media at 90° C.7 In acidic media, imide formation is favored. In neutral and basic media, both hydrolysis to acrylate and imide formation do occur, but hydrolysis is the dominant reaction. We speculate the high conversion of amine to amide is the result of transamidation, amidation and the nucleophilic addition of the amine to the glutarimide intermediate (Reaction 1). 

These can be explained if they involve a third reaction of the protonated ester, i.e. with a molecule or molecules of water, a reaction not, of course, observed in media such as SbF5-FS03H. The activity of water falls rather sharply as the sulphuric acid concentration increases from 60-100%, and we know that most esters become essentially completely protonated in this region. Thus the situation can arise where the increase in the concentration of protonated ester produced by a given increase in acid concentration is proportionately smaller than the concomitant decrease in the activity of water, so that bimolecular (or higher molecularity) hydrolysis goes more slowly as the acidity is increased. Similar behaviour is observed when amides are hydrolyzed in strong acid solutions, but the rate maximum occurs at lower acid concentration, since amides are more basic than esters, and protonation is complete in solutions of lower acidity. 

Generally, amides can be hydrolyzed in either acidic or basic solution. The mechanisms are much like those of ester hydrolysis (Section 18-7A), but the reactions are very much slower, a property of great biological importance (which we will discuss later) ... 

Other API amide hydrolysis examples include chloramphenicol (12), indomethacin under alkaline conditions (13), lidocaine (14), azintamide (15), terazosin (16), flutamide (17), oxazepam, and chlordiazepoxide (18). Lidocaine does not readily hydrolyze in aqueous solution under thermal or basic conditions (Fig. 7) (19). The enhanced stability is due to the steric hindrance of the two o-methyl groups. Hydrolysis does occur more readily in acidic conditions rather than basic conditions presumably because the rate-limiting step, protonation of the carbonyl, is not affected by the steric hindrance of the o-methyl. 

Esters and amides, on the other hand, require the presence of an acid or base catalysis to react with water. These reactions are not instantaneous but require rather strongly acidic or basic conditions and heat to proceed at a reasonable rate. For example, a typical ester saponification is usually conducted with 10% NaOH in water, and the solution is refluxed until the ester layer disappears. (Most esters are not soluble in water.) This may require from 15 minutes up to several hours of reflux. Similarly, a typical amide hydrolysis is often conducted by refluxing the amide in concentrated hydrochloric acid for a period ranging from 15 minutes up to several hours. Esters and amides are relatively stable to the near-neutral conditions found in living organisms, which is one reason why they are important functional groups in biochemistry. 

Other functional groups attached to the cyclopropane can also react when acidic and basic conditions are utilized to obtain cyclopropylamines from the corresponding amides and carbamates. In aqueous solution additional ester and nitrile functions undergo simultaneous hydrolysis thus, the product afforded will be an aminocyclopropanecarboxylic... 

Interestingly, the cyclic ester (73) does not rearrange. A comparison of the hydrolytic behaviour of the esters (74) and (75) has shown that the presence of the triple bond generally increases the rate of hydrolysis under basic conditions. The hydrolysis of the fluorides R R P(0)F (R and R are alkyl or alkoxy) has been examined for both alkaline and neutral aqueous solutions. For the amides Ph2P(0)X (X = NMe2 or NHC6H4NO2-4), the increase in the rate of acid-catalysed hydrolysis in acetonitrile with decreasing concentration of water has been ascribed partly to an increase in the basicity of the substrate under the same conditions. ... 

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