Base hydrolysis of amides

Base hydrolysis of amides also requires quite vigorous conditions, but mechanistically it is exactly equivalent to base hydrolysis of esters. After nucleophilic attack of hydroxide on to the carbonyl, the tetrahedral anionic intermediate is able to lose either an amide anion (care with nomenclature here, the amide anion is quite different from the amide molecule) or hydroxide. Although loss of hydroxide is preferred, since the amide anion is a stronger base than hydroxide, this would merely reverse the reaction. 

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... 

Nitriles are classified as carboxylic acid derivafives because fhey are convened fo car boxylic acids on hydrolysis The condifions required are similar fo fhose for fhe hydrol ysis of amides namely healing m aqueous acid or base for several hours Like fhe hydrolysis of amides nilrile hydrolysis is irreversible m fhe presence of acids or bases Acid hydrolysis yields ammonium ion and a carboxylic acid... 

Nitriles are classified as carboxylic acid derivatives because they are converted to carboxylic acids on hydrolysis. The conditions required are similar- to those for the hydrolysis of amides, namely, heating in aqueous acid or base for several hours. Like the hydrolysis of amides, nitrile hydrolysis is ineversible in the presence of acids or bases. Acid hydrolysis yields fflnmonium ion and a carboxylic acid. 

Hydrolysis of amide groups to carboxylate is a major cause of instability in acrylamide-based polymers, especially at alkaline pH and high temperatures. The performance of oil-recovery polymers may be adversely affected by excessive hydrolysis, which can promote precipitation from sea water solution. This work has studied the effects of the sodium salts of acrylic acid and AMPS, 2-acrylamido-2-methylpropanesulfonic acid, as comonomers, on the rate of hydrolysis of polyacrylamides in alkaline solution at high temperatures. Copolymers were prepared containing from 0-53 mole % of the anionic comonomers, and hydrolyzed in aqueous solution at pH 8.5 at 90°C, 108°C and 120°C. The extent of hydrolysis was measured by a conductometric method, analyzing for the total carboxylate content. 

In an approach toward the tetraponerine family of alkaloids, Piehiers and co-workers utilized base hydrolysis of the ester 90 followed by acid-catalyzed decarboxylation to obtain the corresponding amide 91 in good yield (Equation 19) <2000CJC1030>. 

Spontaneous and metal-ion catalyzed base hydrolysis of esters, amides, etc. ... 

Table 6w4 Effect of Cobalt(lll) Coordination on Rate Constants for Base Hydrolysis of Amino Acid Amides...

Considerable attention has been paid to this transformation (which is sometimes referred to as hydration ) in the past 15 years. 2. early example of the effect was the marked acceleration of the base hydrolysis of 2-cyanophenanthroline by Ni +, Cu + and Zn " " ions. The second-order rate constant is lO -fold higher for the Ni complex than for the free ligand, residing mainly in a more positive AS An external OH attack on the chelate was favored but an internal attack by Ni(II) coordinated OH cannot be ruled out. Nickel-ion catalysis of the hydrolysis of the phenanthroline-2-amide product is much less effective, being only about 4 x 10 times the rate for spontaneous hydrolysis. ... 

The reaction progresses because the amide anion, once a small amount is released, abstracts a proton from the carboxylic acid product. Again, we have an analogy with the last step in the base hydrolysis of esters, and the ionization becomes an essentially... 

Base hydrolysis of secondary and tertiary amides is less readily achieved than with primary amides, and may require stronger basic conditions. 

Proteins are fundamentally polymers of a-amino acids linked by amide linkages (see Section 13.1). It is a pity that biochemists refer to these amide linkages as peptide bonds remember, a peptide is a small protein (less than about 40 amino acid residues), whereas a peptide bond is an amide. Therefore, peptides and proteins may be hydrolysed to their constituent amino acids by either acid or base hydrolysis. The amide bond is quite resistant to hydrolytic conditions (see above), an important feature for natural proteins. 

An additional disadvantage with many penicillin and cephalosporin antibiotics is that bacteria have developed resistance to the drugs by producing enzymes capable of hydrolysing the P-lactam ring these enzymes are called P-lactamases. This type of resistance still poses serious problems. Indeed, methicillin is no longer used, and antibiotic-resistant strains of the most common infective bacterium Staphylococcus aureus are commonly referred to as MRSA (methicillin-resistant Staphylococcus aureus). The action of P-lactamase enzymes resembles simple base hydrolysis of an amide. 

The sequence is completed by base hydrolysis of the amide and removal of the protecting group. This is much the same as an ester hydrolysis, and needs to include as last stage the ionisation of acetic acid since RNH is a poor leaving group, it is this ionisation that allows the reaction to proceed. 

Acid hydrolysis of an amide yields a carboxylic acid and an ammonium ion. The mechanism for acid hydrolysis is shown in Figure 12-36. Base hydrolysis of an amide, on the other hand, yields ammonia and a carboxylate ion. You can see this mechanism in Figure 12-37. To identify similarities, compare these mechanisms to the mechanisms for the hydrolysis of esters (refer to Figures 12-34 and 12-35). 

Amides. Although similar to esters in terms of being a functional derivative of a carboxylic acid, amides, unlike esters, are relatively metabolically stable. In general, amides are stable to acid- and base-catalyzed hydrolysis. This stability is related to the overlapping electron clouds within the amide functionality and the corresponding multiple resonance forms. Amidases are enzymes that can catalyze the hydrolysis of amides. Nevertheless, amides are much more stable than esters. 

Base-catalysed hydrolysis. The hydroxide ion attacks the nitrile carhon, followed hy protonation on the unstable nitrogen anion to generate an imidic acid. The imidic acid tautomerizes to the more stable amide via deprotonation on oxygen and protonation on nitrogen. The base-catalysed amide is converted to carboxylic acid in several steps as discussed earlier for the hydrolysis of amides. 

Simpler evidence for the presence of a tetrahedral intermediate is adduced from a study of the kinetics of alkaline hydrolysis of amides such an anilides26-28, chloroacetamide30, N,N-diacylamines31, and urea32. The rate equations for these reactions contain both first- and second-order terms in hydroxide ion. A reasonable explanation is that the hydrolysis mechanism involves a tetrahedral intermediate, rather than that the second-order term is due to base catalysis of the addition of the hydroxide ion to the carbonyl group. Such a mechanism is... 

The currently accepted mechanism for the hydrolysis of amides and esters catalyzed by the archetypal serine protease chymotrypsin involves the initial formation of a Michaelis complex followed by the acylation of Ser-195 to give an acylenzyme (Chapter 1) (equation 7.1). Much of the kinetic work with the enzyme has been directed toward detecting the acylenzyme. This work can be used to illustrate the available methods that are based on pre-steady state and steady state kinetics. The acylenzyme accumulates in the hydrolysis of activated or specific ester substrates (k2 > k3), so that the detection is relatively straightforward. Accumulation does not occur with the physiologically relevant peptides (k2 < k3), and detection is difficult. 

The palladium(II)-promoted hydrolysis of methyl glycylglycinate and isopropyl glycylglycinate has been investigated over a temperature range.80 Complexes of type (22) are formed in which the amino, deprotonated amide and alkoxycarbonyl groups act as donors. Hydrolysis by both H20 and OH ion is observed. Base hydrolysis of the coordinated peptide esters is ca. 105-fold faster than the unprotonated peptide esters. 

Table 16 Rate Constants for the Base Hydrolysis of Ester, Amide and Peptide Bonds in Various Cobalt(III) Complexes (25 °C, / = 1.0 M)a...

Scheme 8 Base hydrolysis of carbonyl-bonded amides and peptides...

Amides undergo an acid- or base-catalyzed hydrolysis reaction with water in the same way that esters do. Just as an ester yields a carboxylic acid and an alcohol, an amide yields a carboxylic acid and an amine (or ammonia). The net effect is a substitution of -N by -OH. This hydrolysis of amides is the key process that occurs in the stomach during digestion of proteins. 

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