Hydrolysis, of esters, amides, and peptides

Amino acid esters, amides, and peptides can be hydrolyzed in basic solution, and the addition of many different metal ions speeds the reactions. Labile complexes of Cu(II), Co(ll), Ni(II), Mn(II), Ca(II), and Mg(II), as well as other metal ions, promote the reactions. Whether the mechanism is through bidentate coordination of the a-amino group and the carbonyl, or only through the amine, is uncertain, but seems to depend on the 

Other compounds such as phosphate esters, pyrophosphates, and amides of phosphoric acid, are hydrolyzed in similar reactions. Coordination may be through only one oxygen of these phosphate compounds, but the overall effect is similar. 

Ligand Reactivity and Catalysis, Academic Press, New York, 1968. Chapter III summarizes the arguments and mechanisms.. 

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Coordinated a-amino amides can be formed by the nucleophilic addition of amines to coordinated a-amino esters (see Chapter 7.4). This reaction forms the basis of attempts to use suitable metal coordination to promote peptide synthesis. Again, studies have been carried out using coordination of several metals and an interesting early example is amide formation on an amino acid imine complex of magnesium (equation 75).355 However, cobalt(III) complexes, because of their high kinetic stability, have received most serious investigation. These studies have been closely associated with those previously described for the hydrolysis of esters, amides and peptides. Whereas hydrolysis is observed when reactions are carried out in water, reactions in dimethyl-formamide or dimethyl sulfoxide result in peptide bond formation. These comparative results are illustrated in Scheme 91.356-358 The key intermediate (126) has also been reacted with dipeptide... 

The use of kinetically inert cobalt(III) complexes has led to important developments in our understanding of the metal ion-promoted hydrolysis of esters, amides and peptides. These complexes have been particularly useful in helping to define the mechanistic pathways available in reactions of this type. Work in this area has been the subject of a number of reviews.21-24 Although most of the initial work was connected with cobalt(III), investigations are now being extended to other kinetically inert metal centres such as Rhin, lrni and Ru111. 

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...

The use of kinetically inert cobalt(lll) complexes has led to very significant developments in our understanding of metal-ion-promoted hydrolysis of esters amides and peptides. Extensive reviews on the topic are available [1,2,24-26]. 

Table 7.6 Rate constants for the base hydrolysis of ester, amide and peptide bonds in various cobalt(III) complexes (25°C, 1 = 1.0 M)...

A bigger effect for H2O than OH is very unusual and is a behavior certainly not shown by the uncoordinated amide. The effect is ascribed to a benefit from cyclization and concerted loss of protonated amide, without formation of the tetrahedral intermediate. Although the coordinated OH is some 10 times less effective than coordinated HjO (Table 6.4), it is still about 10 times faster with 15 than via external attack by OH at pH 7 on the chelated amide 13. Early studies showed that complexes of the type CoN4(H20)OH can promote the hydrolysis of esters, amides and dipeptides and that this probably arises via formation of ester, amide or peptide chelates. These then hydrolyze in the manner above. 

THE HYDROLYSIS OF AMINO ACID ESTERS, AMIDES AND PEPTIDES 414... 

In addition to the large volume of literature dealing with the metal ion-promoted hydrolysis of a-amino acid esters, amides and peptides a considerable amount of work has been reported on other esters and amides. These developments are considered in the present section. 

Bromelain Hydrolysis of polypeptides, amides, and esters (especially at bonds involving basic amino acids, leucine, or glycine), yielding peptides of lower molecular weight. 

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... 

Digestion (Section 29.1) The first stage of catabolism, in which food is broken down by hydrolysis of ester, glycoside (acetal), and peptide (amide) bonds to yield fatty acids, simple sugars, and amino acids. 

The amide and peptide linkages are much more difficult to hydrolyze than the ester grouping. Both free and metal bound groups hydrolyze with second-order rate constants approximately 10 -10 less than for the corresponding esters. There are two potential sites for coordination in the -CONHR residue, namely at the carbonyl O in 13 and at the amide N in 14 where ionization of the amide proton is induced (Sec. 6.4.3). Cu + promotes hydrolysis of glycinamide at low pH where it is present as 13. However it inhibits hydrolysis at high pH, where it is 14, to such a degree that hydrolysis cannot be observed. ... 

Formation of an amide bond (peptide bond) will take place if an amine and not an alcohol attacks the acyl enzyme. If an amino acid (acid protected) is used, reactions can be continued to form oligo peptides. If an ester is used the process will be a kinetically controlled aminolysis. If an amino acid (amino protected) is used it will be reversed hydrolysis and if it is a protected amide or peptide it will be transpeptidation. Both of the latter methods are thermodynamically controlled. However, synthesis of peptides using biocatalytic methods (esterase, lipase or protease) is only of limited importance for two reasons. Synthesis by either of the above mentioned biocatalytic methods will take place in low water media and low solubility of peptides with more than 2-3 amino acids limits their value. Secondly, there are well developed non-biocatalytic methods for peptide synthesis. For small quantities the automated Merrifield method works well. 

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. 

Co(trien)(NH3)2] + has been isolated, and only the meso trans isomers (197-198) with two different axial ligands, remain to be distinguished. There is also an extensive chemistry of N and C-alkylated derivatives of (178 180) as cA-[Co(OH)(trien)(OH2)] assists the hydrolysis of amino acid esters, amino acid amides, and peptides to form cis-fi (194) and cA-jS2-[Co(OA0(trien)] + (195)(( A = amino acid) complexes. Chiral alkylated trien ligands have the potential for chiral stereospecificity in such reactions. 

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