Hydrolysis carboxylic effects

The use of a lipophilic zinc(II) macrocycle complex, 1-hexadecyl-1,4,7,10-tetraazacyclododecane, to catalyze hydrolysis of lipophilic esters, both phosphate and carboxy (425), links this Section to the previous Section. Here, and in studies of the catalysis of hydrolysis of 4-nitrophenyl acetate by the Zn2+ and Co2+ complexes of tris(4,5-di-n-propyl-2 -imidazolyl)phosphine (426) and of a phosphate triester, a phos-phonate diester, and O-isopropyl methylfluorophosphonate (Sarin) by [Cu(A(A(A/,-trimethyl-A/,-tetradecylethylenediamine)l (427), various micellar effects have been brought into play. Catalysis of carboxylic ester hydrolysis is more effectively catalyzed by A"-methylimidazole-functionalized gold nanoparticles than by micellar catalysis (428). Other reports on mechanisms of metal-assisted carboxy ester hydrolyses deal with copper(II) (429), zinc(II) (430,431), and palladium(II) (432). 

A vigorous Claisen condensation ensues when a homophthalic ester and methyl formate are treated with sodium ethoxide and the active methylene group is formylated. Cyclization takes place with ease in acidic media to produce a methyl isocoumarin-4-carboxylate (50JCS3375). Hydrolysis under acid conditions is sometimes accompanied by polymerization, but the use of boron trifluoride in acetic acid overcomes this problem. Decarboxylation may be effected in the conventional manner with copper bronze, though it sometimes accompanies the hydrolysis. 

Because of the relative simplicity of carboxylic ester hydrolysis, in general, and that of base catalyzed ester hydrolysis, in particular, these reactions have served well as model systems in investigations of micellar effects on reaction rates and activation parameters. In addition, the prevalence in biological systems of carboxylic ester hydrolyses catalyzed by nucleophiles and by enzymes renders the investigation of micelle-catalyzed ester hydrolyses of obvious importance. 

The neutral or uncatalyzed hydrolysis of carboxylic acid derivatives has two very interesting characteristics (1) large negative entropies of activation, and (2) fairly substantial solvent isotope effects. Hydrolysis of carboxylic ester derivatives then must be quite different at the molecular level from hydrolysis of saturated carbon derivatives which... 

An obvious starting point was to look for general acid catalysis of the attack of nucleophiles on a methyoxymethyl acetal known to be subject to efficient carboxyl-catalyzed hydrolysis. Participation by nucleophiles other than water in the hydrolysis of the salicylic acid derivative 3.17 could not be convincingly distinguished from specific salt effects (the range of nucleophiles is limited by the requirement that the COOH group (pKa 3.77) be protonated) [49]. On the other hand there is clear involvement of nucleophiles, including carboxylate anions, in the reaction of the dimethylammonium system 3.18 [44] (Scheme 2.24). The difference is presumably simply quantitative. 

HCl or 0.25 M acetic acid are sufficient to effect hydrolysis of the peptide bonds on both sides of aspartyl residues. For instance the hexapeptide Val-Leu-Gly-Asp-Phe-Pro yields the tripeptide Val-Leu-Gly, the dipeptide Phe-Pro and free aspartic acid. Release of aspartic acid is usually complete after a day of hydrolysis at 100 °C in 0.25 M AcOH while hydrolytic fission of other peptide bonds is negligible. Asparagine creates a notable exception because the carboxamide group in its side chain is fairly sensitive to acid catalyzed hydrolysis and the free carboxyl group of the gradually formed aspartyl residue provides the neighboring group effect which leads to the excision of aspartic acid from the chain. 

Esters can be hydrolyzed in either basic or acidic solution. In acidic solution, the reaction is reversible, and the position of equilibrium depends on the relative concentrations of water and the alcohol. In aqueous solution, hydrolysis occurs in alcoholic solution, the equilibrium is shifted in favor of the ester by the mass law effect. Hydrolysis in aqueous alkaline solution is essentially irreversible. The reverse of the final proton transfer is extremely unfavorable because the carboxylate anion is a much weaker base than the alkoxide ion, and the equilibrium is far to the right. The... 

Most transition states involve charged intermediates, which are stabilized within the active site of an enzyme via ionic bonds in pockets or holes bearing a matching opposite charge. Such charges are derived from acidic or basic amino acid side chains (such as Lys, Arg, Asp, or Glu) ° or are provided by (Lewis acid-type) metal ions, typically Zn +. Computer simulations studies suggested that in enzymes electrostatic effects provide the largest contribution to catalysis [107]. As a prominent example, the tetrahedral intermediate of carboxyl ester hydrolysis is stabilized in serine hydrolases by the so-called oxyanion hole (Scheme 2.1). 

Complexatlon with Ni to form 17 gives a 56x increase in the ester-hydrolysis rate, while ionization of the sallcyl carboxyl produces a further 1.7x increase, leading to the postulate of biTfunctlonal (carboxylate-metal Ion) catalysis. The carboxylate effect is in the wrong direction for... 

These substances, as well as the parent compound, are p-keto esters and undergo hydrol3rtio cleavage in two directions. One type of cleavage, ketonlc hydrolysis, is effected by the action of dilute caustic alkali in the cold, followed by acidification and boiling the free acetoacetic acid produced has a carboxyl and carbonyl group on the same carbon atom and therefore readily undergoes decarboxylation to yield a ketone, for example ... 

Inspired by the many hydrolytically-active metallo enzymes encountered in nature, extensive studies have been performed on so-called metallo micelles. These investigations usually focus on mixed micelles of a common surfactant together with a special chelating surfactant that exhibits a high affinity for transition-metal ions. These aggregates can have remarkable catalytic effects on the hydrolysis of activated carboxylic acid esters, phosphate esters and amides. In these reactions the exact role of the metal ion is not clear and may vary from one system to another. However, there are strong indications that the major function of the metal ion is the coordination of hydroxide anion in the Stem region of the micelle where it is in the proximity of the micelle-bound substrate. The first report of catalysis of a hydrolysis reaction by me tall omi cell es stems from 1978. In the years that... 

Figure 4.10 is plot of the Bronsted relationship for hydrolysis of an enol ether. The plot shows that the effectiveness of the various carboxylic acids as catalysts is related to their dissociation constants. In this particular case, the constant a is 0.79 ... 

Methyl 2,7- and 3,6-dimethyl-l//-azepine-1-carboxylate also show marked differences towards acid hydrolysis. The 3,6-dimethyl isomer, with 10% sulfuric acid at 20°C, forms the expected A,-(ethoxycarbonyl)-2,5-dimethylaniline in high yield (82%) however, the 2,7-dimethyl isomer requires more forcing conditions to effect ring contraction and yields a mixture of A-(methoxycarbonyl)-2,6-dimethylaniline (16% mp 103-105°C), A-(methoxycarbonyl)-2,3-dimethylaniline (1% mp 90-92°C), 2,6-dimethylphenol (1%), and 3,4-dimethylphenol (6% mp 66-67 C).115 A mechanistic rationale for these results has been proposed. 

Hydrolysis of dimethyl 3-methyl-3//-3-benzazepine-2,4-dicarboxyiate (3) with 50% sulfuric acid, or with 20% hydrochloric acid, effects loss of the nitrogen function and formation of the indane-2-carboxylic acid 4.25... 

Aspaityl proteinases are proteinases that utilize the terminal carboxyl moiety of the side chain of aspartic acid to effect peptide bond hydrolysis. 

Taft, following Ingold," assumed that for the hydrolysis of carboxylic esters, steric, and resonance effects will be the same whether the hydrolysis is catalyzed by acid or base (see the discussion of ester-hydrolysis mechanisms. Reaction 10-10). Rate differences would therefore be caused only by the field effects of R and R in RCOOR. This is presumably a good system to use for this purpose because the transition state for acid-catalyzed hydrolysis (7) has a greater positive charge (and is hence destabilized by —I and stabilized by +1 substituents) than the starting ester. 

Huffman, K. R., and Casey, D. J., Effect of Carboxylic end groups on hydrolysis of polyglycolic acid, J. Polym. Sci. 

Buchwald P. Structure-metabolism relationships steric effects and the enzymatic hydrolysis of carboxylic esters. Mini Rev Med Chem 2001 1 101-11. 

Attention has been drawn to the potential of phosphoric acid anhydrides of nucleoside 5 -carboxylic acids (14) as specific reagents for investigating the binding sites of enzymes. For example, (14 B = adenosine) inactivates adenylosuccinate lyase from E. coli almost completely, but has little effect on rabbit muscle AMP deaminase. The rate of hydrolysis of (14) is considerably faster than that of acetyl phosphate, suggesting intramolecular assistance by the 3 -hydroxyl group or the 3-nitrogen atom. 

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