Rate determining step acetal hydrolysis

Hammett treatments show good correlations with large negative p values for the hydrolysis of acetals of aromatic aldehydes. This is consistent with the development of a positive charge at the carbonyl center in the rate-determining step. 

Enol ethers are readily hydrolyzed by acids the rate-determining step is protonation of the substrate. However, protonation does not take place at the oxygen but at the p carbon, because that gives rise to the stable carbocation 104. After that, the mechanism is similar to the A1 mechanism given above for the hydrolysis of acetals. 

Activation parameters that have been measured for Aal1 reactions are generally consistent with a unimolecular rate-determining step. The volume of activation for the hydrolysis of f-butyl acetate in 0.01 M HCI at 60°C is zero, within experimental error70. No significant change in rate is observed from atmospheric pressure up to 2 kbar, although this increase in pressure almost doubles the rate of hydrolysis of ethyl acetate in 0.1 M HCI at 35°C. 

Finally, an important study by Lane38 shows that the 180-excbange and hydrolysis reactions of ethyl acetate in aqueous sulphuric acid at 25°C depend in a closely similar way on the activity of water. Lane s plot of log kobsl [BH+] against logaH o has a slope of 2.07 for hydrolysis, while the similar plot of the data for 180-exchange has a slope of 1.84. Lane interprets this as evidence that two molecules of water are involved in the transition state for each reaction. Since the two reactions are similar in detail it seems more than ever likely that they involve a common rate-determining step. 

In 1954, B. S. Hartley and B. A. Kilby1 examined the reaction of substrate quantities of chymotrypsin with excess p-nitrophenyl acetate or p-riitrophenyl ethyl carbonate. They noted that the release of p-nitrophenol did not extrapolate back to zero but instead involved an initial burst, equal in magnitude to the concentration of the enzyme (Chapter 4, Figure 4.10). They postulated that initially the ester rapidly acylated the enzyme in a mole-to-mole ratio, and that the subsequent turnover of the substrate involved the relatively slow hydrolysis of the acylenzyme as the rate-determining step. This was later verified by the stopped-flow experiments described in section B2. 

Steps in the hydrolysis of p-nitrophenyl acetate by chymotrypsin. In the hydrolysis of this and most other esters, the breakdown of the acyl-enzyme intermediate is the rate-determining step. In the hydrolysis of peptides and amides, the rate-determining step usually is the formation of the acyl-enzyme intermediate. This makes the transient formation of the intermediate more difficult to study because the intermediate breaks down as rapidly as it forms. 

The fact that true general acid catalysis is correct for the slow step in Scheme 9 is established for the hydrolysis of benzylidene-f-butylamine (21) at pH 4 to 5, conditions sufficiently basic that hydration is still the rate-determining step, as shown in Scheme 9, but acidic enough that essentially all of the imine exists in the protonated form. Under these circumstances, the hydrolysis (reverse of Scheme 9) is subject to general base catalysis by acetate ion.97 This... 

The formation or the hydrolysis of an acetal function proceeds by the mechanism described in Fig. 16 in which oxonium ions and hemiacetals occur as intermediates. It has also been established (76) that the rate determining step in acetal hydrolysis is generally the cleavage of the C—bond of the protonated acetal 100 to form the oxonium ion 111, This ion is then rapidly hydrated to yield the protonated hemiacetal 112 which can give the aldehyde product after appropriate proton transfers. It is pertinent therefore to find out if stereoelectronic effects influence the rate determining step (110 111) of this hydrolysis reaction. 

In this problem we examine the rate of hydrolysis of acetals to the corresponding ketone or aldehyde. The rate-determining step is carbocation formation. 

Step (1) involves the formation of methyl iodide, which then reacts with the rhodium complex Rh(I)L by oxidative addition in a rate-determining step (2) to form a methylrhodium(III) complex. Carbon monoxide is incorporated into the coordination sphere in step (3) and via an insertion reaction a rhodium acyl complex is formed in step (4). The final step involves hydrolysis of the acyl complex to form acetic acid and regeneration of the original rhodium complex Rh(I)L and HI. Typical rhodium compounds which are active precursors for this reaction include RhCl3, Rh203, RhCl(CO)(PPh3)2, and Rh(CO)2Cl2. 

We considered the mechanism for this reaction in Chapter 14 but did not then concern ourselves with a label for the first step. It has, in fact, an S l style of rate-determining step the decomposition of the protonated acetal to give an oxonium ion. If you compare this step with the decomposition of the chloroether we have just described you will see that they are very similar, hydrolysis of acetals - SN1 mechanism for the first step... 

The rate of the reaction depends on the pH of the solution. If it is around or higher than the p.JCa of the thiol, thiolate anion will be formed and this opens the epoxide much faster than does the unionized thiol. The nucleophile is regenerated by the oxyanion produced in the rate-determining step. A more familiar example is the base-catalysed hydrolysis of esters we have mentioned several times in this chapter. The full pH-rate profile (Chapter 13) for the hydrolysis of a simple ester such as ethyl acetate shows just two straight lines meeting each other (and zero rate) at about neutrality. Ethyl acetate hydrolysis occurs by SAC or SBC only. 

As one can see from Table 1, the solvent shift determined for the first step of the hydrolysis of methyl acetate (the rate-determining step) by the SVPE calculations at the MP2/6-3H-G(d) level differs from the shift determined at the HF/6-31+G(d) level by less than 0.2 kcal/mol. The calculated energy barrier, 11.4 kcal/mol, is in good agreement with the experimental determinations of activation energy, 10.45 or 12.2 kcal/mol, reported for the hydrolysis of methyl acetate in aqueous solution [61,62]. 

The hydrolysis reactions of acetals, ketals, and orthoesters are catalyzed by acids but not by bases. It has been found that these three groups of substrates are hydrolyzed via a common general mechanism — involving similar types of intermediates — though the rate-determining step may vary from case to case. In the hydrolyses of ethyl orthoacetate, orthopropionate, and orthocarbonate, general acid catalysis was unambiguously established for the first time by Bronsted and Wynne-Jones [158]. 

As pointed out by Skrabal and Schiffrer [173], the rate-determining step must be in the transition from acetal to hemiacetal because the rate coefficient for the hydrolysis of methyl ethyl formal is equal to the mean value of those for the hydrolyses of dimethyl formal and diethyl formal. Wolf and Hero Id [174] supplied more direct evidence on this matter. They found that the UV absorption bands of aldehydes slowly decrease in alcoholic solutions. This indicates that a reaction takes place. The product of the reaction immediately splits off aldehyde under the conditions of a bisulfite titration, therefore it cannot be acetal and it must be hemiacetal. Acetals are much more stable, and they are not hydrolyzed in a bisulfite titration. A quantitative kinetic study of the reaction of aldehyde with alcohol was carried out by Lauder (175] with the aid of dilatometric and refractive index measurements. He observed that hemiacetal is formed in a relatively fast reaction which is followed by a slow reaction leading to acetal. 

The enzyme also has a histidine residue vital for catalysis. iJse your mechanism from the first part of the question to say how the histidine residue might help. The histidine residue Is known to help both the formation and the hydrolysis of the Intermediate. The enzyme hydrolyses both p-nitrophenyl acetate and p-nltrophenyl thiolacetate at the same rate. Which Is the rate-determining step ... 

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