Acetals nucleophilic catalysis

Mechanism I was ruled out by an isotopic labeling experiment. The mixed anhydride of salicylic acid and acetic acid is an intermediate if nucleophilic catalysis occurs by mechanism 1. This molecule is known to hydrolyze in water with about 25% incorporation of solvent water into the salicylic acid. 

Nucleophilic catalysis is catalysis by a general base (electron-pair donor) acting by donating its electron pair to an atom (usually carbon) other than hydrogen. Nucleophilic catalysis is exemplified by the imidazole-catalyzed hydrolysis of a phenyl acetate. (The tetrahedral intermediates are not shown.)... 

We should distinguish between the phrases nucleophilic attack and nucleophilic catalysis. Nucleophilic attack means the bond-forming approach by an electron pair of the nucleophile to an electron-deficient site on the substrate. In nucleophilic catalysis this results in an increase in the rate of reaction relative to the rate in the absence of the catalyst. However, nucleophilic attack may not result in catalysis. Thus, if methylamine is reacted with a phenyl acetate, the reaction observed is amide formation, not hydrolysis, because the product of the nucleophilic attack is more stable than is the ester to hydrolysis. 

These data are for the nucleophilic catalysis of the hydrolysis of p-nitrophenyl acetate by imidazoles and benzimidazoles at pH 8.0. Tbe apparent second-order catalytic rate constants are defined by... 

The reference intermolecular reaction is the nucleophilic attack of acetate on phenyl acetate, calculated by Page (1973) from the data of Gold et al. (1971) by extrapolation (from measurements on aryl acetates which show measurable nucleophilic catalysis). But see notes g and h... 

Anhydrides are somewhat more difficult to hydrolyze than acyl halides, but here too water is usually a strong enough nucleophile. The mechanism is usually tetrahedral. Only under acid catalysis does the SnI mechanism occur and seldom even then.s06 Anhydride hydrolysis can also be catalyzed by bases. Of course, OH- attacks more readily than water, but other bases can also catalyze the reaction. This phenomenon, called nucleophilic catalysis (p. 334). is actually the result of two successive tetrahedral mechanisms. For example, pyridine catalyzes the hydrolysis of acetic anhydride in this manner.507... 

Heterolytic scission of the -S-S- bond in which only electrophilic assistance is involved is the exception rather than the rule in reactions involving bond fission of this type. Kice et a/.165,166 have demonstrated that a variety of S-S bond cleavages involve concomitant electrophilic and nucleophilic catalysis including (a) the formation of aryl thiolsulfones from aryl thiolsulfinates and aryl sulfinic acids and (b) the hydrolysis (acetic acid—1% water and 60%... 

A similar result was obtained by Schowen and Behn280, for the methanolysis of p-nitrophenyl acetate in the presence of tritium-labelled acetate ion. In this case the intermediate anhydride is effectively symmetrical, and methanol will attack equally at the labelled and unlabelled acetyl group. As expected for nucleophilic catalysis, 50% (within experimental error) of the methyl acetate produced was labelled T3CCOOCH3. 

Acetate of pKa of phenol k0" (sec-1) k Acer (imole l sec- ) Fraction of nucleophilic catalysis... 

These results show that nucleophilic catalysis predominates when the leaving group is less basic than acetate, or of comparable basicity. Where the aryl-oxide is more than about 3 pK units more basic, however, the nucleophilic mechanism becomes insignificant. And for p-nitrophenyl acetate, which appears to lie close to the borderline, nucleophilic and general base catalysis proceed at comparable rates. 

If the substituted phenolate ion is less basic than acetate ion it will be lost preferentially from the tetrahedral intermediate, which will be rapidly converted to acetic anhydride. On the other hand, if the substituted phenolate ion is a much poorer leaving group than acetate, the tetrahedral intermediate will revert almost exclusively to products nucleophilic catalysis will then be small, and in particular smaller relative to any alternative mechanism of catalysis. 

These principles appear to hold for nucleophilic catalysis of hydrolysis by other species also. The evidence for catalysis by amino-compounds is discussed below. Catalysis by a wide variety of oxyanions (and other anions) has been measured by several authors, particularly of the hydrolysis of p-nitrophenyl acetate. This is a convenient substrate kinetically, since the release of / -nitrophenoxide is easily followed spectrophotometrically at 400 nm, but perhaps not ideal mechanistically, since, as described above, at least some of its reactions involve a mixture of mechanisms. A selection of data, obtained under the same conditions in one laboratory283, is given in Tables 37 and 38. Some of these data are plotted logarithmically (in Fig. 17) against the... 

Fig. 17. Bronsted plot for the reactions of nucleophiles with p-nitrophenyl acetate in water at 25°C. These reactions involve simple nucleophilic catalysis of hydrolysis. (Data from ref. 283).

Fig. 18. Bronsted plot for the reactions of nucleophiles with phenyl acetate (PA,D)p-nitrophenyl acetate (PNPA, A) and 2,4-dinitrophenylacetate (DNPA,0) at 25°C. The open symbols (and full lines) represent data for the total reaction, which is in most cases nucleophilic catalysis. The closed symbols (and broken lines) represent general base catalysis of hydrolysis.

The above types of catalysis function by stabilizing the transition state of the reaction without changing the mechanism. Catalysts may also involve a different reaction, pathway. A typical example is nucleophilic catalysis in an acyl transfer or hydrolytic reaction. The hydrolysis of acetic anhydride is greatly enhanced by pyridine because of the rapid formation of the highly reactive acetylpyridinium ion (equation 2.12). For nucleophilic catalysis to be efficient, the nucleophile... 

In 30 (R3 = Aik), given that there is possibility of a competing formation of a-naphthylamines 153, the application of acetic acid catalysis, in some cases, leads to an adverse effect by increasing the yields of carbocycli-zation products 153. Such a marked influence of acid catalysis may be explained by the greater susceptibility of a substituted imino group in the ring-opened intermediate 150 toward exhibiting basic, but not nucleophilic, properties, in comparison with ammonium intermediate 136 (Scheme 8). This may lead to the formation of more nucleophilic enamines... 

In general, mechanistic evidence for a reactive intermediate from trapping experiments needs to be linked to arguments against the introduction of an alternative pathway from the reactant, i.e. to show that an intermediate really has been trapped, not the reactant. A classic case is the hydrolysis of 4-nitrophenyl acetate catalysed by imidazole. The mechanism is nucleophile catalysis and the intermediate (N-acetylimidazolium cation) was trapped by aniline (to give acetanilide) with no kinetic effect, i.e. the aniline does not react directly with the substrate [51]. 

In Chapter 12 pyridine was often used as a catalyst in carbonyl substitution reactions. It can act in two ways. In making esters from acid chlorides or anhydrides pyridine can act as a nucleophile as well as a convenient solvent. It is a better nucleophile than the alcohol and this nucleophilic catalysis is discussed in Chapter 12 (p. 282). But nonnucleophilic bases also catalyse these reactions. For example, acetate ion catalyses ester formation from acetic anhydride and alcohols. 

Could this be nucleophilic catalysis too Acetate can certainly attack acetic anhydride, but the products are the same as the starting materials. This irrelevant nucleophilic behaviour of acetate ion cannot catalyse ester formation. 

In other cases, the concentrations of the intermediates are much smaller. The intermediate in the acetate ion catalyzed hydrolysis of phenyl acetates is acetic anhydride. It can be chemically trapped by addition of aniline to the reacting solution, for acetanilide is formed much faster than acetic acid even at low aniline concentrations [264]. Nucleophilic catalysis is highly effective in these examples because phenoxy, substituted phenoxy and ethylthio are very good leaving groups and the intermediates are more reactive with respect to hydrolysis than the substrates. 

In nucleophilic catalysis the catalytic properties are a result of the intermediate formation of a 1-acylimidazole (Scheme 27). When the ester has a good leaving group, e.g. p-nitrophenyl acetate, the effective catalyst is the imidazole neutral molecule which increases in effectiveness as the basic pKa of the heterocycle increases. Where, however, the ester has a poor leaving group, e.g. p-cresol acetate, the imidazole anion becomes involved and general base catalysis predominates. Thus, for imidazoles with pjK"a 4 catalysis by the anion is the main reaction. Imidazole is a much more effective nucleophile than other amines in this type of reaction since it is a tertiary amine with little steric hindrance, and it is able to delocalize the positive charge which results from the nucleophilic addition to... 

Relative reactivity of hindered and unhindered bases k(hindered)/ kfunhindered) same order for bases of same >Ka if general base catalysis, but this ratio very small for nucleophilic catalysis 2,6-Lutidine is much less effective than pyridine in catalysis of acetic anhydride hydrolysis 91... 

Relative reactivity of imidazole and monohydrogen phosphate tfimidazolel/iKHPOj") is order of unity for general base catalysis, but about 10 for nucleophilic catalysis This ratio is 0,25 for ethyl acetate hydrolysis and 4.7 x I0 for p-nitrophenyl acetate hydrolysis 92... 

First-order and second-order rate constants have different dimensions and cannot be directly compared, so the following interpretation is made. The ratio ki k,ma has the units mole per liter and is the molar concentration of reagent Y in Eq. (7-72) that would be required for the intermolecular reaction to proceed (under pseudo-first-order conditions) as fast as the intramolecular reaction. This ratio is called the effective molarity EM), thus EM = kimnJk,Ma- An example is the nucleophilic catalysis of phenyl acetate hydrolysis by tertiary amines, which has been studied as both an intermolecular and an intramolecular process. ... 

---