Nucleophilic catalysis anhydrides

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. 

A.1 Equilibrium data for anhydride formation 225, A.2 Intramolecular nucleophilic catalysis of ester hydrolysis 226, A.3 Intramolecular nucleophilic catalysis of amide... 

The second relevant set of data is for the formation of the anhydride from substituted succinic acid derivatives. Equilibrium constants for the formation of the anhydride from the acid are available for the various methyl-substituted compounds (Table A.l) and the derived EM s are compared in Table 5 with those for intramolecular nucleophilic catalysis in the hydrolysis of half-esters... 

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... 

If the anhydride derived from R"COOH is more reactive than the original anhydride, catalysis of hydrolysis is observed. If it is less reactive, hydrolysis is inhibited. The first case amounts to nucleophilic catalysis of hydrolysis. 

If the anhydride formed is more reactive than the ester, as is generally the case, nucleophilic catalysis of hydrolysis should result. There is ample evidence supporting this mechanism. 

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. 

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. 

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 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. 

An example of intramolecular nucleophilic catalysis is the hydrolysis of aspirin in nearly neutral aqueous solution. The carboxylate group in ortho position attacks the carbonyl carbon of the CH3COO— group to form an anhydride-type intermediate [280]. 

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... 

This chapter presented the current stage of development in the desymmetrization of mt >o-com pounds and (dynamic) kinetic resolution of racemic compounds in which cinchona alkaloids or their derivatives are used as organocatalysts. As shown in many of the examples discussed above, cinchona alkaloids and their derivatives effectively promote these reactions by either a monofunctional base (or nucleophile) catalysis or a bifunctional activation mechanism. Especially, the cinchona-catalyzed alcoholytic desymmetrization of cyclic anhydrides has already reached the level of large-scale synthetic practicability and, thus, has already been successfully applied to the synthesis of key intermediates for a variety of industrially interesting biologically active compounds. However, for other reactions, there is still room for improvement... 

The acylation of alcohols by anhydrides, catalyzed by 4-(dimethylamino)pyridine (DMAP), is one of the most frequently described in the literature examples of nucleophilic catalysis (Figure 5.6). 

According to Menger a simple nucleophilic catalysis is considered to occur in methanolysis of tetrachlorophthalic anhydride ia the presence of pyridine, and charge-transfer complex formation has been confirmed neither by kinetic studies nor by spectrometry. Also, the conductivity of a binary solution anhydride-tertiary amine is much lower than that of the ternary system containing an epoxide and does not change with time. Antoon and Koenig also reject the formation of zwitterions. Hence, the first modification of Fischer s mechanism performed by Tanaka and Kakiuchi is not appropriate, which was later admitted by the authors The formation of ionic species probably proceeds by the anionic mechanism... 

In the preceding examples, the asymmetric catalyst is a Lewis acid and hence the catalytic processes reported so far involve electrophilic activation by a metal-centred chiral Lewis acid. There is another strategy, although less explored, which consists of designing chiral Lewis bases for nucleophilic catalysis. It is well known that Lewis bases such as nitrogen heterocycles and tertiary phosphines and amines catalyse a variety of important chemical processes. For instance 4-(dimethylamino)pyridine (DMAP) catalyses the acylation of alcohols by anhydrides the mechanism by which DMAP accelerates this process provides an instmctive illustration of how nucleophiles can... 

Experimental evidence for such nucleophilic catalysis is sununarized in Figure 7.27. Hydrolysis of 2,4-dinitrophenyl benzoate catalyzed by acetate ion labeled with on both oxygen atoms led to product in which both benzoic acid and acetic acid were labeled with 0, but about 75% of the label derived from one 0 in the reactant was found in the benzoate ion. The data were interpreted as evidence for the intermediacy of the mixed anhydride CH3CO2COC6H5. 

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