General acid intramolecular

The transition state for the rapid hydrolysis of the monoanion has been depicted as involving an intramolecular general acid catalysis by the carboxylic acid group, with participation by the anionic carboxylate group, which becomes bound at the developing electrophilic center... 

A mixed acetal of benzaldehyde, methanol, and salicylic acid has also been studied. It, too, shows a marked rate enhancement attributable to intramolecular general acid catalysis ... 

The relative importance of the potential catalytic mechanisms depends on pH, which also determines the concentration of the other participating species such as water, hydronium ion, and hydroxide ion. At low pH, the general acid catalysis mechanism dominates, and comparison with analogous systems in which the intramolecular proton transfer is not available suggests that the intramolecular catalysis results in a 25- to 100-fold rate enhancement At neutral pH, the intramolecular general base catalysis mechanism begins to operate. It is estimated that the catalytic effect for this mechanism is a factor of about 10. Although the nucleophilic catalysis mechanism was not observed in the parent compound, it occurred in certain substituted derivatives. 

Derive the general expression for the observed rate constant for hydrolysis of A as a function of pH. Assume, as is the case experimentally, that intramolecular general acid catalysis completely outweighs intermolecular catalysis by hydronium ion in the pH range of interest. Does the form of your expression agree with the pH rate profile given for this reaction in Fig. 8.6 (p. 489) ... 

The ionization of (E)-diazo methyl ethers is catalyzed by the general acid mechanism, as shown by Broxton and Stray (1980, 1982) using acetic acid and six other aliphatic and aromatic carboxylic acids. The observation of general acid catalysis is evidence that proton transfer occurs in the rate-determining part of the reaction (Scheme 6-5). The Bronsted a value is 0.32, which indicates that in the transition state the proton is still closer to the carboxylic acid than to the oxygen atom of the methanol to be formed. If the benzene ring of the diazo ether (Ar in Scheme 6-5) contains a carboxy group in the 2-position, intramolecular acid catalysis is observed (Broxton and McLeish, 1983). 

In the pH range 2—3.5 the phosphonate (78) hydrolyses with loss of ROH at approximately 10 times the rate of comparable esters lacking the vicinal oxime function or in which this function is methylated on oxygen. An intramolecular general-acid catalysis mechanism was proposed, but it was not possible to exclude entirely an intramolecular nucleophilic attack at phosphorus. Intramolecular attack by the vicinal dimethylamino-group takes place preferentially at carbon rather than phosphorus in the phos-phonofluoridate (79). ... 

Of the many reagents, both heterogeneous and homogeneous, that can facilitate chemical reactions, the cycloamyloses stand out. Reactions can be catalyzed with many species such as hydronium ions, hydroxide ions, general acids, general bases, nucleophiles, and electrophiles. More effective catalysis can sometimes be achieved by combinations of catalytic species as in multiple catalysis, intramolecular catalysis, and catalysis by com-plexation. Only the latter catalysis can show the real attributes of an efficient catalytic system, namely speed and selectivity. In analogy to molecular sieves, selectivity can be attained by stereospecific complexation and speed can be likewise attained if the stereochemistry within the complex is correct. The cycloamyloses, of any simple chemical compound, come the closest to these goals. 

Intramolecular general acid catalysis in reactions of salicylic acid derivatives 196 Why are EM s for general acid-base catalysed reactions so low 198 EM and the nature of the transition state 200 The formation of small rings 205... 

H. l Intramolecular general acid catalysis by the carboxyl group 271, H.2 Intra-... 

With the important exception of acetals (and possibly certain other derivatives) of salicylic acid (compounds H. 1.6-11 see the following section), which are hydrolysed with intramolecular general acid catalysis by the carboxyl group, with EM s of the order of 104 M... 

INTRAMOLECULAR GENERAL ACID CATALYSIS IN REACTIONS OF SALICYLIC ACID DERIVATIVES... 

Relatively few data are available (Table H) for reactions involving intramolecular general acid catalysis, but in most cases the EM s fall in the same range as those for general base catalysis (Tables E-G). This is expected if EM is a characteristic transition-state property, because a general acid catalysed reaction is always the microscopic reverse of a general base catalysed process as shown in equation (5), although in no case has the EM been measured in both directions. 

As we have seen (Section 4, p. 191) the range of effective molarities associated with ring-closure reactions is very much greater than that characteristic of intramolecular general acid-base catalysis the main classification is therefore in terms of mechanism. By far the largest section (I, Tables A-D) gives EM s for intramolecular nucleophilic reactions. These can be concerted displacements (mostly at tetrahedral carbon), stepwise displacements (mostly addition-elimination reactions at trigonal carbon), or additions, and they have been classified in terms of the nucleophilic and electrophilic centres. 

Section III (Table H), intramolecular general acid catalysis, is the smallest because this mechanism is less common and because where it is observed (mostly in acetal chemistry) the corresponding intermolecular reactions often cannot be detected. 

General acid catalysis is schematized in Fig. 7J,b. Here, an acid A-H increases the polarity of the carbonyl group and, hence, the electrophilicity of the carbonyl C-atom. For entropy reasons, the reaction is greatly facilitated when it is an intramolecular one (Fig. 7J,b2), in other words, when the general acid catalyst is favorably positioned within the molecule itself. Such a mechanism is the one exploited and refined by nature during the evolution of the hydrolases, with the general acid catalyst and the H20 molecule replaced by adequate amino acid side chains, and the enzymatic transition state being de facto a supermolecule (see Chapt. 3). 

Suitably substituted acetals have been shown to hydrolyse rapidly by a mechanism that involves intramolecular general acid catalysis similar to that proposed for Glu-35 in (34), The largest effects have been found for acetals with the salicylate ion as the leaving group. For example, the spontaneous hydrolysis (35) of 2-methoxymethoxybenzoic acid [73] occurs 300-fold more rapidly than the same reaction of 4-methoxymethoxybenzoic acid [74] and ca. 600-fold more rapidly than the reaction of 2-methoxymethoxybenzoic acid methyl ester [75] (Capon et al, 1969 Dunn and Bruice, 1970). The... 

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