Intramolecular nucleophilic catalysis

The extent to which intramolecular nucleophilic catalysis of the type depicted in mechanism I is important is a function of the leaving ability of the alkoxy group. This has been demonstrated by the study of the hydrolysis of a series of monoesters of phthalic acid ... 

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. 

Yet another distinction is between intermolecular catalysis, in which the catalytic function and the reaction site are on different molecules, and intramolecular catalysis, in which the catalytic function and the reaction site are within the same molecule. All of the above examples constitute intermolecular catalyses. The following reaction, the hydrolysis of a monomaleate ester, is an intramolecular nucleophilic catalysis. 

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. 

Baldwin s rules. It is noteworthy that the EM5/EM6 ratio is reduced to a factor as small as about 2, which is less than the intrinsic entropic advantage of 5- over 6-membered ring formation. Kirby (1980) in his review lists a large number of EM data for intramolecular nucleophilic additions to carbonyl. Probably because these data derive from laboratories of chemists mainly interested in intramolecular nucleophilic catalysis and its relevance to understanding enzymic catalysis, the great majority of them refer to reactions occurring via 5- and 6-membered transition states. The only example where a 4-membered transition state is involved is (70), whose kinetics were studied... 

Alkoxides that arise from simple carbonyl additions have also functioned as excellent in situ nucleophiles for intramolecular hydroalkoxylation reactions. Garbinols derived from the addition of allyltin reagents have proved to be potent nucleophiles in reactions of this type (Equation (99)),349 and this approach has also been used for the combined addition-cyclization of alkynals under Pd(n)350 or Cu(i)351 catalysis, and alkynones under Pd(n) catalysis.352... 

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

A. 6 Intramolecular nucleophilic catalysis of the hydrolysis of sulphonamides 238 B Reactions of the hydroxyl group 239... 

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... 

A.3 Intramolecular nucleophilic catalysis of amide hydrolysis by the carboxyl group... 

A.5 Intramolecular nucleophilic catalysis by the carboxyl group of the hydrolysis ofphosphate andphosphonate esters... 

These findings are compatible with a mechanism of intramolecular catalysis for both acyl migration and hydrolysis, as proposed in Fig. 8.5. Also, the possibility that both reactions share a common intermediate is emphasized. Reactions a and b in Fig. 8.5 involve a first step of deprotonation, in agreement with the observed specific base catalysis. Intramolecular nucleophilic attack (Reactions c and d) generates a tetrahedral intermediate that can result in acyl migration or hydrolysis (Reaction e). 

These examples show that enormous rate enhancements come from intramolecular nucleophilic catalysis. 

The lower effective concentrations found in intramolecular base catalysis are due to the loose transition states of these reactions. In nucleophilic reactions, the nucleophile and the electrophile are fairly rigidly aligned so that there is a large entropy loss. In general-base or -acid catalysis, there is considerable spatial freedom in the transition state. The position of the catalyst is not as closely defined as in nucleophilic catalysis. There is consequently a smaller loss in entropy in general-base catalysis, so that the intramolecular reactions are not favored as much as their nucleophilic counterparts. 

Although metal-promoted hydrolysis of phosphate esters is a topic of very current interest (Section 61.4.4), little work has been published dealing with the effects of metal ions on the hydrolysis of sulfate esters. The acid-catalyzed hydrolysis of aryl sulfates has been shown to occur by an A-l mechanism (Scheme 34).434 Nucleophilic catalysis by amines has been observed in the hydrolysis of p-nitrophenyl sulfate435 and intramolecular carboxyl group catalysis occurs with salicyl sulfate436 as with salicyl phosphate. 

Evidence has been provided604 for intramolecular nucleophilic catalysis by the carbonyl group during methanolysis of o- and / -formylbenzenesulfonates in basic media (see Scheme 121). A theoretical study of the zwittazido cleavage of 4-azido-2-pyrrolinones has been undertaken,605 and ab initio calculations have been carried out to examine the possibility of the existence of a hexacoordinate phosphorus intermediate (469) in the migration reaction (468) —> (470) of dimethyloxyphosphorylthreonine.606... 

The reactions of perfluoroolefins with hexafluoroacetone cyanohydrin under conditions of nucleophilic catalysis yield 3-iminotetrahydrofuran. The latter evidently forms via the intermediate carbanion involved in the intramolecular nucleophilic cyclization (91JFC(54)401). This is an example of synthesis following route f. 

These examples demonstrate the efficiency of using the C=C double bond for heterocycle formation. In this case, the intramolecular nucleophilic cyclization involves the nucleophilic center of the nucleophile at the double bond of the functional fragment together with the heteronucleophile generated in the course of the reaction under conditions of nucleophilic catalysis by the fluoride ion. 

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]. 

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. ... 

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