Intermolecular nucleophilic catalysis

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. 

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... 

Fig. 7.2. a) The most common mechanism of base-catalyzed ester hydrolysis, namely specific base catalysis (HCT catalysis) with tetrahedral intermediate and acyl cleavage. Not shown here are an W mechanism with alkyl cleavage observed with some tertiary alkyl esters, and an 5n2 mechanism with alkyl cleavage sometimes observed with primary alkyl esters, particularly methyl esters, b) Schematic mechanism of general base catalysis in ester hydrolysis. Intermolecular catalysis (bl) and intramolecular catalysis (b2). c) The base-catalyzed hydrolysis of esters is but a particular case of nucleophilic attack. Intermolecular (cl) and intramolecular (c2). d) Spontaneous (uncatalyzed) hydrolysis. This becomes possible when the R moiety is... 

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. ... 

Intramolecular reactions are faster because AS - the entropy of activation (the probability of the reactant groups meeting) - is high and fastest when the reaction is a cyclisation (corresponding to intramolecular nucleophilic catalysis), which may be particularly favorable enthalpically. The simple measure of efficiency is the effective molarity (EM), the (often hypothetical) concentration of the neighboring group needed to make the corresponding intermolecular process go at the same rate [36]. It is simply measured, as the ratio of the first order rate constant of the intramolecular reaction and the second order rate constant for the (as far as possible identical) intermolecular process. In some convenient cases both reactions can be observed simultaneously, (Scheme 2.15) [37], and EM = ki/k2 measured di-... 

The reaction in Figure 7.27 involves intermolecular nucleophilic catalysis, but intramolecular nucleophilic catalysis has also been observed. Fersht and Kirby foimd incorporation of 0 in the product when acetyl-3,5-dinitrosa-licylate ion was hydrolyzed in a solvent containing isotopically enriched... 

The term intramolecular catalysis introduced by Bender is also widely used to describe neighboring group effects, especially when analogous intermolecular catalysis is observed. Thus this term is commonly used when referring to reactions that are subject to acid, base, and/or nucleophilic catalysis such as hydrolysis of esters, amides, and acetals the mutarotation of aldoses or the enolization of ketones. It is rarely used when referring to nucleophilic substitution reactions at saturated carbon. 

Covalent catalysis is a general term applied when a catalyst forms full covalent bonds with the substrate, not just intermolecular non-covalent interactions. The nucleophilic catalysis by an amine given in Eq. 9.9 is a specific example where a nucleophile acts as a covalent catalyst. 

Nucleophilic catalysis is defined as the catalytic process in which a catalyst or a catalytic group forms a covalent bond with the reaction center of the substrate in the initial phase of the reaction followed by the recovery of the catalyst by the cleavage of the covalent bond between the reaction center of the substrate and the catalyst in the latter phase of the reaction. Such catalysis is also known as covalent catalysis. Nucleophilic catalysis may be either an intermolecular (if the substrate and the catalyst are not covalently attached to each other in the reactant state) or a semiintramolecular (if the catalyst becomes a part of the structural network of the substrate during the course of the reaction) molecular event. 

In the absence of direct detection of Catam, a skeptic might argue and suggest that the presence of positive catalysis due to tertiary amines could be because of the occurrence of an alternative reaction mechanism as shown by Scheme 2.13, which involves intermolecular general base catalysis instead of nucleophilic catalysis. The formation of reactive intermediate T occurs through the transition state TSg. Although the proposal for the existence of transition states similar to TSg is not uncommon in the vast literature on the related... 

Induced intramolecular nucleophilic catalysis involves the formation of a molecular addition complex (Ad) between the reactant/substrate (R-A) and catalyst (W-B) followed by intramolecular nucleophilic substitution reaction between two reaction sites A and B giving products P3 and P4, where one of the products, say P4, is unstable, i.e., more reactive, and, hence, P4 undergoes further reaction to reproduce catalyst (W-B) and give the final stable product P5. This whole chemical process may be shown by Equation 2.27. Intramolecular induced nucleophilic catalysis involves the intermolecular nucleophihc substitution reaction between R-A and catalyst, (C-W-B), where nucleophilicity of the nucleophile is enhanced owing to intramolecular interaction between molecular sites B and C of catalyst. 

Reports on the rate enhancements in intramolecular nucleophilic reactions compared to analogous intermolecular nucleophilic reactions are plenty. But such reports on induced intramolecular or intramolecular induced nucleophilic catalysis are rare. One might argue that the induced intramolecular/intramolecular induced nucleophilic reactions also represent the corresponding nucleophilic catalysis. But this statement is not totally correct in view of the definition of a catalyst. For example, hydroxide-ion-catalyzed second-order rate constant (koe) for the cleavage of one of the two amide bonds in N,N-dimethylphthalamide (13) at 25.3°C is 7.6 sec. The value of koe for the cleavage of amide bond in... 

The realization of the occurrence of intermolecular GA catalysis comes from the experimental fact of the presence of a kinetic term kgJBH+][NuH][Sub] (where BH+ is the GA, NuH is the nucleophile, and Sub is the substrate) in the rate law for the nucleophilic reaction between NuH and Sub in the presence of BH+. But this kinetic term is kinetically indistinguishable from kinetic term k[H+][B][NuH][Sub], which represents SA-GB catalysis or SA-nucleophilic catalysis. However, these kinetically indistinguishable catalytic mechanisms can be resolved, at least qualitatively, as described in the following text. 

A scheme depicting general base catalysis is shown in Fig. 7.2,b. Because the HO anion is more nucleophilic than any base-activated H20 molecule, intermolecular general base catalysis (Fig. 7.2,bl) is all but impossible in water, except for highly reactive esters (see below). In contrast, entropy may greatly facilitate intramolecular general base catalysis (Fig. 7.2,b2) under conditions of very low HO anion concentrations. Alkaline ester hydrolysis is a particular case of intermolecular nucleophilic attack (Fig. 7.2,cl). Intramolecular nucleophilic attacks (Fig. 7.2,c2) are reactions of cyclization-elimination to be discussed in Chapt. 8. 

Nucleophilic and general species catalysis are most efficient when the catalytic group is held in close, properly orientated proximity to the group under attack. These mechanisms are thus much more important, relative to alkaline and acid catalysis, in intramolecular reactions, and in some cases mechanism not observed in intermolecular reactions become important in intramolecular catalysis. The generalizations described in the previous section are still applicable, however, to intramolecular catalysis, and no new principles are involved that are well-understood at present. 

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