Tetrahedral intermediate in ester hydrolysis

P. Deslongchamps, Stereoelectronic Control in the Cleavage of Tetrahedral Intermediates in the Hydrolysis of Esters and Amides , Tetrahedron 1977, 31, 2463 - 2490 P. Deslongchamps, Stereoelectronic Effects in Organic Chemistry , Pergamon Press, Oxford, 1983. 

J.P. Guthrie and D.C. Pike, Hydration of Acylimidazoles Tetrahedral Intermediates in Acylimidazole Hydrolysis and Nucleophilic Attack by Imidazole on Esters, Can. J. Chem., 1987, 65, 1951. 

Deslongchamps has proposed that in the reactions of tetrahedral intermediates in the hydrolysis of esters and amides the group which leaves is that which has two antiperiplanar lone pairs of electrons in the case of oxygen the two lone pairs are considered as identical sp hybrids, the antiperiplanar one making a dihedral angle of 180° with the bond to be cleaved [37]. The theory as originally formulated considered the lifetime of these intermediates to be short compared to the time of rotation about a C—O or C—N single bond, which has since been shown to be demonstrably incorrect [38,39]. 

Figure 10.18 Catalytic monoclonal antibody (MAb) mediated ester hydrolysis. The MAb was generated through immunoreaction with the illustrated hapten linked to an appropriate carrier protein. The part of the hapten related to the substrate structure is shown in red. The phosphonate link is used as a transition state analogue of the rate determining step transition state leading to the key tetrahedral intermediate of ester hydrolysis. The MAb should optimally bind the rate determining step transition state relative to substrate or products in order to effect maximum catalytic effect.

Deslongchamps P (1975) Stereoelectronic control in the cleavage of tetrahedral intermediates in the hydrolysis of esters and amides. Tetrahedron 31 2463-2490... 

This section is devoted to this question through the presentation of a relatively new concept in organic chemistry, stereoelectronic control, exploited by P. Deslongchamps from the University of Sherbrooke (114,115). It uses the properties of proper orbital orientation in the breakdown of tetrahedral intermediates in hydrolytic reactions. This concept is quite different from Koshland s orbital steering hypothesis where proper orbital alignment is invoked for the formation of a tetrahedral intermediate. Here we are interested by the process that follows the cleavage of the tetrahedral intermediate in the hydrolysis of esters and amides. 

Once It was established that hydroxide ion attacks the carbonyl group in basic ester hydrolysis the next question to be addressed concerned whether the reaction is concerted or involves a tetrahedral intermediate In a concerted reaction the bond to the leaving group breaks at the same time that hydroxide ion attacks the carbonyl... 

The intermediates 74 and 76 can now lose OR to give the acid (not shown in the equations given), or they can lose OH to regenerate the carboxylic ester. If 74 goes back to ester, the ester will still be labeled, but if 76 reverts to ester, the 0 will be lost. A test of the two possible mechanisms is to stop the reaction before completion and to analyze the recovered ester for 0. This is just what was done by Bender, who found that in alkaline hydrolysis of methyl, ethyl, and isopropyl benzoates, the esters had lost 0. A similar experiment carried out for acid-Catalyzed hydrolysis of ethyl benzoate showed that here too the ester lost However, alkaline hydrolysis of substimted benzyl benzoates showed no loss. This result does not necessarily mean that no tetrahedral intermediate is involved in this case. If 74 and 76 do not revert to ester, but go entirely to acid, no loss will be found even with a tetrahedral intermediate. In the case of benzyl benzoates this may very well be happening, because formation of the acid relieves steric strain. Another possibility is that 74 loses OR before it can become protonated to 75. Even the experiments that do show loss do not prove the existence of the tetrahedral intermediate, since it is possible that is lost by some independent process not leading to ester hydrolysis. To deal with this possibility. Bender and Heck measured the rate of loss in the hydrolysis of ethyl trifluorothioloacetate- 0 ... 

As early as 1899, 8tieglitz proposed a tetrahedral intermediate for the hydrolysis of an imino ether to an amide. Thns it was clear qnite early that a complicated overall transformation, imino ether to amide, would make more sense as the result of a series of simple steps. The detailed mechanism proposed, althongh reasonable in terms of what was known and believed at the time, wonld no longer be accepted, but the idea of tetrahedral intermediates was clearly in the air. 8tieglitz stated of the aminolysis of an ester that it is now commonly snpposed that the reaction takes place with the formation of an intermediate prodnct as follows referring to work of Lossen. (Note that the favored tautomer of a hydroxamic acid was as yet unknown.)... 

Fig. 7.1. a) Specific acid catalysis (proton catalysis) with acyl cleavage in ester hydrolysis. Pathway a is the common mechanism involving a tetrahedral intermediate. Pathway b is SN1 mechanism observed in the presence of concentrated inorganic acids. Not shown here is a mechanism of alkyl cleavage, which can also be observed in the presence of concentrated inorganic acids, b) Schematic mechanism of general acid catalysis in ester hydrolysis. 

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... 

In ester hydrolysis, rate-limiting formation of the tetrahedral intermediate usually apphes (Sec. 6.3.1) since the alkoxide group is easily expelled. In contrast, amide hydrolysis at neutral pH involves rate-limiting breakdown of the tetrtihedral intermediate, because RNH is a poor leaving group. The catalytic effect of metal ions on amide hydrolysis has been ascribed to accelerated breakdown of the tetrahedral intermediate. 

Molecular dynamics free-energy perturbation simulations utilizing the empirical valence bond model have been used to study the catalytic action of -cyclodextrin in ester hydrolysis. Reaction routes for nucleophilic attack on m-f-butylphenyl acetate (225) by the secondary alkoxide ions 0(2) and 0(3) of cyclodextrin giving the R and S stereoisomers of ester tetrahedral intermediate were examined. Only the reaction path leading to the S isomer at 0(2) shows an activation barrier that is lower (by about 3kcal mol ) than the barrier for the corresponding reference reaction in water. The calculated rate acceleration was in excellent agreement with experimental data. ... 

Cu " -catalysed hydrolysis and 5 4 for alkaline hydrolysis of 0-labelled ester. Formation of the tetrahedral intermediate in the scheme of equation (31) is indicated by the observed 0-exchange. However, interactions of the carbonyl oxygen and the metal ion... 

However, detection of the tetrahedral intermediate in the addition of a nucleophile to an ester, acid halide, amide or anhydride must be adduced from kinetic evidence, in particular the evidence of oxygen exchange in such an intermediate. Such tracer work has established the presence of symmetrical addition compounds in the hydrolysis of esters23, amides and acid chlorides24. Since the attempts to detect such intermediates have played a considerable part in the development of hydrolysis studies, it is worthwhile considering this point in some detail. 

In base the tetrahedral intermediate is formed in a manner analogous to that proposed for ester saponification. Steps 1 and 2 in Figure 20.8 show the formation of the tetrahedral intermediate in the basic hydrolysis of amides. In step 3 the basic amino group of the tetrahedral intermediate abstracts a proton from water, and in step 4 the derived ammonium ion dissociates. Conversion of the carboxylic acid to its corresponding carboxylate anion in step 5 completes the process and renders the overall reaction irreversible. 

Fig. 6.3. Alkaline hydrolysis of carboxylic esters according to the mechanism of Figure 6.2 proof of the reversibility of the formation of the tetrahedral intermediate. In the alkaline hydrolysis of ethyl pora-methylbenzoate in H20, for example, the ratio kretlo/kelj is at least 0.13 (but certainly not much more).

Scheme 4.1 Hydrolysis of activated aryl esters 2a and carbonates 2b proceeds via an anionic, tetrahedral intermediate (in square brackets). Hydrolytic antibody 48C7 was elicited with an aryl phosphonate derivative 1 that mimics this high energy species and its flanking transition states.

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