Ester hydrolysis steric effects

Taft began the LFER attack on steric effects as part of his separation of electronic and steric effects in aliphatic compounds, which is discussed in Section 7.3. For our present purposes we abstract from that treatment the portion relevant to aromatic substrates. Hammett p values for alkaline ester hydrolysis are in the range +2.2 to +2.8, whereas for acid ester hydrolysis p is close to zero (see Table 7-2). Taft, therefore, concluded that electronic effects of substituents are much greater in the alkaline than in the acid series and. in fact, that they are negligible in the acid series. This left the steric effect alone controlling relative reactivity in the acid series. A steric substituent constant was defined [by analogy with the definition of cr in Eq. (7-22)] by Eq. (7-43), where k is the rate constant for acid-catalyzed hydrolysis of an orr/to-substituted benzoate ester and k is the corresponding rate constant for the on/to-methyl ester note that CH3, not H, is the reference substituent. ... 

In the acidic and alkaline hydrolysis rates of the same ester, the steric and resonance effects. re the same. 

Taft, following Ingold," assumed that for the hydrolysis of carboxylic esters, steric, and resonance effects will be the same whether the hydrolysis is catalyzed by acid or base (see the discussion of ester-hydrolysis mechanisms. Reaction 10-10). Rate differences would therefore be caused only by the field effects of R and R in RCOOR. This is presumably a good system to use for this purpose because the transition state for acid-catalyzed hydrolysis (7) has a greater positive charge (and is hence destabilized by —I and stabilized by +1 substituents) than the starting ester. 

Taft was also able to isolate steric effects. For the acid-catalyzed hydrolysis of esters in aqueous acetone, long (kJh was shown to be insensitive to polar effects. In cases where resonance interaction was absent, this value was proportional only to steric effects (and any others that are not field or resonance). The equation is... 

Buchwald P. Structure-metabolism relationships steric effects and the enzymatic hydrolysis of carboxylic esters. Mini Rev Med Chem 2001 1 101-11. 

From the form of equation [11], the Es value for Me, the reference substituent, will of course be 0. All substituents other than H have -ve Es values because all substituents other than H are larger than Me, and the rate of hydrolysis of any ester RC02Et (R/H) will thus be slower than that of MeC02Et, in a reaction whose rate is governed solely by the steric effect of R. 

The acid-catalyzed ester hydrolysis provides a good target for MM treatments. DeTar first used hydrocarbon models in which an ester was approximated by an isoalkane (74) and the intermediate (75) by a neoalkane (76). He assumed that if the rate of reaction truly is not influenced by polar effects but is governed only by steric effects of R, as has been generally postulated, the rate must be proportional to the energy difference (AAH ) between 74 and 76. The AAH f is mainly determined by the van der Waals strain in these branched alkanes. Nonsteric group increment terms were carefully adjusted, and statistical mechanical corrections for conformer populations... 

The variation in the add-catalyzed hydrolysis of aliphatic carboxylic esters RCOOEt is mostly subject to the steric effect intramolecularly exerted by the substituent R on the formation of the tetrahedral reaction intermediate. Taft4) defined the steric parameter E, as Eq. 3,... 

Since the Es value is determined by the relative activation free energy from the unsaturated initial state to the saturated tetrahedral intermediate state of the ester hydrolysis, Hancock and his coworkers considered that a hyperconjugation effect of a-hydrogen may contribute to the estimate of Es values 19). To separate the hyperconjugation effect from the true steric effect , they defined the parameter E° (corrected steric) as Eq. 20, assuming that the hyperconjugation effect is proportional to the number of a-hydrogen atoms, nH. By definition, E (Me) = 0. 

Since the total steric effect of component substituents R1, R2 and R3 on the reaction center in the transition state of ester hydrolysis is similar, if not identical, to that of three N-substituents of aliphatic amines on a certain electron acceptor or electrophile, we attempted to separate electronic and steric effects of N-substituents of amines NR3R2R3 for various reactions by Eq. 24 where is either the rate or equilibrium constant, Scr is the sum of a values for R1, R2 and R3 and E (R ) E (R2) Si E (R3), and showed that Eq. 24 is generally applicable 22). 

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