Benzoyl esters, hydrolysis

For the cocaine benzoyl ester hydrolysis, the nucleophilic hydroxide ion can approach from the two faces, denoted by Re and Si, of the carbonyl to... 

For the second step of the cocaine methyl ester hydrolysis involving the water-assisted proton transfer, the calculated energy barrier, 4.8 kcal/mol, associated with transition state TS2dW-Me, is also lower than the corresponding first step. So, with the direct participation of the solvent water molecule in the proton transfer process, the first step of the hydrolysis in aqueous solution should be rate-determining, whether for the cocaine benzoyl ester hydrolysis or for the cocaine methyl ester hydrolysis. This conclusion provides theoretical support for the design of analogs of the first transition state for the cocaine benzoyl ester hydrolysis to elicit anti-cocaine catalytic antibodies [22,25]. 

The first-principles reaction coordinate calculations at the B3LYP/6-31-i-G(d) level led to the optimized geometries of the rate-determining transition states (i.e., the transition states for the first reaction step of the ester hydrolysis), as depicted in Fig. 5. For benzoyl ester hydrolysis of protonated cocaine in its chair conformation, the nucleophilic hydroxide ion can also approach from two faces, denoted by Si and Re, of the carbonyl to form two stereoisomer... 

Fig. 5 Transition state structures optimized at the B3LYP/6-31+G(d) level for the ester hydrolysis of protonated cocaine [89] a and b for the benzoyl ester hydrolysis of the chair cocaine c for the methyl ester hydrolysis of the chair cocaine and d for the benzoyl ester hydrolysis of the boat cocaine...

However, the free energy barrier calculated for the methyl ester hydrolysis of protonated cocaine (2.5 kcal/mol at T = 0 K and 12.5 kcal/mol at T = 298.15 K and P = I atm) is significantly lower than that for the dominant pathway of the benzoyl ester hydrolysis (7.0 kcal/mol at T = 0 K and... 

The first anti-cocaine catalytic antibody was reported by Landry and associates in 1993 [22]. The transition-state analog used to ehdt the first anticocaine catalytic antibody was a stable structure of the transition state for the benzoyl ester hydrolysis of chair cocaine [22,25]. Based on the computational analysis discussed above, the new TSA structure depicted in Fig. 4 was synthesized and 85 cocaine esterases out of 450 anti-analog antibodies... 

Perhaps the most informative studies (Anvia and Bowden, 1990) of leaving groups are of the alkaline hydrolysis of 3-substituted phenyl 2-acetyl- and 2-benzoyl-benzoates [20], The Hammett reaction constants p are ca. 0.50 and 1.48 for the 2-acetyl and 2-benzoyl esters respectively, as. shown in Table 2. These were compared with various limiting models in a similar manner to the effective charge model (Williams, 1984,1992). This comparison indicates that all simple phenyl esters of the latter types hydrolyse by a mechanism... 

The specific activity of papain is determined using the synthetic peptide substrate N-benzoyl-L-aigmine ethyl ester. Hydrolysis is carried out at pH 7.0 and 25 X and die consumorion of base, necessary to neutralize the lihemiwl acid, is recorded as a function of time. 

The earliest theoretical calculations of cocaine hydrolysis focused on the first step of the hydrolysis of the benzoyl ester [57,58]. hi these computational studies [57,58], MNDO, AMI, PM3, and SM3 semiempirical molecular orbital methods, as well as ab initio procedure at the HF/3-21G level of theory, were employed to optimize geometries of the transition states for the first step of the hydrolysis of cocaine and model esters, including methyl acetate [59,60] for which experimental activation energy in aqueous solu-... 

As discussed below in detail, first-principles electronic structure calculations have provided accurate predictions of the reaction pathways and the corresponding energy barriers, not only for the first step of hydrolysis of cocaine free base at the benzoyl ester group, but also for the entire reaction processes of hydrolysis of cocaine free base at both the benzoyl ester and methyl ester groups. 

Fig. 2 Geometries of the transition states optimized at the B3LYP/6-31+G(d) level for the first step of the hydrolysis of CH3COOCH3, (CH3)2CHCOOCH3, C6H5COOCH(CH3)2, the cocaine methyl-ester, and the cocaine benzoyl-ester [63], Internuclear distances are given in angstrom...

Further, for antibody catalysis the methyl ester is too small to be an effective epitope but the participation could be induced if an antibody were able to recruit cocaine from the chair conformation to the less stable boat form (see Fig. 4 for the structure) and reorient the syn-protonated amine and benzoyl ester into proximity. Antibodies can provide significant binding energy and in principle antibody binding could effect conformer selection and promotion of substrate-assisted catalysis. To examine this idea, a detailed computational analysis [89] of the energetics of this reaction was also performed for design of novel TSA structures for the alkaline hydrolysis of boat cocaine in comparison with the hydrolysis of chair cocaine. 

Fig. 8 Total average number of hydrogen bonds (a) and the corresponding total hydrogen bonding energy (b) between the carbonyl oxygen of cocaine benzoyl ester and the oxyan-ion hole in the simulated the prereactive BChE-cocaine complex (ES), transition states, intermediates, and product for BChE-catalyzed hydrolysis of (-)-cocaine [115]...

---