First-principle studies of intermolecular and intramolecular catalysis of protonated cocaine.
We have performed a series of first-principles electronic structure calculations to examine the reaction pathways and the corresponding free energy barriers for the ester hydrolysis of protonated cocaine in its chair and boat conformations. The calculated free energy barriers for the benzoyl ester hydrolysis of protonated chair cocaine are close to the corresponding barriers calculated for the benzoyl ester hydrolysis of neutral cocaine. However, the free energy barrier calculated for the methyl ester hydrolysis of protonated cocaine in its chair conformation is significantly lower than for the methyl ester hydrolysis of neutral cocaine and for the dominant pathway of the benzoyl ester hydrolysis of protonated cocaine. The significant decrease of the free energy barrier, approximately 4 kcal/mol, is attributed to the intramolecular acid catalysis of the methyl ester hydrolysis of protonated cocaine, because the transition state structure is stabilized by the strong hydrogen bond between the carbonyl oxygen of the methyl ester moiety and the protonated tropane N. The relative magnitudes of the free energy barriers calculated for different pathways of the ester hydrolysis of protonated chair cocaine are consistent with the experimental kinetic data for cocaine hydrolysis under physiologic conditions. Similar intramolecular acid catalysis also occurs for the benzoyl ester hydrolysis of (protonated) boat cocaine in the physiologic condition, although the contribution of the intramolecular hydrogen bonding to transition state stabilization is negligible. Nonetheless, the predictability of the intramolecular hydrogen bonding could be useful in generating antibody-based catalysts that recruit cocaine to the boat conformation and an analog that elicited antibodies to approximate the protonated tropane N and the benzoyl O more closely than the natural boat conformer might increase the contribution from hydrogen bonding. Such a stable analog of the transition state for intramolecular catalysis of cocaine benzoyl-ester hydrolysis was synthesized and used to successfully elicit a number of anticocaine catalytic antibodies.
Zhan
Chang-Guo
CG
Division of Clinical Pharmacology and Experimental Therapeutics, College of Physicians & Surgeons, Columbia University, 630 West 168th Street, New York, New York 10032, USA. zhan@uky.edu
Deng
Shi-Xian
SX
Skiba
Jaime G
JG
Hayes
Beth A
BA
Tschampel
Sarah M
SM
Shields
George C
GC
Landry
Donald W
DW
D017151:Antibodies, Catalytic / Q000737:chemistry*; D002384:Catalysis; D003042:Cocaine / Q000737:chemistry*; D006868:Hydrolysis; D008968:Molecular Conformation; D015394:Molecular Structure; D013816:Thermodynamics
D017151:Antibodies, Catalytic; D003042:Cocaine