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Hydrolytic stability of allylic and phenolic esters of some synthetic cannabinoids: A theoretical (AM1) study
Author(s) -
Pop Emil,
Brewster Marcus E.,
Huang MingJu,
Bodor Nicholas
Publication year - 1995
Publication title -
international journal of quantum chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.484
H-Index - 105
eISSN - 1097-461X
pISSN - 0020-7608
DOI - 10.1002/qua.560560714
Subject(s) - chemistry , hydrolysis , allylic rearrangement , steric effects , tetrahedral carbonyl addition compound , bifunctional , organic chemistry , medicinal chemistry , leaving group , computational chemistry , stereochemistry , catalysis , nucleophile
The hydrolytic stability of allylic (IA) and phenolic (IB) esters of novel bifunctional nonpsychotropic cannabinoids, homologs of (+)3S,4S‐7‐hydroxy‐Δ 6 ‐tetrahydrocannabinol, is of practical importance due to their possible use as prodrugs. The influence of the bulk and nature of various acyl groups as well as of their position on the base catalyzed hydrolysis has been examined theoretically. Differences (ΔΔH f ) between semiempirical heats of formation (ΔH f ) of products and reactants were calculated for the formation of the tetrahedral intermediates ( IIA, B ) which constitutes the rate‐determining step of the process. An analysis of the ΔΔH f values and of the calculated optimized lowest energy geometries indicates that formation of II and thus the hydrolysis is most favorable for the trifluoroacetyl and trimethylammoniumacetyl as compared to acetyl, glycyl, and dialkylaminoacetyl esters. The bulk of the acyl group in a series of glycinate esters, increasing in the order COCH 2 NH 2 < COCH 2 NMe 2 < COCH 2 NEt 2 < COCH 2 N(iPr) 2 stabilizes I proportionally, by hindering formation of II. By comparing series IA and IB , the formation of II appears to be generally favored for the phenolic esters compared to the allylic esters due to the release of a more significant steric strain. © 1995 John Wiley & Sons, Inc.