41071-33-4Relevant articles and documents
Tunable pH-sensitive 2-carboxybenzyl phosphoramidate cleavable linkers
Backer, Brian S.,Berkman, Clifford E.,Browne, Zachery S.,Choy, Cindy J.,Davis, Austen L.
supporting information, (2020/02/15)
We previously described a pH-sensitive phosphoramidate linker scaffold that can be tuned to release amine-containing drugs at various pH values. In these previous studies it was determined that the tunability of this linker was dependent upon the proximity of an acidic group (e.g., carboxylic acid or pyridinium). In this study, we confirmed that the tunability of pH-triggered amine-release was also dependent upon the pKa of the proximal acidic group. A series of 2-carboxybenzyl phosphoramidates was prepared in which the pKa of the proximal benzoic acid was predictably attenuated by substituents on the benzoate ring consistent with their σ-values.
The tetrahedral intermediate of a lactonization reaction
McClelland, Robert A.,Alibhai, Masuma
, p. 1169 - 1176 (2007/10/02)
The hydrolysis of the ortho ester 1,1-diethoxy-1,3-dihydroisobenzofuran (1) is described.This hydrolysis proceeda with initial expulsion of an exocyclic ethoxy group, producing upon hydration of the oxocarbonium ion 1-hydroxy-1-ethoxy-1,3-dihydroisobenzofuran (7), the tetrahedral intermediate of the lactonization of ethyl (2-hydroxymethyl)benzoate (6) to phthalide (8).Based on the kinetic behaviour of the ortho ester hydrolysis, the pH variation in the ratio of 6:8 initially formed from the ortho ester, and the kinetic behaviour of the lactonization reaction, rate constants for the breakdown of the tetrahedral intermediate 7 have been determined, along with the equilibrium constant for its formation from the hydroxy ester 6.The breakdown occurs in an extremely rapid hydroxide-ion-catalyzed reaction, with the rate being at the diffusion limit.Hydronium ion catalysis is also observed; this breakdown is also rapid although considerably less so than the hydroxide ion reaction.The changeover from H+ to OH- catalysis occurs at pH 3.5.The rate of breakdown is a minimum at this point, and corresponds to a half-life for the tetrahedral intermediate of about 0.1 s.It is concluded that this allows sufficient time for conformational changes in the tetrahedral intermediate prior to breakdown; this factor must be taken into account in stereoelectronic considerations.
