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Updated: Jun 6, 2026
Determination of the Gas-phase Acidities of Oligopeptides
Published on: June 24, 2013
Kinetics and mechanism of N-Boc cleavage: evidence of a second-order dependence upon acid concentration
Ian W Ashworth1, Brian G Cox, Brian Meyrick
1Pharmaceutical Development, AstraZeneca R&D, S41/18 PR&D Building, Silk Road Business Park, Charter Way, Macclesfield, Cheshire, SK10 2NA, United Kingdom. ian.ashworth@astrazeneca.com
Abstract:
The kinetics of the HCl-catalyzed deprotection of the Boc-protected amine, thioester 2 to liberate AZD3409 1 have been studied in a mixture of toluene and propan-2-ol. The reaction rate was found to exhibit a second-order dependence upon the HCl concentration. This behavior was found to have a degree of generality as the deprotection of a second Boc-protected amine, tosylate 3 to yield amine 4 using HCl, sulfuric acid, and methane sulfonic acid showed the same kinetic dependence. In contrast the deprotection of tosylate 3 with trifluoroacetic acid required a large excess of acid to obtain a reasonable rate of reaction and showed an inverse kinetic dependence upon the trifluoroacetate concentration. These observations are rationalized mechanistically in terms of a general acid-catalyzed separation of a reversibly formed ion-molecule pair arising from the fragmentation of the protonated tert-butyl carbamate.
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