Solvent Effects in the Reaction of 5'-O-Benzoyl-2,3'-AnhydroThymidine with Dimethylammonium azide: Kinetics Analysis and Ab Initio Calculations
Elena V. Korchevskaya1, Alexander Yu. Steblyanko2, Alexander A. Malin1, Mikhail B. Shcherbinin, Vladimir A. Ostrovskii1
1Saint-Petersburg State Institute of Technology, 198013, St.-Petersburg, Moskovskii pr., 26, Russia
2Department of Polymer Science & Engineering, Faculty of Engineering, Yamagata University, 4-3-16 Jonan, Yonezawa, Yamagata 992-8510, Japan
The key step of the process for preparation of the important anti-AIDS drug, 3'-azido-2',3'-dezoxythymidine (AZT), is the reaction of a semi-product 5'-O-benzoyl-2,3'-anhydrothymidine (I) with azide agents of various nature.
In this work a plausible mechanism for the reaction of 5'-O-benzoyl-2,3'-anhydro thymidine (I) with dimethylammonium azide (II) in a binary, DMF-1,4-dioxane, solvent system (Scheme) was investigated by means of kinetics studies and ab initio MO computations (GAMESS, RHF/STO3-21G basic set). The suggested mechanism involved the cyclic activated complex (III) formation on the key step of the process. Due to this, the simultaneous protonation of the oxygen atom O2 and nucleophylic addition of azide group with consequential C3'-O2 bond cleavage became possible.
II III I
It was found in our kinetics experiments that the addition of low polar dioxane increased the rate of the reaction of I with II. However, the dependence of this rate from the Kirkwood’s function was shown to be nonlinear. When a significant amount of dioxane was added it was observed that the experimental plot deviated to the values lower than was expected. This was explained by the existence of the effect of specific solvatation. In fact, our model calculations showed that the addition of dioxane to the reaction mixture led to the formation of the dixane complex with a nucleophylic agent II with spatially separated amine and azide parts (Figure) and interrupted the formation of III.
This work was by the RFBR (grant no 01-03-32531)