S(N)Ar displacements with 6-(fluoro, chloro, bromo, iodo, and alkylsulfonyl)purine nucleosides: synthesis, kinetics, and mechanism1.

doi:10.1021/JA070021U

Paper

S(N)Ar displacements with 6-(fluoro, chloro, bromo, iodo, and alkylsulfonyl)purine nucleosides: synthesis, kinetics, and mechanism1.

Published Apr 17, 2007 · Jiangqiong Liu, M. Robins

Journal of the American Chemical Society

Q1 SJR score

56

Citations

0

Influential Citations

Full textSemantic Scholar

Abstract

SNAr reactions with 6-(fluoro, chloro, bromo, iodo, and alkylsulfonyl)purine nucleosides and nitrogen, oxygen, and sulfur nucleophiles were studied. Pseudo-first-order kinetics were measured with 6-halopurine compounds, and comparative reactivities were determined versus a 6-(alkylsulfonyl)purine nucleoside. The displacement reactivity order was: F > Br > Cl > I (with BuNH2/MeCN), F > Cl approximately Br > I (with MeOH/1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)/MeCN), and F > Br > I > Cl [with K+ -SCOCH3/dimethyl sulfoxide (DMSO)]. The order of reactivity with a weakly basic arylamine (aniline) was: I > Br > Cl > F (with 5 equiv of aniline in MeCN at 70 degrees C). However, those reactions with aniline were autocatalytic and had significant induction periods ( approximately 50 min for the iodo compound and approximately 6 h for the fluoro analogue). Addition of trifluoroacetic acid (TFA) eliminated the induction period, and the order then was F > I > Br > Cl (with 5 equiv of aniline and 2 equiv of TFA in MeCN at 50 degrees C). The 6-(alkylsulfonyl)purine nucleoside analogue was more reactive than the 6-fluoropurine compound with both MeOH/DBU/MeCN and iPentSH/DBU/MeCN and was more reactive than the Cl, Br, and I compounds with BuNH2 and aniline/TFA. Titration of the 6-halopurine nucleosides in CDCl3 with TFA showed progressive downfield 1H NMR chemical shifts for H8 (larger) and H2 (smaller). The major site of protonation as N7 for both the 6-fluoro and 6-bromo analogues was confirmed by large upfield shifts ( approximately 16 ppm) of the 15N NMR signal for N7 upon addition of TFA (1.6 equiv). Mechanistic considerations and resolution of prior conflicting results are presented.

Study Snapshot

The displacement reactivity order for SNAr reactions with 6-(fluoro, chloro, bromo, iodo, and alkylsulfonyl)purine nucleosides is F > I > Br > Cl, with 6-(alkylsulfonyl

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

S(N)Ar displacements with 6-(fluoro, chloro, bromo, iodo, and alkylsulfonyl)purine nucleosides: synthesis, kinetics, and mechanism1.

References

Citations