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 approximate to 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 (similar to 50 min for the iodo compound and similar to 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 (i)PentSH/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 H-1 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 (similar to 16 ppm) of the N-15 NMR signal for N7 upon addition of TFA (1.6 equiv). Mechanistic considerations and resolution of prior conflicting results are presented.