Rate-limiting step and micellar catalysis of the non-classical nitro group nucleophilic substitution by thiols in 4-nitro-N-n-butyl-1,8-naphthalimide

Nitronaphthalimides are a particularly interesting group of nitroaromatics used for staining cells in hypoxia and in photodynamic therapy. The kinetics of the aromatic nucleophilic substitution of the nitro‐group of 4‐nitro‐N‐n‐butyl‐1,8‐naphthalimide (4‐NBN) by n‐heptanethiol (RSH), thiophenol (ArSH) and 2‐hydroxy‐1‐ethanethiol (HESH) in aqueous solutions containing micelles and in water–methanol mixtures were analyzed. The substitution of the nitro group by aromatic or aliphatic thiols led to fluorescent substitution products. Hexadecyltrimethylammonium chloride micelles (CTAC) increased the rate of thiolysis of 4‐NBN by 1 × 105 (RSH) and 4 × 105 (ArSH) fold. For the reaction of ArSH with 4‐NBN the calculated second‐order rate constant in the micellar phase, k2m, is 1.4 times higher than that in the aqueous phase, k2w. For the reaction of ArSH with 4‐NBN, k2m/k2w = 0.05. Both k2w and k2m decreased with increasing pKa of the thiol, suggesting that thiolate attack is not rate limiting in either the aqueous phase or micellar pseudophase. The high micellar rate acceleration is therefore largely due to concentration of the reagents in the micellar phase and effects on the thiol acid–base equilibrium. Copyright © 2003 John Wiley & Sons, Ltd.