Table 4.

Kinetic and Thermodynamic Acidity of the C-6 Protons of N-1, N-3 and C-5 Substituted Uracils in Water at 25 °C (Schemes 10 and 11).

Substrate	X	R1	R2	kHO a M−1 s−1	pKCH b
Uridine	H	Ribosyl	H	1.6 × 10−4	28.8 ± 1
Uridine N-3 Anion	H	Ribosyl	Anion	6.3 × 10−9	33.2 ± 1
1,3-Dimethyluracil	H	Me	Me	2 × 10−6 c	30.7 ± 1
5-Fluorouridine	F	Ribosyl	H	0.71	25.1 ± 0.5
5-Fluorouridine N-3 Anion	F	Ribosyl	Anion	2.8 × 10−5	29.6 ± 0.5
1,3-Dimethyl-5-fluorouracil	F	Me	Me	1.8 × 10−2	26.7 ± 0.5

^aSecond-order rate constant for proton transfer from C-6 to hydroxide ion in H₂O, calculated from the value of k_DO for deuterium exchange (Table S8 of the Supporting Information) using a secondary solvent isotope effect of k_DO/k_HO = 2.4 (see text).

^bCarbon acid pK_a for ionization of the substrate at C-6 in H₂O, calculated from k_HO (M⁻¹ s⁻¹) for deprotonation of the carbon acid by hydroxide ion and k_HOH = 10¹¹ s⁻¹ for the reverse protonation of the vinyl carbanion by solvent water, using eq 9.

^cCalculated from data for the competing C-6 deuterium exchange and hydrolysis reactions of the substrate in 1 M NaOD [Ref. 61].