Abstract
Kinetics and mechanisms of the oxidation of methoxyurea and N-methylhydroxyurea were studied in neutral and basic aqueous solutions. The obtained pH dependences of the oxidation rates indicate that for both hydroxyureas the reactive species are the deprotonated ones. The second order rate constants, the activation enthalpies and the activation entropies for the reactions of methoxyurea (O-methylhydroxyurea) and N-methylhydroxyurea anions with Fe(CN)6 3− at 25 oC, I = 2 mol dm−3 (NaClO4) were determined as (5.06 ± 0.01) x 102 mol−1 dm3 s−1, (1.92 ± 0.02) x 104 mol−1 dm3 s−1, 27 ± 1 kJ mol−1, 16 ± 1 kJ mol−1, −101 ± 2 J mol−1 K−1, and −107 ± 4 J mol−1 K−1, respectively. The pKa value of methoxyurea at 25 oC and 2 mol dm−3 ionic strength was determined kinetically as 12.7 ± 0.1 and the thermodynamic parameters for the deprotonation reaction were determined as ΔaH = 43 ± 1 kJ mol−1, and ΔaS = −96 ± 4 J mol−1 K−1. When the kinetic results are compared with the data reported for hydroxyurea, an inverse dependence of the rate constants on the pKa of the hydroxyurea derivatives at 25 oC is observed. Such unexpected behaviour has been explained by the ab initio calculations and NBO analysis of HOMOs for all three hydroxyureates. (doi: 10.5562/cca1799)
Highlights
Hydroxyurea (HU) (Chart 1) is a highly specific low molecular weight inhibitor of ribonucleotide reductase, and, of DNA synthesis,[1] with a broad spectrum of anti-tumor effects,[2] which effectively improves clinical outcomes in patients with sickle cell disease.[3,4]Hydroxyureas belong to the family of hydroxamic acids that may act as nitric-oxide donors under oxidative conditions in vitro.[5,6] In reactions with hemoglobin, myoglobin, or hemin, NO may contribute to the overallChart 1
In this study we investigated the mechanism of oxidation of the hydroxyurea derivatives with hexacyanoferrate(III) in aqueous solutions
The obtained difference in stoichiometric coefficients of the hydroxyurea derivatives indicates a rather different reaction mechanism operative in oxidation of MetU compared to the oxidation of NMHU and HU
Summary
Hydroxyurea (HU) (Chart 1) is a highly specific low molecular weight inhibitor of ribonucleotide reductase, and, of DNA synthesis,[1] with a broad spectrum of anti-tumor effects,[2] which effectively improves clinical outcomes in patients with sickle cell disease.[3,4]Hydroxyureas belong to the family of hydroxamic acids that may act as nitric-oxide donors under oxidative conditions in vitro.[5,6] In reactions with hemoglobin, myoglobin, or hemin, NO may contribute to the overallChart 1. Effect of the Initial Concentration of Hydroxyureas With the hydroxyurea derivatives in a large molar excess over Fe(CN)63−, linear dependencies of the calculated pseudo-first order rate constants, kobs, on the concentration of both hydroxyureas were observed (Figure 4).
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