Acido-base behavior of hydroxamic acids: experimental and ab initio studies on hydroxyureas

Acid-base equilibria of hydroxamic acids have been studied extensively, but the specific behavior of hydroxyureas remains less clear. Prior research has shown that monohydroxamic acids follow predictable thermodynamic trends. However, the presence of multiple deprotonation sites in hydroxyureas introduces complexity. This paper investigates whether deviations from expected patterns in thermodynamic parameters suggest alternative dissociation mechanisms. The study addresses a gap in understanding how hydrogen bonding and molecular structure influence acid-base behavior in aqueous environments. It was already known that hydroxamic acids typically deprotonate at the hydroxyl oxygen. This paper explores whether nitrogen atoms also participate in the process. The focus is on thermodynamic parameters and computational modeling to clarify the dissociation sites. The research aims to resolve uncertainties about the primary deprotonation site in hydroxyureas.

The study aimed to determine the acid dissociation constants (pKa) and thermodynamic parameters (ΔSa, ΔHa) for hydroxyurea and N-methylhydroxyurea. The researchers sought to clarify whether these compounds behave as monoprotic or polyprotic acids in water. They also aimed to identify the specific deprotonation site responsible for acid-base behavior. By comparing experimental data with computational models, the study aimed to explain deviations from expected thermodynamic trends. The goal was to assess the role of hydrogen bonding in stabilizing deprotonated forms of these compounds. The study also aimed to distinguish between contributions from hydroxyl oxygen and nitrogen atoms in the dissociation process. The researchers wanted to test whether the hydroxylamino nitrogen or oxygen is the primary site of deprotonation. The ultimate purpose was to provide a molecular-level explanation for the observed acid-base behavior.

The researchers used potentiometric measurements to determine Ka, ΔSa, and ΔHa for hydroxyurea and N-methylhydroxyurea. They compared these values with those of monohydroxamic acids to identify deviations in thermodynamic trends. Ab initio calculations were performed at the MP2/6-311++G(d,p) level of theory to model deprotonation sites. The study considered multiple hydration states, including isolated, monohydrate, trihydrate, and decahydrate forms. Computational methods were used to evaluate the contribution of each potential deprotonation site. The researchers analyzed the relative reaction enthalpy and entropy for each dissociation pathway. They also examined the role of hydrogen bonding in both gas and aqueous phases. The combination of experimental and computational approaches allowed a detailed assessment of acid-base behavior.

The measurements showed that hydroxyurea and N-methylhydroxyurea behave as weak acids with a single pKa around 10. Thermodynamic parameters deviated from expected trends in ΔSa vs ΔHa plots for these compounds. Ab initio calculations revealed that hydroxylamino nitrogen in hydroxyurea contributes about 94% to deprotonation. In contrast, N-methylhydroxyurea shows nearly 100% contribution from hydroxylamino oxygen. The gas-phase calculations indicated significant hydrogen bonding in deprotonated forms of hydroxyureas. The study found that hydration state affects the stability of deprotonated species in aqueous solution. The calculated enthalpy and entropy values explained the observed deviations in thermodynamic plots. These findings suggest that multiple deprotonation sites contribute to acid-base behavior in hydroxyureas.

The study confirms that hydroxyurea and N-methylhydroxyurea behave as weak acids with a single pKa near 10. The observed deviations in thermodynamic parameters suggest multiple deprotonation sites in hydroxyurea. Ab initio calculations support the hydroxylamino nitrogen as the primary deprotonation site in hydroxyurea. In contrast, N-methylhydroxyurea shows nearly exclusive deprotonation at the hydroxylamino oxygen. The study attributes the deviations in ΔSa vs ΔHa plots to contributions from multiple dissociation sites. Hydrogen bonding plays a significant role in stabilizing deprotonated forms in both gas and aqueous phases. The findings suggest that molecular structure influences the primary deprotonation site in hydroxyureas. The results provide a molecular-level explanation for the acid-base behavior of these compounds.