Kinetics of Cyclization of 3-ureidopropionic Acid to Dihydrouracil in Hydrochloric Acid

The kinetics of cyclization of 3-ureidopropionic acid (UPA) to dihydrouracil (DHU) in hydrochloric acid solution has been studied. The reaction was found to be reversible with the equilibrium shifting in favour of UPA with increasing acid strength. It was shown that the failure to cyclize 3-co-Nphenylureidopropionic acid in HCl is due to an equilibrium under which the extent of cyclization is only 30~~. The rate of cyclization of UPA is proportional to the fraction of ureido acid protonated at the ureido.group. pK. of DHU in HC104 was assayed as ca. -4·5. The "r-value". k( 0 , 0 /k(H,Ol ratio and the entropy of activation indicate a mechanism for the acid hydrolysis of DHU involving nucleophilic attack of water concerted with ring opening as the slow step. THE cyclization of P-ureido acids has been studied systematically by Rodionow and Vyazkova and by Johnson and Livak and that of P-ureido esters more recently by Schlogl. These authors reported high yields of dihydrouracils on heating the ureido acids or esters in hydrochloric acid solution with the exception in some cases of m-N-arylsubstituted derivatives where no cyclic product was obtained. However, in all cases (excepting rather bulky m-substituents as o-toluyl or cyclohexyl) cyclization could be achieved by treating the ureido acids with acetic anhydride or acetyl chloride. Kurtev et al. 5 have studied the cyclization of diastereomeric P-ureido acids or esters and used the difference in yields or rates of formation of dihydrouracils as a method for establishing relative configurations. The effect of the latter on reactivity could be interpreted by assuming that the reaction passes through a tetrahedric transition state of the type usually considered important in ester hydrolysis. With the view to obtain more data relating to the mechanism of the reaction in HCl, a study of the kinetics of cyclization of the simplest representative-3ureidopropionic acid, was undertaken the results of which are reported in the present paper. Notwithstanding the amount of work done on hydantoins, the kinetics of cyclization of hydantoic acids has not been studied. RES UL TS* Reversibility of the reaction The first interesting observation revealed by the kinetic experiments was that the * H 0 -values were taken from M. Paul and F. Long. Chem. Rev. 57. 1 ( 1957). 1 Taken in part from Cand. Chem. Sc. Thesis. Bulg. Acad. Sc. Sofia (I 964). 2 W. Rodionow and S. Vyazkova. Zh. Obsch. Khim. 3. 628 (1933). 3 T. Johnson and I. Livak. J. Am. Chem. Soc. 58, 299 (1936). 4 K. Schlogl. Mh. Chem. 89. 61 (1958). 5 B. Kurtev, M. Lyapova, N. Berova, I. Pojarlieff, A Orahovatz, N. Mollov and P. erneva m press. Reported in part at the XIX'• IUPAC Congress, London (1963).