While the gem-dimethyl effect (GDME) is quantitatively similar for cyclizations to cyclopentane and cyclohexane rings and their homomorphs, in systems containing planar segments the GDME is stronger for the formation of five-membered rings. Planar pentagons have smaller angles than planar hexagons and their formation is helped by the decrease in the potential internal bond angle caused by substituents, as suggested by Thorpe and Ingold for small rings. The phenomenon is illustrated with crystal structure data on five-membered hydantoins and six-membered dihydrouracils containing four-atom planar segments. Such a Thorpe-Ingold effect explains the rearrangement in base of N-alkyl substituted dihydroorotic acids 1 to hydantoinacetic acids 3. The reaction involves initial hydrolysis to N-(N-alkylcarbamoyl)aspartic acids 2 and their subsequent cyclization. The unsubstituted N-carbamoylaspartic acid 2a is stable in 1 M KOH, the N(1)-methyl and ethyl compounds 2b and 2c are in equilibrium with the hydantoinacetic acids 3, while the cyclization of the N(1)-isopropyl and cyclohexyl derivatives 2d and 2e is irreversible. Experimental data on equilibria and pK(a)s for ionization of the carboxy and NH groups allow equilibria and rates involving the N-unsubstituted compounds to be estimated and compared with those for the N-alkyl derivatives. The strongest effect is observed on the equilibrium [3(2-)]/2[(2-)], where substitution of H by methyl increases K 600-fold. In vitro the kinetic regioselectivity for acid catalyzed cyclization of N-carbamoylaspartic to hydantoinacetic acid against dihydroorotic acid is only 10:1. This, together with the weaker acidity of the remote carboxyl group, favours cyclization to dihydroorotic acid under biological conditions.

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The cyclization of the title hydantoinamides, UA, to 3-(4nitrophenyl)hydantoins, Hyd, is general-base catalysed. Reversible hydrolysis of the product hydantoin from the 2,3-dimethylhydantoinamide, 2-UA, above pH = 7 is a complicating feature. The rate profiles for cyclization comprise one acid-catalysed, two neutral and two hydroxide-catalysed regions in the pH-region 0-10. Solvent kinetic isotope effects indicate rate-determining expulsion of the methylamino group in the acid-catalysed reaction. These also agree with general-base catalysis a t low p H being concerted with nucleophillic attack of the ureido group. At high pH the tetrahedral intermediate is in equilibrium with the reactants and the rate is limited by proton transfers producing T'. The accelerations upon methyl substitution vary strongly with the various processes observed and may be explained in terms of a general gem-dimethyl effect increasing along the reaction coordinate from reagent through cyclic tetrahedral intermediate to final ring product. As the effects for the breakdown of the intermediate are opposite in the forward and reverse directions, this changes the partitioning ratio and in turn could change the rate-determining step.Models mimicking bioorganic reactions need to react rapidly to permit their study under the mild conditions of interest. The gem-dimethyl or Thorpe-Ingold effect, the favouring of cyclisation upon alkyl substitution in the chain,' is a useful loo1 for accelerating reactions between the functional groups because of the presumably small perturbation of their intrinsic reactivity, the acceleration being due to steric strain. For example the attack of ureido anion on negatively charged carboxylate has been studied as a model of biotin action.2 With respect to such applications, the cyclization of ethyl hydantoate~,~ UE, turned out to be an unusual case. The rate of acid-catalysed cyclization increased by a factor of ca. 30 upon successive introduction of each methyl group in compounds (1-3)-UE; the base-catalysed cyclization of 3-UE was, however, slower than that of 2-UE and, further, the mechanisms of cyclization of the two compounds were different. 0 -V UE; X = OEt, Ar = Ph; UA; X = NHMe, Ar = p-02NGH, HYd R i R2 1 H H 2 Me H 3 Me MeEvidently, for mechanisms established using sterically strained models to be relevant to their biological counterparts, their dependence on structure must be understood. One way to tackle this is to vary the functional groups in the open-chain compounds and observe the effect of alkyl substitution for a wider range of mechanisms.We now report on the cyclization of the methylamides of 5-(p-nitropheny1)hydantoic acids, compounds (1-3)-UA. Although altogether five reaction pathways could be detected in W rn the pH-region studied, a 'normal' gem-dimethyl effect appeared to operate and no change of mechanism was observed. The difference in acceleration brought about by substitution for methyl in the various processes could be rationalised in terms of a general gem-dimethyl effect increasing al...

The cyclisation of N-substituted hydantoic acids involves general acid-base catalysed attack of urea nitrogen on the CO,H group. The variation of the Brsnsted exponents for the reactions of the Nmethyl and N-phenyl derivatives ( 2) and (3) allows a choice between kinetically equivalent mechanisms. Stereoelectronic effects o n the nucleophilic reactions of urea N H are considered, and a mechanism involving an initial rotation about the terminal C-N bond of the ureido group is suggested. * This value compares well with Guler and Moodie's figure of 0.47, based on a two-point Brsnsted plot, for the cyclisation of N-methylaminocarbony lglycine.