Ivan G. Pojarlieff

β-Ureido acids and dihydrouracils—VII: Applications of proton resonance spectroscopy—XXXII nmr spectra and conformation of dihydrouracils and related compounds

Abstract The NMR spectia of the cis and trans -isomers of 5,6-tetramethylenedihydrouracil (2,4-dioxo-decahydroquinazoline, TMDHU), 5,6-dimethyldihydrouracil (DMeDHU), 5,6-diphenyldihydrouracil (DPhDHU), 5-methyldihydroorotic acid (MeDHO), as well as those of dihydroorotic acid (DHO) and its methyl ester, and 6-phenyldihydrouracil (PhDHU) are reported. The J trans and J 16 coupling constants of these and other dihydrouracils are used in the conformational analysis. Contrary to earlier suggestions 3,4 of widely varying distortion of the dihydrouracil ring, the variation of cis J 56 and J 16 is best explained by electronegativity and equilibrium effects. Carboxy and methoxycarbonyl groups at C-6 prefer the axial orientation. A phenyl group at C-6. and the two phenyls in trans -DPhDHU, are predominantly axial in dimethyl sulphoxide, but equatorial in trifluoroacetic acid. The coupling constants of the cis and trans isomers of 2-ureidocyclohexane carboxylic (UCHA) and of the erytho and threo isomers of 2-methyl-3-ureidobutyric acid (MeUBA) and of 2,3-diphenyl-3-ureidopropionic acid (DPhUPA) indicate that with both isomers of MeUBA conformers with gauche hydrogens are preferred, while in the case of DPhUPA trans hydrogens predominate.

Thorpe–Ingold effects in cyclizations to five-membered and six-membered rings containing planar segments. The rearrangement of N(1)-alkyl-substituted dihydroorotic acids to hydantoinacetic acids in base

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.

Intramolecular nucleophilic attack by urea nitrogen. Reactivity–selectivity relationships for the general acid–base catalysed cyclisations of ureido acids and esters

The cyclisation of N-substituted hydantoic acids involves general acid–base catalysed attack of urea nitrogen on the CO2H group. The variation of the Bronsted exponents for the reactions of the N-methyl and N-phenyl derivatives (2) and (3) allows a choice between kinetically equivalent mechanisms. Stereoelectronic effects on the nucleophilic reactions of urea NH are considered, and a mechanism involving an initial rotation about the terminal C–N bond of the ureido group is suggested.

Kinetics and mechanism of the cyclization of ω-(p-nitrophenyl)-hydantoic acid amides: steric hindrance to proton transfer causes a 104-fold change in rate

The pH-rate profiles for the cyclization of primary 2,3-dimethyl and 2,2,3-trimethyl-hydantoinamides (2-UAm and 3-UAm respectively) differ strikingly from those for the cyclizations of the corresponding N-methylated amides 2-MUAm and 3-MUAm; which are dominated by the water reaction, spanning some 6 pH units. For the cyclization of UAm the plateau extends over no more than two pH units. The difference is due to the slower base-catalyzed cyclization of the N-methylamides. The solvent kinetic isotope effect for this hydroxide-catalyzed reaction is close to 1.2, consistent with a slow protonation by water of the amino-group of the negatively charged tetrahedral intermediate. General base catalysis was observed with bases of pKBH up to 8. The Brønsted beta are compatible with a hydrogen bonding mechanism for the GBC. In the gem-dimethyl compounds 3 the leaving group is flanked by substituents on both sides. The N-methyl group in 3-MUAm hinders frontal access of the proton, causing a 14000 fold decrease in rate. This is only 3800 fold in the compound with one methyl group at position 2.

Conformational energy analysis of substituted diphenylethanes

Abstract The geometry and energy of the stable conformations of the isomeric forms of 1,2-halogeno-1,2-diphenylethanes have been obtained by means of empirical energy functions. A minimization of the conformational energy with respect to the torsion angles and the valence angles around the asymmetrically substituted carbon atoms has been carried out. The evaluated populations of the stable conformations showed good agreement with available experimental data. CNDO/2 calculations on the low-energy conformations of the isomeric forms of 1,2-difluoro-, 1,2-fluorochloro-, and 1,2-dichlorodiphenylethane have been carried out. These yielded improved estimates of the dipole moments for the dichloro isomers.

Intramolecular nucleophilic attack on carboxylate by ureide anion. General acid–base catalysis of the alkaline cyclisation of 2,2,3,5-tetramethylhydantoic acid

The cyclisation of the title compound to the corresponding hydantoin is a model for the carboxylation of biotin by hydrogen carbonate. The reaction is rapid over the whole pH range, and is catalysed by both general acids and general bases. Above pH 9.2 the reaction is first order in hydroxide, which is shown to act as a general bases. The preferred mechanism is specific base–general acid catalysis, involving nucleophilic attack by the ureide anion on the ionised carboxy group, assisted by proton transfer from the general acid. This defines also the mechanism of the reverse reaction, and clarifies for the first time the role of the second hydroxide ion in the [HO–]2 term for the hydrolysis of amides with good leaving groups.

Conformational energy analysis of substituted diphenylethanes: Part VI. Calculations of the solvent dependence of the conformational equilibria in stilbene dihalogenides. Intramolecular interactions in the PCILO fr

Abstract As part of a theoretical analysis of the conformational equilibria of stilbene dihalogenides, the free energy at 300 K of each stable conformational isomer of these molecules has been estimated for a solvent of dielectric constant 3.5. Classical empirical potential functions were used. Interaction with the solvent was considered only in terms of a continuous dielectric medium interacting with the local dipoles and quadrupoles of the molecule. Simulation of the experimental conditions (i.e. appropriate values for the dielectric constant of the solvent) yielded better agreement with the available experimental data, which were mainly dipole moments and optical rotation values. The quadrupole energy term has a very small influence on the calculated conformational populations and can be neglected when dibenzyl derivatives are considered. The mechanism of the intramolecular interactions is discussed within the PCILO framework.

Molecular mechanics of diastereoisomers with phenyl groups on neighbouring carbon atoms

Abstract Results are summarized from systematic studies by the molecular mechanics method of the conformations of diastereoisomeric pairs of 1,2-disubstituted-1,2-diphenylethanes. An overall result in both series is the preference for conformations with the minimal number of synclinal interactions around the C(1)C(2) bond. Special attention is devoted to the performance of the MM2 force field with the 1,2-diarylethane system. With the readjustment of the V 1 parameter for the torsional unit C ar C al C al C ar MM2 operates reasonably well in the case of substituents of a moderate size. For the 1,2,3-triphenylpropane system however, where phenyl groups participate in 1,3-parallel interactions, this force field fails completely. A further more substantial revision of the MM2 force field is necessary in order to achieve internal consistency between different energy contributions in such systems.

1H NMR spectra and structure of safranines. Hindered rotation of the 3-dialkylamino group in 7-azo derivatives

The 1 H NMR spectra of safranine derivatives are reported. Semiempirical calculations indicate that the high shielding of the 4- and 6-proton adjacent to an amino or hydroxyl group (resonating between 5.5 and 6.0 ppm) is due to accumulation of negative charge on the 4- and 6-C atoms, augmented by the magnetic anisotropy effect of the orthogonal 5-phenyl ring. The ortho protons of the latter resonate up field to the meta and para protons. Hindered rotation of dialkylamino groups, altogether unexpected in view of the rather low barriers in similar anilines, is observed only in the azo derivatives. AM 1 suggest that this is due to destabilization of the transition state when an amino group is substituted for an azo group.

β-Ureido acids and dihydrouracils. Part 15. Effect of allylic strain on ring opening of 1,6-disubstituted dihydrouracils

The rate profiles for the alkaline hydrolysis of some dihydrouracil and dihydro-orotic acid derivatives have been measured in order to assess the effect of allylic strain on the ring opening of 1,6-disubstituted dihydrouracils. The introduction of a 1-nitrogen-substituent in the 6-substituted compounds brings about a substantial decrease (40–500 times) in the observed rate constant which is second order in hydroxide ion (k1k3/k–1). The rate decreases of the addition step, k1, are moderate and in the range expected from the observed shifts in conformational equilibria towards the axial conformation which gives rise to a hindered transition state. The major contributions to the rate decreases arise from the ring-opening step, k3/k–1, and have been attributed to strains of the type associated with the gem-dimethyl effect upon ring closure.