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

Abstract

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.

N-Chlorination rate of five-membered heterocyclic nitrogen compounds

“…On the other hand, according to the literature available, the hydantoins in aqueous solution can be hydrolyzed. In this process, in which ring‐opening occurs to give the ureido acids as intermediate, which can hydrolyze to α‐amino acids (Scheme ),, it was observed that the rate constant increase with increasing pH . It suggests that the second process observed corresponds with the hydrolysis reaction of the 3‐chlorohydantoin formed.…”

“…In this process, in which ring-opening occurs to give the ureido acids as intermediate, which can hydrolyze to α-amino acids (Scheme 5), [62,63] , it was observed that the rate constant increase with increasing pH. [64][65][66][67][68] It suggests that the second process observed corresponds with the hydrolysis reaction of the 3-chlorohydantoin formed. The mechanism for this hydrolysis reaction should be analogous to that of the hydantoins proposed in the literature.…”

Monosaccharide Ligands in Organotitanium and Organozirconium Chemistry

“…This amine was selected for initial examination as it was expected that cyclization of this substrate would be facilitated by a geminal Thorpe-Ingold effect [17]. The reaction took place in toluene-d 8 at 100 C and was completed in 3.5 h. The reaction work-up was similar to that described for the previous reaction and ( þ )-Moshers acid was used to convert the enantiomers into diastereomers and thus make them detectable for 1 H NMR spectroscopy.…”

Acid catalyzed intramolecular attack of β‐phenylthioureido group on amide function. Parallel formation of thiodihydrouracil and 4‐iminothiodihydrouracil. Different pathways in the Edman degradation reaction in the formation of six‐ versus five‐membered cyclic intermediates

“…With a planar segment and part of the atoms tetragonal, the sum becomes less than 7208 and partly the conflict is resolved by bond angle opening. We have recently studied [14] the extent of bond angle variation in hydantoins and dihydrouracils with a system four conjugated sp 2 atoms by the analysis of X-ray data from the Cambridge Crystal Structure Database. The average angle at the tetragonal atom of hydantoins (451) is (101.2 AE 1.1)8 while those in dihydrouracils (456 and 561) are (109.9 AE 1.…”

“…9)8 and (109.7 AE 1.6)8. This served to explain [14] the much stronger gem-dimethyl or dialkyl effect in five-membered rings with planar segments because the Thorpe-Ingold (The gem-dimethyl effect is exhibited in ring stabilization upon substitution in the chain; the Thorpe-Ingold effect refers to the reduction of adjacent bond angles upon substitution favoring small ring stability.) component helps to reduce the bond angles demanded in the formation of the five-membered rings.…”