Non-ionic X-ray contrast agents: Detection of ambient temperature isomers of congested hexasubstituted benzenes with multipositional hindered rotations

Serinol amides of triiodoisophthalic acid bearing an acylamino group are non-ionic x-ray contrast agents; in addition to the expected isomerism due to hindered rotations around the amide NCO bonds, the atropoisomerism associated with the hindered rotations around the aryl–CO and aryl–N bonds was investigated by 1H and 13C NMR. The assignment of signal multiplicity to the different rotamers in solution for a series of N, N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-triiodoisophthaldiamides, 5-substituted with (hydroxyacetyl)amino (5), S-(–)- (2-hydroxy-1-oxopropyl)amino (6), (hydroxyacetyl)methylamino (7), and S-(-)-(2-hydroxy-1-oxopropyl)-methylamino (8) groups was approached by interpreting simpler systems such as S-(–)-3-N-[2-hydroxy-1- (hydroxymethyl)ethyl]-5-[(2-hydroxy-1-oxopropyl)amino]-2,4,6-triiodoissophthalmic acid (2) and its corresponding amide 3, or more symmetric molecules such as N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-amino-2,4,6-triiodoisopht haldiamide (4). It is shown that it is possible to discriminate between the contributions of the different types of hindered rotations in order to obtain the appropriate, although approximate, free energies of activation. Secondary aryl carboxamides 5-8 constitute a rare case of aryl–CO hindered rotation detectable at room temperature. Analysis of the NMR data clearly indicates that in 5-8 the population ratio of the syn and anti families is 1: 1 and also that of the E and Z conformers. In addition, the secondary anilides 5 and 6 show fast rotation around the aryl–N bond and exhibit a conformational preference for the endo isomer only. The tertiary anilides 7 and 8, instead, present the coexistence of the endo and exo forms whose ratio is dependent on the solvent.