Appendix: Structure and conformation of bilirubin. Opposing views that invoke tautomeric equilibria, hydrogen bonding and a betaine may be reconciled by a single resonance hybrid

Abstract

A novel conformational structure of bilirubin is presented which obtains maximum stabilization through a system of four intramolecular hydrogen bonds. Two hydrogen bonds link oxygen and nitrogen atoms of each end ring to the contralateral carboxyl group. The proposed structure can explain a variety of uncommon features of bilirubin, and reconciles many seemingly contradictory hypotheses by accommodating them in individual structures which are mesomeric forms of one resonance hybrid. In the light of this newly conceived structure the following characteristics of bilirubin are re-evaluated: the stability of the compound, its reaction with diazomethane, the conformational behaviour of its dimethyl ester, its spectral properties, the chirality of the compound when complexed to serum albumin, and the structure of its metal chelates.

The reaction of bilirubin with diazomethane

“…spectroscopy to exist as two molecular species (Kuenzle, 1970a). In the light of a newly conceived conformational structure for bilirubin and bilirubin dimethyl ester (Kuenzle et al, 1973) the two molecular forms of bilirubin dimethyl ester can now be defined as rotational isomers arising from a hindered rotation about the central methylene bridge. The factor that causes restriction of rotation is a system of intramolecular hydrogen bonds that link the ester carbonyl oxygen atoms attached to rings B and C crosswise to the amide protons of the pyrrolenone rings D and A respectively (Fig.…”

“…It therefore seemed worthwhile to reinvestigate the products of this reaction, particularly since the n.m.r. spectrum of dimethoxybilirubin dimethyl ester may afford crucial evidence in support of a newly conceived bilirubin structure that would be maximally stabilized by intramolecular hydrogen bonds (Kuenzle et al, 1973).…”

Comparison of the biliary excretion of the four isomers of bilirubin-IX in Wistar and homozygous Gunn rats

“…The surprising finding that bilirubin-LXa cannot be excreted efficiently without previous conjugation can be understood if one considers the conformation of the isomers. Multiple intramolecular hydrogen bonds in the a-isomer causing efficient shielding of the polar character of the carboxyl groups and of the NH-CO groups of pyrrole rings A and B have been strongly suggested by the work of Blauer et al (1972), Kuenzle et al (1973), Manitto et al (1974, Knell et al (1975) and Bonnett et al (1976). On the other hand, model building showed that such bonds cannot be formed for the non-a-isomers.…”

“…Apparently, this behaviour is related to its apolar character, but is unexpected, since two carboxyl groups are present in the bile pigment. Probably this originates primarily from the involvement of these groups in the formation of multiple intramolecular hydrogen bonds (Blauer et al, 1972;Kuenzle et al, 1973;Manitto et al, 1974;Knell et al, 1975;Bonnett et al, 1976) inhibiting their ionization.…”

Beiträge zur Chemie der Pyrrolpigmente, XXIII [1] Die Struktur eines Bilatrien-abc-Derivates im gelösten Zustande / On the Chemistry of Pyrrole Pigments, XXIII [1] The Structure of a Bilatriene-abc Derivative in the State of Solution

“…Bedenkt man aber die außerordentlich große Anzahl von Möglichkeiten, die für die räumliche Anordnung eines solchen Systems denkbar sind, so nimmt es nicht wunder, wenn es in dieser Richtung kaum Informationen gibt. Lediglich die Arbeiten von Kuenzle [2] und Manitto [3] haben für das Bilirubin Fortschritte gebracht. Wir haben uns in den bisherigen Untersuchungen dieses Problemkreises des Konzepts vom Studium geeigneter Partialstrukturen bedient und zeigen können, daß es mit einer Kombination von Untersuchungsmethoden (NMR, LIS, NOE, UV-VIS, PPP-SCF-LCAO-MO-CI, pK-Messungen) möglich ist, auch komplexere Systeme erfolgreich zu studieren: So konnte erstmals eine struktur-und konformationsanalytische Untersuchung des Chromophors der Bilivioline (Biladiene-ab) zum Ziele gelangen [4].…”