Rate constants for hydrogen-atom transfer (HAT) from bilirubin dimethyl ester (BRDE) and biliverdin dimethyl ester (BVDE) to peroxyl radicals during inhibited autoxidation of styrene initiated by azobisisobutyronitrile (AIBN) were kinh(BRDE) = 22.5 ×4 and kinh(BVDE) = 10.2 × 104 M-1 s-1, and the stoichiometric factors (n) were 2.0 and 2.7, respectively. A synthetic tetrapyrrole (bis(dipyrromethene)) containing the α-central (2,2′) CH2 linkage gave kinh = 39.9 × 104 M -1 s-1 and n = 2.3, whereas the β-linked (3,3′) isomer was not an active antioxidant. Several dipyrrinones were synthesized as mimics of the two outer heterocyclic rings of bilirubin and biliverdin. The dipyrrinones containing N-H groups in each ring were active antioxidants, whereas those lacking two such "free" N-H groups, such as N-CH 3 dipyrrinones and dipyrromethenes, did not exhibit antioxidant activity. Overall, the relative kinh values compared to those of phenolic antioxidants, 2,6-di-tert-butyl-4-methoxyphenol (DBHA) and 2,6-di-tertbutyl-4-methylphenol (BHT), were 2,2′-bis(dipyrromethene) > BRDE > DBHA > dipyrrinones > BVDE > BHT. This general trend in antioxidant activities was also observed for the inhibited autoxidation of cumene initiated by AIBN. Chemical calculations of the N-H bond dissociation enthalpies (BDEs) of the typical structures support a HAT mechanism from N-H groups to trap peroxyl radicals. Intramolecular hydrogen bonding of intermediate nitrogen radicals has a major influence on the antioxidant activities of all compounds studied. Indeed, chemical calculations showed that the initial nitrogen radical from a dipyrrinone is stabilized by 9.0 kcal/mol because of H-bonding between the N-H remaining on one ring and the ground-state pyrrolyl radical of the adjacent ring in the natural zusammen structure. The calculated minimum structure of bilirubin shows strong intramolecular H-bonding of the N-H groups with carbonyl groups resulting in the known "ridge-tile" structure which is not an active HAT antioxidant. The calculated minimum structure of biliverdin is planar. BRDE is readily converted into BVDE by reaction with the electron-deficient DPPH· radical under argon in chlorobenzene. An electron-transfer mechanism is proposed for the initiating step in this reaction, and this is supported by the relatively low ionizing potential of a model dipyrrole representing the two central rings of bilirubin.

Additional Metadata
Persistent URL dx.doi.org/10.1021/jo051359e
Journal Journal of Organic Chemistry
Chepelev, L.L. (Leonid L.), Beshara, C.S. (Cory S.), MacLean, P.D. (Patricia D.), Hatfield, G.L. (Gillian L.), Rand, A, Thompson, A. (Alison), … Barclay, L.R.C. (L. Ross C.). (2006). Polypyrroles as antioxidants: Kinetic studies on reactions of bilirubin and biliverdin dimethyl esters and synthetic model compounds with peroxyl radicals in solution. Chemical calculations on selected typical structures. Journal of Organic Chemistry, 71(1), 22–30. doi:10.1021/jo051359e