Benzoylbiliverdins from chemical oxidation of dodeca-substituted porphyrins

Article abstract of DOI:10.1039/b306586c

Oxidation of dodeca-substituted porphyrin 1 in the presence of NaNO ₂/TFA and air afforded benzoylbiliverdin 3 in 77% yield; under similar conditions the Ni(II)-porphyrin 2 was mainly nitrated at a cyclohexenyl ring; key X-ray structures are presented.

Full text of DOI:10.1039/b306586c

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Benzoylbiliverdins from chemical oxidation of dodeca-substituted
porphyrins†
Owendi Ongayi, Frank R. Fronczek and M. Graça H. Vicente*
Department of Chemistry, Louisiana State University, Baton Rouge, LA 70803, USA
Received (in Corvallis, OR, USA) 9th June 2003, Accepted 17th July 2003
First published as an Advance Article on the web 4th August 2003
Oxidation of dodeca-substituted porphyrin 1 in the presence
of NaNO2/TFA and air afforded benzoylbiliverdin 3 in 77%
yield; under similar conditions the Ni(II)-porphyrin 2 was
mainly nitrated at a cyclohexenyl ring; key X-ray structures
are presented.
verdins, 4 and 5 were found to be highly stable to air, mildly
acidic and basic conditions, and highly soluble in organic
solvents.
Metallo-porphyrins are traditionally photooxidized to give the
corresponding metallo-formylbiliverdins,1 which can be further
degraded to produce bilirubins and, ultimately, maleimides and
succinimides. This reaction mimics the major biochemical
processes of heme catabolism and chlorophyll degradation.1,2
On the other hand, metallo-meso-tetraarylporphyrins, such as
5,10,15,20-tetraphenylporphyrin (TPP), can be oxidized to
benzoylbiliverdins by chemical oxidation using cerium(IV) or
thallium(III) salts,3 by reactions of metalloporphyrin p-cation
radical with nucleophiles,4 and by photooxygenation.5,6 In
general, the yields reported for the benzoylbiliverdin of TPP
using these procedures are low. Herein we report the ready
preparation of a stable benzoylbiliverdin from a metal-free
The molecular structure‡ of Ni(II)-biliverdin 4 is given in Fig.
1. The oxidized, nonmacrocyclic nature of the ligand forces
distortions from square-planar coordination of the Ni(II) center.
The N atoms at the oxidized ends of the ligand lie 0.65(1) and
20.68(1) Å out of the plane defined by the Ni and the two
central N atoms. Ni–N distances fall within the range
1.835(8)–1.884(7) Å. The benzoyl O atom forms a longer
intramolecular distance of 2.882(7) Å to the Ni atom.
The UV-Vis of benzoylbiliverdins 3–5 are given in Fig. 2.
Typically, porphyrin macrocycles, such as 1 and 2, display
strong absorptions in the visible region of the spectrum, namely
a Soret band between 390–440 nm and less intense Q bands
between 500–680 nm. Oxidation and opening of the porphyrin
macrocycle cause the disappearance of these bands in agree-
ment with literature reports on the biliverdin of TPP.3,5 In
contrast, the Ni(II) and Cu(II) complexes 4 and 5 display strong
absorptions in the visible and near-IR regions (Fig. 2) possibly
as a result of their cyclic conformation. In addition, the
fluorescence spectrum of diamagnetic complex 4 shows a single
dodeca-substituted porphyrin 1, in 77% yield, and of its Ni(II
)
and Cu(II) metal complexes.
Porphyrin 1 was found to be readily oxidized in the presence
of NaNO2 and trifluoroacetic acid (TFA). Under these condi-
tions TPP is regioselectively nitrated at the p-positions of the
meso-phenyl rings.7 However, due to the steric hindrance
caused by the peripheral substituents of 1,8 this porphyrin is
easier to oxidize than TPP under these conditions, and reacts so
as to relieve steric strain. Other examples of the unusual
reactivity of non-planar porphyrin macrocyles are reported in
the literature.9,10
When 6 equiv. of NaNO2 were added to a concentrated green
solution of 111 (45 mg) in TFA (3 mL) under air, the color of the
solution immediately changed to brown. After stirring for 10
minutes under air at room temperature, the reaction mixture was
quenched with water and neutralized. The major purple product
isolated, in 77% yield, was benzoylbiliverdin 3, along with 6%
recovered starting material 1 and trace amounts of polynitrated
products. When the same reaction was performed under an inert
atmosphere of argon, or in the absence of TFA using CH2Cl2 as
solvent, only starting material 1 was recovered. No spectro-
scopic evidence was found during the reaction for the
involvement of an isoporphyrin intermediate, and a radical
scavenger (2,6-di-tert-butyl-4-methylphenol) added to the reac-
tion mixture completely inhibited the formation of benzoylbili-
verdin 3. These results indicate that the mechanism of the
reaction may involve oxidation of the porphyrin macrocycle to
the corresponding p-cation radical by NO+,9,12 followed by
reaction with air oxygen and ring opening. No benzoylbili-
verdin 3 was detected when porphyrin 1 or its Zn(II) or Ni(II
)
complexes were stirred under normal laboratory fluorescent
light and a stream of air for up to 48 h. Metal insertion into 3
using Ni(II) or Cu(II) acetate in refluxing toluene under argon
gave the metal complexes 4 and 5, in quantitative and 80%
yields, respectively. Unlike previously reported metallo-bili-
† Electronic supplementary information (ESI) available: selected data for
3–6; scheme showing the formation of 6 and 7 from Ni(II)-porphyrin 2. See
http://www.rsc.org/suppdata/cc/b3/b306586c/
Fig. 1 Molecular structure of Ni(II)-benzoylbiliverdin 4.
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emission band at 895 nm upon excitation at 438 nm, in CHCl3,
which indicates that such compounds can potentially be
developed as near-IR fluorescent markers.
Under similar conditions, albeit in the presence of a catalytic
amount of TFA to prevent immediate demetalation, the Ni(II)-
porphyrin 2 was mainly nitrated13 at a cyclohexenyl ring,
presumably because NO+ is not formed in significant amount
under these conditions. When a mixture of Ni(II) complex 2 and
1.5 equiv. of NaNO2 in 1% TFA/toluene was stirred at room
temperature under air for 12 hours, the benzoylbiliverdin 4 was
obtained in only 10% yield. The major product of this reaction
was nitro-cyclohexadienylporphyrin 6, in 40% yield, and
recovered starting material 2, in 30% yield. When the reaction
was heated to 50 °C overnight, the major product obtained was
the regioisomer nitro-cyclohexadienylporphyrin 7, in 40%
yield. This compound could also be prepared quantitatively
from 6, by acid catalyzed isomerization, in 1% TFA/toluene.
This double bond isomerization allows the 2A sp2 carbon to
move away from the adjacent meso-phenyl ring by becoming
sp3 hybridized, which decreases steric hindrance. Under the
above reaction conditions, the Ni(II)-porphyrin 2 is probably
initially oxidized to the corresponding cyclohexenylporphyrin
and subsequently nitrated at the double bond to produce 6,
followed by acid catalyzed isomerization to give 7. A similar
nitration of the vinyl groups of protoporphyrin-IX dimethyl
ester has been previously reported.12
Nitrated porphyrins 6 and 7 are characterized by a M+ peak at
m/z 929.1 in their MS (ESI), and the aborption bands of 6 in the
UV-Vis spectrum are red-shifted by 12 nm compared with those
of 7. The molecular structure‡ of Ni(II) complex 7 is given in
Fig. 3. Coordination of the Ni(II) center is square planar with a
slight tetrahedral distortion. N atoms lie alternately 0.16(1) Å
from the N4Ni best plane, in which the Ni lies. Ni–N distances
range 1.905(9)–1.920(8) Å. The molecule has an overall saddle
shape. The NO2 group is occupationally disordered on two
rings, being present 60(1)% of the time in the position shown,
and 40(1)% of the time (not shown) in the position related by a
90° clockwise rotation in Fig. 3. The C atoms shown with open
circles in both rings are also disordered, as the ring is
unsaturated when the NO2 is present.
In summary, we have synthesized novel undeca-substituted
benzoylbiliverdins by mild oxidation, in the presence of air and
NaNO2/TFA, of metal-free dodeca-substituted porphyrin 1. The
Ni(II) and Cu(II) complexes of the benzoylbiliverdin show
intense absorption bands in the visible and near-IR, and the
Ni(II) complex 4 displays a fluorescence band in the IR region.
Nitro-cyclohexadienylporphyrins 6 and 7 were the major
products obtained under similar conditions but using only a
catalytic amount of TFA, from Ni(II)-porphyrin 2.
Fig. 3 Molecular structure of 7. The NO2 group and two six-membered rings
are disordered (see text).
Notes and references
‡ Ni(II) benzoylbiliverdin 4, C60H52N4NiO2·CH2Cl2·MeOH·0.5H2O, Mr
=
1045.7, monoclinic, space group P21/c, a = 18.426(13), b = 13.713(13), c
= 23.955(19) Å, b = 101.90(4)°, V = 5923(8) Å3, Z = 4, rcalc = 1.173 g
cm23, Mo-Ka radiation (l = 0.71073 Å; m = 0.464 mm21), T = 100 K,
28976 data by Nonius KappaCCD, R = 0.130 (F2 > 2s), Rw = 0.370 (all
F2) for 7610 unique data having q < 23.3° and 684 refined parameters.
There is considerable disorder involving the MeOH and water solvent
molecules. Ni(II) nitrocyclohexylporphyrin 7, C60H49N5NiO2·0.5H2O, Mr
= 939.8, monoclinic, space group P21/c, a = 16.369(7), b = 23.960(9), c
= 13.461(5) Å, b = 101.39(2)°, V = 5176(4) Å3, Z = 4, rcalc = 1.206 g
cm23, Mo-Ka radiation (l = 0.71073 Å; m = 0.423 mm21), T = 100 K,
25395 data by Nonius KappaCCD, R = 0.112 (F2 > 2s), Rw = 0.341 (all
F2) for 6891 unique data having q < 22.5° and 594 refined parameters.
CCDC 211040 (4) and 211039 (7). See http://www.rsc.org/suppdata/cc/b3/
b306586c/ for crystallographic data in CIF or other electronic format.
1 F. R. Hopf and D. G. Whitten, in Porphyrins and Metalloporphyrins, ed.
K. M. Smith, Elsevier Science, Amsterdam, 1975, p. 667.
2 B. Krautler, in The Porphyrin Handbook, ed. K. M. Kadish, K. M. Smith
and R. Guilard, Academic Press, Boston, 2003, vol. 13, p. 82.
3 B. Evans, K. M. Smith and J. A. S. Cavaleiro, J. Chem. Soc., Perkin
Trans. 1, 1978, 7, 768.
The work described herein was partially supported by NSF
CRC 304833 and by the LSU BOR LEQSF(02-05)-RD-A-05.
4 H. J. Shine, A. G. Padilla and S. M. Wu, J. Org. Chem., 1979, 44,
4069.
5 K. M. Smith, S. B. Brown, R. F. Troxler and J.-J. Lai, Tetrahedron Lett.,
1980, 21, 2763.
6 K. M. Smith, S. B. Brown, R. F. Troxler and J.-J. Lai, Photochem.
Photobiol., 1982, 36, 147.
7 A. Maderna, R. Huertas, M. F. Hawthorne, R. Luguya and M. G. H.
Vicente, Chem. Commun., 2002, 1784.
8 K. M. Barkigia, M. W. Renner, L. R. Furenlid, C. J. Medforth, K. M.
Smith and J. Fajer, J. Am. Chem. Soc., 1993, 115, 3627.
9 T. Ema, M. O. Senge, N. Y. Nelson, H. Ogoshi and K. M. Smith, Angew.
Chem., Int. Ed. Engl., 1994, 33, 1879.
10 M. O. Senge, in The Porphyrin Handbook, ed. K. M. Kadish, K. M.
Smith and R. Guilard, Academic Press, Boston, 2000, vol. 1, p. 239.
11 C. J. Medforth, M. D. Berber, K. M. Smith and J. A. Shelnutt,
Tetrahedron Lett., 1990, 31, 3719.
12 R. Bonnett, M. B. Hursthouse, P. A. Scourides and J. Trotter, J. Chem.
Soc., Perkin Trans. 1, 1980, 2, 490.
13 S. Uemura, A. Toshimitsu and M. Okano, J. Chem. Soc., Perkin Trans.
1, 1977, 9, 1076.
Fig. 2 Comparison of the absorption spectra (in CH2Cl2) of benzoylbili-
verdins 3 (…), 4 (Ã) and 5 (—).
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