Synthesis of 5-(4-hydroxyphenyl)-10,15,20-tris[3,5-di(tert-butyl)-4- hydroxyphenyl]porphine and 5-(4-palmitoyloxyphenyl)-10,15,20-tris[3,5-di(tert- butyl)-4-hydroxyphenyl]porphine and generation of phenoxyl radicals from them

Article abstract of DOI:10.1007/s11172-007-0124-y

A porphyrin with a lipophilic hydrocarbon substituent, 5-(4- palmitoyloxyphenyl)-10,15,20-tris[3,5-di(tert-butyl)-4-hydroxyphenyl]porphine, was synthesized for the first time by acylation of 5-(4-hydroxyphenyl)-10,15,20- tris[3,5-di(tert-butyl)-4-hydroxyp

Full text of DOI:10.1007/s11172-007-0124-y

Russian Chemical Bulletin, International Edition, Vol. 56, No. 4, pp. 831—834, April, 2007
831
Brief Communications
Synthesis of 5ꢀ(4ꢀhydroxyphenyl)ꢀ10,15,20ꢀtris[3,5ꢀdi(tertꢀbutyl)ꢀ
4ꢀhydroxyphenyl]porphine and 5ꢀ(4ꢀpalmitoyloxyphenyl)ꢀ10,15,20ꢀ
tris[3,5ꢀdi(tertꢀbutyl)ꢀ4ꢀhydroxyphenyl]porphine
and generation of phenoxyl radicals from them
O. A. Gerasimova,аꢀ E. R. Milaeva,а D. B. Shpakovsky,а A. S. Semeikin,b and S. A. Syrbub
аChemistry Department, M. V. Lomonosov Moscow State University,
1 Leninskie Gory, 119992 Moscow, Russian Federation.
Fax: +7 (495) 939 5546. Eꢀmail: olgagerasimova@inbox.ru
bIvanovo State Academy of Chemical Technology,
7 prosp. F. Engelsa, 153460 Ivanovo, Russian Federation.
Fax: +7 (093 2) 41 7742
A porphyrin with a lipophilic hydrocarbon substituent, 5ꢀ(4ꢀpalmitoyloxyphenyl)ꢀ10,15,20ꢀ
tris[3,5ꢀdi(tertꢀbutyl)ꢀ4ꢀhydroxyphenyl]porphine, was synthesized for the first time by acylaꢀ
tion of 5ꢀ(4ꢀhydroxyphenyl)ꢀ10,15,20ꢀtris[3,5ꢀdi(tertꢀbutyl)ꢀ4ꢀhydroxyphenyl]porphine. Oxiꢀ
dation of these compounds with PbO2 in toluene leads to the corresponding phenoxyl radicals.
Key words: porphyrins, 2,6ꢀdi(tertꢀbutyl)phenol, phenoxyl radicals, EPR, lipophilic groups.
Porphyrins are parts of a numerous biochemical sysꢀ
tems, while their synthetic analogs find application in
pharmacology and medicine.1—3 Lipophilic properties of
porphyrins and their complexes with various metals enꢀ
sure the accumulation of these compounds in the lipid
bilayer of cell membranes and transport into the living
cells. At the same time, the structural and functional simiꢀ
larity of synthetic metalloporphyrins with the active cenꢀ
ters of oxidoreductases is the reason for their catalytic
activity in oxidation reactions of organic substrates.4 Inꢀ
teraction of exogenous porphyrins with membraneꢀbound
proteins and transport of porphyrins into the cells can be
accompanied by chemical processes resulting in the deꢀ
struction of the protein structure and in the formation of
byꢀproducts.5 In this connection, the use of porphyrins,
for example, as sensitizers in the diagnostics of tumor
diseases is complicated by side processes of oxidative deꢀ
struction of biological substrates. In this case, the presꢀ
ence of antioxidants is required.
Earlier, it was shown that polyfunctional systems are
formed upon introduction of antioxidant fragments,
2,6ꢀdialkylphenols, into complexes of metals with macroꢀ
cyclic ligands, porphyrins and phthalocyanines.6,7 Such
compounds show catalytic or antioxidant properties deꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 800—803, April, 2007.
1066ꢀ5285/07/5604ꢀ0831 © 2007 Springer Science+Business Media, Inc.

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Gerasimova et al.
pending on the metal nature. A model reaction of lipid
peroxidation with the use of (Z )ꢀoctadecꢀ9ꢀenoic acid
demonstrated8 that tetrakis[3,5ꢀdi(tertꢀbutyl)ꢀ4ꢀhydroxyꢀ
phenyl]porphyrin shows high antioxidant activity.
The present work is aimed at the synthesis of polyꢀ
functional porphyrins combining, in one molecule,
2,6ꢀdi(tertꢀbutyl)phenol moieties as antioxidant substituꢀ
ents and a lipophilic fragment, which enables incorporaꢀ
tion of such a porphyrin into the lipid bilayer of cell
membranes.
leads to porphyrin 2a containing a higher saturated fatty
acid residue (Scheme 1).
Compounds 1a and 2a are crystalline substances stable
in air and in solutions. The structures of the compounds
obtained are confirmed by the IR, UV, 1Н and 13С NMR
spectroscopic data, as well as by analytical data. In the
IR spectra, sharp absorption bands are present in the reꢀ
gion 3620—3640 cm–1 corresponding to the stretching viꢀ
brations of the О—Н bond of the spatially hinꢀ
dered nonassociated phenolic group and in the region
3403—3426 cm–1 (associated OH group of phenol). In
the UV spectra, the absorption bands characteristic of the
free porphyrin bases10,11 are observed: the Soret bands at
424 and 427 nm and four bands of lower intensity in the
regions 652—522 and 650—521 nm, respectively, for comꢀ
pounds 1a and 2a, which confirms the formation of the
porphyrin ring. Introduction of a longꢀchain hydrocarꢀ
bon substituent into the porphyrin molecule results in a
slight shift of the absorption bands toward the shortwave
Results and Discussion
The synthesis of nonꢀsymmetrical porphyrin 1a conꢀ
taining three residues of sterically hindered 2,6ꢀdi(tertꢀ
butyl)phenol and one phenol fragment in mesoꢀpositions
of the macrocycle9 was modified enabling us to increase
the product yield. Acylation of 1a with palmitoyl chloride
Scheme 1

Porphyrins with phenolic and palmitoyl groups
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 4, April, 2007
833
tered on a Bruker ELEXSYS Eꢀ500ꢀ10/12 radiospectrometer in
the Хꢀrange of 9.853 GHz ( 3 cm). The measurements were
λ
carried out following evacuation of the ampoules with the sample
solutions (concentrations of 1•10–4 mol L–1). The oxidizing
reagent was used in tenfold excess.
5ꢀ(4ꢀHydroxyphenyl)ꢀ10,15,20ꢀtris[3,5ꢀdi(tertꢀbutyl)ꢀ4ꢀ
hydroxyphenyl]porphine (1a).9 A mixture of chloroacetic acid
(2.6 g) and оꢀxylene (100 mL) was heated to reflux under argon.
A solution of pyrrole (1 mL, 14.4 mmol), 4ꢀhydroxybenzaldehyde
(0.44 g, 3.6 mmol), and 3,5ꢀdi(tertꢀbutyl)ꢀ4ꢀhydroxybenzꢀ
aldehyde (2.5 g, 10.8 mmol) in оꢀxylene (10 mL) was added to
the resulting mixture. This was refluxed for 0.5 h under argon
and for another 1.5 h with bubbling of air, cooled and neutralꢀ
ized with aq. ammonia. The solvent was evaporated by steam
distillation, the precipitate was filtered off, washed with water,
and dried in open air at 70 °С. The dried precipitate was disꢀ
solved in benzene (100 mL). The product was isolated by twoꢀ
fold column chromatography (benzene—methanol, 100 : 1). The
eluate was concentrated to the minimum volume and porphyrin
was precipitated by addition of methanol (30 mL). The precipiꢀ
tate was filtered off, washed with methanol, and dried in open
air at 70 °С. The yield was 0.45 g (13.6%). Rf 0.60 (benꢀ
zene—methanol, 10 : 1). Found (%): C, 80.44; H, 7.70; N, 5.34.
C68H78N4O4. Calculated (%): C, 80.44; H, 7.74; N, 5.52. IR,
ν/cm–1: 3626 (nonassociated ОН groups), 3403 (associated
ОН group). UV, λmax/nm (logε): 652 (3.86); 595 (3.75); 560
(4.09); 522 (4.15); 425 (5.63). 1H NMR (CDCl3), δ: 1.70 (s,
54 H, 6 CMe3); 5.59 (s, 3 H, 3 OH); 7.04 (d, 2 H, 2 C(17)H, J =
8.0 Hz); 8.09 (d, 2 H, 2 C(18)H, J = 8.0 Hz); 8.13 (s, 6 H,
6 C(3)H); 8.91 (d, 2 H, 2 C(12)H, J = 4.0 Hz); 9.0 (d, 2 Н,
2 C(13)H, J = 4.0 Hz); 9.03 (s, 4 Н, 2 C(7)H, 2 C(8)H).
13C (CDCl3), δ: 30.74 (6 C(CH3)); 34.61 (6 C(CH3)); 113.55,
119.20, 121.27, 131.94, 132.04, 134.02, 135.60, (3 C6H2, C6H4,
4 C4H2N); 153.59 (C(1)); 155.27 (C(19)).
5ꢀ(4ꢀPalmitoyloxyphenyl)ꢀ10,15,20ꢀtris[3,5ꢀdi(tertꢀbutyl)ꢀ4ꢀ
hydroxyphenyl]porphine (2a). A solution of palmitoyl chloride
(1.0 g, 3.64 mmol) in anhydrous pyridine (5 mL) was added to a
solution of porphine 1a (100 mg, 0.11 mmol) in anhydrous
pyridine (15 mL) with stirring at ambient temperature. The
mixture was stirred at this temperature for 20 h and then poured
in water (100 mL). The precipitate was filtered off, washed with
water, and dried in open air at ambient temperature. The prodꢀ
uct was dissolved in chloroform and isolated by column chroꢀ
matography on Al2O3 (Brockmann) with chloroform as the eluꢀ
ent. The eluate was concentrated to the minimum volume and
diluted with methanol (30 mL). The precipitate was filtered off,
washed with methanol, and dried in open air at ambient temꢀ
perature. The yield was 0.11 g (86.4%). Found (%): С, 80.51;
H, 8.59; N, 4.28. С84H108N4O5. Calculated (%): С, 80.46;
H, 8.68; N, 4.46. IR, ν/cm–1: 3639 (nonassociated ОН groups),
3426 (associated ОН group). UV, λmax/nm (logε): 650 (3.93);
593 (3.87); 558 (4.11); 521 (4.22); 424 (5.64). 1Н NMR (CDCl3),
δ: 0.93 (t, Me, J = 8.0 Hz); 1.26—1.99 (m, 26 H, (CH2)12); 1.69
(s, 54 H, 6 CMe3); 2.80 (t, 2 H, CH2CO, J = 8.0 Hz); 5.59 (s,
3 H, 3 OH); 7.55 (d, 2 H, 2 C(17)H, J = 8.0 Hz); 8.10 (s, 6 H,
6 C(3)H); 8.30 (d, 2 Н, 2 С(18)H, J = 8.0 Hz); 8.91 (d, 4 H,
2 C(12)H, 2 C(13)H, J = 4.0 Hz); 8.99 (d, 4 Н, 2 С(7)H,
2 C(8)H, J = 8.0 Hz). 13C NMR (CDCl3), δ: 14.17 (Me); 29.75
(13 CH2); 30.71 (6 C(CH3)); 31.97 (CH2CO); 34.61 (6 C(CH3));
119.81, 121.36, 131.90, 132.04, 133.32, 134.02, 135.29 (3 C6H2,
C6H4, 4 C4H2N); 150.60 (C(19)); 153.59 (C(1)); 172.52 (CO).
0.3 mT
Fig. 1. EPR spectrum of radical 1b• (toluene, 295К).
region. 1H and 13C NMR spectroscopic data also confirm
the structures of the compounds obtained.
It is known that antioxidant activity of 2,6ꢀdi(tertꢀ
butyl)phenols depends on the stability of the correspondꢀ
ing phenoxyl radicals. In this connection, we carried out
the oxidation of compounds 1a and 2a and studied the
thus formed radical species by EPR method. It is known12
that the oxidation of the free base of tetrakis[3,5ꢀdi(tertꢀ
butyl)ꢀ4ꢀhydroxyphenyl]porphyrin affords a biradical,
which is converted into a diamagnetic derivative of
porphodimethenediquinomethide in the fast step. The oxiꢀ
dation steps are reversible and porphodimethenediꢀ
quinomethide and porphyrinogene derivatives can be reꢀ
duced back to the starting porphyrin. The presence of
three sterically hindered phenolic groups in molecules of
compounds 1a and 2a suggests the possibility of registerꢀ
ing the monoradical species 1b• and 2b• (see Scheme 1).
Indeed, the EPR spectra of radicals 1b• and 2b• were
registered during oxidation of 1a and 2a by PbO2. They
show triplets (Figure 1) characterizing interaction of a spin
of the unpaired electron with two equivalent metaꢀprotons
in the phenoxyl residue. Radicals 1b• and 2b• are stable
in solution in the absence of oxygen at room temperature
for a few days. The values of isotropic gꢀfactor are 2.0047
and 2.0048, the superfine coupling constant values on the
ан (1Н) nuclei are equal to 0.19 and 0.18 mTl for 1b•
and 2b•, respectively.
Experimental
The electron absorption spectra were recorded on a Varian
Cariꢀ219 spectrophotometer. The Fourier transform IR absorpꢀ
tion spectra were recorded on a IR200 Thermo Nicolet spectroꢀ
photometer in KBr pellets. The NMR spectra were registered on
a Bruker АМХꢀ400 spectrometer in CDCl3 (1Н, 400 MHz;
13С, 100 MHz). Thinꢀlayer chromatography was performed on
Silufol UVꢀ254 plates. Column chromatography was performed
on alumina (neutral, Brockmann). The EPR spectra were regisꢀ

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Gerasimova et al.
Oxidation of porphyrins 1a and 2a to the corresponding radiꢀ
4. R. A. Sheldon and J. K. Koshi, MetalꢀCatalysed Oxidation of
Organic Compounds, Academic Press, New York, 1981, 643.
5. Y. Kabe, M. Ohmori, K. Shinouchi, Y. Tsuboi, S. Hirao,
M. Azuma, H. Watanabe, I. Okura, and H. Handa, Biol.
Chem., 2006, 281, 31729.
6. Е. R. Milaeva, Russ. Khim. Zh., 2004, 4, 20 [Mendeleev.
Chem. J., 2004, 4 (Engl. Transl.)].
7. Е. R. Milaeva, Izv. Akad. Nauk, Ser. Khim., 2001, 549 [Russ.
Chem. Bull., Int. Ed., 2001, 50, 573].
cals 1b• and 2b•. Porphyrins 1a or 2a (0.1 mmol L–1) were
dissolved in anhydrous toluene (3 mL) and placed in tubes, then
the tenfold excess of PbO2 was added. The tubes with the sample
solutions were evacuated three times at the temperature of liquid
nitrogen, then the temperature was raised to 293 К and the EPR
spectra of the corresponding radicals 1b• and 2b• were regisꢀ
tered. Diphenylpicrylhydrazyl was used as a standard in deterꢀ
mination of gꢀfactor (g = 2.0037).
8. E. Milaeva, D. Shpakovsky, Yu. Gracheva, O. Gerasimova,
V. Tyurin, and V. Petrosyan, J. Porphyrins Phthalocyanines,
2003, 8, 701.
9. L. R. Milgrom, N. Mofidi, C. C. Jones, and A. Harriman,
J. Chem. Soc., Perkin Trans. 2, 1989, 301.
This work was financially supported by the Russian
Foundation for Basic Research (Projects No 06ꢀ03ꢀ32773,
No 05ꢀ03ꢀ32864, and No 07ꢀ03ꢀ00818).
10. А. V. Melezhik and V. D. Pohodenko, Zh. Org. Khim., 1982,
18, 1054 [J. Org. Chem. USSR, 1982, 18 (Engl. Tramsl.)].
11. L. R. Milgrom, C. C. Jones, and A. Harriman, J. Chem.
Soc., Perkin Trans. 2, 1988, 71.
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Received January 26, 2007;
in revised form April 4, 2007