Selective double functionalization of meso-tetraphenylporphyrin complexes on the same pyrrole unit by tandem electrophilic/nucleophilic aromatic substitution

Article abstract of DOI:10.1002/hlca.200590091

The mono-nitrated meso-tetraphenylporphyrin (TPP) complex 2 could be readily functionalized on the substituted pyrrole ring with yields of up to 83%. These transformations were achieved via aromatic substitution with carbanions generated from diverse func

Full text of DOI:10.1002/hlca.200590091

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Helvetica Chimica Acta ± Vol. 88 (2005)
Selective Double Functionalization of meso-Tetraphenylporphyrin Complexes
on the Same Pyrrole Unit by Tandem Electrophilic/Nucleophilic Aromatic
Substitution
by Stanisøaw Ostrowski*a)b) and Anna M. Raczkoa)
a) Institute of Chemistry, University of Podlasie, ul. 3 Maja 54, 08-110 Siedlce, Poland
(fax: ‡ 48-25-644-2045; e-mail: stan@ap.siedlce.pl)
b) Institute of Organic Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44/52, 01-224 Warszawa, Poland
The mono-nitrated meso-tetraphenylporphyrin (TPP) complex 2 could be readily functionalized on the
substituted pyrrole ring with yields of up to 83%. These transformations were achieved via aromatic substitution
with carbanions generated from diverse functionalized compounds containing different leaving groups (3a ± g,
Scheme 1). The resulting TPP compounds 4a ± g, bearing two different b-substituents on the same pyrrole ring,
may be further manipulated. This, in turn, should allow one to tune the solubility of TPP derivatives used in
photodynamic cancer therapy.
Introduction. ± Porphyrins are important compounds intensively studied in recent
years [1]. From a synthetic point of view, the selective functionalization of readily
available meso-tetraphenylporphyrin (TPP) and its derivatives is of significant
importance due to their potential use as sensitizers in photodynamic cancer therapy
[2]. We have recently published two papers describing a convenient method for the
selective mono-nitration in b-position of Zn, Cu, Ni, and Co TPP complexes by means
of 25 ± 50% aqueous HNO3 in CHCl3 [3].
A NO2 group in the ring makes porphyrins, as well as aromatic systems in general,
susceptible to nucleophilic attack. Of particular importance is the nucleophilic
aromatic substitution of a H-atom by a carbanion made from precursors of type
XÀCH2ÀY, where X and Y are leaving and stabilizing groups, respectively.
Mechanistically, this kind of transformation proceeds according to the vicarious
nucleophilic substitution (VNS) scheme [4]. Recently, several papers concerning this
type of substitution in meso-aryl rings have been published [5].
Results and Discussion. ± In continuation of our work, we describe herein the
functionalization of TPP (1) by selective b-nitration to 2, followed by nucleophilic
aromatic substitution with a variety of carbanions derived from the precursors 3. The
resulting porphyrins 4 are unique in that they are doubly functionalized on one pyrrole
ring only (Scheme 1).
For the generation of functionalized carbanions to be reacted with the TPPÀZn
complex 2, different aryl sulfones (3a ± c), a sulfonamide (3d), a nitrile (3e), an ester
(3f), and a sulfane (3g) were used. As leaving groups X, halogen atoms (Cl, Br), a 4-
chlorophenoxy group (in 3e), a dithiocarbamate function (in 3f), or a tosyl1) group (in
1
)
(4-Methylphenyl)sulfonyl (Ts).
ꢀ 2005 Verlag Helvetica Chimica Acta AG, Zürich

Helvetica Chimica Acta ± Vol. 88 (2005)
975
Scheme 1
3g) were used. A similar reaction with the Br analog of 3a has already been reported by
Malinovskii et al. [6].
In the reaction of porphyrin complex 2 with 3a in the presence of t-BuOK in DMSO
at room temperature, substitution took place adjacent to the NO2 group to afford the
porphyrin 4a in high yield (82%). Its structure was readily elucidated based on the
1
disappearance of the diagnostic H-NMR singlet for HÀC(3). Analogously, in the
reaction of 2 with the anions of 3b or 3c under the same conditions, the corresponding
products 4b (83%) and 4a (51%) were obtained. Similarly, compounds 4d (57%) and
4e (76%) could be obtained. The structures of the latter two products were confirmed
by spectroscopic methods. In the case of 4d, the Me2N group was shifted upfield (d(H)
2.29), probably due to local-field effects generated by the ring current of the aromatic
porphyrin system; in addition, this group, with its electron lone pair at the N-atom,
might be partially coordinated to the ZnII center of neighboring TPP molecules.
In the above transformations, the cyanomethylation to 4e is of particular interest,
since it should be possible to convert the CN group into other substituents such as
COOH, CONH2, CH2NH2, CHO, or CH2OH, etc. This, in turn, would allow one to
increase the hydrophilicity of TPP derivatives and to make these compounds water-
soluble, a prerequisite for applications in photodynamic therapy.
The reaction of 2 with the carbanion of the tert-butyl acetate 3f, expected to provide
the very useful porphyrin 4f, was unsatisfactory (14% yield). Several attempts to
optimize this reaction failed. When using t-BuOK/DMSO at room temperature, and
prolonging the reaction time from 30 min to 1 h, we observed three products by TLC.
For two of them, the tautomeric structures 4f/4f' were proposed on the basis of MS and
1
1H-NMR investigations (Scheme 2). Although the H-NMR spectrum of the mixture

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Helvetica Chimica Acta ± Vol. 88 (2005)
Scheme 2
was rather complicated, we managed to assign all signals to the two tautomers. This
type of tautomerism has actually been reported before for (alkoxycarbonyl)methyl,
cyanomethyl, hydroxy, and dichloromethyl derivatives, especially in heterocyclic
systems [7].
Due to the small amount of material, the third product from the reaction leading to
1
4f/4f' could not be isolated in pure form. However, the diagnostic H-NMR signal at
‡
d(H) 6.41 (s, CH) and the molecular ion in the mass spectrum at m/z 954 (1%; M )
suggested compound 5, arising from oxidative nucleophilic substitution [8], without
removal of the (rather poor) dithiocarbamate-type leaving group. Mechanistically, this
process could be rationalized by competing oxidation of the sH adduct (see Scheme 1)
rather than base-induced b-elimination. In the reaction mixture, ca. 25% of the starting
porphyrin 2 was found, which further explains the low yield (14%) of 4f /4f'.
Finally, attempts at reacting 2 with the carbanion of 3g were undertaken, which
would allow the introduction of a sulfur-substituted methyl group into b-position.
However, since the corresponding carbanion is relatively bulky and since both
substituents are rather poor leaving groups [9], this reaction was not very successful.
Several products were, thus, formed (TLC), accompanied by small amounts of the
starting porphyrin 2 (12%). The desired product 4g was isolated only in low yield
(<10%). Herein, the Ts group plays the role of a leaving group, thus confirming the
previously observed preferences for carbanion 3g in the VNS process [10]. However,
despite the low yields, porphyrin 4g, as well as the other derivatives, are attractive
molecules that can be further manipulated, e.g., to tune the solubility of TPP
derivatives used in photodynamic therapy.
Experimental Part
General. (5,10,15,20-Tetraphenylporphyrinato)zinc(II) (1) was obtained in 98% yield as described in [11].
Compounds 3a [12], 3b,c [13], 3d [14], 3e [15], 3f [16], and 3g [10] were prepared according to literature
procedures. TLC analysis was performed on Al plates pre-coated with silica gel 60F254 (Merck). Column
chromatography (CC) was performed on silica gel (200 ± 300 and 230 ± 400 mesh; Merck). UV/VIS Spectra were
recorded on a Beckman DU-68 spectrophotometer; in lmax (log e). 1H-NMR Spectra were recorded on a Varian
GEMINI-200 spectrometer operating at 200 MHz; chemical shifts d in ppm rel. to CHCl3 (7.26 ppm), coupling
constants J in Hz. Mass spectra were recorded on an AMD 604 (AMD Intectra GmbH; Germany) spectrometer
in electron-impact (EI) mode, or on a MARINER (PerSeptive Biosystems) spectrometer in the ESI-TOF mode;
in m/z (rel. %).
(2-Nitro-5,10,15,20-tetraphenylporphyrinato)zinc(II) (2). This compound was obtained by direct nitration
of 1 with 25% aq. HNO3 in CHCl3 according to a previous publication [3b]. Yield: 33%.

Helvetica Chimica Acta ± Vol. 88 (2005)
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General Procedure for the Synthesis of Functionalized Porphyrins 4. In a round-bottomed, light-protected
25-ml flask equipped with a septum, t-BuOK (52 mg, 0.46 mmol; 104 mg for 3f) was dissolved in anh. DMSO
(10 ml) and stirred under Ar gas at r.t. To this mixture, a soln. of 2 (48 mg, 0.066 mmol) and 3 (0.14 mmol) in
anh. DMSO (5 ml) was added dropwise via syringe over a period of ca. 5 min, and the mixture was stirred at r.t.
for 30 min (60 min for 3f and 3g; TLC monitoring). The mixture was poured into ice-cold 3% aq. HCl soln.
(100 ml). The precipitate was filtered off, washed with H2O, dissolved in CHCl3 (30 ml), dried (MgSO4), and
evaporated. The resulting residue was purified by CC to afford 4a [ ˆ 4c; 82% from 3a, 51% from 3c; CC (1.
CHCl3/hexane 2 :1, 2. CHCl3/MeOH 100 :1)]; 4b [83%; CC (1. CHCl3/hexane 3 :1, 2. CHCl3/MeOH 100 :1)]; 4d
(57%; eluent as above); 4e (76%; eluent as above); 4f/4f' [14%; prep. TLC (CHCl3/hexane 3 :1); 2 partly
recovered]; 4g [(ꢀ10%; prep. TLC (as above); 2 partly recovered)].
(3-{[(4-Methylphenyl)sulfonyl]methyl}-2-nitro-5,10,15,20-tetraphenylporphyrinato)zinc(II) (4a). M.p.
> 3008. UV/VIS (CHCl3): 640.5 (4.15), 582.0 (3.93), 453.0 (5.20; Soret). 1H-NMR (200 MHz, CDCl3)2): 8.87
(d, J ˆ 4.8, 1 Hb (pyr)); 8.78 (s, 2 Hb (pyr)); 8.77 ± 8.67 (m, 3 Hb (pyr)); 8.28 ± 8.12 (m, 8 arom. H (Ph)); 7.91 ± 7.58
(m, 12 arom. H (Ph), 4 arom. H (tol)); 4.55 (s, CH2); 2.26 (s, Me). ESI-MS: 918 (4), 917 (8), 916 (12), 915 (11),
‡
914 (20), 913 (12), 912 (21) ([M ‡ Na] isotopes); 895 (4), 894 (7), 893 (9), 892 (10), 891 (13), 890 (13), 889 (5)
‡
‡
‡
(M and [M ‡ H] isotopes); 740 (11), 739 (21), 738 (48), 737 (40), 736 (65), 735 (54), 734 (100) ([M ± Ts]
isotopes); 722 (16), 721 (27), 720 (28), 719 (37), 718 (24), 717 (52), 708 (14), 707 (13), 706 (14), 705 (22), 704
(33), 703 (30), 702 (33), 701 (23), 700 (38), 695 (15), 694 (18), 693 (28), 692 (33), 691 (37), 690 (34), 689 (44),
‡
‡
688 (41). HR-ESI-MS: 912.1579 ([M ‡ Na] , C52H35N5NaO4SZn ; calc. 912.1599). The molecular formula was
‡
also confirmed by comparing the theor. and exper. isotope patterns for the [M ‡ Na] ion.
{2-Nitro-5,10,15,20-tetraphenyl-3-[(phenylsulfonyl)methyl]porphyrinato}zinc(II) (4b). M.p. > 3008. UV/
VIS (CHCl3): 631.5 (4.10), 582.5 (3.90), 453.5 (5.16; Soret). 1H-NMR (200 MHz; CDCl3)2): 8.92 (d, J ˆ 4.9, 1 Hb
(pyr)); 8.83 (d, J ˆ 4.8, 1 Hb (pyr)); 8.80 (s, 2 Hb (pyr)); 8.79 ± 8.71 (m, 2 Hb (pyr)); 8.24 ± 8.12 (m, 8 arom. H
(Ph)); 7.81 ± 7.60, 7.50 ± 7.39, 7.27 ± 7.14 (3m, 12 arom. H (Ph), 5 arom. H (SO2Ph)); 4.71 (s, CH2). ESI-MS: 904
‡
(3), 903 (4), 902 (9), 901 (10), 900 (19), 899 (11), 898 (18) ([M ‡ Na] isotopes); 881 (3), 880 (9), 879 (11), 878
‡
‡
(13), 877 (16), 876 (17), 875 (12) (M and [M ‡ H] isotopes); 740 (6), 739 (18), 738 (42), 737 (37), 736 (87),
‡
735 (48), 734 (100) ([M À SO2Ph] isotopes)]; 721 (5), 719 (11), 717 (8), 690 (6), 688 (8), 413 (8). HR-ESI-MS:
‡
‡
875.2538 (M , C51H33N5O4SZn ; calc. 875.1545). The molecular formula was also confirmed by comparing the
‡
‡
theor. and exper. isotope patterns for the M and [M ‡ Na] ions.
(3-{[(Dimethylamino)sulfonyl]methyl}-2-nitro-5,10,15,20-tetraphenylporphyrinato)zinc(II) (4d). M.p.
> 3008. UV/VIS (CHCl3): 636.5 (4.26), 580.5 (4.09), 449.0 (5.29; Soret). 1H-NMR (200 MHz, CDCl3)2): 8.95
(d, J ˆ 4.9, 1 Hb (pyr)); 8.85 (d, J ˆ 4.9, 1 Hb (pyr)); 8.80 (s, 2 Hb (pyr)); 8.78 (d, J ˆ 4.8, 1 Hb (pyr)); 8.74 (d, J ˆ
4.8, 1 Hb (pyr)); 8.30 ± 8.12 (m, 8 arom. H (Ph)); 7.84 ± 7.65 (m, 12 arom. H (Ph)); 4.58 (s, CH2); 2.29 (s, Me2N).
‡
ESI-MS: 872 (4), 871 (11), 870 (21), 869 (46), 868 (47), 867 (58), 866 (51), 865 (76) ([M ‡ Na] isotopes); 850
‡
‡
(5), 849 (11), 848 (22), 847 (42), 846 (83), 845 (76), 844 (100), 843 (77), 842 (76) (M and [M ‡ H] isotopes);
‡
740 (11), 739 (22), 738 (42), 737 (45), 736 (62), 735 (55), 734 (91) ([M ± Me2NSO2] isotopes). HR-ESI-MS:
‡
842.1685 (M , C47H34N6O4SZn; calc. 842.1654). The molecular formula was also confirmed by comparing the
‡
theoretical and exper. isotope patterns for the [M ‡ Na] ion.
[3-(Cyanomethyl)-2-nitro-5,10,15,20-tetraphenylporphyrinato]zinc(II) (4e). M.p. > 3008. UV/VIS
(CHCl3): 612.0 (3.95), 565.0 (4.03), 429.5 (5.30; Soret). 1H-NMR (200 MHz, CDCl3)2): 8.86 (s, 2 Hb (pyr));
8.85 ± 8.81 (m, 3 Hb (pyr)); 8.66 (d, J ˆ 4.8, 1 Hb (pyr)); 8.26 ± 8.09 (m, 8 arom. H (Ph)); 7.84 ± 7.59, 7.47 ± 7.35
(2m, 12 arom. H (Ph)); 3.30 (s, CH2). ESI-MS: 789 (7), 788 (18), 787 (44), 786 (33), 785 (66), 784 (42), 783
‡
‡
(100) ([M ‡ Na] isotopes); 767 (5), 766 (9), 765 (19), 764 (24), 763 (26), 762 (33), 761 (44), 760 (23) (M and
‡
‡
‡
[M ‡ H] isotopes); 734 (5, [M À CN] ), 720 (9, [M À CH2CN] ), 675 (8), 674 (8), 414 (12), 413 (45). HR-ESI-
‡
‡
‡
‡
MS: 783.1428 ([M ‡ Na] , C46H28N6NaO2Zn ; calc. 783.1463); 761.1609 ([M ‡ H] , C46H29N6O2Zn ; calc.
761.1643).
(3-{[(tert-Butoxy)carbonyl]methyl}-2-nitro-5,10,15,20-tetraphenylporphyrinato)zinc(II) (4f)3). UV/VIS:
not recorded, mixture of compounds. 1H-NMR (200 MHz, CDCl3)2): 9.08 (s, CHÀNO2 of 4f')4); 8.96 ± 8.67 (m,
6 Hb (pyr)); 8.28 ± 8.05 (m, 8 arom. H (Ph)); 7.84 ± 7.66 (m, 12 arom. H (Ph)); 6.98 (s, ˆCHÀCO of 4f')4); 4.23
‡
(s, CH2 of 4f ); 1.43 (s, t-Bu). ESI-MS: 783 (2), 782 (3), 781 (5), 780 (9), 779 (9), 778 (14) ([M À t-Bu]
t
‡
isotopes); 777 (7); 739 (1), 738 (4), 737 (11), 736 (12), 735 (21), 734 (14) ([M À CO2 Bu] isotopes); 733 (34),
2
)
)
)
Abbreviations: Ph, phenyl; pyr, pyrrole; tol, tolyl; Ts, tosyl.
Tautomeric mixture with 4f' (see Scheme 2).
Signals may be interchanged.
3
4

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Helvetica Chimica Acta ± Vol. 88 (2005)
696 (1), 695 (2), 694 (2), 693 (4), 692 (5), 691 (5), 690 (2), 689 (2), 688 (3), 414 (12), 413 (100), 379 (2), 303
t
‡
‡
(11). HR-ESI-MS: 734.1560 ([M À CO2 Bu] , C45H28N5O2Zn ; calc. 734.1534).
{2-Nitro-5,10,15,20-tetraphenyl-3-[(phenylsulfanyl)methyl]porphyrinato}zinc(II) (4g). Impure sample.
UV/VIS (CHCl3): 635.5, 563.5, 431.5 (Soret). 1H-NMR (200 MHz; CDCl3)2): 9.01 ± 8.90 (m, 6 Hb (pyr));
8.32 ± 8.15 (m, 8 arom. H (Ph)); 7.92 ± 7.72 (m, 12 arom. H (Ph)); 7.62 ± 7.53, 7.49 ± 7.25 (2m, PhS); 4.72 (s, CH2).
‡
‡
EI-MS: 724 (1.5), 723 (1.5), 722 (1), 721 (2), 720 (1) ([M À PhSCH2] isotopes); 123 (100, [PhSCH2] ), 44 (34,
‡
‡
[CO2] ). ESI-MS: 846, 845, 844 (all < 1%; [M ‡ H] isotopes); 302 (8), 301 (100).
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Received January 24, 2005