Synthesis of dendritic iron(II) porphyrins with a tethered axial imidazole ligand designed as new model compounds for globins

Article abstract of DOI:10.1039/b007611m

A series of novel dendritic iron(II) porphyrins with an axial imidazole ligand attached to the central porphyrin core was synthesised and fully characterised. The vacancy of the second axial coordination site was demonstrated by their ability to coordinate the diatomic gas molecules CO, O₂ and NO. The formation of NO complexes by dendritic iron(II) porphyrins was observed for the first time.

Full text of DOI:10.1039/b007611m

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Synthesis of dendritic iron(II) porphyrins with a tethered axial
imidazole ligand designed as new model compounds for globins
Philipp Weyermann and François Diederich*
1
(ε/1000 cm2 molϪ1
)
Laboratorium für Organische Chemie, ETH-Zentrum, Universitätstrasse 16,
CH-8092 Zürich, Switzerland.
E-mail: diederich@org.chem.ethz.ch; Fax: (ϩ41)-1-632 1109
Received (in Cambridge, UK) 19th September 2000, Accepted 6th November 2000
First published as an Advance Article on the web 29th November 2000
Table 1 Spectroscopic properties of the complexes formed by [1ؒFeII],
[2ؒFeII] and [3ؒFeII] with CO, O2 and NO, respectively, in CHCl3
A series of novel dendritic iron(II) porphyrins with an axial
imidazole ligand attached to the central porphyrin core was
synthesised and fully characterised. The vacancy of the
second axial coordination site was demonstrated by their
ability to coordinate the diatomic gas molecules CO, O2
and NO. The formation of NO complexes by dendritic
iron(II) porphyrins was observed for the first time.
Soret-Band
λmax/nm
Q-Band
λmax/nm
Complexa
(ε/1000 cm2 molϪ1
)
[1ؒFeIICO]
[2ؒFeIICO]
[3ؒFeIICO]
[1ؒFeIIO2]
[2ؒFeIIO2]
[3ؒFeIIO2]
[1ؒFeIINO]
[2ؒFeIINO]
[3ؒFeIINO]
420 (259000)
420 (218000)
540 (14000)
540 (15000)
The peptidic shell around the iron() containing heme cofactor
in the oxygen-transporting and -storing proteins of the globin
family serves two major purposes, namely steric protection
against autoxidation under formation of µ-oxo-dimers and
creation of an appropriate axial coordination to the metal ion
centre in order to tune gas binding affinities.1 Mimicry of the
steric protection has been achieved by attachment of bulky
substituents onto iron() porphyrins or macrocyclic bridging2
and, recently, by encapsulation of the iron() porphyrin core
into dendritic shells.3–5 Modelling the fine tuning of the gas
binding affinities by the nature of the axial ligation, however, is
more difficult. The T-state of hemoglobin, in which dioxygen
affinity is reduced due to distortion of the iron centre out of
the porphyrin plane, can be readily mimicked by addition of an
external, sterically hindered axial ligand, such as 1,2-dimethyl-
imidazole.2 This ligand ensures formation of a five-coordinate
iron complex with a free axial coordination site available for gas
binding. However, the high-affinity R-state cannot be mimicked
in this simple way, since addition of a sterically non-
encumbered imidazole ligand would exclusively lead to
six-coordinate species, that react only slowly with dioxygen.2a,3b
The preparation of functional hemoglobin R-state mimics
requires the synthesis of model compounds with a defined
five-coordinate ligation pattern and therefore an elaborate
porphyrin core that includes axial ligation.6 Here, we describe
the preparation and characterisation of the first five-coordinate
iron() porphyrin dendrimers comprising such an elaborate
porphyrin core. The title compounds, namely [1ؒFeII], [2ؒFeII],
and [3ؒFeII] (Mr = 11553 Da) which are designed to be functional
hemoglobin R-state models, have been synthesised up to the
second generation. In addition, their ability to bind diatomic
gases (O2, CO and NO) is demonstrated.7
The novel iron porphyrin dendrimers were synthesised by a
convergent strategy (Scheme 1). An appropriately protected
porphyrin core [4ؒZn] was prepared by a high-yielding Suzuki
cross-coupling between the meso-brominated zinc() porphyrin
[5ؒZn]7 and the imidazole containing boronic ester 6. The latter
was obtained from 4-bromo-2-hydroxytoluene (7)8 by MOM-
protection (MOM = methoxymethyl) of the OH-group to give
8, followed by lithiation, reaction with B(OMe)3 and transes-
terification with pinacol to afford 9. MOM-ether deprotection
gave phenol 10 which was alkylated with 1-(6-bromohexyl)-
imidazole (11)9 to give 6. For the synthesis of the zinc() por-
phyrin dendrimers of zero ([1ؒZn]), first ([2ؒZn]) and second
([3ؒZn]) generation, the tetraester [4ؒZn] was hydrolysed to give
core tetraacid [12ؒZn], which was coupled with the triethylene-
glycol monomethyl ether-functionalised dendrons 13–15,
420 (196000)
540 (15000)
b
b
420 (97000)
420 (112000)
426 (167000)
426 (176000)
426 (184000)
544 (15000)
544 (15000)
538 (18000)
538 (19000)
538 (21000)
a At 20 ЊC under atmospheric pressure of the corresponding gas.
b Decay too rapid for the measurement of a conventional absorption
spectrum.
respectively.7,10 The dendritic zinc() porphyrins were purified
by repeated preparative gel permeation chromatography (GPC,
Biorad Biobeads S-X1; CH2Cl2) and fully characterised.†
Demetallation7 was achieved with CF3COOH and FeII inser-
tion6a,7 using FeCl2 and 2,6-dimethylpyridine, followed by
autoxidation gave the air-stable dendritic iron() porphyrins
[1ؒFeIII]Cl, [2ؒFeIII]Cl and [3ؒFeIII]Cl, respectively, which were
purified by preparative thin layer chromatography (SiO2;
CH2Cl2–MeOH 90:10), followed by preparative GPC (Biorad
Biobeads S-X3; CH2Cl2) and fully characterised.‡ The corres-
ponding, highly air-sensitive five-coordinate iron() complexes
[1ؒFeII], [2ؒFeII] and [3ؒFeII], required for gas binding, were
prepared in situ by reduction of carefully degassed CHCl3
solutions of the iron() complexes with 0.1 M aqueous sodium
dithionite solution under two-phase conditions in an argon
atmosphere, and characterised by absorption spectroscopy.‡
The three compounds displayed spectra characteristic of five-
coordinate high-spin iron() porphyrins.2a,6
The availability of their sixth coordination site was demon-
strated by the reaction with gaseous ligands. All three dendritic
iron() porphyrins [1ؒFeII], [2ؒFeII] and [3ؒFeII] instantaneously
reacted with excess CO, O2 and NO at 20 ЊC to yield the corres-
ponding gas complexes. These exhibited absorption spectra
(Table 1) and IR-spectra characteristic of six-coordinate
low-spin iron() porphyrins which compared well with
literature data for similar complexes.2a,11 In particular, clearly
assignable IR-absorptions were found for the ligand stretching
vibrations of CO and NO (νmax(C᎐O) = 1970 cmϪ1; νmax
-
᎐
᎐
(N᎐O) = 1600 cmϪ1), with frequencies typical for six-coordinate
᎐
iron() porphyrins.11 Even in the case of NO, which exerts a
very strong trans-labilising influence,11b the axial imidazole
ligand remained coordinated. This finding underlines the
favorable, non-strained character of the tethered axial ligation.
Whereas both CO and NO adducts did not decompose
at all within 3 days, the O2 complexes all showed gradual
DOI: 10.1039/b007611m
J. Chem. Soc., Perkin Trans. 1, 2000, 4231–4233
This journal is © The Royal Society of Chemistry 2000
4231

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Quantitative gas binding studies to obtain the association
constants as well as evaluation of the new, highly water-soluble
compounds as dendritic NO sensors13 are currently under
way.
This work was supported by the ETH Research Council. We
thank Professor W. H. Koppenol and Dipl.-Chem. R. Meli
from the Laboratorium für Anorganische Chemie, ETH Zürich
for supplying us with purified NO.
Notes and references
† Selected data for [1ؒZn]: viscous purple oil; Rf = 0.34 (SiO2; CH2Cl2–
MeOH 90:10); λmax (CHCl3)/nm (ε/1000 cm2 molϪ1) 596 (4400), 560
(16500), 512 (2400), 427 (389100), 405 (39300), 313 (19400); δH
(500 MHz, CDCl3) 10.03 (s, 1 H), 9.28 (d, J 4.4, 2 H), 8.98 (d, J 4.4, 2
H), 8.85 (d, J 4.5, 2 H), 8.80 (d, J 4.5, 2 H), 7.85 (d, J 7.1, 1 H), 7.70
(t, J 8.5, 2 H), 7.47 (d, J 7.1, 1 H), 7.04 (d, J 8.5, 2 H), 7.00 (s, 1 H), 6.99
(d, J 8.5, 2 H), 4.99 (s, 1 H), 4.96 (s, 2 H), 4.01 (t, J 6.8, 2 H), 3.78–3.99
(m, 8 H), 3.64 (s, 8 H), 3.54 (s, 8 H), 3.34 (s, 6 H), 3.18 (s, 4 H), 3.04 (s, 8
H), 3.02 (s, 6 H), 2.78–2.99 (m, 8 H), 2.50–2.70 (m, 8 H), 2.49 (s, 3 H),
2.18 (s, 1 H), 1.99 (s, 8 H), 1.72 (s, 1 H), 1.55 (br s, 2 H), 1.12–1.38 (m, 8
H), 0.81–1.05 (m, 8 H), 0.73 (br s, 2 H), 0.56 (br s, 2 H), 0.00 (br s, 2 H);
δC (125 MHz, CDCl3) 172.3, 171.4, 159.9, 159.5, 153.3, 150.5, 150.4,
149.2, 149.0, 142.0, 131.6, 131.6, 131.5, 131.1, 130.8, 130.0, 128.8,
125.6, 124.7, 123.1, 121.4, 119.9, 118.5, 115.8, 112.3, 105.7, 104.9,
104.0, 71.9, 71.2, 70.5, 70.5, 70.1, 69.6, 69.6, 69.5, 69.0, 68.9, 67.4, 66.9,
66.0, 59.0, 58.6, 46.3, 38.6, 37.7, 31.2, 31.1, 29.4, 26.5, 24.9, 24.5, 23.8,
16.3; m/z (MALDI-TOF MS, matrix: 2-(4-hydroxyphenylazo)benzoic
acid (HABA)) 1793.9 (37, [M ϩ Na]ϩ, calc. for C92H124N10O21ZnؒNaϩ:
1793.8), 1771.5 (100, Mϩ, calc. for C92H124N10O21Znϩ: 1770.8).
For [2ؒZn]: viscous purple oil; Rf = 0.42 (SiO2; CH2Cl2–MeOH 90:10);
λmax (CHCl3)/nm (ε/1000 cm2 molϪ1) 596 (4400), 560 (17000), 522 (3100),
427 (464000), 405 (sh, 39200), 312 (22600); δH (500 MHz, CDCl3) 9.93
(s, 1 H), 9.20 (d, J 4.4, 2 H), 8.90 (d, J 4.4, 2 H), 8.75 (d, J 4.5, 2 H), 8.71
(d, J 4.5, 2 H), 7.88 (d, J 7.6, 1 H), 7.67 (t, J 8.5, 2 H), 7.45 (d, J 7.6, 1
H), 7.05 (d, J 8.5, 2 H), 7.04 (s, 1 H), 6.98 (d, J 8.5, 2 H), 5.74 (s, 2 H),
5.61 (s, 2 H), 5.04 (s, 1 H), 4.17–4.19 (m, 12 H), 4.02 (t, J 6.8, 2 H), 3.98–
4.00 (m, 12 H), 3.82–3.88 (m, 8 H), 3.39–3.65 (m, 168 H), 3.33 (s, 18 H),
3.29 (s, 18 H), 2.78 (br s, 2 H), 2.52 (t, J 6.4, 12 H), 2.47 (s, 3 H), 2.43
(t, J 6.4, 12 H), 2.10 (s, 1 H), 1.88 (s, 1 H), 1.58 (br s, 2 H), 1.22–1.45
(m, 8 H), 0.97–1.21 (m, 8 H), 0.93 (br s, 2 H), 0.76 (br s, 2 H), 0.06
(br s, 2 H); δC (125 MHz, CDCl3) 172.6, 171.9, 171.3, 171.3, 160.1,
159.5, 153.1, 150.3, 150.0, 149.2, 148.8, 142.7, 131.8, 131.1, 131.0,
130.9, 130.3, 129.5, 128.5, 124.9, 124.9, 123.6, 121.8, 119.2, 118.7,
115.5, 111.5, 105.6, 105.0, 104.1, 71.8, 71.7, 70.5, 70.5, 70.3, 70.3, 69.1,
69.0, 68.8, 67.4, 67.2, 66.6, 66.5, 66.0, 63.5, 63.3, 59.7, 59.6, 58.9, 58.9,
46.1, 34.7, 34.6, 32.3, 32.0, 29.6, 26.6, 24.8, 24.6, 24.4, 23.9, 16.2; m/z
(MALDI-TOF MS, matrix: 2,5-dihydroxybenzoic acid (DHB)) 4245.8
(49, [M ϩ Na]ϩ, calc. for C200H316N10O81ZnؒNaϩ: 4245.0), 4222.7 (100,
Mϩ, calc. for C200H316N10O81Znϩ: 4222.0). For [3ؒZn]: viscous purple
oil; Rf = 0.58 (SiO2; CH2Cl2–MeOH 90:10); λmax (CHCl3)/nm (ε/1000
cm2 molϪ1) 595 (4300), 558 (17000), 522 (3500), 426 (442600), 405 (sh,
45900), 312 (21900); δH (500 MHz, CDCl3) 9.85 (s, 1 H), 9.12 (d, J 4.2, 2
H), 8.83 (d, J 4.2, 2 H), 8.68 (d, J 4.3, 2 H), 8.62 (d, J 4.3, 2 H), 7.81
(d, J 7.4, 1 H), 7.63 (t, J 8.5, 2 H), 7.39 (d, J 7.4, 1 H), 7.07 (d, J 8.5, 2
H), 6.97 (s, 1 H), 6.96 (d, J 8.5, 2 H); 6.09 (s, 6 H), 6.08 (s, 6 H), 6.01 (s, 2
H), 5.98 (s, 2 H), 4.99 (s, 1 H), 4.17 (t, J 6.8, 2 H), 4.14 (t, J 4.9, 36 H),
4.11 (t, J 4.9, 36 H), 3.71–3.82 (m, 8 H), 3.38–3.65 (m, 552 H), 3.30
(s, 54 H), 3.27 (s, 54 H), 2.53 (br s, 2 H), 2.49 (t, J 6.3, 36 H), 2.48
(t, J 6.3, 36 H), 2.42 (s, 3 H), 2.33 (br t, J 6.1, 12 H), 2.32 (br t, J 6.1,
12 H), 1.99 (s, 1 H), 1.00–1.81 (m, 19 H), 0.89 (br s, 2 H), 0.72 (br s, 2
H), 0.01 (br s, 2 H); δC (125 MHz, CDCl3) 172.1, 171.7, 171.3 (2×),
170.8, 170.7, 160.1, 159.3, 153.0, 150.2, 150.0, 149.1, 148.7, 142.7,
131.9, 131.0, 131.0, 130.8, 130.3, 129.5, 128.4, 124.8, 124.7, 123.6,
121.8, 119.1, 118.7, 115.3, 111.4, 105.8, 105.1, 103.9, 71.8, 71.7, 70.4,
70.4 (2×), 70.3, 70.3 (2×), 69.1 (3×), 68.9 (2×), 68.8, 67.9, 67.7, 67.4
(2×), 66.7, 66.6, 59.9, 63.5, 63.4, 60.3 (2×), 59.7, 59.7, 58.9, 58.8, 46.0,
37.0, 36.9, 34.6, 34.6, 31.9, 31.9, 29.5, 26.6, 24.7, 24.1, 23.9, 23.7, 16.2;
m/z (MALDI-TOF MS, matrix: HABA) 11586.1 (100, [M ϩ Na]ϩ,
calc. for C524H904N22O249ZnؒNaϩ: 11584.8), 11562.6 (30, Mϩ, calc. for
C524H904N22O249Znϩ: 11561.8).
Scheme 1 Reagents and conditions: i, MOM-Cl, K2CO3, MeCN,
0 ЊC, 30 min, 99%; ii, nBuLi, TMEDA, THF, Ϫ78 ЊC, 60 min, then
B(OMe)3, 20 ЊC, 2 h, then pinacol, PhH, reflux, 12 h, 74%; iii, conc.
HCl, THF–MeOH, 20 ЊC, 3 d, 84%; iv, 11, Cs2CO3, DMF, 20 ЊC, 4 h,
68%; v, [Pd(PPh3)4], Cs2CO3, PhMe, 90 ЊC, 6 h, 81%; vi, NaOH,
dioxane–H2O, 20 ЊC, 3 d; vii, H2NCH2(CH2OCH2)3H (13), H2NC-
[CH2O(CH2)2CO2CH2(CH2OCH2)3H]3 (14) or H2NC{CH2O(CH2)2-
CONHC[CH2O(CH2)2CO2CH2(CH2OCH2)3H]3}3 (15), HATU (O-
(7-azabenzotriazol-1-yl)-N,N,NЈ,NЈ-tetramethyluronium hexafluoro-
phosphate), Et3N, DMF, Ϫ15 → 0 ЊC, 24 h, 91% ([1ؒZn]), 3 d, 70%
([2ؒZn]), 5 d, 65% ([3ؒZn]) (yields from [4ؒZn]); viii, CF3COOH, CHCl3,
0 ЊC, 5 min; ix, FeCl2, 2,6-dimethylpyridine, THF, reflux, 2–4 h, then 1%
HCl in CHCl3, 20 ЊC, 5 min, then ‘proton sponge’ (1,8-bis(dimethyl-
amino)naphthalene), THF, 20 ЊC, 15 min, 49% ([1ؒFeIII]Cl), 53%
([2ؒFeIII]Cl), 59% ([3ؒFeIII]Cl) (yields from [1ؒZn], [2ؒZn] and [3ؒZn]).
decomposition to iron() species12 with a dramatic increase
in stability with increasing size of the dendritic shell as has
been observed previously.3 In contrast to the zero generation
compound, which was oxidised immediately after exposure to
the gas, the O2 complex of the first generation dendrimer was
stable for a few minutes (t1/2 = ~7 min) and the corresponding
second generation compound decayed only very slowly over the
course of several hours (t1/2 = ~60 min), reflecting the increasing
suppression of autoxidation. This confirms the nature of the
dendrimer as a sterically protecting replacement for the protein
shell.
‡ Selected data for [1ؒFeIII]Cl: viscous red–brown oil; Rf = 0.12 (SiO2;
CH2Cl2–MeOH (90:10); λmax (CHCl3)/nm (ε/1000 cm2 molϪ1) 646
(sh, 2100), 577 (sh, 4500), 507 (10400), 415 (90000), 395 (sh, 50300), 350
(sh, 25200); g-values (X-Band, CHCl3) g⊥ = 5.82, g|| = 1.99 (in addition a
weak rhombic signal was observed); m/z (MALDI-TOF MS, matrix:
HABA) 1762.4 (100, [M Ϫ Cl]ϩ, calc. for C92H124N10O21Feϩ: 1761.8)
and for [1ؒFeII]: viscous orange-red oil; λmax (CHCl3)/nm (ε/1000 cm2
molϪ1) 561 (sh, 7100), 536 (8900), 432 (152400). For [2ؒFeIII]Cl: viscous
red-brown oil; Rf = 0.24 (SiO2; CH2Cl2–MeOH 90:10); λmax (CHCl3)/
nm (ε/1000 dm2 molϪ1) 645 (sh, 3400), 575 (sh, 5700), 507 (12000), 415
4232
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(96000), 385 (sh, 46600), 350 (sh, 27000); g-values (X-Band, CHCl3)
g⊥ = 5.86, g|| = 2.01 (in addition a weak rhombic signal was observed);
m/z (MALDI-TOF MS, matrix: HABA) 4214.6 (100, [M Ϫ Cl]ϩ, calc.
for C200H316N10O81Feϩ: 4212.0) and for [2ؒFeII]: viscous orange–red oil;
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(150600). For [3ؒFeIII]Cl: viscous red-brown oil; Rf = 0.35 (SiO2;
CH2Cl2–MeOH 90:10); λmax (CHCl3)/nm (ε/1000 dm2 molϪ1) 645
(sh, 2200), 585 (sh, 5700), 507 (12200), 415 (99900), 395 (sh, 74000), 350
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HABA) 11552.0 (100, [M Ϫ Cl]ϩ, calc. for C524H904N22O249Feϩ:
11551.8) and for [3ؒFeII]: viscous orange–red oil; λmax (CHCl3)/nm
(ε/1000 dm2 molϪ1) 559 (sh, 11900), 536 (14400), 433 (151200).
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