Dendritic metalloporphyrins with a distal H-bond donor as mimics of haemoglobin.

Article abstract of DOI:10.1039/b212468h

We report the synthesis of iron(II) porphyrins functionalised with first- and second-generation dendrons as mimics of haemoglobin. The porphyrin core bears an ethynyl linker pointing towards the centre of the molecule, in an ideal position for the introdu

Full text of DOI:10.1039/b212468h

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Dendritic metalloporphyrins with a distal H-bond donor as mimics
of haemoglobin†
Beatrice Felber,a Carlos Calle,b Paul Seiler,a Arthur Schweigerb and François Diederich*a
a Laboratorium für Organische Chemie, ETH-Hönggerberg, HCI, CH-8093 Zürich,
Switzerland
b Laboratorium für Physikalische Chemie, ETH-Hönggerberg, HCI, CH-8093 Zürich,
Switzerland
Received 16th December 2002, Accepted 26th February 2003
First published as an Advance Article on the web 12th March 2003
We report the synthesis of iron(II) porphyrins functional-
ised with first- and second-generation dendrons as mimics
of haemoglobin. The porphyrin core bears an ethynyl
linker pointing towards the centre of the molecule, in an
ideal position for the introduction of a series of distal
groups above the gas binding site of the dendritic metallo-
porphyrin. Here we describe the synthesis of dendritic models
for Hb of first- and second-generation (G1 and G2) with a
series of distal ligands that could potentially form an H-bond
with metal-ion-coordinated O2. The five-coordinate high-spin
(S = 2) Fe porphyrin in the T (tense)-state was formed by the
addition of an excess of 1,2-dimethylimidazole (dmim),15 and
some preliminary O2 and CO binding studies are reported.
The synthesis of the targeted dendrimer required the inter-
mediate preparation of meso-triphenylporphyrins 1 or 2
(Scheme 1) bearing an ortho-(trialkylsilyl)acetylene substituent
on the central meso-aryl ring and anchors for dendron attach-
ment on the other two meso-rings in the trans-position. In pre-
vious work,16 this substitution pattern on the porphyrin core
had been conveniently obtained by Suzuki cross-coupling
0
ligands as potential H-bond donors by Pd -catalysed
Sonogashira cross-coupling.
Tetrameric haemoglobin (Hb) is an efficient transport protein
for O2 in aerobic organisms; a highly conserved distal histidine
located near the binding site of the Fe heme co-factor is
thought to play a crucial role in fine-tuning the ligand binding
affinities and selectivities critical for aerobic life. Free Fe heme
binds CO ca. 20 000 times more strongly than O2, but in Hb and
myoglobin (Mb) this factor is reduced to 200 and 25, respect-
ively. Based on early X-ray crystal structures of HbCO and
MbCO,1 it was assumed2 that steric hindrance by the distal
histidine side chain discriminates against the linear CO-binding
geometry in favour of the coordination of O2 which shows an
intrinsically bent binding mode. More recent X-ray crystal
structure analyses of HbCO3 and MbCO,4 however, revealed an
᎐
approximately linear Fe–C᎐O bond geometry with distortions
᎐
too small to account for the discrimination between O2 and CO.
H-bonding and electrostatic effects are therefore assumed to
represent the primary factors influencing gas binding affinities
in Fe heme proteins.5 Polar pocket effects on O2 and CO
coordination have been analysed in a series of model systems,6
and support for the formation of an H-bond between a peri-
pheral (distal ) H-bond donor and bound O2 was obtained by
site-directed mutagenesis of Mb7 and Hb8 and studies of
synthetic metalloporphyrin–O2 complexes.9
Investigations of dendritic Hb mimics10,11 provided evidence
for influences of the dendritic shell on O2 complexation.12,13
A
comparison of gas binding data for five-coordinate Fe por-
phyrins surrounded by secondary amide- and ester-linked den-
drons suggested a stabilising effect of the amide moieties on the
formed O2-adducts. A postulated H-bond between metal-ion-
bound O2 and the secondary amide H–N moieties, however,
could not be demonstrated by electron paramagnetic resonance
(EPR) studies on the corresponding Co porphyrin analogues.14
The question therefore remained open whether micropolarity
effects—possibly resulting from different hydrodynamic vol-
umes of the amide- and ester-containing dendrimers—or H-
bonding was responsible for the observed increased stability of
the Fe–O2 complex within the amide-containing system.
For further investigations, it seemed desirable to precisely
position—in analogy to Hb and Mb—distal H-bond donor
† Electronic supplementary information (ESI) available: procedures
for the synthesis of 1 and 5 and iron() insertion into the dendritic
porphyrins including full spectral characterisation and complete
EPR characterisation of the complex 22ؒCo(dmim) and the corre-
sponding oxygenated complex. See http://www.rsc.org/suppdata/ob/b2/
b212468h/
Scheme 1 Suzuki cross-couplings of porphyrins with meso-halogen or
boronic ester substituents. Reagents and conditions: i, 3, 4, [Pd(PPh3)4],
Cs2CO3, PhMe–THF 1 : 1, reflux, 14 h, 0% (2); ii, 5 and 6, 7 or 8,
[Pd(PPh3)4], Cs2CO3, PhMe–THF 1 : 1, reflux, 14–20 h, 0% (2), 41% (9),
59% (10); iii, 5, 1-bromo-2-iodobenzene, [Pd(PPh3)4], Cs2CO3, PhMe,
reflux, 6 h, 63% (11).
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 0 9 0 – 1 0 9 3
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
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between a meso-brominated trans-meso-diarylated porphyrin
and a phenylboronic ester. Much to our surprise, the Pd-
mediated cross-coupling between bromoporphyrin 316 and
2-phenyl-1,3,2-dioxaborolane 4, with an ortho-(triisopropyl-
silyl)acetylene substituent afforded a complex product mix-
ture.‡ In contrast, the control reaction of 4 with bromobenzene
yielded almost exclusively the expected biphenyl derivative.
Similarly, when the boronic ester-substituted porphyrin 5 was
coupled with the ortho-alkynylated bromobenzene derivative 6,
traces of 2 were detected by mass spectrometry, but no product
could be isolated. On the other hand, coupling of 5 with bro-
i
᎐
mobenzene derivatives 7 and 8, bearing Pr Si–C᎐C– residues in
᎐
3
the meta- and para-position, respectively, afforded the desired
coupling products 9 and 10 in good yield.
In a new approach, 1-bromo-2-iodobenzene was first coupled
with boronic ester 5 to yield meso-triarylated porphyrin 11.
᎐
However, all attempts to subsequently introduce Me Si–C᎐C–
᎐
3
i
᎐
or Pr Si–C᎐C– substituents by Sonogashira cross-coupling
᎐
3
under formation of 1 or 2 failed. Indeed, while such reactions
of meta- and para-bromo- and iodoaryl rings in the meso-
position of porphyrins have found wide application,17 no such
couplings have been reported in the ortho-position.
Fig. 1 X-ray crystal structure of the Zn porphyrin solvate 17ؒ2
MeOH. Atomic displacement parameters obtained at 203 K are drawn
at the 30% probability level. Hydrogen atoms are omitted.
The desired porphyrin 1 was finally prepared in 17% yield by
a mixed condensation of the two dipyrromethanes 12 and 1318
with aldehyde 1419 (ratio 1 : 2 : 3), followed by repeated chrom-
atography (SiO2-H; CHCl3–EtOAc 97 : 3) to separate the mul-
tiple porphyrin products17b,20 formed in the reaction (Scheme 2).
Tetracarboxylic acid 15 with a free ethynyl residue, required for
anchoring both the dendrons and the distal H-bond donor
fragment, was subsequently formed in near quantitative yield
by basic hydrolysis.
comparison suggests that
a distal H-bonding residue,
anchored above the Fe porphyrin by the phenethynyl spacer,
would not sterically interfere with O2-binding, thereby con-
firming predictions from computer-assisted molecular model-
ing studies in the early phase of the project.21 The Si atom of
the trimethylsilyl group is located approximately above C(16)
of the porphyrin subunit. The shortest distance (neglecting
H-atoms) between the trimethylsilyl group and MeOH(1)
(C(53)–O(56)) is 4.09 Å. The absolute value of the dihedral
angle C(46)–C(45)–C(18)–C(19), which defines the relative
orientation of porphyrin and phenethynyl fragments,
amounts to ca. 66Њ.
Esterification of 15 with modified Fréchet-type aryl ether
dendrons22,23 of first (G1; 18) and second (G2; 19) generation
provided dendrimers 20 and 21 as highly viscous oils in 80%
and 66% yield, respectively, after purification by preparative
gel permeation chromatography (BioRad BioBeads S-X1;
CH2Cl2) (Scheme 3). The distal H-bond donors, consisting of
aromatic carboxamide and sulfonamide, benzyl alcohol and
phenolic residues, were subsequently introduced by Sono-
gashira cross-coupling.17 This reaction required high temper-
atures of 90 to 160 ЊC, depending on the nature of the donor
fragment introduced, providing the G1 target compounds
22ؒ2H–25ؒ2H, the corresponding phenyl derivative 26ؒ2H as a
control compound lacking the donor site and the G2 derivative
27ؒ2H.
Iron() insertion into 22ؒ2H–27ؒ2H was carried out with
FeBr2 under N2 and afforded the corresponding Fe porphyrins
22ؒFe–27ؒFe. In toluene in a glove box, the five-coordinate high-
spin complexes with a Soret-band at 435 nm (characteristic
absorbance for trisarylated porphyrins16a) were immediately
formed upon addition of 300 equiv. of dmim in the case of the
G1 dendrimers, whereas the coordination proceeded slowly
with the G2 derivative, even in the presence of 1000 equiv. of
dmim as monitored by UV/Vis spectroscopy. All computer
modeling investigations suggested that, for steric reasons, dmim
ligation can only occur on the porphyrin face opposite to the
one covered by the aromatic H-bond donor.
Upon addition of CO, the Soret band of 22ؒFe(dmim)–
27ؒFe(dmim) shifted hypsochromically to 421 nm, indicative of
quantitative formation of the corresponding six-coordinate
complexes. CO gas binding was reversible, and the initial five-
coordinate compounds could be quantitatively recovered after
4–7 freeze, pump and thaw cycles. Oxygenation did not result in
a defined Fe–O2 complex as rapid decomposition to iron()
species24 took place immediately, even in the case of the second-
generation dendrimer 27ؒFe(dmim). The mechanism of the
Scheme 2 Synthesis of porphyrins with appended ethynyl groups.
Reagents and conditions: i, trifluoroacetic acid (TFA), CH2Cl2, r.t., 18 h;
then p-chloranil, reflux, 1 h, 17% (1), 5% (16); ii, aq. NaOH, dioxane,
r.t., 48 h, quant.; iii, Zn(OAc)2 (10 equiv.), CHCl3–MeOH 1 : 1, r.t.,
14 h, quant.
By a similar condensation, we also prepared tris-meso-
arylated porphyrin 16 and converted it into the Zn complex 17.
Gratifyingly, the latter gave crystals suitable for X-ray analysis
upon slow evaporation of a CH2Cl2–MeOH mixture. In the
crystal, the two enclosed MeOH molecules are involved in short
intermolecular contacts. MeOH(1) coordinates to the Zn
centre of 17 with a binding distance Zn(1)–O(56) of 2.16 Å and
a Zn(1)–O(56)–C(57) angle of 122Њ. It is also in contact with its
neighboring MeOH(2), the O(56)–O(58) distance being 2.74 Å.
MeOH(2) again makes a short contact to 17, with an O(58)–
O(31) distance of 2.93 Å (see Fig. 1). As a result of the 5-fold
coordination, the Zn ion is pulled out of the mean porphyrin
plane by ca. 0.3 Å. The Zn–MeOH(1) binding mode resembles
the bent geometry of heme Fe–O2 complexes, and this
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Scheme 3 Synthesis of the dendritic iron() porphyrins 22ؒFe–27ؒFe of first and second generation. Reagents and conditions: i, 18 (5 equiv.) or 19
(5 equiv.), N,NЈ-dicyclohexylcarbodiimide (DCC, 5 equiv.), 4-(N,N-dimethylamino)pyridine (DMAP, 1 equiv.), 1-hydroxybenzotriazole (HOBt,
cat.), abs. THF, r.t., 3 d, 80% (20), 66% (21); ii, 3-iodobenzamide (2 equiv.), [PdCl2(PPh3)2], PhMe–NEt3 2 : 1, 90 ЊC, 3 h, 57%; iii, 3-
iodobenzenesulfonamide (2 equiv.), [PdCl2(PPh3)2], 1,2-dichlorobenzene (DCB)–NEt3 1 : 1, 160 ЊC, 1 h, 54%; iv, 3-iodobenzyl alcohol (2 equiv.),
[PdCl2(PPh3)2], PhMe–NEt3 1 : 1, 110 ЊC, 2 h, 45%; v, 1-bromo-3-[(tert-butyldimethylsilyl)oxy]benzene (2 equiv.), [PdCl2(PPh3)2], DCB–NEt3 1 : 1,
120 ЊC, 6 h; then Bu4NF, THF, r.t., 10 min, 21%; vi, bromobenzene (2 equiv.), [PdCl2(PPh3)2], PhMe–NEt3 2 : 1, 80 ЊC, 14 h, 63%; vii,
3-iodobenzamide (2 equiv.), [PdCl2(PPh3)2], DCB–NEt3 1 : 1, 110 ЊC, 16 h, 16%; viii, FeBr2 (10 equiv.), 2,6-lutidine, abs. THF, r.t., 2–4 d, quant.
Notes and references
oxidative decomposition was not further analysed. Finally, the
O2 complexes of the dendritic porphyrins 22ؒCo–24ؒCo and
1
‡ All new compounds were fully characterised by UV/Vis, IR, H and
13C NMR, and mass spectrometry and for the non-dendritic com-
pounds, microanalysis was performed. Spectroscopic characterisation
of 27ؒ2H: viscous purple oil; λmax(PhMe)/nm 400sh (ε/dm3 molϪ1 cmϪ1
64 400), 417 (313 200), 510 (16 900), 542 (4 200), 586 (5 100) and 640
(1 300); νmax(CCl4)/cmϪ1 2877, 1735, 1678, 1597, 1456, 1350, 1296, 1249,
1172, 1147 and 1110; δH(500 MHz; CDCl3; Me4Si) 10.02 (1 H, s), 9.19 (2
H, d, J 4.6), 8.90 (2 H, d, J 4.6), 8.80 (2 H, d, J 4.7), 8.75 (2 H, d, J 4.7),
8.19–8.17 (1 H, m), 7.85–7.83 (1 H, m), 7.63 (2 H, t, J 8.5), 7.71–7.67
(1 H, m), 7.60–7.56 (1 H, m), 7.02–7.00 (1 H, m), 6.95 (4 H, d, J 8.5),
6.55 (8 H, d, J 2.1), 6.52 (8 H, d, J 2.1), 6.52–6.36 (22 H, m), 4.89–4.85
(16 H, m), 4.76–4.66 (8 H, m), 4.51 (1 H, br s), 4.05–4.00 (32 H, m),
3.89–3.83 (8 H, m), 3.79–3.74 (32 H, m), 3.67–3.59 (96 H, m), 3.51–3.48
(32 H, m), 3.334 (24 H, s), 3.328 (24 H, s), 3.10–3.13 (2 H, br s), 1.52–
1.06 (16 H, m) and Ϫ2.88 (2 H, br s); δC(125 MHz; CDCl3; Me4Si) 172.4
26ؒCo in the presence of dmim as axial base were prepared, as
evidenced by their characteristic EPR spectra. The frozen solu-
tion EPR spectra are typical of those for oxygenated Co com-
plexes with magnetic parameters comparable to values reported
in the literature (see Electronic Supplementary Inform-
ation†).14,25 Multidimensional and multifrequency pulse EPR
experiments14,26 are planned in order to investigate the formed
O2 complexes; by this technique,27 possible H-bond interactions
between Co-coordinate O2 and the distal H-bond donors could
be revealed.
Financial support by the Roche Research Foundation
(doctoral fellowship to B. F.) is gratefully acknowledged.
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(2×), 166.4, 160.0 (2×), 159.9 (2×), 159.5, 159.3, 148.3–144.8 (br, 4×),
145.3, 139.0, 138.9, 138.4 (2×), 134.2, 132.9, 132.3, 131.2, 131.4–130.3
(br, 4×), 130.5, 130.4 (2×), 128.4, 128.2, 127.7, 126.9, 122.2, 119.5,
117.4, 111.8, 106.9, 106.8, 106.1, 106.0, 105.4, 105.3, 104.4, 101.6,
101.5, 101.1 (2×), 93.2, 91.0, 71.9 (2×), 70.70, 70.69, 70.54 (2×), 70.47
(2×), 69.9 (2×), 69.6 (2×), 67.4 (2×), 67.1, 67.0, 65.7, 65.5, 59.0 (2×),
29.5, 29.3, 23.7 and 23.4; m/z (HR-MALDI-MS, 2,5-dihydroxybenzoic
acid (DHB)) 4892.3362 (MHϩ, C259H352O85N5 requires 4892.3370).
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