Covalently supported porphyrins as ligands for the preparation of heme a3/CuB binuclear active site analogues of heme-copper terminal oxidases and metallation under mild conditions

Article abstract of DOI:10.1039/a707785h

New covalently supported binucleating porphyrins have been prepared as potential structural and/or functional ligands for the iron-copper (heme a₃/Cu_B) active sites of heme-copper oxidases, and the introduction of iron and copper into one porphyrin under mild reaction conditions has been developed.

Full text of DOI:10.1039/a707785h

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Covalently supported porphyrins as ligands for the preparation of heme
a3/CuB binuclear active site analogues of heme–copper terminal oxidases and
metallation under mild conditions
Jin-Ook Baeg and R. H. Holm*
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA
New covalently supported binucleating porphyrins have
been prepared as potential structural and/or functional
ligands for the iron–copper (heme a3/CuB) active sites of
heme–copper oxidases, and the introduction of iron and
copper into one porphyrin under mild reaction conditions
has been developed.
a congruent Michael multiple addition method, including one
ligand whose CoII–CuI derivative shows catalytic activity in the
four-electron reduction of dioxygen to water.9,10 These systems
primarily contain 1,4,7-triazacyclononane-, cyclen-, or cyclam-
adapted copper binding sites. Our previous investigations of
binuclear heme–Cu bridged assemblies have featured a variety
of unsupported bridges suitable for structural and electronic
elucidation.11–20 To extend our investigation to reactivity with
dioxygen and inhibiting ligands such as cyanide, we have
undertaken the design and synthesis of covalent binucleating
ligands and their complexes capable of sustaining various Fe–
X–Cu bridges. Here we report the preparation of three new
porphyrin ligands, using Michael addition methodology for one
of them, with structural features somewhat different than those
previously described.6–9
Essential to the elucidation of the mechanism of dioxygen
reduction to water and its inhibition at the binuclear heme
a3/CuB active sites of heme–copper oxidases1–5 is the construc-
tion of a functional enzyme analogue system. This can
presumably be achieved by synthesizing covalently supported
binucleating heme ligands whose iron–copper arrangement
approaches the enzyme active site stereochemistry. Collman
et al.6–9 have reported the synthesis of several such ligands by
1
3
6
7
4
5
8
9
10
11
Scheme 1 Reagents and conditions: i, H2CNCHCOCl, Et3N, CH2Cl2, 46%; ii, [Fe(OH2)6][BF4]2, 2,6-dimethypyridine, THF, 90%; iii, 9, CH2Cl2, MeOH,
48 h, 32%; iv, [Cu(MeCN)4]PF6, THF, 24 h, 70%; v, I2, THF, 12 h, 82%; vi, 15, SOCl2, DMF, 20 h, 60%; vii, FeSO4, HOAc, O2, NaOH, HCl, 57–60%;
viii, MeCOCl, Et3N, CH2Cl2, 2 h, 50%; ix, PhCHO, 1 N HCl, benzene, molecular sieves, NaBH3CN, 85%; x, HCO2H, HCHO, 110 °C, 12 h, 76%; xi,
Pd(OH)2 on carbon, MeOH, H2 (1 atm), 60 °C, 20 h, 90%; xii, PBr3, quinoline, bromobenzene, 24 h, 165 °C, 65%; xiii, sodium imidazolate, Me2SO, 150
°C, 20 h, 84%
Chem. Commun., 1998
571

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Synthetic pathways for ligands and complexes are depicted in
Scheme 1.† Reactions were carried out at ambient temperature
unless noted otherwise. A key starting material, as in related
work,6–8 is meso-a,a,a,a-tetrakis(o-aminophenyl)porphyrin
1.21 Treatment of 1 with acryloyl chloride and triethylamine in
dichloromethane affords the corresponding tetrakis(acryloyl-
amidophenyl)porphyrin 26 (46%). The new tetraamine 9 was
prepared in three steps from tris(2-aminoethyl)amine 8 in 58%
overall yield. Reaction of 8 with benzaldehyde in dry benzene
containing ethereal 1 m HCl and molecular sieves, followed by
reduction with NaBH3CN, gave tris[2-(benzylamino)ethyl]-
amine 12 (85%). Subsequent reaction of 12 with formic acid and
formaldehyde solution afforded tris[2-(benzylmethylamino)-
ethyl]amine 13 (76%). Palladium hydroxide catalyzed the
selective debenzylation of 13 under 1 atm of dihydrogen at
room temperature for 20 h to afford 9 (90%). Iron(ii) was
inserted into 2 at room temperature by reaction of Fe[BF4]2 in
the presence of 2,6-dimethylpyridine to give [FeII(2)] (90%).
Metal insertion under these mild conditions is necessary to
minimize undesirable porphyrin isomerization. In the next step,
reaction of the Michael acceptor [FeII(2 22H)] with tetraamine
9 in dichloromethane for 48 h gave the covalently capped
iron(ii) porphyrin 3 (32%, lmax 426 nm, m/z 1133) with a vacant
tetraaza binding site. The free ligand of 3 (lmax 424 nm, m/z
1079) was obtained by the same reaction in comparable yield
using 2. Treatment of 3 with 1 equiv. of [Cu(MeCN)4]PF6 in
THF for 24 h afforded the binuclear FeII–CuI assembly 4 (70%,
lmax 426 nm, m/z 1196). Complex 3 was readily oxidized by
excess iodine in THF to give the iron(iii) complex 5 (82%, lmax
417 nm, m/z 1260) in which the iodide ligand is presumed to
occupy an axial position on the unhindered heme face as shown.
covalently supporting Fe–X–Cu bridges. The ligand of 3–5
furnishes a trigonal four-coordinate tetraaza binding site, one
feature of which is direction of the magnetic orbital of CuII
toward a bridging ligand such as dioxygen, hydroxide or
cyanide, thereby optimizing magnetic coupling of the iron atom
across the bridge.20 Complex 6 is favorable to planar coordina-
tion by CuII, while 7 provides the tris(imidazole) binding site of
the native oxidases. The binding sites in 3–5 and 7 are
necessarily displaced off a perpendicular through the iron atom
normal to the heme plane, as is the case for two crystalline
oxidases.3,4 The sterically demanding ligand 11 has been
developed as a promotor of the bridging vs. terminal ligand
binding mode.
This research was supported by National Science Foundation
Grant CHE 94-23830.
Notes and References
* E-mail: holm@chemistry.harvard.edu
† Full experimental details will be published in due course. All new
compounds were fully characterized by spectroscopic methods. UV–VIS
spectra were measured in THF. Masses quoted are from FAB or
electrospray mass spectral measurements and apply to the principal ion (M
+ H)+. Stated yields refer to isolated compounds.
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The EPR spectrum shows 5 to be high spin (g∑ = 2.03, g4
=
5.73; acetonitrile, 10 K).
Ligand binding by complexes 3–5 at the iron site could
introduce ligands internal to the tetraaza cavity or on the
unhindered face. To direct ligands to the desired internal venue,
an exceptionally bulky axial base, incapable of residing in the
cavity, has been prepared. Selective bromination of 1-ada-
mantylmethanol using PBr3 gave 1-bromomethyladamantane
14 (65%). Reaction of 14 with equimolar sodium imidazolate in
Me2SO at 150 °C yielded the N-adamantylimidazole 11
(84%).
Spectroscopic evidence has supported the coordination of
three imidazole groups from histidyl residues by CuB,1,2,5
a
matter recently confirmed by the X-ray structures of two
enzymes in the oxidized form.3,4 To our knowledge, no
binucleating porphyrin having this type of binding potentiality
with copper is available, the closest approach being those with
pyrazolyl binding sites.22 We have sought binucleating ligands
of this sort from the reactions of 1 and the acyl chloride of
3-(N-imidazolyl)propionic acid 15.23 Treatment of 1 with an
excess (5 equiv.) of 15 and SOCl2 in DMF for 20 h produced the
free base of 6 (60%, lmax 421 nm, m/z 1163). In another
experiment, 1 was monoprotected by reaction with 1 equiv. of
acetyl chloride in dichloromethane for 2 h to give the
triphenyl(o-methylamidophenyl)porphyrin, which was resolved
from an isomeric mixture by preparative TLC (acetone–
chloroform, 3:7 v/v; 50%). This compound was subjected to
reaction with 4 equiv. of 15 and SOCl2 in DMF to give the
desired free base of 7 (58%, lmax 420, m/z 1083) containing
three imidazole groups. Both free bases could be metalated by
the FeSO4/HOAc method:24 6 [60%, lmax 425 nm, m/z 1252]; 7
[57%, lmax 424 nm, m/z 1172].
In summary, we have prepared three new types of binu-
cleating porphyrin ligands and their iron complexes capable of
Received in Bloomington, IN, USA, 29th October 1997; 7/07785H
572
Chem. Commun., 1998