Modeling the Syn Disposition of Nitrogen Donors at the Active Sites of Carboxylate-Bridged Diiron Enzymes. Enforcing Dinuclearity and Kinetic Stability with a 1,2-Diethynylbenzene-Based Ligand

Article abstract of DOI:10.1021/ic034928e

The syn coordination of histidine residues at the active sites of several carboxylate-rich non-heme diiron enzymes has been difficult to reproduce with small molecule model compounds. In this study, ligands derived from 1,8-naphthyridine, phthalazine, and 1,2-diethynylbenzene were employed to mimic this geometric feature. The preassembled diiron(II) complex [Fe ₂(μ-O₂CAr^Tol)₂(O ₂CAr^Tol)₂(THF)₂] (1), where Ar ^TolCO₂^- is the sterically hindered carboxylate 2,6-di(p-tolyl)benzoate, served as a convenient starting material for the preparation of iron(II) complexes, all of which were crystallographically characterized. Use of the ligand 2,7-dimethyl-1,8-naphthyridine (Me ₂-napy) afforded the mononuclear complex [Fe(O₂CAr ^Tol)₂(Me₂-napy)] (2), whereas dinuclear [Fe₂(μ-DMP)(μ-O₂CAr^Tol) ₂-(O₂CAr^Tol)₂(THF)] (3) resulted when 1,4-dimethylphthalazine (DMP) was employed. The dinuclear core of compound 3 is kinetically labile, as evidenced by the formation of [Fe(O ₂CAr^Tol)₂(vpy)₂] (4) upon addition of 2-vinylpyridine (vpy). The diiron analogue of 4, [Fe₂(μ-O ₂CAr^Tol)₂(O₂CAr^Tol) ₂(vpy)₂] (5), was prepared directly from 1. When the sterically more demanding ligand 2,6-di(4-tert-butylphenyl)benzoate (Ar ^4-tBuPhCO₂^-) was used, mononuclear [Fe(O ₂CAr^4-tBuPh)₂(THF)₂] (6) and [Fe(O₂CAr^4-tBuPh)₂(DMP)₂] (7) formed. The difficulty in stabilizing a dinuclear core with these simple (N)₂-donor ligands was circumvented by preparing a family of 1,2-diethynylbenzene-based ligands, from which were readily assembled the complexes [Fe₂(Et₂BCQEB^Et)(μ-O ₂CAr^Tol)₃](OTf) (15) and [Cu ₂(Et₂BCQEB^Et)-(μ-l)₂] (16), where Et₂BCQEB^Et is 1,2-bis(3-ethynyl-8-carboxylatequinoline) benzene ethyl ester. The Et ₂BCQEB^Et framework provides both structural flexibility and the desired syn nitrogen donor geometry, thus serving as a good first-generation ligand in this class.

Full text of DOI:10.1021/ic034928e

Inorg. Chem. 2003, 42, 8652−8662
Modeling the Syn Disposition of Nitrogen Donors at the Active Sites of
Carboxylate-Bridged Diiron Enzymes. Enforcing Dinuclearity and Kinetic
Stability with a 1,2-Diethynylbenzene-Based Ligand
Jane Kuzelka, Joshua R. Farrell, and Stephen J. Lippard*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received August 4, 2003
The syn coordination of histidine residues at the active sites of several carboxylate-rich non-heme diiron enzymes
has been difficult to reproduce with small molecule model compounds. In this study, ligands derived from 1,8-
naphthyridine, phthalazine, and 1,2-diethynylbenzene were employed to mimic this geometric feature. The
preassembled diiron(II) complex [Fe2(µ-O CArTol)2(O CArTol)2(THF)2] (1), where ArTolCO - is the sterically hindered
2
2
2
carboxylate 2,6-di(p-tolyl)benzoate, served as a convenient starting material for the preparation of iron(II) complexes,
all of which were crystallographically characterized. Use of the ligand 2,7-dimethyl-1,8-naphthyridine (Me2-napy)
afforded the mononuclear complex [Fe(O CArTol)2(Me2-napy)] (2), whereas dinuclear [Fe2(µ-DMP)(µ-O CArTol)2-
2
2
(O CArTol)2(THF)] (3) resulted when 1,4-dimethylphthalazine (DMP) was employed. The dinuclear core of compound
2
3 is kinetically labile, as evidenced by the formation of [Fe(O CArTol)2(vpy)2] (4) upon addition of 2-vinylpyridine
2
(vpy). The diiron analogue of 4, [Fe2(µ-O CArTol)2(O CArTol)2(vpy)2] (5), was prepared directly from 1. When the
2
2
sterically more demanding ligand 2,6-di(4-tert-butylphenyl)benzoate (Ar4-tBuPhCO -) was used, mononuclear
2
[Fe(O CAr4-tBuPh)2(THF)2] (6) and [Fe(O CAr4-tBuPh)2(DMP)2] (7) formed. The difficulty in stabilizing a dinuclear core
2
2
with these simple (N)2-donor ligands was circumvented by preparing a family of 1,2-diethynylbenzene-based ligands,
from which were readily assembled the complexes [Fe2(Et2BCQEBEt)(µ-O CArTol)3](OTf) (15) and [Cu2(Et2BCQEBEt)-
2
(µ-I)2] (16), where Et2BCQEBEt is 1,2-bis(3-ethynyl-8-carboxylatequinoline)benzene ethyl ester. The Et2BCQEBEt
framework provides both structural flexibility and the desired syn nitrogen donor geometry, thus serving as a good
first-generation ligand in this class.
Introduction
biosynthesis through the generation of a tyrosine radical,6,7
and ∆-9 desaturase (∆9D), the diiron core of which effects
the desaturation of fatty acids.8-11 These functions differ
dramatically, yet X-ray crystallographic studies reveal strik-
ingly similar active sites.12-15 As shown in Chart 1, the
Dioxygen-activating metalloenzymes containing carbox-
ylate-bridged diiron centers perform a variety of remarkable
chemical reactions. Well-studied members of this class of
proteins include the hydroxylase component of soluble
methane monooxygenase (sMMOH), an enzyme that con-
verts CH4 into CH3OH,1-5 the R2 subunit of ribonucleotide
reductase (RNR-R2), responsible for the first step of DNA
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* To whom correspondence should be addressed. E-mail: lippard@
lippard.mit.edu.
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8652 Inorganic Chemistry, Vol. 42, No. 26, 2003
10.1021/ic034928e CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/22/2003

Modeling Aspects of Carboxylate-Bridged Diiron Enzymes
Chart 1
primary coordination spheres of the carboxylate-bridged
diiron centers in sMMOH, RNR-R2, and ∆9D comprise four
glutamate or aspartate side chains and two histidine residues.
Whereas the coordination modes of the carboxylate groups
vary among the enzymes, the two nitrogen donors are
consistently bound in a syn fashion, on the same side of the
Fe‚‚‚Fe vector. This geometric feature is important both in
the activation of dioxygen and subsequent substrate oxida-
tion. For the oxidation of CH4 by sMMOH, which is effected
by a di(µ-oxo)diiron(IV) species, intermediate Q,1,16-18
preliminary DFT calculations reveal the conversion to CH3-
OH to be energetically unfavorable for histidine residues
disposed in the anti geometry.19
than discrete diiron compounds can be overcome with the
use of multidentate nitrogen-rich ligands30 or sterically
hindered carboxylate groups.31,32 The resulting complexes
often reproduce features of non-heme metalloproteins includ-
ing dinuclearity, structural flexibility, and dioxygen-reactiv-
ity. All three properties are modeled especially well with
the use of the bulky m-terphenyl-derived carboxylate ligands
displayed in Chart 2. The occurrence of carboxylate shifts
in [Fe2(O2CAr′)4(N)2] compounds attests to the flexibility
of the building blocks,31,32 and formation of (peroxo)-
diiron(III) or di(µ-oxo)diiron(III,IV) species mimics the
reactive intermediates that form in the catalytic cycles of
the related biological systems.33-37 The activation of strong
C-H bonds by these diiron compounds has not yet been
achieved, however, possibly because of the invariable anti
disposition of the N-donor ligands.
The theoretical prediction that the relative orientation of
nitrogen donors may dramatically influence the reactivity of
intermediate Q inspired us to investigate its validity with
small molecule complexes having this property. Self-
assembly methods have thus far failed to produce many such
complexes, as manifest by the many compounds with
N-donors bound in an anti fashion.31,32 Our strategy, there-
fore, was to employ ligands in which the connectivity would
enforce the desired coordination mode. We report here the
results of our first efforts in this area, in which dimetallic
complexes were assembled with several (N)2-ligands em-
ployed in conjunction with sterically demanding carboxylate
groups. We describe ligands derived from a 1,2-diethynyl-
benzene backbone and their use in the synthesis of diiron(II)
The ability of carboxylate-bridged diiron units in nature
to promote such important chemical transformations has
prompted the synthesis of small molecule analogues. The
propensity of carboxylate units to form oligomers20-29 rather
(15) Lindqvist, Y.; Huang, W.; Schneider, G.; Shanklin, J. EMBO J. 1996,
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previous DFT study (Baik, M.-H.; Gherman, B. F.; Friesner, R. A.;
Lippard, S. J. J. Am. Chem. Soc. 2002, 124, 14608-14615), the
electron-accepting orbital (LUMO) of the reactive intermediate Q was
found to be dominated by metal-based orbitals that are aligned in the
Fe2O2 plane. Significant mixing of the N-donor ligand orbitals plays
an important role for shaping the LUMO, where the metal-ligand
interaction is antibonding as expected for a frontier orbital. The ligand
orbitals of the carboxylate groups, on the other hand, do not contribute
to the LUMO. This asymmetric antibonding interaction between N
and Fe polarizes the metal-based d-orbitals away from the N-donor
side of the Fe2O2 core and increases the LUMO character on the oxo
group trans to the N-donor ligands. This atom is therefore more
electrophilic, which makes the syn orientation of the N-donor ligands
an important structural feature for controlling the reactivity of the Fe2O2
core. Detailed calculations are continuing and will be reported
elsewhere.
Chart 2
(20) Kooijman, H.; Spek, A. L.; Bouwman, E.; Micciche`, F.; Warzeska,
S. T.; Reedijk, J. Acta Crystallogr., Sect. E 2002, 58, m93-m95.
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Acta 1999, 291, 258-265.
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idazine, and phthalazine, see references in: Kuzelka, J.; Spingler, B.;
Lippard, S. J. Inorg. Chim. Acta 2002, 337, 212-222.
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S. J. J. Am. Chem. Soc. 2002, 124, 3993-4007.
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1137.
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Tasker, P. A.; Teat, S. J.; Winpenny, R. E. P. Angew. Chem., Int. Ed.
1998, 37, 3246-3248.
(24) Herold, S.; Lippard, S. J. Inorg. Chem. 1997, 36, 50-58.
(25) Goldberg, D. P.; Telser, J.; Bastos, C. M.; Lippard, S. J. Inorg. Chem.
1995, 34, 3011-3024.
(26) Taft, K. L.; Caneschi, A.; Pence, L. E.; Delfs, C. D.; Papaefthymiou,
G. C.; Lippard, S. J. J. Am. Chem. Soc. 1993, 115, 11753-11766.
(27) Taft, K. L.; Papaefthymiou, G. C.; Lippard, S. J. Science 1993, 259,
1302-1305.
(28) Rardin, R. L.; Poganiuch, P.; Bino, A.; Goldberg, D. P.; Tolman, W.
B.; Liu, S.; Lippard, S. J. J. Am. Chem. Soc. 1992, 114, 5240-5249.
(29) Lippard, S. J. Angew. Chem., Int. Ed. Engl. 1988, 27, 344-361.
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Chem. Soc. 1999, 121, 5230-5237.
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120, 13531-13532.
Inorganic Chemistry, Vol. 42, No. 26, 2003 8653

Kuzelka et al.
evaporated under reduced pressure, and the residue was redissolved
in CH2Cl2. Exposure of this solution to Et2O vapor diffusion yielded
orange crystals of 4 that were suitable for X-ray diffraction (53
mg, 78%). Anal. Calcd for C56H48N2O4Fe: C, 77.41; H, 5.57; N,
3.22. Found: C, 77.22; H, 5.60; N, 3.12.
and dicopper(I) compounds. Comparison of the structural
features of the resulting complexes reveals that the ligand
framework is sufficiently flexible to support features relevant
to the formation of intermediate Q of sMMOH.
[Fe2(µ-O2CArTol)2(O2CArTol)2(vpy)2] (5). To 1 (100 mg, 0.0685
mmol) in CH2Cl2 (2 mL) was added vpy (14.8 µL, 0.137 mmol),
and the resulting bright yellow solution was stirred for 15 min.
The solvent was removed under reduced pressure, and recrystal-
lization of the residue from CH2Cl2 by Et2O vapor diffusion yielded
5‚2CH2Cl2‚MeOH as yellow crystals of X-ray diffraction quality
(88 mg, 85%). Anal. Calcd for C98H82N2O8Fe2: C, 77.06; H, 5.41;
N, 1.83. Found: C, 76.59; H, 5.83; N, 1.54.
[Fe(O2CAr4-tBuPh)2(THF)2] (6). To Fe(OTf)2‚2MeCN (214 mg,
0.491 mmol) in THF (8 mL) was added solid NaO2CAr4-tBuPh (400
mg, 0.980 mmol), and the pale yellow solution was stirred for 30
min. The solvent was evaporated under reduced pressure, and to
the residue was added CH2Cl2. The resulting suspension was filtered
through a medium-porosity frit, and the filtrate was evaporated to
dryness under reduced pressure. The off-white solid was recrystal-
lized from THF by pentane vapor diffusion to yield colorless
crystals of 6 that were suitable for X-ray diffraction study (309
mg, 65%). Anal. Calcd for C62H74O6Fe: C, 76.68; H, 7.68.
Found: C, 76.38; H, 7.65.
[Fe(O2CAr4-tBuPh)2(DMP)2] (7). Treatment of 6 (100 mg, 0.104
mmol) in CH2Cl2 (3 mL) with DMP (33 mg, 0.21 mmol) in CH2Cl2
(1 mL) rapidly generated an orange solution that was stirred for
30 min. The reaction mixture was filtered through Celite, and THF
(1 mL) was added. Exposure of this solution to Et2O vapor diffusion
afforded orange X-ray quality crystals of 7‚2THF (80 mg, 68%).
Anal. Calcd for C74H78N4O4Fe: C, 77.74; H, 6.88; N, 4.90.
Found: C, 77.81; H, 6.73; N, 4.79.
3-Trifluoromethanesulfonate-8-carboxylatequinoline Ethyl
Ester (8). An oven-dried 200 mL three-neck round-bottom flask
was cooled to room temperature under N2 and charged with
3-hydroxy-8-quinolinecarboxylate ethyl ester (4.42 g, 20.4 mmol),
freshly distilled CH2Cl2 (80 mL), and dry pyridine (15 mL). The
resulting pale orange solution was further cooled to 0 °C in an
ice-water bath, and triflic anhydride (3.43 mL, 20.4 mmol) was
slowly added via syringe. The orange solution was warmed to room
temperature over ∼5 h and washed with saturated aqueous NaHCO3
(100 mL), and the product was extracted with CH2Cl2 (3 × 50
mL). The organic layer was dried over MgSO4 and filtered, and
the solvent was removed by rotary evaporation. The resulting pink-
orange solid 8 (6.73 g, 95%) was used in subsequent reactions with
no additional purification. ESI-MS (+m/z) Calcd for (M + Na)+:
372.0130. Found: 372.0113. 1H NMR (300 MHz, CDCl3): δ 8.96
d (J ) 9 Hz, 1H), 8.13-8.09 m (2H), 8.01 dd (1H), 7.72-7.67 m
(1H), 4.54 q (J ) 24 Hz, 2H), 1.47 t (J ) 23 Hz, 3H). 13C NMR
(75 MHz, CDCl3): δ 166.92, 144.61, 144.26, 143.45, 132.36,
131.34, 131.22, 128.01, 127.69, 127.16, 118.79 q, 62.02, 14.59.
19F NMR (282 MHz, CDCl3): δ 103.41. Mp 87-90 °C.
Experimental Section
General Procedures and Methods. Solvents were saturated with
nitrogen and purified by passing over a column of activated Al2O3
under nitrogen.38 The compounds [Fe2(µ-O2CArTol)2(O2CArTol)2-
-
(THF)2] (1) where ArTolCO2 is 2,6-di(p-tolyl)benzoate,31 2,7-
dimethyl-1,8-naphthyridine (Me2-napy),39,40 1,4-dimethylphthal-
azine (DMP),41,42 Fe(OTf)2‚2MeCN where OTf is triflate,43
-
NaO2CAr4-tBuPh where Ar4-tBuPHCO2 is 2,6-di(4-tert-butylphenyl-
benzoate),44-47 8-quinolinecarboxylic acid,48 8-quinolinecarboxylate
ethyl ester,48 3-hydroxy-8-carboxylatequinoline ethyl ester,49 and
1,2-diiodo-4,5-diethylbenzene50 were prepared according to pub-
lished literature procedures. Prior to use, 2-vinylpyridine (vpy) was
freshly distilled. All other reagents were purchased from commercial
sources and used as received. Air sensitive manipulations were
performed by using standard Schlenk techniques or under nitrogen
in an MBraun glovebox. NMR spectra were obtained on a 300 MHz
Varian Unity or Mercury spectrometer, and melting points were
determined with a Thomas-Hoover capillary melting point ap-
paratus. ESI-MS spectra were recorded on a Bruker Daltonics
APEXII 3 T Fourier transform mass spectrometer in the MIT
Department of Chemistry Instrumentation Facility. FT-IR data for
compounds 2-16 are provided in the Supporting Information.
[Fe(O2CArTol)2(Me2-napy)] (2). Treatment of 1 (60 mg, 0.041
mmol) in CH2Cl2 (2 mL) with Me2-napy (14.3 mg, 0.0905 mmol)
in CH2Cl2 (1 mL) afforded a pink-red solution that was stirred for
15 min. The solution was filtered through Celite, and to the filtrate
was added THF (1 mL). Vapor diffusion of Et2O into this solution
yielded 2 as pink prisms that were suitable for X-ray diffraction
study (54 mg, 81%). Anal. Calcd for C52H44N2O4Fe: C, 76.47; H,
5.43; N, 3.43. Found: C, 76.65; H, 5.70; N, 3.70.
[Fe2(µ-DMP)(µ-O2CArTol)2(O2CArTol)2(THF)] (3). To a clear
solution of 1 (200 mg, 0.137 mmol) in CH2Cl2 (2 mL) was added
DMP (24 mg, 0.15 mmol) in CH2Cl2 (1 mL), and the color turned
orange. The reaction mixture was stirred for 15 min and filtered
through Celite. Addition of THF (1 mL) and exposure to pentane
vapor diffusion yielded yellow-orange needles of 3 (204 mg, 94%).
Anal. Calcd for C98H86N2O9Fe2: C, 76.07; H, 5.60; N, 1.81.
Found: C, 76.03; H, 5.51; N, 1.93.
[Fe(O2CArTol)2(vpy)2] (4). Treatment of 3 (61 mg, 0.039 mmol)
in CH2Cl2 (2 mL) with vpy (84 µL, 0.78 mmol) afforded an orange
solution that was stirred for 30 min. Volatile components were
(38) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.;
Timmers, F. J. Organometallics 1996, 15, 1518-1520.
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(41) Guyot, A.; Vallette, F. Ann. Chim. (Paris) 1911, 23, 390-391.
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40, 6774-6781.
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(46) Chen, C.-T.; Siegel, J. S. J. Am. Chem. Soc. 1994, 116, 5959-5960.
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Am. Chem. Soc. 1946, 68, 1844-1846.
3-Trimethylsilanylethynyl-8-carboxylatequinoline Ethyl Ester
(9). A 20 mL scintillation vial was charged with 8 (1.0 g, 2.9 mmol)
and THF (15 mL) under a N2 atmosphere. To the resulting mixture
was added [PdCl2(PPh3)2] (98 mg, 0.14 mmol), PPh3 (19 mg, 0.072
mmol), NEt3 (599.3 µL, 4.308 mmol), and HCCSiMe3 (606.3 µL,
4.386 mmol). The dark red suspension was stirred for 15 min, after
which time CuI (6.5 mg, 0.034 mmol) was added and the mixture
was stirred vigorously overnight. Rotary evaporation of the volatile
components afforded a dark red oil that was dissolved in CH2Cl2
and purified by column chromatography on silica gel (3:1 hexanes/
EtOAc). The resulting pale yellow oil was triturated to yield 9 as
(49) Ochiai, E.; Kaneko, C.; Shimada, I.; Murata, Y.; Kosuge, T.; Miyashita,
S.; Kawasaki, C. Chem. Pharm. Bull. 1960, 8, 126-130.
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1301.
8654 Inorganic Chemistry, Vol. 42, No. 26, 2003

Modeling Aspects of Carboxylate-Bridged Diiron Enzymes
a light yellow solid (0.7 g, 82%). ESI-MS (+m/z) Calcd for (M +
Na)+: 320.1083. Found: 320.1066. 1H NMR (300 MHz, CDCl3):
δ 9.03 d (J ) 7 Hz, 1H), 8.28 d (J ) 7 Hz, 1H), 8.03 dd (1H),
7.89 dd (1H), 7.59 m (1H), 4.54 q (J ) 23 Hz, 2H), 1.46 t (J ) 23
Hz, 3H), 0.31 s (9H). 13C NMR (75 MHz, CDCl3): δ 167.31,
153.15, 144.04, 138.90, 131.86, 130.88, 130.77, 127.25, 126.33,
117.93, 101.67, 99.05, 61.73, 14.60, 0.15. Mp 54-57 °C.
126.54, 122.62, 118.33, 92.45, 89.69, 61.88, 25.67, 15.15, 14.70.
Mp 125-127 °C.
1,2-Bis(3-ethynyl-8-carboxylatequinoline)-4,5-diethylben-
zene, Sodium Salt (Na2BCQEBEt, 14). A suspension of 13 (85
mg, 0.15 mmol) in MeOH (15 mL) was refluxed for 1 h, at which
time the resulting pale yellow solution was treated with an aqueous
solution of NaOH (1 M, 0.31 µL, 0.31 mmol). The mixture was
refluxed overnight, and the solvent was removed under reduced
pressure to afford 14 as a tan powder in quantitative yield. ESI-
MS (-m/z) Calcd for (M - 2Na + H)-: 523.1658. Found:
3-Ethynyl-8-carboxylatequinoline Ethyl Ester (10). To a
solution of 9 (1.02 g, 3.43 mmol) in THF (80 mL) was added a 1
M solution of Bu4NF in THF (3.43 mL, 3.43 mmol), and the
resulting dark red solution was stirred for 2 h under N2. The solvent
was removed under reduced pressure, and the resulting dark red
oil was dissolved in CH2Cl2 and purified by column chromatography
on silica gel (1:1 EtOAc/hexanes). Compound 10 was isolated as
a cream-colored solid (0.39 g, 51%). ESI-MS (+m/z) Calcd for
1
523.1651. H NMR (300 MHz, CD3OD): δ 9.02 m (2H), 8.46 m
(2H), 7.80 m (4H), 7.58 m (2H), 7.50 s (2H), 2.75 q (J ) 20 Hz,
4H), 1.30 t (J ) 26 Hz, 6H). Mp > 300 °C.
[Fe2(Et2BCQEBEt)(µ-O2CArTol)3](OTf) (15). A mixture of
Fe(OTf)2‚2MeCN (60 mg, 0.14 mmol) in THF (3 mL) was treated
with a solution of 13 (40 mg, 0.069 mmol) in THF (2 mL). To the
resulting bright orange solution was added solid NaO2CArTol (67
mg, 0.21 mmol), and the suspension was stirred for 2 h. The solvent
was evaporated under reduced pressure, and the residue was
dissolved in CH2Cl2 and filtered through a plug of Celite. Pink-red
crystals of 15‚3.25CH2Cl2‚Et2O, suitable for X-ray crystallo-
graphic study, were obtained from a saturated solution of CH2Cl2
and Et2O at room temperature (50 mg, 42%). Anal. Calcd for
1
(M + Na)+: 248.0688. Found: 248.0680. H NMR (300 MHz,
CDCl3): δ 9.02 d (J ) 7 Hz, 1H), 8.32 d (J ) 6 Hz, 1H), 8.05 dd
(1H), 7.92 dd (1H), 7.61 m (1H), 4.56 q (J ) 24 Hz, 2H), 3.33 s
(1H), 1.48 t (J ) 24 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ
167.27, 153.17, 144.29, 139.34, 131.95, 131.02, 130.92, 127.19,
126.49, 116.92, 81.35, 80.65, 61.82, 14.63. Mp 90-93 °C.
1,2-Bis(3-ethynyl-8-carboxylatequinoline)benzene Ethyl Ester
(Et2BCQEB, 11). A thick-walled reaction tube was charged with
1,2-diiodobenzene (79.3 µL, 0.61 mmol), 10 (0.30 g, 1.3 mmol),
[PdCl2(PPh3)2] (43 mg, 0.061 mmol), PPh3 (7.8 mg, 0.030 mmol),
CuI (2.7 mg, 0.014 mmol), and Et2NH (10 mL). The reaction vessel
was sealed under N2 with a screw-top lid, and the mixture was
heated at 70 °C overnight behind a blast shield. Rotary evaporation
of the solvent yielded a dark red oil that was dissolved in CH2Cl2
and purified by column chromatography on silica gel (1:1 EtOAc/
hexanes). The resulting oily orange residue was dissolved in hot
MeOH and placed in a -20 °C freezer overnight. Compound 11
was collected as an off-white solid (211 mg, 66%) and washed
with cold MeOH. ESI-MS (+m/z) Calcd for (M + Na)+: 547.1634.
C102H83N2O13F3SFe2: C, 70.19; H, 4.79; N, 1.60. Found: C, 69.98;
H, 4.88; N, 1.61.
[Cu2(Et2BCQEBEt)(µ-I)2] (16). To 13 (50 mg, 0.086 mmol) in
CH2Cl2 (2 mL) was added CuI (33 mg, 0.17 mmol) in Et2NH (2
mL), and the pale yellow solution was stirred for 30 min. The
solvent was evaporated under reduced pressure, and the residue
was dissolved in CH2Cl2 to afford an orange solution. Exposure of
this solution to Et2O vapor diffusion afforded 16 as a flocculent
orange solid (57 mg, 69%), and single crystals of 16‚CH2Cl2,
suitable for X-ray diffraction study, were obtained by slow Et2O
vapor diffusion. Anal. Calcd for C38H32N2O4I2Cu2: C, 47.47; H,
3.35; N, 2.91. Found: C, 47.25; H, 3.31; N, 2.89.
1
Found: 547.1608. H NMR (300 MHz, CDCl3): δ 9.13 d (J ) 7
X-ray Crystallographic Studies. Crystals were mounted in
Paratone N oil on the ends of glass capillaries and frozen into place
under a low-temperature nitrogen cold stream. Data were collected
on a Bruker (formerly Siemens) APEX CCD X-ray diffractometer
running the SMART software package,51 with Mo KR radiation (λ
) 0.71073 Å), and refined using SAINT software.52 Details of the
data collection and reduction protocols are discussed in detail
elsewhere.53 The structures were solved by direct methods using
SHELXS-97 software54 and refined on F2 by using the SHELXL-
97 program55 incorporated in the SHELXTL software package.56
The program SADABS was used to apply empirical absorption
corrections,57 and PLATON was used to check the possibility of
higher symmetry.58 All non-hydrogen atoms were located and their
positions refined with anisotropic thermal parameters by least-
Hz, 2H), 8.31 d (J ) 7 Hz, 2H), 8.00 dd (2H), 7.83 dd (2H), 7.63
m (2H), 7.54 m (2H), 7.37 m (2H), 4.52 q (J ) 23 Hz 4H), 1.44
t (J ) 23 Hz, 6 H). 13C NMR (75 MHz, CDCl3): δ 167.43, 152.87,
144.22, 138.48, 132.34, 132.06, 131.05, 130.91, 128.89, 127.47,
126.55, 125.20, 117.95, 91.87, 90.73, 61.86, 14.68. Mp 91-93 °C.
1,2-Bis(3-ethynyl-8-carboxylatequinoline)benzene, Potassium
Salt (K2BCQEB, 12). To 11 (100 mg, 0.190 mmol) in THF (6
mL) was added KOSiMe3 (54 mg, 0.42 mmol) in THF (5 mL)
under N2, and the resulting suspension was stirred overnight. The
off-white solid 12 was collected and washed with Et2O (100 mg,
97%). ESI-MS (-m/z) Calcd for (M - K)-: 505.0591. Found:
1
505.0575. H NMR (300 MHz, CD3OD): δ 9.02 d (J ) 7 Hz,
2H), 8.49 d (J ) 7 Hz, 2H), 7.79 m (4H), 7.69 m (2H), 7.58 m
(2H), 7.46 m (2H). Mp > 300 °C.
1,2-Bis(3-ethynyl-8-carboxylatequinoline)-4,5-diethylben-
zene Ethyl Ester (Et2BCQEBEt, 13). This compound was prepared
in a procedure analogous to that used for the synthesis of 11 by
substituting 1,2-diiodo-4,5-diethylbenzene for 1,2-diiodobenzene.
Purification was achieved by column chromatography on silica gel
(1:1 EtOAc/hexanes) followed by recrystallization from EtOH to
yield 13 as an off-white solid (45%). ESI-MS (+m/z) Calcd for
(51) SMART V5.626: Software for the CCD Detector System; Bruker
AXS: Madison, WI, 2000.
(52) SAINT V5.01: Software for the CCD Detector System; Bruker AXS:
Madison, WI, 1998.
(53) Feig, A. L.; Bautista, M. T.; Lippard, S. J. Inorg. Chem. 1996, 35,
6892-6898.
(54) Sheldrick, G. M. SHELXS-97: Program for the Solution of Crystal
Structure; University of Go¨ttingen: Go¨ttingen, Germany, 1997.
(55) Sheldrick, G. M. SHELXL-97: Program for the Solution of Crystal
Structure; University of Go¨ttingen: Go¨ttingen, Germany, 1997.
(56) SHELXTL V5.10: Program Library for Structure Solution and
Molecular Graphics; Bruker AXS: Madison, WI, 1998.
(57) Sheldrick, G. M. SADABS: Area-Detector Absorption Correction;
University of Go¨ttingen: Go¨ttingen, Germany, 1996.
(58) Spek, A. L. PLATON, A Multipurpose Crystallographic Tool; Utrecht
University: Utrecht, The Netherlands, 2000.
1
(M + Na)+: 603.2260. Found: 603.2255. H NMR (300 MHz,
CDCl3): δ 9.19 d (J ) 8 Hz, 2H), 8.36 d (J ) 7 Hz 2H), 8.05 dd
(2H), 7.90 dd (2H), 7.60 m (2H), 7.49 s (2H), 4.56 q (J ) 24 Hz,
4H), 2.74 q (J ) 26 Hz, 4H), 1.48 t (J ) 24 Hz, 6H), 1.32 t (J )
26 Hz, 6H). 13C NMR (75 MHz, CDCl3): δ 167.46, 152.97, 144.06,
143.38, 138.38, 132.11, 131.99, 131.06, 130.85, 127.59,
Inorganic Chemistry, Vol. 42, No. 26, 2003 8655

Kuzelka et al.
Scheme 1
squares cycles and Fourier syntheses. Hydrogen atoms were
assigned idealized positions and given a thermal parameter 1.2 times
that of the carbon atom to which each was attached.
fashion, we reasoned that a simple naphthyridine derivative
might, by virtue of its connectivity, be a suitable candidate.
We employed as starting material [Fe2(µ-O2CArTol)2-
(O2CArTol)2(THF)2] (1), a complex with a preassembled,
carboxylate-rich diiron(II) core and two readily displaceable
THF molecules (Scheme 1).31 Reaction of 1 with Me2-napy
in a ratio of 1:1 afforded the mononuclear complex 2, the
yield of which was subsequently optimized (>80%) by
use of 2 equiv of Me2-napy. Disruption of the dinuclear
cores of 1 and the related compound [Fe2(µ-O2CArMes)2-
(O2CArMes)2(MeCN)2] has similarly been observed by addi-
tion of basic N-donor ligands.37,62,63
The crystallographically equivalent dichloromethane solvent
molecules in the structure of 5 have one chlorine atom that was
disordered over two positions and refined with occupancies of 50%.
In addition, there are two half-occupied methanol solvent molecules.
In the structure of 6, the methyl groups of one tert-butyl substituent
-
of the crystallographically equivalent Ar4-tBuPhCO2 ligands were
disordered over two positions and refined with occupancies of 81%
and 19%. In the structure of 15, one ethyl group of the Et2BCQEBEt
backbone is disordered over two positions and was refined with
occupancies of 75% and 25%, and the sulfur atom of the triflate
counterion was modeled over two positions with occupancies of
82% and 18%. Five dichloromethane solvent molecules were found
in the structure of 15. One chlorine atom in two molecules was
disordered over two positions and modeled with occupancies of
50/50% and 75/25%, respectively. Two additional molecules were
refined with 50% occupancy, and one chlorine molecule of each
was shared by another dichloromethane molecule, the occupancy
of which was refined as 25%. In the refinement of 16, high angle
reflections were omitted to remove high residual electron density
located near the iodine atoms resulting from an incomplete
absorption correction. Because several carbon atoms of the
Et2BCQEBEt ligand refined as nonpositive definite, only the
heteroatoms and the dichloromethane solvent molecule were
assigned anisotropic thermal parameters. Details of this structure
are provided in Supporting Information. The structures of 2, 4-7,
and 15 are shown in Figures 1 and 3, crystallographic data are listed
in Table 1, and selected bond lengths and angles are provided in
Tables 2 and 3.
The structure of 2 reveals that the two nitrogen atoms of
Me2-napy chelate a single highly distorted octahedral metal
ion (Figure 1, Table 2). The N-Fe-N bite angle of 60.93(9)°
is within the range reported for other transition-metal
complexes coordinated by bidentate 1,8-naphthyridine
fragments,64-68 and this small angle is responsible for the
-
pronounced distortion at the metal center. The two ArTolCO2
ligands are bound quite symmetrically to the iron(II) ion in
an η2-fashion, with Fe-O bond lengths of 2.137(2) and
2.180(2) Å. Similar structures result with other N-donors and
sterically demanding m-terphenyl-derived carboxylate li-
gands,62,63 but not with simpler carboxylates such as acetate
(59) Kuzelka, J.; Mukhopadhyay, S.; Spingler, B.; Lippard, S. J. Inorg.
Chem. 2003, 42, 6447-6457.
(60) He, C.; Lippard, S. J. Inorg. Chem. 2001, 40, 1414-1420.
(61) He, C.; Barrios, A. M.; Lee, D.; Kuzelka, J.; Davydov, R. M.; Lippard,
S. J. J. Am. Chem. Soc. 2000, 122, 12683-12690.
(62) Lee, D.; Lippard, S. J. Inorg. Chim. Acta 2002, 341, 1-11.
(63) Hagadorn, J. R.; Que, L., Jr.; Tolman, W. B. Inorg. Chem. 2000, 39,
6086-6090.
Results
(64) Nakajima, H.; Nagao, H.; Tanaka, K. J. Chem. Soc., Dalton Trans.
1996, 1405-1409.
A Simple Naphthyridine Ligand: Synthesis and Struc-
tural Characterization of [Fe(O2CArTol)2(Me2-napy)] (2).
Our laboratory has previously employed multidentate 1,8-
naphthyridine-based ligands to prepare a variety of diiron(II)
compounds.59-61 In search for a unit that would provide two
nitrogen donors for coordination to the diiron core in a syn
(65) Bermejo, M.-J.; Ruiz, J.-I.; Solans, X.; Vinaixa, J. J. Organomet. Chem.
1993, 463, 143-150.
(66) Dewan, J. C.; Kepert, D. L.; White, A. H. J. Chem. Soc., Dalton Trans.
1975, 490-492.
(67) Epstein, J. M.; Dewan, J. C.; Kepert, D. L.; White, A. H. J. Chem.
Soc., Dalton Trans. 1974, 1949-1954.
(68) Singh, P.; Clearfield, A.; Bernal, I. J. Coord. Chem. 1971, 1, 29-37.
8656 Inorganic Chemistry, Vol. 42, No. 26, 2003

Modeling Aspects of Carboxylate-Bridged Diiron Enzymes
Figure 1. ORTEP diagrams of [Fe(O2CArTol)2(Me2-napy)] (2), [Fe(O2CArTol)2(vpy)2] (4), [Fe2(µ-O2CArTol)2(O2CArTol)2(vpy)2] (5), [Fe(O2CAr4-tBuPh)2-
(THF)2] (6), and [Fe(O2CAr4-tBuPh)2(DMP)2] (7) showing 50% probability thermal ellipsoids for all non-hydrogen atoms (left to right, top to bottom). The
-
phenyl rings of the bridging ArTolCO2 ligands in 5 are omitted for clarity.
or benzoate, attesting to the ability of the flanking phenyl
groups to prevent undesired oligomerization reactions. In the
absence of additional donor atoms, the 1,8-naphthyridine unit
frequently adopts the chelating coordination mode evident
in 2,64-68 whereas the bridging mode is more common when
a metal-metal interaction is present to stabilize the dinuclear
core,69-75 a feature lacking in our system.
Synthesis and Reactivity of [Fe2(µ-DMP)(µ-O2CArTol)2-
(O2CArTol)2(THF)] (3). Preparation and Crystallographic
Analysis of [Fe(O2CArTol)2(vpy)2] (4) and [Fe2(µ-O2CArTol)2-
(O2CArTol)2(vpy)2] (5). Whereas the flexible disposition of
the nitrogen lone pairs of the 1,8-naphthyridine unit permits
the formation of both mononuclear and dinuclear species,
the phthalazine moiety should promote dinuclearity because
the lone pairs point away from one another. In support of
this expectation, we note that no mononuclear compounds
with η2-bound phthalazine have been crystallographically
characterized. Upon treatment of 1 with DMP, the dinuclear
core remained intact, and complex 3 was isolated in excellent
yield (94%). The data quality of repeated X-ray crystal-
lographic analyses was sufficient to ascertain the gross
structure of the compound, but was unsatisfactory for full
complete refinement. The coordination environment of 3,
shown in Scheme 1, features two asymmetric iron sites,
separated by ∼3.4 Å, that are bridged by DMP and two
-
ArTolCO2 ligands. One iron is additionally coordinated by
a bidentate carboxylate ligand, and a monodentate carbox-
ylate and an additional solvent molecule complete the
coordination sphere of the remaining iron center. Dinuclear
compounds generally form with multidentate ligands derived
from phthalazine,76-86 but such structures are rare with
phthalazine units lacking additional donor groups.72,87-89
Compound 3 is significant because it reproduces the syn
coordination geometry of the two nitrogen donors present
(69) Døssing, A.; Larsen, S.; van Lelieveld, A.; Bruun, R. M. Acta Chem.
Scand. 1999, 53, 230-234.
(70) Griffith, W. P.; Koh, T. Y.; White, A. J. P.; Williams, D. J. Polyhedron
1995, 14, 2019-2025.
(71) Munakata, M.; Maekawa, M.; Kitagawa, S.; Adachi, M. Inorg. Chim.
Acta 1990, 167, 181-188.
(72) Tsuda, T.; Ohba, S.; Takahashi, M.; Ito, M. Acta Crystallogr., Sect.
C 1989, C45, 887-890.
(73) Tiripicchio, A.; Camellini, M. T.; Uso´n, R.; Oro, L. A.; Ciriano, M.
A.; Viguri, F. J. Chem. Soc., Dalton Trans. 1984, 125-131.
(74) Gatteschi, D.; Mealli, C.; Sacconi, L. Inorg. Chem. 1976, 15, 2774-
2778.
(75) Gatteschi, D.; Mealli, C.; Sacconi, L. J. Am. Chem. Soc. 1973, 95,
2736-2738.
(76) Barrios, A. M.; Lippard, S. J. Inorg. Chem. 2001, 40, 1250-1255.
(77) Barrios, A. M.; Lippard, S. J. Inorg. Chem. 2001, 40, 1060-1064.
(78) Barrios, A. M.; Lippard, S. J. J. Am. Chem. Soc. 2000, 122, 9172-
9177.
(79) Barrios, A. M.; Lippard, S. J. J. Am. Chem. Soc. 1999, 121, 11751-
11757.
Inorganic Chemistry, Vol. 42, No. 26, 2003 8657

Kuzelka et al.
Table 1. Summary of X-ray Crystallographic Data for Compounds 2, 4, 5·2CH2Cl2·MeOH, 6, 7·2THF, and 15‚3.25CH2Cl2‚Et2O
2
4
5‚2CH2Cl2‚MeOH
6
7‚2THF
15‚3.25CH2Cl2‚Et2O
formula
fw
C52H44N2FeO4
816.74
C56H48N2FeO4
868.81
C101H82N2Fe2O9Cl4
1721.19
C62H56FeO6
952.92
C82H94N4FeO6
1287.46
C109.25H93N2Fe2SO14F3Cl6.5
2089.04
space group
a, Å
b, Å
C2/c
P21/c
P21/n
15.161(2)
10.8129(16)
26.267(4)
C2/c
C2/c
P21/c
27.237(7)
14.188(4)
29.326(8)
21.272(5)
16.099(5)
13.652(5)
14.543(5)
11.941(5)
26.988(5)
35.297(6)
11.092(2)
15.225(3)
14.8112(10)
31.795(2)
16.8180(12)
c, Å
R, deg
â, deg
γ, deg
V, Å3
Z
114.962(5)
103.030(5)
93.126(3)
114.840(3)
104.9430(10)
113.644(4)
4239(2)
4
4566(3)
4
4299.7(11)
2
5409.4(17)
4
7652.0(9)
4
10381(5)
4
T, °C
F
-100
-70
-70
-70
-70
-100
calcd, g cm-3
1.280
1.264
1.329
1.170
1.118
1.337
µ(Mo KR), mm-1
θ range, deg
total data
0.404
0.380
0.523
0.328
0.249
0.535
1.67-25.00
75408
18275
14971
1306
0.0805
0.2048
1.320, -1.002
1.99-28.28
13206
4885
3598
269
0.0447
0.1035
0.339, -0.234
1.55-28.17
27049
10101
8261
2.04-28.26
25519
9737
7379
550
0.0609
0.1454
0.713, -0.535
1.94-28.24
15913
6117
4836
420
0.0477
0.1344
0.431, -0.317
1.28-25.00
19849
6730
5466
420
0.0791
0.2487
1.032, -0.542
unique data
obsd dataa
params
569
Rb
0.0625
0.1281
0.344, -0.346
wR2 c
max, min peaks, e Å-3
2
2
2
a Observation criterion: I > 2σ(I). b R ) ∑||Fo| - |Fc||/∑|Fo|. c wR2 ) {∑[w(Fo - Fc )2]/∑[w(Fo )2]}1/2
.
Table 2. Selected Bond Lengths (Å) and Angles (deg) for 2, 4, and
5·2CH2Cl2·MeOHa
Table 3. Selected Bond Lengths (Å) and Angles (deg) for 6, 7·2THF,
15‚3.25CH2Cl2‚Et2Oa
bond length
bond angle
bond length
bond angle
2
6
Fe(1)-N(1)
2.214(2)
2.137(2)
2.180(2)
N(1)-Fe(1)-N(1A)
60.93(9)
104.86(6)
100.87(6)
60.83(5)
161.86(8)
107.90(6)
Fe(1)-O(1)
2.250(1)
2.118(2)
2.099(2)
O(3)-Fe(1)-O(3A)
O(3)-Fe(1)-O(1)
O(3)-Fe(1)-O(2)
O(3)-Fe(1)-O(1A)
O(3)-Fe(1)-O(2A)
O(1)-Fe(1)-O(1A)
O(1)-Fe(1)-O(2A)
O(2)-Fe(1)-O(2A)
95.93(8)
149.54(5)
89.81(5)
92.76(6)
97.22(6)
94.38(7)
111.98(5)
169.52(7)
Fe(1)-O(1)
Fe(1)-O(2)
N(1)-Fe(1)-O(1)
N(1)-Fe(1)-O(2)
O(1)-Fe(1)-O(2)
O(1)-Fe(1)-O(1A)
O(1)-Fe(1)-O(2A)
Fe(1)-O(2)
Fe(1)-O(3)
4
Fe(1)-N(1)
Fe(1)-N(2)
Fe(1)-O(1)
Fe(1)-O(2)
Fe(1)-O(3)
Fe(1)-O(4)
2.163(2)
2.194(2)
2.303(2)
2.065(2)
2.102(2)
2.265(2)
N(1)-Fe(1)-N(2)
N(1)-Fe(1)-O(1)
N(1)-Fe(1)-O(2)
N(1)-Fe(1)-O(3)
N(1)-Fe(1)-O(4)
N(2)-Fe(1)-O(1)
N(2)-Fe(1)-O(2)
N(2)-Fe(1)-O(3)
N(2)-Fe(1)-O(4)
97.84(9)
165.00(8)
105.48(8)
92.10(8)
95.16(8)
89.19(8)
100.68(8)
91.42(8)
149.14(8)
7‚2THF
Fe(1)-N(1)
Fe(1)-O(1)
Fe(1)-O(2)
2.163(3)
2.059(2)
2.384(3)
N(1)-Fe(1)-N(1A)
N(1)-Fe(1)-O(1)
N(1)-Fe(1)-O(2)
N(1)-Fe(1)-O(1A)
N(1)-Fe(1)-O(2A)
95.28(17)
101.23(11)
93.77(11)
95.55(11)
158.83(10)
15‚3.25CH2Cl2‚Et2O
Fe(1)‚‚‚Fe(2)
N(1)‚‚‚N(2)
Fe(1)-N(1)
Fe(1)-O(1)
Fe(1)-O(3)
Fe(1)-O(5)
Fe(1)-O(7)
Fe(2)-N(2)
Fe(2)-O(2)
Fe(2)-O(4)
Fe(2)-O(6)
Fe(2)-O(9)
3.576(1)
6.077(5)
2.164(3)
2.054(3)
2.017(3)
2.048(3)
2.081(3)
2.193(3)
2.084(3)
2.034(3)
1.974(3)
2.081(3)
O(1)-Fe(1)-O(3)
O(1)-Fe(1)-O(5)
O(1)-Fe(1)-O(7)
O(1)-Fe(1)-N(1)
O(3)-Fe(1)-O(5)
O(3)-Fe(1)-O(7)
O(5)-Fe(1)-O(7)
O(7)-Fe(1)-N(1)
O(2)-Fe(2)-O(4)
O(2)-Fe(2)-O(6)
O(2)-Fe(2)-O(9)
O(2)-Fe(2)-N(2)
O(4)-Fe(2)-O(9)
O(6)-Fe(2)-O(9)
O(9)-Fe(2)-N(2)
96.57(12)
101.03(12)
85.66(12)
160.96(13)
116.99(13)
154.85(13)
86.88(12)
82.22(13)
96.57(12)
99.44(12)
87.66(12)
167.37(12)
94.18(12)
134.94(13)
82.17(12)
5‚2CH2Cl2‚MeOH
Fe(1)‚‚‚Fe(1A)
Fe(1)-O(1)
Fe(1)-O(2)
Fe(1)-O(3)
Fe(1)-N(1)
4.3429(8)
2.013(2)
1.958(2)
2.030(2)
2.154(2)
O(1)-Fe(1)-O(2)
O(1)-Fe(1)-O(3)
O(1)-Fe(1)-N(1)
O(2)-Fe(1)-O(3)
O(2)-Fe(1)-N(1)
O(3)-Fe(1)-N(1)
114.46(8)
115.98(8)
97.02(8)
124.58(8)
103.08(9)
92.20(8)
a Numbers in parentheses are estimated standard deviations of the last
significant figure. Atoms are labeled as indicated in Figure 1.
at the active sites of sMMOH, RNR-R2, and ∆9D. To our
knowledge, the only other diiron(II) compound that dis-
plays this feature in a carboxylate-rich environment is
Et4N[Fe2(µ-H2O)(µ-O2CCH3)2(O2CCH3)3(C5H5N)2].90,91 Al-
a Number in parentheses are estimated standard deviations of the last
significant figure. Atoms are labeled as indicated in Figures 1 and 3.
(80) Tandon, S. S.; Thompson, L. K.; Manuel, M. E.; Bridson, J. N. Inorg.
Chem. 1994, 33, 5555-5570.
though this complex was formed by self-assembly, kinetic
lability of the core was evident in the subsequent reaction
with dioxygen to afford a (µ3-oxo)triiron(III) basic acetate
complex.90 Not surprisingly, the dinuclear core in 3 also does
not remain intact upon oxidation, and preliminary reactivity
studies indicate that a hexanuclear iron(III) complex forms
upon exposure to dioxygen.92
(81) Chen, L.; Thompson, L. K.; Bridson, J. N. Inorg. Chem. 1993, 32,
2938-2943.
(82) Mandal, S. K.; Thompson, L. K.; Newlands, M. J.; Charland, J.-P.;
Gabe, E. J. Inorg. Chim. Acta 1990, 178, 169-178.
(83) Mandal, S. K.; Woon, T. C.; Thompson, L. K.; Newlands, M. J.; Gabe,
E. J. Aust. J. Chem. 1986, 39, 1007-1021.
(84) Mandal, S. K.; Thompson, L. K.; Hanson, A. W. J. Chem. Soc., Chem.
Commun. 1985, 1709-1711.
8658 Inorganic Chemistry, Vol. 42, No. 26, 2003

Modeling Aspects of Carboxylate-Bridged Diiron Enzymes
Scheme 2a
a (a) Tf2O/CH2Cl2/pyridine, 95%; (b) Me3SiCCH/NEt3/THF, [PdCl2(PPh3)2]/CuI (cat.), 80%; (c) nBu4NF/THF, 50%; (d) R ) H; 1,2-diiodobenzene/
Et2NH, [PdCl2(PPh3)2]/CuI (cat.), ∆, 66%; (e) R ) Et; 1,2-diiodo-4,5-diethylbenzene/Et2NH, [PdCl2(PPh3)2]/CuI (cat.), ∆, 45%; (f) R ) H; KOSiMe3/THF;
(g) R ) Et; NaOH/MeOH.
The lability of the dinuclear core in 3 is further manifest
by reaction with vpy to generate mononuclear 4 (Scheme
1). The pseudo-octahedral iron(II) center in this compound
-
is ligated by two bidentate ArTolCO2 ligands and two vpy
groups. The coordination of the carboxylate ligands is
asymmetric, with Fe-O bond lengths ranging from 2.065(2)
to 2.303(2) Å. The N-Fe-N bond angle of 97.84(9)° is
substantially larger than that in 2, resulting in a less distorted
octahedral geometry at the iron center.
-
A combination of ArTolCO2 and vpy ligands can also
support a diiron(II) core, as seen by the synthesis of 5 when
1 reacts with vpy in a ratio of 1:2 (Scheme 1). A survey of
Figure 2. Representation of [Fe2(BQEB)(µ-OH)(µ-O2CArTol)(O2CArTol)2-
(THF)(H2O)] displaying syn nitrogen donor ligands.
the Cambridge Structural Database revealed that 4 and 5 are
the only crystallographically characterized iron compounds
pensity of the {Fe2(O2CArTol)4} core to be disrupted prompted
us to modify the substituents of the m-terphenyl carboxylate
ligands in an effort to stabilize the dimetallic unit. In order
to restrict access to bimolecular reaction pathways that lead
to high-nuclearity species upon oxidation, we employed the
sterically demanding 4-tert-butyl derivative. Reaction of
Fe(OTf)2‚2MeCN with NaO2CAr4-tBuPh in a ratio of 1:2 in
THF generated mononuclear 6, and prolonged reaction times
(>12 h) did not afford a dinuclear compound. This result
differs from the chemistry of diiron analogues supported by
ArTolCO2 , Ar4-FPhCO2 , and ArMesCO2 ligands.37 The
stereochemistry at the iron(II) center in 6 is similar to that
of 4, with two bidentate carboxylate ligands and two THF
molecules coordinating to the metal ion. The Fe-O bonds
located trans to the coordinated THF molecules are elongated
relative to the other bonds (∆Fe-O ) 0.132(1) Å), and the
OTHF-Fe-OTHF bond angle of 95.93(8)° is close to the
N-Fe-N angle in 4.
ligated by vpy ligands. Not surprisingly, the vpy groups in
5 are bound in an anti fashion with Fe-N bond lengths of
2.154(2) Å, and the alkene units are directed away from the
metal centers. The arrangement of the four carboxylate
ligands in a windmill rather than paddlewheel fashion results
in an Fe‚‚‚Fe separation of 4.343(1) Å that is slightly
elongated relative to the intermetal distances found in related
diiron compounds.31,33,37,93 The Fe-O bond lengths of the
-
monodentate ArTolCO2 ligands of 2.030(2) Å are shorter
- 31
- 31
-
than those of the chelating carboxylates in 2 and 4, although
a weak Fe‚‚‚Odangling interaction is suggested by the ∼2.48
Å separation between Fe(1) and O(4).
A More Sterically Demanding Carboxylate Ligand.
Synthesis and Crystal Structures of [Fe(O2Ar4-tBuPh)2-
(THF)2] (6) and [Fe(O2Ar4-tBuPh)2(DMP)2] (7). The pro-
(85) Thompson, L. K.; Hanson, A. W.; Ramaswamy, B. S. Inorg. Chem.
1984, 23, 2459-2465.
(86) Sullivan, D. A.; Palenik, G. J. Inorg. Chem. 1977, 16, 1127-1133.
(87) Whitcomb, D. R.; Rogers, R. D. Inorg. Chim. Acta 1997, 256, 263-
267.
(88) Li, C.; Kanehisa, N.; Miyagi, Y.; Nakao, Y.; Takamizawa, S.; Mori,
W.; Kai, Y. Bull. Chem. Soc. Jpn. 1997, 70, 2429-2436.
(89) Whitcomb, D. R.; Rogers, R. D. J. Chem. Crystallogr. 1995, 25, 137-
142.
Addition of either 1 or 2 equiv of DMP to 6 affords
mononuclear 7 by exchange of the THF ligands, and the
stereochemistry at the iron center of this compound is similar
to that of 4 and 6. One nitrogen atom of each DMP ligand
remains unmetalated. Such η1-coordination of the phthalazine
unit has been observed in other compounds.72,94-97 The tert-
(90) Reynolds, R. A., III; Dunham, W. R.; Coucouvanis, D. Inorg. Chem.
1998, 37, 1232-1241.
(91) Coucouvanis, D.; Reynolds, R. A., III; Dunham, W. R. J. Am. Chem.
Soc. 1995, 117, 7570-7571.
(94) Kettler, P. B.; Chang, Y.-D.; Chen, Q.; Zubieta, J.; Abrams, M. J.;
Larsen, S. K. Inorg. Chim. Acta 1995, 231, 13-20.
(92) Kuzelka, J.; Lippard, S. J. Unpublished results. Pentane vapor diffusion
into an O2-saturated THF solution of 3 afforded red-brown crystals
of [Fe6(µ3-O)2(µ-OH)6(µ-O2CR)8(THF)2].
(95) Abrams, M. J.; Larsen, S. K.; Shaikh, S. N.; Zubieta, J. Inorg. Chim.
Acta 1991, 185, 7-15.
(96) Nicholson, T.; Zubieta, J. Polyhedron 1988, 7, 171-185.
(97) Bushnell, G. W.; Dixon, K. R. Can. J. Chem. 1978, 56, 878-883.
(93) Lee, D.; Lippard, S. J. J. Am. Chem. Soc. 2001, 123, 4611-4612.
Inorganic Chemistry, Vol. 42, No. 26, 2003 8659

Kuzelka et al.
Figure 3. ORTEP diagram of the cation in [Fe2(Et2BCQEBEt)(µ-O2CArTol)3](OTf) (15) showing 50% probability thermal ellipsoids for all non-hydrogen
-
atoms and ball-and-stick diagram showing the connectivity of [Cu2(Et2BCQEBEt)(µ-I)2] (16) (left to right). The phenyl rings of the bridging ArTolCO2
ligands in 15 are omitted for clarity.
butyl substituents of the carboxylate ligands presumably
confer too much steric bulk to permit the formation of a
carboxylate-rich diiron core similar to that of 3.
and treatment with triflic anhydride100,101 in CH2Cl2 and
pyridine yielded 8 in nearly quantitative yield. Efficient
Sonogashira coupling102 between 8 and HCCSiMe3 in THF
afforded 9, the trimethylsilyl group of which was subse-
quently deprotected with nBu4NF in THF to yield 10.
Compound 11 was synthesized in >65% yield by a second
Sonogashira reaction, and the ethyl ester was removed by
Design and Synthesis of BCQEB Derivatives. Studies
with the ligands Me2-napy and DMP illustrate the difficulty
of controlling nuclearity and kinetic lability with simple units.
We therefore reasoned that a ligand in which the connectivity
enforces the relative disposition of the N-donors and ad-
ditional donor groups promote dinuclearity should address
these shortcomings. Exploratory work in our laboratory with
1,2-diethynylbenzene as a spacer between two pyridine or
quinoline groups proved to be an effective strategy to enforce
the desired syn coordination of two nitrogen donors, as dem-
onstrated by the synthesis and characterization of [Fe2(BQEB)-
(µ-OH)(µ-O2CArTol)(O2CArTol)2(THF)(H2O)],98 where BQEB
is 1,2-bis(3-ethynylquinoline)benzene.99 This complex, de-
picted in Figure 2, displays the desired geometry and reveals
that the 1,2-diethynylbenzene spacer can support a dimetallic
unit with a single atom bridge, a feature important for
modeling high-valent intermediates formed in the related
diiron metalloenzymes. The hydroxide-bridged diiron com-
pound, however, could be isolated only in low yield by a
synthetic route that was difficult to reproduce. Moreover,
reactions with dioxygen afforded mainly oligomeric species.98
We hypothesized that additional chelating groups should
enhance the stability of the resulting diiron complex, and
that incorporation of carboxylate groups into the quinoline
unit would be a good strategy for producing the desired
biomimetic compounds.
103
treatment with KOSiMe3 in THF to yield the potassium
salt 12, K2BCQEB. In an analogous procedure, Et2BCQEBEt
(13) was prepared by using 1,2-diiodo-4,5-diethylbenzene,50
and ester deprotection was achieved with NaOH in MeOH
affording Na2BCQEBEt (14).
Synthesis and Structural Characterization of [Fe2-
(Et2BCQEBEt)(µ-O2CArTol)3](OTf) (15). Metalation of
K2BCQEB or Na2BCQEBEt with iron(II) proved to be
difficult because reaction with 1 or iron(II) salts and a variety
of different carboxylate ligands invariably led to materials
with poor solubility in common organic solvents, suggesting
the formation of an oligomeric product. Extended structures
might arise from interaction of the dangling carbonyl oxygen
atom of the BCQEB scaffold and other metal ions such as
Fe(II) or K+/Na+. We therefore employed as ligand
Et2BCQEBEt, the ethyl ester of which protects one oxygen
atom and precludes the formation of higher nuclearity
species.
Reaction of Fe(OTf)2‚2MeCN with Et2BCQEBEt and
NaO2CArTol in a ratio of 2:1:3 in THF affords compound 15
in moderate yield. As shown in Figure 3, the two iron centers
adopt square pyramidal geometry and are separated by
3.576(1) Å. The diiron core is spanned by three bridging
Scheme 2 outlines the synthesis of 1,2-bis(3-ethynyl-8-
carboxylatequinoline)benzene (BCQEB) derivatives. Multi-
gram quantities of 3-hydroxy-8-carboxylatequinoline ethyl
ester were synthesized following literature procedures,48,49
-
ArTolCO2 groups, two of which are bound in a syn, syn
(100) Subramanyam, C.; Chatterjee, S.; Mallamo, J. P. Tetrahedron Lett.
1996, 37, 459-462.
(101) Draper, T. L.; Bailey, T. R. Synlett 1995, 157-158.
(102) Thorand, S.; Krause, N. J. Org. Chem. 1998, 63, 8551-8553.
(103) Laganis, E. D.; Chenard, B. L. Tetrahedron Lett. 1984, 25, 5831-
5834.
(98) Farrell, J. R.; Stiles, D.; Lippard, S. J. Unpublished results.
(99) Rawat, D. S.; Benites, P. J.; Incarvito, C. D.; Rheingold, A. L.; Zaleski,
J. M. Inorg. Chem. 2001, 40, 1846-1857.
8660 Inorganic Chemistry, Vol. 42, No. 26, 2003

Modeling Aspects of Carboxylate-Bridged Diiron Enzymes
fashion, whereas the third carboxylate adopts the less
common syn, anti coordination mode.104 The Et2BCQEBEt
ligand coordinates each metal ion through the nitrogen and
carbonyl oxygen atoms of the quinolinic acid unit, forming
six-membered chelate rings with O-Fe-N bite angles of
82.17(12)° and 82.22(13)°. The dinuclear core is thus
stabilized, permitting a reliable synthesis of 15. Significantly,
the N-donors are bound to the iron centers in a syn fashion
with Fe-N bond lengths of 2.164(3) and 2.193(3) Å. The
N‚‚‚N separation of 6.077(5) Å is comparable to that of the
donor nitrogen atoms of the two histidine residues at the
diiron(II) active sites of sMMOH (∼5 Å),12 RNR-R2 (∼5.4
Å),14 and ∆9D (∼6 Å).15 The Fe-O bond lengths of the
carboxylate ligands range from 1.974(3) to 2.084(3) Å, with
the longer bonds located trans to the quinoline nitrogen
atoms. The ester unit has Fe-O bond distances of 2.081(3)
Å, which fall in the upper range of other crystallographically
characterized Fe-O(C)OR units.105-118
Preparation and Crystallographic Characterization of
[Cu2(Et2BCQEBEt)(µ-I)2] (16). To probe the ability of
Et2BCQEBEt to support dinuclear cores displaying a range
of geometries and metal-metal distances, a dicopper(I)
complex was prepared. Reaction of Et2BCQEBEt with 2 equiv
of CuI in a mixture of CH2Cl2 and Et2NH afforded 16. The
amine solvent is necessary to dissolve CuI, and no reaction
occurs in pure CH2Cl2. Although a full refinement of the
crystal structure of 16 was not possible because of poor data
quality, the geometry at the copper centers could be
unambiguously established. In 16, there are two pseudo-
tetrahedral copper(I) centers bound to bidentate units of
Et2BCQEBEt and two iodide ligands. The Cu-N bond
lengths, ∼2.08 Å, are shorter than the Fe-N bond distances
in 15 (∆M-N ∼0.1 Å), as expected for a complex with lower
coordination number. The M-O bond lengths in 16 are
longer by ∼0.05 Å relative to those in 15, however, reflecting
the soft character of Cu(I) compared to Fe(II). The iodide
ligands form two single atom bridges between the copper
sites with Cu-I bond lengths of ∼2.59 Å. The Cu-I-Cu
and I-Cu-I bond angles of ∼120° and 59°, respectively,
give rise to a short Cu‚‚‚Cu separation (∼2.54 Å). This
distance is slightly less than the intermetal separation in
metallic copper (2.56 Å), suggesting that there may be a weak
copper-copper interaction. The two nitrogen atoms of Et2-
BCQEBEt are ∼5.41 Å apart in 16, a substantial reduction
compared to that in 15 (∆N‚‚‚N > 0.6 Å). Di(µ-iodo)dicopper-
(I) compounds supported by alkyl esters of quinaldic acid
have similar geometric parameters.119
Discussion
Complexes of Me2-napy and DMP. Use of sterically
hindered m-terphenyl-derived carboxylate ligands with the
1,8-naphthyridine and phthalazine units Me2-napy and DMP
afforded both mononuclear and dinuclear compounds. Com-
plexes 2, 4, and 7 all feature a pseudo-octahedral iron(II)
center coordinated by two carboxylates and two nitrogen
donor ligands (Figure 1). Relatively long Fe-N bonds
(2.163(2)-2.214(2) Å) promote bidentate, rather than mono-
-
-
dentate, coordination of the ArTolCO2 and Ar4-tBuPhCO2
groups.62,63 The carboxylate ligands in 4 and 7 are bound
asymmetrically, with the Fe-O bonds located trans to the
N-donors being substantially elongated (∼0.2 Å). Because
of the highly distorted stereochemistry at the iron(II) center
-
in 2, neither of the ArTolCO2 ligands is bound directly
opposite the Me2-napy unit, and the coordination of the
carboxylates is symmetric (∆Fe-O ∼ 0.04 Å). The coordina-
tion mode of the phthalazine moiety appears to be dictated
by the nature of the ancillary ligands, binding in an η1 fashion
in 7 and in an η2 manner in 3. Unfavorable steric interactions
-
arising from the large tert-butyl groups of Ar4-tBuPhCO2
would appear to preclude the formation of a dinuclear
compound, whereas the smaller methyl substituents of
ArTolCO2- readily support a carboxylate-rich dimetallic unit.
Preparation of BCQEB Ligands and Metal Complexes.
The BCQEB ligands were designed and synthesized to
enforce dinuclearity and kinetic stability on the diiron(II)
unit, features that were difficult to maintain with Me2-napy
and DMP. Compound 8 serves as a convenient starting
material, and a series of Sonogashira coupling reactions
afforded the BCQEB derivatives in three to four synthetic
steps (Scheme 2). The connectivity of the molecular scaffold
ensures that the separation of nitrogen atoms remains close
to that observed for the N-donors of the histidine residues
in sMMOH, RNR-R2, and ∆9D (∼5-6 Å),12,14,15 and
incorporation of a chelating moiety, ester or carboxylate, is
an effective strategy for promoting dinuclearity upon meta-
lation. The syntheses of compounds with well-defined
dimetallic cores were effected with the ligand Et2BCQEBEt,
affording [Fe2(Et2BCQEBEt)(µ-O2CArTol)3](OTf) (15) and
[Cu2(Et2BCQEBEt)(µ-I)2] (16), illustrated in Figure 3.
Utilization of BCQEB-Derived Ligands and Relevance
to High-Valent Intermediates in Non-Heme Diiron En-
(104) Rardin, R. L.; Tolman, W. B.; Lippard, S. J. New J. Chem. 1991,
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1999, 291, 91-100.
(109) Kandler, H.; Bidell, W.; Ja¨nicke, M.; Knickmeier, M.; Veghini, D.;
Berke, H. Organometallics 1998, 17, 960-971.
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metallics 1997, 16, 1186-1192.
(111) Akita, M.; Terada, M.; Moro-oka, Y. Chem. Commun. 1997, 265-
266.
(112) Almeida, S. S. P.; Duarte, M. T.; Ribeiro, L. M. D.; Gormley, F.;
Galva˜o, A. M.; Frau´sto da Silva, J. J. R.; Pombeiro, A. J. L. J.
Organomet. Chem. 1996, 524, 63-66.
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1994, 24, 197-202.
(114) Go¨rls, H.; Ja¨ger, E.-G. Cryst. Res. Technol. 1991, 26, 349-355.
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9, 2933-2937.
(117) Mitsudo, T.; Watanabe, H.; Watanabe, K.; Watanabe, Y.; Kafuku,
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Inorganic Chemistry, Vol. 42, No. 26, 2003 8661

Kuzelka et al.
zymes. A comparison of structures 15 and 16 allows the
efficacy of the BCQEB framework to facilitate modeling of
non-heme diiron enzymes to be evaluated. The ligand
Et2BCQEBEt supports both four- and five-coordinate com-
plexes, and accommodates either three µ-1,3-carboxylate
ligands (15) or two single-atom bridging groups (16). The
structural flexibility of the ligand scaffold is manifest in the
range of metal-metal and N‚‚‚N distances, ∼1 and 0.6 Å,
respectively, supported by Et2BCQEBEt. Significantly, the
syn disposition of the nitrogen donors is enforced with this
ligand, which thus mimics histidine residues supplied by the
four-helix bundle surrounding the diiron active sites of
sMMOH, RNR-R2, and ∆9D. The geometry of catalytically
active species in these non-heme diiron enzymes differs
substantially from their reduced and oxidized forms, and the
ability of a ligand to support such variety of the dinuclear
core structure is crucial for the preparation of functional
model analogues. The flexibility of Et2BCQEBEt satisfies this
requirement, thus representing a significant achievement
toward the goal. Moreover, compound 16 accommodates the
short metal-metal separation in the {M2O2} core of inter-
mediate Q in MMOH. The ability of the BCQEB framework
to support such a structure indicates its suitability for
modeling biologically relevant dimetallic species.
thyridine and phthalazine fragments yielded iron(II) com-
pounds, the nuclearity and kinetic stability of which were
difficult to control. To address these challenges, the BCQEB-
derived ligands were prepared and employed in the syn-
thesis of [Fe2(Et2BCQEBEt)(µ-O2CArTol)3](OTf) (15) and
[Cu2(Et2BCQEBEt)(µ-I)2] (16). Both 15 and 16 feature
dinuclear cores in which the desired syn disposition of
nitrogen donors is enforced, and the range of M‚‚‚M and
N‚‚‚N distances observed in these compounds attests to the
structural flexibility of the BCQEB framework. The synthesis
and diiron(II) complexes of other BCQEB derivatives and
exploration of their oxidation chemistry are currently under
investigation.
Acknowledgment. This work was funded by grants from
the National Science Foundation and National Institute of
General Medical Sciences. J.K. acknowledges NSERC for
a graduate student fellowship. J.R.F. was an NIH postdoctoral
fellow. We thank Dylan Stiles for assistance in preparing
the first diethynylbenzene ligands and complexes investigated
in our laboratory, Ms. Li Li of the MIT Department of
Chemistry Instrumentation Facility for collecting the ESI-
MS spectra, and Prof. M.-H. Baik for helpful discussion.
Supporting Information Available: FT-IR data for compounds
2-16, the full numbering schemes of compounds 2, 4-7, 15, and
16, and corresponding X-ray crystallographic files in CIF format.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Summary and Conclusions
The ligands Me2-napy and DMP were introduced in an
attempt to model the syn coordination of the two histidine
residues at the diiron cores of sMMOH, RNR-R2, and ∆9D.
In the absence of additional donor groups, the 1,8-naph-
IC034928E
8662 Inorganic Chemistry, Vol. 42, No. 26, 2003