Dinickel complexes of disubstituted benzoate polydentate ligands: Mimics for the active site of urease

Article abstract of DOI:10.1039/b803094b

Two dinickel mimics, [LNi₂(DMF)₄](ClO ₄)₃ (1) and [L′Ni₂(CH₃CN) ₄](ClO₄)₃ (3), for the active site of urease supported by a disubstituted benzoate polydenta

Full text of DOI:10.1039/b803094b

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Dinickel complexes of disubstituted benzoate polydentate ligands: mimics for
the active site of urease†
Way-Zen Lee,*a Huan-Sheng Tseng,a Meng-Yu Kua and Ting-Shen Kuob
Received 21st February 2008, Accepted 6th March 2008
First published as an Advance Article on the web 28th March 2008
DOI: 10.1039/b803094b
Two dinickel mimics, [LNi2(DMF)4](ClO4)3 (1) and
[LꢀNi2(CH3CN)4](ClO4)3 (3), for the active site of urease sup-
ported by a disubstituted benzoate polydentate ligand were
synthesized and fully characterized, subsequently addition of
urea afforded two urea adducts, [LNi2(urea)4](ClO4)3 (4) and
[LꢀNi2(urea)4](ClO4)3 (5).
Urease, a historic landmark in enzymology, was the first enzyme
to be crystallized.1 Its rapid catalysis for the hydrolysis of urea to
Fig. 1 Schematic representation of the active site of urease.
ammonia and carbon dioxide plays an essential role in agriculture
characterized by H and 13C NMR spectroscopy and elemental
analysis (see ESI†). The synthesis of the benzoate-based ligands is
outlined in Scheme 1. Methyl 2,6-bis(bromomethyl)benzoate was
prepared according to a literature method.10 Reflux of methyl 2,6-
bis(bromomethyl)benzoate and two equivalents of dipicolyl-amine
in the presence of triethylamine in THF for 3 d afforded methyl
2,6-bis[di(pyridinyl-2-methyl)aminomethyl]benzoate (MeL). HL
was then obtained from the hydrolysis of MeL by refluxing with
potassium hydroxide in ethanol. The overall yield of the two
steps for preparing HL is about 84%. The 1-methylbenzimidazolyl
derivative, HLꢀ, was prepared using a similar procedure with a
yield of 88%.
1
and human health.2,3 The active site of the enzyme (Fig. 1),
determined by X-ray crystallography,4 contains two nickel ions
bridged by a carbamylated lysine and a hydroxide ion. Each
nickel coordinates two histidine residues and a water molecule.
The coordination sphere of one nickel center, Ni(2), is completed
by an additional terminally bound aspartate resulting in a pseudo-
octahedral ligand environment; whereas another nickel ion, Ni(1),
having a vacant site possesses a distorted square pyramidal
geometry. It has been confirmed that carbon dioxide is required
for nickel binding to apo-urease.5 The active site structure reveals
that a lysine residue reacts with carbon dioxide and converts to
a carbamate which captures the nickel ions into the active site.
Many model complexes have been synthesized using phthalazine-,
phenolate-, or alkyloxide-based polydentate ligands.6–8 However,
to our knoweldge, the synthetic mimics supported by a benzoate-
based ligand, which can mimic the carbamate in the active site of
urease, have not been reported in the literature. Herein we wish to
demonstrate the first example of dinickel mimics supported by a
disubstituted benzoate polydentate ligand.
Recently, we have reported a dinickel complex supported by
the tripodal ligand bis(1-methylbenzimidazolyl-2-methyl)amine.9
Urea is found not to bind to the nickel centers of the com-
plex due to the coordinate saturation of the dinickel complex
by three acetates. In order to generate vacant sites on dinickel
mimics which also have a similar coordination environment
to the active site of urease, 2,6-bis[di(pyridinyl-2-methyl)amino-
methyl]benzoic acid (HL) and 2,6-bis[di(1-methylbenzimidazolyl-
2-methyl)aminomethyl]benzoic acid (HLꢀ), where a benzoate
group is fused with two tripodal ligands, were synthesized and
aDepartment of Chemistry, National Taiwan Normal University, 88 Sec.
4 Ting-Chow Rd., Taipei, 11677, Taiwan. E-mail: wzlee@ntnu.edu.tw;
Fax: +886 2 29324249; Tel: +886 2 29318166
bInstrumentation Center, Department of Chemistry, National Taiwan Nor-
mal University, 88 Sec. 4 Ting-Chow Rd., Taipei, 11677, Taiwan
Scheme 1
† Electronic supplementary information (ESI) available: Experimental
details, UV-vis spectra of all complexes, and 1H NMR spectra of complexes
1, 3, 4, and 5. CCDC reference numbers 667937–667941. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/b803094b
HL was deprotonated by sodium methoxide in methanol to form
a pale-yellow solution, subsequently transferred to an acetonitrile
solution of Ni(ClO4)2·6H2O to form a light blue solution of
[LNi2(DMF)4](ClO4)3 (1, Scheme 2). After purification, complex
2538 | Dalton Trans., 2008, 2538–2541
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Scheme 2
1 was recrystallized by slow diffusion of diethyl ether into a
DMF solution of the product. Nice needle-like crystals were
obtained in a yield of 83%. The molecular structure of complex
1, determined by X-ray analysis,‡ reveals a dinickel complex, in
which two nickel ions are bridged by the benzoate group of L.
The C–C bond between the phenyl and the carboxylate group is
twisted with a torsion angle of 63◦. Each nickel ion is facially
coordinated by three nitrogen donors, i.e. one amine and two
pyridines, from a side arm of L, and the coordination sphere of
each nickel center is completed by two DMF molecules (Fig. 2a).
Due to the short length of the side arms and the torsion of
the benzoate group in L, the two nickel ions and the bridging
benzoate form a W-shaped dinuclear core, a rare arrangement
˚
for a bridging carboxylate, with a Ni · · · Ni separation of 6.0 A,
˚
longer than that of urease (3.5 A). When L was treated with an
alternate nickel source, Ni(NO3)2·6H2O, in acetonitrile, a light
blue complex of [LNi2(NO3)2](NO3) (2) was produced. The X-
ray structure of 2 (Fig. 2b) displays a dinickel complex similar to
complex 1. Interestingly, the NO3− anions coordinate to the nickel
centers occupying two coordination sites. Moreover, both nickels
are coordinated by the N3 donor side arm of L but in different
conformations, one in a meridional and the other in a facial
fashion. The coordination of NO3− implies that the dinickel moiety
of [LNi2]3+ is very electron deficient. The average bond length of
Fig. 2 Thermal ellipsoid representation of (a) [LNi2(DMF)4](ClO4)3 (1),
(b) [LNi2(NO3)2](NO3) (2), and (c) [LꢀNi2(CH3CN)4](ClO4)3 (3) at 50%
probability level. Hydrogen atoms, solvent molecules, and the counter
anions of 1, 2, and 3 are omitted for clarity.
˚
−
Ni–ODMF in 1 is 0.070 A shorter than those of Ni–ONO in 2, and
3
˚
the average Ni–N distance in 1 is 0.033 A longer than that in 2. The
difference between Ni–N and Ni–O bond lengths in complexes 1
and 2 illustrates that the coordination of the DMF molecules to
−
the nickel centers is stronger than that of the NO3 anions. The
mimicking the bound amino acid residues around the active site
of urease, and the benzoate models the carbamylated lysine. The
nickel centers in complexes 1 and 3 all have a N3O donor set,
and each nickel is coordinated with two labile solvent molecules,
suggesting the coordination of urea to the nickel centers of the
dinickel mimics. As excess urea was added to the acetonitrile
solution of 1 and 3, two urea adducts, [LNi2(urea)4](ClO4)3 (4) and
[LꢀNi2(urea)4](ClO4)3 (5) were obtained. The X-ray structures of 4
and 5 (Fig. 3a and 3b) reveal that urea molecules are coordinated
to the nickel centers of the complexes through the oxygen atom of
1-methyl-benzimidazolyl derivative of 1, [LꢀNi2(CH3CN)4](ClO4)3
(3), was also prepared in the same manner. The molecular structure
of complex 3 is similar to that of 1 except for the bound solvent
molecules of acetonitrile (Fig. 2c).
The electronic absorption spectra of 1, 2, and 3 displayed similar
absorption bands consisting of three weak d–d transitions in the
visible region (see ESI† Fig. S1). The coordination environment
of complexes 1 and 3 is related to the active site of urease.
The polydentate ligands, L and Lꢀ, provide coordinating groups
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Fig. 4 Thermal ellipsoid representation of hydrogen bond inter-actions
(dashed lines) between the bound urea molecules and the bridging benzoate
group in 4 and 5.
In summary, we have successfully prepared the first example
of dinickel mimics, in which two nickel ions are bridged by
a disubstituted benzoate polydentate ligand, for the active site
of urease. Coordination of urea to the dinickel mimics was
1
characterized by FTIR, H NMR, and ESI-MS spectroscopies,
and X-ray crystallography. Two isolated urea adducts, complexes
4 and 5, represent the initial intermediate in the urease catalytic
cycle. Both 1H NMR and ESI-MS spectroscopies illustrate that the
bound urea molecules in 4 and 5 do not dissociate from the nickel
centers of the complexes in solution. The hydrolysis of urea by our
dinickel mimics is currently undergoing further investigation.
Fig. 3 Thermal ellipsoid representation of (a) [LNi2(urea)4](ClO4)3 (4)
and (b) [LꢀNi2(urea)4](ClO4)3 (5) at 50% probability level. Hydrogen atoms,
solvent molecules, and the counter anion of 4 and 5 are omitted for clarity.
Notes and references
‡ Crystal data for 1·DMF·MeOH: Ni2C49H70N11Cl3O20, M = 1356.93, T =
200 K, monoclinic,◦P21/n, a = 13.4365(3), b = 34.4541(8), c = 14.4644(4)
A, b = 97.1670(10) , V = 6643.9(3) A , Z = 4, Dc = 1.357 Mg m−3, l =
0.761 mm−1, 0.45 × 0.35 × 0.20 mm, GoF = 1.056, R1 = 0.0615, wR2 =
0.1724 (I > 2r(I)). Crystal data for 2·CH3CN·H2O: Ni2C35H36N10O12,
M = 906.16, T = 200 K, triclinic, P1¯, a = 8.6704(4), b = 14.8713(6),
3
˚
˚
˚
the carbonyl group with a Ni–O bond length of 2.084 and 2.092 A,
respectively. The solid FTIR spectra (KBr pellets) of 4 and 5 also
exhibit a shift in the carbonyl stretching frequency of urea from
1690 to 1664 and 1668 cm−1, respectively. We have also taken the 1H
NMR spectra of complexes 1, 3, 4, and 5 (see ESI† Fig. S2), which
exhibited relatively sharp resonances for high spin six-coordinated
dinickel(II) species.11 From a comparison of the spectra for 4 and
5 to those for 1 and 3, pronounced signals for the bound urea
molecules were seen in the spectra of 4 and 5 at 5.65 (CD3OD)
and 5.25 ppm (CD3CN), respectively, downfield shifted from free
urea at 4.81 ppm (CD3CN). In addition, the ESI-MS spectra of
4 and 5 indicate that the urea molecules remain coordinated to
the nickel centers of the complexes in the solution. (ESI-MS (m/z,
amu): 260 for [LNi2(urea)2]3+, 240 for [LNi2(urea)]3+, and 311 for
[LꢀNi2(urea)2]3+.)
◦
˚
c = 15.0500(8) A, a = 81.222(2), b = 82.826(2), c = 89.510(2) , V =
3
1902.70(15) A , Z = 2, Dc = 1.582 Mg m−3, l = 1.067 mm−1, 0.11 × 0.10 ×
˚
0.04 mm, GoF = 1.003, R1 = 0.0693, wR2 = 0.1682 (I > 2r(I)). Crystal
data for 3·2CH3CN·0.5H2O: Ni2C57H62N16Cl3O14.5, M = 1427.00, T =
200 K, monoclinic◦, C2/c, a = 21.9140(7), b = 26.5340(11), c = 13.9360(5)
A, b = 119.740(2) , V = 7036.0(4) A , Z = 4, Dc = 1.347 Mg m−3, l =
0.719 mm−1, 0.22 × 0.12 × 0.11 mm, GoF = 1.050, R1 = 0.0760, wR2 =
0.1999 (I > 2r(I)), with crystallographically imposed twofold symmetry.
Crystal data for 4·2MeOH·urea: Ni2C40H59N16Cl3O21, M = 1323.80, T =
200 K, monoclinic, Cc, a = 13.6282(4), b = 18.4465(5), c = 22.9362(8)
3
˚
˚
◦
3
−3
˚
˚
A, b = 101.0440(10) , V = 5659.2(3) A , Z = 4, Dc = 1.554 Mg m
,
l = 0.895 mm−1, 0.16 × 0.14 × 0.04 mm, R1 = 0.0598, wR2 = 0.1547
(I > 2r(I)). Crystal data for 5: Ni2C49H59N18Cl3O18, M = 1411.91, T =
200 K, monoclinic, C2/c, a = 18.4897(4), b =15.2943(3), c = 24.4927(6)
◦
A, b = 110.4140(10) , V = 6491.2(2) A , Z = 4, Dc = 1.445 Mg m−3, l =
0.783 mm−1, 0.50 × 0.28 × 0.12 mm, R1 = 0.0778, Rw = 0.2235 (I > 2r(I)),
with crystallographically imposed twofold symmetry.
3
˚
˚
It is noteworthy that the conformation of each nickel center in 4
and 5 changes to a meridional fashion from a facial arrangement
in 1 and 3. The rearrangement of the N3 side arm coordination is
due to the hydrogen bond interactions between two urea molecules
and the bridging benzoate oxygen coordinated on the same nickel
ion. The hydrogen bond interactions cause the two urea oxygens
and the bridging benzoate oxygen to lie on a meridional plane
(Fig. 4). The hydrogen bond interactions were proposed to be a
significant factor in the catalytic cycle of urease.12 Such hydrogen
bond interactions have also been seen in other enzymes such as
phosphotriesterase (PTE).13
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