2-{[Bis(2-pyridylmethyl)amino]-methyl}-6-[(2-hydroxy-anilino)-methyl] -4-methyl-phenol: A novel binucleating asymmetric ligand as a precursor to synthetic models for metalloenzymes

Article abstract of DOI:10.1107/S0108270106050517

The title compound (H2 L), C27H28N4O2, is an asymmetric binucleating ligand with well defined soft (N3O-donor) and hard (NO2-donor) sides. H2 L was designed as a ligand for the preparation of heterodinuclear mixed-valence M ^III/M′^II

Full text of DOI:10.1107/S0108270106050517

organic compounds
the other hand, the ZnII centre shows a distorted trigonal±
bipyramidal geometry formed by three O atoms from Asp118,
Asn150 and the bridging water molecule, and two N atoms
from His199 and His281 (Kissinger et al., 1995).
Acta Crystallographica Section C
Crystal Structure
Communications
ISSN 0108-2701
2-{[Bis(2-pyridylmethyl)amino]-
methyl}-6-[(2-hydroxyanilino)methyl]-
4-methylphenol: a novel binucleating
asymmetric ligand as a precursor to
synthetic models for metalloenzymes
In recent years, the study of models based on simple
dinuclear metal complexes has become an important tool for
gaining insight into the biological functions of such bimetallic
cores. In this context, the design of binucleating ligands
capable of providing asymmetric dinuclear complexes is a
subject of great interest. It is convenient to classify bi-
nucleating ligands by the bridging groups that are used for
assembling the two metal ions in close proximity (Gavrilova &
Bosnich, 2004). Our research group has extensive experience
in the development of asymmetric binucleating ligands
Â
Adailton J. Bortoluzzi,* Ademir Neves and Nicolas A. Rey
Â
Departamento de Quõmica±UFSC, Universidade Federal de Santa Catarina, 88040-
Â
900 Florianopolis, SC, Brazil
Correspondence e-mail: adajb@qmc.ufsc.br
Received 2 October 2006
Accepted 23 November 2006
Online 13 January 2007
Â
containing alkoxide (Rossi et al., 2005) and phenoxide (Mitic
The title compound (H2L), C27H28N4O2, is an asymmetric
binucleating ligand with well de®ned soft (N3O-donor) and
hard (NO2-donor) sides. H2L was designed as a ligand for the
et al., 2006) bridging units, which have been used in the
synthesis of numerous bimetallic complexes. We report here
the structure of a new phenoxide-based binucleating hexa-
dentate ligand, H2L, which presents donor, geometry and
coordination-number asymmetries, thereby constituting a
versatile precursor to synthetic models for the active sites of
asymmetric metalloenzymes, with a special focus on calci-
neurin. It should be emphasized that H2L possesses a softer
N3O-donor side, de®ned by the tertiary amine, both pyridine
rings and the bridging phenolate group, capable of accom-
modating divalent metal ions, and a harder NO2-donor side,
II
preparation of heterodinuclear mixed-valence MIII/M0
complexes which are models for heterobimetallic active sites
of enzymes, principally calcineurin. The molecular structure of
H2L shows a spatial pre-organization of the donor groups for
coordination. This conformation is stabilized by bifurcated
intra- and intermolecular OÐHÁ Á ÁN hydrogen bonds invol-
ving both phenol groups. The intermolecular hydrogen bonds
link molecules of H2L into chains running parallel to the
crystallographic c axis.
Comment
Many enzymes contain bimetallic cores within their catalytic
sites and can be classi®ed as either homobinuclear [e.g. cate-
chol oxidase, with its CuIICuII centre (Klabunde et al., 1998)]
or heterobinuclear [e.g. kbPAP, with its FeIIIZnII centre
È
(Strater et al., 1995)] metalloenzymes, depending on the
nature of the metals present. Recent X-ray crystallographic
studies have indicated that, even for homobinuclear sites, the
two metal centres usually reside in chemically different
environments, an asymmetry that may also involve the coor-
dination numbers and the geometry of the metal centres
(Belle & Pierre, 2003). Calcineurin, a phosphatase found
predominantly in neural tissues, constitutes an interesting
example of total asymmetry in heterobinuclear sites: the
metal, coordination number, donor and geometry all exhibit
asymmetry. This enzyme contains an FeIIIZnII bimetallic core
in its active centre, which comprises an octahedral FeIII
nucleus coordinated by one O atom from Asp90, one N atom
from His92, an O-bridging carboxylate from Asp118 and three
water molecules, one of which acts as an exogenous bridge. On
Figure 1
The molecular structure of H2L, showing the atom-labelling scheme.
Displacement ellipsoids are drawn at the 40% probability level. All H
atoms are shown and the intramolecular hydrogen bonds are drawn as
dashed lines.
o84 # 2007 International Union of Crystallography
DOI: 10.1107/S0108270106050517
Acta Cryst. (2007). C63, o84±o86

organic compounds
comprising the secondary amine and the terminal and bridging
phenol moieties, which binds preferentially to trivalent
cations. This represents a convenient strategy for the attain-
ment of mixed-valence heterobimetallic systems.
a second bifurcated hydrogen bond involving the interactions
Ê
O1ÐH1OÁ Á ÁN4 [moderate, OÁ Á ÁN = 2.758 (3) A] and O1Ð
Ê
H1OÁ Á ÁN42 [weak, OÁ Á ÁN = 3.309 (4) A]. It is interesting to
note that the shorter component of this bifurcated hydrogen
bond is associated with a narrower angle [N4ÐC3ÐC13 =
112.7 (2)ꢀ] compared with N1ÐC2ÐC11 [116.1 (2)ꢀ].
The title ligand has a direct linkage between the terminal
phenolic ring and the secondary amine, allowing the formation
of a more rigid ®ve-membered chelate during the complex-
ation process. The constriction induced in the complexes by
going from a six-membered to a ®ve-membered ring can give
rise to modi®ed spectroscopic and electrochemical properties.
This was observed by Neves et al. (1992) for a mononuclear
MnIII complex with the ligand N,N0-bis(2-hydroxybenzyl)-
N,N0-bis(2-methylpyridyl)ethylenediamine. As far as we know,
there is only one previous example in the literature of a
phenoxide-bridging ligand with such a structural feature
(Campbell et al., 1993).
The structure of H2L is shown in Fig. 1, and selected bond
lengths and angles are given in Table 1. The bond distances
and angles for the aromatic and heteroaromatic rings
are not signi®cantly different from those found in similar
compounds containing these groups, for example, 2,6-bis-
{[(2-hydroxyphenyl)(2-pyridylmethyl)amino]methyl}-4-methyl-
phenol (Campbell et al., 1993) and 4-tert-butyl-2,6-bis[(4-
methylpiperazin-1-yl)methyl]phenol (Shanmuga Sundara Raj
et al., 1994). An interesting trend in the three-dimensional
arrangement of the molecule is that H2L shows a self-induced
spatial pre-organization of the donor groups for coordination:
with the exception of atom N32, all donor atoms point
towards bridging atom O1. The respective O20Á Á ÁO1 and
Ê
N42Á Á ÁO1 distances are 3.622 (3) and 3.310 (4) A, very similar
to the values observed for a hydroxo-bridged FeIIIZnII
Moderate intermolecular hydrogen bonds (Table 2) of the
i
Ê
complex [3.950 (8) and 3.354 (8) A, respectively] of the
Ê
type O20ÐH20OÁ Á ÁN1 [2.814 (3) A; symmetry code: (i) x,
1
2
asymmetric ligand 2-[bis(2-pyridylmethyl)aminomethyl]-6-
{[(2-hydroxybenzyl)(2-pyridylmethyl)amino]methyl}-4-methyl-
phenol (Neves et al., 2007).
y, z
12] link the molecules of H2L into zigzag chains
(Fig. 2) which run parallel to the crystallographic c axis.
The molecular conformation is in¯uenced by intra- and
intermolecular hydrogen bonds involving both phenol groups
(Table 2). Within each molecule, the N1ÐH1N donor interacts
Experimental
H2L was synthesized from the precursor compound 3-[N,N-bis-
(2-pyridylmethyl)aminomethyl]-5-methylsalicylaldehyde (bpmamff),
which was prepared as described by Uozumi et al. (1998) by
nucleophilic substitution of bis(2-pyridylmethyl)amine in 3-chloro-
methyl-5-methylsalicylaldehyde. A methanolic solution (10 ml) of
2-aminophenol (0.32 g, 2.9 mmol) was added dropwise to a stirred
solution of bpmamff (1.0 g, 2.9 mmol) in methanol±tetrahydrofuran
(1:1, 20 ml) and the mixture was left to react for 30 min. A strong
orange colour appeared progressively due to the formation of the
Schiff base. Reduction of the imine was performed by the addition, in
portions, of NaBH4 (0.11 g, 2.9 mmol) in an ice bath. The pH of the
medium was then carefully adjusted to 6.0±7.0 with 4 M HCl, and the
solvent was evaporated to half of its initial volume. The solution was
then ®ltered to eliminate any undesirable precipitate. After a few
hours, crystals of H2L suitable for X-ray determination were isolated
by ®ltration, washed with small amounts of cold methanol and diethyl
ether, and dried in vacuo (yield 0.56 g, 44%; m.p. 416 K). Analysis
found: C 73.56, H 6.33, N 12.55%; calculated for C27H28N4O2: C 73.61,
H 6.41, N 12.72%.
Ê
with the acceptors O1 [NÁ Á ÁO = 2.896 (3) A] and O20
Ê
[NÁ Á ÁO = 2.662 (3) A], although the latter only achieves a less
favourable ®ve-membered ring. The bridging phenol acts as an
acceptor in the N1ÐH1NÁ Á ÁO1 interaction, and as a donor in
Crystal data
C27H28N4O2
Mr = 440.53
Monoclinic, P21=c
a = 12.651 (1) A
Ê
b = 21.071 (5) A
Z = 4
Dx = 1.233 Mg m
Mo Kꢁ radiation
ꢂ = 0.08 mm
T = 293 (2) K
Irregular block, pale yellow
0.46 Â 0.30 Â 0.23 mm
3
1
Ê
Ê
c = 9.262 (1) A
ꢀ = 106.09 (1)ꢀ
V = 2372.2 (7) A
3
Ê
Data collection
Enraf±Nonius CAD-4
diffractometer
Rint = 0.039
ꢃmax = 25.1ꢀ
!/2ꢃ scans
3 standard re¯ections
every 200 re¯ections
intensity decay: 1%
Figure 2
A view of H2L, showing the hydrogen-bonding network. Intermolecular
hydrogen bonds are drawn as dashed lines.
4338 measured re¯ections
4142 independent re¯ections
2138 re¯ections with I > 2ꢄ(I)
ꢁ
Acta Cryst. (2007). C63, o84±o86
Bortoluzzi et al. C27H28N4O2 o85

organic compounds
Re®nement
(Spek, 1996); program(s) used to solve structure: SIR97 (Altomare et
al., 1999); program(s) used to re®ne structure: SHELXL97 (Shel-
drick, 1997); molecular graphics: PLATON (Spek, 2003); software
used to prepare material for publication: SHELXL97.
Re®nement on F2
R[F2 > 2ꢄ(F2)] = 0.053
wR(F2) = 0.155
S = 1.02
4142 re¯ections
305 parameters
H atoms treated by a mixture of
independent and constrained
re®nement
w = 1/[ꢄ2(Fo2) + (0.056P)2
+ 0.792P]
where P = (Fo2 + 2Fc2)/3
(Á/ꢄ)max < 0.001
3
Ê
Áꢅmax = 0.23 e A
3
Ê
0.18 e A
Áꢅmin
=
Â
The authors thank CoordenacaÄo de Aperfeicoamento de
Pessoal de Nõvel Superior (CAPES), Conselho Nacional de
Â
Extinction correction: SHELXL97
(Sheldrick, 1997)
Extinction coef®cient: 0.0072 (11)
Â
Â
Â
Desenvolvimento Cientõ®co e Tecnologico (CNPq) and
Financiadora de Estudos e Projetos (FINEP) for ®nancial
support of this work. NAR is grateful to CNPq for a fellow-
ship.
Table 1
Selected geometric parameters (A, ).
ꢀ
Ê
O1ÐC12
O20ÐC22
N1ÐC21
N1ÐC2
1.374 (3)
1.362 (3)
1.408 (4)
1.474 (4)
N4ÐC40
N4ÐC30
N4ÐC3
1.465 (4)
1.466 (4)
1.475 (4)
1.511 (4)
Supplementary data for this paper are available from the IUCr electronic
archives (Reference: BM3018). Services for accessing these data are
described at the back of the journal.
C2ÐC11
C21ÐN1ÐC2
C40ÐN4ÐC30
C40ÐN4ÐC3
119.0 (3)
111.0 (2)
109.6 (2)
C30ÐN4ÐC3
N1ÐC2ÐC11
N4ÐC3ÐC13
110.2 (2)
116.1 (2)
112.7 (2)
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Hydrogen-bond geometry (A, ).
ꢀ
Ê
DÐHÁ Á ÁA
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0.86 (1)
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0.82
0.82
0.82
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2.22 (3)
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124 (2)
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Ê
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Ê
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Ê
Ê
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È
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ꢀ
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ꢁ
o86 Bortoluzzi et al.
C27H28N4O2
Acta Cryst. (2007). C63, o84±o86