Calix[4]arenes Linked to Multiple Bidentate N-Donors: Potential Ligands for Synthetic Modeling of Multinuclear Metalloenzymes

Article abstract of DOI:10.1021/ol025715g

(Matrix Presented) A series of calix[4]arenes incorporating three or four bidentate diamines or pyridylamines attached at the upper rim were synthesized via practical protocols. Proof of structure was obtained in one instance by X-ray crystallography. These molecules are designed for general use as ligands for the preparation of multinuclear active site models of metalloenzymes.

Full text of DOI:10.1021/ol025715g

ORGANIC
LETTERS
2002
Vol. 4, No. 8
1391-1393
Calix[4]arenes Linked to Multiple
Bidentate N-Donors: Potential Ligands
for Synthetic Modeling of Multinuclear
Metalloenzymes
,‡,§
Douglas J. E. Spencer,† Bryan J. Johnson,‡ Brian J. Johnson,* and
,†
William B. Tolman*
Department of Chemistry and Center for Metals in Biocatalysis,
UniVersity of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, and
Department of Chemistry, College of St. Benedict and St. John’s UniVersity,
37 S. College AVenue, St. Joseph, Minnesota 56374
tolman@chem.umn.edu
Received February 13, 2002
ABSTRACT
A series of calix[4]arenes incorporating three or four bidentate diamines or pyridylamines attached at the “upper rim” were synthesized via
practical protocols. Proof of structure was obtained in one instance by X-ray crystallography. These molecules are designed for general use
as ligands for the preparation of multinuclear active site models of metalloenzymes.
Multinuclear metal arrays are ubiquitous components of
metalloprotein active sites that participate in a number of
important biological reactions. For example, tricopper sites
have been identified in the multicopper oxidases1-3 and in
particulate methane monooxygenase (pMMO),4 which use
O2 to couple the four-electron reduction of O2 to H2O with
the oxidation of substrate or to functionalize hydrocarbons,
respectively. A tetracopper site (“CuZ”) that features e2
N-donors per metal has been identified in an important
respiratory enzyme, nitrous oxide reductase.5 Zinc enzymes
that use two or three metal ions to catalyze various hydrolytic
reactions also are known.6 Studies of suitably designed
synthetic model compounds can provide new insights into
the structures, spectroscopic properties, and catalytic mech-
anisms of these and other metalloprotein active sites.7 For
the purposes of modeling the aforementioned biological
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† University of Minnesota.
‡ College of St. Benedict and St. John’s University.
§ Email for additional corresponding author: bjohnson@csbsju.edu.
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10.1021/ol025715g CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/20/2002

multimetal centers, it would be advantageous to use multi-
dentate ligand systems that can accommodate g3 metal
centers held sufficiently close to one another to enable coop-
erative interactions in reactions with exogeneous substrates.
were required to obtain 2 in reasonable yield. This alkylation
of the “lower rim” of the calix[4]arene was necessary to
maintain the cone conformation15 (which may be varied by
binding alkali metal ions) and ensure that the chelating
N-donors covalently linked to the “upper rim” all remain
above the calix[4]arene frame. In all subsequent steps from
Calixarenes have been found to be a useful scaffold for
constructing such ligands for metalloprotein active site
modeling studies, and complexes typically containing one
or two Cu,8,9 Zn,10 or Ni11 ions have been examined. Higher
nuclearity species with three or four bound metal ions are
less common,10b however, as are those that feature ligands
comprising bidentate9g,10a (rather than tridentate) donors that
would be expected to afford enhanced reactivity at the metal
centers due to greater accessibility of lower coordination
numbers. To address these deficiencies, we targeted a new
class of multidentate ligands that feature three or four
bidentate N-donors attached to the upper rim of a calix[4]-
arene scaffold, and we report their successful syntheses
herein. It is our ultimate hope that the ligand framework,
while providing enough flexibility to incorporate up to four
metal centers, will possess enough rigidity and steric bulk
to prevent intermolecular aggregation yet still bind the metal
ions close enough to facilitate cooperative interactions upon
small molecule activation.
1
2, retention of the cone conformation was confirmed in H
NMR spectra by the presence of two doublets in the range
2.9-3.3 and 4.3-4.6 ppm (J ) 12-13 Hz).15 We attached
three or four chloromethyl groups to 2 to generate 5 and 8,
which were designed to serve as common precursors for the
new target ligands (Scheme 1). Compound 5 had been
reported previously via a one-pot protocol,14 but in our hands
this method proved to be unreliable, so an alternative route
analogous to one reported for disubstituted calix[4]arene
syntheses was developed.16 Thus, 2 was tetraformylated by
an adapted method17 and then reduced and chlorinated to
yield 5. Compound 8 was prepared similarly, by triformyl-
ating 210b followed by reduction and chlorination.
Attachment of secondary amines to the chloromethyl
derivatives 5 and 8 led to the desired ligands (Schemes 2
Scheme 2a
The preparation of the new ligands began with calix[4]-
arene (1),12,13 which was converted to 25,26,27,28-tetrakis-
(2-ethoxyethyl)calix[4]arene (2, Scheme 1) via an adaption
Scheme 1a
a Reagents and conditions: (a) MeCN, xs Na2CO3, 100%.
and 3). The indicated amines were chosen in order to span
a range of donor atom types (amine vs pyridyl), chelate ring
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Engbersen, J. F. J.; Kooijman, H.; Spek, A. L.; Reinhoudt, D. N. J. Am.
Chem. Soc. 1998, 120, 6726-6737.
a Reagents and conditions: (a) (i) hexamethylenetetramine,
trifluoroacetic acid, 125 °C; (ii) CH2Cl2/1 M HCl; (iii) MeOH, 47%;
(b) (i) EtOH/THF, NaBH4, 4 equiv; (ii) 4 M HCl, 100% (5) and
(8); (c) (i) CH2Cl2/SOCl2, xs; (ii) MeOH, 100% (8) and 60% (5);
(d) ref 10b.
(10) (a) Molenveld, P.; Engbersen, J. F. J.; Reinhoudt, D. N. J. Org.
Chem. 1999, 64, 6337-6341. (b) Molenveld, P.; Stikvoort, W. M. G.;
Kooijman, H.; Spek, A. L.; Engbersen, J. F. J.; Reinhoudt, D. N. J. Org.
Chem. 1999, 64, 3896-3906. (c) Molenveld, P.; Kapsabelis, S.; Engbersen,
J. F. J.; Reinhoudt, D. N. J. Am. Chem. Soc. 1997, 119, 2948-2949.
(11) Beer, P. D.; Drew, M. G. B.; Leeson, P. B.; Lyssenko, K.; Ogden,
M. I. Chem. Commun. 1995, 929.
of a published procedure.14 In contrast to the original report,
we found that a vast excess of both NaH and 2-bromoethyl
ether, as well as an increased temperature and reaction time,
(12) Gutsche, C. D.; Iqbal, M. In Organic Syntheses; Wiley: New York,
1988; Collect. Vol. VIII, p 75.
(7) Selected reviews: (a) Karlin, K. D. Science 1993, 261, 701-708.
(b) Kopf, M.-A.; Karlin, K. D. In Biomimetic Oxidations Catalyzed by
Transition Metal Complexes; Meunier, B., Ed.; Imperial College Press:
London, 2000; pp 309-362. (c) Parkin, G. Chem. Commun. 2000, 1971-
1985. (d) Blackman, A. G.; Tolman, W. B. In Metal-Oxo and Metal-Peroxo
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Org. Lett., Vol. 4, No. 8, 2002

by high-resolution fast-atom bombardment mass spectrom-
etry (FAB-MS), NMR spectroscopy, and in one instance (15),
X-ray crystallography. X-ray quality crystals of (15) were
grown by slow diffusion of Et2O into a MeCN solution. The
structure shows that the calix[4]arene framework is in the
“cone” conformation, tetrasubstituted on the upper rim with
N-benzyl-N-(2-methylpyridine) (Figure 1). The ligand pre-
Scheme 3a
Figure 1. X-ray crystal structure representation of 15, shown at
50% thermal ellipsoids with only heteroatoms labeled and hydrogen
atoms omitted for clarity.
organization can clearly be seen, as the covalently linked
amine donors are positioned above the calix[4]arene frame-
work in preparation for metal ion complexation.
In summary, we have developed straightforward, depend-
able syntheses of a new set of multidentate ligands 12-16.
Each incorporates g3 bidentate N-donors that are covalently
linked to and preorganized by the calix[4]arene framework
for metal complexation. These ligands will enable future
investigations aimed at binding metal ions and exploring the
chemistry of the resulting complexes, with the ultimate
objective being to understand the reactivity, structures, and
spectroscopic properties of multinuclear metal arrays found
in Nature.
a Reagents and conditions: (a) MeCN, xs Na2CO3, 81%; (b) (i)
MeCN, xs Na2CO3; (ii) Sephadex G-10 (MeOH), 60%; (c) (i)
MeCN, xs Na2CO3; (ii) Sephadex G-10 (MeOH), 50%; (d) (i)
MeCN, xs Na2CO3; (ii) Sephadex G-10 (MeOH), 62%.
Acknowledgment. We thank the NIH (GM47365) and
St. John’s University Rooney fund for providing financial
support for this research.
Supporting Information Available: Experimental pro-
cedures and X-ray crystallographic data in CIF format. This
material is available free of charge via the Internet at
http://pubs.acs.org.
sizes when bound to a metal ion (5 vs 6), and steric bulk.
The pyridylamines N-isopropyl-N-(2-methylpyridine)18 (9),
N-benzyl-N-(2-methylpyridine)19 (10), and N-isopropyl-N-
(2-methylquinoline)20 (11) had been reported previously, but
we developed more convenient one-pot reductive amination
procedures for their syntheses. In general, the alkylation
reactions leading to ligands 12-16 were found to proceed
best when a large excess of the amine and Na2CO3 as base
were heated with 5 or 8 in refluxing MeCN for 3-7 days.
Compounds 12-16 were isolated as brown oils and identified
OL025715G
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