Metal-coordinated water-soluble cavitands act as C - H oxidation catalysts

Article abstract of DOI:10.1021/ol203243j

Cavitands can be smoothly derivatized by CuAAC chemistry to incorporate ligand species at the upper rim. These species can coordinate metal species in a number of different conformations, leading to self-assembly. The metal-coordination confers water solu

Full text of DOI:10.1021/ol203243j

ORGANIC
LETTERS
2012
Vol. 14, No. 3
788–791
Metal-Coordinated Water-Soluble
Cavitands Act as CꢀH Oxidation Catalysts
Katherine E. Djernes, Orly Moshe, Magi Mettry, Donald D. Richards, and
Richard J. Hooley*
Department of Chemistry, University of California, Riverside, California 92521,
United States
richard.hooley@ucr.edu
Received December 13, 2011
ABSTRACT
Cavitands can be smoothly derivatized by CuAAC chemistry to incorporate ligand species at the upper rim. These species can coordinate metal
species in a number of different conformations, leading to self-assembly. The metal-coordination confers water solubility on the cavitands, and
the iron-bound species are capable of catalytic CꢀH oxidations of fluorene under mild conditions.
A central feature of metalloenzymes is the presence of
reactive metal species in the active site in close proximity
with a defined cavity for substrate recognition.1 Synthetic
mimics of enzyme active sites often incorporate either a
defined cavity2 or an active metal species,3 but seldom
both. Combination of metal species with cavity-containing
molecules is generally restricted to the formation of self-
assembled cages where the metals play a purely structural
role.4 Reactive metal species have been coordinated to
synthetic receptors,5 but in the form of preformed por-
phyrins or salen complexes that are covalently attached.
The scope of cavitands as catalysts can be increased by
exploiting metal coordination to self-fold the host, leaving
empty (or at least weakly coordinated) sites at the metal
for reactions. Self-folding of cavitands is well-known via
self-complementary hydrogen bonding, but this strategy is
challenged when aqueous environments are desirable.6
Metal coordination is commonly used in self-assembled
systems to bring multiple ligand units together, but the use
of metals as agents for organization (or self-folding) of
cavitands is underutilized. Cavitands provide an alluring
scaffold for the complexation of metal ions, in that they are
capable of displaying four rigid coordinating motifs at
defined distances.7 The 4-fold symmetry of resorcinarene-
based cavitands allows for binding of two octahedral
metals by bidentate ligands, leaving empty sites for further
reactivity at the metal sites.
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Rev. 1996, 96, 721–758.
Despite the advantages of using water as a solvent, most
studies of metal-coordinated cavitands have been confined
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10.1021/ol203243j
Published on Web 01/24/2012
2012 American Chemical Society

to organic solvents, and few water-soluble examples have
been developed. This is in contrast with the extensive
literature on self-assembled metalꢀligand cages.8 Water
solubility can be conferred by a variety of methods includ-
ing the incorporation of phosphate, sulfate, and/or car-
boxylate groups to the covalent structure.9 In most cases,
the polar groups are added solely for the purpose of
solubility, and care must be taken so that the solubilizing
groups do not interfere with the catalytically active groups.
Here we describe a novel approach to derivatizing cavit-
ands whereby we confer water solubility upon the system
via metal coordination and exploit this coordination for
CꢀH oxidation catalysis.
As can be seen by the structure in Figure 1, no hindrance is
expected at the cavitand rim. The four azide groups in 2b
allow reaction with various substituted acetylenes by
CuAAC chemistry to yield cavitands with multiple sub-
stituted triazoles at the rim. These triazoles can be tailored
for variable metal coordination, and the initial tests are
shown in Scheme 1. Two different arms were targeted to
allow metal coordination. Reaction of 2a with 2-ethynyl-
pyridine 4 allows access to cavitand 7a, which features a
bidentate coordination motif between the triazole nitrogen
and the 2-pyridyl, whereas the 3-pyridyl (8a) and phenyl
(9a) counterparts should be unable to coordinate in this
manner.
Scheme 1. Synthesis of Metal-Coordinating Water-Soluble Ca-
vitands
Figure 1. ORTEP representations of the structure of 2b, as
determined by X-ray diffraction analysis. The large ellipsoids
for the azides are due to their disorder in the solid state structure.
Interestingly, CuAAC reaction of tetrazide cavitand 2a
proved challenging. Benzylic azides are well-known to react
quickly at room temperature under standard CuAAC
conditions.11 In this case, however, forcing conditions were
required for the coupling of acetylenes 4, 5, and 6 with 2a.
Reaction at ambient temperature gave very little conver-
sion, and solvent mixtures such as CH2Cl2/MeOH or THF/
water/t-BuOH (3:1:1) were ineffective. Performing the
transformation at elevated temperatures (100 °C in a 4:1
DMSO/water mixture) and the use of B(Im)3 catalyst 312
allowed access to cavitands 7a and 8a in 78 and 99% yield,
respectively. Simple saponification with Cs2CO3 gave the
corresponding alcohol-footed cavitands 7b and 8b.
The sluggish CuAAC reaction could be ascribed to
coordination of the catalyst by the products. While the
azides in 2a/b are not hindered in their reaction, the
cycloaddition products are capable of binding the catalytic
copper ions, reducing the effectiveness of reaction. The
four triazole units that result from CuAAC reaction with
suitable acetylenes are positioned so that their dipoles can
be oriented directly toward the center of the cavitand and
coordinate suitable metal ions. Residual copper that was
coordinatedduringthe CuAACreactioncouldberemoved
by heating the product mixture in the presence of sodium
EDTA.
The core scaffold is shown in Scheme 1. Tetrabromoca-
vitand 1a9e,10 can be accessed from 2-methyl resorcinol and
2,3-dihydrofuran in four steps, and reaction with sodium
azide provides tetrazide cavitand 2a in 87% yield. The
cavitands were synthesized with their alcohol “feet” pro-
tected as acetate groups in order to increase their solubility
in organic solvents. Simple saponification with Cs2CO3
cleaved the protecting groups, allowing access to the alco-
hol counterparts.
Slow evaporation of a chloroform/methanol solution
of 2b allowed access to single crystals that were suitable
for X-ray diffraction analysis; ORTEP representations are
shown in Figure 1 (CCDC #862080: for full details, see the
Supporting Information). In the solid state, the cavitands
were oriented in a “head-to-head” conformation so that
the alcohol feet were intercalated. The cavities (and inter-
stitial space between cavities) were occupied by disordered
chloroform solvent. The azide groups at the rim showed
significant disorder in the solid state due to free rotation.
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Gan, H.; Benjamin, C. J.; Gibb, B. C. J. Am. Chem. Soc. 2011, 13, 4770–
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Org. Lett., Vol. 14, No. 3, 2012
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While the triazole arms in 7 and 8 (and presumably the
azide arms in 2) are freely rotating in the absence of metal,
addition of copper(I) salts rigidifies the system through
coordination with the donor atoms. Because of their well-
known abilities in hydrocarbon oxidation reactions,13 we
focused on the coordination of copper and iron salts by
pyridyl cavitands 7 and 8. The metal-containing complexes
could be isolated by reaction of either acetate or hydroxyl-
footed cavitand 7a/b with a weakly coordinated metal salt
(e.g., Cu(CH3CN)4BF4, FeSO4) in methanol. The metal
complexes precipitated from solution and could be isolated
by simple filtration. 1H NMR and MALDI mass spectro-
metric analysis were used to analyze the metal binding
properties of the system.
Only free cavitand was observed by MALDI-MS, and no
change was observed in the 1H NMR spectra.
In contrast, upon reaction of 7b with Cu(CH3CN)4BF4,
only one copper ion is bound by the cavitand ([M þ Cu]þ
observed at m/z = 1465, see the Supporting Information).
Molecular modeling illustrates the most favorable conforma-
tion of the complex, as shown in Figure 3. The Cu(I) can
adopt a square pyramidal geometry and coordinate all four
triazole units through their N3 atoms (the final empty valence
is occupied by solvent in Figure 3, although no solvent was
observed in the molecular ion in the MS). This conformation
is possible for all cavitands 7ꢀ9, and copper coordination is
observed in each case upon sonication at ambient temperature
with Cu(CH3CN)4BF4. While iron(II) salts are poorly co-
ordinated at the triazoles, copper(I) salts are strongly bound,
no matter the rim functionality; this indicates that coordina-
tion of the copper catalyst in the CuAAC reaction occurs at
the triazole motif, limiting conversion under mild conditions.
It is notable that the hydroxyl-footed metal-coordinated
cavitands are soluble in pure water. Iron coordination confers
greater water solubility than copper(I), and while 7b Fe2 is
3
soluble to 4 mM, 7b Cu is only sparingly soluble. All metal-
coordinated cavitands are soluble in water upon addition of a
small amount of acetonitrile.
3
Figure 2. Coordination of iron(II) ions by the pyridylꢀtriazole
unit (SPARTAN, HartreeꢀFock forcefield).
Molecular modeling suggested that cavitand 7 would
coordinate two octahedral metals, where each metal is co-
ordinated between two bidentate ligands formed by the
triazole nitrogen and the 2-pyridyl groups (Figure 2). Sonicat-
ing cavitand 7b with excess FeSO4 for 5 min at room
temperature allowed the formation of our predicted structure
Figure 3. Coordination of copper(I) ions by the pyridylꢀtriazole
unit (SPARTAN, HartreeꢀFock forcefield).
(7b Fe2), where four binding sites are occupied by the triazole
3
We were unable to grow X-ray quality crystals of the
7b Cu complex, so to corroborate the modeling experiment,
and pyridyl groups and the remaining two sites coordinate
water. Formation of product was analyzed by MALDI mass
spectrometry m/z1645, which corresponds to the monocation
of cavitand 7b þ 2Fe, incorporating sulfate ion, water, and
hydroxide. The isotope pattern matches well with that pre-
dicted for cavitand 7b binding two iron atoms. In order to
further test the accuracy of our model, cavitands 8b and 9b
were synthesized and tested for their ability to bind iron(II)
salts. We rationalized that neither the 3-pyridyl group in 8b
nor the phenyl group in 9b would be able to form a bidentate
ligand with the triazole and should consequently not coordi-
nate iron. Both cavitands 8b and 9b were sonicated with
FeSO4, and as expected no coordination of iron was observed.
3
alternate coordinating motifs were added to the cavitand
rim. To verify that the triazole ligands were the primary
coordinators of the metal ions, the pyridyl group was moved
away from the cavitand core by the introduction of amide
spacers. Ligands 10 and 11 were synthesized from propar-
gylamine and the corresponding 2- and 4-pyridylcarboxylic
acids in good yields. CuAAC coupling with 2a proceeded
smoothly as before to yield amide cavitands 12a and 13a.
Saponification gave alcoholic cavitands 12b and 13b, andthe
metal-coordinating properties were tested as before. 4-Pyr-
idylamide cavitand 13b behaved as expected; a single copper
ion was coordinated by the complex (13b Cu showed an ESI
3
peak at 1693.5797 (M þ H)þ), and no affinity was observed
for iron because the 4-pyridyl groups are unable to con-
tribute toward metal coordination.
The 2-pyridylamide cavitand 12b showed anomalous
behavior. Upon treatment of 12b with Cu(CH3CN)4BF4,
(13) (a) Chen, M. S.; White, M. C. Science 2007, 318, 783–787. (b)
Litvinas, N. D.; Brodsky, B. H.; DuBois, J. Angew. Chem., Int. Ed. 2009,
48, 4513–4516. (c) Gomez, L.; Garcia-Bosch, I.; Company, A.;
Benet-Buchholz, J.; Polo, A.; Sala, X.; Ribas, X.; Costas, M. Angew.
Chem., Int. Ed. 2009, 48, 5720–5723. (d) Que, L.; Tolman, W. B. Nature
2008, 455, 333–340.
ꢀ
790
Org. Lett., Vol. 14, No. 3, 2012

two species were observed by MALDI analysis, corre-
sponding to the presence of one and two copper ions
(Mþ = 1692 and 1755, respectively). While the singly bound
copper species is most likely the conformation shown in
Figure 4, the structure of the doubly bound species is
unclear. The 1H NMR spectrum is broad, so determination
of the products was not possible, and crystal growth from
the product mixture was unsuccessful.
successful oxidant, and GC analysis showed clean oxidation
of 14 to 15.
Interestingly, 2-pyridylamide cavitand 12b was also able
to coordinate a single iron(II) cation, despite the poor
affinity of the smaller cavitands 8 and 9 for iron(II). Treat-
ment of 12b with FeSO4 allowed the isolation of cavitand
12b Fe, m/z 1684.
3
Figure 5. Fluorene oxidation by metalated cavitands.
Both cavitands 12b Fe and 7b Fe2 were capable oxi-
3
3
dants. The bis-iron catalyst 7b Fe2 showed the fastest
oxidation, with 100% conversion (GC) after 24 h. Mono-
iron amide cavitand 12b Fe was a less effective catalyst
3
3
(Figure 5) but showed significant conversion of 14 to 15
after 48 h. Some oxidation of 14 to 15 was observed when
FeSO4 was used as control catalyst, but FeSO4 was far less
effective than 12b Fe and 7b Fe2 and essentially only
3
3
displayed substoichiometric reactivity. It is important to
note that the cavitands are stable to the conditions of the
oxidation, even over a period of 7 days: the coordination of
cavitand to the oxidizing metal stabilizes the active species,
allowing turnover and catalysis.
In conclusion, we have shown that cavitands can be
smoothly derivatized by CuAAC chemistry to incorporate
ligand species at the cavitand rim. Depending on the rim
functionality, these species can coordinate metal ions in
one of two conformations, with the metal positioned either
directly over the central cavity through triazole coordina-
tion, or with two metal species bound at the sides, via
coordination with both triazole and appended 2-pyridyl
groups. Metal coordination confers water solubility on
complexes without the need for covalent introduction of
solubilizing groups such as sulfates or phosphates, and the
molecules are capable of CꢀH oxidation reactions of
fluorene under mild conditions due to the empty coordina-
tion sites on the bound metal. Further study of the proper-
ties of metal-bound cavitandsin molecular recognition and
directed oxidation reactions are underway.
Figure 4. Synthesis of amide cavitands and their coordination
of copper(I) ions by the pyridylꢀtriazole unit (SPARTAN,
HartreeꢀFock forcefield).
The iron-coordinated cavitands 12b Fe and 7b Fe2 are
3
3
underligated; i.e., the ligands only occupy four of the six
coordination sites at the metal. Ligands of this type are well-
precedented to perform CꢀH oxidation reactions under
mild conditions, inspired by the mode of action of the Rieske
nonheme iron oxygenases.1,14 The ability of 12b Fe and
3
7b Fe2 to perform oxidation reactions was tested. Activation
3
of hydrocarbons such as cyclohexane or methylcyclohexane
was unsuccessful, but the more activated fluorene 14 could
be smoothly converted to fluorenone 15. Reactions were
performed at room temperature in water/acetonitrile with
catalytic acetic acid (0.5 equiv) and 10ꢀ20 mol % loading of
the cavitand catalyst. Hydrogen peroxide and benzoyl per-
oxide were tested as oxidants; however, no reaction was
observed using hydrogen peroxide, and oxidation with ben-
zoyl peroxide lead to the formation of multiple unidentified
side-products. tert-Butyl hydroperoxide (TBHP) was a
Acknowledgment. R.J.H. acknowledges the donors of
the American Chemical Society Petroleum Research Fund
for support of this research. D.D.R. is a MARC-U-STAR
Scholar.
Supporting Information Available. Experimental details
and full characterization of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org
(14) Abu-Omar, M. M.; Loaiza, A.; Hontzeas, N. Chem. Rev. 2005,
105, 2227–2252.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 3, 2012
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