Synthesis and physico-chemical properties of the first water soluble Cu(ii)@hemicryptophane complex

Article abstract of DOI:10.1039/c4ob02085e

A hemicryptophane ligand soluble in water at neutral pH was obtained thanks to the derivatization of the cyclotribenzylene unit with three carboxylate groups. The corresponding Cu(ii) complex was then synthesized and its spectroscopic and electrochemical

Full text of DOI:10.1039/c4ob02085e

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ARTICLE TYPE
Synthesis and physico-chemical properties of the first water soluble
Cu(II)@hemicryptophane complex
Aline Schmitt,[a] Solène Collin,[a] Christophe Bucher,[a] Vincent Maurel,[b] Jean-Pierre Dutasta*[a] and
Alexandre Martinez*[a,c]
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
A hemicryptophane ligand soluble in water at neutral pH was obtained thanks to the derivatization of the
cyclotribenzylene unit with three carboxylate groups. The corresponding Cu(II) complex was then
synthesized and its spectroscopic and electrochemical properties in water were investigated, showing that
10 the water solubilisation retains the geometry of the complex around the metal center but strongly affects
its redox properties, compared to previously reported Cu(II)@hemicryptophane complexes soluble in
organic solvents.
Recently, we have reported several supramolecular systems,
Introduction
35 based on hemicryptophane ligands, combining a biomimetic
copper(II) coordination core and a lipophilic cavity.14 The Cu(II)
complexes have been found to be efficient catalysts in organic
Hemicryptophanes1 have revealed to be attractive molecular
15 receptors2 and they have been used for the design of
supramolecular catalysts3 and molecular propellers or gyroscopic
systems.4 In particular, The introduction of a vanadium atom in
the cavity of hemicryptophanes have for instance been found to
yield oxidovanadium-hosts acting as haloperoxidase enzyme
20 mimics catalyzing sulfoxidation reactions.3a
solution
for
the
conversion
of
cyclohexane
to
cyclohexanol/cyclohexanone, using H2O2 as oxygen source. Both
40 the stability and the selectivity of the catalyst have been improved
by encapsulating the active site.3d We have also described the
first synthesis of a water-soluble hemicryptophane host and its
recognition properties toward choline in
medium.15
a basic aqueous
As a general statement, the versatility and modularity of these
host compounds have proved particularly suited to mimic
enzymatic systems by combining lipophilic cavity and catalytic
25 site.5-9 By this way, original nanoreactors can be synthesized and
give rise to artificial metallo-enzymes. Such systems have been
already studied in organic solvents.10 Obviously, most
biocatalytic processes in nature occur in aqueous media and to
obtain a better understanding and control of such biological
30 processes, any synthetic systems should be able to work in
water.11 Water-solubilisation of biomimetic entities is highly
challenging,12 and very few water-soluble metalloenzymes
models have been reported in the literature.13
45 By combining both water-solubility and Cu(II) complexation in a
unique cage molecule we expected to get rise to a water-soluble
metallo-enzyme model, presenting a copper site encaged in a
closed-shell cavity. Herein, we thus report the synthesis of the
first water-soluble copper@hemicryptophane complex together
50 with its spectroscopic characterization and redox properties.
Results and discussion
Synthesis of the water-soluble complex
Hemicryptophane 1 was synthesized in 6 steps, following a
Scheme 1. Synthesis of the water soluble ligand 3.
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previously published procedure (Scheme S-1).15 The strongly
Electronic Spectroscopy
basic conditions (pH = 12) which are required to solubilize 1 in
water are not compatible with its use in biological environments.
The substitution of the phenol groups in 1 by carboxylate
moieties was performed in order to obtain the hemicryptophane 3,
which was found to be soluble in water at physiological pH (pH ≈
7). The strategy used to synthesize compound 3 is depicted in
Scheme 1. The first step involves the reaction of compound 1
with tert-butyl-bromoacetate in DMF in the presence of Cs2CO3
5
10 to yield the protected tri-ester derivative 2. Deprotection of both
the amine and the ester functions in 2, using trifluoroacetic acid,
afforded the water-soluble hemicryptophane 3. Following this
synthetic pathway, host 3 has been obtained from commercially
available products in 8 steps with an overall yield of 6 %.
15
Figure 2. Near-IR/vis spectrum of Cu(II)@hemicryptophane-3
35
(H2O/NaOH, pH ≈ 8, 298 K)
The Near-IR/vis absorption spectrum of the hemicryptophane
complex Cu(II)@3 in CH2Cl2 displays a broad asymmetrical
band centred at 850 nm which is a diagnostic signature
supporting the trigonal-bipyramidal geometry of the complexed
40 copper (II) ions (Figure 2). These observations are fully
consistent with those previously observed with the parent
Cu(II)@4 complex soluble in organic solvents (Scheme 2(b)).14,16
H2O
EPR Measurements
45 The EPR spectrum of the Cu(II)@3 complex was recorded in
frozen water at 70 K (Figure 3). A pseudo-axial EPR signal (g1 =
2.015, g2 = 2.135 and g3 = 2.220) with a resolved hyperfine
structure (A1 = 193 MHz, A2 = 158 MHz and A3 = 363 MHz) was
obtained, giving a R value (g2–g1)/(g3–g2) equals to 1.41.17 These
50 values (g1 < 2.04 and R > 1) are typical for a N4X coordination
sphere with a distorted geometry close to trigonal-bipyramidal
geometry.18 The g-values are very similar to that previously
obtained with the Cu(II)@4 complex (g1 = 2.010, g2 = 2.136, g3 =
2.220; R = 1.50),14 indicating that water solubilisation did not
55 induce strong distortion of the initial geometry. Complexes
Cu(II)@3 and Cu(II)@4 present a five-coordination sphere with
the copper ion bound to the four nitrogen atoms of the tren unit
and to one solvent molecule.
He
Ha
Figure 1. 1H NMR spectrum (500.1 MHz, D2O, 298 K, pD ≈ 7) of
hemicryptophane 3
1
The H NMR spectrum of 3 in D2O (pD ≈ 7) indicates that this
20 molecule is on average of C3 symmetry. It displays the expected
signals for the cyclotribenzylene unit (Figure 1): two singlets for
the aromatic protons, and the characteristic AB system for the
ArCH2 bridges. Two doublets for the aromatic protons of the
linkers and the multiplets for the OCH2 groups are also observed
25 in the spectra. The NCH2 protons of the tren unit appear as a
complex pattern between 2.0 and 2.25 ppm.
The hemicryptophane copper(II) complex was then synthesized
by reaction of 3 with a stoechiometric amount of copper(II)
perchlorate in water to produce Cu(II)@3 isolated in a 50 % yield
30 as a pale green solid (Scheme 2).
Scheme 2. (a) Synthesis of the water soluble Cu(II)@hemicryptophane-3 complex. (b) structure of its no-water soluble parent Cu(II)@4.
2
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1
0
X
-1
-2
-3
-4
-0.8 -0.7 -0.6 -0.5 -0.4 -0.3 -0.2 -0.1
E (Volt vs SCE)
0
0.1
0.2
0.3
0.4
Figure 4 : Cyclic voltammogram of Cu(II)@3 recorded under
argon in water (NaNO3 (0,1 M), NaOH (1,5 mM)) (carb., Ø = 3
mm;  = 0.05 V s-1).
40
Figure 3 : EPR spectra of Cu-(II)@3 in frozen water solution
(H2O/NaOH, pH ≈ 8, T = 70 K) (black= line: experimental spectra ; red
line: simulated spectra). ). Experimental conditions:  = 9.655 GHz,
5 power = 2 mW and modulation amplitude = 2.0 G. Best fit parameters: g1
= 2.015, g2 = 2.135 and g3 = 2.220 ,A1 = 193 MHz, A2 = 158 MHz and A3
= 363 MHz for a lwpp=70G Gaussian lineshape.
Conclusion
In conclusion, the synthesis of the first water soluble
copper@hemicryptophane complex has been described. This
represents a rare example of water-soluble cage compound
45 trapping a copper ion in the confined space of its cavity. The
physico-chemical studies indicated that the solubilisation in water
affects only weakly the geometry of the complex, but strongly
modifies its redox behavior. This novel water-soluble metallo-
enzyme model featuring a copper (II) site encaged in a closed-
50 shell cavity open up the way to new bio-inspired catalytic
systems.
Electrochemical Studies.
10
The CV curve recorded for Cu-(II)@3 in an electrolytic aqueous
medium exhibits a fully irreversible reduction waves Epc = –
0.59V attributed to the formation of Cu-(I)@3 at the electrode
interface. This irreversible feature, observed at all the
15 investigated scan rates, ie from 0,02 to 10 V.s-1, is due to the
existence of an isomerisation process triggered by the
electrochemical reduction of the Cu(II) center. The associated EC
process19 can indeed be modelled as a classic square scheme
involving changes in the coordination sphere around the Cu(I)
20 center in the pentacoordinated Cu-(I)@3 species to produce a
more stable tetrahedral Cu(I) complex noted Cu-(I)@3’.20 These
hypotheses are supported by the observation of an irreversible
oxidation wave at Epa= 0.14 V on the reverse scan, the large
amplitude of the potential shift seen between Epc and Epa being in
25 agreement with a net decrease of the number of coordinated
atoms on the copper center, from 5 in Cu-(II)@3 to 4 in Cu-
(I)@3’. It should be mentioned that a similar EC process was
postulated for Cu(II)@4 in dichloromethane; the reduction wave
and the associated re-oxidation being observed in theses
30 conditions at Epc= – 0.91V / ECS and Epa = 0.45 V / ECS,
respectively.14
Experimental Section
General methods
55 All reactions were carried out under argon by means of an inert
gas/vacuum double manifold and standard Schlenk techniques.
Dichloromethane was first dried over molecular sieves and then
passed through an activated alumina column followed by an
1
argon flush on a solvent station. H and 13C NMR spectra were
60 recorded at 500.10 MHz and 125.76 MHz, respectively. Chemical
shifts are reported relative to the residual protonated solvent
signal (CDCl3), or relative to residual ethanol for the spectra in
D2O. Mass spectra were recorded by the Centre de Spectrométrie
de Masse, Institute of Chemistry, Lyon. Compound 1 was
65 prepared according to the published procedure.15 EPR spectra
were obtained from a Bruker EMX spectrometer and fitted with
Easyspin21 software.
Cyclic voltammetry (CV) data were recorded using an ESP-300
Biologic potentiostat equipped with a 1 A/48 V booster and an
70 analog linear scan generator. All the experiments were conducted
under an argon atmosphere in a standard one-compartment, three-
electrode electrochemical cell placed in a faraday cage. An
automatic ohmic drop compensation procedure was
systematically implemented prior to recording CV data. All the
75 electrodes were purchased from ALS Co. Ltd. Vitreous carbon (Φ
= 3 mm) working electrodes were polished with 1 mm diamond
paste before each recording. A saturated ECS electrode was used
as a reference. HPLC grade water + sodium nitrate (0.1M) was
used as the electrolyte.
These differences observed between organic and aqueous media
highlight the key role of water which is most probably both
involved in the solvation and coordination shells of the cupric and
35 cuprous complexes.
80 Syntheses
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Hemicryptophane 2
Complex Cu(II)@hemicryptophane-3.
Hemicryptophane 1, (257 mg, 0.212 mmol) was dissolved in 60 To a solution of hemicryptophane 3 (15.6 mg, 14 μmol) in milli-
anhydrous DMF (20 mL) and Cs2CO3 (276 mg, 0.848 mmol) was
added to the solution which was stirred at 60°C for 15 minutes.
Then tert-butylbromoacetate (0.141 mL, 0.945 mmol) was added
and the mixture was stirred at 60°C for 2 hours, then at room
Q water (3 mL) was added Cu(ClO4)2.6H2O (5.1 mg, 14 μmol)
and Et3N (9 μL, 67 μmol). The solution was stirred for 5 minutes
and water and Et3N were removed under vacuum. Milli-Q water
(1.5 mL) was added and the blue solid was triturated in this
5
temperature overnight. The solvent was removed and CHCl3 (20 65 solvent. The solution was centrifugated and the supernatant was
mL) and H2O (20 mL) were added to the residue. The two layers
were separated and the aqueous phase was extracted with CHCl3
10 (20 mL). The combined organic solutions were washed with H2O
(2 x 20 mL) and dried over anhydrous Na2SO4. The solvent was
removed. This last step was repeated with 1 mL of milli-Q water
and the residue was dried under vacuum. A blue solid was
obtained (7.9 mg, 50 %). ESI-MS m/z observed 1142.3646 ([M]-,
calculated 1142.3591 for C60H63CuN4O15). EPR (H2O/NaOH; pH
evaporated and the crude product was purified by column 70 = 8; 70 K) g1 = 2.015 (A1 = 193 MHz); g2 = 2.135 (A2 = 158
chromatography on silica gel, using CH2Cl2 and a gradient of
EtOAc (10% to 50%) as eluent. Compound 2 was obtained as a
15 foamy white solid (252 mg, 77 %). ESI-MS m/z observed
1551.7991 ([M + H]+, calculated 1551.7991 for C87H115N4O21).
MHz); g3 = 2.220 (A3 = 363 MHz).Vis-Near IR spectroscopy
(H2O, 298 K) λmax = 850 nm, ε = 237 M-1.cm-1, shoulder band
around 700 nm, ε = 165 M-1.cm-1. Cyclic Voltammetry: Epc = -
0.34 V and Epa = 0.30 V vs E1/2 [FcMeOH0/+] (H2O, NaOH (1.5
1H NMR (CDCl3, 298 K, 500.10 MHz): δ 7.13-6.91 (br, 6H, 75 mM), 12-CuII (5.10-4 M), NaNO3 (0.1 M), working electrode:
ArH), 6.91-6.82 (br, 6H, ArH) , 6.82-6.66 (br, 6H, ArH), 4.65 (d,
3H, J=13.7 Hz, ArCH2Ar), 4.56 (d, 3H, J=16.0 Hz, CH2COO)
20 4.48-4.05 (m, 21H, CH2COO; O(CH2)2O; ArCH2N), 3.47 (d, 3H,
J=13.7 Hz, ArCH2Ar), 3.07-2.60 (br, 6H, N(CH2)2N), 2.50-2.15
carbone, 50 mV.s-1)
Notes and references
[a] Dr. A. Schmitt, Dr. C. Bucher, Dr. J.-P. Dutasta, Pr. A. Martinez
Laboratoire de Chimie, École Normale Supérieure de Lyon, CNRS,
80 UCBL, 46, Allée d'Italie, F-69364 Lyon, France
t
(br, 6H, N(CH2)2N), 1.51-1.32 (br, 54H, C(CH3)3 BOC et Bu-
ester). 13C NMR (CDCl3, 298 K, 125.76 MHz): δ 168.59
(CH2C(O)O) 157.97, 155.92 and 155.36 (NC(O)O), 147.49 (CAr),
25 147.30 (CAr), 134.00 (CAr), 133.08 (CAr), 130.99 (CAr), 129.42
(CAr), 128.74 (CAr), 118.77 (CAr), 117.53 (CAr), 115.19 (CAr),
82.06 (OC (CH3)3), 79.70 (OC(CH3)3), 68.49 and 68.25 (OCH2),
66.77 (OCH2), 52.92 (N(CH2)2N), 50.45 and 49.78 (NCH2Ar),
45.12 (N(CH2)2N), 36.52 (ArCH2Ar), 28.67 (CH3), 28.26 (CH3).
30 Mp: 229.185 °C. IR ν = 2974, 2918, 1749, 1686, 1612, 1509,
1456, 1408, 1365, 1246, 1143cm-1.
[b] Dr Vincent Maurel, Laboratoire de Résonances Magnétiques, CEA-
Grenoble/INAC/SCIB/LRM, UMR-E 3 CEA-UJF, 17, rue des Martyrs
38054 Grenoble CEDEX 09
[c] Pr. A. Martinez, Aix Marseille Universite, Centrale Marseille, CNRS,
85 iSm2 UMR 7313, 13397, Marseille, France
† Electronic Supplementary Information (ESI) available: [Syntheis of 1,
1H and 13C NMR spectra of compounds
DOI: 10.1039/b000000x/
2
and 3]. See
‡ Footnotes should appear here. These might include comments relevant
90 to but not central to the matter under discussion, limited experimental and
spectral data, and crystallographic data.
Hemicryptophane 3
Trifluoroacetic acid (TFA, 780 µL, 10 mmol) was added to a
solution of hemicryptophane 2 (120 mg, 77 µmol) in CH2Cl2 (2
35 mL). The mixture was stirred for 2h at room temperature and the
solvent and TFA were removed under vacuum. Several additions
and evaporations of CHCl3 were carried out to facilitate the
evaporation of TFA. Distilled water (1.5 mL) and NaOH (19.6
mg, 490 µmol) were added to the residue and the mixture was
40 stirred for 30 minutes. Water was then evaporated to give 3 as a
yellow solid (quantitative). ESI-MS m/z observed 1081.4500 ([M
1
2
J. Canceill, A. Collet, J. Gabard, F. Kotzyba-Hibert and J.-M.
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95
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2011, 76, 3531-3535. (d) O. Perraud, A. Martinez and J.-P.
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1
+ 2H]-, 1081.4452 calculated for C60H65N4O15). H NMR (D2O,
298 K, 500.10 MHz): δ 7.36 (s, 3H, ArH), 6.91 (s, 3H, ArH),
6.45 (d, 6H, J=8.4 Hz, ArH), 6.19 (d, 6H, J=8.4 Hz, ArH), 4.80
45 (d, 3H, J=13.8 Hz, ArCH2Ar), 4.69-4.65 (m, 3H, O(CH2)2O),
4.42-4.36 (m, 3H, O(CH2)2O), 4.36-4.28 (m, 3H, O(CH2)2O),
4.19-4.10 (m, 3H, O(CH2)2O), 4.03 (d, 3H, J=15.4 Hz,
OCH2COO), 3.80 (d, 3H, J=15.4 Hz, OCH2COO), 3.59 (d, 3H,
J=13.8 Hz, ArCH2Ar), 3.41 (d, 3H, J=13.6 Hz, ArCH2N), 3.17 (d,
50 3H, J=13.6 Hz, ArCH2N), 2.25-2.00 (m, 12H, N(CH2)2N).13C
NMR (D2O, 298 K, 125.76 MHz): δ 176.07 ((C=O)O), 157.68
(CArO), 145.85 (CArO), 145.47 (CArO), 133.41 (CAr), 132.79
(CAr), 130.00 (CArH), 129.27 (CAr), 116.38 (CArH), 115.82
(CArH), 114.19 (CArH), 69.12 (O(CH2)2O), 66.71 (OCH2C(O)O),
55 66.32 (O(CH2)2O), 52.92 (N(CH2)2N), 50.51 (ArCH2N), 44.79
(N(CH2)2N), 35.26 (ArCH2Ar). Mp: 219.3 °C. IR ν = 3400,
2923., 2856., 1681, 1605, 1509, 1425, 1335, 1259, 1204, 1176,
1127 cm-1.
3
4
115
120
5
6
7
4
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far in the literature for electrogenerated Cu(I) complexes is the
stabilization of the Cu(I) ion in a tetrahedral environment : See
for instance ref 18 or J.-P. Sauvage, J.-P. Collin, S. Durot, J.
Frey, V. Heitz, A. Sour and C. Tock, Compte Rendus Chimie
2010, 13, 315-328.
21 S. Stoll, A. Schweiger, J. Magn. Reson. 2006, 178, 42-55.
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DOI: 10.1039/C4OB02085E
Organic & Biomolecular Chemistry
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Table of contents entry
A water-soluble metallo-enzyme model featuring
a copper (II) site encaged in a closed-shell cavity
of a hemicryptophane has been synthesized and
30 studied.
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This journal is © The Royal Society of Chemistry [year]