Kinetic studies on the copper(II)-mediated oxygenolysis of the flavonolate ligand. Crystal structures of [Cu(fla)2] (fla = flavonolate) and [Cu(O-bs)2(py)3] (O-bs = O-benzoylsalicylate)

Article abstract of DOI:10.1039/a905684j

The complex [Cu(fla)₂] has been prepared by treating copper(n) chloride with sodium flavonolate in tetrahydrofuran solution. Crystallographic characterisation of the complex [Cu(fla)₂]·2CHCl₃ has shown that the co-ordination geometry around the copper(II) ion is square planar. Oxygenation of [Cu(fla)₂] in dimethylformamide solution at ambient conditions gives [Cu(O-bs)₂] (O-bs = O-benzoylsalicylate) and carbon monoxide. Crystallographic characterisation of [Cu(O-bs)₂] on crystals obtained from pyridine as [Cu(O-bs)₂(py)₃]·0.91py revealed that the coordination geometry of the copper(n) ion is square pyramidal with trans O atoms of O-bs and N atoms of py ligands in basal and an N atom of py in apical position. The oxygenolysis of [Cu(fla)₂] in DMF was followed by electron spectroscopy and the rate constants were determined according to the rate law -d[Cu(fla)₂]/dt = k[Cu(fla)₂][O₂]. The rate constant, activation enthalpy, entropy and free energy at 373 K are as follows: k/mol dm^-3s^-1 = (1.57 ± 0.08) × 10^-2, ΔH^?/kJ mol^-1 = 53 ± 6, ΔS^?/J K^-1 mol^-1 = -138 ± 11, ΔG^?/kJ mol^-1 = 105 ± 2. The reaction fits a Hammett linear free energy relationship and a higher electron density on copper results in a faster oxygenation reaction. The Royal Society of Chemistry 1999.

Full text of DOI:10.1039/a905684j

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Kinetic studies on the copper(II)-mediated oxygenolysis of the
flavonolate ligand. Crystal structures of [Cu(fla)2] (fla ؍
flavonolate) and [Cu(O-bs)2(py)3] (O-bs ؍ O-benzoylsalicylate)†
Éva Balogh-Hergovich,a József Kaizer,b Gábor Speier,*b Gyula Argayc and László Párkányic
a Research Group for Petrochemistry of the Hungarian Academy of Sciences, 8201 Veszprém,
Hungary
b Department of Organic Chemistry, University of Veszprém, 8201 Veszprém, Hungary
c Central Research Institute for Chemistry, Hungarian Academy of Sciences, 1525 Budapest,
Hungary
Received 14th July 1999, Accepted 3rd September 1999
The complex [Cu(fla)2] has been prepared by treating copper() chloride with sodium flavonolate in tetrahydrofuran
solution. Crystallographic characterisation of the complex [Cu(fla)2]ؒ2CHCl3 has shown that the co-ordination
geometry around the copper() ion is square planar. Oxygenation of [Cu(fla)2] in dimethylformamide solution at
ambient conditions gives [Cu(O-bs)2] (O-bs = O-benzoylsalicylate) and carbon monoxide. Crystallographic
characterisation of [Cu(O-bs)2] on crystals obtained from pyridine as [Cu(O-bs)2(py)3]ؒ0.91py revealed that the co-
ordination geometry of the copper() ion is square pyramidal with trans O atoms of O-bs and N atoms of py ligands
in basal and an N atom of py in apical position. The oxygenolysis of [Cu(fla)2] in DMF was followed by electron
spectroscopy and the rate constants were determined according to the rate law Ϫd[Cu(fla)2]/dt = k[Cu(fla)2][O2]. The
rateconstant, activationenthalpy, entropyandfreeenergyat373Kareasfollows:k/moldmϪ3 sϪ1 = (1.57 0.08) × 10Ϫ2
∆H‡/kJ molϪ1 = 53 6, ∆S‡/J KϪ1 molϪ1 = Ϫ138 11, ∆G‡/kJ molϪ1 = 105 2. The reaction fits a Hammett linear
free energy relationship and a higher electron density on copper results in a faster oxygenation reaction.
,
2,3-dioxygenase is responsible for this reaction. In the resting
state of the enzyme copper is in the copper() form, its ligand
Introduction
The oxidative degradation of organic molecules by the use of
environment is still obscure and the flavonol moiety seems to be
dioxygen is accomplished widely in nature aided by a variety of
co-ordinated through its 3-hydroxy and 4-carbonyl group to the
enzyme systems. Some of these metalloenzymes contain copper
metal.5
and/or iron ions at their active sites. Oxygenases catalyse the
Few model reactions on the oxygenation of flavonol (Ib)
and quercetin (Ia) have been carried out with the aim to
incorporation of oxygen atom(s) (mono- and di-oxygenases) of
molecular oxygen into the substrate under ambient conditions.1
shed light on this curious reaction leading to oxidative ring
There is great interest for the elucidation of the structures and
cleavage of the pyranone ring with concomitant extrusion of
mechanistic features of such enzymes. The question is put
carbon monoxide. Base catalysed oxygenation of quercetin
forward as to how the reactions are accelerated and what is the
role of the redox metal ions in terms of activation of either
and 3-hydroxyflavones under aqueous6 and non-aqueous con-
ditions,7 photosensitised oxygenations,8 and reactions with
dioxygen or the substrate.2 Besides direct enzymatic methods,
superoxide anions9 have been studied. Cobalt10 and copper11
studies on structural and functional models are thought to
complexes were applied as suitable catalysts for the oxygenation
be helpful means for obtaining information on the mode of
reaction. Copper()12 and copper()13 flavonolate complexes
activation of reactants and understanding the mechanism
were also found to catalyse the reaction.
of oxygenations and the chemistry of metal-based oxidation
Following our studies on the preparation, characterisation
reactions.3
and oxygenation of copper() flavonolate complexes12,14 we
Fungi such as Aspergillus or Pullularia species metabolise
quercetin (Ia, 3Ј,4Ј,5,7-tetrahydroxyflavonol) into a depside
tried to isolate and characterise copper() flavonolate com-
plexes and to study their oxygenation. This paper deals with
(IIa, phenolic carboxylic acid ester) and carbon monoxide
the preparation and structural characterisation of a copper()
[eqn. (1)].4 The copper-containing metalloenzyme quercetin
flavonolate complex13 and its oxygenated product copper()
O-benzoylsalicylate and with the kinetics of this reaction.
Experimental
Materials and methods
All manipulations were performed under a pure dinitrogen
or argon atmosphere unless otherwise stated using standard
Schlenk-type inert gas techniques.15 The compounds Cu-
(OMe)2,16 3-hydroxyflavone,6 3-hydroxy-4Ј-methoxyflavone,6
3-hydroxy-4Ј-methylflavone,17
4Ј-chloro-3-hydroxyflavone,17
and O-benzoylsalicylic acid18 were prepared according to
literature methods; CuCl2 was prepared from CuCl2ؒ5H2O
† Supplementary data available: rotatable 3-D crystal structure diagram
in CHIME format. See http://www.rsc.org/suppdata/dt/1999/3847/
J. Chem. Soc., Dalton Trans., 1999, 3847–3854
This journal is © The Royal Society of Chemistry 1999
3847

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Table 1 Analyticala and physical data for green complexes [Cu(4ЈR-
by heating at 180 ЊC in vacuum for 8 h. Dichloromethane,
chloroform, toluene, acetonitrile, pyridine, and DMF were
purified in the usual manner and stored under argon.19 All
other chemicals were commercial products used as received
without further purification. Infrared spectra were recorded on
a Specord 75 IR (Carl Zeiss) spectrophotometer using samples
mulled in Nujol between KBr plates or in KBr pellets. GC
Analyses were performed on a HP 583OA gas chromatograph
equipped with a flame ionisation detector and a 25 m (0.2 mm
i.d., 0.25 µm film thickness) CP-SIL-8CB fused silica capillary
column, and a thermal conductivity detector and a 27.5 m (0.53
mm i.d., 0.2 µm film thickness) Poraplot Q fused silica capillary
column. GC-MS Analyses were performed on a HP 5890II/
5971 GC/MSD apparatus equipped with a column identical to
that used for GC analyses. ESR Spectra were recorded on a
JEOL.JES-FE3X spectrometer at temperatures given either on
solid samples or solutions sealed under argon and referenced
to MnII as external standard. Magnetic susceptibilities were
determined on a Bruker-B-E 10B8 magnetometer.20 Reactions
under controlled pressure of O2 were performed with a double-
wall reaction vessel equipped with a mercury manometer, inlet
for sampling, and a Carl Zeiss (Jena) temperature controller.
UV-vis Spectra were recorded on a Shimadzu UV-160 spectro-
photometer using quartz cells. CV Measurements were carried
out on a BAS CV-1B cyclic voltammeter in DMF solution at
room temperature with ca. 10Ϫ3 M solutions and NBu4PF6
as supporting electrolyte, and scan speeds 100 mV cmϪ1 unless
otherwise stated, the potential values are relative to the satur-
ated calomel electrode (SCE) using an Ag–AgCl reference
electrode, the potential of which was Ϫ0.02 V vs. SCE.21
fla)2] 1a–1d
Analysis (%)
C
Com-
pound
Yieldb
(%)
R
mp/ЊC
H
1a
1b
1c
1d
H
CH3
Cl
88
80
90
90
295–297
294–296
297–299
323–325
66.03 (66.97)
67.45 (67.89)
60.84 (59.37)
64.90 (64.26)
3.38 (3.37)
4.03 (3.91)
2.77 (2.65)
3.77 (3.71)
OCH3
a Required values are given in parentheses. b Isolated yields.
Table 2 Characteristic absorption bands of complexes [Cu(4ЈR-fla)2]
1a–1d
ν(CO)a/
Complex cmϪ1
∆ν(CO)/
UV-vis (DMF) λ/nm
(log ε/MϪ1 cmϪ1
cmϪ1
)
1a
1b
1c
1d
1537
1534
1548
1538
71
81
67
70
268 (3.54) 433 (4.45) 719 (1.72)
263 (4.61) 435 (4.58) 702 (1.56)
263 (4.46) 434 (4.29) 703 (2.14)
268 (4.37) 440 (4.24) 769 (1.56)
a In Nujol.
Table 3 Magnetic properties of complexes [Cu(4ЈR-fla)2] 1a–1d
a
Complex
µeff/µB
g⊥
g||
ga
Gb
1a
1b
1c
1d
1.76
1.98
1.64
1.49
2.0849
2.0722
2.0969
2.0687
2.2519
2.2476
2.2908
2.2438
2.1420
2.1323
2.1635
2.1287
2.97
3.43
3.00
1.87
Preparations
[Cu(fla)2] 1a. To a stirred solution of flavonol (2.38 g, 10
mmol) in anhydrous dichloromethane (100 cm3) Cu(OMe)2
(0.63 g, 5 mmol) was added under argon. The mixture was
stirred for 8 h, the solvent evaporated off in vacuum, and the
residue treated with diethyl ether, filtered off and dried to give
a greenish yellow powder of complex 1a (2.4 g, 88%), mp 295–
297 ЊC (Found: C, 66.03; H, 3.38. C30H18CuO6 requires C,
66.97; H, 3.37%); λmax/nm (CH2Cl2) 240(sh) (log ε/molϪ1 dm3
cmϪ1 4.52), 258 (4.63), 273(sh) (4.53), 329 (4.18), 410 (4.53) and
426 (4.58); νmax/cmϪ1 (KBr) 1609w, 1590m, 1567w, 1537s, 1508s,
1491s, 1456w, 1432m, 1416s, 1353m, 1319m, 1309w, 1296w,
1249w, 1229w, 1215s, 1183w, 1153m, 1115w, 1096w, 1070w,
907m, 760(sh), 750s, 705w, 674m, 659w, 569m and 476m;
µB = 1.76; ESR parameters g|| = 2.2519 and g⊥ = 2.0849. On
recrystallisation from CHCl3 yellow plates of [Cu(fla)2]ؒ2CHCl3
were formed suitable for X-ray diffraction experiments.
a ga = [(2g⊥2 ϩ g||2)/3]1/2 b G = (g|| Ϫ 2)/(g⊥ Ϫ 2).
.
(log ε/molϪ1 dm3 cmϪ1 3.95) and 730 (2.31); νmax/cmϪ1 (Nujol)
3614, 1740, 1627, 1447, 1406, 1256, 1207, 1094, 1056, 1014, 774
and 700; µB = 1.30. Crystals of [Cu(O-bs)2(py)3]ؒ0.91py
2aؒ3.91py suitable for crystallographic studies were obtained
from pyridine on layering diethyl ether onto the solution, mp
76 ЊC (decomp.); νmax/cmϪ1 (KBr) 3614, 1734, 1625, 1454, 1375,
1274, 1194, 1067, 1030, 760 and 714; µB = 2.12.
Crystal structure determination
[Cu(fla)2]ؒ2CHCl3 1aؒ2CHCl3. Single crystals were obtained
by recrystallization of 3a from dichloromethane. Crystal data
and experimental conditions are listed in Table 4. The structure
was solved by direct methods (SHELXS 8622) and then sub-
jected to full-matrix least squares refinement based on F2
(SHELXL 9323).
[Cu(4ЈR-fla)2] 1b–1d. Complexes 1b–1d were prepared by
the same method as described above. Properties, analyses, IR,
UV-vis, µB and ESR data of the complexes are summarized
in Tables 1, 2 and 3.
[Cu(O-bs)2(py)3]ؒ0.91py 2aؒ3.91py. Crystals obtained by re-
crystallisation of complex 2a from pyridine were mounted in a
sealed capillary. Crystallographic data are recorded in Table 4.
The structure was solved by direct methods (SHELXS 9724)
and then subjected to full-matrix least squares refinement based
on F2 (SHELXL 9725).
The C13–C18 phenyl ring is disordered. The C13–C18,
C13a–C18a moieties were refined as rigid groups (regular
hexagons, C–C 1.390 Å). A three atom moiety was detected in a
difference map around the inversion centre at (1/4,Ϫ1/4,1/2)
that is expanded to a hexagon by symmetry. This solvent
molecule was considered as pyridine that must be disordered by
site symmetry as the nitrogen atom is reflected through the
inversion center. The occupancy factor for the solvent atoms
was refined by isotropic refinement that resulted in full
occupancy. The disordered positions, are, therefore, filled by
[Cu(O-bs)2] 2a. Method A. The complex [Cu(fla)2] (0.538 g,
1 mmol) in DMF (50 cm3) was treated with dioxygen (1 atm)
at 80 ЊC for 5 h yielding a greenish yellow solution. On addition
of ether a blue solid precipitated, from which after filtration
and recrystallisation from ethanol [{Cu(O-bs)2ؒC2H5OH}2]
[2aؒEtOH]2 was obtained (280 mg, 46%).
Method B. To a solution of Cu(OAc)2ؒ2H2O (2.00 g, 10
mmol) in ethanol (80 cm3) benzoylsalicylic acid (4.84 g,
20 mmol) in ethanol (20 cm3) was added with stirring at 40 ЊC.
The solution was stirred for 3 h and allowed to cool to room
temperature. The blue crystalline product was collected by
filtration, washed with ethanol and dried under vacuum to
give [{Cu(O-bs)2ؒC2H5OH}2] [2aؒEtOH]2 (5.12 g, 85%); mp
136–138 ЊC (Found: C, 59.55; H, 3.97; Cu, 10.38. C30H24CuO9
requires C, 59.84; H, 4.01; Cu, 10.55%); λmax/nm (DMF) 263
3848
J. Chem. Soc., Dalton Trans., 1999, 3847–3854

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1/2 nitrogen and 1/2 carbon atoms that were introduced in
the same position. There must also be a hydrogen atom with
half occupancy linked to the disordered carbon. The atoms
of the solvent behaved well in the final anisotropic refinement
cycles.
CCDC reference number 186/1640.
See http://www.rsc.org/suppdata/dt/1999/3847/ for crystallo-
graphic files in .cif format.
Kinetic measurements
Reactions between [Cu(fla)2] and O2 were performed in DMF
solutions. In a typical experiment [Cu(fla)2] was dissolved under
an argon atmosphere in a thermostatted reaction vessel with
inlets for taking samples by a syringe, and connected to a
mercury manometer to regulate constant pressure. The solution
was then heated to the appropriate temperature. A sample was
taken by syringe and the initial concentration of [Cu(fla)2]
determined by UV-vis spectroscopy measuring the absorbance
at 430.5 nm (λmax of a typical band of [Cu(fla)2]). Then the
argon was replaced with dioxygen and the consumption of
[Cu(fla)2] analysed periodically (ca. every 5 min). Experimental
temperatures were determined with an accuracy of 0.5 ЊC; the
concentrations of [Cu(fla)2] were measured with a relative mean
error of ca. 2%; the pressure of dioxygen was determined with
an accuracy of 0.5%. The O2 concentration was calculated
from literature data26 taking into account the partial pressure
of DMF,27 and assuming the validity of Dalton’s law.
Results
Potassium or sodium salts of flavonol react with copper()
and copper() chloride to give the corresponding flavonolato
copper complexes.12 In the presence of phosphine coligand
tetrahedral [Cu(PR3)2(fla)] products are obtained; with
nitrogen-donor ligands the formation of similar compounds
failed.28 The complex [Cu(fla)2] 1a was obtained in small
quantities, which could be prepared in excellent yield starting
from Cu(OMe)2 and flavonol, eqn. (2).
Cu(OMe)2 ϩ 2Hfla → [Cu(fla)2] ϩ 2 MeOH (2)
1a
Oxygenation of [Cu(fla)2] in several solvents under ambient
conditions (and even faster at temperatures around 100 ЊC)
resulted in the bis(O-benzoylsalicylato)copper() complex 2a
and carbon monoxide contaminated with a small amount of
CO2 (GC analyses), eqn. (3). Both complexes have been fully
characterised and the results of this investigation are described
below. Complex 2a has been recrystallised from ethanol to
give blue [{Cu(O-bs)2ؒEtOH}2]. It shows an IR absorption at
1740 cmϪ1 [ν(CO)] indicating that the carbonyl group of the
benzoyl group is not co-ordinated; ν(OH) absorption due to
the co-ordinated ethanol could be found at 3614 cmϪ1. The
absorptions at 1627 and 1406 cmϪ1 are due to the co-ordinated
carboxylato group. The difference between the asymmetric and
symmetric stretching frequencies of the carboxylato group,
∆ν = νasym(CO2) Ϫ νsym(CO2), is 221 cmϪ1 rendering these to a
bridging carboxylate bonding mode. In the UV-vis spectrum
the d–d transition may be assigned to the 730 nm absorption
and the ligand to metal charge transfer at 263 nm. The room
temperature magnetic susceptibility of µB = 1.30 is less than
expected for two d9 atoms due to antiferromagnetic interactions
as found in many other dicopper carboxylato complexes.29
For the complex [Cu(O-bs)2(py)3] 2aؒ3py absorptions due to
ethanol are missing and the difference in the asymmetric and
symmetric stretching frequencies of the carboxylato group
(250 cmϪ1) is characteristic for monodentate carboxylate co-
ordination.29 The magnetic moment of µB = 2.12 indicates a
mononuclear complex as usually found for d9 ions.
[Cu(fla)2]ؒ2CHCl3 1aؒ2CHCl3. Crystallographic charac-
terisation of [Cu(fla)2]ؒ2CHCl3 isolated from a chloroform
solution shows that the molecule is monomeric with two solvate
molecules. The view of the molecule in Fig. 1 shows the square
planar co-ordination geometry around the metal ion; the
flavonolate ligands are arranged in trans position. The molecule
is centrosymmetric at copper. Selected bond distances and
angles are given in Table 5 and show that the Cu–O lengths
[Cu(1)–O(2) 1.900(2) and Cu(1)–O(3) 1.942(2) Å] are sig-
nificantly shorter than those in [Cu(PPh3)2(fla)] [2.051(4)
and 2.167(5) Å].12 These are even a bit longer than the Cu–O
bond lengths in the terminal alkoxide [Cu4(OBut)4] [Cu–Oav
1.854(9) Å]30 but shorter than those in bridging alkoxides,
e.g. [Cu2Cl2(OMe)2(py)2]2 [1.932(4) and 1.940(6) Å].31 That
means that the flavonolate ligand is more strongly bonded to
copper() than to copper().12 The C(2)–O(2) bond distance is
shorter and the C(3)–O(3) bond length longer than those in free
flavonol [1.357(3) and 1.232(3) Å].32
J. Chem. Soc., Dalton Trans., 1999, 3847–3854
3849

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Table 4 Crystallographic data for complexes 1aؒ2CHCl3 and 2aؒ3.91py
1aؒ2CHCl3
2aؒ3.91py
Molecular formula
M
T/K
C32H20Cl6CuO6
776.72
293(2)
C43H33CuN3O8ؒ0.91C5H5N
855.84
293(2)
Crystal system
Space group
Triclinic
P1
Monoclinic
C2/c
¯
a/Å
b/Å
c/Å
α/Њ
7.273(1)
30.948(3)
9.641(1)
16.159(1)
10.691(1)
11.229(1)
103.77(2)
105.76(2)
99.61(2)
790.7(2)
1
β/Њ
115.53(1)
γ/Њ
U/Å3
4350.6(7)
4
1.184
Z
µ/mmϪ1
6.023
Reflections collected
Independent reflections
Final R1, wR2 [I > 2σ(I)]
(all data)
3250
4650
3250 [R(int) = 0.000]
0.0529, 0.1472
0.0714, 0.1717
4478 [R(int) = 0.0117]
0.0463, 0.1376
0.0486, 0.1404
Table
5
Selected bond lengths (Å) and angles (Њ) of complex
1aؒ2CHCl3
Table 6 Selected bond lengths (Å) and angles (Њ) for complex
2aؒ3.91py
Cu(1)–O(2)
Cu(1)–O(2Ј)
Cu(1)–O(3Ј)
Cu(1)–O(3)
O(1)–C(1)
1.900(2)
1.900(2)
1.942(2)
1.942(2)
1.366(4)
1.357(4)
O(2)–C(2)
O(3)–C(3)
C(1)–C(2)
C(1)–C(11)
C(2)–C(3)
C(3)–C(4)
1.321(4)
1.268(4)
1.383(4)
1.456(4)
1.445(4)
1.431(4)
Cu–O(1)
1.973(1)
1.973(1)
2.030(1)
2.030(1)
2.280(2)
1.272(2)
C(2)–O(3)
C(2)–C(4)
C(9)–O(10)
O(10)–C(11)
C(11)–O(12)
C(11)–C(13)
1.222(2)
1.508(3)
1.398(3)
1.364(4)
1.181(4)
1.494(3)
Cu–O(1a)
Cu–N(19)
Cu–N(19a)
Cu–N(25)
O(1)–C(2)
O(1)–C(9)
O(2)–Cu(1)–O(2Ј)
O(2)–Cu(1)–O(3Ј)
O(2Ј)–Cu(1)–O(3Ј)
O(2)–Cu(1)–O(3)
O(2Ј)–Cu(1)–O(3)
O(3Ј)–Cu(1)–O(3)
C(1)–O(1)–C(9)
179.999(1)
94.31(9)
85.69(9)
85.69(9)
94.31(9)
180.0
112.2(3)
110.6(2)
110.0(2)
O(1)–C(1)–C(2)
O(1)–C(1)–C(11)
C(2)–C(1)–C(11)
O(2)–C(2)–C(1)
O(2)–C(2)–C(3)
C(1)–C(2)–C(3)
O(3)–C(3)–C(4)
O(3)–C(3)–C(2)
C(4)–C(3)–C(2)
120.1(3)
111.8(3)
128.1(3)
125.1(3)
115.7(3)
119.2(3)
123.2(3)
118.0(3)
118.8(3)
O(1)–Cu–O(1a)
O(1)–Cu–N(19a)
O(1a)–Cu–N(19a)
O(1)–Cu–N(19)
N(19a)–Cu–N(19)
O(1)–Cu–N(25)
N(19)–Cu–N(25)
C(2)–O(1)–Cu
178.90(7)
90.24(6)
89.89(6)
89.89(6)
165.9(1)
89.45(4)
97.02(5)
119.0(1)
124.9(2)
O(3)–C(2)–C(4)
O(1)–C(2)–C(4)
119.3(2)
115.8(2)
116.6(2)
123.1(2)
117.6(8)
119.2(8)
121.4(2)
120.5(1)
121.4(1)
C(11)–O(10)–C(9)
O(12)–C(11)–O(10)
O(12)–C(11)–C(13)
O(10)–C(11)–C(13)
C(24)–N(19)–Cu
C(20)–N(19)–Cu
C(26)–N(25)–Cu
C(2)–O(2)–Cu(1)
C(3)–O(3)–Cu(1)
O(3)–C(2)–O(1)
1
Symmetry operation 1 Ϫ x ϩ 2; Ϫy; Ϫz ϩ 2.
–
Symmetry operation 1 Ϫ x; y; Ϫz ϩ 2.
Fig. 1 View of [Cu(fla)2]ؒ2CHCl3 1aؒ2CHCl3.
Fig. 2 View of [Cu(O-bs)2(py)3]ؒ0.91py 2aؒ3.91py.
[Cu(O-bs)2(py)3]ؒ0.91py 2aؒ3.91py. Crystallographic charac-
terisation of [Cu(O-bs)2(py)3]ؒ0.91py crystallised from a pyri-
dine solution shows that the co-ordination geometry around
the copper ion is square pyramidal. A view of the molecule is
shown in Fig. 2 and selected bond distances and angles are
listed in Table 6. Monodentate carboxylato ligands (O-bs) and
two pyridine nitrogens occupy trans positions in the basal
plane. The Cu–O bond lengths are identical [1.9727(13) Å] and
the same is true for the Cu–N bond distances [2.0301(16) Å]
as well. The Cu–N distance of the apical pyridine ligand is
however longer [2.280(2) Å]. The same geometry and similar
values were obtained for the complex [Cu(PhCO2)2(py)3]33
[Cu–O 1.9471(1) and 1.96(3); Cu–N 2.045(4), 2.049(4) and
2.367(4) Å] and for the square planar [Cu(PhCO2)2(tmeda)]34
[Cu–O 1.985(2) and Cu–N 2.038(3) Å]. Comparing these bond
distances with those of the dinuclear copper benzoate complex
[{Cu(PhCO2)2(py)}2]35 [Cu–O from 1.960 to 1.979 and Cu–N
2.170 Å] not much difference can be seen. The C13–C18 phenyl
ring is disordered.
Electrochemistry
A solution of complex [Cu(fla)2] in DMF containing NBu4PF6
(0.1 M) under argon showed very weak redox currents in a
3850
J. Chem. Soc., Dalton Trans., 1999, 3847–3854

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Table 7 Kinetic data for the oxygenation of [Cu(fla)2] in DMF solution
103[O2]/
104[Cu]a/
102kobs/molϪ1
108d[Cu]/dt
Expt. no.
T/ЊC
mol dmϪ3
mol dmϪ3
104kЈ/sϪ1
Rb(%)
dm3 sϪ1
mol dmϪ3 sϪ1
1
2
3
4
5
6
7
8
9
100
100
100
100
100
100
100
100
100
100
100
7.70
7.70
7.70
7.70
7.70
7.70
1.93
4.90
7.70
9.95
11.65
0.62
1.27
1.62
1.71
2.02
2.99
2.64
2.63
2.65
2.64
2.62
0.26 0.02
1.71 0.07
2.23 0.15
1.49 0.12
1.21 0.06
0.91 0.06
0.14 0.01
0.83 0.03
0.89 0.06
1.24 0.04
1.93 0.15
97.31
99.60
99.66
98.34
99.34
97.07
99.48
99.31
98.56
99.37
98.87
0.34 0.03
2.22 0.09
2.89 0.20
1.93 0.16
1.57 0.08
1.19 0.08
0.75 0.02
1.70 0.07
1.16 0.08
1.25 0.04
1.66 0.20
0.87 0.15c
0.99 0.08
3.50 0.08
4.07 0.12
0.60
1.90
2.70
3.15
3.46
5.58
0.57
2.02
2.73
3.83
4.40
10
11
12
90
116
100
7.84
6.73
7.70
2.38
1.94
2.03
0.78 0.06
2.36 0.08
3.13 0.09
98.61
99.67
99.24
13
14d
a In 50 cm3 DMF. b Correlation coefficients of least-squares regressions. c Mean value of the kinetic constant k and its standard deviation σ(k) were
calculated as k = (Σiwi/Σiwi) and σ(k) = (Σiwi(ki Ϫ k)2/(n Ϫ 1)Σiwi)1/2, where wi = 1/σi2. d In DMF–py (48 cm3–2 cm3).
Kinetic measurements
The kinetics of the oxygenation reaction was followed by
determining the concentration of [Cu(fla)2] in the reaction
solution as a function of time by UV-vis spectroscopic
measurements under constant dioxygen pressure, determining
the variations of the absorbance maxima of the flavonolate
band at 430.5 nm. A simple rate law for the reaction between
[Cu(fla)2] and O2 is given in eqn. (4). In order to determine the
Ϫd[Cu(fla)2)]/dt = d[Cu(O-bs)2]/dt = k[Cu(fla)2]m [O2]n (4)
rate dependence on the various reactants, oxygenation runs
were performed at various initial substrate concentrations
(Table 7; experiments 1–6) and at different dioxygen pressures
(Table 7, experiments 7–11 under pseudo first order conditions
with a constant dioxygen pressure). Eqn. (4) can then have a
more simple feature as written in eqn. (5), kЈ being the pseudo
first order rate constant.
Ϫd[Cu(fla)2]/dt = kЈ[Cu(fla)2]m
(5)
Fig. 3 Cyclic voltammograms upon oxygenation of [Cu(fla)2]ؒ1a
in DMF–py.
The time dependence of the change of concentration of
[Cu(fla)2] during the oxygenation and plots of log[Cu(fla)2]
versus time were linear in experiments 1–6, indicating that the
reaction is first order with respect to substrate concentration.
Columns kЈ and R in Table 7 report slopes and the correlation
coefficients obtained by the least-squares method for these
linear regressions. A typical first order plot is shown in Fig. 4
for experiment 5; the reaction remains first order for the whole
time in which the experiment was followed (63% conversion,
platinum electrode system. The oxygenated product [Cu(O-
bs)2]ؒEtOH showed an irreversible redox current at 1090 mV.
After addition of pyridine to the solution of [Cu(fla)2] in DMF
a strong anodic peak current at Ϫ280 mV emerges rapidly
under argon. This can be rationalised by assuming that complex
1a dissociates in DMF to generate a free flavonolate anion and
[Cu(fla)(py)3]ϩ. When oxygen was bubbled through the solution
(5 min) with disconnection of the electrode and then measure-
ments were made under argon a decrease in ipa of flaϪ was
observed (Fig. 3). These results provide evidence that the oxy-
genation of [Cu(fla)2] occurs also after dissociation has taken
place. However the rate of oxygenation of [Cu(fla)2] in DMF is
much smaller (kDMF/molϪ1 dm3 sϪ1 = (1.57 0.08) × 10Ϫ2) than
2
h). From variations of the reaction rates, plots of
Ϫd[Cu(fla)2]/dt versus [Cu(fla)2] were also linear in experiments
1–6, reinforcing that the reaction is indeed first order with
respect to substrate concentration.
Experiments made at different dioxygen concentrations
(calculated from literature data assuming the validity of
Dalton’s law, the dissolved concentration of O2 being 7.7 ×
10Ϫ3 mol dmϪ3 at 100 ЊC and 760 mmHg O2 pressure) show that
the dioxygen concentration affects the rate of the reaction
(experiments 7–11; columns kЈ and R in Table 7) and that the
reaction is first order with respect to dioxygen concentration.
According to the kinetic data obtained the oxygenation of
[Cu(fla)2] obeys a second order rate equation with m = n = 1
[eqn. (4)], from which a mean value of the kinetic constant
k of (0.87 0.15) × 10Ϫ2 molϪ1 dm3 sϪ1 at 373 K was obtained
(Table 7).
in a DMF ϩ pyridine mixture (kpy/molϪ1 dm3 Ϫ1 = (4.07
s
0.12) × 10Ϫ2) (experiments 5, 14; in Table 7). This difference in
reaction rate indicates that there are two pathways for the oxy-
genation of 1a, namely a slower process in DMF where the
flavonolate ligand is bonded to copper, and a faster one in the
presence of an excess of py ligand where dissociation is
enforced by the strongly ligating py and the dissociated fla-
vonolate is being oxygenated.
J. Chem. Soc., Dalton Trans., 1999, 3847–3854
3851

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Table 8 Hammett data for the oxygenation of [Cu(4ЈR-fla)2]
Complex
σ
102kobs a/molϪ1 dm3 sϪ1
1a
1b
1c
1d
0.000
Ϫ0.170
ϩ0.227
Ϫ0.268
3.23 0.30
3.53 0.35
2.11 0.16
4.59 0.15
a In DMF at 120 ЊC.
Fig. 4 Time course for the oxygenation of [Cu(fla)2] in DMF (᭺) and
plot of log[Cu(fla)2] (∆) versus reaction time for the oxygenation of
[Cu(fla)2] (experiment 5, Table 7).
Fig. 5 Hammett plot for the oxygenation of [Cu(4ЈR-fla)2] complexes
(Table 8).
Scheme 1
The activation parameters for the oxygenation reaction were
determined from the temperature dependence of the kinetic
constant k. The Eyring plot of log (k/T) versus 1/T (k is
expressed in molϪ1 dm3 sϪ1 and ∆H‡ and ∆S‡ are assumed
temperature-independent in the range examined) by using
the k values at 373, 363 and 389 K (experiments 5, 12, 13 in
Table 7) was linear with a correlation coefficient of 99.88%. The
slope and the ordinate intercept of this line gave ∆H‡ = 53
6 kJ molϪ1, ∆S‡ = Ϫ138 11 J KϪ1 molϪ1, and ∆G‡(373 K) =
enzyme reactions. Copper() has been found in the resting state
of quercetinase.5 Copper() ions differ from copper() ions in
their reactivity toward dioxygen. The latter has a rich dioxygen
chemistry38 while the former is very stable and non-reactive.39
Now in the case of flavonolatocopper complexes the question
arises as to whether simple deprotonation (formation of
the copper complex) is the activation step producing free
flavonolate ions through dissociation of the complex as found
in the case of cobalt complexes,10b leading to a direct reaction
of it with dioxygen, or a certain role of copper may also be
rendered to the activation process. The overall second order
reaction expression and the CV measurements, which exclude
dissociation of the flavonolate ligand of [Cu(fla)2] in DMF,
support the proposal that in a fast preequilibrium the copper()
105 2 kJ molϪ1
.
Reaction rates for the oxygenation of 4Ј-substituted
flavonolato copper complexes [Cu(4ЈR-fla)2] 1a–1e [eqn. (3)]
under identical conditions were determined (with various
electron-withdrawing and releasing substituents R) in order to
determine electronic effects on the reaction rate. The Hammett
plot obtained is shown in Fig. 5. Electron-releasing substituents
enhanced the reaction rate and the reaction constant ρ was
found to be Ϫ0.63.
flavonolate complex
1 undergoes intramolecular electron
transfer from the ligand flaϪ to CuII resulting in the copper()
flavonoxy radical complex 3 (Scheme 1). The equilibrium
is largely shifted to the left (K1 is rather small). In 3 there are
two redox-active centers, the radical ligand and the copper()
species. The biradical dioxygen may react at both sites, in an
oxidative addition to the copper leading to a superoxocopper
complex 4, or in a radical–radical reaction with the flavonoxy
ligand. We believe the former is the rate determining step,
supported by the kinetic data and the negative entropy of
activation. This is followed then in a fast consecutive formation
of the trioxametallocycle 5 which reacts by a nucleophilic
addition on the C4 carbon to give the endoperoxide 6. The
endoperoxide decomposes then in a fast step to the O-
benzoylsalicylato copper complex 7 and carbon monoxide.
Discussion
From the experimental data a mechanism for the reaction of
the flavonolatocopper complex 1 with dioxygen can be pro-
posed (Scheme 1). Catechols36 and quercetin (and 3-
hydroxyflavone as well)5 are assumed to be reactive substrates
in enzyme reactions. However it is known that these sub-
strates are inert towards dioxygen in their protonated forms.
Deprotonation of catechols37 and also of 3-hydroxyflavone10b
enhances the activity of the corresponding anions toward
dioxygen, yielding cleavage products such as those found in the
3852
J. Chem. Soc., Dalton Trans., 1999, 3847–3854

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X. Wang, J. V. G. Young, C. J. Cramer, L. Que, Jr. and W. B. Tolman,
J. Am. Chem. Soc., 1996, 119, 11555.
Owing to a ligand scrambling reaction, thereafter the starting
copper flavonolate complex 1 and the bis(O-benzoylsali-
cylato)copper() complex 2 is formed.
Assuming steady state conditions for species 3, the rate
eqn. (6) can be deduced which after some simplification
3 T. Funabiki, Catalysis by Metal Complexes, Oxygenases and Model
Systems, Kluwer Academic Press, Dordrecht, 1997, vol. 19;
M. Sono, M. P. Roach, E. D. Coulter and J. H. Dawson, Chem. Rev.,
1996, 96, 2841; G. Speier, New J. Chem., 1994, 18, 143; G. Speier,
Z. Tyeklár, L. Szabó II, P. Tóth, C. G. Pierpont and D. N.
Hendrickson, in The Activation of Dioxygen and Homogeneous
Catalytic Oxidation, eds. D. H. R. Barton, A. E. Martell and D. T.
Sawyer, Plenum Press, New York, 1993, pp. 423–436; L. Que, Jr.
and R. Y. N. Ho, Chem. Rev., 1996, 96, 2607; C. G. Pierpont and
C. W. Lange, Prog. Inorg. Chem., 1994, 41, 331.
d[Cu]
dt
k1k2[Cu][O2]
k1k2[Cu][O2]
k1 ϩ kϪ1
(6)
Ϫ
=
=
= kobs[Cu][O2]
k1 ϩ kϪ1 ϩ k2[O2]
(k2[O2] Ӷ k1 ϩ kϪ1 and [Cu] means the total complex) is in good
agreement with an overall second order dependence according
the experimental data obtained in the kinetic measurements.
The Hammett relationship shows that higher electron density
at the copper ion enhances the rate of the reaction, which
is consistent with an electrophilic attack of dioxygen at the
copper() center, however the reaction constant of the oxygen-
ation reaction is somewhat less (ρ = Ϫ0.63, R = 0.977) than
that found for oxygenation of copper() chloride in pyridine
(ρ = Ϫ1.24).40 This may be due to the buffering effect of the
other flavonolato ligand still co-ordinated to the copper
ion which reduces the redox potential on the copper, reducing
also the sensitivity of the reaction rate to electronic effects.
The reaction rate in acetonitrile was found to be rather slow.
In order to isolate or at least detect any intermediates during
the oxygenation reaction of complex 1 we conducted oxygena-
tions at room temperature for a few days. In that case the
presence of peroxidic products could be demonstrated either
by titration by iodide or oxidising triphenylphosphine to tri-
phenylphosphine oxide by the oxygenated product. In the IR
spectrum bands at 1820 and at 860 cmϪ1 were found which were
4 D. W. Westlake, G. Talbot, E. R. Blakely and F. J. Simpson, Can J.
Microbiol., 1959, 5, 62; S. Hattori and I. Noguchi, Nature (London),
1959, 184, 1145; H. Sakamoto, Seikagu (J. Jpn. Biochem. Soc.),
1963, 35, 633; T. Oka, F. J. Simpson and H. G. Krishnamurty, Can.
J. Microbiol., 1977, 16, 493.
5 E. Makasheva and N. T. Golovkina, Zh. Obsch. Khim., 1973, 43,
1640; M. Thomson and C. R. Williams, Anal. Chim. Acta, 1976,
85, 375; K. Takamura and M. Ito, Chem. Pharm. Bull., 1977, 25,
3218.
6 A. Nishinaga, T. Tojo, H. Tomita and T. Matsuura, J. Chem. Soc.,
Perkin Trans. 1, 1979, 2511.
7 V. Rajananda and S. B. Brown, Tetrahedron Lett., 1981, 22, 4331.
8 T. Matsuura, H. Matsushima and R. Nakashima, Tetrahedron,
1970, 26, 435.
9 M. M. A. El-Sukkary and G. Speier, J. Chem. Soc., Chem.
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10 (a) A. Nishinaga, T. Tojo and T. Matsuura, J. Chem. Soc., Chem.
Commun., 1974, 896; (b) A. Nishinaga, T. Kuwashige, T. Tsutsui,
T. Mashino and K. Maruyama, J. Chem. Soc., Dalton Trans., 1994,
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11 M. Utaka, M. Hojo, Y. Fujii and A. Takeda, Chem. Lett., 1984, 635;
M. Utaka and A. Takeda, J. Chem. Soc., Chem. Commun., 1985,
1824; É. Balogh-Hergovich and G. Speier, J. Mol. Catal., 1992,
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12 G. Speier, V. Fülöp and L. Párkányi, J. Chem. Soc., Chem.
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assigned to the ν(CO) absorption of the 3C᎐O in 6 and the
᎐
ν(OO) of the endoperoxide. Unfortunately the endoperoxide
was not stable enough to make the determinations quantitative
and to make a firm characterisation of it. However the data
presented here unequivocally show its presence during the
oxygenation. It seems likely that endoperoxides of the type 6
can extrude CO easily and the stable carbonyl compounds
formed are good driving forces for their decomposition.
13 É. Balogh-Hergovich, G. Speier and G. Argay, J. Chem. Soc., Chem.
Commun., 1991, 551.
14 I. Lippai, G. Speier, G. Huttner and L. Zsolnai, Chem. Commun.,
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I. Lippai, G. Speier, G. Huttner and L. Zsolnai, Acta Crystallogr.,
Sect. C, 1997, 53, 1547; É. Balogh-Hergovich, J. Kaizer and
G. Speier, Inorg. Chim. Acta, 1997, 256, 9.
As a conclusion it can be said that in the enzyme-like oxygen-
ation of the co-ordinated flavonolato ligand of copper() the
formation of an endoperoxide in the bimolecular reaction
can be assumed and the unique decomposition of this endo-
peroxide accompanied by loss of carbon monoxide results in
the copper() O-benzoylsalicylate complex as a good mimic of
the enzyme action. Work is still in progress on model studies to
disclose more details of this cleavage reaction.
15 D. F. Shriver and M. A. Drezdzon, The Manipulation of Air-sensitive
Compounds, Wiley, New York, 1986.
16 R. W. Adams, E. Bishop, R. L. Martin and G. Winter, Aust.
J. Chem., 1966, 19, 207.
17 M. A. Smith, R. M. Newman and R. A. Webb, J. Heterocycl. Chem.,
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18 A. Einhorn, L. Rothlauf and R. Seuffert, Chem. Ber., 1911, 44,
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19 D. D. Perrin, W. L. Armarego and D. R. Perrin, Purification of
Laboratory Chemicals, Pergamon, New York, 2nd edn., 1990.
20 R. L. Carlin, Magnetochemistry, Springer, Berlin, 1986, p. 311.
21 A. B. P. Lever, E. R. Milaeva and G. Speier, in Phthalocyanines
Properties and Applications, eds. C. C. Leznoff and A. B. P. Lever,
VCH, New York, 1993, vol. 3, p. 8.
22 G. M. Sheldrick, SHELXS 86, Program for Crystal Structure
Determinations, University of Göttingen, 1990.
23 G. M. Sheldrick, SHELXL 93, Program for Crystal Structure
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Acknowledgements
Financial support of the Hungarian National Research Fund
(OTKA T-7443, T-016285 and T-30400) is gratefully
acknowledged.
24 G. M. Sheldrick, SHELXS 97, Program for Crystal Structure
Determinations, University of Göttingen, 1997.
25 G. M. Sheldrick, SHELXL 97, Program for Crystal Structure
Determinations, University of Göttingen, 1997.
26 A. Kruis, in Landolt-Börnstein, Springer, Berlin, 1976, bd. 4, teil 4,
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27 G. Ram and A. R. Sharaf, J. Indian Chem. Soc., 1968, 45, 13.
28 G. Speier, in Bioinorganic Chemistry of Copper, eds. K. D. Karlin
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29 R. C. Mehrotra and R. Bohra, Metal Carboxylates, Academic Press,
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30 T. Grezier and E. Weiss, Chem. Ber., 1976, 109, 3142.
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33 G. Speier, K. Selmeczi, Z. Pintér, G. Huttner and L. Zsolnai,
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