Oxidative degradation of amino acids and aminophosphonic acids by 2,2′-bipyridine complexes of copper(II)

Article abstract of DOI:10.1002/ejic.201400133

Copper(II)-amino acid (AA) complexes that contain 2,2′-bipyridine (bpy) as supporting ligand were investigated. X-ray structural analysis of three new bpy-based complexes revealed a bidentate coordination of the AAs on the copper(II) centers similar to that proposed for the substrate on the iron(II) center of the 1-aminocyclopropane-1-carboxylic acid oxidase (ACCO). Similar complexes with two aminophosphonic acids (APAs), 1-aminocyclopropane-1- phosphonic acid (ACP) and (1-amino-1-methyl)ethylphosphonic acid (AMEP), were also investigated, and the latter complex was structurally characterized. This structure reveals the bidentate coordination of α-aminophosphonate on the copper(II) ion. The oxidation of the bound amino acids (AAs) and aminophosphonates (APAs), which model the reaction catalyzed by ACCO, was investigated. The complexes react with H₂O₂ and give oxidation products that were identified by gas chromatography. Reduction of Cu^II to Cu^I was detected by UV/Vis spectroscopy upon reaction with H₂O₂ or ascorbate. This reduction is proposed to be the initial step for the peroxide/copper activation prior to the oxidation of the AA and APA ligands by means of a radical mechanism. The oxidation of bound amino acids or aminophosphonic acids by copper(II) complexes, which models the reaction catalyzed by the 1-aminocyclopropane carboxylic acid oxidase, was investigated in the presence of hydrogen peroxide. A reaction mechanism that involves a Cu^I intermediate is discussed. Copyright

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DOI:10.1002/ejic.201400133
Oxidative Degradation of Amino Acids and
Aminophosphonic Acids by 2,2Ј-Bipyridine Complexes of
Copper(II)
József S. Pap,[a] Nadia El Bakkali-Tahéri,[b] Antoine Fadel,[c]
Szabina Góger,[a] Dóra Bogáth,[a] Milán Molnár,[a] Michel Giorgi,[d]
Gábor Speier,[a] A. Jalila Simaan,*[b] and József Kaizer*[a]
Keywords: Bioinorganic chemistry / Amino acids / Copper / Oxidation
Copper(II)–amino acid (AA) complexes that contain 2,2Ј-bi-
pyridine (bpy) as supporting ligand were investigated. X-ray
structural analysis of three new bpy-based complexes re-
vealed a bidentate coordination of the AAs on the copper(II)
centers similar to that proposed for the substrate on the
iron(II) center of the 1-aminocyclopropane-1-carboxylic acid
oxidase (ACCO). Similar complexes with two aminophos-
phonic acids (APAs), 1-aminocyclopropane-1-phosphonic
acid (ACP) and (1-amino-1-methyl)ethylphosphonic acid
(AMEP), were also investigated, and the latter complex was
structurally characterized. This structure reveals the biden-
tate coordination of α-aminophosphonate on the copper(II)
ion. The oxidation of the bound amino acids (AAs) and ami-
nophosphonates (APAs), which model the reaction catalyzed
by ACCO, was investigated. The complexes react with H2O2
and give oxidation products that were identified by gas
chromatography. Reduction of CuII to CuI was detected by
UV/Vis spectroscopy upon reaction with H2O2 or ascorbate.
This reduction is proposed to be the initial step for the perox-
ide/copper activation prior to the oxidation of the AA and
APA ligands by means of a radical mechanism.
fense mechanisms.[4,5] In 1979, Adams and Yang reported
that ethylene is directly biosynthesized from 1-aminocyclo-
propane-1-carboxylic acid (ACC), a metabolite of methio-
nine.[6] The last step of ethylene biosynthesis is catalyzed by
1-aminocyclopropane-1-carboxylic acid oxidase (ACCO), a
nonheme iron(II)-containing enzyme. It implies a two-elec-
tron oxidation of ACC in the presence of dioxygen and as-
corbate to produce ethylene, cyanhydric acid, and carbon
dioxide. (Scheme 1).[7,8]
Introduction
Biological transformations of amino acids (AAs) are at
the junction of numerous metabolic processes.[1] One of the
main functions of amino acids is to act as monomer units in
proteins. Twenty-two amino acids (including selenocysteine
and pyrrolysine)[2,3] have been shown to participate in trans-
lation, although scientists have discovered more than five
hundred amino acids in nature. Besides their role in protein
synthesis, amino acids can be substrates or intermediates
for biosynthetic reactions, and a number of hormones and
neurotransmitters are derived from their transformations.
This is the case for ethylene, the gaseous plant hormone
essential for many aspects of plant life including root devel-
opment, germination, senescence, fruit ripening, and de-
Scheme 1. Reaction catalyzed by ACCO.
The crystallographic structure of ACCO from Petunia
hybrida reveals that the active site contains a single FeII ion
linked to the side chains of two histidines and one aspartate
(H177, H234, and D179) in a 2-His, 1-Asp facial triad.[9]
ACCO is a member of a superfamily of iron(II)-containing
oxidases and oxygenases that catalyze a wide range of oxi-
dation reactions, most of them utilizing α-ketoglutarate as
a cosubstrate (which is transformed into succinate and car-
bon dioxide).[10] Although ACCO uses ascorbate and not
α-ketoglutarate as cofactor, it presents strong sequence and
structural analogies with some members of this α-ketogluta-
rate-dependent family.
[a] Department of Chemistry, University of Pannonia,
8201 Veszprém, Wartha Vince u. 1., Hungary
E-mail: kaizer@almos.vein.hu
[b] Aix Marseille Université, CNRS, Centrale Marseille, iSm2
UMR 7313,
13397 Marseille, France
E-mail: jalila.simaan@univ-amu.fr
http://ism2.univ-amu.fr/equipes/Biosciences_1.htm
[c] Université Paris-Sud, Laboratoire de Méthodologie, Synthèse
et Molécules Thérapeutiques, ICMMO – UMR 8182,
91405 Orsay Cedex, France
[d] Aix-Marseille Université, FR1739, Spectropole, Campus St.
Jérôme, Avenue Escadrille Normandie-Niemen,
13397 Marseille Cedex 20, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejic.201400133.
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Scheme 2. Possible pathways leading to the different products after oxidation of amino acids by ACCO.
The ability of ACCO to oxidize various cyclic analogues the amino acid on an iron(II) ion has yet been reported.
of ACC into ethylene and various acyclic amino acid sub- Very recently, we have demonstrated that the complex
strates into the corresponding carbonyl compound, CO2 [FeIII(salen)Cl] [salen = N,NЈ-bis(salicylidene)ethylenedi-
and ammonia, has been reported in the literature; this abil- aminato] highly selectively and efficiently catalyzes the oxi-
ity has been extensively used as a tool to decipher the oxi- dation of ACC and various amino acid substrates in the
dation mechanism.[11–14] It is now known that the conver- presence of several oxidants (such as H2O2), thus serving as
sion of amino acid substrates by ACCO proceeds by means one of the first functional models of ACCO.[22,23] However,
of a radical mechanism and the formation of an aminyl no data on the interaction between the metal ion and the
radical was proposed.[15] From this radical intermediate, substrate could be obtained. In addition, the oxidation of
there are different possible pathways to form products. ACBC led to a mixture of products, thus indicating that
These are OH rebound (path A), radical-based decarboxyl- several competing mechanisms occur.
ation (path B), and ring-opening (path C), which are pre-
A few years ago, we have reported on a series of structur-
sented in Scheme 2. In the case of the oxidations catalyzed ally characterized copper–ACC complexes in which ACC is
by ACCO, it has been clearly demonstrated that N-hydrox- coordinated on the copper ion in a bidentate manner.[24,25]
ylation of the substrates (path A) does not occur.[16,11,13] These complexes are able to oxidize the bound ACC into
The oxidation of ACC (Scheme 2, n = 0) into ethylene pro- ethylene in the presence of hydrogen peroxide and thus
ceeds through path C.[15,17] When using an ACC analogue, serve as Cu-based bioinspired models for ACCO creating
1-aminocyclobutane-1-carboxylic acid (ACBC, n = 1), as a counterparts to the Cu-based model of α-ketoglutarate-de-
substrate, oxidation by ACCO only leads to dehydroproline pendent enzymes reported by Tolman’s group.[26] During
(Δl-pyrroline-2-carboxylic acid) following path C.[11] How- the oxidation reaction, a “CuI–ACC” intermediate could be
ever, when n Ͼ 1, or when using open-chain amino acids, detected that was formed upon reduction of the CuII ion by
path B becomes predominant, and only the carbonyl prod- H2O2 in the presence of base. Very recently, we also de-
ucts that arise from the hydrolysis of the corresponding scribed the copper-mediated catalytic oxidation of various
imines are detected.
amino acids.[27] To gain more insight into the mechanism
Yet little is known about the role of the metal ion of these copper-based oxidations, we investigated the ability
and the catalytic intermediates in these mechanistic path- of a system based on the ligand 2,2Ј-bipyridine (bpy) to
ways. The use of EPR/electron nuclear double resonance oxidize various amino acids (AAs) as well as two α-amino-
(ENDOR) spectroscopy has allowed to propose that one of phosphonic acids (APAs), used as surrogates of the corre-
the first steps of the reaction consists of the coordination sponding α-aminocarboxylic acids, that have been shown to
of the substrate ACC on the FeII ion in a bidentate manner interact at the metal center and to inhibit the activity of
through the nitrogen of the amine and one oxygen of the ACCO.[28] Several “(bpy)Cu(AA/APA)” complexes were
carboxylate groups, respectively.[18] There are only a few thus prepared using ACC, AIB (α-aminoisobutyric acid),
spectroscopic data on the interaction mode of the other co- ACBC (1-aminocyclobutane-1-carboxylic acid), ACPC (1-
factors/cosubstrates at the active site, and several catalytic aminocyclopentane-1-carboxylic acid), ACHC (1-aminocy-
mechanisms have been proposed.[19,20]
clohexane-1-carboxylic acid), MAIB [α-(methylamino) iso-
The use of model complexes is a powerful strategy to butyric acid], 1-aminocyclopropane-1-phosphonic acid
gain better insight into the catalytic mechanism of the me- (ACP), and (1-amino-1-methyl)ethylphosphonic acid
talloenzyme. To the best of our knowledge, there are very (AMEP) (see Table 1 for the list of the complexes studied).
few structural data available on iron–ACC complexes,[21] The ability of the Cu–AA or Cu–APA complexes to oxidize
and no complex that displays the bidentate coordination of the bound substrates was investigated in the presence of hy-
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Table 1. Summary of the studied [Cu(bpy)(AA/APA)(ϮH2O)](ClO4)·xH2O complexes.
[a] See the literature.[24,25] [b] Compound 1-p has not been isolated but prepared in situ prior to experiments. [c] [Cu2(AMEP)(bpy)2-
(H2O)3](ClO4)2·3H2O.
drogen peroxide. The implication of a CuI intermediate and crystallographic data are reported in Table 2. The structure
product distribution are discussed in line with a possible of the molecular cations of complexes 2, 3, and 4 are dis-
mechanism.
played in Figure 1, and selected bond lengths and angles
are reported in Table 3. In each complex, the CuII ions are
in distorted-square-pyramidal geometries as indicated by
the values of the structural indices (τ = 0.02–0.12) that mea-
sure the degree of trigonality for five-coordinate structures
(τ = 0 for a perfect square-based pyramid geometry and
Results
Structural Characterization of the AA Complexes
Complexes based on the bpy ligand were prepared with τ = 1 for perfectly trigonal-bipyramidal geometry).[29] The
the different amino acids displayed on Table 1. The com- equatorial positions are occupied by the bpy ligand and by
plexes were synthesized in methanol as previously re- the O and N atoms of the amino acid moiety. This κ2N,O-
ported.[25] Crystalline products were obtained by slow evap- coordination mode is typical for amino acid complexes[30]
oration of methanol from the reaction mixture. Selected and was also suggested for the enzyme–substrate complex
Table 2. Crystal structure details for 2, 3, 4, and 5-p.
2
3
4
5-p
Chemical formula
Formula mass
Crystal system
a [Å]
b [Å]
c [Å]
C15H18Cu1Cl1N3O7
451.31
monoclinic
12.3898(2)
8.0417(1)
19.3665(4)
90
108.163(1)
90
1833.44(5)
293(2)
C16H20Cu1Cl1N3O7
465.34
monoclinic
9.9783(2)
8.1230(2)
23.9669(5)
90
105.705(1)
90
1870.09(7)
293(2)
C17H22Cu1Cl1N3O7
479.37
orthorhombic
23.8007(8)
10.3423(3)
8.2427(3)
90
C23H36Cl2Cu2N5O17P
883.52
triclinic
7.8553(3)
12.1483(4)
19.4059(8)
81.629(1)
87.324(2)
75.527(4)
1773.90(12)
243(2)
α [°]
β [°]
γ [°]
90
90
Unit-cell volume [Å3]
T [K]
2028.97(12)
293(2)
Pna21
¯
P1
2
Space group
Z
P21/c
4
P21/c
4
4
Radiation type
Mo-Kα
1.381
17326
4747
0.044
Mo-Kα
1.356
20554
4235
0.03
Mo-Kα
1.253
13425
2702
0.064
0.0569
0.1437
0.0803
1.043
Mo-Kα
1.473
19622
8256
0.1006
0.1073
0.2639
0.1653
1.128
μ [mm–1]
Reflections measured
Independent reflections
Rint
Final R1 values [IϾ2σ(I)]
Final wR values [IϾ2σ(I)]
Final R1 values (all data)
Goodness of fit
0.049
0.047
0.1248
0.0735
1.05
0.1366
0.0568
1.043
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Figure 1. Thermal ellipsoid plots of the bpy-containing complexes 2, 3, and 4 showing the atomic displacement parameters at the 30%
probability level. Counteranions are omitted for clarity. Symmetry elements: i: –x, –1/2 + y,3/2 –z; ii: 2 –x,1/2 + y,3/2 – z; iii: –x, –y,
–1/2 + z.
in ACCO.[18] The bpy ligands are coordinated to the copper tances of CuII–amino acid complexes found in the Cam-
ions at distances that range from 1.94 to 2.01 Å and the bridge Structural Database.[30]
CuII–amino acid distances, Cu1–N3 and Cu1–O1, range
In the axial position a second carboxylic O donor is
from 1.93 to 1.99 Å and 1.93 to 1.97 Å, respectively. These found that comes from a neighboring carboxylate entity, so
bond lengths are in good agreement with the average dis- each carboxylate function acts as bridging ligand. The oxy-
gen atoms on the axial position stand at distances between
2.32 and 2.45 Å. The bpy-based amino acid complexes 2, 3,
and 4 thus form coordination polymer chains in the solid
state (see Figures S1 to S3 in the Supporting Information).
Table 3. Selected bond lengths [Å] and angles [°] for the bpy-con-
taining complexes 2, 3, and 4.
2
3
4
These polymeric structures were also found in similar com-
plexes: [Cu(ACC)(phen)](ClO4) and [Cu(ACC)(2-picolyl-
amine)](ClO4) in which phen = 1,10-phenanthroline.[25] Fi-
nally, these new bpy-based complexes are very similar to
our previously described complexes [Cu(ACC)(bpy)-
(OH2)](ClO4) (1) and [Cu(AIB)(bpy)(OH2)](ClO4) (5) that
display a water molecule coordinated in the axial posi-
tion.[25]
Bond lengths [Å]
Cu1–N1
Cu1–N2
Cu1–N3
Cu1–O1
Cu1–O2
2.010(3)
1.991(3)
1.962(3)
1.943(2)
2.325(2)
2.008(2)
1.945(2)
1.932(3)
1.934(2)
2.454(3)
1.980(6)
1.984(5)
1.977(6)
1.971(5)
2.347(5)
Angles [°]
N1–Cu1–N2
N1–Cu1–O1
N2–Cu1–N3
C13–C12–C15
N1–Cu1–O2
N3–Cu1–O1
N3–Cu1–O2
81.50(12)
174.99(11)
167.53(13)
87.3(3)
89.39(10)
84.22(10)
102.79(12)
81.73(10)
174.03(9)
168.27(12)
105.2(3)
93.85(10)
85.01(9)
81.7(2)
172.9(2)
171.6(3)
108.8(5)
91.6(2)
82.3(2)
94.0(2)
Structural Characterization of Complex 5-p
The synthesis of [(bpy)2Cu2(AMEP)(OH2)3](ClO4)2·
3H2O (5-p) was performed in a MeOH/H2O mixture and
blue crystals suitable for X-ray diffraction analysis were ob-
tained by slow evaporation. Selected crystallographic data
are reported in Table 2. The structure reveals the presence
98.20(10)
Structural index
τ
0.12
0.10
0.02
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Figure 2. Thermal ellipsoid plot of the complex 5-p showing the atomic displacement parameters at 30% probability level. Hydrogen
atoms, counteranions, and noncoordinated water molecules are omitted for clarity.
Table 4. Selected structural parameters for complex 5-p.
Bond lengths [Å]
Angles [°] and structural index
Cu1–N1
Cu1–N2
Cu1–N3
Cu2–N4
Cu2–N5
2.019(7)
2.007(8)
2.026(7)
2.029(8)
2.000(7)
Cu1–O1
Cu1–O4
Cu2–O3
Cu2–O5
Cu2–O6
1.949(6)
2.380(7)
1.938(6)
1.962(6)
2.200(7)
N2–Cu1–N3
N2–Cu1–O1
N1–Cu1–N3
N1–Cu1–O4
N1–Cu1–O1
168.9(3)
93.0(3)
97.4(3)
88.9(3)
171.5(3)
N2–Cu1–O4
N2–Cu1–N1
C3–C2–C4
τ
93.4(3)
81.4(3)
111.3(5)
0.11
of two copper ions bridged by the phosphonate group. The EPR spectra (see Figure S4 in the Supporting Information)
ORTEP drawing of the cation of 5-p is presented in Fig- are of axial type, which is consistent with CuII ions in
ure 2. Selected bond lengths and angles are presented in square-pyramidal geometries and thus in agreement with
Table 4.
the solid-state structures of the complexes. These spectra
The structural index for Cu1 (τ = 0.04) indicates that the are very similar to those described for complexes 1 and 5.[25]
copper ion displays almost perfect square-based pyramidal Simulations were performed and good fits were obtained
geometry with the bipyridine and the aminophosphonate by assuming two distinct superhyperfine nitrogen tensors.
moieties that form the basal plane around the metal ion. A Among them two nitrogen tensors were equivalent and the
water molecule occupies the axial position. The aminophos- third was different, which supports the presence of three N
phonate group is coordinated in a bidentate mode with the atoms in the equatorial plane. The EPR parameters are
nitrogen of the amine group and one oxygen of the phos- listed in Table S1 of the Supporting Information.
phonate group. This structure confirms the ability of α-
aminophosphonates to coordinate a metal ion in a biden-
Oxidation of Bound Amino Acids in the Presence of
Hydrogen Peroxide
tate fashion through the nitrogen and one oxygen, as the
amino acid analogues do. The copper–AMEP distances
Cu1–N3 and Cu1–O1 are 2.026 and 1.949 Å, respectively,
and fall in the range of those obtained with amino acids.
These bond lengths are also in good agreement with the
average distances of equatorial Cu–O distances that range
from 1.896 to 1.989 Å in aminophosphonate complexes
found in the Cambridge Structural Database.[30] The second
oxygen of the phosphonate group is ligated on the equato-
rial plane of a second copper ion (Cu2). The Cu2 ion is in
a distorted-square-pyramidal geometry (τ = 0.28) with the
basal plane completed by the bipyridine moiety and a water
molecule. A second water molecule is bound on the axial
position.
We first investigated the ability of the isolated “(bipy)-
CuII(AA)” complexes to oxidize the bound substrate in the
presence of hydrogen peroxide. Complexes 1 to 5-m were
placed in a 3:1 DMF/water mixture, and the reactions were
initiated by adding 5 equiv. of ammonium hydroxide as base
and 30 equiv. of H2O2 as oxidant. Products were monitored
by gas chromatography after 1 h following our previously
reported procedure.[22,23] Oxidation yields ranged from 5 to
92% (Table 5). When using complex 1, the production of
ethylene was detected (path C, Scheme 2). Complexes 3, 4,
5, and 5-m provided the corresponding ketones (path B).
Interestingly, complex 2, which was obtained with ACBC,
only provided dehydroproline together with n-butyronitrile
in an approximately 2:1 ratio (67% dehydroproline and
33% of n-butyronitrile), whereas cyclobutanone could only
EPR Characterization of the Complexes
The X-band EPR spectra of complexes 2–4 were re- be detected in trace amounts. Pirrung et al. reported that
corded at 120 K in frozen MeOH solutions. The recorded dehydroproline is the only product detected upon oxidation
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Table 5. Kinetic data and oxidation yields for the oxidation of the AA or APA by the bpy-based complexes. Reactions were performed
in DMF/water (3:1) at 35 °C; [complex]0 = 12 mm, [H2O2]0 = 36 mm, [NH4OH]0 = 60 mm.
kЈH
kЈD
SIE
Yield
BDEN–H
[b]
Complex
Products
10–4 s–1[a]
10–4 s–1[a]
kЈH/kЈD
%
kcalmol–1
1
ethylene
ethylene
dehydroproline 67%
butyronitrile 33%
cyclopentanone
cyclohexanone
acetone
acetone
acetone
acetone
2.6
7.0
5.5
1.4
–
2.3
1.9
–
2.4
5
70
20
96.1
98.9
98.6
1-p[c]
2
3
7.6
9.6
15.9
17.4
7.5
4.3
3.9
10.1
–
–
–
1.8
2.5
1.6
–
–
–
22
38
80
77
47
92
102.0
–
4
5
100.0[d]
5[e]
5-m
5-p
–
–
41.1
[a] The value of kЈH(D) was calculated from the ln[product] versus t plots. [b] Rounded to integer relative to the initial concentration of
AA/AP bound in the complex. [c] In methanol at 20 °C using [complex]0 = 1 mm, [H2O2]0 = 10 mm, [NaOH]0 = 4 mm. [d] From the
literature.[14] [e] Under argon.
of ACBC by the enzyme ACCO.[11] A two-electron oxi- electron-proton transfer (ET-PT) [proton-coupled electron
dation to produce N-hydroxylated ACBC was shown to transfer (PCET)] mechanism.[31]
lead to decarboxylation products (i.e., to the ketone). In our
case, the presence of dehydroproline supports, as in the case
of the enzyme, a metal-centered, two sequential single-elec- Oxidation of the Bound Aminophosphonates in the Presence
tron-transfer oxidation mechanism (path C). Butyronitrile of Hydrogen Peroxide
was produced by decarboxylation of the ring-opening prod-
Under the same experimental conditions, oxidation of
uct of ACBC after the first oxidation and is therefore also AMEP into acetone when using complex 5-p appeared to
derived from path C.[23] In our previously reported iron– be highly efficient (quasi-quantitative yield, high reaction
salen or copper-based catalytic oxidation of amino acids, rate; see Table 5). The ability of complex 1-p to perform the
HACBC was oxidized following multiple pathways to give oxidation of ACP into ethylene by gas chromatography was
cyclobutanone together with dehydroproline and n-but- also investigated. The reaction was performed in methanol
yronitrile.[23,27] Therefore, although using copper instead of owing to the very low solubility of the free HACP substrate
iron, these bpy-based complexes represent good functional in DMF/H2O mixture. The reaction was performed by add-
models of ACCO in which the single turnover oxidations of ing hydrogen peroxide to a solution with equimolar quanti-
the substrates probably follow a sequential radical mecha- ties of bpy, CuII, and HACP in methanol set at 1 mm con-
nism similar to that described for the enzymatic system.
centrations. Different conditions were tested (concentration
When using complex 5, the reaction was performed of H2O2, reaction time) to define the optimal conditions
either under argon or under air. No significant difference (see Figure S5 in the Supporting Information). Ethylene
between the conversion yields and the formation rates were production was then measured in the presence of 10 equiv.
observed, thus indicating that O2 has a negligible role in the of H2O2 and after 1 h of reaction time. In the absence of
oxidation process, as previously reported.[25] Finally, meth- added base, no ethylene could be detected (Figure S6 in the
ylation of the amine group does not prevent the oxidation Supporting Information). An increase in pH was followed
of the MAIB. The ability of ACCO to oxidize N-methylated by an increase in ethylene production, and the yield of
ACC has been reported,[14] and the Michaelis constant (Km) evolved ethylene reached approximately 70% in the pres-
values for N-MeACC were not found to be significantly al- ence of 3–4 equiv. of NaOH. This conversion yield is similar
tered relative to that of ACC, thus indicating that N-Me- to that obtained from ACC using similar conditions (in
ACC can likely form a bidentate ligand on the FeII center. methanol, same concentrations).[24,25] As a control experi-
In our case, it is also highly likely that the N-methylation ment, ethylene production was also investigated in the ab-
of AIB does not prevent the bidentate coordination of the sence of bpy and by applying the same conditions (1 mm of
substrate on the CuII ion, thus leading to rather efficient ACP, 1 mm of CuII in MeOH, 10 mm of hydrogen peroxide)
oxidation of MAIB into acetone in the presence of hydro- as a function of added NaOH (Figure S6 in the Supporting
gen peroxide, although with a slower reaction rate (Table 5). Information). Ethylene production was found to be three
The reactions were followed versus time, and the product times lower under the best conditions (i.e., 4 equiv. of
formation rates using DMF/H2O or DMF/D2O mixtures NaOH) than that observed in the presence of bpy. The
[kЈH(D) values] were determined from the slope of the rather high conversion of ACP into ethylene in the presence
ln[product] versus time plots. These rate constants (Table 5) of bpy indicates that the observed activity is due to the pres-
appear to be affected by isotopic substitution with solvent ence of the exogenous ligand. These results highlight that
isotopic effects (SIE) ranging from 1.6 to 2.5. Such SIEs are exchanging the carboxylate group of ACC to phosphonate
similar to those found for the enzymatic system and for (in ACP) does not affect ethylene production. It is likely
Fe-based ACCO model reactions[20,23] and are typical for that ACP oxidation proceeds by means of a similar mecha-
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nism (path C), thus leading to ethylene and cyanophos- ture led to a drastic color change, and a brown-yellow inter-
phonate. mediate could be detected that was stable from a few sec-
One surprising finding is that the phosphonate ana- onds to a few minutes at low temperature. This intermediate
logues, 1-p and 5-p, react with H2O2 since these phos- is characterized by an absorption centered at approximately
phonate analogues have been reported as inhibitors of 440 nm. Chromophores with identical spectral features were
ACCO activity and since no enzymatic oxidation of ACP detected when ascorbate was added to the complex solu-
and AMEP could be detected.[28] The structure of complex tions at –10 °C in methanol (Figure 3). A few years ago, we
5-p confirms the ability of phosphonate derivatives to act observed the formation of CuI–ACC brown intermediate,
as bidentate ligands on metal ions. In combined experimen- characterized by an absorbance around 440 nm, formed
tal and theoretical studies we have proposed that ACP and upon reduction of several “CuII–ACC” complexes by hy-
AMEP binding interlocks both with ACC and hydrogen drogen peroxide.[25] Base-dependent reactivity has been ob-
carbonate binding sites in the active pocket of the en- served and attributed to the need of deprotonating H2O2 to
zyme.[28] These unsuitable positions would lead to inhibi- obtain a more reducing form. The geometry of these CuI
tion and prevent their oxidation by the enzyme, thereby species was optimized by DFT calculations, and reduction
strengthening the importance of hydrogen carbonate cofac- was followed by a change from square-pyramidal to tetra-
tor in the catalytic mechanism of ACCO. Our results, which hedral geometries. The detected intermediates using com-
demonstrate the degradability of ACP and AMEP, strongly plexes 2–5-p can be therefore assigned to “(bpy)CuI(AA/
support these conclusions.
APA)” species. Remarkably, the maximum absorption λmax
is only marginally influenced by the nature of the bound
substrate, which is in accordance with the metal-to-ligand
charge-transfer (MLCT) assignment from a 3d orbital of
the CuI to a low-lying π* orbital of bpy moiety.
Redox Properties
The redox properties of complexes 1–5 were studied by
cyclic voltammetry (CV) in methanol at room temperature.
The CV curves are shown in the Supporting Information
(Figure S7), and the redox properties are listed in Table 6.
Scanning to the negative potential range produces peaks
that range from –350 to –380 mV versus AgCl/Ag. These
cathodic peaks can be attributed to the CuII to CuI re-
duction. The reduction peaks are very similar for all com-
plexes, which is as expected given the high similarity be-
tween the CuII complexes and the small differences between
the bound substrates. In the reverse direction, one anodic
peak is present (at potentials that range from +20 to
+100 mV versus AgCl/Ag) in each case. The differences be-
tween reduction and oxidation peaks are much higher than
the expected 60 mV for fully reversible one-electron pro-
cesses. However, repeated cycles can be performed without
altering the cathodic and anodic waves, therefore the com-
plexes are not decomposed irreversibly during the electro-
chemical steps. This rather classical behavior of CuII com-
plexes might be associated with geometrical changes from
square-pyramidal CuII to tetrahedral CuI to achieve stabili-
zation, as supported by DFT calculations that have pre-
viously been carried out.[25]
Figure 3. UV/Vis spectra of the bpy-containing complexes 1–5-p
(1 mm) instantly after the addition of 1 equiv. of ascorbate in meth-
anol, at –10 °C (spectra are colored according to the bound sub-
strate).
Reactivity of the Isolated CuI Intermediate
Table 6. Electrochemical data for the bpy-containing complexes in
The copper(I) intermediates were prepared in methanol
at –10 °C in the presence of 10 equiv. of hydrogen peroxide.
The decay of the intermediates was then monitored by spec-
trophotometry following the 440 nm absorption bands. At
the end of the reaction, we could identify oxidation prod-
ucts after the complete decay of the reduced form. These
products were identical to those obtained in DMF/H2O
mixture. The different CuI intermediates were also prepared
in methanol at –10 °C by the addition of 1 equiv. of ascorb-
ate. Interestingly, no products from AA or APA oxidation
could be detected after the addition of ascorbate to com-
plexes 1–5 (m,p) in the presence of dioxygen, although the
methanol (the E°Ј1/2 of Fc+/Fc was 0.34 V) at 100 mVs–1 scan rate.
Epc [mV]
Epa [mV]
1
2
3
4
5
–377
–380
–365
–355
–366
+95
+105
+90
+20
+55
Brown CuI Intermediate in the Presence of Hydrogen
Peroxide
The AA or APA complexes 2–5-p were placed in meth- same CuI intermediates are detected. The reoxidation by O2
anol at –10 °C. Addition of H2O2 to the blue reaction mix- thus appears to be a nonproductive route.
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Possible Mechanism
03 calculations were used to estimate the N–H bond-disso-
ciation energies (BDEs) that correspond to the abstraction
of one hydrogen to the amine function for several AP of
AA substrates (Table 5). BDE values are very similar for all
substrates and fall in the range of those obtained experi-
mentally or theoretically for aliphatic amines[32] and several
cyclic and acyclic substrates of ACCO, including ACC.[14]
Interestingly, these values do not corrolate with the reactiv-
ity order. Finally, SIE is found in the range of 1.5–2, which
indicates that a PCET occurs in a rate-limiting step of the
mechanism. Similar SIEs are found in the enzymatic system
and the nature of the PCET step is not yet clearly iden-
tified.[20] In the present case, a rate-limiting step could
correspond to (i) the first oxidation step that leads to the
formation of the aminyl radical, or (ii) the formation of an
oxidizing intermediate from the CuI–OOH intermediate
that involves a PCET step.
Analysis using ESI-MS on complexes 1 and 5 as well as
on similar complexes based on slightly different ligands has
been reported.[25] The presence of the [(L)Cu(AA)]+ cations
has been evidenced (L = bpy, 1,10-phenanthroline, or 2-
picolylamine), which supports the fact that the amino acids
remain coordinated in solution and that the coordination
polymers (as found in the solid-state structure of complexes
2–4) totally or partially dissociate in solution to provide the
corresponding monomers. In the present study, both EPR
and electrochemistry data support the same behavior, and
it is likely that the polymeric structures are dissociated and
that the AAs remain coordinated in solution. The first step
of the reaction mechanism appears to be the reduction of
the CuII complexes into the corresponding CuI complexes.
Product distribution upon oxidation of bound ACBC in
complex 2 suggests that the oxidation of the substrates is
metal-controlled in contrast to the results obtained with our
iron- or copper-based catalytic systems that indicate several
competing mechanisms.[23,27] This strongly supports the fact
that the substrate remains coordinated on the copper center
in agreement with the proposed nature, [(bpy)CuI(AA/AP)],
of the brown intermediate. We can also propose the implica-
tion a CuI-hydroperoxo intermediate formed upon reaction
of the reduced CuI species with an excess amount of H2O2.
Such species could not be detected but can be suspected to
be responsible for the first oxidation step (see Scheme 3).
The question arises as to the contributing factors for the
different reaction rates and yields. The redox properties of
the different complexes are essentially identical. Gaussian
Conclusion
We have reported on the preparation of a series of bpy-
based copper(II)–AA and CuII–APA complexes, most of
which have been characterized by X-ray diffraction analysis.
These complexes share very similar structures with the sub-
strates bound in a bidentate fashion through the nitrogen
and one oxygen. This binding mode is reminiscent of that
proposed for the enzyme ACCO,[18] thus placing the cop-
per(II)–amino acid complexes among the few well-charac-
terized structural models for the enzyme–substrate adduct
in ACCO. The demonstration of the ability of phosphonate
derivatives to bind on the metal ion and to be efficiently
oxidized supports our models of interactions at the enzyme
active site derived from both experimental and theoretical
studies.[28] Finally, these complexes also appear to be good
functional models for the enzymatic system. Although the
nature of the oxidizing species involved in these copper-
based systems is probably different from those involved in
the iron(II)-dependent enzyme, these new complexes turned
out to follow pathways for the oxidation of the substrates
that share similarities with the enzymatic ones. We propose
a mechanism that involves a CuI–OOH species as oxidizing
intermediate. This mechanism may be of high interest for
understanding the mechanism of copper-containing oxy-
genases such peptidylglycine α-hydroxylating monooxygen-
ase (PHM).[33]
Experimental Section
Materials: Solvents used for the reactions were purified by litera-
ture methods and stored under argon. 2,2Ј-Bipyridine (bpy),
Cu(ClO4)2·6H2O, the amino acid substrates, and AMEP were pur-
chased from commercial sources. ACP was synthesized following a
previously described procedure.[34] Caution! Perchlorate salts are
potentially explosive. Only a small amount of material should be
prepared and handled with caution.
Synthesis: The general procedure for the synthesis of the complexes
is as follows: 2,2Ј-Bipyridine (0.156 g, 1 mmol) and the selected
Scheme 3. Mechanism suggestion for the stoichiometric oxidation
reaction for complexes 1 to 5.
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amino acid substrate (1 mmol) were added to a stirred solution of
Cyclic voltammograms were taken with a BioLogic SP-150 po-
Cu(ClO4)2·6H2O (0.372 g, 1 mmol) in methanol (20 mL). Dropwise tentiostat running with EC-Lab 5.40 software. The complexes were
addition of triethylamine (140 μL, ca. 1 mmol, freshly distilled and
stored under argon) resulted in dark blue solutions. After stirring
for 1 hour at room temperature, the solutions were filtered and left
to evaporate slowly. Crystalline products were formed, filtered, and
washed with a minimal amount of cold methanol. Complexes
placed at concentrations around 2 mm in methanol that contained
0.1 m of tetrabutylammonium perchlorate (TBAP) as supporting
electrolyte. The electrodes were as follows: Pt (working), Pt (auxil-
iary), and Ag/AgCl in 3 m KCl (reference). The potential of ferro-
cenium/ferrocene (Fc+/Fc) redox couple was found at +340 mV in
[CuII(bpy)(ACC)(H2O)]ClO4 (1) and [CuII(bpy)(AIB)(H2O)]ClO4 our setup.
(5) have already been described.[25]
The crystal evaluations and intensity data collections were per-
[CuII(bpy)(ACBC)]ClO4·H2O (2): Yield 75%. C15H18ClCuN3O7
(451.32): calcd. C 39.92, H 4.02, N 9.31; found C 40.1, H 4.0, N
formed with a Bruker-Nonius Kappa CCD single-crystal dif-
fractometer using Mo-Kα radiation (λ = 0.71070 Å). Crystallo-
graphic data and details of the structure determination are given
in Table 2, whereas selected bond lengths and angles are listed in
Tables 3 and 4. SHELX-97[36] was used for structure solution and
full-matrix least-squares refinement on F2.
9.4. FTIR (KBr pellet): ν = 3469, 3409, 3195, 3071, 2989, 2950,
˜
1630, 1600, 1474, 1442, 1372, 1315, 1252, 1142, 1113, 1088, 1029,
779, 731, 636, 626, 597 cm–1. UV/Vis (CH3OH): λmax (logε) = 302
(4.20), 313 (4.19), 376 (2.29), 598 (2.02) nm. Crystals suitable for
X-ray structural determination were obtained from CH3OH.
CCDC-784930 (for 5-p), -941367 (for 2), -941368 (for 4), and
-941369 (for 3) contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
[CuII(bpy)(ACPC)]ClO4·H2O (3): Yield 73%. C16H20ClCuN3O7
(465.35): calcd. C 41.30, H 4.33, N 9.03; found C 41.4, H 4.4, N
8.9. FTIR (KBr pellet): ν = 3486, 3207, 3122, 3073, 2938, 2864,
˜
1648, 1604, 1474, 1442, 1389, 1314, 1247, 1147, 1119, 1077, 1030,
766, 730, 636, 625, 500 cm–1. UV/Vis (CH3OH): λmax (logε) = 302
(4.18), 312 (4.17), 372 (2.12), 588 (1.86) nm. Crystals suitable for
X-ray structural determination were obtained from CH3OH.
Determination of N–H Bond-Dissociation Energies (BDEs): Quan-
tum calculations were carried out using the Gaussian 03 pack-
age.[37] The Gaussian 03 composite approach[38] is known to give
very accurate BDEs. To reduce the computational cost, the basis-
set correction was done at the second-order Moller–Plesset pertur-
bation (MP2) level of theory using geometries and frequencies
computed with density functional theory [B3LYP functional and
6-31G(d) basis set]. The calculations were performed considering
that the carboxylate and the phosphonate groups of ACC and ACP,
respectively, were fully protonated. The bond-dissociation energies
were determined at 298 K as the change in enthalpies following the
N–H dissociation reactions.
[CuII(bpy)(ACHC)]ClO4·H2O (4): Yield 83%. C17H22ClCuN3O7
(479.38): calcd. C 42.59, H 4.63, N 8.77; found C 42.7, H 4.7, N
8.8. FTIR (KBr pellet): ν = 3461, 3304, 3247, 3112, 3026, 2929,
˜
2868, 1642, 1602, 1478, 1447, 1381, 1146, 1117, 1089, 1033, 772,
732, 624, 570 cm–1. UV/Vis (CH3OH): λmax (logε) = 302 (4.16),
313 (4.15), 368 (2.13), 590 (1.71) nm. Crystals suitable for X-ray
structural determination were obtained from CH3OH.
[CuII(bpy)(MAIB)]ClO4·H2O (5-m): Yield 77%. C15H20ClCuN3O7
(453.34): calcd. C 39.74, H 4.45, N 9.27; found C 39.5, H 4.3, N
9.4. FTIR (KBr pellet): ν = 3446, 3308, 2974, 2925, 2872, 1660,
˜
Determination of Products and Kinetic Measurements: The reactiv-
ity of the isolated complexes (1, 2, 3, 4, 5, 5-m, and 5-p) was exam-
ined in a 3:1 DMF/H2O (or D2O) mixture at 35 °C. In a standard
20 mL screw-cap vial 8.76ϫ10–4 mol of complex was dissolved in
DMF (5.5 mL), and H2O (or D2O) (1.8 mL) was added. Aceto-
nitrile was used as internal standard (7.3 μL). NH4OH was used as
base (5 equiv. versus the complex). The vial was sealed with a rub-
ber septum, and concentrated H2O2 was carefully injected
(30 equiv. versus the complex). The solution was stirred at 35 °C,
and samples were taken from the headspace with appropriate time
intervals using a gas-tight syringe according to the rate of the reac-
tion and to obtain at least seven time-dependent data points. GC
measurements were performed with an HP 5890 gas chromato-
graph. The GC setup was: Supelcowax 30 m capillary column,
heating from 100 to 170 °C at a rate of 20 °Cmin–1. Products of
the reactions were identified according to our previously reported
procedure.[23]
1604, 1475, 1445, 1388, 1318, 1219, 1111, 1087, 1033, 903, 768,
732, 624, 587 cm–1. UV/Vis (CH3OH): λmax (logε) = 301 (4.04), 311
(4.04), 360 (sh) (1.71), 592 (1.68) nm.
[CuII2(bpy)2(AMEP)(H2O)3](ClO4)2·3H2O (5-p): The synthesis was
performed with 0.5 mmol quantities and the product was isolated
as blue microcrystalline solid, yield 48%. C23H36Cl2Cu2N5O17P
(883.53): calcd. C 31.27, H 4.11, N 7.93; found C 31.7, H 4.0, N
8.2. FTIR (KBr pellet): ν = 3435, 3153, 2929, 2853, 1605, 1543,
˜
1473, 1448, 1303, 1185, 1160, 1082, 1054, 1030, 902, 772, 624 cm–1.
UV/Vis (CH3OH): λmax (logε) = 300 (4.22), 311 (4.21), 371 (1.80),
611 (1.73) nm. Crystals suitable for X-ray structural determination
were obtained from CH3OH.
Analytical and Physical Measurements: Infrared spectra were re-
corded with an Avatar 330 FTIR Thermo Nicolet instrument.
UV/Vis spectra were recorded with a Cary 60 spectrophotometer
equipped with a fiber-optic probe with 1 cm path length.
Stoichiometric oxidation of ACP was performed at 20 °C in meth-
anol (final volume 200 μL) in 1.7 mL hermetically sealed vials.
Owing to the limited amount of sample, the complex was generated
in situ. The following conditions were used: 1 mm of ACP and 1 mm
of CuSO4·5H2O in the presence (or absence) of bpy (1 mm). NaOH
(0 to 10 mm) was used in the assays. The reaction was initiated by
injection of concentrated H2O2 through the septum (final concen-
tration ranging from 1 to 50 mm). Gas from the headspace was
analyzed by gas chromatography. Measurements were performed
with a Shimadzu GC-2014A equipped with a Poropak Q 80/100
column (1/8Љ) and an FID detector. The following conditions were
Microanalyses were performed by the Microanalytical Service of
the University of Pannonia.
EPR spectra were measured with a Bruker ELEXSYS 500 X-band
CW-EPR spectrometer equipped with a Dewar tube-holder filled
with liquid N2. The spectra were recorded at 120 K in frozen meth-
anol solutions. Simulations with automatic parameter fitting were
performed for axial symmetry by using published software.[35] The
contribution of naturally abundant 63Cu and 65Cu was considered,
but the values given in the text refer to 63Cu. All principal axes
were supposed parallel.
used: vector = N2, Tinjector = 250 °C, Toven = 100 °C, Tdetector
=
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Reactivity tests with the CuI intermediates generated in situ were
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5-p were dissolved in methanol (9 mL) at –10 °C (1.11 mm), and
ascorbate (10 mm in 1 mL methanol at –10 °C) or H2O2 and base
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The financial support of the Hungarian National Research Fund
(OTKA
K108489,
TÁMOP-4.2.2.A-11/1/KONV-2012-0071,
TÁMOP-4.2.4.A/2-11-1-2012-0001) (grants to S. G.), and the Euo-
pean Cooperation in Science and Technology (CMST COST action
CM1003 is gratefully acknowedged. This project was also sup-
ported by the János Bolyai Scolarship of the Hungarian Academy
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Published Online: ᭿
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Job/Unit: I40133
/KAP1
Date: 19-05-14 11:49:44
Pages: 11
www.eurjic.org
FULL PAPER
Bio-Inspired Oxidations
J. S. Pap, N. El Bakkali-Tahéri, A. Fadel,
S. Góger, D. Bogáth, M. Molnár,
M. Giorgi, G. Speier, A. J. Simaan,*
J. Kaizer* ........................................ 1–11
Oxidative Degradation of Amino Acids
and Aminophosphonic Acids by 2,2Ј-Bi-
pyridine Complexes of Copper(II)
The oxidation of bound amino acids or
aminophosphonic acids by copper(II) com-
plexes, which models the reaction catalyzed
by the 1-aminocyclopropane carboxylic
acid oxidase, was investigated in the pres-
ence of hydrogen peroxide. A reaction
mechanism that involves a CuI intermedi-
ate is discussed.
Keywords: Bioinorganic chemistry / Amino
acids / Copper / Oxidation
Eur. J. Inorg. Chem. 0000, 0–0
11
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim