Investigation of dioxygen activation by copper(ii)-iminate/aminate complexes

Article abstract of DOI:10.1039/c8dt03137a

The activation of dioxygen by metal ions is critical in chemical and bio-chemical processes. A scientific challenge is the elucidation of the activation site of dioxygen in some copper metalloproteins, which is either the metal center or the substrate. In an effort to address this challenge, we prepared a series of new copper(ii) complexes (1·2H₂O, 2·CH₃OH, 3) with bio-inspired amidate ligands and investigated their activity towards dioxygen activation. The secondary amine group ligated to copper(ii) of the complex 1·2H₂O in methyl alcohol is oxidized (2e^?) by air dioxygen in a stepwise fashion to an imine group, affording complex 2. The copper(ii) complex 2 in methyl alcohol induces the 4e^? oxidation by air dioxygen of the imine functionality ligated to copper(ii) to an azinate group, resulting in the isolation of a dinuclear azinate copper(ii) compound (4). Experimental and computational studies, including X-band c. w. EPR, UV-vis and ESI-MS spectroscopy and density functional theory computations, indicate a direct attack of the dioxygen on the-HC═N-group ligated to copper(ii), and a possible mechanism of the oxidation of the-HC═N-functionality ligated to copper(ii) to an azinate group is provided. This unprecedented activation of dioxygen by a copper substrate paves the way for further exploration of the O₂ activation mechanisms in enzymes and the development of effective catalysts in O₂-involved green organic synthesis.

Full text of DOI:10.1039/c8dt03137a

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PAPER
Investigation of dioxygen activation by copper(II)–
iminate/aminate complexes†
Michael G. Papanikolaou,‡a Sofia Hadjithoma,‡b Dimitra S. Chatzikypraiou,a
Dionysios Papaioannou,*c Chryssoula Drouza,d Athanassios C. Tsipis,*a
Haralampos N. Miras,*e Anastasios D. Keramidas *b and Themistoklis A. Kabanos*a
Cite this: Dalton Trans., 2018, 47,
16242
The activation of dioxygen by metal ions is critical in chemical and bio-chemical processes. A scientific
challenge is the elucidation of the activation site of dioxygen in some copper metalloproteins, which is
either the metal center or the substrate. In an effort to address this challenge, we prepared a series of
new copper(II) complexes (1·2H2O, 2·CH3OH, 3) with bio-inspired amidate ligands and investigated their
activity towards dioxygen activation. The secondary amine group ligated to copper(II) of the complex
1·2H2O in methyl alcohol is oxidized (2e−) by air dioxygen in a stepwise fashion to an imine group,
affording complex 2. The copper(II) complex 2 in methyl alcohol induces the 4e− oxidation by air dioxygen
of the imine functionality ligated to copper(II) to an azinate group, resulting in the isolation of a dinuclear
azinate copper(II) compound (4). Experimental and computational studies, including X-band c. w. EPR,
UV-vis and ESI-MS spectroscopy and density functional theory computations, indicate a direct attack of
the dioxygen on the –HCvN– group ligated to copper(II), and a possible mechanism of the oxidation of
the –HCvN– functionality ligated to copper(II) to an azinate group is provided. This unprecedented acti-
vation of dioxygen by a copper substrate paves the way for further exploration of the O2 activation
mechanisms in enzymes and the development of effective catalysts in O2-involved green organic
synthesis.
Received 1st August 2018,
Accepted 22nd October 2018
DOI: 10.1039/c8dt03137a
rsc.li/dalton
Copper is one of the most frequently used metals in
enzymes to activate dioxygen;20–25 to date, a variety of model
Introduction
The activation of dioxygen by metal ions1 is a central reaction copper compounds have been developed to stabilize mono-
in biological,2–5 catalytic6–8 and energy storage9–12 processes. nuclear CuII-superoxide species.26–37 The most common oxi-
Several copper-based metalloenzymes activate dioxygen in a dation states of copper found in biological systems are I and
variety of biological functions,13–20 such as regulation of neuro- II; however, in recent years, a strong belief has emerged that
transmitters, dioxygen transport, and cellular respiration.
oxidation state III has biological importance in copper
enzymes.38–43
Combined enzymatic and model studies have been used to
elucidate the mechanisms of dioxygen activation by copper
proteins.5,25,44–47 It has been suggested for the most copper
enzymes, the first step in dioxygen activation is the coordi-
nation of dioxygen to copper ion and the formation of the
metal superoxo species.18 Although several modes of dioxygen
ligation to copper have been observed in model compounds,
only the η1-superoxide and the μ–η2:η2-peroxide modes of lig-
ation have been identified crystallographically in mononuclear
and dinuclear copper metalloprotein active sites, respectively
(Scheme 1A).
aSection of Inorganic and Analytical Chemistry, Department of Chemistry,
University of Ioannina, Ioannina 45110, Greece. E-mail: tkampano@cc.uoi.gr,
attsipis@uoi.gr
bDepartment of Chemistry, University of Cyprus, Nicosia 1678, Cyprus.
E-mail: akeramid@ucy.ac.cy
cLaboratory of Synthetic Organic Chemistry, Department of Chemistry,
University of Patras, GR-26504 Patras, Greece. E-mail: dapapaio@upatras.gr
dDepartment of Agricultural Sciences, Biotechnology and Food Science,
Cyprus University of Technology, Limassol 3036, Cyprus
eWest CHEM, School of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK.
E-mail: harism@chem.gla.ac.uk
†Electronic supplementary information (ESI) available. CCDC 1576869, 1576874,
1858742 and 1576873. For ESI and crystallographic data in CIF or other elec-
tronic format see DOI: 10.1039/c8dt03137a
An example of the η1-superoxide mode of ligation has been
found in copper amine oxidases (CAOs), which utilize dioxygen
to promote aerobic oxidation of primary amines to aldehydes.
‡The designated authors have contributed equally.
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Scheme 2 The three ligands used for the synthesis of the copper(II)
complexes.
Very recently, Marchetti and co-workers demostrated the
activation of CvN bonds by high-valent metal halides63,64 The
copper(II) complex 2·CH3OH in this work constitutes the first
example of direct activation of dioxygen by a –HCvN– moiety
ligated to copper(II); this was proven experimentally and com-
putationally. The mechanism of the oxidation of the –HCvN–
functionality ligated to copper(II) to an azinate group by means
of a computational approach based on density functional
theory (DFT) is also reported.
Scheme 1 The crystallographically identified modes of dioxygen
ligation in copper metalloproteins (A); the aerobic oxidation reactions
catalysed by CAOs and NspF, respectively.
Mechanistic studies in CAOs and model systems revealed that
the reaction proceeds via a transamination pathway; however,
the mechanism is still a subject of controversy.17,48–51 Electron
transfer from aminotopaquinol to dioxygen results in the for-
mation of superoxide, which oxidizes imino-topaquinone
(Scheme 1B).17,50,52–54 An elegant example of a copper enzyme
with a μ–η2:η2-peroxide mode of ligation is the recently discov-
ered binuclear copper enzyme NspF, which activates dioxygen
to convert 3-amino-4-hydroxybenzamide to 4-hydroxy-3-nitroso-
benzamide (Scheme 1B).55 The NspF enzyme, like other
copper monoxygenases, reacts with dioxygen to form a μ–η2:η2-
peroxide adduct.
In some other copper metalloproteins, the activation site of
dioxygen is under debate; it is either the metal center or the
substrate. For example, a mechanism of dioxygen activation
that has been proposed for quercetinase,56 a copper dioxygen-
ase which breaks down quercetin and other flavonols to dep-
sides, is its direct reaction with the radical of the substrate.57
Studies on catechol58–60 and p-semiquinone12,61 radical metal-
complexes, models of oxidases, proved that dioxygen is acti-
vated by the ligand radical; this supports the proposed mecha-
nism for quercetinase.
In this study, new bioinspired model copper(II) complexes
have been employed in order to better understand the mecha-
nism of O2 activation by copper-based metalloproteins.62 More
specifically, the synthesis and structural and physicochemical
characterization of a series of copper(II) compounds with tetra-
dentate amidate ligands, N-{2-[(2-pyridylmethylene)amino]
phenyl}pyridine-2-carboxamide (Hcapca, Scheme 2) and its
reduced analogue N-{2-[(pyridylmethyl)amino]phenyl}pyridine-
2-carboxamide (H2capcah, Scheme 2), are reported. These
ligands were chosen because they contain nitrogen donor
atoms to mimic the environment of copper in oxidases, oxyge-
nases and dioxygenases.
Experimental
Experimental materials
All chemicals and solvents were purchased from Sigma-Aldrich
and Merck, were of reagent grade and were used without
further purification except pyridine-2-carboxaldehyde and
2-acetylpyridine, which were distilled under high vacuum
immediately prior to use. The condensation reaction of
N-(2-aminophenyl)pyridine-2-carboxamide
(Hpyca,
see
Scheme 3) with pyridine-2-carboxaldehyde or with 2-acetylpyri-
dine was performed under high purity argon. The mono-
nuclear copper(II) compounds 1·2H2O-3 were synthesized
under high purity argon at ambient temperature (≈20 °C),
although compound 3 is stable in solution in air. C, H, and N
analyses were conducted by the micro-analytical service of the
School of Chemistry, the University of Glasgow. Copper was
determined by atomic absorption and chloride gravimetrically
as AgCl. Merck silica gel 60 F254 TLC plates were used for thin
layer chromatography.
The CuII/Hcapcah− and CuII/capca− compounds mimic the
activities of oxidases and oxygenases, respectively; they induce
2e− oxidation of the amine to an imine and deamination of
the aromatic imine by 4e− oxidation of the imine nitrogen
atom to an azinate group.
Scheme 3 The synthesis of the three ligands used in this study and the
structural formula of the ligand H2pipyaz.
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N-(2-Nitrophenyl)pyridine-2-carboxamide (Hpycan). To
a
{1H} NMR (100.6 MHz, CDCl3, 24 °C): δ 49.6, 113.58, 118.47,
mixture of pyridine-2-carboxylic acid (71.48 g, 580.6 mmol) 121.49, 122.54, 124.19, 124.11, 126.43, 127.04, 136.95, 137.57,
and 2-nitroaniline (80.12 g, 580.6 mmol), pyridine (25 mL) and 141.66, 148.15, 148.89, 149.80, 158.51, 162.80. IR (KBr, cm−1):
triphenylphosphite (76.25 mL, 89.98 g, 290.3 mmol) were 3333 (s), 3055 (w), 1663 (vs), 1589 (m), 1520 (vs), 1452 (m),
added. The mixture was refluxed for 12 h under magnetic stir- 1431 (m), 1313 (s), 1272 (w), 1136 (w), 999 (w), 818 (w), 744 (s),
ring. The resulting solution was refrigerated overnight at 704 (w), 654 (w), 621 (m). Anal. calcd for C18H16N4O (Mr =
−20 °C to yield a brown-yellow precipitate. The solid was fil- 304.18): C, 71.02; H, 5.30; N, 18.41. Found: C, 71.05; H, 5.31;
tered, washed with ethyl alcohol (2 × 50 mL) and diethyl ether N, 18.39. Mp: 104–105 °C. Rf = 0.07 (4 : 1 chloroform/n-hexane,
(2 × 50 mL), and vacuum-dried. The yellow-brown solid was tri- v/v). [HR-ESI(+)-MS]: calcd for (C18H16N4ONa) {[M + Na]+} m/z
turated with cold (≈10 °C) ethyl alcohol (50 mL), filtered, 327.1216, found 327.1212 (100%).
washed with diethyl ether (2 × 30 mL) and vacuum-dried to
N-{2-[1-(Pyridine-2-yl)ethylideneamino]phenyl}picolinamide
afford 61.13 g of a bright yellow solid. Yield, 43%. Mp: 167 °C. (Hmcapca). The ligand Hmcapca was prepared in a similar
Anal. calcd for C12H9N3O3 (Mr = 243.10): C, 59.24; H, 3.73; N, fashion to Hcapca except that 2-acetylpyridine was used
17.29. Found: C, 59.31; H, 3.76; N, 17.25. Rf = 0.55 (4 : 1 chloro- instead of pyridine-2-carboxaldehyde. Yield: 50%. Melting
form/n-hexane). [HR-ESI(+)-MS]: calcd for (C12H10N3O3Na) point: 94–95 °C. IR (KBr, cm−1): 3285 (w), 1686 (vs), 1629 (m),
{[M + Na]+} m/z 266.0536, found 266.0532 (100%).
1585 (s), 1529 (vs), 1452 (s), 1435 (s), 1363 (m), 1316 (m), 1299
N-{2-[(2-Pyridylmethylene)amino]phenyl}pyridine-2-carbox- (m), 1103 (m), 997(m), 788 (m), 746 (s), 669(m), 621 (m). 1H
amide (Hcapca). To a suspension of Hpycan (10.00 g, NMR (CDCl3, 400 MHz, 24 °C): δ 10.09 (br s, 1H, –CONH–),
41.14 mmol) and 1.50 g of hydrogenation catalyst (10% Pd on 8.71 (d, 1H), 8.64(d, 1H), 8.30(d, 1H), 7.93 (t, 1H), 7.85 (t, 1H),
activated carbon) in acetone (350 mL), pure hydrogen was 7.52 (dd, 1H), 7.43 (t, 1H), 7.20 (t, 1H), 7.07 (dd, 1H), 1.27 (s,
admitted for 24 h under magnetic stirring. The mixture was 3H).13C{1H} NMR (100.6 MHz, CDCl3, 24 °C): δ 162.7, 153, 149,
filtered, and the filtrate was evaporated to dryness to yield 148, 136, 126, 124, 122, 121, 119, 153, 120 153, 25. Anal. calcd
N-(2-aminophenyl)pyridine-2-carboxamide (Hpyca, Scheme 3) for C18H14N4O (Mr = 316.15): C, 72.13; H, 5.10; N, 17.71.
as a gold-yellow oil. The oil was re-dissolved in methyl alcohol Found: C, 72.03; H, 5.05; N, 17.65. Rf = 0.12 (4 : 1 chloroform/
(70 mL), and 3.91 mL of pyridine-2-carboxaldehyde (4.410 g, n-hexane, v/v). [HR-ESI(+)MS]: calcd for (C18H14N4ONa) {[M +
41.14 mmol) was added in one portion. The mixture was Na]+} m/z 339.1216, found 339.1211 (100%).
refluxed overnight under argon. Then, the solution was cooled
N-{2-[(Pyridylmethyl)amino]phenyl}pyridine-2-carboxamido-
to −20 °C for 5 h and the resulting yellow-brown precipitate (Npy,Nam,Nim,Npy) chloridocopper(II), [CuII(Hcapcah)Cl]·2H2O
was filtered, washed with diethyl ether (3 × 20 mL) and (1·2H2O). CuCl2·2H2O (0.112 g, 0.657 mmol) was dissolved
vacuum-dried. The product was purified by Soxhlet extraction under argon in methyl alcohol (5 mL); then, solid H2capcah
with n-hexane (200 mL) overnight. The volume of hexane was (0.200 g, 0.657 mmol) was added in one portion to the stirred
reduced to 50 mL; the mixture was cooled to room temperature solution. Upon addition of the ligand, the blue colour of the
(≈20 °C) and then cooled to 0 °C for one hour. The resulting solution turned green and a green precipitate was formed. The
bright yellow precipitate was filtered, washed with cold hexane mixture was stirred for three hours; then, the solid was filtered,
(2 × 10 mL), and vacuum-dried to afford 9.95 g of product washed with cold methyl alcohol (2 × 3 mL) and diethyl
(80% based on Hpycan). Mp: 116–117 °C. IR (KBr, cm−1): 3283 ether (2 × 5 mL), and vacuum-dried to afford 0.275 g of a
(m), 1686 (vs), 1630 (w), 1589 (s), 1533 (vs), 1474 (m), 1454 (s), green solid. Yield, 95% (based on CuCl2·2H2O). IR (KBr, cm−1):
1433 (s), 1377(m), 1277 (m), 997 (m), 777 (m) 743 (s), 689 (m), 3205 (w), 1622 (s), 1597 (vs), 1585 (s), 1485 (s), 1450 (m), 1393
619 (m). Anal. calcd for C18H14N4O (Mr = 302.16): C, 71.49; H, (s), 1346 (m), 1290 (w), 972 (w), 764 (s), 750 (m), 685 (m) 652
1
4.67; N, 18.54. H NMR (CDCl3, 400 MHz, 24 °C): δ 7.15 (dd, (m). Anal. calcd for 1·2H2O, [C18H19ClCuN4O3 (Mr = 438.19)]:
J = 8.4 Hz, 7.6 Hz, 1H), 7.33–7.42 (m, 3H), 7.42–7.49 (m, 1H), C, 49.30; H, 4.37; Cl, 8.09; Cu, 14.50; N, 12.79. Found: C, 49.26;
7.83–7.89 (m, 2H), 8.30 [d, J = 7.9 Hz, 1H], 8.56 [d, J = 7.9 Hz, H, 4.38; Cl, 8.18; Cu, 14.67; N, 12.77. [HR-ESI(+)-MS]: calcd for
1H], 8.65 [d, J = 4.6 Hz, 1H], 8.68–8.77 (m, 2H), 8.79 [s, 1H, C18H15N4OCu {[M − Cl − 2H2O]+} m/z 366.0536, found
Ph–NvC–H], 11.60 (br s, 1H, –CONH–). 13C{1H} NMR 366.0531 (100%).
(100.6 MHz, CDCl3, 24 °C): δ 116.28, 119.47, 121.63, 122.31,
Green crystals of 1 suitable for X-ray diffraction analysis
123.90, 125.21, 126.22, 128.86, 134.19, 136.59, 137.50, 137.58, were obtained by layering a methyl alcohol solution of
148.13, 149.64, 150.45, 154.78, 158.40, 161.75. [HR-ESI(+)-MS]: H2capcah into a methyl alcohol solution of CuCl2·2H2O.
calcd for (C18H15N4ONa) {[M + Na]+} m/z 325.1060, found
325.1056 (100%).
{N-[2-((2-Pyridylmethylene)amino)phenyl]pyridine-2-carbox-
amido-(Npy,Nam,Nim,Npy)} chloridocopper(II), [CuII(capca)
N-{2-[(Pyridylmethyl)amino]phenyl}pyridine-2-carboxamide Cl]·CH3OH (2·CH3OH). The compound 2·CH3OH was prepared
(H2capcah). The organic molecule was synthesized according (in 88% yield) in the same way as compound 1·2H2O except
to the literature65 and its purity was checked with positive that Hcapca was used instead of H2capcah. The color of the
HR-ESI-MS, 1H-, 13C-NMR spectra and elemental analysis. 1H compound 2·2H2O was brick red. IR (KBr, cm−1): 1630 (s),
NMR (CDCl3, 400 MHz, 24 °C): δ 4.56 (s, 2H), 6.72 (d, 1H), 6.82 1597 (s), 1481 (m), 1389 (s), 1294 (m), 1148 (m), 1090 (w), 764
(t, 1H), 7.18 (t, 1H), 7.43 (d, 1H), 7.55 (d, 1H), 7.64 (t, 1H), 7.90 (m), 687 (m), 650 (w). Yield: Anal. calcd for 2·CH3OH,
(t, 1H), 8.26 (d, 1H), 8.63 (d, 1H), 9.95 (s, 1H, –CONH–). 13C [C19H17ClCuN4O2 (Mr = 432.18)]: C, 52.76; H, 3.96; Cl, 8.20; Cu,
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14.70; N, 12.96. Found: C, 52.66; H, 3.89; Cl, 8.18; Cu, 14.67; isolation of Hpyca (Scheme 3); the organic molecule H2capcah
N, 12.88. [HR-ESI(+)-MS]: calcd for C18H13CuN4O {[M − Cl − was prepared according to the literature.65 The completion of
CH3OH]+} m/z 364.0380, found 364.0374 (100%).
the reduction of Hpycan to Hpyca (–NO2 to –NH2) and of
Crystals of 2·CH3OH suitable for X-ray diffraction analysis Hcapca to H2capcah (–NvCH– to –NH–CH2–) was monitored
were obtained by layering a methyl alcohol solution of Hcapca by TLC. The molecule Hpyca was not isolated; it was con-
into a methyl alcohol solution of CuCl2·2H2O.
densed with pyridine-2-carboxaldehyde or 2-acetylpyridine
{N-(2-(1-(Pyridine-2-yl)ethylideneamino)phenyl)picolinamido- under high purity argon to avoid oxidation of the amine
(Npyr,Nam,Nim,Npyr)} chloridocopper(II), [CuII(mcapca)Cl] (3). group. Soxhlet extraction of the crude Hcapca or Hmcapca
Complex 3 was prepared in a similar way to complex 2·CH3OH proved to be an effective purification method.
except that Hmcapca was used instead of Hcapca. Yield: 91%
The synthesis of the copper(II) compounds with the ligands
(based on CuCl2·2H2O). Anal. calcd for, [C19H17ClCuN4O2 H2capcah, Hcapca and Hmcapca is depicted in Scheme 4. The
(Mr = 432.16)]: C, 52.70; H, 3.96; Cl, 8.20; Cu, 14.70; N, 12.96. methyl alcohol solutions of the mononuclear copper(II) com-
IR (KBr, cm−1): 1626 (vs), 1597 (s), 1469 (m), 1390 (s), 1265 (w), pounds, 1·2H2O and 2·CH3OH, were oxidized by air to complex
1090 (m)m 1024 (m), 795 (m), 761 (s), 686 (m), 644 (w). Found: 4, while the methyl alcohol solution of the copper(II) com-
C, 52.67; H, 3.84; Cl, 8.18; Cu, 14.67; N, 13.18. [HR-ESI(+)-MS]: pound 3 remained stable in air.
calcd for (C19H15CuN4O) {[M − Cl]+} m/z 378.0536, found
378.0532 (100%).
X-ray crystallographic results
Crystals of 3 suitable for X-ray diffraction analysis were
obtained by layering diethyl ether into a concentrated methyl
alcohol solution of 3.
μ-Bis-{(Z)-[(E)-2-(2-(picolinamido)phenylimino)-2-(pyridin-2-yl)
ethylidene]azinate}dicopper(II), [Cu2II(μ–η1,η1-pipyaz-O,O′)2], (4).
Method A. Compound 1·2H2OH or 2·CH3OH was dissolved in
CH3OH (≈4 mg ml−1) at ambient temperature (30 °C). The
solution was magnetically stirred for 5 hours in air. Then,
diethyl ether was layered on the solution to obtain only a few
A summary of the crystallographic data and the final refine-
ment details for compounds 1–4 are given in Table S1.†
Interatomic distances and bond angles relevant to the copper(II)
coordination spheres are listed in Table 1. Fig. 1A shows a
perspective view of compound 1. In 1, the copper(II) atom is
bonded to two pyridines [N(1) and N(4)], the deprotonated
amide N(2), the secondary amine N(3) nitrogen atoms of the
singly deprotonated ligand Hcapcah− and one chloride ion.
The coordination geometry for the CuII center is best
described as distorted square pyramidal; the distortion para-
meter τ68 was calculated to be 0.090. The copper(II) atom is dis-
placed from the N3Cl coordination plane [root mean square
(rms) 0.149 Å] by 0.254(2) Å towards the pyridine nitrogen
atom N(4), which occupies the apical position. Of the four
CuII–N bonds, the bond length to N(2) [d(CuII–Namide) =
1.942(2) Å], that is, the deprotonated amide nitrogen, is con-
sistent with literature values.69–71 The bond length to N(3)
[2.046(2) Å], the secondary amine nitrogen, is substantially
longer (about 0.1 Å) than the CuII–Nimine bond length [1.942(3)
Å] of compound 2·CH3OH (vide infra). The bond lengths to
N(1) [1.994(2) Å] and N(4) [2.273(1) Å], the pyridine nitrogens,
yellow-brown crystals of
analysis.
4 suitable for X-ray diffraction
Method B. Compound 4, as yellow-brown crystals, was
prepared in 10% yield using the same method for the prepa-
ration of 2·CH3OH except that (i) [CuII(CH3COO)2]·H2O
was substituted for CuCl2·2H2O, (ii) the experiment was
conducted in air at ambient temperature (30 °C) for 4 hours,
and (iii) the solution was layered with diethyl ether. IR
(KBr, cm−1): 1628 (s), 1599 (s), 1566(m), 1470(s), 1454 (s), 1387
(s), 1348 (s), 1313 (m), 1281 (m), 1246 (m), 1146 (m), 1045 (m),
962 (m), 943 (m), 804 (m), 750 (s), 689 (m), 645 (w), 569 (m).
Anal. calcd for [C38H26Cu2N10O6] (Mr = 845.40): C, 53.81;
H, 3.09; Cu, 14.99; N, 16.52. Found: C, 53.90; H, 3.13; Cu,
14.97; N, 16.44.
Results and discussion
Synthesis of the ligands and copper(II) compounds
The synthesis of the three ligands, i.e., Hcapca and its reduced
and methylated analogues H2capcah and Hmcapca, respect-
ively used in this study for the synthesis of the copper(II) com-
pounds, as well as the structure of the azinate molecule
H2pipyaz formed as its copper(II) complex from the interaction
of the species [CuII(capca)]+ with dioxygen (vide infra), are
depicted in Scheme 3.
The organic molecules Hpycan and Hcapca (Scheme 3)
were synthesized by modified versions of reported pro-
cedures66,67 to obtain better product yields and to avoid the Scheme 4 The synthesis of the copper(II) complexes 1, 2, 3, and 4.
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Table 1 Interatomic distances (Å) and angles (°) relevant to the copper
(II) coordination sphere
able delocalization of π-electron density in the skeleton of the
ligand capca−. The CuII–Namide and CuII–Npyridine bond lengths
are in the expected ranges.69–71
Parameter
1
2·CH3OH
3
4
It is worth noting that the large difference in the CuII–Cl
bond lengths, 2.2684(6) Å vs. 2.527(1) Å in compounds 1 and
2·CH3OH, respectively, is nicely reflected in their Far-IR
spectra, with ν(Cu–Cl) at 359 (1) and 268 cm−1 (2·CH3OH).
Compound 3, with d(CuII–Cl) = 2.473(1) Å, gave ν(Cu–Cl) at
306 cm−1. Details of the IR spectra of all the copper(II) com-
pounds are presented in the ESI (pages S5, S6 and Table S2†).
The structural features of complex 3 (Fig. 2) are very similar
to those of 2·CH3OH; therefore, this structure will not be
further discussed.
Cu(1)–Xa
Cu(1)–N(1)
Cu(1)–N(2)
Cu(1)–N(3)
2.2684(6)
1.994(2)
1.942(2)
2.046(2)
2.273(1)
98.68(5)
160.09(5)
94.21(5)
99.16(4)
82.18(6)
165.48(6)
105.96(6)
83.43(6)
99.70(6)
78.35(6)
2.527(1)
2.041(3)
1.939(4)
1.942(3)
2.060(4)
94.9(1)
102.7(1)
99.7(1)
94.5(1)
2.473(1)
2.015(2)
1.942(2)
1.982(2)
2.039(2)
96.9(7)
104.5(6)
104.2(7)
95.8(6)
2.685(2)
1.989(2)
1.891(3)
1.945(2)
1.897(2)
93.33(7)
94.01(9)
92.57(8)
86.48(7)
83.6(1)
167.72(9)
94.36(8)
85.2(1)
178.0(1)
96.75(9)
Cu(1)–N(4)
X–Cu(1)–N(1)
X–Cu(1)–N(2)
X–Cu(1)–N(3)
X–Cu(1)–N(4)
N(1)–Cu(1)–N(2)
N(1)–Cu(1)–N(3)
N(1)–Cu(1)–N(4)
N(2)–Cu(1)–N(3)
N(2)–Cu(1)–N(4)
N(3)–Cu(1)–N(4)
82.1(1)
81.9(8)
160.5(1)
110.9(1)
82.0(2)
157.6(1)
81.0(1)
155.8(8)
109.6(8)
81.3(8)
155.4(8)
80.4(7)
The molecular structure of the compound [CuI2I(μ–η1–η1-
pipyaz-O,O′)2] (Fig. 3) is a centrosymmetric dimer formed by
two bridging azinate O,O′-ligands. This represents the first
structurally characterized copper(II) complex that contains a
bridging η1–η1 azinate-O,O′ coordination mode where the
azinate group is part of a chelate ring (Scheme 5c); this is gen-
erally unique among all transition metal complexes. The
coordination modes 5a and 5b for azinates have been observed
for copper(II)72 compounds, and mode 5d has been observed
for copper(II)73 and iridium(III)74 compounds. In [CuI2I(μ–η1–η1-
pipyaz-O,O′)2], each copper(II) atom is coordinated by the three
a X corresponds to Cl(1) and O(3) for compounds 1, 2·CH3OH, 3 and 4,
respectively.
Fig. 1 Structural representations of 1 (A) and 2·CH3OH (B) with thermal
ellipsoids drawn at the 50% probability level. Hydrogen atoms and
solvent molecules are omitted for clarity.
are longer than the CuII–Namide bond length and different
from each other as a consequence of the difference in their
positions: basal plane for [N(1)] versus apex for [N(4)] of the
square pyramid.
Fig. 2 Structural representation of compound 3 (thermal ellipsoids rep-
resent 50% probability). Hydrogen atoms are omitted for clarity.
The crystal structure of 2·CH3OH is shown in Fig. 1B. A
notable difference between the X-ray crystal structures of 1 and
2·CH3OH is the almost planar conformation of the ligand
capca− in the latter as opposed to the non-planar confor-
mation of the ligand Hcapcah− in 1 due to the sp3 hybridiz-
ation of C(13) (Fig. 1A). The coordination geometry for the CuII
center in 2·CH3OH is best described as slightly distorted
square pyramidal; the distortion parameter τ68 was calculated
to be 0.048. The copper(II) ion is displaced from the N4 basal
plane [root mean square (rms) 0.025 Å] by 0.261 Å towards Cl
(1), which is the apex of the square pyramid. The chloride pro-
vides the longest bond to the copper(II) ion, 2.527(1) Å, and the
two pyridine nitrogen bond distances [2.041(3) and 2.060(4) Å]
are longer than the amide [1.939(4) Å] and imine [1.942(3) Å]
bond distances. The almost identical CuII–Namide and CuII–
Fig. 3 Structural representation of the centrosymmetric dinuclear
compound [CuI2I(μ–η1–η1-pipyaz-O,O’)2] (4) with thermal ellipsoids at
Nimine bond lengths in compound 2·CH3OH imply consider- 50% probability. Hydrogen atoms are omitted for clarity.
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in the spectrum of complex 3, are assigned to the stretching
vibrations of the vC–CvNO2 bonds. The high intensity of
these peaks is attributed to the high dipole moments of the
bonds caused by the electron withdrawing –NO2 moiety.
UV-vis spectroscopy
The UV-vis spectral data of compounds 1·2H2O-4 are listed in
Table 2. The peaks of all the complexes were assigned to intra-
ligand and charge transfer transitions. In addition to these
peaks, 1·2H2O gave one peak at 675 nm, which was assigned to
a d–d transition. The oxidation of compounds 1·2H2O and
2·CH3OH in CH3OH by air was monitored with UV-vis spec-
troscopy. Fig. 4A shows the variation of the absorbance in the
UV-vis spectrum of the compound 1·2H2O (0.16 mM) in
CH3OH with time. The initial rates of the oxidation of com-
plexes 1·2H2O and 2·CH3OH by air dioxygen are linearly depen-
dent on their concentrations (Fig. 4B). The rate constants of
the oxidation reactions, calculated from the slopes of the lines
(Fig. 4B), were 0.013 0.001 min−1, 0.10 0.01 min−1, and
2.3 0.1 min−1 for 1·2H2O, 2·CH3OH, and 2·CH3OH with one
equivalent of Et3N, respectively. The lower rate of oxidation of
1·2H2O in comparison to that of 2·CH3OH reflects the
additional oxidation step required for 1·2H2O (1·2H2O is oxi-
dized to 2·CH3OH). The addition of base dramatically
increases the reaction rate, which is in agreement with the pro-
posed proton release mechanism of the formation of com-
pound 4 (vide infra).
Scheme 5 The bonding modes (a, b and d) of the azinate group
observed in transition metal complexes and the new bonding mode (c)
present in [Cu2II(μ–η1,η2-pipyaz-O,O’)2] (4).
nitrogen atoms provided by the same doubly deprotonated
pipyaz2− ligand [i.e., the pyridine [N(1)], the deprotonated
amide N(2), and the imine N(3) nitrogen] and by two oxygen
atoms, O(2) and O(3)′, from the two azinate moieties; one of
these is provided by the symmetry-related unit, while the pyri-
dine nitrogen [N(4)] and its symmetry-related [N(4)]′ atoms
remain uncoordinated. The two oxygen donor atoms bridge
the two copper(II) atoms in the complex, keeping them 5.118 Å
apart. The configurations of the pipyaz2− ligand with respect
to the N(3) = C(13) and C(19) = N(5) bonds are E and Z,
respectively.
The coordination sphere around each copper(II) atom in
[CuI2I(μ–η1–η1-pipyaz-O,O′)2] can be described as distorted
square pyramidal; the distortion parameter τ68 is calculated to
be 0.171. The oxygen O(3)′ occupies the apex at a distance of
2.685 Å, while the three nitrogen atoms and the azinate oxygen
atom O(2) of the bridging ligand pipyaz2− constitute the basal
plane around Cu(II). The root mean squared (r.m.s.) deviation
of the four basally coordinated atoms of Cu(1) from the mean
plane is 0.217 Å, with the metal atom placed at 0.071(1) Å away
from the plane, toward the O(3)′ atom.
The UV-vis spectral changes of compounds 2·CH3OH
(0.080 mM) and 3 (0.080 mM) in CH3OH with time (0 to
30 min) are shown in Fig. 5. The spectrum of 3 does not show
any significant change up to 24 hours; this suggests that the
Table 2 UV-vis spectral data for the copper(II) compounds 1·2H2O-4
It is worth noting that the two azinate units in the dinuclear
compound [CuI2I(μ–η1–η1-pipyaz-O,O′)2] form an eight-mem-
bered ring with the two copper atoms (Fig. 3).
Compound
Solvent
λmax [nm] (ε [M−1 cm−1])
1·2H2O
2·CH3OH
3
4
Acetonitrile
Acetonitrile
Methanol
675 (100), 336 (4600)
449 (1500), 332 (5000)
274 (17 500), 325 sh (8000)
647 (600), 448 (8700), 327 (26 000),
292 (14 500)
IR spectroscopy
Methanol
The obtained infrared data for the complexes are listed in the
Experimental section. The structural information obtained
from the infrared spectra are in agreement with the results
from the relevant crystal structures. All complexes showed
peaks at ∼1630 and ∼1600 cm−1, assigned to the amide I and
amide II bands, respectively. These bands are shifted
∼30 cm−1 to lower energies from the respective bands of the
free ligand, suggesting coordination of the metal ion from the
deprotonated amide nitrogen.75,76 The stretching bands of the
imine ligated to the metal ion are expected between 1650 and
1600 cm−1; therefore, they are being masked by the amide
peaks. Complex 4 gave a strong peak at 1348 cm−1, assigned to
the asymmetric stretching vibration of the –NO2 moiety,
whereas the symmetric stretching vibration peak may be
underneath the amide bands. The strong peaks at 1470 and
Fig. 4 (A) Variation of the absorbance in the UV-vis spectrum of the
compound 1·2H2O (0.16 mM) in CH3OH with time. (B) Diagram of the
initial oxidation rates of the copper(II) complexes 1·2H2O, 2·CH3OH, and
2·CH3OH with one equivalent of Et3N in methyl alcohol in relation to
1454 cm−1 in the spectrum of complex 4, which did not appear their concentration.
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Fig. 5 Variation of the absorbance in the UV-vis spectra of the com-
pounds 2·CH3OH (black line) and 3 (red line) in CH3OH with time.
Fig. 7 The X-band c. w. EPR spectrum of compound 4 (0.16 mM) in
frozen MeOH (black line) and its simulated band (red line).
oxidation rate of 3 by air dioxygen is much slower than that
of 2.
which the bond length of Cu–ON(O), which is primarily
responsible for the dimerization in 4, is very long (2.685 Å)
and consequently very weak. Apparently, in solution, the
solvent molecules ligate the complex, resulting in two mono-
mers from the breakdown of 4.
EPR spectroscopy
The X-band c. w. EPR spectra of frozen methyl alcohol solu-
tions of complexes 1·2H2O, and 2·CH3OH gave unresolved
broad peaks for each complex at g = 2.048 and 2.191, respect-
ively. The X-band c. w. EPR spectrum of a frozen methyl
alcohol solution of 3 gave a rhombic anisotropic spectrum
exhibiting superhyperfine splitting with the four equatorial
nitrogen atoms (Fig. 6). The simulated spectrum was best
fitted using the following parameters: gz = 2.211, gy = 2.063,
gy = 2.034 and Az = 182, Ay = 12, Ax = 12, AzN1 = 8, AyN1 = 7,
AxN1 = 11, AzN2 = 11, AyN2 = 11, AxN2 = 17, AzN3 = 13, AyN3 = 12,
The oxidation of 1·2H2O and 2·CH3OH to 4 in CH3OH by
air was also monitored by X-band c. w. EPR spectroscopy. In
Fig. 8, the X-band c. w. EPR spectra of 2·CH3OH are shown as
a function of the reaction time. In addition to the peaks of
compound 4, a broad (∼20 gauss) peak at g = 1.941 was
formed. This value is very low for a CuII-centered radical; thus,
it was assigned to an organic centered radical.78 The formation
of the organic radical is justified by the first step of the mecha-
nism of oxidation of [CuII(capca)]+ to the azinate complex pro-
posed by the computational studies, in which the O2 binds to
the carbon atom of the imine group of [CuII(capca)]+, trans-
forming dioxygen to a superoxy radical. The X-band c. w. EPR
spectrum of 3 in CH3OH does not show any change after
exposure of the solution to air for 24 h.
A
xN3 = 8, AzN4 = 12, AyN4 = 11, AxN4 = 16 × 10–4 cm−1. These para-
meters are consistent with a CuII–N4 system.77
The X-band c. w. EPR spectrum of complex 4 in frozen
CH3OH also gave a rhombic anisotropic spectrum exhibiting
superhyperfine splitting with the three equatorial nitrogen
atoms (Fig. 7). The simulated spectrum was best fitted using
the following parameters: gz = 2.213, gy = 2.067, gy = 2.035 and
Az = 186, Ay = 11, Ax = 11, AzN1 = 7, AyN1 = 12, AxN1 = 14, AzN2
=
.
ESI-MS spectroscopy
16, AyN2 = 10, AxN2 = 12, AzN3 = 10, AyN3 = 15, AxN3 = 5 × 10–4 cm−1
The oxidation of [CuII(Hcapcah)]+ (1′) to [CuII(capca)]+ (2′) in
CH3OH solution was monitored by ESI-MS in real time.79–83
The conversion of 1′ to 2′ required approximately 24 h;
however, in the presence of one equivalent of Et3N, the reac-
tion proceeded to completion almost instantly, in agreement
with the results of the UV-vis studies. Concurrently with the
distribution envelopes of the species [CuII(Hcapcah)]+ and
[CuII(capca)]+, centred at m/z = 364.03 and 366.05, respectively,
These parameters are consistent with a CuII–N3O system.77
The fact that 4 gave a well-resolved c. w. EPR spectrum
suggests that the complex in solution does not retain the
dinuclear structure found in the solid state. This is in agree-
ment with the crystallographic data of the compound, in
Fig. 6 X-band c. w. EPR spectrum of 3 (0.16 mM) in frozen MeOH
(black line) and the simulated band (red line).
Fig. 8 The X-band c. w. EPR spectra of 2·CH3OH in frozen CH3OH
(0.80 mM) at different times.
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an additional envelope centred at m/z = 786.09 was observed;
this can be assigned to {[CuII(pipyaz)][CuII(capca)]+}, which
became dominant after 24 h (Fig. S1†). This is in agreement
with the results of the UV-vis kinetic studies, which showed
that the oxidation of [CuII(capca)]+ to [CuII(pipyaz)] is faster
than the oxidation of [CuII(Hcapcah)]+ to [CuII(capca)]+.
In addition, MS studies were conducted in solutions con-
taining one equivalent of [CuII(CH3COO)2]·H2O and one or two
equivalents of Hcapca immediately and 6 hours after mixing
the solutions. The recorded spectra revealed a major distri-
bution envelope centered at 364.03, which can be assigned to
[CuII(capca)]+. The additional distribution envelope centered at
286.11 was assigned to the [Hcapca(-H2O) + H+] species,
Fig. 9 Geometric and energetic reaction profile for the 1’ → 2’ trans-
formation by air oxidation, calculated at the PBE0/Def2-TZVP level of
theory in methyl alcohol solution.
whereas minor envelopes centered at 303.20 and 325.12 can be corresponding to a [CuII(Hcapcah)(OOH)]+ association, invol-
assigned to [Hcapca + H+] and [Hcapca + Na+], respectively. ving coordination of a hydroperoxyl group to the Cu(II) metal
The 1 : 2 solutions revealed an additional envelope assigned center through abstraction of a homolytic amine H atom by
to {[Cu(capca)]+
+ Hcapca} (m/z = 666.25) adduct. The dioxygen. The estimated O–O bond distance of 1.390 Å and the
envelope observed at m/z 786.09 can be assigned to the harmonic vibrational stretching frequency, νO–O, of 988 cm−1
•
{[CuII(pipyaz)][CuII(capca)]+} species. This peak is present in characterize the hydroperoxyl nature of the coordinated OOH
both CuII(CH3COO)2–Hcapca mixtures and becomes dominant radical.
in the m/z value region of 300 to 900 after 6 hours. The envel-
The [CuII(Hcapcah)(OOH)]+ intermediate is a transient
•
opes originating from [CuII(capca)]+-Hcapca adducts as well species; it immediately releases the OOH radical, yielding the
the ionized and dehydrated Hcapca species decreased as a [CuII(capcah•)]+ (S = 1) intermediate, which abstracts a methyl-
function of time as the amount of Hcapca present in the reac- enic H atom to produce the imine–Cu(II) species 2′. The
tion mixture was consumed.
release of the •OOH radical followed by the methylenic H atom
Finally, MS studies were conducted in CH3OH solutions abstraction corresponds to an exothermic process (ΔH =
•
containing one equivalent of CuIICl2·H2O and one equivalent −46.8 kcal mol−1). Alternatively, the coordinated OOH radical
of Hmcapca immediately, 6 hours and 24 hours after mixing may attack and abstract the methylenic H atom, which is
•
the solutions (Fig. S2†). The recorded spectra revealed a major found 2.628 Å from the coordinated O donor atom of OOH,
distribution envelope centered at 378.06, which can be yielding the imine–Cu(II) species 2′.
assigned to [CuII(mcapca)]+, with traces of [(CuII mcapca)2Cl]+
To understand why the copper(II) atom in the complex 1′
(798.08) (Fig. S2†) and some tiny peaks of unreacted material. coordinates the dioxygen reduced species (•OOH) and does not
After 6 h, the only difference is that the unreacted material is coordinate molecular O2, we examined the frontier molecular
almost consumed and the peak which corresponds to two indi- orbitals (FMOs) and the natural atomic charge distributions of
vidual clusters “flying” together becomes more intense the complexes and the possible transient intermediate
(Fig. S2†). Finally, after 24 h, the unreacted material has com- (Fig. S3†).
pletely disappeared and the two remaining distribution envel-
Inspection of Fig. S3† reveals that the singly occupied mole-
opes attributed to the complex are the only species that can be cular orbital (SOMO) and the lowest unoccupied molecular
detected (Fig. S2†).
orbital (LUMO) of [CuII(Hcapcah)]+ are mainly localized on the
aromatic phenyl moieties of the [CuII(Hcapcah)]+ species. The
SOMO involves only very small components located on the
Computational studies
First, we calculated the potential energy surface (PES) for the amine N (0.55%) and H (0.36%) atoms as well as on the
transformation of the amine–Cu(II) complex, [CuII(Hcapcah)]+ methylenic C atom (0.12%). Therefore, the interaction of the
(1′), to the imine–Cu(II) complex, [CuII(capca)]+ (2′), by air oxi- highest occupied molecular orbital (HOMO) of triplet dioxygen
dation. The geometric and energetic reaction profile for the (π1g* MO) with the SOMO and LUMO of [CuII(Hcapcah)]+
1′ → 2′ transformation by air oxidation, calculated at the PBE0/ cannot drive the coordination of dioxygen to Cu(II) to form a
Def2-TZVP level of theory in methyl alcohol solution, is [Cu(Hcapcah)(O2)]+ adduct. In effect, the dioxygen that
depicted schematically in Fig. 9. The PBE0 functional was abstracts the amine H atom from the Hcapcah− ligand is con-
chosen because it is well established to be suitable for per- verted to a hydroperoxyl (•OOH) radical, which can coordinate
forming calculations of the geometric and energetic properties to the Cu(II) metal center and yield the transient [CuII(capcah)
of transition metal complexes, providing good quality geome- (•OOH)]+ intermediate. The natural atomic charges on the
tries and energies with the best agreement with high-level coordinated O donor atom of OOH (qO = −0.342|e|) and the
CCSD(T) computations (references are given in the ESI†).
methylenic H atom (qH = 0.255|e|) in the transient
The first step of the reaction pathway of the oxidation of [CuII(capcah)(•OOH)]+ intermediate support that electrostatic
•
1′ to 2′ involves the activation of dioxygen by interaction with interactions are responsible for the H atom abstraction and
1′. Calculations located on the PES revealed a local minimum formation of hydrogen peroxide, H2O2.84
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Next, we calculated the potential energy surface (PES) for moiety forms a weak N(3)–O(2) bond with a bond length of
the transformation of the imine–CuII complex 2′ to the azinate- 1.469 Å (WBI = 0.917), while O(2′) forms a slightly stronger
CuII, [CuII(pipyaz)] complex by air oxidation. The formation of C(13)–O(2′) bond with a bond length of 1.433 Å (WBI = 0.931)
azinate-CuII from oxidation of the solvent molecules in the (Fig. 10). The estimated WBI for the N(3)–C(13) bond is 0.939;
reaction mechanism was excluded because the ligand is more this indicates remarkable weakening of the N(3)–C(13) bond
susceptible to oxidation. As is the case for the [CuII(Hcapcah)]+ compared to the N(3)–C(13) bond of complex 2′, which has a
(1′) complex, coordination of dioxygen to the CuII metal center WBI value of 1.664.
either in an end-on or a side-on coordination mode was not
The interaction of the peroxy group with the N(3)–C(13)
possible. Indeed, all attempts to locate a [CuII(capca)(O2)]+ moiety of the ligand capca− introduces remarkable structural
complex with O2 coordinated to Cu(II) in either an end-on or a changes into complex 2′. The CuII–N(3) distance is elongated
side-on coordination mode on the potential energy surface by 0.059 Å with respect to the corresponding distance in
(PES) were unsuccessful. When we used possible [CuII(capca) complex 2′, while the CuII–N(4), CuII–N(1) and CuII–N(2)
(O2)]+ adducts involving coordination of dioxygen to the Cu(II) coordination bonds are shortened by 0.040, 0.019 and 0.021 Å,
metal center either in an end-on or a side-on coordination respectively (Fig. 10 and Table 1). It is worth noting the signifi-
mode as starting geometries, the optimization procedures cant weakening of the N(3)–C(13) and N(3)–C(12) bonds, which
pushed the dioxygen to dissociate. No local minimum corres- are elongated by 0.198 and 0.037 Å, respectively. The charge
ponding to 1 : 1 CuII : O2 adducts formed, as [CuII(capca)(O2)]+ transfer of the natural atomic charge towards dioxygen that
was found even in some cases of solving the SCF convergence occurred in the [CuII(capca-O2)]+ intermediate amounted to
problems. Coordination of O2 to the Cu(II) center in complex 2′ −0.322|e|, which was distributed on the O(2) (−0.099|e|) and
could not be supported by the nature of the FMOs and the O(2′) (−0.223|e|) oxygen atoms. Perusal of the 3D plots of the
natural atomic charge distribution of complex 2′ (Fig. S3†). Mulliken spin density distribution in 2′ (Fig. S3†) and
Apparently, the lack of coordination of O2 to the CuII center [CuII(capca-O2)]+ (Fig. 10) shows that fractions of spin density
excludes the possibility of the formation of dinuclear amounting to 0.128 and 0.106 au, respectively, were trans-
Cu–O–O–Cu peroxo species. The experiments also did not ferred to N(3). In the [CuII(capca-O2)]+ intermediate, the O(2)
support the formation of dinuclear peroxo species. The SOMO of the peroxy moiety also acquires a small amount (0.013 au)
and LUMO of complex 2′ are mainly localized on the (Fig. 10) of spin density, giving radical character to the co-
N(3)–C(13) bond [20.1% on N(3) and 4.8% on C(13) and 14.3% ordinated peroxy moiety. The copper metal center in the
on N(3) and 23.1% on C(13), respectively]. Therefore, the inter- [CuII(capca-O2)]+ intermediate maintains its oxidation state of
3
action of the π1g*-HOMO of O2 with the SOMO and LUMO of II. The natural atomic charges on the copper(II) central atoms
2′ is localized on the N(3)–C(13) bond, yielding the [CuII(capca- in 2′ (QCu = 1.026|e|) and [CuII(capca-O2)]+ (QCu = 1.015|e|)
O2)]+ intermediate shown in Fig. 10.
remain practically unchanged.
In [CuII(capca-O2)]+, the dioxygen is activated and trans-
The energy barriers of the activation of O2 by the Cu(II) com-
formed to a peroxy group with a O–O bond distance of 1.447 Å plexes whether dioxygen binds Cu(II) (oxidation of 1 to 2,
(estimated Wiberg bond index (WBI) = 0.982), which is longer 35.7 kcal mol−1) or dioxygen binds the ligand (oxidation of 2
than the O–O bond distance of 1.423 Å in H2O2 (WBI = 1.014) to 4, 39.3 kcal mol−1) suggest a relatively high energy demand
calculated at the same level of theory. The O(2) of the peroxy for dioxygen activation by the Cu(II) complex. These values are
in agreement with the values found experimentally for the acti-
vation of O2 by other Cu(II) complexes.85–87
In the next step, the [CuII(capca-O2)]+ intermediate reacts
with either CH3OH or H2O (Fig. 11) to afford 5 or 5′ and
nitroso(pyridin-2-yl)methanol, PyCH(OH)(NO), via an exother-
mic process with predicted exothermicities of 26.1 and
23.4 kcal mol−1, respectively (Fig. 11). Subsequently, nitroso
(pyridin-2-yl)methanol is transformed to the more stable (by
2.0 kcal mol−1) 2-(nitromethyl)pyridine isomer, PyCH2(NO2).
The alternative PyCH(NOOH) tautomer was found to be less
stable than PyCH2(NO2) by 8.2 kcal mol−1
.
Furthermore, PyCH2(NO2) undergoes a simple Nitro-Mannich
reaction at the imine bond of a second [CuII(capca)]+.88 The
PyCH2(NO2) isomer contains an active methylene group and is
easily deprotonated in the presence of base (B), yielding the
[PyCH(NO2)]− nucleophile (Fig. 11). The estimated proton
affinity of the [PyCH(NO2)]− nucleophile is 188.6 kcal mol−1 at
the PBE0/def2-TZVP level in methyl alcohol solution.
Fig. 10 Selected structural parameters, natural atomic charges, frontier
molecular orbitals (FMOs) and 3D plots of the spin density (isosurface =
0.002) calculated at the PBE0/def2-TZVP level in methyl alcohol solu-
tion (arbitrary numbering) of the complex intermediate [CuII(capca-
O2)]+.
Next, the [PyCH(NO2)]− nucleophile attacks the C(13) elec-
trophillic center (QC(2) = 0.143|e|) of complex 2′, yielding inter-
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Scheme 6 Combination of two species B in CH3OH to obtain the
dinuclear compound 4.
hydrogen atom of the imino group. The design of the ligand
Hmcapca was based on (i) the steric hindrance induced by the
methyl group, which is larger than the hydrogen atom, and (ii)
the lower electrophilicity of the carbon atom of the imine
group due to the electron-releasing effect of the methyl group
(+I effect).
Gratifyingly, the complex [CuII(mcapca)]+ was stable under
dioxygen, as proved by UV-vis, c.w. EPR and ESI-MS spec-
troscopy, in marked contrast to [CuII(capca)]+.
This fully clarifies that the site of activation of dioxygen is
the ligand and not the copper(II) atom. In line with the experi-
mental data, theory also predicts that the interaction of
[CuII(mcapca)]+ with dioxygen towards the formation of the
[CuII(mcapca-O2)]+ species requires a higher energy barrier by
2.1 kcal mol−1 in comparison with the species [CuII(capca)]+.
Fig. 11 Geometric and energetic profiles of oxidation of 2’ by air, cal-
culated at the PBE0/def2-TZVP level in methyl alcohol solution.
mediate Im1 (Fig. 12) with an energy demand of 11.2 kcal
mol−1. Im1, surmounting an energy barrier of 5.3 kcal mol−1
,
Conclusions
releases the pyridine to yield intermediate A, which is trans-
formed to the final product B (see Scheme 6). Species B is
more stable than A by 2.7 kcal mol−1. It is obvious that two
units of B are combined in CH3OH solution to afford the
dinuclear compound 4 (see Scheme 6).
In conclusion, a series of mononuclear and dinuclear azinate
copper(II) compounds with three biologically relevant amidate
ligands was synthesized and structurally and physicochem-
ically characterized. The secondary amine group ligated to the
copper(II) of the complex [CuII(Hcapcah)]+ in methyl alcohol is
oxidized by air in a stepwise fashion to an imine, affording the
complex [CuII(capca)]+, and its ligated imine group is oxidized
The reason for the synthesis of ligand Hmcapa
to copper(II)-azinate species
B (Fig. 12 and Scheme 6).
To unambiguously prove that the site of interaction of dioxy-
gen with [CuII(capca)]+ is indeed the >CvN– group and not
the copper(II) atom, the ligand Hmcapca (Scheme 1) was syn-
thesized, in which a methyl group was substituted for the
Computational calculations for the system [CuII(capca)]+/O2,
supported by c. w. EPR measurements, proved that the imine
copper(II) complex 2·CH3OH is able to activate dioxygen by
direct attack of O2 to the organic substrate ligated to copper(II).
The formation of 4 occurs as a result of the oxidation of the
imine bond of one [CuII(capca)]+ to an azinate molecule com-
bined with a simple Nitro-Mannich reaction of the produced
azinate compound at the imine bond of a second [CuII(capca)]+.
This study supports that the coordination of O2 to the copper
ion is not mandatory in order for copper complexes (enzymes or
model species) to exhibit oxidase or oxygenase activity.
Author contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Fig. 12 Geometric and energetic profiles of the aza-Henry reaction of
complex 2’, with the [PyCH(NO2)]− nucleophile calculated at the PBE0/
def2-TZVP level in methyl alcohol solution.
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18 A. C. Rosenzweig and M. H. Sazinsky, Curr. Opin. Struct.
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Conflicts of interest
There are no conflicts to declare.
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Acknowledgements
The authors acknowledge the financial support by the
Research Promotional Foundation (RPF) of Cyprus and the
European Structural Funds ANABAΘMIΣH/ΠAΓIO/0308/32, the
Unit ORBITRAP-LC-MS, as well as Prof. Dr Spyros Perlepes and
Professor Leroy (Lee) Cronin. The authors would like to thank
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