Copper(ii) complexes with 2,2′:6′,2′′-terpyridine, 2,6-di(thiazol-2-yl)pyridine and 2,6-di(pyrazin-2-yl)pyridine substituted with quinolines. Synthesis, structure, antiproliferative activity, and catalytic activity in the oxidation of alkanes and alcohols with peroxides

Article abstract of DOI:10.1039/c9dt01922g

A series of 2,2′:6′,2′′-terpyridine (terpy), 2,6-di(thiazol-2-yl)pyridine (dtpy) and 2,6-di(pyrazin-2-yl)pyridine (dppy) derivatives with n-quinolyl substituents (n = 2 and 4) was used to synthesize five-coordinate complexes [CuCl₂(n-quinolyl-terpy)] (1-2), [CuCl₂(n-quinolyl-dtpy)] (3-4) and [CuCl₂(n-quinolyl-dppy)] (5-6), respectively. The main emphasis of the research was to investigate the impact of the triimine skeleton (terpy, dtpy and dppy) and n-quinolyl pendant substituent on the antiproliferative and catalytic properties of 1-6. The obtained Cu(ii) compounds were studied as antiproliferative agents against human colorectal (HCT116) and ovarian (A2780) carcinoma, and they were used as catalysts for the oxidation of alkanes and alcohols with peroxides under mild conditions. The kinetic characteristics of the oxidizing species generated by the catalytic system Cu(ii) complex-H₂O₂ in CH₃CN were obtained from the dependence of the alkane oxidation rate on its initial concentration. A model of competitive interaction of hydroxyl radicals with CH₃CN and RH in the catalyst cavity has been proposed which is based on the simultaneous study of kinetics and selectivity in alkane oxidations.

Full text of DOI:10.1039/c9dt01922g

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R. Raposo, Dalton Trans., 2019, DOI: 10.1039/C9DT01922G.
Volume 46
Number 10
14 March 2017
Pages 3073-3412
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Page 1 of 33
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DOI: 10.1039/C9DT01922G
Copper(II) complexes with 2,2’:6’,2”-terpyridine, 2,6-di(thiazol-2-yl)pyridine and 2,6-di(pyrazin-2-yl)pyridine
substituted with quinolines. Synthesis, structure, antiproliferative activity, and catalytic activity in oxidation of
alkanes and alcohols with peroxides †
Katarzyna Choroba,a Barbara Machura,*a Slawomir Kula,a Luis R. Raposo,b Alexandra R. Fernandes,*b
Rafal Kruszynski,c Karol Erfurt,d Lidia S. Shul’pina,e Yuriy N. Kozlov f,e and Georgiy B. Shul’pin *f,g,h
__________________________________________________________________________
a Institute of Chemistry, University of Silesia, Szkolna 9, 40-006 Katowice, Poland.
b UCIBIO, Departamento de Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa,
Campus de Caparica, 2829-516 Caparica, Portugal.
c Institute of General and Ecological Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924 Lodz, Poland
d Department of Chemical Organic Technology and Petrochemistry, Silesian University of Technology, Krzywoustego
4, 44-100 Gliwice, Poland
e Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
ulitsa Vavilova, dom 28, Moscow 119991, Russia
f Semenov Institute of Chemical Physics, Russian Academy of Sciences, ulitsa Kosygina, dom 4, Moscow 119991,
Russia.
g Plekhanov Russian University of Economics, Stremyannyi pereulok, dom 36, Moscow 117997, Russia
h People's Friendship University of Russia, ul. Miklukho-Maklaya, dom 6, Moscow 117198, Russia
† Electronic supplementary information (ESI) available. CCDC 1914390–1914395. For ESI and crystallographic data in
CIF or other electronic format see DOI: xxxxx
orcid.org/0000-0002-1448-9228 (Shulpina)
orcid.org/0000-0002-7053-4812 (Shulpin)
orcid.org/0000-0003-0168-5753 (Choroba)
orcid.org/0000-0001-7688-6491 (Machura)
orcid.org/0000-0003-4520-1570 (Kula)
_______________________________________________________________________
* Corresponding authors. Tel.: +7 495 7118443; fax: +7495 6512191 (GBS). E-mail addresses:
shulpin@chph.ras.ru (GBS), ma.fernandes@fct.unl.pt (AF), bmachura@poczta.onet.pl (BM).
Keywords:
1

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Alkanes
Complexes of copper
Functionalization of CH bonds
Hydroxyl radicals
Antiproliferative properties
Anti-cancer drugs
Highlights
- A series of 2,2’:6’,2”-terpyridine, 2,6-di(thiazol-2-yl)pyridine and 2,6-di(pyrazin-2-yl)pyridine derivatives
with n-quinolyl substituents (n = 2 and 4) was used to synthetize five-coordinate complexes.
- The obtained compounds were studied as anticancer agents against human colorectal (HCT116) and ovarian
(A2780) carcinoma.
- The complexes are good catalysts in oxidation of alkanes with H2O2 and of 1-phenylethanol with tert-butyl
hydroperoxide in acetonitrile.
- The complexes exhibited unusual selectivity in competitive oxidation of cyclohexane and acetonitrile.
- Hydroxyl radicals take part in the reaction.
______________________________________________________________
<Abstract:> A series of 2,2’:6’,2”-terpyridine, 2,6-di(thiazol-2-yl)pyridine and 2,6-di(pyrazin-2-yl)pyridine
derivatives with n-quinolyl substituents (n = 2 and 4) was used to synthesize five-coordinate complexes
[CuCl2(κ3-L)]. The main emphasis of the research was put to investigate the impact of the triimine skeleton
(terpy, dtpy and dppy) and n-quinolyl pendant substituent on the antiproliferative and catalytic properties of
[CuCl2(κ3-L)]. The obtained Cu(II) compounds were studied as antiproliferative agents against human
colorectal (HCT116) and ovarian (A2780) carcinoma and they were used as catalysts for the oxidation of
alkanes and alcohols with peroxides under mild conditions. The kinetic characteristics of the oxidizing
species generated by the catalytic system Cu(II) complex–H2O2 in CH3CN were obtained from the
dependence of the alkane oxidation rate on its initial concentration. A model of competitive interaction of
hydroxyl radicals with CH3CN and RH in the catalyst cavity has been proposed which is based on the study
simultaneously of kinetics and selectivity in alkane oxidations.
1. Introduction
Copper(I) and copper(II) complexes play important role in coordination chemistry, catalysis and
biochemistry (see, for example, Refs. [1-10]). In this research, three structurally related types of triimine
ligands (Fig. 1), 2,2’:6’,2”-terpyridine, 2,6-di(thiazol-2-yl)pyridine and 2,6-di(pyrazin-2-yl)pyridine
substituted with quinolines in 4’-position of the central pyridine, have been utilized to synthesize the
complexes [CuCl2(κ3-L)], which were studied as anticancer agents against human colorectal (HCT116) and
ovarian (A2780) carcinoma and were used as catalysts for the oxidation of alkanes and alcohols with
peroxides under mild conditions. The main aim of the work was to explore the impact of the triimine skeleton
2

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and n-quinolyl substituent on biological and catalytic activity of [CuCl2(κ3-L)]. Pyridine, thiazole and
pyrazine, used as perihedral rings in the employed ligands, significantly differ in σ-donor and π-acceptor
properties (pKa = 5.23, 2.52, 0.65 for pyridine, thiazole and pyrazine respectively). On the other hand,
depending on the position of nitrogen atom in pendant pyridyl ring, the ligands L1-L6: 4’-(quinol-2-yl)-terpy,
4’-(quinol-4-yl)-terpy, 4’-(quinol-2-yl)-dtpy, 4’-(quinol-4-yl)-dtpy, 4’-(quinol-2-yl)-dppy and 4’-(quinol-4-
yl)-dppy are expected to show significant difference in the dihedral angle between the plane of the central
pyridine and that of the pendant substituent, due to the inter-ring H•••H repulsions and H•••N hydrogen
bonds. It should be also noted that quinolines and their derivatives are well known for their antimalarial,
antimycobacterial, anticancer and antiviral behaviour [11-18].
Fig. 1 2,2’:6’,2”-terpyridine, 2,6-di(thiazol-2-yl)pyridine (4-R-dtpy) and 2,6-di(pyrazin-2-yl)pyridine (4-R-
dppy) ligands L1-L6 employed in this research.
Cisplatin and its analogues (carboplatin and oxaliplatin) are currently employed in the vast majority
of cancer treatments, including bladder, head and neck, ovarian and testicular cancers [19-23]. The
mechanism of their action involves formation of the coordination bond between the platinum(II) central ion
and the nitrogen atoms at the N7 position of the guanine in the DNA helix molecule. The formed 1,2- and
1,3-intrastrand DNA cross-links induce helical stretches in DNA and transcriptional inhibition, which results
in death of cancer cells via apoptosis [24-27]. Despite the clinical success of cisplatin-like drugs, however,
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there is a still need for novel com pounds of antiproliferative properties and new therapeutic solutions. It is a
result of severe side effects of platinum-based drugs, such as emetogenesis, neurotoxicity, myelotoxicity or
nephrotoxicity as well as the emergence of tumor cells with resistance to platinum-agents [27].
Promising solutions in this field involve the development of non-platinum anticancer agents with
bio-essential metal ions [28-39]. Among them, copper – the third most abundant transition metal present in
the cellular body – draws special scientific attention. It serves an important role in many biological processes
such as electron transfer, oxidation and dioxygen transport. Enzymes like dis-mutase have their key roles in
maintaining cellular metabolic waste [40-44]. Most importantly, numerous Cu(II) compounds have been
proven to be promising anticancer agents [45-50]. A remarkable anti-cancer activity was found for
copper(II)–terpyridine systems [51-59]. The complexes with unsubstituted 2,2’:6’,2”-terpyridine ligand -
[Cu(terpy)(ClO4)2(H2O)] and [Cu(terpy)2](CF3SO3)2‧2H2O [60], interacting with DNA via major groove
were found to display significant antiproliferative activity against non-small cell lung cancer cell line (A549).
The vast majority of 4’-substituted terpyridine copper(II) coordination compounds bind to double helix DNA
through intercalation, and their cytotoxicity behavior is strongly dependent on the substituent introduced into
2,2’:6’,2”-terpyridine moiety, which affect the geometry of the coordination compound and controls self-
assembly processes. The enhanced antiproliferative activity, higher in comparison with cisplatin, was
reported for [Cu(Anth-terpy)2](ClO4)2 against the cancer cell lines MCF-7, HepG2, H1299, HeLa, SiHa and
Ca Ski [61].
It should be also noted that copper complexes and among them copper-containing terpy compounds
are of a high potential interest as catalysts, especially in oxidation processes [62-65]. These complexes
contain the so-called redox ligands [66-70]. Noncovalent interactions play important role in catalysis.[71,72]
2. Experimental
2.1. Materials
.
The salt CuCl2 2H2O used in the synthesis was commercially available and was used without further
purification. Ligands L1-L6 were prepared according to the modified method employed in our previous
studies [73-75]. All solvents for the synthesis of the ligands and complexes were of reagent grade and
were used as received.
2.2. Instrumentation
The IR spectra were recorded using a Nicolet iS5 spectrophotometer in the range 4000-400 cm1 with
the samples in the form of KBr pellets. The electronic spectra were obtained using Nicolet Evolution
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220 in the spectral range 210–1000 nm in methanol and in the spectral range 190–1100 nm in the
solid state.
2.3. X-ray crystallographic analysis
The X-ray diffraction data was collected on Oxford Diffraction four-circle diffractometer Gemini A
Ultra with Atlas CCD detector using graphite monochromated Mo Ka radiation ( = 0.71073 Å) at
room temperature. Details concerning crystal data and refinement are given in Table 1. Diffraction data
collection, cell refinement and data reduction. were performed using the CrysAlisPro software [76]. The
structures were solved by the Patterson method using SHELXS97 and refined by full-matrix least-
squares on F2 using SHELXL97 [77,78]. All the non-hydrogen atoms were refined anisotropically, and
hydrogen atoms were placed in calculated positions refined using idealized geometries (riding model)
and assigned fixed isotropic displacement parameters, d(C–H) = 0.93 Å, Uiso(H) = 1.2 Ueq(C) (for
aromatic) and d(C–H) = 0.96 Å, Uiso(H) = 1.5 Ueq(C) (for methyl) and Uiso(H) = 1.5 Ueq(O) (for water).
The methyl groups were allowed to rotate about their local threefold axis. The water solvent molecule
of compound 5 is disordered over two positions with the 14:11 participation of the disordered domains.
Table 1 Crystal data and structure refinement for copper(II) compounds.
5

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Complex
(1)
(2)
(3)
(4)
(5)
(6)
used ligand
4’-(2-quinoline)-terpy
4’-(4-quinoline)-terpy
4’-(2-quinoline)-dtpy
4’-(4-quinoline)-dtpy
4’-(2-quinoline)-dppy
4’-(4-quinoline)-dppy
Empirical formula
Formula weight
C24H16Cl2CuN4
494.85
C24H16Cl2CuN4
494.85
C20H12Cl2CuN4S2
506.90
C20H18Cl2CuN4O3S2
560.94
C22H16Cl2CuN6O
514.85
C23H18Cl2CuN6O
528.87
Temperature [K]
Wavelength [Å]
295.0(2)
295.0(2)
295.0(2)
295.0(2)
295.0(2)
295.0(2)
0.71073
0.71073
0.71073
0.71073
0.71073
0.71073
Crystal system
Monoclinic
P21/c
Monoclinic
P21/n
Orthorhombic
Pna21
Triclinic
Monoclinic
I2/a
Triclinic
Space group
P-1
P-1
a = 7.7287(3)
b = 14.2823(7)
c = 18.7465(9)
α = 90
a = 7.9474(5)
b = 22.7151(11)
c = 11.6628(6)
α = 90
a = 23.3543(15)
b = 11.0536(6)
c = 7.7194(4)
α = 90
a = 7.8923(5)
b = 11.31080(10)
c = 13.6000(14)
α = 71.716(9)
β = 74.885(7)
γ = 87.322(6)
1112.06(15)
2
a = 13.4958(6)
b = 12.6508(6)
c = 25.5678(10)
α = 90
a = 7.8743(3)
b = 10.5456(7)
c = 13.8368(9)
α = 97.810(5)
β = 96.724(4)
γ = 93.962(4)
1126.28(11)
2
Unit cell dimensions [Å,]
β = 97.268(4)
γ = 90
β = 92.888(6)
γ = 90
β = 90
β = 101.202(5)
γ = 90
γ = 90
Volume [Å3]
Z
2052.68(16)
4
2102.8(2)
4
1992.8(2)
4
4282.1(3)
8
Density (calculated)
[Mg/m3]
1.601
1.563
1.690
1.675
1.597
1.559
Absorption coefficient
1.345
1.313
1.589
1.442
1.298
1.236
[mm-1]
F(000)
1004
1004
1020
570
2088
538
Crystal size [mm]
0.58 × 0.23 × 0.08
3.32 to 25.05
0.19 × 0.07 × 0.04
3.30 to 25.05
0.21 × 0.04 × 0.04
3.49 to 25.05
0.19 × 0.05 × 0.02
3.48 to 25.05
0.14 x 0.08 x 0.07
3.43 to 25.05
0.32 × 0.15 × 0.04
3.33 to 25.04
 range for data collection
[]
Index ranges
-9 h 8
-16 k 17
-21 l22
9696
-9 h 7
-27 k 23
-13 l13
8451
-27 h 23
-13 k 11
-9 l7
-9 h 9
-13 k 13
-12 l16
8252
-16 h 15
-14 k 15
-25 l30
9458
-9 h 9
-12 k 12
-16 l16
10462
Reflections collected
Independent reflections
Completeness to 2theta
Min. and max. transm.
Data / restraints / parameters
Goodness-of-fit on F2
8115
3624 (Rint = 0.0297) 3711 (Rint = 0.0541) 2947 (Rint = 0.0286) 3779 (Rint = 0.0698) 3771 (Rint = 0.0214) 3993 (Rint = 0.0298)
99.8%
0.848 and 1.000
3624 / 0 / 280
1.026
99.8%
0.609 and 1.000
3711 / 0 / 280
1.069
99.6%
0.759 and 1.000
2947 / 1 / 262
1.046
95.7%
0.764 and 1.000
3779 / 0 / 298
1.033
99.7%
0.783 and 1.000
3771 / 0 / 299
1.077
99.8%
0.813 and 1.000
3993 / 0 / 300
1.049
R1 = 0.0323
wR2 = 0.0725
R1 = 0.0466
R1 = 0.0629
wR2 = 0.1201
R1 = 0.1058
R1 = 0.0284
wR2 = 0.0609
R1 = 0.0338
R1 = 0.0490
wR2 = 0.1171
R1 = 0.0794
R1 = 0.0357
wR2 = 0.0876
R1 = 0.0485
R1 = 0.0328
wR2 = 0.0759
R1 = 0.0439
Final R indices [I>2(I)]
R indices (all data)
wR2 = 0.0776
0.22 and -0.34
wR2 = 0.1310
0.59 and -0.44
wR2 = 0.0640
0.31 and -0.27
wR2 = 0.1470
0.58 and -0.76
wR2 = 0.0926
0.58 and -0.31
wR2 = 0.0810
0.25 and -0.34
Largest diff. peak and hole
[e Å-3]
CCDC number
1914390
1914391
1914392
1914393
1914394
1914395
2.4. Synthesis of the complexes
General synthesis of [CuCl2(Rn-terpy)], [CuCl2(Rn-dtpy)] and [CuCl2(Rn-dppy)] (1-6).
.
The salt CuCl2 2H2O (0.17 g, 1 mmol) dissolved in methanol (10 ml) was added dropwise to a hot
methanolic solution of the corresponding Ln (1 mmol). The resulting solution was stirred at room
temperature for 2 h, and after a few days green crystalline solids were precipitated. Single crystals of
[Cu(Ln)Cl2] with ligands L1-L4 suitable for X-ray were obtained directly from the mother liquor. To obtain
single crystals of [Cu(Ln)Cl2] with 2,6-di(pyrazin-2-yl)pyridine ligands (L5 and L6) slow diffusion technique
.
in a H-tube was used. The one arm of the H-tube was filled with a methanolic solution of CuCl2 2H2O, while
a CH2Cl2/CH3OH solution of the appropriate ligand L5 or L6 was placed in the other arm of the H-tube. The
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H-tubes were allowed to stand for a period of about two weeks, and well-shaped X-quality crystals of 5 and 6
were obtained.
[CuCl2(L1)] (1): Yield 55%. HRMS (ESI): calcd for C24H16N4ClCu+ 458.0359 found 458.0359. IR
(KBr, cm-1): 3055 (m), 3018 (m), 1611 (s), 1568 (m), 1552 (m), 1508 (m), 1475 (s), 1438 (m), 1416
(m), 1380 (w), 1336 (m), 1304 (w), 1248 (m), 1160 (m), 1125 (w), 1033 (m), 1019 (m), 902 (w), 893
(w), 835 (m), 802 (m), 790 (s), 747 (m), 728 (w), 690 (m), 656 (m), 645 (m), 623 (w), 569 (w), 480
(w), 418 (w). UV-Vis (MeOH, λmax, nm (ε ‧ 104, dm3‧mol-1‧cm-1)): 216 (4.78), 226 (5.48), 276 (3.99),
330 (2.89), 701 (0.01). UV-Vis (solid, nm): 232, 283, 331, 423, 753.
[CuCl2(L2)] (2): Yield 50%. HRMS (ESI): calcd for C24H16N4ClCu+ 458.0359 found 458.0359. IR
(KBr, cm-1): 3062 (m), 3014 (m), 1616 (s), 1603 (m), 1588 (m), 1567 (m), 1555 (s), 1509 (m), 1477
(s), 1447 (w), 1428 (m), 1412 (m), 1391 (w), 1362 (w), 1306 (m), 1288 (w), 1248 (m), 1220 (w),
1207 (w), 1161 (m), 1129 (w), 1048 (w), 1035 (m), 1018 (m), 923 (m), 874 (w), 855 (w), 846 (w),
808 (m), 795 (m), 767 (s), 737 (w), 671 (m), 646 (m), 623 (m), 425 (w). UV-Vis (MeOH, λmax, nm (ε
‧ 104, dm3‧mol-1‧cm-1)): 216 (5.12), 224 (5.38), 263 (2.71), 287 (2.06), 328 (1.65), 340 (1.51), 703
(0.01). UV-Vis (solid, nm): 227, 291, 329, 680, 747.
[CuCl2(L3)] (3): Yield 70%. HRMS (ESI): calcd for C20H12N4S2ClCu+ 469.9488 found 469.9488. IR
(KBr, cm-1): 3107 (w), 3069 (m), 2988 (m), 1846 (w), 1793 (w), 1668 (w), 1608 (s), 1591 (m), 1548
(m), 1508 (m), 1494 (m), 1480 (s), 1452 (s), 1437 (m), 1426 (m), 1379 (m), 1356 (m), 1336 (m),
1314 (m), 1280 (w), 1248 (m), 1232 (m), 1214 (m), 1191 (s), 1158 (w), 1143 (w), 1123 (w), 1086
(m), 1023 (m), 928 (w), 899 (m), 888 (w), 839 (s), 790 (s), 773 (s), 759 (s), 741 (m), 697 (w), 642
(m), 621 (w), 595 (m), 573 (w), 514 (w), 474 (w). UV-Vis (MeOH, λmax, nm (ε ‧ 104, dm3‧mol-1‧cm-
1)): 213 (3.47), 230 (3.33), 282 (3.03), 307 (2.68), 333 (2.38), 372 (1.02), 748 (0.008). UV-Vis
(solid, nm): 228, 279, 333, 383, 814.
[CuCl2(L4)] (4): Yield 65%. HRMS (ESI): calcd for C20H12N4S2ClCu+ 469.9488 found 469.9490. IR
(KBr, cm-1): 3421 (m), 3028 (m), 1609 (s), 1584 (m), 1567 (w), 1549 (m), 1509 (w), 1494 (m), 1482
(s), 1446 (s), 1422 (m), 1350 (m), 1302 (w), 1245 (m), 1198 (s), 1127 (w), 1077 (w), 1026 (w), 892
(w), 877 (w), 866 (w), 855 (w), 791 (s), 744 (m), 720 (w), 679 (w), 630 (m), 615 (m), 594 (w), 443
(w), 424 (w). UV-Vis (MeOH, λmax, nm (ε ‧ 104, dm3‧mol-1‧cm-1)): 214 (4.46), 224 (4.24), 253 (2.05),
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278 (2.43), 304 (2.33), 346 (1.55), 364 (1.17), 745 (0.008). UV-Vis (solid, nm): 230, 278, 331, 402,
787.
+
[CuCl2(L5)] (5): Yield 90%. HRMS (ESI): calcd for C22H14ClCuN6 460.0264 found 460.0271. IR
(KBr, cm-1): 3576 (w), 3472 (m), 3042 (w), 1608 (s), 1591 (m), 1550 (m), 1508 (m), 1470 (w), 1454
(m), 1436 (m), 1418 (w), 1394 (m), 1377 (m), 1359 (w), 1336 (w), 1314 (w), 1293 (w), 1233 (w),
1181 (s), 1146 (m), 1082 (w), 1039 (s), 1025 (m), 945 (w), 901 (m), 856 (m), 841 (s), 792 (w), 785
(w), 770 (m), 720 (m), 691 (w), 685 (w), 621 (w), 568 (w), 518 (w), 475 (m), 414 (m). UV-Vis
(MeOH, λmax, nm (ε ‧ 104, dm3‧mol-1‧cm-1)): 213 (2.95), 224 (2.90), 286 (2.02), 339 (1.66), 355
(1.31), 745 (0.006). UV-Vis (solid, nm): 230, 278, 330, 392, 450, 777.
+
[CuCl2(L6)] (6): Yield 95%. HRMS (ESI): calcd for C22H14ClCuN6 460.0264 found 460.0267. IR
(KBr, cm-1): 3421 (s), 3061 (m), 1653 (w), 1615 (s), 1586 (m), 1553 (m), 1511 (w), 1477 (m), 1459
(s), 1432 (w), 1404 (m), 1383 (m), 1307 (m), 1283 (w), 1252 (w), 1185 (s), 1151 (m), 1096 (w),
1074 (w), 1039 (s), 901 (w), 868 (m), 847 (m), 767 (m), 743 (w), 689 (w), 669 (w), 627 (m), 493
(m), 428 (m). UV-Vis (MeOH, λmax, nm (ε ‧ 104, dm3‧mol-1‧cm-1)): 216 (4.34), 226 (4.86), 276
(2.37), 338 (1.43), 350 (1.96), 735 (0.007). UV-Vis (solid, nm): 229, 275, 325, 390, 450, 750.
2.5. Biological assays
Cell culture
Cancer derived cell lines HCT116 (colorectal carcinoma) and A2780 (ovarian carcinoma) and Human normal
primary fibroblasts were grown in Dulbecco’s modified Eagle medium (DMEM) supplemented with 10%
(v/v) fetal bovine serum (FBS) and 1% PenStrep solution (all solutions from Thermo Fischer Scientific,
Waltham, MA, USA), and maintained at 37ºC in a humidified atmosphere with 5% (v/v) CO2 as previously
described [79,80, 88,89]. HCT116 and human epidermal fibroblasts from American Type Culture Collection
(ATCC, Manassas, VA, USA and A2780 cell line was purchased from Merck (Darmstadt, Germany).
Determination of dose response curves - Viability assays
In 96-well plates.7500 cells/well were seeded and after 24 h, the culture media was replaced and cells
incubated for another 48 h with increasing concentrations of DMSO or Cu(II) complexes bearing quinol-
substituted terpy, dtpy or dppy ligands [79-81]. After this incubation, cell viability was evaluated with the
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CellTiter 96® Aqueous Non-Radioactive Proliferation assay (MTS assay) (Promega, Madison, WI, USA).
The dehydrogenase enzymes of viable cells (metabolically active) reduce 3-(4,5-dimethylthiazol-2-yl)-5-(3-
carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS), with phenazinemethosulfate
(PMS), an electron coupling reagent, to form formazan that can measured. Absorbance at 490 nm in a Bio-
Rad microplate reader, model 680 (Bio-Rad, Hercules, CA, USA) is used to determine the amount of
formazan formed by viable cells. The quantity of formazan formed is directly proportional to viable cells.
The GraphPad Prism 7.00 program (GraphPad Software, La Jolla, CA, USA) is used to determine the
concentration that inhibits 50% of the cellular proliferation (IC50) as compared to the respective solvent
control (DMSO 0.1% v/v) using dose response curves.
Evaluation of apoptosis in HCT116 cells by fluorescence microscopy (Hoechst staining)
In 24-well plates, 3.75x104 HCT116 cells were seeded per well and incubated for 24 h and then incubated for
48 h with IC50 concentrations of Cu(II)quinolyl-4-yl-terpy (2) and Cu(II)quinolyl-2yl-dppy (5), as previously
described [82,83]. DMSO 0.1% (v/v) was used as solvent control. After the 48 h incubation, cells were
washed with PBS 1X, and then fixed with 4% (w/v) paraformaldehyde and stained for 15 min with 7.5
µg/mL Hoechst 33258 (Thermo Fischer Scientific). Again, cells were washed thrice in PBS 1X and then.
photographed with a Ti-U Eclipse inverted fluorescence microscope (Nikon, Tokyo, Japan) using a “DAPI”
fluorescence filter cube (Nikon) and images were captured with the NIS Elements Basic software (Nikon). At
least 50 nuclei from 3 random microscopic fields were scored per replicate and the condensation and
fragmentation of HCT116 nuclei, were used to identify apoptotic cells.
Reactive oxygen species (ROS) production of in HCT116 cells
As previously described [82,83,84], 6-well plates with 3.75x104 HCT116 cells per well were incubated with
DMSO 0.1% (v/v) (vehicle control), 25 µM H2O2 (positive control) and IC50 concentrations of
Cu(II)quinolyl-4-yl-terpy (2) and Cu(II)quinolyl-2yl-dppy (5) for 48 h. Then followed an incubation with 10
μM 2′,7′-dichlorodihydrofluorescein diacetate (H2DCF-DA) (ThermoFisher Scientific) for 30 min at 37 ºC.
The acetate groups of the compound are removed by intracellular esterases in the presence of ROS,
increasing the fluorescence of the compound. A Attune acoustic focusing cytometer (ThermoFisher
Scientific) was used to measure the fluorescence of HCT116 cells and the retrieved data analyzed in the
respective software (Attune Cytometric Software, vs. 2.1).
Statistical analysis
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Data presented in this work are expressed as the mean±SD of at least three independent experiments.
Statistical significance was determined using the Student t-test. Differences were considered significative if
p<0.05. The GraphPad Prism v7.00 (GraphPad Software, La Jolla, CA, USA) was used to determine IC50 and
perform statistical analysis.
2.6 Oxidation reactions
The oxidation reactions were typically carried out in air in thermostated Pyrex cylindrical vessels with
vigorous stirring; total volume of the reaction solution was 2.5 mL (CAUTION: the combination of air or
molecular oxygen and H2O2 with organic compounds at elevated temperatures may be explosive!). Initially, a
portion of 50% aqueous solution of hydrogen peroxide or 70% aqueous tert-butyl hydroperoxide was added
to the solution of the catalyst and substrate in acetonitrile. The reaction solutions were analyzed by GC
(instruments DANI-86.10, capillary column 50 m × 0.25 mm × 0.25 m, Carbowax 20M; the carrier gas was
helium, and LKhM-80-6, columns 2 m with 5% Carbowax 1500 on 0.25–0.315 mm Inerton AW-HMDS;
carrier gas was argon). Usually samples were analyzed twice, i.e. before and after the addition of the excess
of solid PPh3. This method was developed and used previously by Shul’pin [85-91]. Since alkyl
hydroperoxides, which are transformed in the GC injector into a mixture of the corresponding ketone and
alcohol, are quantitatively reduced with PPh3 to give the corresponding alcohol, this method allows us to
calculate the real concentrations not only of the hydroperoxide but of the alcohols and ketones present in the
solution at a given moment.
3. Results and discussion
3.1 Synthesis and characterization of compounds 1-6
The quinolyl-substituted 2,2′:6′,2′′-terpyridine, 2,6-di(thiazol-2-yl)pyridine and 2,6-di(pyrazin-2-yl)pyridine
derivatives (Fig. 1) were synthesized according to the modified one-pot method [92,93,94] based on
condensation of the corresponding aldehyde (2-quinolinylcarboxaldehyde or 4-quinolinylcarboxaldehyde)
with 2-acetylpyridine, 2-acetylthiazole and 2-acetylpyrazine, respectively. The Cu(II) complexes [Cu(Ln)Cl2]
were isolated as green solids by reaction of methanol solution of the appropriate quinolyl-substituted triimine
ligand (Ln) with methanolic solution of CuCl2 ‧ 2H2O.
The molecular formulae of the Cu(II) complexes were determined by single crystal X-ray diffraction analysis
and confirmed by high resolution mass spectrometry HR-MS (Fig. S1, ESI†). In the IR spectra, the
vibrational bands ν(C=C) and ν(C=N) assigned to coordinated N–heterocyclic ligands are observed in the range
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1608–1549 cm–1 (see Fig. S2, ESI†) and are slightly shifted towards higher wavenumbers compared to the
free ligands.
Perspective views showing the molecular structures of 1-6 with the atom numbering are presented in
Fig. 2. The selected bond distances and bond angles of 1-6 are given in Table S1, ESI†.
(1)
(2)
(3)
(4)
(5)
(6)
Fig. 2 Perspective views showing the molecular structures of the copper(II) complexes with the atom
numbering. Displacement ellipsoids are drawn at the 50% probability level.
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The copper(II) centre, coordinated to the triimine ligand (Ln) and chloride ion, displays a distorted
square-pyramidal geometry. The angular structural index parameter , expressed as the difference between
the two largest angles divided by 60 [95], adopts value close to 0, it is 0.093 for 1, 0.056 for 2, 0.092 for 3,
0.003 for 4, 0.014 for 5 and 0.090 for 6. The deviations of N–Cu–N angles in the basal plane from the
idealized values of 90 and 180 are attributed to the geometrical constraints issued from 3N coordination of
the Ln ligand. Occurrence of the five-membered chelate rings of tridentate Ln results in N(2)–Cu(1)–N(1) and
in N(2)–Cu(1)–N(3) angles falling in the range 77.90(14)–79.71(8). The nitrogen N(1), N(2), N(3) and
chlorine Cl(1) atoms in the basal plane are nearly coplanar within 0.1160(11) Å for 1, 0.1364 (22) Å for 2,
0.1209(20) Å for 3, 0.1837(22) Å for 4, 0.2021(13) Å for 5 and 0.1067(10) Å for 6, while the copper
center is displaced 0.2136(7) Å for 1, 0.2388(15) Å for 2, 0.2530(14) Å for 3, 0.2876(15) Å for 4, 0.2527(9)
Å for 5 and 0.2677(7) Å for 6 from the least-squares plane towards the chloride ion in the apical site.
In analogy to the related square-pyramidal Cu(II) complexes, the Cu–N bond of the central pyridine is
shorter compared to those of peripheral triimine rings, and the Cu–Cl apical bond length is longer than the
Cu–Cl basal distance. The elongation of Cu(1)–Cl(2) is attributed to Jahn Teller distortion [96].
The striking difference between the Cu(II) complexes bearing quinol-2-yl substituted ligands (1, 3
and 5) and those with quinol-4-yl group (2, 4 and 6) concerns relative orientation of the pendant substituent
and central pyridine ring. Due to the inter-ring H•••H repulsions. The quinol-4-yl unit is strongly inclined to
the central pyridine at 53.96(14) in 2, 49.10(15) in 4 and 52.50(6) in 6. On the contrary, the pendant
substituent of 1, 3 and 5 is quite coplanar with the central pyridine ring, with dihedral angles of 7.91(13) in
1, 13.91(16) in 3 and 4.68(8) in 5. In all the complexes, the triimine skeleton is approximately planar. The
maximum value of the dihedral angle between the mean planes of the central pyridine and peripheral piryd-2-
yl/thiazol-2-yl/pyrazin-2-yl rings was found for 6 (8.58(13)°).
A summary of the intermolecular contacts in the crystal structures 1-6 is given in Fig. S3 and Tables
S2-S4, ESI†. Crystal packing of 4, 5, and 6 appears to be strongly affected by hydrogen bonds C—H•••O,
O—H•••Cl and O—H•••N formed with participation of lattice solvent molecules (H2O in 4 and 5 and MeOH
in 6). Furthermore, the reported crystal structures are stabilized by weaker C–H•••Cl, ••• and •••Cl
interactions. Most remarkably, in the crystal lattice of 4, the water molecules O(2)W and O(3)W are arranged
into four-membered rings, as shown in Fig. 3. In each water tetramer (H2O)4, the O(2)W and O(3)W act as
both hydrogen donors and acceptors molecules. The O–O–O angles are 84.0(3)° and 96.0(3)°, and the O···O
separations equal to 2.761(9) Å and 2.823(9) Å. Noteworthy, the O···O distances are close to the
experimental values for liquid water at 298 K (2.854 Å) [97-100] and hexagonal ice (Ih) at 183K (2.759 Å)
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[101] as well as they fall in the range 2.70–2.94 Å obtained by quantum mechanical and semiempirical
methods for four-membered water cycles [102- 107]. They are also well correlated with the values reported
for other compounds containing tetramer assembly, including {[Co2(bib)2(fum)(HCOO)2(H2O)2].10H2O}n
.
.
(2.731 Å and 2.846 Å) [108], [Co(phen)3]S4O6 7H2O (2.785 Å and 2.910 Å) [109], [Ag2(pda)(bipy)2]n 4nH2O
(2.775 Å and 2.793 Å) [110], [Co2(bta)(H2O)8]n·4nH2O (2.772 Å, 2.751 Å and 2.780 Å, 2.773 Å) [111],
[Cu(adipate)(4,4-bipyridine)].(H2O)2 (2.775 Å, 2.896 Å) [112], [(Bpyph)(SCN)2]·2H2O (2.83 Å and 2.80 Å),
{(HBpyph)[Fe(CN)6]}·5.5H2O (2.69 Å and 2.76 Å) [113], [Tc4(CO)12-(μ3-OH)4·4H2O] (2.940 Å) [114] and
2-
{[Ni(IP)(H2O)4].(2H2O)(SO4 )} (2.723 Å) [115].
Fig. 3 Supramolecular double chains and hydrogen bonds involving water molecules in complex4.
The water tetramers are linked through O(2)—H(2A)•••Cl(1) with two complex molecules
[Cu(Ln)Cl ] giving rise to the formation of a supramolecular double chains along [
], additionally
111
2
stabilized by O(1)—H(1B)•••Cl(1), O(1)—H(1A)•••N(4) and C(14)—H(14)•••O(2). The formed double
chains are further interlinked into 3D network by C(2)—H(2)•••Cl(2) and O(3)—H(3A)•••Cl(2) hydrogen
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bonds
and
•••
interactions
involving
thiazole:
[-1-x,1-y,2-z]
Cg(S(1)/C(3)/N(1)/C(1)/C(2))•••Cg(S(1)/C(3)/N(1)/C(1)/C(2))
;
Cg(S(1)/C(3)/N(1)/C(1)/C(2))•••Cg(S(2)/C(9)/N(3)/C(10)/C(11)) [-1+x,y,z]; Cg(S(2)/C(9)/N(3)/C(10)/C(11)) •••
[-x,-y,2-z]
Cg(S(2)/C(9)/N(3)/C(10)/C(11))
and quinoline rings (Cg(N(4)/C(12)/C(13)/C(14)/C(15)/C(16)) •••
[-x,1-y,1-z]
Cg(N(4)/C(12)/C(13)/C(14)/C(15)/C(16))
Cg(C(15)/C(16)/C(17)/C(18)/C(19)/C(20)) [1-x,1-y,1-z]
and
Cg(N(4)/C(12)/C(13)/C(14)/C(15)/C(16)•••
.
3.2 Cytotoxicity studies
The toxicity of the Cu(II) complexes 1-6 was evaluated in A2780 (ovarian cancer derived cell line), HCT116
(colorectal cancer derived cell line) and in normal dermal fibroblasts (Figs. 4 and 5). Dose response curves
were obtained and the toxicity between the compounds was compared using the IC50 values (concentration
that inhibits 50% of cell proliferation) for each complex in each cell line (Table 2).
1
2
3
120
100
80
60
40
20
0
120
100
80
60
40
20
0
120
100
80
60
40
20
0
HCT116
A2780
*
*
*
*
*
*
*
1
1
1
2
3
5
10 50
10
50
75
0.1
0.2
0.3
0.4
0.5
0.7
0.1 0.2 0.3 0.4 0.5
0.1
100
0.05
0.75
0.05
0.75
1.25
Concentration (M)
Concentration (M)
Concentration (M)
4
5
6
120
100
80
60
40
20
0
120
100
80
60
40
20
0
120
100
80
60
40
20
0
HCT116
A2780
*
*
*
*
*
*
*
1
1
1
10
30
50
75
10
50
10
50
75
0.1
0.5
0.1
0.2
0.3
0.5
0.1
100
100
0.05
0.75
Concentration (M)
Concentration (M)
Concentration (M)
Fig. 4 Cytotoxicity of complexes 1-6 in HCT116 (red) and A2780 (blue) cancer cell lines. Cell viability was
determined by the MTS method performed after 48 h of exposure to increasing concentrations of each
complex. DMSO 0.1% (v/v) was used as solvent control. The results presented are mean ± SD of three
independent assays. A p-value <0.05 is indicated by the symbol *.
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120
100
80
60
40
20
0
1
2
3
4
5
6
*
*
*
1
5
10
20
30
40
50
7.5
Concentration (M)
Fig. 5 Cytotoxicity of complexes 1-6 in human normal primary fibroblasts. evaluated after 48 h of exposure
to increasing concentrations of each complex. Cell viability was determined by the MTS method. DMSO
0.1% (v/v) was used as solvent control condition. The results presented are mean ± SD of three independent
assays. A p-value <0.05 is indicated by the symbol *.
Table 2 Values of relative IC50 (µM) of Cu(II) complexes 1-6 in HCT116 and A2780 cancer lines and in
human normal dermal fibroblasts. The results presented are mean ± SD of three independent assays.
Cell lines
HCT116
A2780
1 (µM)
0.3±0.09
0.5±0.08
9.4±0.02
2 (µM)
0.3±0.06
0.5±0.09
>50
3 (µM)
>100
4 (µM)
>100
5 (µM)
6 (µM)
0.2±0.08
>100
2.4±0.13
>50
16.5±0.14
>50
0.6±0.06 75<IC50<100
27.64±0.11 >50
Fibroblasts
_________________________________________________________________________________
Antiproliferative activities of the complexes followed the trend 1~2~5 > 3~4 > 6 in both cancer cell
lines, HCT116 and A2780 (Fig. 3 and table 1). In fibroblasts, the trend was slightly different, 1 > 5 >
2~3~4~6, with 2 and 6 showing antiproliferative effect (higher cell viability) than 1 and 5 (Fig. 4 and Table
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1). The Cu(II) complexes with quinolyl-substituted 2,2′:6′,2′′-terpyridines (terpy), 1 and 2, showed to be the
most active compared to other complexes in both cancer cell lines, HCT116 and A2780 (Figure 3 and Table
1). Less active were the Cu(II) complexes with quinolyl-substituted 2,6-di(thiazol-2-yl)pyridines (dtpy),
complexes 3 and 4, that displayed an antiproliferative effect only in the A2780 ovarian cancer cell line (Figs.
3 and 4 and Table 1). This specificity for the A2780 is corroborated by our previously results with other
Cu(II) and Pt(II) complexes with different 4’-dtpy substitutions [65]. Interestingly, the loss of cell viability
induced by Cu(II) complexes with ligands bearing quinol-2-yl moieties (1 and 5) is higher than that presented
by the Cu(II) complexes bearing ligands with quinol-4-yl moieties (2 and 6) (Table 1). The Cu(II)quinolyl-2-
yl-dppy, complex 5, exhibited loss of cell viability similar to both Cu(II)terpy complexes, 1 and 2, while the
Cu(II)quinolyl-4-yl-dppy, complex 6, presented no significative antiproliferative effect in none of the cell
lines tested. It is possible to observe an effect of the quinolyl bond position on cytotoxicity within Cu(II)dtpy
and Cu(II)dppy complexes in A2780 cell line and for the Cu(II)terpy complexes also in fibroblasts: the
Cu(II) complexes with quinolyl-2-yl substitutions are more cytotoxic than the complexes with quinolyl-4-yl
substitutions (Figures 3 and 4 and table 1).
Our previous work have shown a selective antiproliferative activity towards A2780 cell line of the
Pt(II) and Cu(II) complexes with dtpy ligands [65]. Comparing the antiproliferative effect the Cu(II)quinolyl-
2-yl-dtpy with other complexes with 4’-dtpy ligands already tested by us, it is possible to observe that this
antiproliferative effect is similar in A2780, ranging from 2.4 µM (this report) to 11 µM [65]. Comparing
metal complexes with terpy ligands in this report with others already published by us, the IC50 ranges from
0.27 µM (this report 0.3 µM, the lowest in Cu(II) complexes) to > 100 µM µM in the HCT116 cell line and
in the A2780 cell line ranges from 0.5 µM (this report) to > 100 µM (Table 1) [101,65,116]. In normal
human fibroblasts, metal complexes with terpy displayed cytotoxicity ranging from 0.3 µM to > 100 µM
(Table 1) [65,116]. In this report, as well as in our previous works, it is possible to observe that the 4’-terpy
substitution can attenuate the antiproliferative effect of the terpy ligand in fibroblasts (65, 82, 116, Table 1).
The Cu(II)quinolyl-4-yl-terpy complex has a decreased cytotoxicity for normal human fibroblast cells while
maintaining cytotoxicity towards both cancer cell lines tested, HCT116 and A2780 (Figs. 3 and 4 and Table
1).
Considering the higher antiproliferative effect in cancer cell lines and low activity in normal cells complexes
2 and 5 were selected for further biological studies in order to gain insights into the mechanisms that
selectively reduce cancer cell line viability. HCT116 cells were incubated for 48 h with IC50 concentrations
of either complex. Fluorescence microscopy of cells stained with Hoechst 33258 enable the observation of
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cell nuclei and, if present, the identification of apoptotic bodies which result from the chromosome
condensation and fragmentation (Fig. 5). These apoptotic bodies are a hallmark apoptosis in cells [65,116].
B
A
D40
C
*
*
30
20
10
0
2
5
DMSO
Fig. 6 Apoptosis induced after 48 h exposure of HCT116 cells to 0.1% (v/v) DMSO (A), IC50 concentration
of (2) (B) and of (3) (C) evaluated by nuclei staining with Hoechst 33258. (D) % of apoptotic cells calculated
based on the analysis of more than 5 different Hoechst fluorescence images for each condition. DMSO 0.1%
(v/v) was used as solvent control. The symbol * indicates that the p-value < 0.001. Scale bars have a 20 µm
length. White arrows indicate nuclei with apoptotic bodies.
It is possible to observe that exposure to both Cu(II) 4’-quinolyl-4-yl-terpy (2) and Cu(II) 4’quinolyl-
2-yl-dppy (5) complexes increases the percentage of cells in apoptosis when compared to the control
condition (Fig. 6). Apoptotic figures increase approximately 124 % and 192 % in cells treated with IC50
concentrations of 2 and 5, respectively (Fig. 6). The results for complex 2 are in accordance with our
previous published results for with other metal complexes with terpy and dtpy ligands [65,116]. The results
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for the Cu(II) quinolyl-2yl-dppy complex (5), indicates that apoptosis may also play a role in the cytotoxicity
of Cu(II) dppy complexes in cancer cells (Fig. 6).
One of the underlying mechanisms that can potentially trigger apoptosis in cancer cells is the increase
in the production reactive oxygen species (ROS) [117]. For this reason, ROS production was investigated
HCTT116 cells exposed for 48 h to IC50 concentrations of complexes 2 and 5 (Fig. 7).
8
6
*
4
2
0
2O2
2
5
H
DMSO
Fig. 7 Production of reactive oxygen species (ROS) in HCT116 cells exposed for 48 h to IC50 concentrations
of complex 2 and 5. DMSO 0.1% (v/v) was used as solvent control and 25 µM H2O2 was used as positive
control. The symbol * indicates that the p-value ≤ 0.0001.
It is possible to observe a significant increase of 97% of ROS in HCT116 cells exposed to complex 5
when compared to the solvent control (Fig. 7). Although not statistically significant, an increase of 31% was
also observed in HCT116 cells exposed to 2 (Fig. 7). In our previous published results, there was also a
correlation between an increase in the percentage of apoptotic cells with increase in ROS in cells exposed to
metal complexes with terpy ligands [65,116].
Our results show that Cu(II)terpy and Cu(II)dppy complexes have an antiproliferative potential
against colorectal and ovarian carcinoma cells. The most cytotoxic are the terpy complexes. Some 4’terpy
substitutions can alleviate toxicity for normal human fibroblasts. In particular, the 4’quinolyl-4-yl-terpy
substitution significantly diminishes cytotoxicity in normal fibroblasts while maintaining cytotoxicity in
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cancer cells (HCT116 and A2780) (Figs. 4 and 5 and Table 2). The dtpy complexes show a specificity
towards the ovarian cancer derived cell line, A2780 (Figs. 4 and 5 and Table 2 and Ref. [65 ]. The Cu(II)
quinolyl-2-yl-dppy complex, 5, toxicity was associated with the increase in percentage of cells in apoptosis,
an increase accompanied with higher levels of ROS in HCT116 cells (Figs. 6 and 7). Exposure of Cu(II)
quinolyl-4-yl-terpy complex, 2, displayed the ability to induce apoptosis in HCT116, an ability displayed by
terpy metal complexes studied by our group regardless of the 4’terpy substitution (65, 116). Although the
increase in ROS levels was not statistically significative for this terpy complex, a higher percentage of
apoptotic cells are accompanied by higher levels of ROS in cells in other terpy complexes synthetized by our
group [65,116].
2.3 Compounds 1-6 catalyze oxidations of alkanes and alcohols with hydroperoxides
In many cases, copper derivatives are known to efficiently catalyze the oxidation of hydrocarbons and
alcohols with peroxides [118-131] affording alkyl hydroperoxides and ketones (aldehydes). Here, we have
found that compounds 1-6 catalyze the oxidation of alkanes with H2O2 in acetonitrile. Accumulation of
cyclohexanol and cyclohexanone (after reduction of reaction samples with PPh3) in oxidation of cyclohexane
with hydrogen peroxide catalyzed by compound 3 and 4 is demonstrated by Fig. 8.
0.08
A
OH
0.06
0.04
O
0.02
0
4
2
0
Time (h)
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B
0.12
0.08
0.04
0
OH
O
0
2
6
8
4
Time (h)
Fig. 8 Accumulation of cyclohexanol and cyclohexanone in oxidation of cyclohexane (0.46 M) with
hydrogen peroxide (2.0 M, 50 % aqueous) catalyzed by compound 3 (graph A) and 4 (graph
B)(concentration for all complexes 5 × 10–4 M) in MeCN at 50 °C. Concentrations of cyclohexanone and
cyclohexanol were measured after reduction of the aliquots with solid PPh3.
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A
10
5
0
0.6
[Cyclohexane]0
0.4
0.8
0.2
0
B
2

1
0
8
2
4
6
0
1/[Cyclohexane]0 (M1)
Fig. 9 Dependence of the initial rate of oxygenate formation W0 on initial concentration of cyclohexane is
shown in graph A. Linearization of the curve from graph A in coordinates W0–1 – 1/[C6H12] is presented in
graph B. Concentrations of cyclohexanone and cyclohexanol were determined after reduction of the aliquots
with solid PPh3.
Earlier we studied the catalytic systems, based on the data on selectivity of alkane oxidation and we
concluded that the oxidizing species is a hydroxyl radical. This conclusion has received kinetic confirmation
[132]. We determined the ratio of the rate constants on the basis of experimental data within the framework
of a model of competitive interaction of the generated by catalytic system species with acetonitrile on the one
hand and cyclohexane on the other hand. These ratios were close to the value determined during the
oxidation of cyclohexane in acetonitrile, when the species inducing oxidation is certainly a hydroxyl radical,
arising from the photodissociation of H2O2 as the primary product [132].
The kinetic characteristics of the oxidizing species X generated by the catalytic system under
discussion were obtained from the dependence of the alkane oxidation rate on its initial concentration (Fig.
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9). The nature of the dependence corresponds to the assumption of the competitive interaction of the
oxidizing species X with acetonitrile and cyclohexane (RH):
H2O2 + compound 1 → X
X + CH3CN →...→ products
X + RH →...→ ROOH
(1)
(2)
(3)
Here, stage (1) is the effective reaction of generating oxidizing species X at a rate of W1; stages (2) and (3)
are the transformations of CH3CN and RH with the formation, in particular, of alkyl hydroperoxide ROOH,
induced by interactions that limit their speed with X. The rate constants of these interactions are k2 and k3,
respectively. If we assume that the concentration of species X is quasi-stationary, we obtain the following
expression for the initial rate of formation of ROOH:
d[ROOH]/dt)0 = W1/(1 + k2[CH3CN]/k3[RH]0)
(4)
Equation (4) can be transformed into expression (5), convenient for the analysis of experimental data:
‒1
(d[ROOH]/dt)0‒1 = W1 ×(1 + k2[CH3CN]/k3[RH]0)
(5)
The experimental data shown in Fig. 9 (graph A) are in accord with equation (5), which indicates the
validity of the model of competitive interaction of species X with CH3CN and RH. It follows from Fig. 9
(graph B) that W1 = 1.4 × 10‒5 M s‒1 and k2/k3 = 0.029. The obtained value is noticeably different from the
0.006‒0.01 ratio which characterized the reactions involving hydroxyl radicals [132-134].
The low selectivity in the oxidation of alkanes with X species obtained in the present work, is close to
the selectivity found for reactions involving hydroxyl radicals (see Table 3). This indicates that hydroxyl
radicals are generated in the catalytic systems studied in this work. Similar results were obtained earlier by us
on the nature of the oxidizing species in the course of the decomposition of H2O2 catalyzed with the complex
Cu4Na4 silsesquioxane (Table 3, Entry 2 Ref. [135]) and using aluminum nitrate (Table 3, Entry 7,
Ref.[136].)
Table 3 Selectivity Parameters in H2O2 Oxidations of Alkanes by Certain Catalytic Systems a
__________________________________________________________________________________
C(1):C(2):C(3):C(4) 1º:2º:3º
_________________ _______
trans/cis
______________________
Entry Catalytic system
n-Heptane
MCH
cis-1,2-DMCH
trans-1,2-DMCH
___________________________________________________________________________________
Catalyst 4 1.0:2.6:2.6:2.5 1.0:4.7:8.8 0.8
1
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2
Cu4Na4-silsesquioxane b
1.0:5.6:5.6:5.0
1:6:16
1:9:37
1:2:6
0.96
0.75
0.90
1.30
–
3
4
5
6
7
8
9
VO3 /PCA c
1:6:7:5
0.80
1.00
1.20
h d
1:10:7:6
1:5:5:4.5
1:6:7:6
d
FeSO4
e
Ni(ClO4)2/L
1:7:15
f
Al(NO3)3
1:5:5:5
1:6:23
0.80
0.34
0.80
4.1
g
NaAuCl4
1:35:25:23
1:46:35:34
1:116:255
1:26:200
[Mn2L2(O)3]2+/MeCO2H h
__________________________________________________________________________________________
a Parameter C(1):C(2):C(3):C(4) is relative normalized (calculated taking into account the number of
hydrogen atoms at each carbon) reactivities of hydrogen atoms at carbons 1, 2, 3 and 4 of the chain of n-
heptane (in some cases this parameter was determined for n-octane instead of n-heptane). Parameter 1º:2º:3º
is relative normalized reactivities of hydrogen atoms at primary, secondary and tertiary carbons of
methylcyclohexane and isooctane. Parameter trans/cis is the ratio of isomers of tert-alcohols with mutual
trans- and cis-orientation of the methyl groups formed in the oxidation of cis- and trans-1,2-
dimethylcyclohexane. All parameters were measured after reduction of the reaction mixtures with
triphenylphosphine before GC analysis and calculated based on the ratios of isomeric alcohols.
b Catalyst Cu4Na4 -silsesquioxane [135].
c For this system, see Ref. 136.
d. For this system, see Ref. 132. .
e L is 1,4,7-trimethyl-1,4,7-triazacyclononane. For this system, see: Ref. 137.
f For this system, see: Ref. 138.
g
For this system, see Ref. 139.
h L is 1,4,7-trimethyl-1,4,7-triazacyclononane. For this system, see Refs. 140,141.
Assuming that the concentrations of acetonitrile and cyclohexane near the reaction centre differ from
their concentrations in the solution volume [142-146] we can resolve the contradiction The obtained results
indicate that the ratio of acetonitrile and cyclohexane concentrations inside the cluster of the catalytic
particle (near the reaction center) exceeds their ratio in volume. Possibly, this difference is due to a higher
concentration of both components inside a cavity in the catalyst globule. If so, the concentration in the case
of small acetonitrile molecules, CH3CN, is higher in comparison with concentration of the hydrophobic
relatively voluminous cyclohexane molecules [142].
Alcohols can be transformed into corresponding ketones by the oxidation with tert-butyl hydroperoxide
catalysed with complex 4 (see, for example, Fig. 10).
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0.5
0.4
0.3
Acetophenone
3
2-Heptanone
2
0.2
0.1
Cyclohexanone
1b
1a
0
10
2
4
8
6
0
Time (h)
Fig. 10 Accumulation of cyclohexanone (curve 1), 2-heptanone (curve 2) and acetophenone (curve 3) in the
oxidation of cyclohexanol (curve 1a: 0.23 M; curve 1b: 0.46 M), 2-heptanol (0.46 M) or 1-phenylethanol (0.5
M), respectively, with tert-butyl hydroperoxide (1.5 M) catalyzed by complex 4 (5 × 10−4 M) at 50 °C in
acetonitrile. Concentrations of products were measured by GC after the reduction of the reaction sample with
solid PPh3.
3. Conclusions
In this work, structure−property relationship was investigated for a series of five-coordinate complexes
[CuCl2(κ3-L)] bearing 2,2′:6′,2′′-terpyridines (terpy), 2,6-di(thiazol-2-yl)pyridines (dtpy) and 2,6-di(pyrazin-
2-yl)pyridines (dppy) functionalized with n-quinolyl substituents (n = 2 and 4). X-Ray analysis revealed
striking difference in the relative orientation of the pendant substituent and central pyridine ring between the
Cu(II) complexes bearing quinol-2-yl substituted ligands and those with quinol-4-yl group. While the quinol-
4-yl unit was strongly inclined to the central pyridine of terpy, dtpy and dppy, the pendant substituent in the
Cu(II) complexes bearing quinol-2-yl substituted ligands was quite coplanar with the central pyridine ring.
Cu(II)terpy and Cu(II)dppy complexes have an antiproliferative activity against colorectal and
ovarian carcinoma cells with terpy complexes being the most antiproliferative in this cell line. 4’quinolyl-4-
yl-terpy substitution significantly reduced the antiproliferative effect in normal fibroblasts while maintaining
their effect in cancer cells (HCT116 and A2780). Dtpy complexes show a specificity towards A2780 cell
line. The Cu(II) quinolyl-2-yl-dppy complex, 5, was able to induce the loss of cell viability that correlated
with an increase in the percentage of HCT116 cells in apoptosis and an increase in the levels of ROS.
Exposure of Cu(II) quinolyl-4-yl-terpy complex, 2, also displayed the ability to induce apoptosis in HCT116
but with a neglectful capability to induce ROS levels.
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The first evaluation of compounds 1-6 in catalysis reveals that these complexes catalyze oxidation of
alkanes into alkyl hydroperoxides with hydrogen peroxide as well as alcohols with tert-butyl hydroperoxide.
A model of competitive interaction of hydroxyl radicals with CH3CN and RH in the catalyst cavity has been
proposed which is based on the study simultaneously of kinetics and selectivity in alkane oxidations.
Analysis of the regioselectivity parameters found for the oxidation of linear and branched alkanes led the
authors to a conclusion that the reaction mechanism includes the formation of hydroxyl radicals. The kinetic
peculiarities of the cyclohexane oxidation with H2O2 in acetonitrile allowed us to assume that the oxidation
proceeds in part in a cavity generated inside of the tris-heteroleptic copper cage.
Acknowledgement
The publication has been prepared with the support of the «RUDN University Program 5-100» and funded by
RFBR according to Research Project Grant No. 19-03-00142, as well as by the Initiative Program (State
registration number AAAA-A16-116020350251-6) in the frames of the State Tasks 0082-2014-0004 and
0082-2014-0007 “Fundamental regularities of heterogeneous and homogeneous catalysis”. This work was
also performed within the framework of the Program of Fundamental Research of the Russian Academy of
Sciences for 1013-2020 on the research issue of IChP RAS No. 47.16. State registration number of Center of
Information Technologies and Systems for Executive Power Authorities (CITIS): AAAA-A17-
1170406l0283-3. This work was supported by the Applied Molecular Biosciences Unit- UCIBIO which is
financed by national funds from FCT/MCTES (UID/Multi/04378/2019). LRR acknowledges project
PTDC/CVT/EPI/6685/2014.
No conflict of interest.
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