Dual investigation of lanthanide complexes with cinnamate and phenylacetate ligands: Study of the cytotoxic properties and the catalytic oxidation of styrene

Article abstract of DOI:10.1016/j.poly.2014.02.040

Eleven lanthanide compounds [Y(cinn)₃] (1), [La(cinn) ₃] (2), [La(4-OMecinn)₃]·2H₂O (3), [La(4-Clcinn)₃]·2H₂O (4), [La(4-OMephac) ₃]·4H₂O (5), [La(4-Clphac)₃] ·3H₂O (6), [Ce(cinn)₃] (7), [Nd(cinn)₃] (8), [Sm(cinn)₃]·H₂O (9), [Yb(cinn)₃] (10) and [Sm(4-OMephac)₃]·H₂O (11) containing carboxylato ligands (cinn = cinnamate; 4-OMecinn = 4-methoxicinnamate; Clcinn = 4-chlorocinnamate; 4-OMephac = 4-methoxyphenylacetate; 4-Clphac = 4-chlorophenylacetate) have been synthesized and characterized by elemental analysis, IR, ¹H and ¹³C NMR spectroscopy, thermal analysis and X-ray diffraction powder patterns. In addition, compound 11 was characterized by single crystal X-ray diffraction studies. The cytotoxic activity of these complexes has been tested against three different human tumour cell lines HL60 (human promyelocytic leukemia), K562 (human erythromyeloblastoid leukemia) and MCF7 (breast cancer), observing a very modest cytotoxic activity for all tested compounds. In addition, toxicity tests to macrophages and erythrocytes have also been carried out, observing that none of the compounds is toxic against these immunocompetent cells. Finally, all the synthesized compounds have been tested as catalysts for styrene oxidation observing conversions higher than 50% after 19 h of reaction as well as a relatively high selectivity to two main products benzaldehyde (BzA) and 1-phenylethane-1,2-diol (PhED). Complex 7 presents the higher conversion (99.56%) with a relatively high selectivity towards PhED of 72.07%.

Full text of DOI:10.1016/j.poly.2014.02.040

Polyhedron xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Polyhedron
journal homepage: www.elsevier.com/locate/poly
Dual investigation of lanthanide complexes with cinnamate
and phenylacetate ligands: Study of the cytotoxic properties
and the catalytic oxidation of styrene
Alberto Aragón-Muriel a, María Camprubí-Robles b, Elena González-Rey b, Alfonso Salinas-Castillo c,
Antonio Rodríguez-Diéguez d, Santiago Gómez-Ruiz e, , Dorian Polo-Cerón a,
⇑
⇑
a Departamento de Química, Universidad del Valle, Calle 13 No 100-00, Cali 76001000, Colombia
b Institute of Parasitology and Biomedicine ‘‘López-Neyra’’, Spanish National Research Council (CSIC), Granada E-18016, Spain
c ECsens, Department of Analytical Chemistry, Faculty of Sciences, University of Granada, E-18071 Granada, Spain
d Departamento de Química Inorgánica, Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain
e Departamento de Química Inorgánica y Analítica, E.S.C.E.T., Universidad Rey Juan Carlos, E-28933 Móstoles, Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Eleven lanthanide compounds [Y(cinn)3] (1), [La(cinn)3] (2), [La(4-OMecinn)3]ꢀ2H2O (3), [La(4-Clcinn)3]-
ꢀ2H2O (4), [La(4-OMephac)3]ꢀ4H2O (5), [La(4-Clphac)3]ꢀ3H2O (6), [Ce(cinn)3] (7), [Nd(cinn)3] (8),
[Sm(cinn)3]ꢀH2O (9), [Yb(cinn)3] (10) and [Sm(4-OMephac)3]ꢀH2O (11) containing carboxylato ligands
(cinn = cinnamate; 4-OMecinn = 4-methoxicinnamate; Clcinn = 4-chlorocinnamate; 4-OMephac = 4-
methoxyphenylacetate; 4-Clphac = 4-chlorophenylacetate) have been synthesized and characterized by
elemental analysis, IR, 1H and 13C NMR spectroscopy, thermal analysis and X-ray diffraction powder
patterns. In addition, compound 11 was characterized by single crystal X-ray diffraction studies. The
cytotoxic activity of these complexes has been tested against three different human tumour cell lines
HL60 (human promyelocytic leukemia), K562 (human erythromyeloblastoid leukemia) and MCF7 (breast
cancer), observing a very modest cytotoxic activity for all tested compounds. In addition, toxicity tests to
macrophages and erythrocytes have also been carried out, observing that none of the compounds is toxic
against these immunocompetent cells. Finally, all the synthesized compounds have been tested as cata-
lysts for styrene oxidation observing conversions higher than 50% after 19 h of reaction as well as a rel-
atively high selectivity to two main products benzaldehyde (BzA) and 1-phenylethane-1,2-diol (PhED).
Complex 7 presents the higher conversion (99.56%) with a relatively high selectivity towards PhED of
72.07%.
Received 5 December 2013
Accepted 25 February 2014
Available online xxxx
Keywords:
Cytotoxicity
Toxicity
Lanthanide
Cinnamate
Phenylacetate
Styrene oxidation
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
attracting the interest of the scientists because they could be
employed as potential drugs.
Metal coordination complexes have shown interesting
physico-chemical properties which have been exploited not only
in homogeneous catalysis or in the preparation of novel materials
with fascinating properties, but also in medicinal purposes as
cytotoxic agents [1]. Lanthanide complexes have also attracted
attention in pharmaceutical applications due to the results
presented in recent research [2–6]. Especially, studies on cinnamic
acid derivatives have shown anti-tumoral properties [7–12],
In addition, lanthanide complexes possess unique properties
that make them attractive and promising for research, in both stoi-
chiometric and catalytic reactions. The particular combination of
their ionic radii, the Lewis acidity and the presence of unemployed
5d and 6s orbitals, provide a great advantage in coordination com-
plexes. A remarkable variation of the ionic radius of the lanthanide
series, gives the possibility of adjusting the geometrical parameters
of the metal coordination sphere, optimizing the selectivity for
choosing the central atom of the substrate with a radius appropri-
ate to the specifications of the catalytic reaction [13].
Thus, another common application of lanthanide complexes
may be their use as catalyst for the preparation of different com-
pounds and/or materials. Many studies of the oxidation and epox-
idation of organic substrates with lanthanide complexes have been
⇑
Corresponding authors. Tel.: +34 914888507; fax: +34 914888143
(S. Gómez-Ruiz).
E-mail addresses: santiago.gomez@urjc.es (S. Gómez-Ruiz), dorian.polo@
correounivalle.edu.co (D. Polo-Cerón).
http://dx.doi.org/10.1016/j.poly.2014.02.040
0277-5387/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: A. Aragón-Muriel et al., Polyhedron (2014), http://dx.doi.org/10.1016/j.poly.2014.02.040

2
A. Aragón-Muriel et al. / Polyhedron xxx (2014) xxx–xxx
reported [14–17], and for basic chemistry, the study of the oxida-
tion of styrene is interesting because it is the simplest vinyl aro-
matic derivative and the catalytic studies may be the basis for
further research, for example to the cosmetics industry, flavorings
and pharmaceuticals [18–22].
scans were run at room temperature and powder patterns were
generated by using X’Pert Data Collector software. TG-DTG analy-
ses were performed with the NETZSCH STA 409 simultaneous ther-
mal analyzer. Heating was conducted under static condition in air
with a range of 298–1073 K at 10 K minꢁ1
.
Thus, having in mind the potential application of lanthanide
complexes in biologic and catalytic processes and based on previ-
ous reports by our group on the application of metal complexes
with biological activity [23,24], and catalytic properties of metal
complexes [25,26], we report here the synthesis and characteriza-
tion of Y(III), La(III), Ce(III), Nd(III), Sm(III) and Yb(III) complexes
with p-substituted-cinnamate and p-substituted phenylacetate li-
gands (Fig. 1) and the toxicity against immunocompetent cells
(mice macrophages and erythrocytes) and cytotoxicity against spe-
cific human cancer cells line (HL60 (human promyelocytic leuke-
mia), K562 (human erythromyeloblastoid leukemia) and MCF7
(breast cancer). In addition, the study of the catalytic activity and
selectivity of these compounds on styrene oxidation is reported.
2.2. Synthesis of lanthanide compounds
The Ln(III) complexes were prepared by using similar methods
to those described in literature [27,28] (Fig. 2).
2.2.1. Synthesis of [Y(cinn)3] (1)
An aqueous solution (10 ml) of Na(cinn) (3 eq: 842 mg,
4.95 mmol) was slowly added to the aqueous solution (15 ml) of
YCl3ꢀ6H2O (500 mg, 1.65 mmol) and a precipitate formed instantly.
Upon the addition of the sodium salt, the solution was adjusted to
pH 5 with drops of 0.1 M HCl or NaOH solution, controlled by pH-
meter, then stirred for 3 h and filtered. The white precipitate was
then washed with distilled water and dried in a desiccator for
2 days. Yield: 730 mg, 83 %. C27H21YO6, Elemental analysis; C,
58.50 (calc. 61.15); H, 3.99 (3.99); Y, 16.54 (16.76)%. IR (KBr pellet
cmꢁ1): 3033 w, 2924 w, 1638 s, 1597 m, 1516 s, 1451 m, sh, 1412 s,
1386 s, 1290 w, 1237 s, 1177 w, 1071 w, 987 s, 876 s, 852 w, 779 s,
749 m, 724 m, 686 s, 593 s, 554 m, 484 m. 1H NMR (DMSO-d6) d
2. Experimental
2.1. Materials and methods
trans-Cinnamic acid (cinnH), 4-methoxycinnamic acid (4-
OMecinnH), 4-chlorocinnamic acid (4-ClcinnH), 4-methoxyphenyl-
acetic acid (4-OMephacH), 4-chlorophenylacetic acid (4-ClphacH)
and LnCl3 xH2O (Ln = Y, La, Ce, Nd, Sm, Yb) were purchased from
Sigma–Aldrich and other chemicals were obtained commercially
and used without further purification. The sodium cinnamates
were synthesized in an equimolar reaction by the neutralization
of the respective acid with NaOH solution in ethanol, the mixture
was held at room temperature for 1 h with constant stirring, the
solid obtained was filtered, washed with ethanol:water (1:1) and
dried under vacuum. For synthesis of sodium 4-methoxyphenyl-
acetate and sodium 4-chlorophenylacetate, the methodology de-
scribed above was performed using pentane and ethyl acetate as
solvents respectively. Microanalyses were carried out with a Flash
EA 1112 Series CHN Analyzer. Metal concentrations were
determined by EDTA titration. Infrared spectra were recorded with
a NICOLET 6700 Spectrometer (4000–225 cmꢁ1 with recording
accuracy of 1 cmꢁ1). 1H NMR and 13C NMR spectra were recorded
in DMSO-d6 at 25 °C on a Bruker Avance II 400 spectrometer.
Chemical shifts are recorded in d values (ppm) respect to residual
signals of deuterated solvents and coupling constants (J) are given
in Hz. The multiplicities of carbon signals were obtained from
distortionless enhancement by polarization transfer experiments
(DEPT). Powder X-ray diffractograms of different samples were
recorded on Panalytical X’Pert PRO X-ray diffractometer equipped
3
(ppm) 6.51 (d, 3H, J = 15.61 Hz, H-20), 7.33 (s, 9H, H-3 and H-4
3
overlapped), 7.49 (d, 3H, J = 16.00 Hz, H-10), and 7.56 (d, 6H,
13
3J = 2.34 Hz, H-2); C NMR d (ppm) 124.87 (C-20), 128.13 (C-4),
129.24 (C-2), 129.77 (C-3), 135.64 (C-1), 136.42 (C-10), and
0
176.86 (C@O). Powder XRD [d-spacings/ÅA (I/I°)]- 12.93 (100),
11.46 (72), 8.95 (39), 8.33 (35), 6.51 (58), 5.93 (17), 5.85 (19),
5.75 (21), 5.50 (17), 5.40 (11), 5.13 (10), 4.70 (15), 4.65 (33), 4.46
(42), 4.16 (15), 3.97 (33), 3.89 (21), 3.71 (21).
2.2.2. Synthesis of [La(cinn)3] (2)
The synthesis of 2 was carried out in identical manner to 1.
White powder, yield: 750 mg, 96%. C27H21LaO6, Elemental analysis;
C, 55.47 (calc. 55.88); H, 3.95 (3.65); La, 23.71 (23.93)%. IR (KBr pel-
let cmꢁ1): 3051 w, 1636 s, 1575 m, 1529 m, sh, 1499 s, 1450 m,
1394 s, 1289 w, 1243 s, 1200 w, 1071 w, 982 s, 879 m, 850 m,
779 s, 737 s, 688 m, 589 s, 539 m, 482 m. 1H NMR (DMSO-d6) d
3
(ppm) 6.47 (d, 3H, J = 16.06 Hz, H-20), 7.31 (s, 9H, H-3 and H-4
3
overlapped), 7.43 (d, 3H, J = 15.81 Hz, H-10), and 7.53 (d, 6H,
13
3J = 2.76 Hz, H-2); C NMR d (ppm) 125.62 (C-20), 127.51 (C-4),
128.72 (C-2), 129.07 (C-3), 135.31 (C-1), 139.89 (C-10), and
0
176.62 (C@O). Powder XRD [d-spacings/ÅA (I/I°)]- 11.89 (100),
8.99 (6), 6.54 (29), 5.67 (28), 4.50 (9), 4.28 (22), 3.92 (10), 3.88
(4), 3.78 (5), 3.51 (5), 3.36 (4), 3.27 (6), 3.14 (8), 2.99 (8), 2.64
(4). TGA mass loss 44.00% (295–500 °C, 1 step, calc. La2O3 forma-
tion = 43.86 %).
with a Co K
a radiation source. The scanning range used was at
least 2h = 5–40° at at 0.02° sꢁ1 with a 0.25° divergence slit,
2.2.3. Synthesis of [La(4-OMecinn)3]ꢀ2H2O (3)
0.04 rad soller slit, 0.76 mm anti-scatter slit and a Fe filter. All
The synthesis of 3 was carried out in identical manner to 1.
White powder, yield: 800 mg, 84%. C30H31LaO11, Elemental analy-
sis; C, 49.81 (calc. 51.00); H, 4.37 (4.42); La, 19.79 (19.66)%. IR
(KBr pellet cmꢁ1): 3342 m, br, 2935 w, 2837 w, 1638 s, 1606 s,
1573 w, 1513 s, 1426 s, 1404 s, 1305 m, 1246 s, 1174 s, 1109 m,
1032 s, 985 s, 879 m, 832 s, 781 m, 722 m, 558 m, 519 w, 268 s,
238 s. 1H NMR (DMSO-d6) d (ppm) 3.73 (s, 9H, –O–CH3), 6.35 (d,
3
3H, J = 15.65 Hz, H-20), 6.83 (d, 6H, 3J = 7.34 Hz, H-3), 7.41 (d,
3
3H, J = 16.14 Hz, H-10), and 7.45 (d, 6H, 3J = 8.31 Hz, H-2); 13C
NMR d (ppm) 55.65 (–O–CH3), 114.64 (C-3), 123.40 (C-20), 128.36
(C-1), 129.62 (C-2), 140.50 (C-1’), 160.55(C-4), and 177.30 (C@O).
0
Fig. 1. The structural formula of the sodium ligand precursors (NaL): (a) sodium
cinnamate Na(cinn), (b) sodium 4-methoxycinnamate Na(4-OMecinn), (c) sodium
4-chlorocinnamate Na(4-Clcinn), (d) sodium 4-methoxyphenylacetate Na(4-OMe-
phac) and (e) sodium 4-cholorophenylacetate Na(4-Clphac).
Powder XRD [d-spacings/AÅ (I/I°)]- 24.21 (100), 9.36 (14), 8.49 (4),
7.61 (19), 7.24 (17), 7.02 (64), 5.89 (7), 5.53 (9), 4.66 (13), 4.44
(4), 4.29 (4), 4.04 (5), 3.80 (5). TGA mass loss 4.89% (70–120 °C, 1
Please cite this article in press as: A. Aragón-Muriel et al., Polyhedron (2014), http://dx.doi.org/10.1016/j.poly.2014.02.040

A. Aragón-Muriel et al. / Polyhedron xxx (2014) xxx–xxx
3
Fig. 2. Synthetic method for the preparation of La(III) complexes with cinnamate and phenylacetate ligands.
step, calc. 2 ꢂ H2O = 5.10%), 41.90% (300–600 °C, 2 steps, calc. La2-
3.48 (7), 2.85 (7). TGA mass loss 8.12% (55–120 °C, 1 step, calc.
O2CO3 formation = 44.84%).
3 ꢂ H2O = 7.70%), 49.30% (300–450 °C,
1
step, calc. La2O3
formation = 49.70%).
2.2.4. Synthesis of [La(4-Clcinn)3]ꢀ2H2O (4)
2.2.7. Synthesis of [Ce(cinn)3] (7)
The synthesis of 4 was carried out in identical manner to 1.
White powder, yield: 780 mg, 81%. C27H22Cl3LaO8, Elemental anal-
ysis; C, 44.81 (calc. 45.06); H, 2.93 (3.08); La, 19.80 (19.30)%. IR
(KBr pellet cmꢁ1): 3410 w, br, 1639 s, 1572 m, 1509 vs 1494 sh,
1423 vs 1398 s, 1285 w, 1249 m, 1092 s, 1012 m, 983 s, 828 vs
749 m, 720 m, 664 w, 554 w, 541 w, 499 m, 455 m, 266 m,
243 m. 1H NMR (DMSO-d6) d (ppm) 6.48 (d, 3H, 3J = 16.14 Hz, H-
The synthesis of 7 was carried out in identical manner to 1. Pale
yellow powder, yield: 710 mg, 91%. C27H21CeO6, Elemental analy-
sis; C, 54.54 (calc. 55.76); H, 4.03 (3.64); Ce, 24.37 (24.09)%. IR
(KBr pellet cmꢁ1): 3050 w, 1636 s, 1575 w, 1529 m, 1499 vs
1450 m, 1395 vs 1290 w, 1243 s, 982 s, 879 m, 850 m, 7709 s,
737 s, 688 m, 589 s, 540 m, 481 w. Powder XRD [d-spacings/ÅA (I/
I°)]- 11.31 (100), 6.53 (39), 5.66 (30), 5.41 (2), 4.48 (12), 4.28
(27), 3.91 (6), 3.77 (5), 3.67 (3), 3.49 (3).
20), 7.35 (d, 6H, 3J = 7.83 Hz, H-3), 7.41 (d, 3H, J = 16.14 Hz, H-10),
3
and 7.55 (d, 6H, 3J = 7.83 Hz, H-2); 13C NMR d (ppm) 125.75 (C-
20), 129.23 (C-3), 129.80 (C-2), 134.23 (C-1), 134.530 (C-4), 139.76
(C-10), and 175.07 (C@O). Powder XRD [d-spacings/ÅA (I/I°)]- 22.09
(100), 10.74 (31), 7.30 (15), 6.63 (10), 6.14 (4), 5.47 (14), 5.43
(19), 5.37 (7), 4.84 (19), 4.10 (9), 3.97 (4), 3.63 (15), 3.25 (11),
2.2.8. Synthesis of [Nd(cinn)3] (8)
The synthesis of 8 was carried out in identical manner to 1. Pale
blue powder, yield: 690 mg, 85%. C27H21NdO6, Elemental analysis;
C, 53.21 (calc. 55.37); H, 3.83 (3.61); Nd, 24.86 (24.63)%. IR (KBr
pellet cmꢁ1): 3053 w, 1636 s, 1575 m, 1530 m, 1500 vs 1450 m,
1398 vs 1290 w, 1244 s, 1201 w, 1072 w, 983 s, 879 m, 850 m,
2.72 (8). TGA mass loss 4.51% (80–125 °C,
1 step, calc.
2 ꢂ H2O = 5.01 %), 15.00% (160–320 °C,
2
steps, calc. 3 ꢂ Cl
[La(cinn)3 formation] = 15.11%), 34.20% (330–550 °C, 1 step, calc.
La2O2CO3 formation = 36.28%).
780 s, 742 s, 688 m, 589 s, 540 m, 483 m. Powder XRD [d-spac-
0
ings/AÅ (I/I°)]- 11.21 (100), 6.53 (29), 5.66 (29), 5.38 (7), 4.47 (25),
4.28 (20), 3.90 (11), 3.77 (4), 3.63 (4), 3.46 (3), 3.35 (4), 3.27 (5).
2.2.5. Synthesis of [La(4-OMephac)3]ꢀ4H2O (5)
The synthesis of 5 was carried out in identical manner to 1.
White powder, yield: 740 mg, 78%. C27H35LaO13, Elemental analy-
sis; C, 45.30 (calc. 45.90); H, 4.75 (4.99); La, 19.97 (19.66)%. IR
(KBr pellet cmꢁ1): 3221 m, br, 2959 w, 2836 w, 1557 s, 1516 s,
1431 s, 1401 s, 1283 m, 1248 s, 1179 m, 1108 w, 1034 m, 937 w,
822 m, 733 m, 697 m, 568 w, 259 m, 236 m. 1H NMR (DMSO-d6)
d (ppm) 3.26 (s, 6H, H-10), 3.71 (s, 9H, –O–CH3), 6.79 (d, 6H,
3J = 8.53 Hz, H-3), and 7.14 (d, 6H, 3J = 8.53 Hz, H-2); 13C NMR d
(ppm) 43.55 (C-10), 54.95 (–O–CH3), 113.17 (C-3), 129.21 (C-1),
2.2.9. Synthesis of [Sm(cinn)3]ꢀH2O (9)
The synthesis of 9 was carried out in identical manner to 1.
Beige powder, yield: 740 mg, 88%. C27H23SmO7, Elemental analy-
sis; C, 53.27 (calc. 53.18); H, 3.49 (3.80); Sm, 24.88 (24.66)%. IR
(KBr pellet cmꢁ1): 3422 w, br,3054 w, 1636 s, 1576 m, 1500 vs
1449 m, 1394 vs 1291 w, 1243 s, 1200 w, 1073 w, 983 s, 880 m,
850 m, 780 s, 743 s, 730 m, sh, 689 m, 589 s, 542 m, 482 m, 371
m, 335 m, 282 m, 251 m, 236 m, 227 s. Powder XRD [d-spacings/
0
ÅA (I/I°)]- 11.47 (100), 6.53 (31), 5.65 (29), 5.36 (7), 4.45 (9), 4.28
(23), 3.89 (11), 3.77 (10), 3.61 (7), 3.44 (4), 3.34 (5), 3.27 (5),
3.14 (7).
130.36 (C-2), 157.39 (C-4), 181.67 (C@O). Powder XRD [d-spac-
0
ings/AÅ (I/I°)]- 9.77 (82), 8.73 (29), 7.97 (33), 6.52 (100), 6.11 (6),
5.22 (7), 4.89 (8), 4.71 (7), 4.59 (4), 4.36 (4), 4.26 (14), 3.99 (9),
3.20 (5), 3.05 (6), 2.79 (4), 2.76 (6), 2.42 (7), 2.16 (5). TGA mass loss
10.41% (50–125 °C,
(300–530 °C, 1 step, calc. La2O3 formation = 48.63%).
1
step, calc. 4 ꢂ H2O = 10.20%), 50.06%
2.2.10. Synthesis of [Yb(cinn)3] (10)
The synthesis of 10 was carried out in identical manner to 1.
White powder, yield: 630 mg, 79%. C27H21YbO6, Elemental analy-
sis; C, 50.25 (calc. 52.77); H, 3.35 (3.44); Yb, 28.84 (28.16)%. IR
(KBr pellet cmꢁ1): 3028 w, 1636 vs 1577 s, 1518 vs 1452 vs
sh,1419 vs 1291 m, 1253 s, 1238 s, 1204 w, 1180 w, 1072 w, 985
2.2.6. Synthesis of [La(4-Clphac)3]ꢀ3H2O (6)
The synthesis of 6 was carried out in identical manner to 1.
White powder, yield: 780 mg, 83%. C24H24LaCl3O9, Elemental anal-
ysis; C, 39.19 (calc. 41.08); H, 3.32 (3.45); La, 19.48 (19.80)%. IR
(KBr pellet cmꢁ1): 3410 m, br, 2915 w, 1544 vs 1493 m, 1422 s,
1397 vs 1288 s, 1202 w, 1177 w, 1092 s, 1017 m, 934 w, 857 m,
810 s, 743 s, 685 s, 633 w, 581 m, 504 m, 469 m, 302 w, 277 w,
s, 876 s, 852 w, 779 s, 747 s, 725 m, 686 s, 592 s, 556 m, 485 m.
0
Powder XRD [d-spacings/AÅ (I/I°)]- 12.96 (100), 11.50 (31), 8.95
(22), 8.31 (25), 6.49 (57), 5.84 (8), 5.76 (6), 5.48 (14), 5.42 (4),
5.12 (6), 4.69 (4), 4.46 (8), 4.16 (6), 3.96 (19), 3.89 (5), 3.75 (4),
3.67 (6), 3.19 (5), 3.07 (6).
1
259 m, 231 w. H NMR (DMSO-d6) d (ppm) 3.32 (s, 6H, H-10),
7.21 (d, 6H, 3J = 8.78 Hz, H-3), and 7.24 (d, 6H, 3J = 8.53 Hz, H-2);
13C NMR d (ppm) 43.58 (C-10), 127.58 (C-3), 130.34 (C-1), 131.27
2.2.11. Synthesis of [Sm(4-OMephac)3]ꢀH2O (11)
0
(C-2), 136.15 (C-4), 180.80 (C@O). Powder XRD [d-spacings/AÅ (I/
I°)]- 9.40 (26), 8.96 (100), 8.32 (45), 8.09 (5), 6.48 (33), 5.97 (49),
5.04 (8), 4.94 (5), 4.70 (5), 4.61 (6), 4.48 (5), 4.05 (6), 3.68 (6),
The synthesis of 11 was carried out in identical manner to 1.
White powder, yield: 690 mg, 76%. C27H29SmO10, Elemental analy-
sis; C, 48.71 (calc. 48.85); H, 4.24 (4.40); Sm, 22.55 (22.65)%. IR
Please cite this article in press as: A. Aragón-Muriel et al., Polyhedron (2014), http://dx.doi.org/10.1016/j.poly.2014.02.040

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A. Aragón-Muriel et al. / Polyhedron xxx (2014) xxx–xxx
(KBr pellet cmꢁ1): 3435 m,br, 2959 w, 2835 w, 1616 m, 1537 s,
1516 s, 1432 m, 1402 m, 1285 w, 1249 m,sh, 1177 m, 1106 w,
one day of culture, peritoneal macrophages were treated with
increasing concentrations of the studied compounds (50, 300,
1035 m, 820 w, 794 w, 732 w, 700 w, 616 w, 476 w. Powder
750 and 950 lM) and the corresponding vehicle solutions (DMSO
0
XRD [d-spacings/AÅ (I/I°)]- 9.57 (82), 7.93 (29), 7.22 (33), 6.99
(100), 6.22 (6), 5.67 (7), 5.03 (8), 4.79 (7), 4.66 (4), 4.11 (4), 3.78
(7), 3.51 (5).
and EtOH). After 96 h of treatment Alamar Blue cytotoxicity test
was performed as described above (see cytotoxicity assay section).
Compounds toxicity to macrophages was considered acceptable if
the fluorescence was within 80% of that observed for the untreated
macrophages.
2.3. Cytotoxic activity
2.3.1. Tumor cell culture
2.3.4. Hemolysis assay
HL60 (human promyelocytic leukemia) and K562 (human ery-
thromyeloblastoid leukemia) cell lines in suspension and MCF7
(breast cancer) as monolayer were maintained in RPMI-1640 cul-
ture medium (Gibco) supplemented with 10% heat inactivated fetal
bovine serum (FBS, Gibco), 1% penicillin/streptomycin (Invitrogen)
Approximately 400 lL of blood was carefully extracted with a
syringe-connected needle from C57BL/6 mice previously eutha-
nized by cardiac puncture and added to a 1.5 mL eppendorf con-
taining 4% Sodium Citrate (120 lL). Several blood dilutions were
prepared in PBS (3 ꢂ 1:20). The blood suspension was then diluted
and 1%
L-glutamine (Invitrogen) at 37 °C in a humidified atmo-
with 2% (v/v) citrate in PBS and erythrocytes were counted with a
sphere of 5% (v/v) CO2.
Neubauer camera. A density of 10 x 106 erythrocytes (125
l
L) was
added to centrifuge tubes and then treated with different concen-
trations of compounds (1–10) (250, 550, 750 and 950 M) and
2.3.2. Cytotoxicity assay
l
The cytotoxic activity of the compounds was evaluated using
the Alamar Blue assay that has been previously demonstrated to
be a rapid and inexpensive method for the medium through put
screening of compounds [29]. The Alamar Blue oxidation–reduc-
tion dye is a common used indicator of cell viability. The blue,
non-fluorescent compound, Resazurin, is reduced to the pink, fluo-
rescent Resorufin within the cytoplasm of a viable cell, and the
fluorescence is directly proportional to cell number. In short,
HL60, K562 and MCF7 exponentially growing cells were seeded
into 96-well plates on day 0 at 10000 cells/well to prevent cell con-
fluence during the period of experiment.
vehicle solutions (DMSO and EtOH). Hemolysis 0% (Blank) was pre-
pared by mixing both blood and PBS solutions (1:1) and hemolysis
100% was achieved by mixing blood solution and 0.1 % Triton. The
tubes were incubated for 1 h at 37 °C under continuous agitation.
After incubation period, erythrocytes were separated by centrifu-
gation (1000g, at room temperature, 5 min). A 100 lL portion of
each supernatant was further transferred to a 96-well plate to
measure the absorbance at 540 nm into a microplate reader (Ver-
samax tunable, Molecular devices). All values were normalized to
the control untreated (PBS) samples.
All stock compounds (1–9) solutions (30 mM) were prepared in
100% DMSO (Sigma) and stock solution of 10 was prepared in Eth-
anol (100%). A first dose of increasing concentrations of the studied
compounds (1–10) was added to each well per triplicate at 37 °C.
After 24 h, cells were treated with a second dose of the compounds
and kept for 96 h at 37 °C. Final concentrations achieved in treated
2.4. Catalytic oxidation of styrene
Catalytic reactions were carried out in a condensation system
with stirrer, using acetonitrile as solvent and hydrogen peroxide
solution as oxidant. A mixture of styrene (10.0 mmol), lanthanide
catalyst (0.01 mmol) and solvent (10.0 mL) was stirred for few
minutes at room temperature. H2O2 (17.6 mmol) was then added
and the reaction mixture was stirred for 19 h at 70 °C. Analysis of
the content of the reaction mixtures were carried out in duplicate
with an Agilent 6890 series GC (Gas Chromatography system) with
a flame ionization detector (FID). Injection conditions were: injec-
tor temperature at 280 °C, FID detector at 295 °C with a ramp start-
ing at 70 °C, then the temperature increases by 15 °C/min until
reaching 220 °C (2 min) and finally, a rate of 10 °C/min until reach-
ing 270 °C (3 min). Helium was used as carrier gas with a pressure
of 9.5 Psi, a flow of 1.8 mL/min and a HP-INNOWax 19091 N-133
wells were 10, 20, 30, 50, 100, 200, 350, 550, 750 and 1000 lM for
each suspension. Equal concentrations of vehicle were added and
served as control wells. The percentage of surviving cells relative
to untreated controls was calculated 96 h after the beginning of
compounds exposure. After 96 h treatment, we added ready-to-
use solution of Resazurin (100X in PBS) to each well and kept the
plates were kept in darkness conditions at 37 °C. After 4 h incuba-
tion 100 lL of 3% sodium dodecyl sulfate (SDS) was added to each
well of the plate to end the Resazurin reaction. Fluorescence was
measured with a excitation k of 550 nm and emission at 590 nm
using a 96-well plate reader (Infinite F200 Tecan Fluorimeter).
The IC50 value was defined as the percentage of the compound at
which 50% cell toxicity was observed. Data from this study were
analyzed with GraphPad Prism 5.0 and OriginLab Pro 8 software.
column (30 m ꢂ 0,25 mm, 0,25
lm). Oxidation products of styrene
were identified (mass spectra) using a gas chromatography system
coupled to a mass spectrometer SHIMADZU GCMS-QP2010, tech-
nique electron impact ionization (EI) at 70 eV.
2.3.3. Isolation of murine peritoneal macrophages
2.5. Single-crystal structure determination
Healthy 6 weeks old C57BL/6 mice were used for extraction of
macrophages from the peritoneal cavity. C57BL/6 mice were
euthanized under CO2 gas and around 5 mL of cold harvest RPMI
1640 medium was injected into the peritoneal region of the mice.
A massage in the peritoneal region of the mouse was performed
during the next 5 min to allow the cells to detach from the perito-
neal wall. Rapidly, the peritoneal fluid was removed and dispensed
into a 50 mL conical polypropylene centrifuge tube on ice. The per-
itoneal exudate cells were centrifuged in a refrigerated centrifuge
10 min at 2000 rpm at 4 °C. A density of 100000 macrophages
per well was plated into a 96-well plate and kept at 37 °C in a
humidified atmosphere of 5% (v/v) CO2. After 2 h in culture the
complete cultured medium (RPMI 1640,1 % Penicillin/Streptomy-
cin, 10% FBS) was changed and the plate was kept at 37 °C. After
It should be noted that all crystals undergo a very fast degrada-
tion when they are removed from the mother liquor which has a
high impact on the quality of the data. Several crystals of 11 were
measured and the structure was solved from the best data we were
able to collect. A suitable crystal of 11 was mounted on a glass fibre
and used for data collection on a Bruker AXS APEX CCD area detec-
tor equipped with graphite monochromated Mo K
a radiation
(k = 0.71073 Å) by applying the -scan method. Lorentz-polariza-
x
tion and empirical absorption corrections were applied [30]. The
structure was solved by direct methods and refined with full-ma-
trix least-squares calculations on F2 using the program SHELXS-97
[31]. Anisotropic temperature factors were assigned to all atoms.
Hydrogen atoms bonded to water molecules could not be reliably
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A. Aragón-Muriel et al. / Polyhedron xxx (2014) xxx–xxx
5
positioned, but the rest of the hydrogen atoms were treated as
riding atoms using the SHELX-97 default parameters. Refinement re-
duced R1 to 0.0506. Final R(F), wR(F2) and goodness of fit agree-
ment factors, details on the data collection and analysis can be
found in Table S1 (Electronic Supplementary material). Selected
bond lengths are given in Table S2 (ESI).
3. Results and discussion
3.1. Synthesis and characterization of lanthanide complexes
The Ln(III) complexes 1–11 were isolated as crystalline solids,
soluble in DMSO, and mildly soluble in DMF and acetone, but only
sparingly soluble in water and ethyl acetate. The results obtained
by elemental analysis (carbon and hydrogen), EDTA complexome-
try, and TG-DTG analysis, agree with all structures proposed. The
X-ray powder patterns (Fig. 3) verified that the compounds have
a crystalline structure, with evidence of the formation of an iso-
morphous series for [Ln(cinn)3] (Ln = La, Ce, Nd and Sm). The
highly similarity of d-spacings and relative intensities for both yt-
trium and ytterbium complexes indicate that they have similar
carboxylate binding modes (see Experimental). The X-ray powder
patterns are almost identical, and furthermore, match the patterns
of the published single crystal structures of [Y(cinn)3] and
[Nd(cinn)3] [28]. However, attempts to acquire single crystals suit-
able for X-ray crystallography were unsuccessful for complexes
with cinnamate ligands.
Fig. 4. X-ray molecular structure of compound 11.
slightly shorter than the distances of 4.074 and 4.104 Å corre-
sponding to Sm2–Sm3 and Sm1–Sm4 bridges, in which, these
metallic atoms are bridged by two tridentate bridging ligands
and one bidentate carboxylato ligand. The Sm3+ atoms have
SmO9 environments in which Sm2 and Sm4 centers are coordi-
nated with oxygen atoms pertaining to six different (4-OMephac)
ligands and one water molecule while Sm1 and Sm3 are coordi-
nated only to six different (4-OMephac) ligands. Sm–O bond dis-
tances have values in the range of 2.364(4)–2.702(5) Å. Benzene
rings in the structure are parallel with perpendicular dispositions
among them with dihedral angles near to 4.65° and 75.57°, respec-
tively. Chains running along the b axis are not isolated but
connected by hydrogen bonds involving some carboxylate groups
and crystallization water molecules. As a consequence of these
hydrogen bond interactions (range of 2.755–2.940 Å) in the ab
plane, metallic centers pertaining to different chains have an
inter-chain distance value of 10.032 Å.
On the other hand, we were able to obtain suitable crystals of
compound 11 (with the 4-methoxyphenylacetate (4-OMephac),
which were analyzed by single crystal X-ray diffraction studies.
ꢀ
11 crystallizes in the triclinic system and P1 space group. The
structure is formed by zig-zag chains (Fig. 4) built from Sm3+ metal
centers coordinated through 4-metoxyphenylacetic acid (4-OMe-
phac) ligands and crystallization water molecules. Two coordina-
tion modes of the ligand are evident in this complex, bidentate
and tridentate bridging, forming an extended one-dimensional
polymer along b axis.
The asymmetric unit contains four Sm3+ centers, twelve mono-
anionic ligands and four water molecules. Three tridentate bridg-
ing ligands link Sm1 with Sm2 and Sm3 with Sm4 with bond
lengths of 3.867 and 3.851 Å, respectively. These distances are
In the characterization of the compounds 1–11 by IR spectros-
copy, several characteristic absorption bands of the cinnamate
and phenylacetate ligands could be observed in the infrared spec-
tra of the complexes, verifying coordination by the absence of
Fig. 3. X-ray powder diffraction patterns of the compounds: [La(4-OMephac)3]ꢀ4H2O (5); [La(4-Clphac)3]ꢀ4H2O (6); [Ce(cinn)3] (7) and [Yb(cinn)3] (10).
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6
A. Aragón-Muriel et al. / Polyhedron xxx (2014) xxx–xxx
m
(COOH) absorption bands from the corresponding acids. Table 1
A significant decrease in the dmꢁCOO value confirms that the lantha-
nide ions are coordinated to the ligands through the oxygen atoms
of the carboxylate groups, and the ligands acts as a bidentate che-
lating agent. Additionally, the difference between the asymmetric
and symmetric vibrations of less than 200 cmꢁ1 indicates biden-
tate coordination of the carboxylate ligand [34].
presents experimental data obtained by IR spectroscopy. For the
compounds 3–6, 9 and 11 the bands in the 3600–3050 cmꢁ1 region
are assigned to the stretching of the OH group,
tion water. For 1–4 and 7–10, the bands in the 1642–1636 cmꢁ1-
region are assigned to the (C@C) vibrations, and are not affected
compared to sodium salts, confirming that the metal ions are not
coordinated with the
[27,32].
Stretching of the Ln–O bond (metal-carboxylate) has been
attributed to the (Ln–O) bands that have been reported for lantha-
num complex [33], finding the frequency of this band is observed
approximately at 779 cmꢁ1, shifted in complexes 3–6 and 11 due
to the presence of substituents in the aromatic ring and the
(C@C)propenyl bond. For all complexes, a bathochromic effect was
m(OH)w, from hydra-
m
In the characterization of the complexes 1–6 by 1H and 13C
NMR, the corresponding signals were observed. For 1–4 two dou-
blets assigned to the olefinic protons at d ꢃ 6.40 and 7.40 ppm
were observed while for 3–6 the signals attributed to the aromatic
protons were found as two doublets observed in the aromatic re-
gion with 3J between 7.3 and 8.8 Hz. A singlet at high field
(d ꢃ 3.70 ppm) in 1H NMR spectra of 3 and 5 was assigned to the
methoxy group protons. Another characteristic signal for 5 and 6
is a singlet at d ꢃ 3.30 ppm, corresponding to the protons of the ali-
phatic chain of the ligand, verifying that these protons are not
p-electron system of the olefinic double bond
m
observed in the stretching m(COO) compared to the sodium salts.
Table 1
Selected IR bands of the sodium ligands and their Ln(III) complexes.
Compound
Main bands (cmꢁ1
(OH)w
)
m
m
(C@C)
m
as(COO)
ms(COO)
d
m*
d(C–H)ip
d(@CH)
d(C–H)op
m(Ln–O)
NaL1
1
2
7
8
–
–
–
–
1641
1638
1636
1636
1636
1636
1636
1642
1638
1639
1639
–
1548
1516
1500
1499
1500
1500
1518
1547
1513
1562
1509
1560
1516
1537
1567
1544
1411
1412
1394
1395
1398
1394
1419
1399
1404
1429
1398
1404
1401
1402
1390
1422
137
104
106
104
102
106
99
148
109
133
111
156
115
135
177
122
1244
1237
1243
1243
1244
1243
1238
1241
1244
1238
1249
1248
1248
1249
1289
1288
970
987
982
982
983
983
985
971
985
970
983
–
773, 713
724, 686
736, 687
737, 688
742, 688
743, 689
747, 686
829
832
827
828
816
–
779
779
779
780
780
779
–
781
–
749
–
–
3422
–
9
10
NaL2
3
NaL3
4
NaL4
5
11
NaL5
6
–
3342
3424
3410
3411
3221
3435
3441
3410
–
–
–
–
–
–
–
–
822
820
816
810
733
732
–
743
L1 = (cinn), L2 = (4-MeOcinn), L3 = (4-Clcinn), L4 = (4-OMephac), L5 = (4-Clphac).
mꢁCOO as(COOꢁ)– s(COOꢁ).
= m m
*
D
Fig. 5. Macrophage viability.
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A. Aragón-Muriel et al. / Polyhedron xxx (2014) xxx–xxx
7
Fig. 6. Hemolysis assay. Erythrocytes viability.
The results showed that increasing doses (50, 300, 750 and
950 M) of all the studied compounds (1–10) were practically
non-toxic to macrophages as it can be clearly observed in Fig. 5.
For the highest concentration (950 M) of the studied compounds
cell survivals higher than 60% were observed in all cases indicating
an absence of toxicity to these cells.
Similarly, the hemolysis assay for the study of the erythrocyte
viability using doses of the lanthanide compounds (1–10) of 250,
550, 750 and 950 lM showed cell survivals higher than 80% in
all cases indicating that these compounds are non-toxic to red
blood cells (Fig. 6).
Table 2
IC50 values (lM) after 96 h incubation with lanthanide compounds 1–10.
l
Compound
IC50 values (
lM)
l
HL60
K562
MCF7
1
2
3
4
5
6
7
8
9
10
>750
728.7 1.1
>750
721.9 1.2
629.2 1.1
>750
>750
>750
>750
749.2 1.1
>750
>750
>750
>750
597.9 2.0
>750
>750
>750
>750
>750
681.3 5.0
577.9 5.3
542.7 5.0
>750
647.7 4.0
672.5 5.0
>750
>750
>750
743.5 1.1
3.2.2. Cytotoxicity studies against human cancer cell lines
In view of the very low, almost inexistent, toxicity of these com-
pounds to macrophages and erythrocytes and with the aim to
determine the potential use of these compounds as anticancer
drugs, we decided to explore the in vitro cytotoxicity of 1–10
against HL60 (human promyelocytic leukemia), K562 (human ery-
thromyeloblastoid leukemia) and MCF7 (breast cancer) cell lines
by Alamar blue-based assays [29]. The IC50 values of the investi-
gated compounds are summarized in Table 2.
The cytotoxicity experiments in cancer cells showed a dose-
dependent toxic activity (Fig. 7) of the lanthanide compounds
which began to be significant from 400 lM concentration. How-
ever, we observed that the cytotoxic activity of all the synthesized
compounds was very low, showing IC50 values between 542.7 5.0
being part of a conjugated system. Different types of carbons in the
organic ligands were assigned in the13C NMR spectra. For all com-
plexes, the carbonyl signal was observed at d ꢃ 180 ppm, while the
carbon of the methoxy group for 3 and 5 were identified at 55 ppm.
Quaternary carbons like C-1 and C-4 were verified when the
corresponding signal disappeared by dept-135. For 5 and 6, the
secondary carbon of the aliphatic chain (C-10), was observed in
the dept-135 spectrum as a negative signal.
The thermal behavior of 2–6 was determined by TG-DTG anal-
ysis. Waters of hydration were calculated through mass loss in a
step shown in the endothermic decomposition between 50 and
130 °C. Two stages of decomposition were identified: the
decomposition of the anhydrous cinnamate to the dioxycarbonate,
La2O2CO3 [35,36], is observed between 300–600 °C for 3 and 4
complexes, and the sesquioxide (La2O3) formation was found for
2, 5 and 6 complexes.
and >750 lM, which corresponded to a non-toxic effect in human
cancer cell lines. This result indicated that the studied lanthanide
compounds are not appropriate for anticancer therapy, in contrast
to some other lanthanide compounds [37].
3.2. Biological studies
3.3. Preliminary catalytic studies
3.2.1. Toxicity to macrophages and erythrocytes
3.3.1. Determination of the conversion rate and selectivity in the
oxidation of styrene
In view of the low applicability of the synthesized lanthanide
compounds as anticancer drugs, some catalytic applications were
studied. Thus, the catalytic potential of the complexes 1–11 have
been tested for the oxidation of styrene to give styrene oxide,
The in vitro toxicity of all the studied compounds (1–10) was
firstly tested in primary cell culture of mice peritoneal macro-
phages and mice erythrocytes in order to determine whether lan-
thanide compounds could be used in preclinical trials against
cancer cell lines.
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A. Aragón-Muriel et al. / Polyhedron xxx (2014) xxx–xxx
Fig. 7. Dose dependent cytotoxicity.
Fig. 8. Oxidation products of styrene with H2O2 catalyzed by lanthanide complexes with cinnamate and phenylacetate ligands.
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A. Aragón-Muriel et al. / Polyhedron xxx (2014) xxx–xxx
9
Table 3
Ce(III) complex (7) showed the highest activity reaching nearly
100% conversion with a relatively high selectivity (72%) towards
1-phenylethane-1,2-diol (PhED) (Table 3). This high activity may
be due to redox reactions in where Ce(III) is easily oxidized to
Ce(IV) by the oxidant of the reaction generating an intermediate
which may increase the catalytic activity. Experimentally, Ce(III)
complex was not recovered after the reaction, unlike the other
compounds, in this case a yellow polymer product was observed
after finishing reaction which was not characterized.
In the case of complexes 2–5, 8 and 10–11, they all have mod-
erate activity (with conversion rates between 60 and 80%) using
acetonitrile at 1:1000 (catalyst:styrene), 2:1 (peroxide:styrene),
15 h and 70 °C. It is also noteworthy that Sm(III) complex (9)
showed high catalytic activity (89% conversion) and was used to
study the influence of reaction time (see next Section 3.3.3). In
addition, the study of the influence of the concentration of catalyst
was conducted using the Ce(III) complex (7), while the oxidizing
effect was studied for Nd(III) complex (8) (see Section 3.3.4).
Effect of catalysts on the oxidation of styrene and the product selectivity.
Catalysta
Conversion (%)
Selectivity (%)
BzA
SO
AcPh
HyPhEt
PhED
1
2
3
4
5
6
7
8
57.15
77.78
66.81
67.56
74.41
54.11
99.56
65.36
88.53
76.53
71.38
50.51
63.47
58.47
36.84
26.56
58.68
27.39
39.78
55.43
31.33
47.04
3.56
3.21
3.51
5.43
2.26
3.06
0.00
4.32
2.51
4.72
8.46
1.77
1.84
1.71
3.38
2.65
1.96
0.54
3.38
2.08
2.43
2.83
1.93
2.88
1.67
1.21
3.80
1.14
5.33
0.90
2.02
2.91
24.43
44.16
31.49
36.32
54.35
68.54
36.30
72.07
52.52
39.98
61.51
17.23
9
10
11
a
Reaction conditions: styrene (1.04 g); catalyst (0.01 mmol); H2O2 (17.6 mmol);
acetonitrile (10 mL), temperature 70 °C. Oxidation products were identified and
quantified by Agilent 6890 series gas chromatographer equipped with an FID
detector and a HP-INNOWax column.
3.3.2. Study of the influence of temperature
benzaldehyde, 2-hydroxy-1-phenylethanone, 1-phenylethane-1,2-
diol and acetophenone in presence of aqueous 30% H2O2 as oxidant
(Fig. 8). The catalytic performances of all complexes are compared
in Table 3, Figs. 9 and 10.
The effect of temperature variation, reaction time, catalyst:sub-
strate ratio and oxidant:substrate ratio on the styrene conversion
and product selectivity over all catalysts have been examined. All
complexes proved to be catalytically active with conversions that
exceeded 40% after 15 h of reaction. The relatively high selectivity
to two main products (BzA and PhED) suggest that the complexes
may be used as heterogeneous catalysts in other oxidation reac-
tions, although a complete optimization of the reaction conditions
would be necessary to obtain the best catalytic results.
The response of the reaction towards an increase of the temper-
ature has been studied and the results are presented in Fig. 9(a–c).
It is clearly seen that the higher the temperature, the conversion
increases at shorter times. At 85 °C all the catalysts with cinnamate
ligands (without substituent) exceed 70% conversion after 8 h,
however after 15 h, all exceed 80% conversion. At 55 °C the effect
of the substituent in the La(III) complexes is observed. Complexes
4 and 6, with 4-Clcinn and 4-Clphac ligands respectively, have
higher conversion (>85%) after 15 h compared to the La(III) com-
plexes with methoxy substituent on the aromatic ring or without
substituent. In the selectivity to oxidation products, is generally
found that at 55 °C the selectivity towards any specific products
is less than at 85 °C. For complexes 3–7, the major product is
benzaldehyde (>75% selectivity) when the reaction takes place at
85 °C, whereas for complexes 1, 2, 8 and 10, the major product is
2-hydroxy-1-phenylethanone. At studied temperatures a clear
As all experiments were conducted using similar conditions, in
this preliminary study is possible to compare the effect of the me-
tal in the oxidation reactions of styrene studied here. Clearly,
Fig. 9. Conversion rates in the oxidation of styrene at different times by using: (a) catalysts 1–10, 1:1000 (catalyst:styrene), 2:1 (peroxide: styrene), 55 °C; (b) catalysts 1–10,
1:1000 (catalyst:styrene), 2:1 (peroxide:styrene), 85 °C; (c) catalyst 9, 1:1000 (catalyst:styrene), 2:1 (peroxide:styrene), 55, 70 and 85 °C; (d) catalyst 7, 1:1000, 1:2000 and
1:4000 (catalyst:styrene), 2:1 (peroxide:styrene), 70 °C; (e) catalyst 8, 1:1000 (catalyst:styrene), 1:1, 2:1 and 4:1 (peroxide:styrene), 70 °C.
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A. Aragón-Muriel et al. / Polyhedron xxx (2014) xxx–xxx
Fig. 10. Selectivity (%).a Effect of catalysts (1–11) on the oxidation of styrene at different temperatures (55, 70 y 85 °C), 15 h.a Reaction conditions: styrene (1.04 g,); catalyst
(0.01 mmol); H2O2 (17.6 mmol); acetonitrile (10 mL).
Fig. 11. Chromatograms of styrene oxidation with H2O2 using samarium complex (9) as catalysts at different reaction times.
influence of the ionic radius of the metal center of the complex in
the catalytic process is not observed. Fig. 9(c) shows the effect of
the temperature until 15 h for the Sm(III) complex (9). Increase
in temperature is found to be favorable for styrene oxidation, so
that, an increase of temperature led to much higher styrene con-
version. For this catalyst, the influence of reaction time in the
selectivity is discussed in Section 3.3.3.
selectivity of 40%. In general, the conversion of styrene is
favored with increasing reaction time, but the selectivity is being
affected.
3.3.3. Study of the influence of reaction time in the selectivity
The conversion and selectivity of styrene oxidation was moni-
tored at different time periods until 19 h (at 70 °C) to evaluate
the influence of reaction time in the catalytic activity of complex
9. Fig. 11 shows the chromatograms of styrene oxidation with
H2O2 in the presence of samarium complex 9 at different reaction
times where is easily observed how the styrene concentration is
decreasing with time (a decrease in the peak area is observed),
while the concentration of BzA and PhED are increasing with time
(an increase in the peak area is shown).
Fig. 12 shows the change in the conversion rate as well as the
variation of the selectivity towards both of the main products of
the reaction (BzA and PhED) with time. Initially, 20% styrene
conversion and 98% BzA selectivity were obtained, a significant
difference in the styrene conversion was subsequently observed
when the reaction time was increased, reaching 89% conver-
sion after 19 h, although with a decrease in the selectivity of
BzA to 55%, offset by increased PhED selectivity that reached a
Fig. 12. Conversion of styrene and variation in the selectivity of different reaction
products as a function of time using [Sm(cinn)3]ꢀH2O (9) as catalyst.
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A. Aragón-Muriel et al. / Polyhedron xxx (2014) xxx–xxx
11
Table 4
Effect of catalysts on the oxidation of styrene at different concentration of H2O2, catalyst concentration and reaction time, product selectivity and turn over number (TON).a
Catalyst
Catal:styrene
Time
(h)
Selectivity (%)
BzA
TON
SO
AcPh
HyPhEt
PhED
7
1:1000
2
5
8
12
15
2
5
8
81.25
64.14
31.59
29.08
28.06
71.04
64.89
28.42
46.59
22.94
0.90
0.30
0.00
2.94
0.00
1.29
1.51
2.42
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.33
0.00
0.00
0.00
6.20
4.12
12.13
6.86
6.26
5.36
4.83
11.38
13.33
16.86
10.88
30.24
56.28
61.13
65.03
19.88
27.02
57.77
16.71
58.35
628
738
756
902
995
1:2000
1:4000
1182
1434
1661
1791
1983
12
15
2
5
8
12
15
100.0
67.68
42.61
48.18
55.78
0.00
0.00
0.00
2.96
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
21.25
16.68
0.00
799
789
1547
2770
3779
32.32
19.76
27.61
20.10
H2O2:styrene
1:1
8
2
5
8
12
15
2
5
8
12
15
2
5
8
53.26
53.18
48.16
45.13
72.86
58.02
56.22
55.39
38.86
45.94
53.97
70.93
27.26
25.92
24.60
3.33
2.42
3.77
4.48
3.25
1.99
0.00
3.48
5.94
4.63
0.00
0.78
1.86
2.00
2.35
0.00
0.00
0.00
1.78
1.25
0.00
0.00
0.94
2.27
1.87
0.00
0.00
0.00
0.48
0.52
17.85
15.16
20.02
23.33
11.59
10.05
13.45
11.05
27.39
17.14
19.72
12.58
30.13
51.87
52.91
25.56
29.24
28.05
21.54
11.06
26.42
30.33
23.67
24.02
21.76
26.31
13.45
30.58
16.99
15.95
337
458
607
657
812
313
343
466
643
690
879
909
939
959
973
2:1
4:1
12
15
a
Reaction conditions: styrene (500 mg); acetonitrile; 70 °C. Turn over number (TON): moles converted/moles of active site.
3.3.4. Study of the influence of the catalyst and oxidant concentration
The influence of H2O2:styrene and catalyst:styrene molar ratio
on the conversion and selectivity has been studied and the results
are presented in Fig. 9(d and e) and Table 4. In the effect of oxidant
concentration, when the ratio is 4:1 (oxidant:substrate) from 2 h a
high conversion rate (>85%) is observed, indicating that the perox-
ide has a great influence in this study. Before 15 h at 2:1 ratio
(oxidant:substrate) the conversion is higher than 1:1, however,
after 15 h, 1:1 ratio exceeds to 2:1 in conversion, notably improv-
ing the selectivity toward benzaldehyde. About the Oxidant effect
one can also envisage that after 15 h of reaction, the peroxide con-
centration is directly proportional to the formation of HyPhEt and
inversely proportional to BZA.
The influence of the concentration of catalyst is clearly seen
when analyzing the results of Table 4. For the ratio 1:4000 (cata-
lyst:substrate) a TON value of 3779 after 15 h is achieved, which
is the highest value of all calculated. These results indicate that cat-
alyst 7 is efficient even at very low concentrations. For the three
concentrations tested, conversion ratio above 90% is obtained after
15 h. At shorter times, the conversion was always lower at 1:4000
ratio.
and erythrocytes was tested observing non-toxicity in the studied
range of concentrations which was up to 950 M, indicating that
these compounds can be considered as non-toxic for these primary
cells. In view of the low toxicity showed by the compounds, the
cytotoxicity effect in three different cancer cell lines was also as-
sessed, observing, unfortunately, that the IC50 values of the lantha-
l
nide complexes were very high (between 542.7 5.0 and >750 lM)
which reflected a non-toxic activity against these cancer cell lines.
This result indicated that these lanthanide compounds with cinna-
mate and/or phenylacetate ligands cannot be considered to be
studied as potential anticancer agents. However, the catalytic stud-
ies on the styrene oxidation carried out for 1–11, showed catalytic
conversions of up to 99% with a selectivity towards PhED of ca.
70%. A detailed study of the catalytic reaction mixture at different
time periods shows that the reaction conditions strongly affect the
behavior of styrene oxidation reaction. Thus, an increase in the
reaction time leads to a decrease of the selectivity towards BzA,
indicating that reaction times longer than 19 h may lead to equi-
molar mixtures of BzA and PhED. Increase in temperature is found
to be favorable for styrene oxidation. The selectivity to BzA and
efficiency of H2O2 for oxidation of styrene could be raised by keep-
ing a low concentration of hydrogen peroxide during short reaction
times. Further investigations employing this type of catalyst in
other reactions are currently in progress in our laboratory.
The selectivity toward products was moderately affected be-
cause at 1:4000 ratio the main product was BzA (56%), however,
when using a higher concentration of catalyst the major product
was PhED (55–65%).
Acknowledgements
4. Conclusions
The authors are grateful to Colciencias, Universidad del Valle
and the ‘‘Jóvenes Investigadores e Innovadores 2012’’ program
for financial support to the master student. We would also like
to thank financial support from the Ministerio de Economía y
Competitividad, Spain (Grant No. CTQ2012-30762).
A series of lanthanide complexes containing different cinna-
mate and phenylacetate ligands has been synthesized and charac-
terized. The molecular structure of compound 11 has been
determined. The toxicity of these compounds to macrophages
Please cite this article in press as: A. Aragón-Muriel et al., Polyhedron (2014), http://dx.doi.org/10.1016/j.poly.2014.02.040

12
A. Aragón-Muriel et al. / Polyhedron xxx (2014) xxx–xxx
[16] R. Sen, D.K. Hazra, S. Koner, M. Helliwell, M. Mukherjee, A. Bhattacharjee,
Appendix A. Supplementary data
Polyhedron 29 (2010) 3183.
[17] T. Ohshima, T. Nemoto, S.Y. Tosaki, H. Kakei, V. Gnanadesikan, M. Shibasaki,
CCDC 985957 contains the supplementary crystallographic data
for 11. These data can be obtained free of charge via http://
www.ccdc.cam.ac.uk/conts/retrieving.html, or from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ,
UK; fax: (+44) 1223-336-033; or e-mail: deposit@ccdc.cam.ac.uk.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.poly.2014.02.040.
Tetrahedron 59 (2003) 10485.
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