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Copper(II) complexes with 4-amino-α-(t-butylaminomethyl)-3,5-dichlorobenzyl alcohol hydrochloride (Clenbuterol). Crystal structures of the binuclear and mononuclear Cu(II) complexes with Clenbuterol
Polyhedron 24 (2005) 1983–1990 www.elsevier.com/locate/poly
Copper(II) complexes with 4-amino-a-(t-butylaminomethyl)-3,5-dichlorobenzyl alcohol hydrochloride (Clenbuterol). Crystal structures of the binuclear and mononuclear Cu(II) complexes with Clenbuterol V.T. Getova a, R.P. Bontchev b, D.R. Mehandjiev c, V. Skumryev d, P.R. Bontchev
c,*
a Faculty of Chemistry, Sofia University, 1, J. Bourchier Blvd., Sofia 1164, Bulgaria Sandia National Laboratories, P.O. Box 5800, MS 0779, Albuquerque, NM 87185-0779, USA c Institute of General and Inorganic Chemistry, Bulgarian Academy of Sciences, Sofia 1113, Bulgaria Institucio´ Catalana de Recerca i Estudis Avanc¸ats (ICREA) and Universitat Auto`noma de Barcelona, 08193 Bellaterra (Barcelona), Spain b
d
Received 13 April 2005; accepted 11 May 2005 Available online 21 July 2005
Abstract Two new copper(II) complexes with the bronchodilator Clenbuterol (HL) have been synthesized: the binuclear complex Cu2L2Cl2 Æ 4DMSO (1) and the mononuclear CuL2 Æ 2CH3OH (2) and have been studied using electronic, IR and EPR spectra, magnetochemical, thermogravimetric and single-crystal X-ray diffraction methods. Each of the Cu(II) centres in the binuclear complex 1 is four coordinated by one terminal chlorine and one nitrogen atom, and by two bridging oxygen atoms from two different ligand molecules. Each molecule of the binuclear complex also links four DMSO molecules by hydrogen bonds of the types S@O H2N and S@O HN. The overall structure is built by sheets of Cu2L2Cl2, parallel to the ab plane, separated by layers of DMSO. In the mononuclear moiety 2, Cu(II) is coordinated bidentately with the N and O atoms of two Clenbuterol ligands, forming a nearly square-planar complex CuL2. Two CH3OH molecules are also incorporated in the unit cell, forming hydrogen bonds between the hydroxyl hydrogen atom of CH3OH and the oxygen atoms of the ligands, CH3OH O(1). Both structures correlate well with the spectral, magnetochemical and thermal behaviour of complexes 1 and 2. 2005 Elsevier Ltd. All rights reserved. Keywords: Cu(II) complexes; Clenbuterol; X-ray data; Magnetochemical properties; Binuclear complex; Structures
1. Introduction Over the last 15 years we have demonstrated that medications of different types and chemical nature used for normalization of the arterial blood pressure both for hyper- and hypotension form stable complexes with copper [1–15], the latter being involved in blood pressure regulation together with zinc. The detailed chemical and
*
Corresponding author. Tel.: +359 2 8161345; fax: 359 2 9625438. E-mail address: [email protected]fia.bg (P.R. Bontchev).
0277-5387/$ - see front matter 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.poly.2005.05.017
structural examination of such complexes led to the idea that despite the very broad spectrum of different chemical properties and mechanisms of action, at least a large part of the observed biological effects may be related to the coordination of the drug with copper [12,13]. This idea could be used in the future as a potential guide-line in the formulation and development of new, more effective drugs. Some encouraging examples in this direction have been already reported [11,12,15]. Throughout these studies special attention has been paid to copper(II) complexes with b-blockers – one of the most widely used group of antihypertensives. From
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V.T. Getova et al. / Polyhedron 24 (2005) 1983–1990
a chemical point of view these medications represent aminoalcohols, forming stable chelate mono- and binuclear complexes with copper(II), which have been thoroughly examined and characterized [4–6,9–11]. In some cases we were able to prove directly that the corresponding copper complexes are more active and have longer biological effects compared to the pure non-coordinated drugs [11,12]. Developing further the above ideas, it seemed challenging to study other aminoalcohols that have been used as medicines for treatment of different diseases and to try to clarify the following major topics: do they also form complexes with copper; are their compositions and structures analogous to those of the b-blocker complexes and finally – what is the biological effect of their copper complexes compared to the pure non-complexed drugs. The medication selected for the present study was the b2-adrenergetic agonist Clenbuterol: 4-aminoa-(t-butylaminomethyl)-3,5-dichlorobenzyl alcohol hydrochloride, used in the clinical practice as a bronchodilator in the treatment of bronchial asthma, as bronchorelaxant and tokolytic agent in a series of other respiratory diseases. Due to its influence on the heart and respiratory rates it is used also as a doping agent. Cl
CH3
OH NH
NH2
C
CH3
CH3
Cl HL
Although formally an aminoalcohol, Clenbuterol differs from the b-blockers by two features: (i) the aminoalcohol chain is directly attached to the phenyl ring and not through an oxygen atom as in the b-blockers; (ii) there is a second donor group (–NH2) in the phenyl ring of HL capable of coordination, although it is sterically hindered by the two adjacent chlorine atoms. These differences in the ligand structure could change the complexation of copper, its homeostasis and hence – the effect of the drug. Even the first preliminary experiments have shown that the aminoalcohol HL forms two types of complexes, depending mainly on the molar metal-to-ligand ratio and the solvent used as a reaction medium. With an excess of the ligand (M:HL = 1:10), in the presence of NaOH (HL Æ HCl:NaOH = 1:2) and in methanolic solution, the mononuclear violet complex 2 was obtained, while with comparable amounts of the reagents (M:HL = 1:1) and in a mixed solvent of higher polarity (CH3OH + DMSO), 50% v/v, the binuclear green complex 1 was formed.
2. Experimental 2.1. Materials and synthesis The aminoalcohol Clenbuterol, HL Æ HCl was supplied by Sopharma, Bulgaria, and used without any further purification. CuCl2 Æ 2H2O and NaOH were obtained from Riedel E. de Hae¨n AG, CH3OH from Fluka and DMSO from Merck. All reagents and solvents used were of analytical grade. The binuclear complex 1 was obtained at ambient temperature when a 0.025 M solution of the ligand in DMSO (0.0784 g HL Æ HCl in 10 cm3 DMSO) was mixed with 0.025 M CuCl2 (0.0426 g CuCl2 Æ 2H2O in 10 cm3 DMSO). Dropwise addition of 0.025 M NaOH (0.0200 g NaOH in 20 cm3 CH3OH) to the latter solution resulted in a green coloration, the molar ratio of the reagents being Cu:HL Æ HCl:NaOH = 1:1:2. Green prismatic crystals began to form and precipitate after one day at room temperature. The crystals were filtered, washed with 5 cm3 of the DMSO + CH3OH mixed solvent and dried over P2O5. Yield 40%; Chemical analysis: Calc. for Cu2L2Cl2 Æ 4DMSO: C, 36.16; H, 5.50; N, 5.27; Cl, 20.01; Cu, 11.96. Found: C, 35.88; H, 5.37; N, 5.38; Cl, 19.79; Cu, 11.42%. Melting point 157 C. The mononuclear complex 2 was obtained from a MeOH solution in the presence of a large excess of the ligand. A methanolic 0.025 M solution of HL Æ HCl (0.0784 g in 10 cm3 MeOH) was mixed with 0.025 M CuCl2 Æ 2H2O (0.0043 g in 1.0 cm3 MeOH) at a molar ratio Cu:HL Æ HCl = 1:10, followed by dropwise addition of 0.025 M NaOH in MeOH; HL Æ HCl:NaOH = 1:2. The above procedures led to a blue-violet coloration and violet crystals precipitated after 2 days at room temperature. They were filtered, washed with 5 cm3 MeOH and dried over P2O5 (yield ca 21%). Calc. for CuL2 Æ 2CH3OH: C, 45.92; H, 6.23; N, 8.24; Cl, 20.85; Cu, 9.34. Found: C, 46.32; H, 5.89; N, 8.59; Cl, 21.58; Cu, 8.92%. Melting point 111 C. 2.2. Instrumentation and analysis Electronic spectra were obtained on a Specord UV– Vis (Carl-Zeiss, Jena) instrument. IR spectra were recorded in the range 4000–400 cm1 on a Specord-75 IR spectrometer, and in the range 500–75 cm1 on a Bruker 113 V instrument in polyethylene. Thermogravimetric analyses were performed using a Perkin–Elmer TGS-2 instrument. The EPR spectra in the X-band were obtained with an ERS 220/Q instrument, using Mn/ZnS standard. Magnetic susceptibilities were measured between 2 and 300 K in a magnetic field of 1 kOe using a commercial SQUID magnetometer (Quantum Design MPMS-XL) with sensitivity in the range of 107 emu. The data were corrected for the diamagnetic response of the sample holder and for the diamagnetic contribu-
V.T. Getova et al. / Polyhedron 24 (2005) 1983–1990
tion from the sample (Pascals constants). Elemental analyses were performed according to classical methods: C, H were determined as CO2 and H2O, N through the Dumas method, chlorine by titration with Hg(NO3)2 after wet digestion of the sample. Copper was determined by atomic absorption after wet digestion of the sample. For the structure determinations a rod-shaped green crystal, 0.20 · 0.06 · 0.05 mm in size, of compound 1 and a rod-shaped violet crystal, 0.24 · 0.05 · 0.06 mm in size, of compound 2 were selected and mounted on a SIEMENS SMART X-ray diffractometer with a 1 K CCD area detector. Data sets were collected at room temperature using graphite monochromatized Mo Ka ˚ ). Hemispheres of data (1271 radiation (k = 0.71073 A frames each at 5 cm detector distance) were collected using a narrow-frame method with scan widths of 0.30 in x and an exposure time of 30 s/frame. The first 50 frames were measured again at the end of each data collection to monitor instrument and crystal stability. The data were integrated using the Siemens SAINT program [16]. The program SADABS was used for the absorption corrections [17]. Both structures were solved by direct methods and refined by full matrix leastsquares techniques with the SHELX 97 software package [18]. Initially all non-hydrogen atoms were found from
1985
the Fourier maps. For compound 1 the hydrogen atoms have been added to the refinement model and their thermal parameters refined isotropically. Supplementary calculations when the hydrogen atoms were added and refined as riding models by using the appropriate AFIX commands resulted in a less satisfactory model not included in this manuscript [18]. The refinement of compound 2 has been carried out introducing all hydrogen atoms as riding models [18]. The main crystallographic details for complexes 1 and 2 are summarized in Table 1.
3. Results and discussion 3.1. Binuclear Cu2L2Cl2 Æ 4DMSO complex 1 3.1.1. X-ray data and crystal structure The experimental data revealed that the green complex 1 has a binuclear structure with a general formula of Cu2L2Cl2 Æ 4DMSO. In the structure all atoms occupy general (2i: x, y, z) positions. The asymmetric unit of the title compound consists of one copper and one Cl atom, one ligand and two DMSO molecules, i.e., one half of the complex and solvent molecules (Fig. 1). Each copper atom is coordinated by one terminal chlorine, one nitrogen and two oxygen atoms
Table 1 Crystal data and structure refinement for Cu2L2Cl2 Æ 4DMSO (1) and CuL2 Æ 2CH3OH (2) Complex 2
Complex 1
Empirical formula C26H44CuCl4N4O4 C32H58C16Cu2N4O6S4 Formula weight 682.02 1062.84 Temperature (K) 293(2) 293(2) ˚) Wavelength (A 0.71073 0.71073 Crystal system, space group triclinic, P 1 ð#2Þ triclinic, P 1 ð#2Þ Unit cell dimensions ˚) a (A 9.284(4) 8.8110(6) ˚) b (A 9.769(4) 10.9536(7) ˚) c (A 9.984(4) 12.7832(8) a () 99.675(8) 93.0840(10) b () 110.372(7) 102.4080(10) c () 105.211(8) 104.4110(10) ˚ 3) Z, volume (A 1784.7(5) 11,159.48(13) 1.443 1.522 Calculated density (g/cm3) Absorption coefficient (mm1) 1.074 1.486 F(000) 357 550 Crystal size (mm) 0.24 · 0.05 · 0.06 0.20 · 0.06 · 0.05 h Range for data collection () 2.26–26.00 1.64–23.99 Limiting indices 10 6 h 6 10, 10 6 k 6 10, 10 6 l 6 10 10 6 h 6 10, 12 6 k 6 12, 14 6 l 6 14 Reflections collected/unique [Rint] 4925/2177 [0.0369] 8609/3626 [0.0278] full-matrix least-squares on F2 Refinement method full-matrix least-squares on F2 Data/parameters 2177/206 3626/361 Goodness-of-fit on F2 1.091 1.062 a a Final R indices [I > 2r(I)] R1 = 0.0523, wR2 = 0.1273 R1 = 0.0358, wR2 = 0.0959 R1 = 0.0446, cwR2 = 0.1006 R indices (all data) R1 = 0.0676, bwR2 = 0.1338 Large differential peak and hole (e A3) 0.566 and 0.468 0.239 and 0.380 P P a R1 = ||Fo| Fc|/ |Fo| (based on reflections with I > 2r(I)). P P b wR2 ¼ ½ wðjF o j jF c jÞ2 = wjF o j21=2 ; w ¼ 1=½r2 ðF 2o Þ þ ð0.0702Þ2 þ 1.01P . P 2 P c wR2 ¼ ½ ðwjF o j jF c jÞ = wjF o j21=2 ; w ¼ 1=½r2 ðF 2o Þ þ ð0.0657P Þ2 ; P ¼ ½maxðF 2o ; 0Þ þ 2F 2c =3 ðall dataÞ.
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V.T. Getova et al. / Polyhedron 24 (2005) 1983–1990
C14
C15
Cl3
N1
O2
C11
O3
C13
S2
C10
C12
S1
C16
C5
C1
C6
N2
C7
C4 C2
C9
C8
Cl2
O1
C3
Cl1
Cu1
Fig. 1. Asymmetric unit, 50% thermal ellipsoids and labelling scheme of the binuclear complex 1.
Table 2 ˚ ) and angles () for the binuclear complex 1 Selected bond lengths (A Cu(1)–O(1)#1 Cu(1)–O(1)#2 Cu(1)–N(2)#3 Cu(1)–Cl(1) Cu(1)–Cu(1)#3 N(1)–H(13) O(2) H(13)H-bond N(2)–H(1) O(3) H(1)H-bond O(1)#1–Cu(1)–O(1)#2 O(1)#1–Cu(1)–N(2)#3 O(1)#2–Cu(1)–N(2)#3 O(1)#1–Cu(1)–Cl(1) O(1)#2–Cu(1)–Cl(1) N(2)#3–Cu(1)–Cl(1) Cl(1)–Cu(1)–O(1)–O(1) N(2)–Cu(1)–O(1)–O(1)
1.914(1) 1.926(1) 1.994(2) 2.2249(6) 2.9827(5) 0.86(1) 2.13(2) 0.80(1) 2.16(2) 78.09(7) 85.15(6) 149.01(6) 158.52(4) 100.66(4) 104.26(5) 16.77(7) 17.02(8)
Symmetry transformations used to generate equivalent atoms. #1: x + 1, y, z + 1; #2: x + 1, y, z; #3: x + 2, y, z + 1; #4: x 1, y, z.
cules oriented parallel to the ab plane, separated by double layers of solvent DMSO molecules (Fig. 4).
Fig. 2. Copper coordination of the binuclear complex 1.
of two different ligand molecules (Fig. 2). Both oxygen atoms are connected to two adjacent copper atoms and thus act as bridges between them. The Cu2O2 structural core represents a flat rhomboid (distorted plain square) ˚ and with Cu–O distances of 1.914(1) and 1.926(1) A O–Cu–O angles of 78.09(7) (Table 2). The nitrogen and chlorine atoms completing the copper coordination reside out of the Cu2O2 plane at angles of 16.77(6) and 17.02(6), respectively (Fig. 2, Table 2), the corresponding Cu–N and Cu–Cl distances being essentially the same as found in other similar complexes [12]. Each molecule of the binuclear complex participates also in the formation of H-bonds with four molecules of DMSO, two of them bonded with hydrogen atoms of the coordinated NH functions and two with the uncoordinated free NH2 groups of the ligands (Fig. 3). Due to the different length of the two type H-bonds (N1– ˚ , H13 O2 = 2.13(2) A ˚ , N2–H1 = H13 = 0.86(1) A ˚ and H1 O3 = 2.16(2) A ˚ , Table 2), they differ 0.80(1) A in their bond-strength, confirmed also by the corresponding thermogravimetric data (see below). The overall structure of complex 1 could be described as a layered one consisting of slabs of Cu2L2Cl2 mole-
3.1.2. Thermogravimetric data The thermogravimetric (TG) study revealed that in the temperature range 110–195 C the mass of the complex diminished by 29.1%, equivalent to the release of four molecules of DMSO. The relatively low temperature for the beginning of the process could be related to the fact that DMSO is not directly coordinated to copper(II) but is incorporated in the crystal lattice by hydrogen bond formation. The process of the DMSO removal proceeds in two stages. The first one that takes place at 110–165 C is obviously due to the loss of the two DMSO molecules bound by weaker H-bonds with the hydrogens from ˚ ), while the the NH-functions (O3 H1, r = 2.16(2) A last two DMSO molecules are associated with the hydro˚ ) and gens of the NH2 group (O2 H13, r = 2.13(2) A are lost at higher temperatures (165–195 C). 3.1.3. EPR and magnetochemical data The intramolecular distance between the two copper(II) centres needs special attention, as it determines to a great extent the magnetochemical and EPR behaviour of the complex. In both frozen solution and solid samples at 77 K the green binuclear complex 1 is EPR silent and does not show any signals, a fact that correlates well with the short Cu–Cu distance of about ˚ (Table 1). Evidently, the close vicinity and the 2.98 A proper orientation of the corresponding overlapping orbitals lead to a significant antiferromagnetic exchange interaction and to quenching of the signal. These conclusions are in accordance with the magnetochemical data as well. As can be seen in Fig. 5, the
V.T. Getova et al. / Polyhedron 24 (2005) 1983–1990
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Fig. 3. Connectivity and H-bonding in Cu2L2Cl2 Æ 4DMSO.
Fig. 4. Unit cell and 3-D packing of the binuclear complex 1. The copper, nitrogen, chlorine, sulfur, carbon and oxygen atoms are shown as crosshatched, hatched, dark-grey, black, grey and open circles, respectively, hydrogen atoms are omitted for clarity.
-5
1.4x10
magn. susceptibility (emu/Oe.g)
-5
1.2x10
-5
1.0x10
-6
8.0x10
-6
6.0x10
-6
4.0x10
-6
2.0x10
0
50
100
150
200
250
300
temperature(K)
Fig. 5. Magnetic susceptibility vs. T for the binuclear complex 1, measured at 1 kOe applied field.
magnetic susceptibility versus temperature curve has a complicated character with a maximum at TN 80 K and an exponential course at lower temperatures. This later in-
crease is signalling a paramagnetic contribution to the susceptibility at very low temperatures. At 125–300 K the Curie–Weiss law is followed with a large correlation coefficient of R = 0.9993. The effective magnetic moment calculated from the experimental data is 2.71 BM (the Weiss constant Cm = 0.92). Note that subtraction of the low-temperature paramagnetic component has negligible effect on both, the value of the effective magnetic moment and TN. The absolute value of the paramagnetic asymptotic temperature, hN 80 K, is close to TN suggesting that a paramagnetic-antiferromagnetic transition takes place at 80 K. The experimentally found magnetic moment is close to the theoretical one, which for a crystal field of D = 3000 cm1 is 2.65 BM [19–21]. Obviously, at temperatures over 125 K the antiferromagnetic interactions vanish and the Cu(II) centres show their paramagnetic character. 3.1.4. Electronic spectra The binuclear complex 1 shows absorption bands at 750 and 380 nm in the mixed MeOH + DMSO solvent
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described above. The first relatively weak band was assigned to a d–d transition in a near square-planar copper(II) structure, while the second more intense one at 380 nm (e 460 l mol1 cm1) was attributed to a charge-transfer transition O ! Cu. The last band is typical for copper(II) polynuclear complexes with bridging oxygen atoms of the type Cu–O–Cu [22–24].
Cl2 C9 C10
C7
3.2. Mononuclear CuL2 Æ 2CH3OH complex 2 3.2.1. X-ray data and crystal structure The X-ray analysis and structure refinement showed that the violet compound 2 is a mononuclear complex with a square-planar structure and a general formula of CuL2 Æ 2CH3OH. In the structure the copper atoms are located on an inversion centre and occupy one crystallographically independent special position (1c: 0, 1/2, 0), while all other atoms occupy general (2i: x, y, z) positions. The asymmetric unit of the complex consists of one copper atom, one ligand molecule, coordinated through its oxygen and nitrogen atoms, and one CH3OH molecule, i.e., one half of the complex and solvent molecules (Fig. 6). The CuO2N2 core has a nearly squareplanar structure with O–Cu–O and N–Cu–N angles of 180 (Fig. 7, Table 3). The Cu–O and Cu–N distances (Table 3) are in good agreement with those for other aminoalcohol complexes of Cu(II) [7,12]. The methanol molecules included in the overall structure are not directly coordinated to Cu(II) but form hydrogen bonds of the type CH3OH O with the oxygen atom of the ligand (Fig. 8) with O2–H15 and H15 O1 distances of ˚ , respectively. 0.778(2) and 1.870(2) A
O2 N1
N2
C6 C11
3.1.5. IR spectra The pure ligand HL Æ HCl shows absorption bands at 3400, 3355, 3320–3120 cm1 within the range 3500– 3000 cm1, which are assigned to the stretching vibrations of hydroxyl, imino and aminogroups engaged in H-bonding of the intra- and intermolecular type [25]. This assignment is also supported by the fact that the coordination with Cu(II) leads to a pronounced decrease of the absorbance in the 2800–2300 cm1 range due to the formation of H-bonds. Complex 1 shows only three bands at 3420, 3330 and 3180 cm1, ascribed to mas(NH2), msym(NH2) and m(NH). The reduction of the number of bands in this range after complexation could be related to deprotonation of the hydroxyl group and hence to the disappearance of the m(OH) stretching vibration. At the same time three new bands in the far IR-spectrum appear at 490, 382 and 254 cm1, assigned to m(Cu–N), m(Cu–O) and m(Cu–Cl), respectively [25]. Another broad and intensive band appears at 1030 cm1 attributed to the stretching vibration m(S@O) of the SO-group from the DMSO molecules [25].
C13
Cu1
O1 C8
Cl1
C12
C2
C5 C3
C1 C4
Fig. 6. Asymmetric unit, numbering scheme and thermal ellipsoids (50%) of the mononuclear complex 2.
Fig. 7. Copper coordination of the mononuclear complex 2.
Table 3 ˚ ) and angles () for the mononuclear complex Selected bond lengths (A 2 Cu(1)–O(1) Cu(1)–N(1)#1 Cu(1)–O(1)#1 Cu(1)–N(1) O(1) H(15)H-bond O(1)–Cu(1)–O(1)#1 O(1)#1–Cu(1)–N(1)#1 O(1)–Cu(1)–N(1) O(1)#1–Cu(1)–N(1) O(1)–Cu(1)–N(1)#1 N(1)–Cu(1)–N(1)#1
1.898(2) 2.043(3) 1.898(2) 2.043(3) 1.870(2) 180.0 85.61(10) 85.61(10) 94.39(10) 94.39(10) 180.0
Symmetry transformations used to generate equivalent atoms. #1: x, y + 1, z; #2: x 1, y, z; #3: x + 1, y, z.
Fig. 8. Unit cell, 3-D packing and H-bonds in CuL2 Æ 2CH3OH. The copper, nitrogen, chlorine, carbon and oxygen atoms are shown as cross-hatched, hatched, dark-grey, grey and open circles, respectively, hydrogen atoms are omitted for clarity.
V.T. Getova et al. / Polyhedron 24 (2005) 1983–1990
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3.2.2. Electronic, IR and EPR spectra The electronic spectrum of the mononuclear complex 2 in methanol shows one broad asymmetric absorption band at 580 nm (e 200 l mol1 cm1) assigned to the d–d transition in a distorted tetragonal structure of the Cu(II) complex, where copper is bound with oxygen and nitrogen donor atoms. The IR spectrum of 2 shows five bands in the 3470– 3100 cm1 range, assigned to the stretching vibrations of NH2 and NH, shifted as a result of the coordination to Cu(II), and of (OH) from CH3OH. In addition two new bands in the far IR spectrum appeared at 490 and 396 cm1, ascribed to m(Cu–N) and m(Cu–O), respectively [25]. The strong absorbance of the free ligand in the 2800–2300 cm1 range is reduced in intensity due to the ligand coordination and the H-bond rupture caused by it. The X-band EPR spectra of the complex, both in the solid phase and in frozen solutions (77 K), are typical for mononuclear paramagnetic Cu(II) complexes. The EPR parameters gi = 2.245, g^ = 2.022, A = 160 G and the relation gi > g^ show that the unpaired d-electron of Cu(II) occupies predominately the dx2 y 2 -orbital. Thus the formation of a strongly distorted (practically a square-planar) complex was confirmed again. The frozen solution spectra reveal also an unresolved SHFS from 14N in the perpendicular magnetic field, due to the coordination of the NH-function to Cu(II). The same solution shows an isotropic signal with giso = 2.120 and Aiso = 68 G at 293 K. The experimental EPR data correlate well with those reported for similar copper(II) complexes [12].
In the solid phase, solvent molecules (4DMSO or 2CH3OH per molecule of the complex) are also incorporated in the crystal lattice, linked through H-bonds with the ligand. There is a marked difference, however, between the bonding of the two solvents. In 1 the DMSO molecules with their S@O groups serve as H-atom acceptors, the hydrogen atoms of the bond coming from NH and NH2 of the ligand, while in 2 the H-atom acceptor is the oxygen of the deprotonated ligand, the H-atom donor being the OH function of CH3OH.
4. Conclusions
References
Clenbuterol forms two complexes with copper(II) – the binuclear Cu2L2Cl2 Æ 4DMSO and the mononuclear CuL2 Æ 2CH3OH, acting as a bidentate chelate forming ligand with its imino and deprotonated hydroxyl functions. In both complexes copper has a slightly distorted square-planar coordination. In complex 1 the two copper atoms are linked together through oxygen atom bridges from two ligand molecules. Thus the coordination sphere around each of the two Cu centres includes two oxygen, one nitrogen and one terminal Cl atom. In complex 2 Cu(II) is coordinated with two oxygen and two nitrogen atoms from two ligand molecules. The relatively short distance between the two copper atoms in 1 is responsible for a strong antiferromagnetic exchange interaction, that determines its interesting magnetic properties – a complete quenching of the EPR signals and a specific temperature dependence of the magnetic susceptibility. As for complex 2, it shows the typical behaviour of a normal paramagnetic Cu(II) complex.
[1] P.R. Bontchev, H. Kadum, G. Gochev, B. Evtimova, J. Macicek, Ch. Nachev, Polyhedron 11 (1992) 1973. [2] P.R. Bontchev, G. Gochev, B. Evtimova, H. Kadum, Ch. Nachev, J. Inorg. Biochem. 46 (1992) 23. [3] P.R. Bontchev, B. Ivanova, K. Koicheva, in: Proceedings of the 5th International Symposium on Applied Inorganic and Bioinorganic Chemistry, Corfu, Greece, 1999, p. 138. [4] P.R. Bontchev, H. Kadum, B. Evtimova, Ch. Nachev, E. Zhecheva, D. Mehandjiev, D. Ivanov, J. Inorg. Biochem. 48 (1992) 153. [5] P.R. Bontchev, I.N. Pantcheva, B. Ivanova, D.R. Mehandjiev, Bulg. Chem. Commun. 31 (1999) 59. [6] P.R. Bontchev, I.N. Pantcheva, G. Gochev, D.R. Mehandjiev, D.S. Ivanov, Transition Met. Chem. 25 (2000) 196. [7] P.R. Bontchev, B.B. Ivanova, R.P. Bontchev, D.R. Mehandjiev, D.S. Ivanov, Polyhedron 19 (2000) 1843. [8] P.R. Bontchev, B.B. Ivanova, R.P. Bontchev, D. Mehandjiev, Polyhedron 20 (2001) 231. [9] P.R. Bontchev, I.N. Pantcheva, T. Todorov, D.R. Mehandjiev, N.S. Savov, J. Inorg. Biochem. 83 (2001) 25. [10] P.R. Bontchev, B.B. Ivanova, R.P. Bontchev, D. Mehandjiev, J. Coord. Chem. 54 (2001) 117. [11] P.R. Bontchev, I.N. Pantcheva, R.P. Bontchev, D.S. Ivanov, N. Danchev, BioMetals 15 (2002) 79.
5. Supplementary information Full crystallographic details have been deposited in cifformat with the Cambridge Crystallographic Data Centre, CCDC 268587 for 1 and 268588 for 2. Copies of this information can be obtained free of charge from the Director, CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK, fax: +44 1223 336 033, e-mail: deposit@ccdc. cam.ac.uk, Web: http://www.ccdc.cam.ac.uk/conts/ retrieving/html.
Acknowledgements The authors greatly acknowledge the financial support provided by the National Research Fund of Bulgaria. They also thank Dr. R. Stoyanova from the Institute of General and Inorganic Chemistry, Bulgarian Academy of Sciences, for some of the EPR data.
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[12] P.R. Bontchev, I.N. Pantcheva, Transition Met. Chem. 27 (2002) 1. [13] P.R. Bontchev, D.R. Mehandjiev, B.B. Ivanova, R.P. Bontchev, Transition Met. Chem. 28 (2003) 745. [14] P.R. Bontchev, B.B. Ivanova, D.R. Mehandjiev, Bulg. Chem. Commun. 35 (2003) 21. [15] P.R. Bontchev, Ch. Nachev, B. Evtimova, N.D. Yordanov, E. Zhecheva, D. Mehandjiev, in: Proceedings of the 12th International Conference on Coordination Chemistry, Smolenice, Slovakia, 1989, p. 47. [16] Siemens Analytical X-ray Instruments; SAINT, Version 4.05, Madison, WI, USA, 1995. [17] G.M. Sheldrick, Program SADABS, University of Go¨ttingen, 1995. [18] G.M. Sheldrick, SHELX 97 (Includes SHELXS 97, SHELXL97, CIFTAB) – Programs for Crystal Structure Analysis (Release 97-2).
[19] [20] [21] [22] [23] [24] [25]
Institut fu¨r Anorganische Chemie der Universita¨t, Tammanstrasse 4, D-3400 Go¨ttingen, Germany, 1998. R. Bocˇa, Theoretical Foundations of Molecular Magnetism, Elsevier, Amsterdam, 1999. E.A. Bondreaux, L.N. Mulay, Theory and Applications of Molecular Paramagnetism, Wiley, New York, 1976. O. Kahn, Molecular Magnetism, Wiley, Chichester, UK, 1994. T. Lindgren, R. Sillanpaeae, T. Nortia, K. Pihladja, Inorg. Chim. Acta 73 (1983) 153. G.A. van Albada, M.T. Lakin, N. Veldman, A.L. Spek, J. Reedijk, Inorg. Chem. 34 (1995) 4910. G.A. van Albada, W.J.J. Smeets, A.L. Spek, J. Reedijk, Inorg. Chim. Acta 260 (1997) 151. K. Nakamoto, Infrared and Raman Spectra of Inorganic and Coordination Compounds, 5th ed., Wiley, New York, Toronto, 1997.
Copper(II) complexes with 4-amino-a-(t-butylaminomethyl)-3,5-dichlorobenzyl alcohol hydrochloride (Clenbuterol). Crystal structures of the binuclear and mononuclear Cu(II) complexes with Clenbuterol V.T. Getova a, R.P. Bontchev b, D.R. Mehandjiev c, V. Skumryev d, P.R. Bontchev
c,*
a Faculty of Chemistry, Sofia University, 1, J. Bourchier Blvd., Sofia 1164, Bulgaria Sandia National Laboratories, P.O. Box 5800, MS 0779, Albuquerque, NM 87185-0779, USA c Institute of General and Inorganic Chemistry, Bulgarian Academy of Sciences, Sofia 1113, Bulgaria Institucio´ Catalana de Recerca i Estudis Avanc¸ats (ICREA) and Universitat Auto`noma de Barcelona, 08193 Bellaterra (Barcelona), Spain b
d
Received 13 April 2005; accepted 11 May 2005 Available online 21 July 2005
Abstract Two new copper(II) complexes with the bronchodilator Clenbuterol (HL) have been synthesized: the binuclear complex Cu2L2Cl2 Æ 4DMSO (1) and the mononuclear CuL2 Æ 2CH3OH (2) and have been studied using electronic, IR and EPR spectra, magnetochemical, thermogravimetric and single-crystal X-ray diffraction methods. Each of the Cu(II) centres in the binuclear complex 1 is four coordinated by one terminal chlorine and one nitrogen atom, and by two bridging oxygen atoms from two different ligand molecules. Each molecule of the binuclear complex also links four DMSO molecules by hydrogen bonds of the types S@O H2N and S@O HN. The overall structure is built by sheets of Cu2L2Cl2, parallel to the ab plane, separated by layers of DMSO. In the mononuclear moiety 2, Cu(II) is coordinated bidentately with the N and O atoms of two Clenbuterol ligands, forming a nearly square-planar complex CuL2. Two CH3OH molecules are also incorporated in the unit cell, forming hydrogen bonds between the hydroxyl hydrogen atom of CH3OH and the oxygen atoms of the ligands, CH3OH O(1). Both structures correlate well with the spectral, magnetochemical and thermal behaviour of complexes 1 and 2. 2005 Elsevier Ltd. All rights reserved. Keywords: Cu(II) complexes; Clenbuterol; X-ray data; Magnetochemical properties; Binuclear complex; Structures
1. Introduction Over the last 15 years we have demonstrated that medications of different types and chemical nature used for normalization of the arterial blood pressure both for hyper- and hypotension form stable complexes with copper [1–15], the latter being involved in blood pressure regulation together with zinc. The detailed chemical and
*
Corresponding author. Tel.: +359 2 8161345; fax: 359 2 9625438. E-mail address: [email protected]fia.bg (P.R. Bontchev).
0277-5387/$ - see front matter 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.poly.2005.05.017
structural examination of such complexes led to the idea that despite the very broad spectrum of different chemical properties and mechanisms of action, at least a large part of the observed biological effects may be related to the coordination of the drug with copper [12,13]. This idea could be used in the future as a potential guide-line in the formulation and development of new, more effective drugs. Some encouraging examples in this direction have been already reported [11,12,15]. Throughout these studies special attention has been paid to copper(II) complexes with b-blockers – one of the most widely used group of antihypertensives. From
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V.T. Getova et al. / Polyhedron 24 (2005) 1983–1990
a chemical point of view these medications represent aminoalcohols, forming stable chelate mono- and binuclear complexes with copper(II), which have been thoroughly examined and characterized [4–6,9–11]. In some cases we were able to prove directly that the corresponding copper complexes are more active and have longer biological effects compared to the pure non-coordinated drugs [11,12]. Developing further the above ideas, it seemed challenging to study other aminoalcohols that have been used as medicines for treatment of different diseases and to try to clarify the following major topics: do they also form complexes with copper; are their compositions and structures analogous to those of the b-blocker complexes and finally – what is the biological effect of their copper complexes compared to the pure non-complexed drugs. The medication selected for the present study was the b2-adrenergetic agonist Clenbuterol: 4-aminoa-(t-butylaminomethyl)-3,5-dichlorobenzyl alcohol hydrochloride, used in the clinical practice as a bronchodilator in the treatment of bronchial asthma, as bronchorelaxant and tokolytic agent in a series of other respiratory diseases. Due to its influence on the heart and respiratory rates it is used also as a doping agent. Cl
CH3
OH NH
NH2
C
CH3
CH3
Cl HL
Although formally an aminoalcohol, Clenbuterol differs from the b-blockers by two features: (i) the aminoalcohol chain is directly attached to the phenyl ring and not through an oxygen atom as in the b-blockers; (ii) there is a second donor group (–NH2) in the phenyl ring of HL capable of coordination, although it is sterically hindered by the two adjacent chlorine atoms. These differences in the ligand structure could change the complexation of copper, its homeostasis and hence – the effect of the drug. Even the first preliminary experiments have shown that the aminoalcohol HL forms two types of complexes, depending mainly on the molar metal-to-ligand ratio and the solvent used as a reaction medium. With an excess of the ligand (M:HL = 1:10), in the presence of NaOH (HL Æ HCl:NaOH = 1:2) and in methanolic solution, the mononuclear violet complex 2 was obtained, while with comparable amounts of the reagents (M:HL = 1:1) and in a mixed solvent of higher polarity (CH3OH + DMSO), 50% v/v, the binuclear green complex 1 was formed.
2. Experimental 2.1. Materials and synthesis The aminoalcohol Clenbuterol, HL Æ HCl was supplied by Sopharma, Bulgaria, and used without any further purification. CuCl2 Æ 2H2O and NaOH were obtained from Riedel E. de Hae¨n AG, CH3OH from Fluka and DMSO from Merck. All reagents and solvents used were of analytical grade. The binuclear complex 1 was obtained at ambient temperature when a 0.025 M solution of the ligand in DMSO (0.0784 g HL Æ HCl in 10 cm3 DMSO) was mixed with 0.025 M CuCl2 (0.0426 g CuCl2 Æ 2H2O in 10 cm3 DMSO). Dropwise addition of 0.025 M NaOH (0.0200 g NaOH in 20 cm3 CH3OH) to the latter solution resulted in a green coloration, the molar ratio of the reagents being Cu:HL Æ HCl:NaOH = 1:1:2. Green prismatic crystals began to form and precipitate after one day at room temperature. The crystals were filtered, washed with 5 cm3 of the DMSO + CH3OH mixed solvent and dried over P2O5. Yield 40%; Chemical analysis: Calc. for Cu2L2Cl2 Æ 4DMSO: C, 36.16; H, 5.50; N, 5.27; Cl, 20.01; Cu, 11.96. Found: C, 35.88; H, 5.37; N, 5.38; Cl, 19.79; Cu, 11.42%. Melting point 157 C. The mononuclear complex 2 was obtained from a MeOH solution in the presence of a large excess of the ligand. A methanolic 0.025 M solution of HL Æ HCl (0.0784 g in 10 cm3 MeOH) was mixed with 0.025 M CuCl2 Æ 2H2O (0.0043 g in 1.0 cm3 MeOH) at a molar ratio Cu:HL Æ HCl = 1:10, followed by dropwise addition of 0.025 M NaOH in MeOH; HL Æ HCl:NaOH = 1:2. The above procedures led to a blue-violet coloration and violet crystals precipitated after 2 days at room temperature. They were filtered, washed with 5 cm3 MeOH and dried over P2O5 (yield ca 21%). Calc. for CuL2 Æ 2CH3OH: C, 45.92; H, 6.23; N, 8.24; Cl, 20.85; Cu, 9.34. Found: C, 46.32; H, 5.89; N, 8.59; Cl, 21.58; Cu, 8.92%. Melting point 111 C. 2.2. Instrumentation and analysis Electronic spectra were obtained on a Specord UV– Vis (Carl-Zeiss, Jena) instrument. IR spectra were recorded in the range 4000–400 cm1 on a Specord-75 IR spectrometer, and in the range 500–75 cm1 on a Bruker 113 V instrument in polyethylene. Thermogravimetric analyses were performed using a Perkin–Elmer TGS-2 instrument. The EPR spectra in the X-band were obtained with an ERS 220/Q instrument, using Mn/ZnS standard. Magnetic susceptibilities were measured between 2 and 300 K in a magnetic field of 1 kOe using a commercial SQUID magnetometer (Quantum Design MPMS-XL) with sensitivity in the range of 107 emu. The data were corrected for the diamagnetic response of the sample holder and for the diamagnetic contribu-
V.T. Getova et al. / Polyhedron 24 (2005) 1983–1990
tion from the sample (Pascals constants). Elemental analyses were performed according to classical methods: C, H were determined as CO2 and H2O, N through the Dumas method, chlorine by titration with Hg(NO3)2 after wet digestion of the sample. Copper was determined by atomic absorption after wet digestion of the sample. For the structure determinations a rod-shaped green crystal, 0.20 · 0.06 · 0.05 mm in size, of compound 1 and a rod-shaped violet crystal, 0.24 · 0.05 · 0.06 mm in size, of compound 2 were selected and mounted on a SIEMENS SMART X-ray diffractometer with a 1 K CCD area detector. Data sets were collected at room temperature using graphite monochromatized Mo Ka ˚ ). Hemispheres of data (1271 radiation (k = 0.71073 A frames each at 5 cm detector distance) were collected using a narrow-frame method with scan widths of 0.30 in x and an exposure time of 30 s/frame. The first 50 frames were measured again at the end of each data collection to monitor instrument and crystal stability. The data were integrated using the Siemens SAINT program [16]. The program SADABS was used for the absorption corrections [17]. Both structures were solved by direct methods and refined by full matrix leastsquares techniques with the SHELX 97 software package [18]. Initially all non-hydrogen atoms were found from
1985
the Fourier maps. For compound 1 the hydrogen atoms have been added to the refinement model and their thermal parameters refined isotropically. Supplementary calculations when the hydrogen atoms were added and refined as riding models by using the appropriate AFIX commands resulted in a less satisfactory model not included in this manuscript [18]. The refinement of compound 2 has been carried out introducing all hydrogen atoms as riding models [18]. The main crystallographic details for complexes 1 and 2 are summarized in Table 1.
3. Results and discussion 3.1. Binuclear Cu2L2Cl2 Æ 4DMSO complex 1 3.1.1. X-ray data and crystal structure The experimental data revealed that the green complex 1 has a binuclear structure with a general formula of Cu2L2Cl2 Æ 4DMSO. In the structure all atoms occupy general (2i: x, y, z) positions. The asymmetric unit of the title compound consists of one copper and one Cl atom, one ligand and two DMSO molecules, i.e., one half of the complex and solvent molecules (Fig. 1). Each copper atom is coordinated by one terminal chlorine, one nitrogen and two oxygen atoms
Table 1 Crystal data and structure refinement for Cu2L2Cl2 Æ 4DMSO (1) and CuL2 Æ 2CH3OH (2) Complex 2
Complex 1
Empirical formula C26H44CuCl4N4O4 C32H58C16Cu2N4O6S4 Formula weight 682.02 1062.84 Temperature (K) 293(2) 293(2) ˚) Wavelength (A 0.71073 0.71073 Crystal system, space group triclinic, P 1 ð#2Þ triclinic, P 1 ð#2Þ Unit cell dimensions ˚) a (A 9.284(4) 8.8110(6) ˚) b (A 9.769(4) 10.9536(7) ˚) c (A 9.984(4) 12.7832(8) a () 99.675(8) 93.0840(10) b () 110.372(7) 102.4080(10) c () 105.211(8) 104.4110(10) ˚ 3) Z, volume (A 1784.7(5) 11,159.48(13) 1.443 1.522 Calculated density (g/cm3) Absorption coefficient (mm1) 1.074 1.486 F(000) 357 550 Crystal size (mm) 0.24 · 0.05 · 0.06 0.20 · 0.06 · 0.05 h Range for data collection () 2.26–26.00 1.64–23.99 Limiting indices 10 6 h 6 10, 10 6 k 6 10, 10 6 l 6 10 10 6 h 6 10, 12 6 k 6 12, 14 6 l 6 14 Reflections collected/unique [Rint] 4925/2177 [0.0369] 8609/3626 [0.0278] full-matrix least-squares on F2 Refinement method full-matrix least-squares on F2 Data/parameters 2177/206 3626/361 Goodness-of-fit on F2 1.091 1.062 a a Final R indices [I > 2r(I)] R1 = 0.0523, wR2 = 0.1273 R1 = 0.0358, wR2 = 0.0959 R1 = 0.0446, cwR2 = 0.1006 R indices (all data) R1 = 0.0676, bwR2 = 0.1338 Large differential peak and hole (e A3) 0.566 and 0.468 0.239 and 0.380 P P a R1 = ||Fo| Fc|/ |Fo| (based on reflections with I > 2r(I)). P P b wR2 ¼ ½ wðjF o j jF c jÞ2 = wjF o j21=2 ; w ¼ 1=½r2 ðF 2o Þ þ ð0.0702Þ2 þ 1.01P . P 2 P c wR2 ¼ ½ ðwjF o j jF c jÞ = wjF o j21=2 ; w ¼ 1=½r2 ðF 2o Þ þ ð0.0657P Þ2 ; P ¼ ½maxðF 2o ; 0Þ þ 2F 2c =3 ðall dataÞ.
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V.T. Getova et al. / Polyhedron 24 (2005) 1983–1990
C14
C15
Cl3
N1
O2
C11
O3
C13
S2
C10
C12
S1
C16
C5
C1
C6
N2
C7
C4 C2
C9
C8
Cl2
O1
C3
Cl1
Cu1
Fig. 1. Asymmetric unit, 50% thermal ellipsoids and labelling scheme of the binuclear complex 1.
Table 2 ˚ ) and angles () for the binuclear complex 1 Selected bond lengths (A Cu(1)–O(1)#1 Cu(1)–O(1)#2 Cu(1)–N(2)#3 Cu(1)–Cl(1) Cu(1)–Cu(1)#3 N(1)–H(13) O(2) H(13)H-bond N(2)–H(1) O(3) H(1)H-bond O(1)#1–Cu(1)–O(1)#2 O(1)#1–Cu(1)–N(2)#3 O(1)#2–Cu(1)–N(2)#3 O(1)#1–Cu(1)–Cl(1) O(1)#2–Cu(1)–Cl(1) N(2)#3–Cu(1)–Cl(1) Cl(1)–Cu(1)–O(1)–O(1) N(2)–Cu(1)–O(1)–O(1)
1.914(1) 1.926(1) 1.994(2) 2.2249(6) 2.9827(5) 0.86(1) 2.13(2) 0.80(1) 2.16(2) 78.09(7) 85.15(6) 149.01(6) 158.52(4) 100.66(4) 104.26(5) 16.77(7) 17.02(8)
Symmetry transformations used to generate equivalent atoms. #1: x + 1, y, z + 1; #2: x + 1, y, z; #3: x + 2, y, z + 1; #4: x 1, y, z.
cules oriented parallel to the ab plane, separated by double layers of solvent DMSO molecules (Fig. 4).
Fig. 2. Copper coordination of the binuclear complex 1.
of two different ligand molecules (Fig. 2). Both oxygen atoms are connected to two adjacent copper atoms and thus act as bridges between them. The Cu2O2 structural core represents a flat rhomboid (distorted plain square) ˚ and with Cu–O distances of 1.914(1) and 1.926(1) A O–Cu–O angles of 78.09(7) (Table 2). The nitrogen and chlorine atoms completing the copper coordination reside out of the Cu2O2 plane at angles of 16.77(6) and 17.02(6), respectively (Fig. 2, Table 2), the corresponding Cu–N and Cu–Cl distances being essentially the same as found in other similar complexes [12]. Each molecule of the binuclear complex participates also in the formation of H-bonds with four molecules of DMSO, two of them bonded with hydrogen atoms of the coordinated NH functions and two with the uncoordinated free NH2 groups of the ligands (Fig. 3). Due to the different length of the two type H-bonds (N1– ˚ , H13 O2 = 2.13(2) A ˚ , N2–H1 = H13 = 0.86(1) A ˚ and H1 O3 = 2.16(2) A ˚ , Table 2), they differ 0.80(1) A in their bond-strength, confirmed also by the corresponding thermogravimetric data (see below). The overall structure of complex 1 could be described as a layered one consisting of slabs of Cu2L2Cl2 mole-
3.1.2. Thermogravimetric data The thermogravimetric (TG) study revealed that in the temperature range 110–195 C the mass of the complex diminished by 29.1%, equivalent to the release of four molecules of DMSO. The relatively low temperature for the beginning of the process could be related to the fact that DMSO is not directly coordinated to copper(II) but is incorporated in the crystal lattice by hydrogen bond formation. The process of the DMSO removal proceeds in two stages. The first one that takes place at 110–165 C is obviously due to the loss of the two DMSO molecules bound by weaker H-bonds with the hydrogens from ˚ ), while the the NH-functions (O3 H1, r = 2.16(2) A last two DMSO molecules are associated with the hydro˚ ) and gens of the NH2 group (O2 H13, r = 2.13(2) A are lost at higher temperatures (165–195 C). 3.1.3. EPR and magnetochemical data The intramolecular distance between the two copper(II) centres needs special attention, as it determines to a great extent the magnetochemical and EPR behaviour of the complex. In both frozen solution and solid samples at 77 K the green binuclear complex 1 is EPR silent and does not show any signals, a fact that correlates well with the short Cu–Cu distance of about ˚ (Table 1). Evidently, the close vicinity and the 2.98 A proper orientation of the corresponding overlapping orbitals lead to a significant antiferromagnetic exchange interaction and to quenching of the signal. These conclusions are in accordance with the magnetochemical data as well. As can be seen in Fig. 5, the
V.T. Getova et al. / Polyhedron 24 (2005) 1983–1990
1987
Fig. 3. Connectivity and H-bonding in Cu2L2Cl2 Æ 4DMSO.
Fig. 4. Unit cell and 3-D packing of the binuclear complex 1. The copper, nitrogen, chlorine, sulfur, carbon and oxygen atoms are shown as crosshatched, hatched, dark-grey, black, grey and open circles, respectively, hydrogen atoms are omitted for clarity.
-5
1.4x10
magn. susceptibility (emu/Oe.g)
-5
1.2x10
-5
1.0x10
-6
8.0x10
-6
6.0x10
-6
4.0x10
-6
2.0x10
0
50
100
150
200
250
300
temperature(K)
Fig. 5. Magnetic susceptibility vs. T for the binuclear complex 1, measured at 1 kOe applied field.
magnetic susceptibility versus temperature curve has a complicated character with a maximum at TN 80 K and an exponential course at lower temperatures. This later in-
crease is signalling a paramagnetic contribution to the susceptibility at very low temperatures. At 125–300 K the Curie–Weiss law is followed with a large correlation coefficient of R = 0.9993. The effective magnetic moment calculated from the experimental data is 2.71 BM (the Weiss constant Cm = 0.92). Note that subtraction of the low-temperature paramagnetic component has negligible effect on both, the value of the effective magnetic moment and TN. The absolute value of the paramagnetic asymptotic temperature, hN 80 K, is close to TN suggesting that a paramagnetic-antiferromagnetic transition takes place at 80 K. The experimentally found magnetic moment is close to the theoretical one, which for a crystal field of D = 3000 cm1 is 2.65 BM [19–21]. Obviously, at temperatures over 125 K the antiferromagnetic interactions vanish and the Cu(II) centres show their paramagnetic character. 3.1.4. Electronic spectra The binuclear complex 1 shows absorption bands at 750 and 380 nm in the mixed MeOH + DMSO solvent
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V.T. Getova et al. / Polyhedron 24 (2005) 1983–1990
described above. The first relatively weak band was assigned to a d–d transition in a near square-planar copper(II) structure, while the second more intense one at 380 nm (e 460 l mol1 cm1) was attributed to a charge-transfer transition O ! Cu. The last band is typical for copper(II) polynuclear complexes with bridging oxygen atoms of the type Cu–O–Cu [22–24].
Cl2 C9 C10
C7
3.2. Mononuclear CuL2 Æ 2CH3OH complex 2 3.2.1. X-ray data and crystal structure The X-ray analysis and structure refinement showed that the violet compound 2 is a mononuclear complex with a square-planar structure and a general formula of CuL2 Æ 2CH3OH. In the structure the copper atoms are located on an inversion centre and occupy one crystallographically independent special position (1c: 0, 1/2, 0), while all other atoms occupy general (2i: x, y, z) positions. The asymmetric unit of the complex consists of one copper atom, one ligand molecule, coordinated through its oxygen and nitrogen atoms, and one CH3OH molecule, i.e., one half of the complex and solvent molecules (Fig. 6). The CuO2N2 core has a nearly squareplanar structure with O–Cu–O and N–Cu–N angles of 180 (Fig. 7, Table 3). The Cu–O and Cu–N distances (Table 3) are in good agreement with those for other aminoalcohol complexes of Cu(II) [7,12]. The methanol molecules included in the overall structure are not directly coordinated to Cu(II) but form hydrogen bonds of the type CH3OH O with the oxygen atom of the ligand (Fig. 8) with O2–H15 and H15 O1 distances of ˚ , respectively. 0.778(2) and 1.870(2) A
O2 N1
N2
C6 C11
3.1.5. IR spectra The pure ligand HL Æ HCl shows absorption bands at 3400, 3355, 3320–3120 cm1 within the range 3500– 3000 cm1, which are assigned to the stretching vibrations of hydroxyl, imino and aminogroups engaged in H-bonding of the intra- and intermolecular type [25]. This assignment is also supported by the fact that the coordination with Cu(II) leads to a pronounced decrease of the absorbance in the 2800–2300 cm1 range due to the formation of H-bonds. Complex 1 shows only three bands at 3420, 3330 and 3180 cm1, ascribed to mas(NH2), msym(NH2) and m(NH). The reduction of the number of bands in this range after complexation could be related to deprotonation of the hydroxyl group and hence to the disappearance of the m(OH) stretching vibration. At the same time three new bands in the far IR-spectrum appear at 490, 382 and 254 cm1, assigned to m(Cu–N), m(Cu–O) and m(Cu–Cl), respectively [25]. Another broad and intensive band appears at 1030 cm1 attributed to the stretching vibration m(S@O) of the SO-group from the DMSO molecules [25].
C13
Cu1
O1 C8
Cl1
C12
C2
C5 C3
C1 C4
Fig. 6. Asymmetric unit, numbering scheme and thermal ellipsoids (50%) of the mononuclear complex 2.
Fig. 7. Copper coordination of the mononuclear complex 2.
Table 3 ˚ ) and angles () for the mononuclear complex Selected bond lengths (A 2 Cu(1)–O(1) Cu(1)–N(1)#1 Cu(1)–O(1)#1 Cu(1)–N(1) O(1) H(15)H-bond O(1)–Cu(1)–O(1)#1 O(1)#1–Cu(1)–N(1)#1 O(1)–Cu(1)–N(1) O(1)#1–Cu(1)–N(1) O(1)–Cu(1)–N(1)#1 N(1)–Cu(1)–N(1)#1
1.898(2) 2.043(3) 1.898(2) 2.043(3) 1.870(2) 180.0 85.61(10) 85.61(10) 94.39(10) 94.39(10) 180.0
Symmetry transformations used to generate equivalent atoms. #1: x, y + 1, z; #2: x 1, y, z; #3: x + 1, y, z.
Fig. 8. Unit cell, 3-D packing and H-bonds in CuL2 Æ 2CH3OH. The copper, nitrogen, chlorine, carbon and oxygen atoms are shown as cross-hatched, hatched, dark-grey, grey and open circles, respectively, hydrogen atoms are omitted for clarity.
V.T. Getova et al. / Polyhedron 24 (2005) 1983–1990
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3.2.2. Electronic, IR and EPR spectra The electronic spectrum of the mononuclear complex 2 in methanol shows one broad asymmetric absorption band at 580 nm (e 200 l mol1 cm1) assigned to the d–d transition in a distorted tetragonal structure of the Cu(II) complex, where copper is bound with oxygen and nitrogen donor atoms. The IR spectrum of 2 shows five bands in the 3470– 3100 cm1 range, assigned to the stretching vibrations of NH2 and NH, shifted as a result of the coordination to Cu(II), and of (OH) from CH3OH. In addition two new bands in the far IR spectrum appeared at 490 and 396 cm1, ascribed to m(Cu–N) and m(Cu–O), respectively [25]. The strong absorbance of the free ligand in the 2800–2300 cm1 range is reduced in intensity due to the ligand coordination and the H-bond rupture caused by it. The X-band EPR spectra of the complex, both in the solid phase and in frozen solutions (77 K), are typical for mononuclear paramagnetic Cu(II) complexes. The EPR parameters gi = 2.245, g^ = 2.022, A = 160 G and the relation gi > g^ show that the unpaired d-electron of Cu(II) occupies predominately the dx2 y 2 -orbital. Thus the formation of a strongly distorted (practically a square-planar) complex was confirmed again. The frozen solution spectra reveal also an unresolved SHFS from 14N in the perpendicular magnetic field, due to the coordination of the NH-function to Cu(II). The same solution shows an isotropic signal with giso = 2.120 and Aiso = 68 G at 293 K. The experimental EPR data correlate well with those reported for similar copper(II) complexes [12].
In the solid phase, solvent molecules (4DMSO or 2CH3OH per molecule of the complex) are also incorporated in the crystal lattice, linked through H-bonds with the ligand. There is a marked difference, however, between the bonding of the two solvents. In 1 the DMSO molecules with their S@O groups serve as H-atom acceptors, the hydrogen atoms of the bond coming from NH and NH2 of the ligand, while in 2 the H-atom acceptor is the oxygen of the deprotonated ligand, the H-atom donor being the OH function of CH3OH.
4. Conclusions
References
Clenbuterol forms two complexes with copper(II) – the binuclear Cu2L2Cl2 Æ 4DMSO and the mononuclear CuL2 Æ 2CH3OH, acting as a bidentate chelate forming ligand with its imino and deprotonated hydroxyl functions. In both complexes copper has a slightly distorted square-planar coordination. In complex 1 the two copper atoms are linked together through oxygen atom bridges from two ligand molecules. Thus the coordination sphere around each of the two Cu centres includes two oxygen, one nitrogen and one terminal Cl atom. In complex 2 Cu(II) is coordinated with two oxygen and two nitrogen atoms from two ligand molecules. The relatively short distance between the two copper atoms in 1 is responsible for a strong antiferromagnetic exchange interaction, that determines its interesting magnetic properties – a complete quenching of the EPR signals and a specific temperature dependence of the magnetic susceptibility. As for complex 2, it shows the typical behaviour of a normal paramagnetic Cu(II) complex.
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5. Supplementary information Full crystallographic details have been deposited in cifformat with the Cambridge Crystallographic Data Centre, CCDC 268587 for 1 and 268588 for 2. Copies of this information can be obtained free of charge from the Director, CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK, fax: +44 1223 336 033, e-mail: deposit@ccdc. cam.ac.uk, Web: http://www.ccdc.cam.ac.uk/conts/ retrieving/html.
Acknowledgements The authors greatly acknowledge the financial support provided by the National Research Fund of Bulgaria. They also thank Dr. R. Stoyanova from the Institute of General and Inorganic Chemistry, Bulgarian Academy of Sciences, for some of the EPR data.
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