Mononuclear and polynuclear copper(I) complexes with a new N,N′,S-donor ligand and with structural analogies to the copper thionein core

Article abstract of DOI:10.1021/ic701189b

The N,N′,S-donor ligand 4-methoxy-3,5-dimethyl-2-((3-(2-(methylthio) phenyl)-1H-pyrazol-1-yl)methyl)pyridine (L) was prepared from 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine hydrochloride and 3-(2-(methylthio)phenyl)-1H-pyrazole. The Cu(I) complexes [CU ₂(L)₂CH₃CN][CU(L)CH₃CN](BF ₄)₃ (1), [Cu(L)PPh₃]BF₄ (2), and [Cu₆(L)₂(C₆F₅S)₆] (3) were prepared and characterized by X-ray crystallography (PPh₃ = triphenylphosphine, C₆F₅S^- = pentafluorothiophenolate). The unit cell of compound 1 consists of cocrystallized mononuclear and dinuclear entities in which all of the copper atoms exhibit distorted tetrahedral coordination. Compound 2 is monomeric with L bound in the κ³-N,N′,S mode and a PPh₃ molecule that completes the coordination environment. Compound 2 presents a fluxional behavior in CDCl₃ solution due to the boat inversion of the six-membered N,N′ chelate ring (ΔH^? = +43.6(3) kJ mol^-1, ΔS^? = -16(1) J mol^-1 K^-1). Crystallization of 3 in acetonitrile leads to a polynuclear structure that contains a CH₃CN molecule coordinated to one of the copper atoms: [Cu₆(L)₂(C₆F₅S) ₆CH₃CN] (3a). The core of 3a partially resembles a {Cu₄S₆} adamantane-like moiety, the only difference being that the Cu-NCCH₃ interaction leads to the opening of the cluster by disrupting a Cu-Cu interaction. Part of this assembly is found in the yeast metallothionein copper(I)-cysteinate core whose crystal structure has recently been reported. Two additional [Cu(L)]⁺ peripheral moieties interact with the cluster by means of bridging thiolates. ESI-mass spectrometry, conductivity measurements, and ¹H/¹⁹F pulsed gradient spin echo (PGSE) NMR experiments suggest that 3a dissociates in acetonitrile solution: 3a + CH₃CN → [Cu₄(C₆F ₅S)₆]^2- + 2[Cu(L)CH₃CN]⁺. The stability of the cluster with respect to the hypothetical mononuclear species, [Cu(L)(C₆F₅S)], is confirmed by DFT calculations (B3LYP), which illustrate the exergonic character of the reaction: 6[Cu(L′)(C₆H₅S)] → [Cu₆(L′) ₂(C₆H₅S)₆] + 4L′ (ΔG₂₉₈ = -58.6 kJ mol^-1, where L′ and C ₆H₅S^- are simplified models for L and C ₆F₅S^-, respectively). The energetics pertinent to the ionic dissociation of the cluster in acetonitrile is computed using the polarizable continuum model (PCM) approach.

Full text of DOI:10.1021/ic701189b

Inorg. Chem. 2007, 46, 10143−10152
Mononuclear and Polynuclear Copper(I) Complexes with a New
N,N ,S-Donor Ligand and with Structural Analogies to the Copper
Thionein Core
′
Marcello Gennari, Maurizio Lanfranchi, Roberto Cammi, Maria Angela Pellinghelli, and
Luciano Marchio`*
Dipartimento di Chimica Generale ed Inorganica, Chimica Analitica, Chimica Fisica,
UniVersita` degli Studi di Parma, V.le G.P. Usberti 17/a, I 43100 Parma, Italy
Received June 18, 2007
The N,N′,S-donor ligand 4-methoxy-3,5-dimethyl-2-((3-(2-(methylthio)phenyl)-1H-pyrazol-1-yl)methyl)pyridine (L) was
prepared from 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine hydrochloride and 3-(2-(methylthio)phenyl)-1H-pyrazole.
The Cu(I) complexes [Cu2(L)2CH3CN][Cu(L)CH3CN](BF4)3 (1), [Cu(L)PPh3]BF4 (2), and [Cu6(L)2(C6F5S)6] (3) were
prepared and characterized by X-ray crystallography (PPh3
The unit cell of compound 1 consists of cocrystallized mononuclear and dinuclear entities in which all of the copper
atoms exhibit distorted tetrahedral coordination. Compound 2 is monomeric with L bound in the ,S mode
3-N,N
) ) pentafluorothiophenolate).
triphenylphosphine, C6F5S-
κ
′
and a PPh3 molecule that completes the coordination environment. Compound 2 presents a fluxional behavior in
1
CDCl3 solution due to the boat inversion of the six-membered N,N
′
chelate ring (
∆
Hq ) +43.6(3) kJ mol-
,
∆
Sq
) −16(1) J mol- K-1). Crystallization of 3 in acetonitrile leads to a polynuclear structure that contains a CH3CN
1
molecule coordinated to one of the copper atoms: [Cu6(L)2(C6F5S)6CH3CN] (3a). The core of 3a partially resembles
a
{
Cu4S6
of the cluster by disrupting a Cu
(I)
cysteinate core whose crystal structure has recently been reported. Two additional [Cu(L)]+ peripheral moieties
}
adamantane-like moiety, the only difference being that the Cu
−NCCH3 interaction leads to the opening
−Cu interaction. Part of this assembly is found in the yeast metallothionein copper-
−
interact with the cluster by means of bridging thiolates. ESI-mass spectrometry, conductivity measurements, and
1H/19F pulsed gradient spin echo (PGSE) NMR experiments suggest that 3a dissociates in acetonitrile solution: 3a
-
+
CH3CN
f
[Cu4(C6F5S)6]2
+
2[Cu(L)CH3CN]+. The stability of the cluster with respect to the hypothetical
mononuclear species, [Cu(L)(C6F5S)], is confirmed by DFT calculations (B3LYP), which illustrate the exergonic
character of the reaction: 6[Cu(L′)(C6H5S)] f [Cu6(L′)2(C6H5S)6] + 4L′ (∆ ′ and
G298 ) −58.6 kJ mol-1, where L
C6H5S- are simplified models for L and C6F5S-, respectively). The energetics pertinent to the ionic dissociation of
the cluster in acetonitrile is computed using the polarizable continuum model (PCM) approach.
Introduction
storage, and detoxification (thioneins9). The metal coordina-
tion is fundamental in the definition of the functional
properties of these copper proteins.10,11
The bioinorganic relevance of copper is evidenced through
its involvement in many crucial biological functions.1 These
can be classified as follows: (a) dioxygen activation (tyro-
sinase2,3); (b) dioxygen transport (hemocyanin4); (c) electron
transfer (blue copper proteins5-8); (d) copper delivery,
(4) Solomon, E. I.; Tuczek, F.; Root, D. E.; Brown, C. A. Chem. ReV.
1994, 94, 827-856.
(5) Colman, P. M.; Freeman, H. C.; Guss, J. M.; Murata, M.; Norris, V.
A.; Ramshaw, J. A. M.; Venkatappa, M. P. Nature 1978, 272, 319-
324.
* To whom correspondence should be addressed. E-mail: marchio@
unipr.it.
(6) Durley, R.; Chen, L. Y.; Mathews, F. S.; Davidson, V. L. Protein
Sci. 1993, 2, 739-752.
(7) Hart, P. J.; Nersissian, A. M.; Herrmann, R. G.; Nalbandyan, R. M.;
Valentine, J. S.; Eisenberg, D. Protein Sci. 1996, 5, 2175-2183.
(8) Shibata, N.; Inoue, T.; Nagano, C.; Nishio, N.; Kohzuma, T.; Onodera,
K.; Yoshizaki, F.; Sugimura, Y.; Kai, Y. J. Biol. Chem. 1999, 274,
4225-4230.
(1) Malmstrom, B. G.; Leckner, J. Curr. Opin. Chem. Biol. 1998, 2, 286-
292.
(2) Solomon, E. I.; Sundaram, U. M.; Machonkin, T. E. Chem. ReV. 1996,
96, 2563-2605.
(3) Solomon, E. I.; Chen, P.; Metz, M.; Lee, S. K.; Palmer, A. E. Angew.
Chem., Int. Ed. 2001, 40, 4570-4590.
10.1021/ic701189b CCC: $37.00
Published on Web 11/01/2007
© 2007 American Chemical Society
Inorganic Chemistry, Vol. 46, No. 24, 2007 10143

Gennari et al.
Scheme 1
steric hindrance on the ligand L. This copper-sulfur
structural arrangement can be found in metallothionein
models,19 and it bears similarities with the copper(I)-thiolate
core of the yeast copper thionein, whose crystal structure
has recently been reported.20 We also wished to evaluate the
stability of the cluster structure of 3 in solution. For this
purpose, 1H and 19F PGSE (pulsed gradient spin echo) NMR
spectroscopy was employed,21 affording a hydrodynamic
radius (rH) and the corresponding volume (VH), which are
consistent with the multinuclear solid-state structure, even
thoughsomedegreeofdissociationof3intothe[Cu4(C6F5S)6]2-
and [Cu(L)CH3CN]+ ions can be envisaged. This hypothesis
was also supported by conductivity measurements and ESI-
mass spectrometry. DFT calculations were also employed
to investigate the stability of 3 with respect to the hypotheti-
cal mononuclear entity [Cu(L)(C6F5S)] and to investigate the
stability of the [Cu4(C6F5S)6]2- moiety in the presence of a
coordinating solvent such as acetonitrile. The PCM (polariz-
able continuum model)22 approach was employed to evaluate
the influence of the solvent on the ionic dissociation energy
of the cluster.
We are interested in preparing new Cu complexes with
nitrogen-sulfur donor ligands suitable as mimics of copper
sites in biological systems. Previously, we employed scor-
pionate boron-centered ligands to reproduce the metal
coordination environment of blue copper proteins in their
reduced state, but their stereochemical flexibility and low
tunability in terms of donor atom types posed considerable
limits for the role of their respective Cu complexes as good
functional models.12 For this reason, we directed our interest
toward new ligand structures that may be able to bind copper
in a ligand-determined geometric environment. The facile
synthesis of a variously substituted pyrazole-pyridine
platform13 prompted us to investigate the coordination ability
of new ligands belonging to this class with opportune
pyrazole substituents (Scheme 1). It is noteworthy that, due
to the easy deprotonation of the bridging methylene group
and further functionalization, these ligands can be considered
as parent compounds for the synthesis of new scorpionates,
which should produce a more preorganized coordination
environment.
In this work, we used a thioether-substituted pyrazole,
3-(2-(methylthio)phenyl)pyrazole, which is known to bind
Cu(II) once incorporated in a N3S3 hydrotris(pyrazolyl)borato
derivative,14 as a precursor. Here we describe the coordina-
tion properties of the new N,N′,S-donor ligand L with
copper(I). To complete the coordination at the metal, PPh3
and C6F5S- were also employed as coligands. The crystal
structures of [Cu2(L)2CH3CN][Cu(L)CH3CN](BF4)3 (1), [Cu-
(L)PPh3]BF4 (2), and [Cu6(L)2(C6F5S)6CH3CN] (3a) are
reported, and they point to a certain coordination flexibility
of L, which appears not to be able to impose a definite
geometry at the metal. After using PPh3, which led to the
isolation of 2 as a mononuclear complex, we employed the
C6F5S- thiolate ligand to mimic the -S-Cys fragment of
proteins. In the present case, the ternary ensemble Cu(I)/L/
C6F5S- affords the polynuclear structure 3, which can be
rationalized in terms of the general property of the thiolates
to form M-S-M bridges15-18 and by the lack of specific
Experimental Methods
General Procedures. All reagents and solvents were com-
mercially available, except for 3-(2-(methylthio)phenyl)-1H-pyra-
zole14 and [Cu(CH3CN)4]BF4,23 which were prepared as previously
reported. Dichloromethane and acetonitrile were dried over CaH2
and distilled before use. The syntheses of the complexes were
performed in inert gas (N2) using Schlenk techniques.
Synthesis of 4-Methoxy-3,5-dimethyl-2-((3-(2-(methylthio)-
phenyl)-1H-pyrazol-1-yl)methyl)pyridine (L). 2-(Chloromethyl)-
4-methoxy-3,5-dimethylpyridine hydrochloride (5.84 g, 26.29 mmol)
and 3-(2-(methylthio)phenyl)-1H-pyrazole (5.00 g, 26.28 mmol)
were mixed in toluene (150 mL). After addition of a 40% NaOH
water solution (50 mL) and a 40% NBu4OH water solution (30
drops), the mixture was refluxed for 3 h. The organic phase was
separated, washed with water (30 mL), and dried with Na2SO4.
The solvents were removed under vacuum. Purification of the
product by flash chromatography using ethyl acetate as the eluent
produced a yellow oil, which was washed and triturated with hexane
and finally dried under vacuum, yielding a light orange microc-
rystalline powder (5.35 g, 15.77 mmol, 60%). Colorless crystals
suitable for X-ray diffraction were obtained by layering hexane over
a dichloromethane solution of the product, corresponding to L. IR
(cm-1): 3146 w, 3122 m, 3059 w, 3047 w, 2999 m, 2957 m, 2943
m, 2918 m, 1586 m, 1569 m, 1480 m, 1450 s, 1437 m, 1401 m,
1332 m, 1255s, 1213 m, 1086 m, 1050 m, 999 m, 867 w br, 753
(9) Chan, J. N.; Huang, Z. Y.; Merrifield, M. E.; Salgado, M. T.; Stillman,
M. J. Coord. Chem. ReV. 2002, 233, 319-339.
(10) Belle, C.; Rammal, W.; Pierre, J. L. J. Inorg. Biochem. 2005, 99,
1929-1936.
1
vs. H NMR (300 MHz, CDCl3): δ 2.28 (s, 3H, CH3 py o-CH),
2.33 (s, 3H, CH3 py p-CH), 2.43 (s, 3H, CH3S), 3.77 (s, 3H, CH3O),
5.51 (s, 2H, CH2), 6.60 (d, J ) 2.2 Hz, 1H, CH pz(ph)), 7.18 (dt,
J ) 7.0, 1.9 Hz, 1H, CH ph), 7.29 (m, 2H, CH ph), 7.45 (d, J )
(11) Holm, R. H.; Kennepohl, P.; Solomon, E. I. Chem. ReV. 1996, 96,
2239-2314.
(12) Cammi, R.; Gennari, M.; Giannetto, M.; Lanfranchi, M.; Marchio,
L.; Mori, G.; Paiola, C.; Pellinghelli, M. A. Inorg. Chem. 2005, 44,
4333-4345.
(18) Coucouvanis, D.; Murphy, C. N.; Kanodia, S. K. Inorg. Chem. 1980,
19, 2993-2998.
(13) Gennari, M.; Tegoni, M.; Lanfranchi, M.; Pellinghelli, M. A.; Marchio,
L. Inorg. Chem. 2007, 46, 3367-3377.
(19) Presta, A.; Fowle, D. A.; Stillman, M. J. J. Chem. Soc., Dalton Trans.
1997, 977-984.
(14) Humphrey, E. R.; Mann, K. L. V.; Reeves, Z. R.; Behrendt, A.; Jeffery,
J. C.; Maher, J. P.; McCleverty, J. A.; Ward, M. D. New J. Chem.
1999, 23, 417-423.
(20) Calderone, V.; Dolderer, B.; Hartmann, H. J.; Echner, H.; Luchinat,
C.; Del, Bianco, C.; Mangani, S.; Weser, U. Proc. Natl. Acad. Sci.
U.S.A. 2005, 102, 51-56.
(15) Dance, I. G. Polyhedron 1986, 5, 1037-1104.
(16) Fujisawa, K.; Imai, S.; Kitajima, N.; Moro-oka, Y. Inorg. Chem. 1998,
37, 168-169.
(21) Zuccaccia, D.; Macchioni, A. Organometallics 2005, 24, 3476-3486.
(22) Tomasi, J.; Mennucci, B.; Cammi, R. Chem. ReV. 2005, 105, 2999-
3093.
(17) Henkel, G.; Krebs, B. Chem. ReV. 2004, 104, 801-824.
(23) Leftin, J. H. Chem. Abstr. 1967, 66, 46487e.
10144 Inorganic Chemistry, Vol. 46, No. 24, 2007

Cu Complexes with Analogies to the Cu Thionein Core
2.2 Hz, 1H, CH pz(CH2)), 7.56 (d, J ) 7.4 Hz, 1H, CH ph), 8.26
(s, 1H, CH py). 13C NMR (75 MHz, CDCl3): 10.7 (CH3 py p-CH),
13.0 (CH3 py o-CH), 15.7 (CH3S), 56.1 (CH2), 59.5 (CH3O), 106.2
(CH pz(ph)), 124.1 (CH ph), 124.9 (CH ph), 125.9 (C quat py),
125.9 (C quat py), 127.7 (CH ph), 129.2 (CH pz(CH2R)), 129.3
(CH ph), 132.1 (C quat ph), 137.0 (C quat ph), 149.0 (CH py),
149.6 (C quat), 153.4 (C quat), 164.0 (C quat CH3O). ESI-MS (p.i.,
cone 50 V, MeOH, m/z, I %): 340.5, 100, [LH]+. Anal. Calcd for
C19H21N3OS (Mr ) 339.46): C, 67.23; H, 6.23; N, 12.38. Found:
C, 67.14; H, 6.30; N, 12.44.
to [Cu6(L)2(C6F5S)6CH3CN] (3a). The solution characterization of
3 was performed in acetonitrile (see Results and Discussion). H
1
NMR (300 MHz, CD3CN): δ 2.12 (s, 3H, CH3), 2.20 (s, 3H, CH3),
2.42 (s, 3H, CH3S), 3.78 (s, 3H, CH3O), 5.50 (s, 2H, CH2), 6.50
(d, J ) 2.2 Hz, 1H, CH pz(ph)), 7.30 (m, 3H, CH ph), 7.42 (m,
1H, CH ph), 7.83 (d, J ) 2.2 Hz, 1H, CH pz(CH2)), 8.16 (s, 1H,
CH py). 13C NMR (75 MHz, CD3CN): δ 11.7, 13.4, 18.2, 53.0,
107.0, 128.0, 129.8, 130.1, 131.3, 132.8, 136.3 (m), 139.6 (m), 145.4
(m), 148.5 (m), 151.3. 19F NMR (564 MHz, CD3CN): δ -200.7
(d, J ) 28 Hz, 2F), -233.0 (t, J ) 25 Hz, 1F), -233.8 (t, J ) 23
Hz, 2F). ESI-MS (n.i., cone -41 V, CH3CN, m/z, I %): 461.0,
100, [Cu(C6F5S)2)]-; 724.8, 25, [Cu2(C6F5S)3)]-; 986.6, 30,
[Cu3(C6F5S)4)]-;1248.7,12,[Cu4(C6F5S)5)]-;1512.5,8,[Cu5(C6F5S)6)]-.
ESI-MS (p.i., cone 85 V, CH3CN, m/z, I %): 387.3, 100; 402.3,
40, [Cu(L)]+.
Synthesis of [Cu2(L)2CH3CN][Cu(L)CH3CN](BF4)3 (1). A
solution of [Cu(CH3CN)4]BF4 (264 mg, 0.84 mmol) in dichlo-
romethane (20 mL) was added to a solution of L (272 mg, 0.80
mmol) in dichloromethane (20 mL) at room temperature while
stirring. After 1 h, the solution was concentrated to ∼5 mL under
vacuum; a white product was precipitated with hexane (25 mL)
and then filtered out and dried under vacuum, yielding a colorless
powder (1, 250 mg, 0.16 mmol, 62%). Colorless crystals suitable
for X-ray diffraction were obtained by evaporation from an
acetonitrile-water solution of the product. IR (cm-1): 3138 m,
3016 w, 2946 w, 1591 m, 1521 w, 1494 m, 1473 s, 1434 s, 1411
Physical Techniques. 1H, 13C, and 2D NMR spectra were
recorded on a Bruker Avance 300 spectrometer using standard
Bruker pulse sequences. Chemical shifts are reported in ppm
referenced to residual solvent protons (CDCl3, CD2Cl2, CD3CN).
1H and 19F PGSE NMR measurements were performed in a solution
of 3 (10-3 M) in CD3CN using a standard stimulated echo (STE)
sequence on a Varian Inova spectrometer (600 MHz) at 300 K and
without spinning. An external reference (trifluorotoluene, -63.72
ppm) was used for the 19F chemical shift calibration. Tetrakis-
(methylsilyl)silane (TMSS, hydrodynamic radius rH ≈ rvdw ) 4.28
Å) was used as an internal standard. The hydrodynamic radius (rH)
and volume (VH ) (4/3)πrH3) were obtained as described in the
1
m, 1366 m, 1298 m, 1256 s, ∼1050 vs br, 761 s. H NMR (300
MHz, CD2Cl2): δ 2.22 (s br, 6H, CH3 py), 2.48 (s, 3H, CH3S),
3.82 (s br, 3H, CH3O), 5.29 (s br, 2H, CH2), 6.43 (s br, 1H, CH
pz(ph)), 7.45 (s br, 4H, CH(ph)), 7.87 (s br, 1H, CH pz(CH2), 8.20
(s br, 1H, CH py). 13C NMR (75 MHz, CD2Cl2): δ 2.80, 11.40,
13.29, 20.89, 51.90, 60.41, 106.40, 127.55, 128.28, 129.37, 129.70,
130.28, 131.02, 131.75, 132.16, 132.60, 148.85, 151.08, 165.64.
Anal. Calcd for C61H69B3F12N11O3S3Cu3 (Mr ) 1551.54): C, 47.22;
H, 4.48; N, 9.93. Found: C, 47.02; H, 4.35; N, 9.49.
literature (Supporting Information).21,24 The van der Waals volumes
25
(VvdW) and the solvent-excluded volumes (Vsoft
)
were computed
on 3a and on the mononuclear unit of 1 starting from the X-ray
coordinates using the software package DS Viewer Pro 5.0.
Mass spectra were obtained with a Micromass ZMD spectrom-
eter. The mixtures were analyzed in the positive and negative
ionization modes by direct perfusion in ESI-MS interface. Infrared
spectra were recorded from 4000 to 700 cm-1 on a Perkin-Elmer
FT-IR Nexus spectrometer equipped with a Thermo-Nicolet
microscope. Elemental analyses (C, H, N) were performed with a
Carlo Erba EA 1108 automated analyzer. The luminescence
spectrum of 3 (yellow powder) was recorded on a Horiba Jobin
Yvon SPEX FluoroMax 4 spectrofluorometer, using a UG11 band-
pass filter on the excitation slit and a long-pass filter GG475 on
the emission slit. Conductivity measurements were performed on
a Crison microCM 2202 conductometer operating at 25 °C.
X-ray Crystallography. A summary of data collection and
structure refinement for L, 1, 2, and 3a is reported in Table 1.
Single-crystal data were collected with a Bruker Smart 1000 area
detector diffractometer (Mo KR; λ ) 0.710 73 Å). Cell parameters
were refined from the observed setting angles and detector positions
of selected strong reflections. Intensities were integrated from
several series of exposure frames covering the sphere of reciprocal
space.26 No crystal decay was observed. Absorption corrections
using the program SADABS27 was applied for L, 2, and 3a, which
resulted in transmission factors ranging from 0.720 to 1.000 (L),
0.653 to 1.000 (2), and 0.834 to 1.000 (3a), whereas the program
Synthesis of [Cu(L)PPh3]BF4 (2). A solution of [Cu(CH3CN)4]-
BF4 (195 mg, 0.62 mmol) in acetonitrile (5 mL) was added to a
solution of L (206 mg, 0.61 mmol) and PPh3 (155 mg, 0.59 mmol)
in acetonitrile (20 mL) at room temperature while stirring. After 1
h, the solution was dried under a vacuum, producing a colorless
solid, which was recrystallized in dichloromethane-hexane, yield-
ing a white powder (2, 400 mg, 0.53 mmol, 90%). Colorless crystals
suitable for X-ray diffraction were obtained by layering hexane over
a THF solution of the product. IR (cm-1): 3139 w, 3054 w, 3005
w, 1591 m, 1569 m, 1475 m, 1433 s, 1256 m, 1061 vs br, 755 s br,
1
695 s. H NMR (300 MHz, CDCl3): δ 1.78 (s, 3H, CH3S), 2.20
(s, 3H, CH3 py o-CH), 2.57 (s, 3H, CH3 py p-CH), 3.82 (s, 3H,
CH3O), 5.49 (s br, 2H, CH2), 6.52 (s, 1H, CH pz(ph)), 7.15-7.30
(m, 17H, CH ph), 7.46 (t, J ) 6.9 Hz, 1H, CH ph), 7.58 (d, J )
7.2 Hz, 1H, CH ph), 7.99 (s, 1H, CH py), 8.25 (s, 1H, CH pz-
(CH2)). ESI-MS (p.i., cone 29 V, MeOH, m/z, I %): 402.2, 100,
[Cu(L)]+; 664.2, 70, [Cu(L)PPh3]+. Anal. Calcd for C37H36BF4N3-
OPSCu (Mr ) 752.09): C, 59.09; H, 4.82; N, 5.59. Found: C,
59.17; H, 4.90; N, 5.51.
Synthesis of [Cu6(L)2(C6F5S)6] (3). L (720 mg, 2.12 mmol) was
added to a suspension of CuCl (630 mg, 6.36 mmol) in acetonitrile
(20 mL), which then produced an orange solution. After few
minutes, C6F5SH (0.85 mL, d ) 1.5 g/mL, 6.37 mmol) and NH4-
OH 15.71 M (0.41 mL, 6.44 mmol) were added, with consequent
formation of a precipitate. After 30 min, water (10 mL) was added
and the white solid was filtered out and dried under vacuum,
yielding a bright yellow powder (3, 1.68 g, 0.74 mmol, 70%). IR
(cm-1): ∼2920 w, 1636 w, 1626 w, 1508 vs, 1473 vs, 1373 w,
1357 w, 1294 w, 1260 w, 1138 w, 1082 vs, 1009 w, 968 vs, 850
vs, 761 w. Anal. Calcd for C74H42F30N6O2S8Cu6 (Mr ) 2254.92):
C, 39.42; H, 1.88; N, 3.73. Found: C, 39.51; H, 1.79; N, 3.65.
Colorless crystals suitable for X-ray diffraction were obtained by
cooling to 8 °C an acetonitrile-water solution of 3, corresponding
(24) Pregosin, P. S. Prog. Nucl. Magn. Reson. Spectrosc. 2006, 49, 261-
288.
(25) Vsoft is calculated by considering that the interstitial parts of the solute
molecule are not accessible to the solvent. The solvent-excluded
volume is the sum of the Van der Waals volume plus the interstitial
volume. See: Connolly, M. L. J. Am. Chem. Soc. 1985, 107, 1118-
1124.
(26) SMART (control) and SAINT (integration) software for CCD systems;
Bruker AXS, Madison, WI, 1994.
(27) Area-Detector Absorption Correction; Siemens Industrial Automation
Inc.: Madison, WI, 1996.
Inorganic Chemistry, Vol. 46, No. 24, 2007 10145

Gennari et al.
Table 1. Summary of X-ray Crystallographic Data for L, 1, 2, and 3a
param
L
1
2
3a
empirical formula
fw
C38H42N2S2
678.90
colorless, block
0.45 × 0.20 × 0.15
monoclinic
P21/c
16.984(3)
7.628(1)
28.302(5)
90
98.15(1)
90
C61H69B3Cu3F12N11O3S3
1551.50
colorless, block
0.18 × 0.10 × 0.08
monoclinic
P21
12.430(9)
20.105(9)
14.665(8)
90
C37H36B4CuF4N3OPS
752.07
colorless, block
0.38 × 0.30 × 0.10
triclinic
C76H45Cu6F30N7O2S8
2295.91
colorless, plate
0.35 × 0.15 × 0.10
triclinic
color, habit
cryst size, mm
cryst system
space group
a, Å
P1h
P1h
10.431(1)
12.378(1)
15.213(2)
78.13(1)
15.502(2)
16.672(2)
18.535(2)
106.93(1)
100.92(1)
93.45(1)
b, Å
c, Å
R, deg
â, deg
107.10(3)
90
3503(4)
78.95(1)
70.41(1)
1794.8(3)
2
γ, deg
V, Å3
3630(1)
4
4465.7(9)
2
Z
2
T, K
293(2)
1.242
0.188
1.45-27.04
38 065/4095
1.006
293(2)
1.471
1.075
1.45-24.00
10 942/4747
0.892
293(2)
1.392
1.766
1.77-27.97
19 539/4898
1.009
293(2)
1.707
1.701
1.35-25.00
42 725/3759
0.979
F(calcd), Mg/m3
µ, mm-1
θ range, deg
no. of rflcns/obsvns
GooF
Flack param
0.04(1)
0.0587
0.0675
R1a
0.0409
0.0841
0.0357
0.0683
0.0780
0.0843
wR2a
2
2
2
2
2
2
a R1 ) ∑||Fo| - |Fc||/∑|Fo|; wR2 ) [∑[w(Fo - Fc )2]/∑[w(Fo )2]]1/2, w ) 1/[σ2(Fo ) + (aP)2 + bP], where P ) [max(Fo ,0) + 2Fc ]/3.
XABS228 was used for 1 (maximum and minimum absorption
correction coefficients of 1.000-0.497). For 1, the space group
(P21) was chosen on the basis of the systematic extinction and
intensity statistics; the absolute configuration has been confirmed
at the 3σ level of the Flack parameter (0.04(1)).29 The structures
were solved by direct methods (SIR97)30 and refined with full-
matrix least squares (SHELXL-97),31 using the Wingx software
package.32 Non-hydrogen atoms were refined anisotropically for
L and 2. The BF4- anions in 1 were severely disordered and were
refined isotropically. The carbon atoms in 3a were also refined
isotropically due to the poor quality of the crystal and the limited
number of observed reflections available. The hydrogen atoms were
placed at their calculated positions. Ortep diagrams were prepared
using the ORTEP-3 for Windows program.33
starting from a pseudotetrahedral copper coordination as found in
2, by substituting PPh3 with C6H5S- and by substituting the -CH3
and -OCH3 groups of the pyridine ring of L with hydrogen atoms,
thus giving the model ligand L′. The CH3CN molecule and the
isolated model ligand L′ were also optimized. The complex [Cu-
(L′)CH3CN]+ was optimized by starting from the X-ray coordinates
of the mononuclear species of 1. The polynuclear model complexes
[Cu6(L′)2(C6H5S)6] and [Cu4(C6H5S)6]2- were optimized by starting
from the [Cu4(C6F5S)6]2- adamantane-like core as found in various
copper(I)-thiolate clusters,17 whereas [Cu4(C6H5S)6CH3CN]2- was
optimized starting from the X-ray geometry of 3a by removing the
peripheral [Cu(L)]+ moieties. The gradient-corrected hybrid density
functional B3LYP35,36 and the lanl2dz basis set with Hay and Wadt
effective core potential (ECP) were employed.37,38 Vibrational
frequencies were calculated at the same level of theory to ensure
that the stationary points were true minima and for the calculation
of zero-point energies. Thermal corrections and free energy of
reaction were calculated at 298 K. In order to take into account
the effect of the solvent on the energy of reactions involving ionic
dissociation, the solvation energies (∆Gsolv) were estimated using
the polarizable continuum model (PCM)39-42 at the B3LYP/lanl2dz
level. ∆Gsolv represents the energy required to bring a molecule of
solute from the gas phase to a polarizable dielectric media. This
requires the opening of a cavity in the solvent where the solute
can be fitted (∆Gcav), giving rise to solvent-solute electrostatic
interactions (∆Geletr), to van der Waals solvent-solute contributions
DFT Calculations. Theoretical calculations were carried out
using the Gaussian 03 program suite.34 Geometry optimization of
the mononuclear model compound [Cu(L′)(C6H5S)] was performed
(28) Parkin, S.; Moezzi, B.; Hope, H. J. Appl. Crystallogr. 1995, 28, 53-
56.
(29) Flack, H. D. Acta Crystallogr. 1983, A39, 876-881.
(30) Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G. L.; Giaco-
vazzo, C.; Guagliardi, A.; Moliterni, A. G. G.; Polidori, G.; Spagna,
R. J. Appl. Crystallogr. 1999, 32, 115-119.
(31) Sheldrick, G. M. SHELX97. Programs for Crystal Structure Analysis,
release 97-2; University of Go¨ttingen: Go¨ttingen, Germany, 1997.
(32) Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837-838.
(33) Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 568.
(34) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin,
K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone,
V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G.
A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;
Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai,
H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.;
Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R.
E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J.
W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.;
Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari,
K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.;
Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.;
Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A.
Gaussian 03, revision C.02; Gaussian, Inc.: Wallingford, CT, 2004.
(∆Gdisp), and to some steric repulsion (∆Grep), so that ∆Gsolv
∆Gcav + ∆Grep + ∆Gdisp + ∆Gelectr 43
Single-point energy calcula-
)
.
(35) Becke, A. D. Phys. ReV. A: At., Mol., Opt. Phy. 1988, 38, 3098-
3100.
(36) Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652.
(37) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 299-310.
(38) Wadt, W. R.; Hay, P. J. J. Chem. Phys. 1985, 82, 284-298.
(39) Tomasi, J.; Mennucci, B.; Cances, E. J. Mol. Struct. 1999, 464, 211-
226.
(40) Mennucci, B.; Cances, E.; Tomasi, J. J. Phys. Chem. B 1997, 101,
10506-10517.
(41) Mennucci, B.; Tomasi, J. J. Chem. Phys. 1997, 106, 5151-5158.
(42) Cances, E.; Mennucci, B.; Tomasi, J. J. Chem. Phys. 1997, 107, 3032-
3041.
(43) Cossi, M.; Barone, V.; Cammi, R.; Tomasi, J. Chem. Phys. Lett. 1996,
255, 327-335.
10146 Inorganic Chemistry, Vol. 46, No. 24, 2007

Cu Complexes with Analogies to the Cu Thionein Core
Table 2. Selected Bond Lengths (Å) for 1, 2, and 3a
Compound 1
Cu(1)-S(11)
Cu(1)-N(21)
Cu(1)-N(13)
Cu(1)-N(14)
Cu(2)-S(15)
Cu(2)-N(25)
2.304(3)
2.033(7)
2.054(8)
1.919(9)
2.462(3)
1.988(7)
Cu(2)-N(17)
Cu(2)-N(18)
Cu(3)-S(15)
Cu(3)-S(19)
Cu(3)-N(29)
Cu(3)-N(111)
2.044(7)
1.890(8)
2.230(3)
2.390(3)
2.016(6)
2.062(7)
Compound 2
Cu-S(11)
Cu-P(14)
2.4482(7)
2.1957(7)
Cu-N(13)
Cu-N(21)
2.092(2)
2.014(2)
Compound 3a
Cu(1)-N(21)
Cu(1)-N(13)
Cu(1)-S(17)
Cu(2)-N(16)
Cu(2)-N(24)
Cu(2)-S(14)
Cu(2)-S(111)
Cu(3)-S(110)
Cu(3)-S(111)
Cu(3)-S(112)
Cu(4)-S(110)
Cu(4)-S(17)
1.937(8)
2.072(7)
2.156(3)
2.028(8)
2.03(1)
2.399(4)
2.254(3)
2.261(3)
2.223(3)
2.244(3)
2.241(3)
2.330(3)
Cu(4)-S(19)
Cu(5)-S(18)
Cu(5)-S(19)
Cu(5)-N(1)
Cu(6)-S(17)
Cu(6)-S(18)
Cu(6)-S(112)
Cu(4)-Cu(5)
Cu(5)-Cu(6)
Cu(4)-Cu(6)
Cu(3)-Cu(4)
Cu(3)-Cu(6)
2.214(3)
2.234(4)
2.259(3)
1.88(1)
2.297(3)
2.341(3)
2.244(3)
2.768(2)
2.814(2)
2.842(2)
3.489(2)
3.396(2)
Figure 1. Ortep drawing of 1 at the 30% thermal ellipsoids probability
level. A mononuclear and a dinuclear unit are present in the unit cell.
Scheme 2. Thermodynamic Cycle for the Calculation of the
Reactions Free Energies in Solution, ∆Gsolution ) ∆G298 + ∆∆Gsolv
(∆∆Gsolv ) ∆GP - ∆GR
)
solv
solv
tances (Table 2) within the sulfur bridge are not equivalent
since Cu(3)-S(15) (2.230(3) Å) is significantly shorter than
Cu(2)-S(15) (2.462(3) Å). This is related to the different
geometry of the Cu(2) and Cu(3) atoms since the latter
exhibits a more regular tetrahedral geometry, which is
distorted as a consequence of the constraints imposed by the
chelate ligand. Conversely, Cu(2) is in a tetrahedral geometry
severely distorted toward the trigonal one (equatorial at-
oms: N(17), N(25), N(18)) due to the long Cu(2)-S(15)
interaction. The nearly trigonal geometry of Cu(2) is sup-
ported by the sum of the equatorial angle values, 353.1(3)°,
which is close to the theoretical value of 360°, and by the
fact that Cu(2) is only 0.282(1) Å out of the equatorial plane
and is directed toward the apical sulfur S(15). The three
metals are stereogenic centers, and they all exhibit an S
configuration. Interestingly, this leads to a spontaneous
resolution at the solid state since 1 crystallizes in the chiral
tions at the PCM level were performed on the gas-phase structures
without further optimization, assuming that the stationary points
in the gas phase are also stationary points in solution. We therefore
approximated ∆Gsolv as the difference between the free energy in
solution (Gsolv) and the gas-phase total energy (E) without zero-
point or thermal correction. Inside the cavity that hosts the solute,
the dielectric constant is the same as in vacuum, whereas outside
it takes the value of the solvent (acetonitrile, ꢀ ) 36.6). Finally,
the free energy of reaction in solution (∆Gsolution) was computed as
the sum of the gas-phase free energy (∆G298) and the solvation
solv
free energy ∆Gsolution ) ∆G298 + ∆∆Gsolv (where ∆∆Gsolv ) ∆GP
- ∆GRsolv), according to the thermodynamic cycle reported in
Scheme 2.
-
space group P21. Each of the three BF4 counterions are
disordered in two positions that roughly define a spherical
structural site occupation. In light of these results, it can be
concluded that the nuclearity of 1 cannot be defined a priori,
due to the flexibility and the lack of appropriate sterical
hindrance of L.
Results and Discussion
Solid-State Structure of [Cu2(L)2CH3CN][Cu(L)CH3CN]-
(BF4)3 (1). At first, the coordination capabilities of the
N,N′,S-donor ligand L versus Cu(I) were tested through
reaction with [Cu(CH3CN)4]BF4 in acetonitrile in a 1:1 ratio
to yield compound 1. As can be seen in Figure 1, a
mononuclear and a dinuclear complex cocrystallize in the
unit cell. The first entity is comprised of a copper(I) center,
Cu(1), bound by a κ3-N,N′,S chelate ligand and a CH3CN
molecule. The metal geometry is distorted tetrahedral since
the coordination angles range from 122.1(3) to 89.6(3)°. The
dinuclear unit exhibits two metal centers in different
coordination environments. In particular, Cu(2) is bound by
an acetonitrile molecule and by a N,N′S chelate ligand, which
in turn bridges to the Cu(3) atom with the thioether sulfur
atom S(15). The coordination of Cu(3) is completed by
another N,N′S chelate ligand. Interestingly, the bond dis-
Solid-State Structure and Solution Properties of [Cu-
(L)PPh3]BF4 (2). The hypothesis that an ancillary σ-donor
ligand such as PPh3 would complement the coordination
properties of L to yield a mononuclear species has led to
the synthesis and isolation of 2. The copper coordination is
achieved through the N(21), N(13), and S(11) atoms of L
and by PPh3, Figure 2. The metal geometry is intermediate
between trigonal pyramidal and tetrahedral: the trigonal
plane can be defined by P(14), N(21), and N(13) with S(11)
in the apical position (Cu-S(11) ) 2.4482(7) Å). This
geometry is supported by the following criteria: (i) The sum
of equatorial angles is 344.23(5)° (cf. 328.5° for a tetrahedral
geometry and 360° for trigonal planar geometry). (ii) The
Inorganic Chemistry, Vol. 46, No. 24, 2007 10147

Gennari et al.
shape analysis44,45 to be the following: ∆Hq ) +43.6(3)
kJ‚mol-1; ∆Sq ) -16(1) J mol-1 K-1. These values suggest
a nondissociative rearrangement, which is most likely the
inversion of the boat, as shown by some examples reported
in the literature.46-48 This implies a fast inversion (on the
NMR time scale) around the Cu center, which probably
involves the stretching or rupture of the labile Cu(I)-S-
thioether bond.
Solid-State Structure, Solution Properties, and DFT
Calculations for [Cu6(L)2(C6F5S)6] (3). By using the
monodentate sulfur donor ligand C6F5S- as a coligand in
place of PPh3, additional complications became evident. The
idea of obtaining a neutral copper(I) complex exhibiting an
approximately tetrahedral structure with a N,N′,S,S′ donor
set is difficult to fulfill, mainly because of the absence of
steric hindrance on both L and on the thiolate group, which
enables the thiolate to bridge metal centers. In the first stage,
the 1:1:1 Cu:C6F5S-:L stoichiometric ratio was employed
for the synthesis, but this led nonetheless to the isolation
and X-ray characterization of a 3:3:1 hexanuclear complex
(3a). We therefore optimized the synthesis in 3:3:1 conditions
to give 3, which crystallized as 3a by incorporating an
acetonitrile molecule. An exemplified molecular drawing,
depicting the coordination environment of the six copper
atoms, is reported in Figure 4. The structure consists of six
metal atoms, six thiolate groups, and two L ligands arranged
in a clusterlike fashion. Cu(1) and Cu(2) are the only atoms
that are bound to L, and they are located in the peripheral
part of a [Cu4(C6F5S)6]2- copper-thiolate cluster. The four
metals of the core adopt a trigonal geometry determined by
bridging thiolate groups and, in the case of Cu(5), also by
an acetonitrile molecule (crystallization solvent). The struc-
ture of the copper-thiolate cluster is likely derived from a
closed [Cu4(C6F5S)6]2- adamantane-like structure,15,17,49 by
disruption of S-Cu-S links and subsequent insertion of CH3-
CN, now bound to Cu(5) to give an “open” structure. The
negative charge (2-) of the open [Cu4(C6F5S)6CH3CN]2-
cluster is compensated by two [Cu(L)]+ peripheral moieties,
which are bound to the former by means of thiolate groups.
As a consequence of the open structure, three Cu-Cu
interactions are shorter, ∼2.8 Å (between Cu(4), Cu(5), and
Cu(6)), and two are longer, ∼3.4 Å (Cu(3)-Cu(4) and Cu-
(3)-Cu(6)). Interestingly, part of this structure reproduces
that present in the core of the yeast copper metallothionein
(Cu-MT),20 a protein rich in cysteine residues that can bind
up to eight copper(I) ions, six of which are in a trigonal
Figure 2. Ortep drawing of the cationic unit of 2 at the 30% thermal
ellipsoids probability level.
1
Figure 3. Experimental (a) and simulated (b) H NMR spectrum of 2 in
the region of the Ha and Hb diasterotopic protons. A description of the boat
inversion process is reported in (c).
metal lies out of the trigonal plane by ∼0.46 Å in the
-
direction of S(11). The BF4 counterion is statically disor-
dered in three positions that occupy a structural spherical
site.
Complex 2 presents a fluxional behavior in solution, as
1
shown by the H VT NMR spectrum in CDCl3, Figure 3.
(44) Sandstrom, J. Dynamic NMR Spectroscopy; Academic Press: London,
1982.
(45) Reich, H. J. WINDNMR software: NMR Spectrum Calculations,
version 7.1.11; 2005.
The bridging methylene of the ligand gives a broad signal
at 270 K, which splits into two sharp doublets by lowering
the temperature to 210 K, while the other peaks exhibit only
a chemical shift temperature dependence. This behavior is
justified with the diastereotopic nature of the methylene
group at low temperatures, which can be explained in two
ways: (a) the presence of the stereogenic Cu(I) center; (b)
the boat conformation of the N,N′ chelate six-membered ring
around the metal center. The kinetic parameters of the
exchange process were determined from the complete line
(46) Byers, P. K.; Canty, A. J.; Honeyman, R. T. AdV. Organomet. Chem.
1992, 34, 1-65.
(47) Tejel, C.; Villoro, J. M.; Ciriano, M. A.; Lopez, J. A.; Eguizabal, E.;
Lahoz, F. J.; Bakhmutov, V. I.; Oro, L. A. Organometallics 1996, 15,
2967-2978.
(48) Antinolo, A.; Carrillo-Hermosilla, F.; Diez-Barra, E.; Fernandez-Baeza,
J.; Fernandez-Lopez, M.; Lara-Sanchez, A.; Moreno, A.; Otero, A.;
Rodriguez, A. M.; Tejeda, J. J. Chem. Soc., Dalton Trans. 1998, 3737-
3743.
(49) Janssen, M. D.; Grove, D. M.; vanKoten, G. Prog. Inorg. Chem. 1997,
46, 97-149.
10148 Inorganic Chemistry, Vol. 46, No. 24, 2007

Cu Complexes with Analogies to the Cu Thionein Core
Figure 6. Emission spectrum of 3 (yellow powder) at 298 K, with an
excitation wavelength of 300 nm.
large stoke shift (380 nm) is typical of multinuclear copper
compounds.50 On the basis of these observations and also
according to known Cu(I) adamantane-like structures re-
ported in the literature,17,18 a closed adamantane-like structure
(Scheme 3), derived from the X-ray structure by elimination
of the coordinated acetonitrile and by the closure of S(111)
on Cu(5), may be proposed for the yellow solid 3.
Figure 4. X-ray molecular structure of the copper(I)-SC6F5 cluster
crystallized from an acetonitrile-water solution (3a). The hydrogen atoms
have been omitted for clarity.
Acetonitrile is the only common organic medium in which
3 is quite soluble, so that the solution characterization of 3
was performed in this solvent. The presence of a Cu(I)-
thiolate cluster in solution is confirmed by the ESI-mass
spectrometry and by 19F PGSE NMR experiments. In
particular, the mass spectrum in negative ionization mode
reveals the presence of monoanionic [Cun(C6F5S)n+1]- (n )
1-5) fragments of the cluster (Supporting Information,
Figures S4 and S5), whereas in positive ionization mode,
only the [Cu(L)]+ fragment is present. This could arise during
the ESI-mass ionization process or be present in solution
according to a ionic dissociation equilibrium: 3a + CH3-
CN ) [Cu4(C6F5S)6]2- (3b) + 2[Cu(L)CH3CN]+ (see
Scheme 3). The latter hypothesis is in agreement with
conductivity measurements performed on a 10-3 M solution
of 3, which afford a molar conductivity value of 131(1) Ω-1
cm2 mol-1, slightly less than the range reported for 1:2
electrolytes in acetonitrile (145-336 Ω-1 cm2 mol-1).51 This
would give credit to the hypothesis of the ionic dissociation
of 3a in solution.
Figure 5. Copper-donor atom connectivity in 3a (left) and in the yeast
copper metallothionein (right). Structural analogies are highlighted in the
dashed boxes.
geometry whereas two are in a digonal arrangement. It has
been proposed that these two labile peripheral metals confer
on the protein the ability to regulate copper homeostasis and
they are also involved in the delivery of copper to apo-copper
chaperones. Figure 5 reports, for comparison, the atom
connectivity of the Cu-MT core and that found in 3a. Even
though the Cu-MT cluster is more complex and it hosts
more metal ions, some similarities with 3a are evident. It is
interesting to note that the Cu-MT core may be imagined
as a superposition of open {Cu4S6} clusters.
When acetonitrile, which is present in the structure of 3a
(colorless crystals), is removed under vacuum, the deep
yellow product 3 forms. This process is reversible: by
addition of a few drops of acetonitrile, the product turns
white. The complex 3 is luminescent in the solid state,
emitting at 680 nm (excitation: 300 nm, 298 K, Figure 6),
whereas in acetonitrile solution there is no evidence of
emitting properties. This can be readily explained by a direct
solvent-cluster interaction, also supported by the solid-state
structure 3a, that results in luminescence quenching. The
1H and 19F PGSE NMR experiments were performed to
obtain the hydrodynamic radius (rH) and volume (VH) of 3.
The measurements based on 19F afford a rH of 6.8(1) Å and
1
a VH of 1300(60) Å3, while the H PGSE values point to
significantly smaller dimensions (rH ) 5.2(1) Å and VH )
600(30) Å3). This discrepancy can be explained by consider-
ing the aforementioned dissociation equilibrium: the 19F
nucleus, in fact, is present only in the exhanging 3a,b clusters
(large), while protons are shared by 3a (large) and [Cu(L)-
1
CH3CN]+ (small). Hence, the VH value derived from H
PGSE (VH(1H)) would correspond to the weighted average
between the volumes of 3a and [Cu(L)CH3CN]+ and should
result as significantly smaller than VH(19F). In addition, a
comparison between the experimental VH(1H) with the van
(50) Ford, P. C.; Cariati, E.; Bourassa, J. Chem. ReV. 1999, 99, 3625-
3647.
(51) Geary, W. J. Coord. Chem. ReV. 1971, 7, 81-122.
Inorganic Chemistry, Vol. 46, No. 24, 2007 10149

Gennari et al.
Scheme 3
Table 3. Computed Energetic Properties in the Gas Phases, E (0 K) and G298 (298 K), and in Solution, Gsolv, for the Mononuclear and Polynuclear
Structures Reported in Figure 7 (B3LYP/lanl2dz) (∆Gsolv ) Gsolv - E)a
compd
E (hartree)
G298 (hartree)
Gsolv (hartree)
∆Gelectr (kJ mol-1
)
∆Gnonelectr (kJ mol-1
)
∆Gsolv (kJ mol-1
)
[Cu(L′)(C6H5S)]
[Cu6(L′)2(C6H5S)6]
L′
-1230.876 04
-4213.597 08
-792.926 75
-1121.721 64
-2235.355 89
-132.728 28
-2368.099 57
-1230.564 33
-4212.626 77
-792.695 38
-1121.449 57
-2234.899 41
-132.706 77
-2367.605 32
-4213.548 92
-228.4
354.9
126.5
[Cu(L′)CH3CN]+
[Cu4(C6H5S)6]2-
CH3CN
-1121.753 96
-2235.523 92
-132.728 42
-2368.257 63
-176.5
-613.9
-23.2
91.7
172.7
22.8
-84.8
-441.2
-0.4
[Cu4(C6H5S)6CH3CN]2-
-614.7
199.7
-415.0
a ∆Gnonelectr ) ∆Gcav + ∆Grep + ∆Gdisp; 1 hartree ) 2625.5 kJ mol-1
Table 4. Computed Thermodynamic Properties for Gas- (∆E, ∆E298
∆G298)a and Solution-Phase (∆Gsolution)b Reactions a-c Reported in
Figure 7 (kJ mol-1, B3LYP/lanl2dz)
,
der Waals volumes (VVdW) of 3a (1228 Å3) and [Cu(L)CH3-
CN]+ (327 Å3) would suggest only a partial ionic dissociation
of 3a, since VH(1H) is intermediate between the above-
mentioned values. On the other hand, by considering the
solvent-excluded volume (Vsoft) as an estimate of the
hydrodynamic volume of the respective species (2039 Å3
for 3a and 605 Å3 for [Cu(L)CH3CN]+), we infer a nearly
complete ionic dissociation, as VH(1H) becomes comparable
to the Vsoft of [Cu(L)CH3CN]+. Since VVdW represents the
reacn
∆E
∆E298
∆G298
∆Gsolution
a
b
c
-125.6
668.1
-40.4
-114.0
682.5
-23.5
-58.6
634.7
2.3
-101.8
28.8
a Calculated as the difference between the corresponding thermodynamic
properties of products and reactants, ∆G298 ) ΣGProduct - ΣGReactant
b Calculated according to the thermodynamic cycle reported in Scheme 2,
∆Gsolution ) ∆G298 + ∆∆Gsolv
.
.
52
lower limit of VH and assuming that Vsoft represents the
upper VH limit, the dissociation of 3a is partial or complete
according to which theoretical volume, VVdW or Vsoft, is taken
as reference. However, a complete ionic dissociation appears
quite plausible, as attested by the following evidence: (1)
As stated above, the molar conductivity is close to that
reported for completely dissociated 1:2 electrolytes in
acetonitrile. (2) No peaks of a [Cun(L)(C6F5S)n+1]- species
complex, DFT calculations were performed to compute the
free energy of the gas-phase reaction 6[Cu(L′)(C6H5S)] f
[Cu6(L′)2(C6H5S)6] + 4L′ as well as to evaluate the stability
of the hexanuclear cluster in acetonitrile solution (Tables 3
and 4 and Figure 7). The C6H5S- thiolate was employed
instead of the less electron-donating C6F5S- to save com-
putational resources, so some caution is required when
inferring properties of the real system by using these models.
As an example, the comparison between the [Cu(L′)(C6H5S)]
and [Cu(L′)(C6F5S)] optimized models reveals that in the
former case the copper geometry is trigonal planar with the
thioether sulfur not coordinated, whereas in the latter the
metal geometry is tetrahedral with the thioether bound to
copper and a longer Cu-SC6F5 bond distance (Figure S2 of
the Supporting Information). This comes as a consequence
of the minor donor ability of the fluorinated thiolate as
evidenced from a comparison of the natural bond orbital
1
appear in the ESI-mass spectrum. (3) Both the H and 19F
NMR spectra exhibit only a set of signals, and it would be
consistent with the presence of a more symmetrical 3b
species (if compared to 3a) and [Cu(L)CH3CN]+. If this is
not the case, a fast-exchange equilibrium with 3a should be
invoked.
To further support the hypothesis that a Cu(I)-thiolate
cluster structure is energetically favored over a mononuclear
(52) Zuccaccia, D.; Bellachioma, G.; Cardaci, G.; Ciancaleoni, G.; Zuc-
caccia, C.; Clot, E.; Macchioni, A. Organometallics 2007, 26, 3930-
3946.
10150 Inorganic Chemistry, Vol. 46, No. 24, 2007

Cu Complexes with Analogies to the Cu Thionein Core
solvent such as acetonitrile on the ionic products of the
reaction, it appears that the reaction is exergonic (∆Gsolution
) -101.8 kJ mol-1), making the dissociation even more
favored in the presence of a large excess of solvent.
The reaction reported in Figure 7c describes the “opening”
of the closed [Cu4(C6H5S)6]2- cluster by acetonitrile. The
gas-phase reaction is exothermic (∆E ) -40.4 kJ mol-1)
but endergonic (∆G298 ) +2.3 kJ mol-1) since it is
entropically disfavored. Moreover, the reaction is even more
endergonic in CH3CN solution (∆Gsolution ) +28.8 kJ mol-1),
suggesting the greater stability of the closed [Cu4(C6H5S)6]2-
cluster with respect to the open form. This is in agreement
with the proposed 3b structure, which is supported also by
the absence of CH3CN in all of the ESI-mass fragments and
by the reported crystallization of [(C6H5)4P]2[Cu4(SC6H5)6]
from acetonitrile, in which the cluster is in the closed form.18
Conclusions
The coordination capabilities of the N,N′,S ligand 4-meth-
oxy-3,5-dimethyl-2-((3-(2-(methylthio)phenyl)-1H-pyrazol-
1-yl)methyl)pyridine (L) were evaluated with Cu(I). Since
the ligand possesses a weakly coordinating thioether group,
ancillary monodentate ligands were employed (PPh3 and
C6F5S-) to complete the copper coordination requirements.
However, as evidenced by the X-ray structures, the nuclearity
of the complexes cannot be easily controlled, and only the
ternary complex [Cu(L)PPh3]BF4 (1) is mononuclear, whereas
the L/Cu(I) binary mixture in acetonitrile produces two
cocrystallized entities: a monomeric [Cu(L)CH3CN]+ and
a dinuclear [Cu2(L)2CH3CN]2+complex. In addition, the
ternary Cu(I)/L/C6F5S- system gives rise to the isolation of
a polynuclear compound, [Cu6(L)2(C6F5S)6CH3CN] (3a),
which bears similarities to an open adamantane-like {Cu4S6}
cluster. Part of this copper(I)-thiolate framework is found
in the structure of the yeast metallothionein core, which
exhibits eight copper(I) metals bound by cysteinate residues.
The propensity of the thiolate ligands to bridge metal centers
is probably the driving force that leads to the isolation of a
multinuclear structure. This is also evidenced by DFT
calculations that show how the hexanuclear unit is favored,
in the gas phase, over a hypothetical mononuclear complex.
So, to better control the nuclearity of Cu(I) centers, especially
in presence of thiolates, it would be necessary to employ a
more sterically demanding and preorganized ligand.55 This
can be obtained, for example, by functionalization of the
prochiral methylene group of L with proper donor moieties
to yield tetradentate N,N′,S,S′ heteroscorpionates, which may
alone satisfy the electronic and steric requirement of copper-
(I) without additional monodentate coligands.
Figure 7. Optimized molecular structures for the Cu(I)/L′/C6H5S- system
(B3LYP/lanl2dz): (a) oligomerization reaction 6[Cu(L′)(C6H5S)] f [Cu6-
(L′)2(C6H5S)6] + 4L′; (b) ionic dissociation of the [Cu6(L′)2(C6H5S)6] cluster;
(c) acetonitrile interaction with the [Cu4(C6H5S)6]2- cluster.
charges53 of the sulfur atom calculated for C6H5S- and
C6F5S- (Figure S3 of the Supporting Information). These
considerations should be kept in mind during the following
discussion, where the thermodynamic properties are il-
lustrated for the optimized molecular structures reported in
Figure 7. The in vacuo free energy of reaction (∆G298) for
the production of the cluster from mononuclear entities is
-58.6 kJ mol-1, supporting the stability of the former. This
is in agreement with previous DFT calculations performed
on cyclic copper(I)-thiolate assemblies showing that oli-
gomerization is energetically favored.54 The [Cu4(C6H5S)6]2-
inner core of the [Cu6(L′)2(C6H5S)6] optimized structure
presents three copper atoms in trigonal planar arrangements
and one copper atom in a distorted digonal geometry. The
two outer trigonal copper centers are bound by two κ2-N,N′
ligands, and they are linked to the [Cu4(C6H5S)6]2- unit by
bridging thiolates. We propose that this structure may model
that adopted by 3 when acetonitrile is removed under vacuum
(see Scheme 3).
Since there is experimental evidence that the two periph-
eral [Cu(L)]+ moieties of 3 may be subject to dissociation
from the [Cu4(C6H5S)6]2- cluster in acetonitrile solution, we
computed the energetics of this reaction to substantiate this
hypothesis (Figure 7b). The computed ∆E and ∆G298 of the
ionic dissociation reaction are positive in the gas phase (668.1
and 634.7 kJ mol-1, respectively), pointing to a considerable
stabilization of the neutral [Cu6(L′)2(C6H5S)6] assembly.
However, if we take into account the effect of the solvent
and, in particular, the stabilization that derives from a polar
Acknowledgment. This work was supported by the
Ministero dell’Istruzione, dell’Universita` e Ricerca (Rome,
Italy).
Supporting Information Available: CIF files for L, 1, 2, and
3a, an Ortep molecular structure of L, DFT-optimized geometries
(53) Reed, A. E.; Curtiss, L. A.; Weinhold, F. Chem. ReV. 1988, 88, 899-
(55) Fujisawa, K.; Fujita, K.; Takahashi, T.; Kitajima, N.; Moro-oka, Y.;
Matsunaga, Y.; Miyashita, Y.; Okamoto, K. Inorg. Chem. Commun.
2004, 7, 1188-1190.
926.
(54) Howell, J. A. S. Polyhedron 2006, 25, 2993-3005.
Inorganic Chemistry, Vol. 46, No. 24, 2007 10151

Gennari et al.
(B3LYP/lanl2dz) of the mononuclear models [Cu(L′)(C6H5S)] and
[Cu(L′)(C6F5S)], NBO charges of C6H5S- and C6F5S-, Cartesian
coordinates of the optimized structures L′, [Cu(L′)CH3CN]+,
[Cu(L′)(C6H5S)], [Cu4(C6H5S)6]2-, [Cu4(C6H5S)6CH3CN]2-, and
for 3, and the ESI-mass spectrum and isotopic pattern of 3. This
material is available free of charge via the Internet at http://
www.pubs.acs.org.
1
[Cu6(L′)2(C6H5S)6], H and 19F PGSE NMR experimental details
IC701189B
10152 Inorganic Chemistry, Vol. 46, No. 24, 2007