Synthesis and hydrolysis of thiol derivatives of molybdocene dichloride incorporating electron-withdrawing substituents

Article abstract of DOI:10.1021/om060133e

Hydrolysis studies of derivatives of molybdocene dichloride in which the two chloride ligands were replaced by 3,5-bis(trifluoromethyl)thiophenol, 3,5-bis(trifluoromethyl)benzyl thiol, and 2,2,2-trifluoro-ethane thiol ligands confirmed that the electron-w

Full text of DOI:10.1021/om060133e

Organometallics 2006, 25, 3417-3421
3417
Synthesis and Hydrolysis of Thiol Derivatives of Molybdocene
Dichloride Incorporating Electron-Withdrawing Substituents
Jenny B. Waern,† Peter Turner,† and Margaret M. Harding*,‡
School of Chemistry, The UniVersity of Sydney, NSW 2006, Australia, and School of Chemistry,
The UniVersity of New South Wales, NSW 2052, Australia
ReceiVed February 11, 2006
Hydrolysis studies of derivatives of molybdocene dichloride in which the two chloride ligands were
replaced by 3,5-bis(trifluoromethyl)thiophenol, 3,5-bis(trifluoromethyl)benzyl thiol, and 2,2,2-trifluoro-
ethane thiol ligands confirmed that the electron-withdrawing groups affect the lability of the Mo-S
bonds and promote slow generation of the putative biologically active species “Cp2Mo2+”; the
trifluoroethane thiol derivative underwent 50% hydrolysis in 14 h in 10% D2O/DMSO-d6. The structure
of molybdocene bis(S-3,5-bis(trifluoromethyl)benzyl thiol) was confirmed by X-ray crystal structure
analysis.
Introduction
The bioorganometallic chemistry of the antitumor metal-
locenes, particularly titanocenes,1,2 has attracted significant
attention, given the promising preclinical and phase I clinical
trials of titanocene dichloride.3,4 Given the hydrolytic instabil-
ity5,6 and disappointing phase II results of titanocene dichlo-
ride,7,8 we have focused on evaluation of molybdocene dichlo-
ride,
Cp2MoCl2 (1), and derivatives based on this framework as a
potential new class of organometallic antitumor agents.9-12 In
contrast to the extensive testing of titanocene dichloride against
animal and human cancers,1,2 only limited antitumor data have
been reported for molybdocene dichloride (1) with cytotoxicity
studies restricted to Erhlich Ascites tumors13 and two human
cancer cell lines.9
* To whom correspondence should be addressed. E-mail:
harding@chem.usyd.edu.au.
† The University of Sydney.
‡ The University of New South Wales.
Figure 1. Trifluoromethyl derivatives of molybdocene dichloride
and the previously studied9 tetrafluorinated derivative 2.
(1) Reviews that summize the extensive testing results on titanocence
dichloride: (a) Ko¨pf-Maier, P.; Ko¨pf, H. Struct. Bonding 1988, 70, 103-
185. (b) Ko¨pf-Maier, P. Antitumour Bis(cyclopentadienyl)metal Complexes.
In Metal Complexes in Cancer Chemotherapy; Keppler, B. K., Ed.; VCH
Verlagsgesellschaft: Weinheim, 1993; pp 259-296.
(2) For recent examples see: (a) Allen, O. R.; Croll, L.; Gott, A. L.;
Knox, R. J.; McGowan, P. C. Organometallics 2004, 23 288-292. (b)
Meyer, R.; Brink, S.; van Rensburg, C. E. J.; Joone, G. K.; Go¨rls, H.; Lotz,
S. J. Organomet. Chem. 2005, 690, 117-125. (c) Causey, P. W.; Baird,
M. C.; Cole, S. P. C. Organometallics 2004, 23, 4486-4494.
(3) Christodoulou, C. V.; Ferry, D. R.; Fyfe, D. W.; Young, A.; Doran,
J.; Sheehan, T. M. T.; Eliopoulos, A.; Hale, K.; Baumgart, J.; Sass, G.;
Kerr, D. J. J. Clin. Oncol. 1998, 16, 2761-2769.
The coordination chemistry and proposed mechanism of
antitumor action of molybdocene chemistry (1) is significantly
different from titanocene dichloride.11 The complex 1 forms
strong, nonlabile complexes with thiols,10,14,15 including glu-
tathione, which almost certainly leads to deactivation and
excretion of a large amount of administered complex. We have
demonstrated that the in vitro cytotoxicity of molybdocene
dichloride (1) against V79 cells is dependent on the lability of
the Mo-X ligand.9 An unexpected outcome of this study was
the high cellular uptake of molybdocene bis(S-4-thiol-2,3,5,6-
tetrafluorobenzoic acid) (2) (Figure 1), which was attributed to
the combination of the lipophilic aromatic rings and good water
solubility.9 This derivative incorporated electron-withdrawing
fluorine substituents on the aromatic rings in order to decrease
the strength of the Mo-S bond and promote formation of the
putative active species “Cp2Mo2+” in vivo.16 However, while
(4) Korfel, A.; Scheulen, M. E.; Schmoll, H. J.; Gru¨ndel, O.; Harstrick,
A.; Knoche, M.; Fels, L. M.; Skorzec, M.; Bach, F.; Baumgart, J.; Sass,
G.; Seeber, S.; Thiel, E.; Berdel, W. E. Clin. Cancer Res. 1998, 4, 2701-
2708.
(5) Toney, J. H.; Marks, T. J. J. Am. Chem. Soc. 1985, 107, 947-953.
(6) Murray, J. H.; Harding, M. M. J. Med. Chem. 1994, 37, 1936-1941.
(7) Kro¨ger, N.; Kleeberg, U. R.; Mross, K.; Edler, L.; Sass, G.; Hossfeld,
D. K. Onkologie 2000, 23, 60-62.
(8) Lu¨mmen, G.; Sperling, S.; Luboldt, H.; Otto, T.; Ru¨bben, H. Cancer
Chemother. Pharmacol. 1998, 42, 415-417.
(9) Waern, J. B.; Dillon, C. T.; Harding, M. M. J. Med. Chem. 2005,
48, 2093-2099.
(10) Waern, J. B.; Harding, M. M. Inorg. Chem. 2004, 43, 206-213.
(11) Waern, J. B.; Harding, M. M. J. Organomet. Chem. 2004, 689,
4655-4668.
(13) Ko¨pf-Maier, P.; Leitner, M.; Voigtla¨nder, R.; Ko¨pf, H. Z. Natur-
forsch. 1979, 34c, 1174-1176.
(14) Mokdsi, G.; Harding, M. M. J. Inorg. Biochem. 2001, 86, 611-
(12) Waern, J. B.; Harris, H.; Lai, B.; Zhai, Z.; Harding, M. M.; Dillon,
C. T. J. Biol. Inorg. Chem. 2005, 10, 443-452.
616.
(15) Erxleben, A. Inorg. Chem. 2005, 44, 1082-1094.
10.1021/om060133e CCC: $33.50 © 2006 American Chemical Society
Publication on Web 05/28/2006

3418 Organometallics, Vol. 25, No. 14, 2006
Waern et al.
Table 1. Crystallographic Data and Details of Refinement
for Molybdocene Bis(S-3,5-bis(trifluoromethyl)benzyl thiol)
Scheme 1
(4)
formula of the refinement model
model molecular weight
C28H20F12MoS2
744.50
cryst syst
space group
monoclinic
C2/c (#15)
a
b
c
â
V
Dc
Z
14.787(2) Å
6.9222(9) Å
27.656(4) Å
96.901(7)°
2810.4(7) Å3
1.760 g cm-3
4
cryst size
cryst color
cryst habit
temperature
λ(synchrotron)
µ(synchrotron)
2θmax
hkl range
N
Nind
0.120 × 0.030 × 0.015 mm
orange
needle
103(2) K
0.48595 Å
1.792 mm-1
45.02°
hydrolysis of the thiol ligands in 2 occurred in aqueous solutions,
the rate of formation of “Cp2Mo2+” was too slow to be relevant
on a biological time scale. Hence while significantly higher
amounts of complex 2 entered the cell compared with 1 at the
same concentration, 2 was not cytotoxic, as the thiol ligands
remained metal bound.9
-22 22, -10 10, -41 43
38 587
5266 (Rmerge 0.0735)
4698 (I > 2σ(I))
195
Nobs
Nvar
residualsa R1(F), wR2(F2)
GoF(all)
0.0481, 0.1230
1.305
In this paper, the design, synthesis, and hydrolytic stability
of thiol derivatives 3, 4, and 5 (Figure 1) are reported. These
derivatives were studied in order to evaluate the effect of the
trifluoromethyl groups on the stability of the Mo-S bond and
thus provide fundamental data needed to guide the design of
potential prodrugs of Cp2MoCl2 that hydrolyze on an hour time
scale to release the active “Cp2Mo2+” species16 in the cell. Given
the excellent cellular uptake of the aromatic derivative 2,9
lipophilic ligands were incorporated into the design of com-
plexes 3 and 4 in an effort to maximize both cellular uptake
and subsequent release of “Cp2Mo2+” in the cell and thus test
the hypothesis that increased delivery of the active species would
translate to improved cytotoxicity. For comparison, derivative
5 lacked a lipophilic ligand but was designed to measure the
effect of a single trifluoromethyl group on the hydrolytic stability
of the Mo-S bonds. Given that the derivatives were designed
to hydrolyze in water, making purification difficult, derivatives
3, 4, and 5 were designed to be soluble in water-miscible
solvents in order to facilitate isolation of analytically pure
material for biological testing.
residual extrema
-1.317, 1.645 e Å-3
2
2
a R1 ) ∑||Fo| - |Fc||/∑|Fo| for Fo > 2σ(Fo); wR2 ) (∑w(Fo - Fc )2/
2
2
∑(wFc )2)1/2 all reflections. w ) 1/[σ2(Fo ) + (0.05P)2 + 5.0P], where P )
2
2
(Fo + 2Fc )/3.
Results and Discussion
Molybdocenes 3, 4, and 5 were prepared by reaction of the
relevant thiol with an aqueous solution of Cp2MoCl2 (1)
(Scheme 1), which resulted in the precipitation of the crude
product. Crystals of 4 suitable for X-ray diffraction analysis
were obtained by slow crystallization from aqueous acetonitrile.
The crystals were thin and weakly diffracting, and a structure
was ultimately obtained from a data collection at the Chem-
MatCARS beamline of the Advanced Photon Source. The
ORTEP17 depiction of the structure is shown in Figure 2, and
key crystallographic details are summarized in Table 1. The
Mo-S distance of 2.4643(7) Å is comparable to those reported
in the literature, which range from 2.455 Å for Mo-S-Cys15
complexes to 2.516 Å for Mo-S-thiouracil complexes.18
Figure 2. ORTEP depiction of molybdocene bis(S-3,5-bis(trifluoromethyl)benzyl thiol) (4), with 20% atomic ellipsoids. Selected bond
lengths (Å), angles (deg), and torsional angles (deg): Mo(1)-S(1) 2.4643(7), S(1)-C(6) 1.830(2), C(6)-C(7) 1.5043(3), Mo(1)-C(1)
2.376(3), Mo(1)-C(2) 2.326(3), Mo(1)-C(3) 2.292(3), Mo(1)-C(4) 2.294(3), Mo(1)-C(5) 2.341(3), S(1)-Mo(1)-S(1) 73.03(3), Mo-
(1)-S(1)-C(6) 111.47(8), S(1)-C(6)-C(7) 106.16(16), S(1)-Mo(1)-S(1)-C(6)-178.32(11), Mo(1)-S(1)-C(6)-C(7) 178.52(14).

Thiol DeriVatiVes of Molybdocene Dichloride
Organometallics, Vol. 25, No. 14, 2006 3419
Scheme 2
Table 2. Summary of Percent Hydrolysis of Thiol Ligands
in Derivatives 2-5 in Solvents Indicated after 12 and 24 h
Figure 3. 1H (300 MHz) and 19F (282 MHz) NMR spectra (310
K; acetonitrile-d3) of 4: (a) prior to D2O addition, (b) after addition
of D2O, 5 h, (c) 3 days. The resonances arising from the hydrolyzed
ligand are indicated by L.
2
3
4
5
12 h
10% D2O/DMSO-d6
10% D2O/CD3CN
24 h
10% D2O/DMSO-d6
10% D2O/CD3CN
<10
0
0
nda
20
50
<5
nda
<10
0
nda
30
75
5-10
nda
5-10
a Not determined.
Thiophenol 8, required for the preparation of 3, was prepared
as shown in Scheme 2. The diazonium salt of aniline 6 was
converted to the corresponding xanthate salt, followed by
hydrolysis to the disulfide 7 and reduction to the thiol 8 with
sodium borohydride. As the thiol 8 was particularly prone to
reoxidation to the disulfide 7, thiol 8 was not fully characterized
but used immediately in the next reaction. 3,5-Bis(trifluoro-
methyl)benzyl thiol, required for the preparation of 4, was
prepared in two steps from the corresponding benzyl bromide.
As expected, due to the lack of ionizable or hydrogen-bonding
functionality, none of the derivatives 3, 4, or 5 were water
soluble. Hence hydrolysis experiments were carried out in
aqueous DMSO or aqueous acetonitrile, to determine the effect
of the electron-withdrawing substituents on the lability of the
Mo-S bond. Hydrolysis experiments were carried out by
addition of 10% D2O to a solution of the complex at 37 °C,
and the reactions were monitored by 1H and 19F NMR
spectroscopy. Under these conditions, the Cp ligands remain
metal bound, as evidenced by the appearance of the character-
Figure 4. 1H (300 MHz) and 19F (282 MHz) NMR spectra (310
K; acetonitrile-d3) of 5: (a) prior to D2O addition, (b) after addition
of D2O, 22 h. Arrows indicate resonances arising from the
hydrolysis product trifluoroethanol.
to a DMSO solution of the complex resulted in complete and
immediate precipitation of the complex. In aqueous acetonitrile,
there was some free thiol ligand (labeled L) present in the
acetonitrile solution before the addition of water (Figure 3a).
The signals arising from the hydrolyzed ligand (labeled L, plus
aromatic resonaces at δ 7.9 ppm) increased over time after the
addition of 10% D2O, and after 5 h, approximately 20%
hydrolysis of the thiol ligand had occurred (Figure 3b), while
after 3 days, approximately 50% hydrolysis of the thiol ligands
had occurred (Figure 3c).
1
istic Cp signal in the H NMR spectrum.19 The hydrolysis of
the thiol ligands in complex 2, which has been studied
previously in water (pH 7),9 was also determined in aqueous
DMSO to allow direct comparison of the results with those
obtained with 3-5. In both aqueous DMSO and aqueous
acetonitrile, there was some precipitation of unidentified hy-
drolysis species.
Table 2 summarizes the rates of hydrolysis of the derivatives
in different solvents. The rate of hydrolysis of the thiophenol
ligands in 2 in aqueous DMSO was similar to previously
reported data in D2O (50 mM NaCl), where <5% hydrolysis
was observed after 48 h.9 In contrast, significant solvent effects
on the rate of hydrolysis were observed with the other
derivatives. Thus, while there was no evidence for hydrolysis
of the thiophenol ligands in 3 in aqueous DMSO after 24 h,
new signals in both the 1H and 19F NMR spectra were observed
in aqueous acetonitrile, consistent with 5-10% hydrolysis of
the thiol ligands after 24 h.
Hydrolysis of molybdocene bis(S-2,2,2-trifluoroethane thiol)
(5) was studied in both aqueous DMSO and aqueous acetonitrile
at 310 K, by monitoring the appearance of the methylene group
by 1H and 19F NMR spectroscopy and the Cp resonance by 1H
NMR spectroscopy. While in aqueous acetonitrile only 5-10%
of the thiol had hydrolyzed after 24 h (Figure 4), in aqueous
DMSO approximately 50% hydrolysis occurred within 14 h.
Quantitative measurement of the amount of hydrolysis was
difficult, as the overlap of the ligand methylene resonance and
the residual water peak did not permit accurate signal integration
of this signal relative to the Cp resonances.
The limited aqueous solubility of the derivatives makes direct
comparison of the hydrolysis results in Table 2 difficult. The
rate of hydrolysis of the thiol ligands is clearly highly dependent
on the solvent mixture, as illustrated by the different results for
3 and 5 in 10% D2O/DMSO-d6 or 10% D2O/acetonitrile-d3.
Presumably, this is related to the different properties of DMSO
The hydrolysis of the benzyl thiol derivative 4 could be
studied only in aqueous acetonitrile since addition of 10% water

3420 Organometallics, Vol. 25, No. 14, 2006
Waern et al.
the residual oil dissolved in ethanol (95%, 50 mL). A solution of
potassium hydroxide (1 g) in water (5 mL) was added, and the
reaction mixture was heated at reflux for 14 h. The reaction mixture
was acidified with concentrated HCl, the product was extracted
into diethyl ether and dried over sodium sulfate, and the solvent
was removed to give the crude product. Purification by flash
chromatography (hexanes) and recrystallization from methanol
afforded pure 7 (270 mg, 25%) as white crystals, mp 62-64 °C
(lit.20 74-75 °C). IR (CHCl3) νmax 845, 887, 1107, 1146, 1184,
versus acetonitrile stabilizing the transition states and hydrolysis
products differently.
Surprisingly, the rate of hydrolysis of 4 was faster than the
hydrolysis of 3. On consideration of the inductive effects of
two meta-oriented trifluoromethyl groups, the thiophenol ligands
were predicted to reduce the Mo-S bond strength in 3 relative
to the thiobenzylic ligands in 4. The difference between the
predicted results and the observed result may be related to
differences in solubility of the complexes.
1
1220, 1263, 1279, 1348 cm-1. H NMR (300 MHz; CDCl3): δ
7.78 (1 H, s, H4), 7.93 (2 H, s, H2, H6) ppm. 13C NMR (100 MHz;
Conclusions
1
CDCl3): δ 121.8 (m, C4), 122.7 (q, JCF ) 273 Hz, CF3), 127.5
(m, C2, C6), 132.9 (q, 2JCF ) 34 Hz, C3, C5), 139.0 (s, C1) ppm.
19F NMR (282 MHz; CDCl3): δ -63.4 (s) ppm. ESI-MS (negative
ion): m/z 245 ([M - [Ph(CF3)3S]]-, 100%), 490 ([M]-, 20%). ESI-
HRMS (negative ion): C16H5S2F12- ([M - H]-) requires 488.9650,
found 488.9640.
The hydrolysis of the trifluoroethane thiol ligands in 5 clearly
demonstrates that the incorporation of a trifluoromethyl group
one carbon away from the Mo-S bond results in increased
lability of the Mo-S bonds in molybdocene derivatives Cp2-
Mo(SR)2. In aqueous DMSO, the rate of hydrolysis (ap-
proximately 50% in 14 h) is on a time scale that is potentially
useful in the design of prodrugs of Cp2MoCl2. However as this
complex lacks the lipophilic aromatic groups of 2, which
exhibited high cellular uptake relative to other neutral and polar
thiol derivatives of molybdocene dichloride previously studied,9
the derivative 5 is predicted to show reduced cellular uptake
relative to derivative 2. The results show that incorporation of
electron-withdrawing groups on the aromatic rings of thiol
ligands is insufficient to achieve hydrolysis within hours and
strongly suggests that if a lipophilic analogue of 5 can be
prepared that retains the trifluoroethane thiol fragment, high cell
uptake followed by slow hydrolysis can be achieved in cells.
3,5-Bis(trifluoromethyl)thiophenol (8). 3,5-Bis(trifluorometh-
yl)phenyl disulfide (277 mg, 0.57 mmol) was dissolved in tetrahy-
drofuran (10 mL) and ethanol (10 mL), and the mixture cooled to
0 °C. Sodium borohydride (75 mg, 2 mmol) was added slowly,
and the reaction was warmed to room temperature and stirred for
4 h. The solvent was removed, water (10 mL) was added, and the
solution was acidified to pH 4 with dilute HCl. The resultant white
precipitate was extracted into diethyl ether and dried over sodium
sulfate, and the solvent was removed to give 8 as a malodorous
liquid (141 mg, 51%), which was used immediately without
purification in the following step. IR (CHCl3): νmax 843, 883, 999,
1107, 1136, 1182, 1279, 1356, 1456, 1604, 1618, 1789, 2584 (S-
H), 2856, 2926, 2958 cm-1. 1H NMR (300 MHz; CDCl3): δ 3.76
(1 H, s, -SH), 7.65 (1 H, s, H4), 7.69 (2 H, s, H2, H6) ppm. 13C
NMR (100 MHz; CDCl3): δ 119.4 (m, C4), 122.9 (q, 1JCF ) 273
Experimental Section
2
Hz, CF3), 128.7 (m, C2, C6), 132.4 (q, JCF ) 33.5 Hz, C3, C5),
134.9 (s, C1) ppm. 19F NMR (282 MHz; CDCl3): δ -63.8 (s) ppm.
ESI-MS (negative ion): m/z 245 ([M]-, 50%), 490 ([2M]]-, 100%).
General Procedures. Molybdocene dichloride was obtained
from the Aldrich Chemical Company and was used as provided.
NMR spectra were recorded using a Bruker WM AMX 400 (400
MHz, 1H; 100 MHz, 13C) or a Bruker Avance 300 (300 MHz, 1H;
282 MHz, 19F) spectrometer at 300 K, unless otherwise indicated,
in the solvent stated, and referenced to 3-(trimethylsilyl)propionic
acid-d4, sodium salt at δ 0 ppm (1H), to external CDCl3 at δ 77
ppm (13C), or to external hexafluorobenzene at δ -163 ppm (19F).
Electrospray ionization mass spectra were recorded on a Finnigan
LCQ ion trap mass spectrometer. High-resolution electrospray
ionization mass spectra were recorded on a Bruker ApexII Fourier
transform ion cyclotron resonance mass spectrometer, with a 7.0
T magnet fitted with an off-axis analytical electrospray source.
Melting points were recorded on a Reichert melting point stage
and are uncorrected. Molybdocene bis(S-4-thiol-2,3,5,6-tetrafluo-
robenzoic acid) (2) was synthesized as described previously.9
3,5-Bis(trifluoromethyl)phenyl Disulfide (7). 3,5-Bis(trifluo-
romethyl)aniline (1 g, 4.4 mmol) was dissolved in water (10 mL),
and concentrated sulfuric acid (1 mL) was added with stirring. The
solution was cooled to <5 °C, and a solution of sodium nitrite (0.45
g, 6.5 mmol) in water (5 mL) was added dropwise. The resulting
solution was added to a solution of potassium methyl xanthate (0.95
g, 6.5 mmol) and potassium hydroxide (1 g) in water (5 mL) at 40
°C. The reaction mixture was then stirred at 60 °C for 1 h. The
product was extracted into diethyl ether, the solvent removed, and
-
ESI-HRMS (negative ion): C8H3S2F6 ([M - H]-) requires
244.9867, found 244.9862.
3,5-Bis(trifluoromethyl)benzyl Thiol. Crude 3,5-bis(trifluo-
romethyl)benzyl disulfide from the previous step was dissolved in
ethanol, and dithiothreitol was added. The reaction mixture was
heated at reflux for 14 h, and the product was extracted into diethyl
ether. The organic phase was washed with saturated sodium chloride
and water and dried over sodium sulfate, and the solvent was
removed to give the crude 3,5-bis(trifluoromethyl)benzyl thiol as
1
a yellow oil. H NMR (300 MHz; CDCl3): δ 1.88 (1 H, t, J ) 8
Hz, SH), 3.85 (2 H, d, J ) 8 Hz, CH2), 7.77 (1 H, s, H4), 7.81 (2
H, s, H2, H6) ppm. 13C NMR (100 MHz; CDCl3): δ 28.8 (CH2),
121.1 (p, 3JCF ) 3.7 Hz, C4), 123.2 (q, 1JCF ) 272 Hz, CF3), 128.3
2
(m), 132.4 (q, JCF ) 33.5 Hz, C3, C5), 143.6 (s, C1) ppm. 19F
NMR (282 MHz; CDCl3): δ -63.39 (s) ppm. ESI-HRMS (negative
ion): m/z 227 ([M - SH]-, 100%), 259 ([M - H]-, 25%). As rapid
oxidation of the thiol to the corresponding disulfide occurred if
further purification was attempted, the thiol was directly treated
with molybdocene dichloride in the next step.
Molybdocene Bis(S-3,5-bis(trifluoromethyl)thiophenol) (3).
Molybdocene dichloride (1) (8.9 mg, 30 mmol) was sonicated in
water (2 mL) until dissolution was complete (2-3 h) to form a
deep maroon solution. The pH was adjusted to 6 with dilute sodium
hydroxide. A solution of 3,5-bis(trifluoromethyl)thiophenol (8) (22
mg, 90 mmol) in water (1 mL, pH 8) was added, resulting in the
immediate precipitation of a pink-brown solid, and the reaction
mixture was stirred at room temperature for 14 h. The reaction
mixture was acidified to pH 2 with dilute hydrochloric acid, the
product was extracted into diethyl ether and dried over sodium
sulfate, and the solvent was removed to give the crude product as
a green-brown residue. Purification by flash chromatography (30%
(16) The exact species formed in solution is highly dependent on the
solution pH, concentration, and ionic strength, and hence the notation “Cp2-
Mo2+” is used to indicate that a number of different labile pseudohalide
ligands may be present to give species Cp2Mo(OH)2, [Cp2Mo(OH)(OH2)]+,
Cp2Mo(OH)(Cl), etc.
(17) Johnson, C. K. ORTEPII. Report ORNL-5138; Oak Ridge National
Laboratory: Oak Ridge, TN, 1976.
(18) Dias, A. R.; Duarte, M. T.; Galva˜o, A. M.; Garcia, M. H.; Marques,
M. M.; Salema, M. S. Polyhedron 1995, 14, 675-685.
(19) Kuo, L. Y.; Kanatzidis, M. G.; Sabat, M.; Tipton, A. L.; Marks, T.
J. J. Am. Chem. Soc. 1991, 113, 9027-9045.
(20) Pilgram, K.; Korte, F. Tetrahedron 1965, 21, 1999-2013.

Thiol DeriVatiVes of Molybdocene Dichloride
Organometallics, Vol. 25, No. 14, 2006 3421
1
ethyl acetate in hexanes) afforded 3 as a red solid. H NMR (300
MHz; CDCl3): δ 5.35 (10 H, s, CpH), 7.46 (2 H, s, H4), 7.65 (4
H, s, H2, H6) ppm. 19F NMR (282 MHz; CDCl3): δ -63.26 (s)
ppm. ESI-HRMS (negative ion): m/z 245 ([Ph(CF3)2S]-, 100%),
718 ([M]-, 35%), ([M + 2Na]-, 55%).
SMART 6000 CCD detector was used for the data collection. Cell
constants were obtained from a least-squares refinement against
1015 reflections located between 4° and 45° 2θ. Data were collected
at 103(2) K with ω/φ scans to 45° 2θ. The data integration and
reduction were undertaken with SAINT and XPREP,21 and subse-
quent computations were carried out with the WinGX22 and XTAL23
graphical user interfaces. Data were normalized to the incident
radiation; no absorption correction was applied.
Molybdocene Bis(S-3,5-bis(trifluoromethyl)benzyl thiol) (4).
Molybdocene dichloride (1) (33.4 mg, 120 mmol) was sonicated
in water (6 mL) until dissolution was complete (2-3 h) to form a
deep maroon solution. The pH was adjusted to 6 with dilute sodium
hydroxide. A solution of 3,5-bis(trifluoromethyl)benzyl thiol (15)
(61.4 mg, 240 mmol) in water (1 mL, pH 8) was added, resulting
in the immediate precipitation of a green-brown precipitate. The
reaction mixture was stirred for 2 days, after which the suspension
was pink-brown in color. The product was extracted into diethyl
ether and dried over sodium sulfate, and the solvent was removed
to give the crude product as a brown residue. Recrystallization from
The structure was solved in the space group C2/c (#15) by direct
methods with SIR9724 and extended and refined with SHELXL-
97.25 The asymmetric unit contains half of the complex, with a
2-fold axis passing through the metal center. The non-hydrogen
atoms were modeled with anisotropic displacement parameters, and
a riding atom model with group displacement parameters was used
for the hydrogen atoms. An ORTEP17 depiction of the molecule
with 20% displacement ellipsoids is provided in Figure 2.
1
aqueous acetonitrile afforded 4 as brown needlelike crystals. H
NMR Hydrolysis Experiments. The appropriate molybdocene
complex 3, 4, or 5 (0.010 mmol) was dissolved in DMSO-d6 or
acetonitrile-d3 (500 µL), and water-d2 (50 µL) was added. The
NMR (300 MHz; acetonitrile-d3; 310 K): δ 3.89 (4 H, s, CH2),
5.34 (10 H, s, CpH), 7.78 (2 H, s, H4), 7.89 (4 H, s, H2, H6) ppm.
19F NMR (282 MHz; CDCl3): δ -62.93 (s) ppm. ESI-HRMS
(positive ion): m/z 700 (100%), 769 ([M + Na]+, 35%), 785 ([M
+ K]+, 75%). ESI-HRMS (negative ion): C28H19S2F12Mo- ([M -
H]-) requires 744.9797, found 744.9789. Crystals suitable for X-ray
diffraction were obtained by slow diffusion of water into a solution
of 4 in acetonitrile.
1
reaction mixture was shaken, then maintained at 37 °C, and H
and 19F NMR spectra were recorded at 310 K periodically. The
percent hydrolysis was estimated by integration of the metal-bound
Cp resonances relative to the bound and hydrolyzed thiol ligand
resonances.
Molybdocene Bis(S-2,2,2-trifluoroethane thiol) (5). Molyb-
docene dichloride (1) (19.6 mg, 66 mmol) was sonicated in water
(3 mL) until dissolution was complete (2-3 h) to form a deep
maroon solution. The pH was adjusted to 6 with dilute sodium
hydroxide. This was added to a solution of 2,2,2-trifluoroethane
thiol (76 mg, 660 mmol) in water (5 mL, pH 9.5) at < 5 °C, and
the reaction mixture was stirred with gradual warming to room
temperature for 14 h. After this time, a precipitate had formed,
which was filtered to give 5 as a purple, amorphous solid (15.8
Acknowledgment. Use of the ChemMatCARS Sector 15
at the Advanced Photon Source was supported by the Australian
Synchrotron Research Program, which is funded by the Com-
monwealth of Australia under the Major National Research
Facilities Program. ChemMatCARS Sector 15 is also supported
by the National Science Foundation/Department of Energy under
grant numbers CHE9522232 and CHE0087817 and by the
Illinois Board of Higher Education. The Advanced Photon
Source is supported by the U.S. Department of Energy, Basic
Energy Sciences, Office of Science, under Contract No. W-31-
109-Eng-38.
1
mg, 53%). H NMR (300 MHz; acetonitrile-d3): δ 2.91 (4 H, q,
2JHF ) 11 Hz, CH2), 5.32 (10 H, s, CpH) ppm. 13C{1H} NMR
2
(100 MHz; acetonitrile-d3): δ 38.9 (q, JCF ) 28 Hz, CH2), 98.2
(s, CpC), 128.3 (q, 2JCF ) 275 Hz, CF3) ppm. 19F NMR (282 MHz;
2
acetonitrile-d3): δ -66.22 (s, JHF ) 11.5 Hz) ppm. ESI-MS
Supporting Information Available: Crystallographic data for
4 as a CIF file is available free of charge via the Internet at
http://pubs.acs.org.
(positive ion): m/z 228 ([Cp2Mo]+, 100%), 259 ([Cp2MoS]+, 85%),
343 ([M - SCH2CF3]+, 20%), 458 ([M]+, 15%). ESI-HRMS
(negative ion): C14H14S2F6MoNa+ ([M + Na]+) requires 480.9385,
found 480.9398.
OM060133E
X-ray Crystallography. Data were collected at the ChemMat
CARS facility at the Advanced Photon Source of the Argonne
National Laboratory, Argonne, IL. Double diamond (111) reflec-
tions were used to obtain monochromated 0.48595 Å radiation from
the synchrotron source, and harmonics were eliminated with mirrors.
A small, orange needlelike crystal was attached with Exxon
Paratone N to a short length of fiber supported on a thin piece of
copper wire inserted in a copper mounting pin. The crystal was
quenched in a cold nitrogen gas stream from an Oxford Diffraction
Cryojet. A Bruker three-circle diffractometer platform with a
(21) Bruker. SMART, SAINT, and XPREP. Area detector control and
data integration and reduction software; Bruker Analytical X-ray Instru-
ments Inc: Madison, WI, 1995.
(22) Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837-838.
(23) Hall, S. R.; du Boulay, D. J.; Olthof-Hazekamp, R. E. Xtal3.6
System; University of Western Australia, 1999.
(24) Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G. L.;
Giacovazzo, C.; Guagliardi, A.; Moliterni, A. G. G.; Polidori, G.; Spagna,
R. J. J. Appl. Crystallogr. 1998, 32, 115-119.
(25) Sheldrick, G. M. SHELX97, Program for Crystal Structure Analysis;
University of Go¨ttingen: Go¨ttingen, Germany, 1998.