Preferred bonding motif for indium aminoethanethiolate complexes: Structural characterization of (Me2NCH2CH 2S)2InX/SR (X = Cl, I; R = 4-MeC6H4, 4-MeOC6H4)

Article abstract of DOI:10.1021/ic061132h

The metathesis reaction of InCl₃ with Me₂NCH ₂CH₂SNa or the redox reaction of indium metal with elemental iodine and the disulfide (Me₂NCH₂CH ₂S)₂ yield the indium bis(thiolate) complexes (Me ₂NCH₂CH₂S)₂InX [X = Cl (3) and I (4)], respectively. Compounds 3 and 4 may be further reacted with the appropriate sodium thiolate salts to afford the heteroleptic tris(thiolate) complexes (Me₂NCH₂CH₂S)₂InSR [R = 4-MeC₆H₄ (5), 4-MeOC₆H₄ (6), and Pr (7)]. Reaction of 2,6-Me₂C₆H₃SNa with 4 affords (Me₂NCH₂CH₂S)₂InS(2,6-Me ₂C₆H₃) (8), while no reaction is observed with 3, suggesting a greater reactivity for 4. All isolated compounds were characterized by elemental analysis, melting point, and Fourier transform IR and ¹H and ¹³C{¹H} NMR spectroscopies. X-ray crystallographic analyses of 3-6 show a bicyclic arrangement and a distorted trigonal-bipyramidal geometry for In in all cases. The two sulfur and one halogen (3 and 4) or three sulfur (5 and 6) atoms occupy equatorial positions, while the nitrogen atoms of the chelating (dimethylamino)ethanethiolate ligands occupy the axial positions. The metric parameters of the (Me₂NCH ₂CH₂S)₂In framework were found to change minimally upon variation of the X/SR ligand, while the solubility of the corresponding compounds in organic solvents varied greatly. ¹H NMR studies in D₂O showed that 6 and 7 react slowly with an excess of the tripeptide L-glutathione and that the rate of reaction is affected by the pendant thiolate ligand -SR.

Full text of DOI:10.1021/ic061132h

Inorg. Chem. 2006, 45, 8423−8429
Preferred Bonding Motif for Indium Aminoethanethiolate Complexes:
Structural Characterization of (Me2NCH2CH2S)2InX/SR (X
4-MeC6H4, 4-MeOC6H4)
) Cl, I; R )
Glen G. Briand,*,† Benjamin F. T. Cooper,† David B. S. MacDonald,† Caleb D. Martin,† and
Gabriele Schatte‡
Department of Chemistry, Mount Allison UniVersity, SackVille, New Brunswick, Canada E4L 1G8,
and Saskatchewan Structural Sciences Centre, UniVersity of Saskatchewan, Saskatoon,
Saskatchewan, Canada S7N 5C9
Received June 22, 2006
The metathesis reaction of InCl3 with Me2NCH2CH2SNa or the redox reaction of indium metal with elemental iodine
and the disulfide (Me2NCH2CH2S)2 yield the indium bis(thiolate) complexes (Me2NCH2CH2S)2InX [X Cl (3) and
I (4)], respectively. Compounds 3 and 4 may be further reacted with the appropriate sodium thiolate salts to afford
the heteroleptic tris(thiolate) complexes (Me2NCH2CH2S)2InSR [R 4-MeC6H4 (5), 4-MeOC6H4 (6), and Pr (7)].
)
)
Reaction of 2,6-Me2C6H3SNa with 4 affords (Me2NCH2CH2S)2InS(2,6-Me2C6H3) (8), while no reaction is observed
with 3, suggesting a greater reactivity for 4. All isolated compounds were characterized by elemental analysis,
1
melting point, and Fourier transform IR and H and 13C
{
1H
}
NMR spectroscopies. X-ray crystallographic analyses
of 3−6 show a bicyclic arrangement and a distorted trigonal-bipyramidal geometry for In in all cases. The two sulfur
and one halogen (3 and 4) or three sulfur (5 and 6) atoms occupy equatorial positions, while the nitrogen atoms
of the chelating (dimethylamino)ethanethiolate ligands occupy the axial positions. The metric parameters of the
(Me2NCH2CH2S)2In framework were found to change minimally upon variation of the X/SR ligand, while the solubility
of the corresponding compounds in organic solvents varied greatly. 1H NMR studies in D2O showed that 6 and 7
react slowly with an excess of the tripeptide
thiolate ligand SR.
L-glutathione and that the rate of reaction is affected by the pendant
−
Introduction
pentaacetic acid. Despite the useful decay properties of the
radioisotope, indium compounds are often unstable in vivo,
In recent years, indium-111 has been found to be a very
useful radionuclide for incorporation in radiopharmaceuticals
for diagnostic imaging.1 The isotope was first used in the
labeling of white blood cells, which are then used to help
diagnose inflammation and to determine the success of organ
transplants. More recently, the focus has been on the
preparation of bioconjugates, in which the metal is bound
to a peptide or monoclonal antibody (MAb) via a tethered
chelating ligand, usually N,N,N′,N′′,N′′-diethylenetriamine-
and retention in the liver is common because of reactions
with sulfur-containing proteins.2,3 Further, indium complexes
are often found to be unstable in the presence of intercellular
blood proteins, such as the iron transport protein transferrin.4
As a result, ligand design for indium radiopharmaceuticals
is an important area of research, with the preparation of
kinetically inert and metabolically stable complexes being
crucial for the control of in vivo distribution.
* To whom correspondence should be addressed. E-mail: gbriand@mta.ca.
Tel: (506) 364-2346. Fax: (506) 364-2313.
(2) (a) Anderson, C. J.; John, C. S.; Li, Y.; Hancock, R. D.; McCarthy,
T. J.; Martell, A. E.; Welch, M. J. Nucl. Med. Biol. 1995, 22, 165-
173. (b) Madsen, S. L.; Bannochie, C. J.; Martell, A. E.; Mathias, C.
J.; Welch, M. J. J. Nucl. Med. 1990, 31, 1662-1668. (c) Madsen, S.
L.; Bannochie, C. J.; Welch, M. J.; Mathias, C. J.; Martell, A. E. Nucl.
Med. Biol. 1991, 18, 289.
(3) Li, Y.; Martell, A. E.; Hancock, R. D.; Reibenspies, J. H.; Anderson,
C. J.; Welch, M. J. Inorg. Chem. 1996, 35, 404-414.
(4) Harris, W. R.; Messori, L. Coord. Chem. ReV. 2002, 228, 237-262
and references cited therein.
† Mount Allison University.
‡ University of Saskatchewan.
(1) For reviews of the topic, see: (a) Handbook of Radiopharmaceuti-
cals: Radiochemistry and Applications; Welch, M. J., Redvanly, C.
S., Eds.; Wiley: Chippenham, U.K., 2003. (b) Anderson, C. J.; Welch,
M. J. Chem. ReV. 1999, 99, 2219-2234. (c) Guo, Z.; Sadler, P. J.
Angew. Chem., Int. Ed. 1999, 38, 1512-1231. (d) Liu, S.; Edwards,
D. S. Chem. ReV. 1999, 99, 2235-2268 and references cited therein.
10.1021/ic061132h CCC: $33.50
Published on Web 09/09/2006
© 2006 American Chemical Society
Inorganic Chemistry, Vol. 45, No. 20, 2006 8423

Briand et al.
Chart 1
Chart 2
The N-In-N [75.1(5)°] and N-In-S [79.8-82.1(3)°] bond
angles are similar to those in 1. Deviations from ideal
geometry in these structures are a result of the restrictions
imposed by the ligand framework, which result in less stable
complexes.5 Interestingly, complexes of the untethered
aminoethanethiolate ligand have been studied in solution8a
but not in the solid state, and no examples have been
structurally characterized.
To study the preferred coordination geometries of indium
with the untethered aminoethanethiolate ligand, we have
prepared the bis[(dimethylamino)ethanethiolato]indium ha-
lide complexes (Me2NCH2CH2S)2InX [X ) Cl (3) and I (4);
Chart 2]. Further, compounds 3 and 4 were used as
intermediates in the preparation of the novel heteroleptic tris-
(thiolate) complexes (Me2NCH2CH2S)2InSR [R ) 4-MeC6H4
(5), 4-MeOC6H4 (6), Pr (7), and 2,6-Me2C6H3 (8); Chart 2].
Synthetic details and spectroscopic, structural, solubility, and
stability data are reported herein.
Several previous studies aimed at identifying kinetically
stable indium complexes have focused on tethered amino-
ethanethiolate ligands, such as 1,4,7-tris(2-mercaptoethyl)-
1,4,7-triazacyclononane (H3tacn-tm) and tetramethylbis-
(aminoethanethiol) (H2bat-tm), ethylenedi-L-cysteine (H4ec),
and N,N′-bis(2-mercaptoethyl)ethylenediamine-N,N′-diacetic
acid (H4eddass) (Chart 1). The thiolate sulfur atoms of these
ligands bind to In3+ with high stability constants, while the
amine nitrogen atoms form strong dative bonds and fill
coordination sites at the metal.3,5-9 Interestingly, the majority
of this work focuses on potentiometric solution studies of
protonation and metal complex stability constants, while few
indium complexes have been isolated and definitively
characterized. Structural studies are limited to the complexes
(tacn-tm)In (1)7 and (bat-tm)InX [X ) Cl (2), NCS,
O2CC6H5].9 The six-coordinate InS3N3 core of 1, which
features three tethered aminoethanethiolate groups in the
ligand, exhibits a very distorted facial octahedral geometry
at indium. Here, the nonlinear trans S-In-N bond angles
(153-156°) are a result of the acute N-In-N (73.8-74.5°)
and N-In-S (79.8-81.6°) bond angles. Compound 2 shows
indium chelated by the two tethered aminoethanethiolate
groups of the (bat-tm)2- ligand, the two sulfur and two
nitrogen atoms of which provide the basal atoms for the
distorted square-pyramidal bonding environment at indium.
Results and Discussion
Syntheses. Metathesis or ligand-exchange reactions of
InCl3 and NaSR are an established synthetic route in
preparing (RS)3In.10 We employed this approach in the
reaction of 2 equiv of sodium 2-(dimethylamino)ethanethi-
olate with a refluxing methanol solution of indium(III)
chloride. After 3 h, the resulting reaction mixture was filtered
and slowly concentrated at 23 °C to yield 3 as a white powder
(method A). Interestingly, the analogous reaction involving
3 equiv of the sodium thiolate ligand also resulted in the
precipitation of the bis(thiolate) chloride complex 3 as
colorless crystals. This suggests that the 2:1 bicyclic product
is more kinetically favorable than the 3:1 complex and that
five-coordinate, trigonal-bipyramidal geometries are favored
(vide infra). Our inability to isolate the 3:1 complex via this
reaction route is interesting given the previously reported
preparation of the tris(thiolate) complex (pmq)3In (Hpmq )
2-phenyl-8-mercaptoquinoline), which exhibits a five-
coordinate bonding environment at indium.11,12 Further, the
preparation of 3 in air suggests significant hydrolytic stability.
This observation is in accordance with previous potentio-
metric studies of the aminoethanethiolate/In3+ system in
(5) Motekaitis, R. J.; Martell, A. E.; Koch, S. A.; Hwang, J.; Quarless,
D. A., Jr.; Welch, M. J. Inorg. Chem. 1998, 37, 5902-5911.
(6) Rose, D. J.; Chang, Y. D.; Chen, Q.; Kettler, P. B.; Zubieta, J. Inorg.
Chem. 1995, 34, 3973-3979.
(7) Ma, R.; Welch, M. J.; Reibenspies, J.; Martell, A. E. Inorg. Chim.
Acta 1995, 236, 75-82.
(8) (a) Li, Y.; Martell, A. E. Inorg. Chim. Acta 1995, 231, 159-165. (b)
Sun, Y.; Martell, A. E.; Motekaitis, R. J.; Welch, M. J. Tetrahedron
1998, 54, 4203-4210. (c) Sun, Y.; Martell, A. E.; Motekaitis, R. J.;
Welch, M. J. Inorg. Chim. Acta 1995, 228, 77-79. (d) Sun, Y.;
Motekaitis, R. J.; Martell, A. E.; Welch, M. J. J. Coord. Chem. 1995,
36, 235-246.
(10) (a) Chadha, R. K.; Hayes, P. C.; Mabrouk, H. E.; Tuck, D. G. Can.
J. Chem. 1987, 65, 804-808. (b) Bertel, N.; Noltemeyer, M.; Roesky,
H. W. Z. Anorg. Allg. Chem. 1990, 588, 102-108.
(11) Berzina, I.; Matyukhina, O. G.; Sobolev, A. N.; Asaks, J.; Bankovskii,
Yu. A.; Fundamenskii, V. S. LatV. PSR Zinat. Akad. Vestis, Khim.
Ser. 1985, 25-31.
(9) Zheng, Y. Y.; Saluja, S.; Yap, G. P. A.; Blumestein, M.; Rheingold,
A. L.; Francesconi, L. Inorg. Chem. 1996, 35, 6656-6666.
(12) Fleischer, H. Coord. Chem. ReV. 2005, 249, 799-827.
8424 Inorganic Chemistry, Vol. 45, No. 20, 2006

Indium Aminoethanethiolate Complexes
aqueous solution, in which the presence of 2:1 complexes
and the absence of 3:1 complexes were noted.8a The
preparation of 3 under an inert atmosphere in toluene was
adopted in an attempt to obtain higher yields and minimize
NCH2CH2S resonances in comparison to 3. Methylene peaks
were found to shift upfield by δ 0.04-0.16 in 5-7, while
shifts in the methyl resonances were negligible. When the
1H NMR spectrum of 4 is compared to that of 8, the
methylene peaks shifted upfield by δ 0.18 and 0.11, while
the methyl peak shifted by δ 0.16.
1
the formation of hydrolysis products (method B). Here, H
NMR analysis of the reaction mixture shows that 3 is formed
in near-quantitative yield. Solvent removal yielded crude 3‚
4NaCl, which could be used without purification for further
metathesis reactions.
Although the changes in the (dimethylamino)ethanethiolate
1
ligand H NMR resonances were useful in determining
product formation, comparisons of the spectra of the sodium
thiolate reactants and corresponding tris(thiolate) products
(5-8) proved to be more unambiguous. Aryl peaks in 5, 6,
and 8 were found to shift downfield by δ 0.18-0.32, while
methyl peaks shifted downfield by δ 0.06-0.24. For the
propanethiolate analogue (7), downfield shifts of δ 0.30 and
0.09 (methylene) and δ 0.07 (methyl) were observed. This
downfield trend is as expected upon incorporation of the
anion ligand into a neutral complex.
The presence of a chloride ligand on indium in 3 suggested
the potential for further reaction to afford heteroleptic tris-
(thiolate) species. This was achieved through reaction with
a stoichiometric amount of the corresponding sodium aryl-
and alkythiolate salts in toluene to give 5-7. Product yields
were determined to be near-quantitative by 1H NMR analysis
of the reaction mixtures. However, crystalline yields were
moderate (30-49%).
1
Interestingly, H NMR analysis of the reaction mixture
X-ray Structural Analysis. Crystals suitable for X-ray
crystallographic analysis were isolated from the reaction
mixtures by slow evaporation (3 and 4) or by solvent
diffusion of a hexane overlayer (5 and 6). Crystallographic
data are given in Table 1. Selected bond distances and angles
are given in Table 2.
of 3 with the bulky thiolate ligand NaS-2,6-Me2C6H3 showed
minimal formation (∼20%) of the desired tris(thiolate)
product. Therefore, 4 was prepared in order to exploit the
expected greater lability of the In-I versus In-Cl bond in
3. Unlike the metathesis reaction utilized for the preparation
of 3, compound 4 was prepared as an analytically pure
powder in moderate yield through the redox reaction of
indium metal, diiodine, and (dimethylamino)ethane disulfide.
A similar reaction was reported previously by Tuck et al. to
prepare (PhS)2InI;13 however, the synthetic route was not
found to be general.14 The analogous stoichiometric reaction
of 4 and 2,6-Me2C6H3SNa afforded the corresponding
heteroleptic tris(thiolate) 8. Further, 1H NMR analysis of the
reaction mixture showed the reaction to proceed near
quantitatively. Compounds 5-7 may also be prepared from
4, thus suggesting that the metathesis reaction of 4 and a
sodium thiolate salt is a general reaction route to the
formation of (Me2NCH2CH2S)2InSR (R ) aryl, alkyl)
species.
It should be noted that these are, to the best of our
knowledge, the first heteroleptic indium tris(thiolate) com-
pounds reported, and their syntheses represent a new reaction
route to these types of compounds. Further, attempts to
prepare 5 though a one-pot 2:2:1 redox reaction of elemental
indium with (Me2NCH2CH2S)2 and (4-MeC6H4S)2 were
unsuccessful. The addition of catalytic amounts of diiodine
had no effect on the result. This is interesting considering
the formation of 4 and (4-MeC6H4S)3In15 via similar redox
reactions.
The structures of 3-6 (Figures 1-4) all show a similar
bicyclic (Me2NCH2CH2S)2In arrangement, with indium in a
five-coordinate, distorted trigonal-bipyramidal geometry. The
two axial positions are occupied by the nitrogen atoms of
the chelating (dimethylamino)ethanethiolate ligands, while
the sulfur atoms occupy two equatorial positions. The third
equatorial position is occupied by a halogen atom [i.e., Cl
(3) or I (4)] or a sulfur atom of a monodentate thiolate ligand
[i.e., 4-MeC6H4S (5) or 4-MeOC6H4S (6)]. Bond length and
angle parameters for the bicyclic (Me2NCH2CH2S)2In frag-
ment vary only slightly and are most significantly different
for the chloride analogue (3).
The differences in In1-Cl1, In1-I1, and In1-S3 bond
distances are mainly a result of the varying covalent radii of
chlorine (0.99 Å), iodine (1.33 Å), and sulfur (1.03 Å),
respectively.16 However, observation of the bond distances
of the dative axial In-N bonds for 3-6 shows a smaller
average value for 3, which is accompanied by slightly lower
calculated bond valency for the In1-Cl1 bond in 3 (0.67)
versus the In1-I1 bond in 4 (0.72) and In1-S3 bonds in 5
and 6 (0.70 and 0.72, respectively).17 This may be a result
of the higher polarity of the In-Cl bond in 3, which produces
a greater positive charge on the indium center. It is also worth
noting that in 5 and 6 the In1-S3 bond distances involving
the monodentate thiolate ligands (SR) are significantly longer
than the In1-S1 and In1-S2 bond distances involving the
chelating aminothiolate ligands.
Solution NMR Studies. Compounds 3-8 were character-
1
ized by both H and 13C{1H} NMR spectroscopy using
methanol-d4 as the solvent. The 1H NMR spectra of all tris-
(thiolate) compounds (5-7) show slight changes for the Me2-
Distortions from the ideal trigonal-bipyramidal geometry
are partially a result of the small (<90°) bite angle of the
aminoethanethiolate ligands [S-In-N 81.63(8)-83.3(2)°],
resulting in Nax-In-Nax bond angles of 166.5(2)-173.7-
(13) (a) Kumar, R.; Mabrouk, H. E.; Tuck, D. G. Inorg. Synth. 1992, 29,
15-19. (b) Kumar, R.; Mabrouk, H. E.; Tuck, D. G. J. Chem. Soc.,
Dalton Trans. 1988, 1045-1047. (c) Peppe, C.; Tuck, D. G. Can. J.
Chem. 1984, 2798-2802.
(14) Ichimura, A.; Nosco, D. L.; Deutsh, E. J. Am. Chem. Soc. 1983, 105,
844-850.
(15) Briand, G. G.; Davidson, R. J.; Decken, A. Inorg. Chem. 1995, 34,
9914-9920.
(16) Housecroft, C. E.; Sharpe, A. G. Inorganic Chemistry, 2nd ed.;
Pearson: Essex, U.K., 2005.
(17) O’Keefe, M.; Brese, N. E. J. Am. Chem. Soc. 1991, 113, 3226-3229.
Inorganic Chemistry, Vol. 45, No. 20, 2006 8425

Briand et al.
Table 1. Crystallographic Data for 3-6
3
4
5
6
formula
fw
cryst syst
space group
a (Å)
C8H20Cl1In1N2S2
358.65
C8H20I1In1N2S2
450.10
C15H27In1N2S3
446.39
C15H27In1N2OS3
462.39
orthorhombic
Pc21n (No. 33)
7.1598(1)
8.7840(1)
31.3428(3)
90
monoclinic
P21/n (No. 14)
10.5150(2)
9.6190(2)
13.6770(3)
90
94.1160(8)
90
1379.78(5)
4
monoclinic
P21/c (No. 14)
10.8640(3)
9.6860(3)
17.2470(3)
90
126.348(1)
90
1461.76(7)
4
triclinic
P1h (No. 2)
7.4499(3)
10.2419(5)
13.1509(6)
92.147(3)
104.192(3)
95.171(3)
967.00(8)
2
b (Å)
c (Å)
R (deg)
â (deg)
γ (deg)
V (Å3)
Z
90
90
1971.30(4)
8
F(000)
720
1.727
2.179
173(2)
0.710 73
0.0390
0.0966
864
2.045
3.986
173(2)
0.710 73
0.0304
0.0703
456
1.533
1.542
173(2)
0.710 73
0.0517
0.1230
1888
1.558
1.519
173(2)
0.710 73
0.0359
0.0885
F
calcd (Mg/m3)
µ (mm-1
T (K)
λ (Å)
R1a
)
wR2b
a R1 ) [∑||Fo| - |Fc||]/∑|Fo| for Fo > 2σ(Fo ). b wR2 ) {[∑w(Fo - Fc )2]/[∑w(Fo )]}1/2 for all data.
Table 2. Selected Bond Distances (Å) and Angles (deg) for 3-6a
2
2
2
2
4
3
4
5
6
In1-N1
In1-N2
In1-S1
In1-S2
In1-S3
In1-Cl1
In1-I1
2.343(7)
2.364(8)
2.437(2)
2.440(2)
2.390(3)
2.384(3)
2.4436(8)
2.4412(8)
2.400(4)
2.377(4)
2.446(1)
2.440(1)
2.476(1)
2.380(3)
2.409(3)
2.444(1)
2.4449(9)
2.471(1)
2.424(2)
2.7602(3)
Figure 2. X-ray structure of 4 (30% probability ellipsoids). Hydrogen
atoms are removed for clarity.
N1-In1-N2
S1-In1-S2
S1-In1-X
S2-In1-X
S1-In1-N1
S2-In1-N1
X-In1-N1
S1-In1-N2
S2-In1-N2
X-In1-N2
173.7(3)
128.68(9)
117.6(1)
113.59(9)
83.3(2)
96.0(2)
94.8(2)
92.3(2)
83.2(2)
169.56(9)
130.84(3)
111.54(2)
117.50(2)
82.23(7)
91.09(7)
93.95(6)
94.86(7)
83.21(7)
96.44(7)
166.5(2)
130.28(5)
120.21(4)
109.46(5)
82.3(1)
90.9(1)
96.2(1)
92.9(1)
82.6(1)
168.8(1)
129.89(4)
105.90(4)
124.20(4)
82.89(9)
92.48(9)
95.68(8)
93.52(8)
81.63(8)
95.53(8)
91.2(2)
97.1(1)
a X ) Cl1 (3), I1 (4), and S3 (5 and 6).
Figure 3. X-ray structure of 5 (30% probability ellipsoids). Hydrogen
atoms are removed for clarity.
Figure 1. X-ray structure of 3 (30% probability ellipsoids). Hydrogen
atoms are removed for clarity.
Figure 4. X-ray structure of 6 (30% probability ellipsoids). Hydrogen
atoms are removed for clarity.
(3)°. The majority of equatorial bond angles deviate signifi-
cantly from the idealized 120° [111.54(2)-130.84(3)°], with
the largest in each compound (S1-In-S2) involving the
sulfur atoms of the aminoethanethiolate ligands. Despite this,
the sum of the equatorial bond angles is approximately 360°
for all compounds. InN2S2Cl and InN2S3 bonding environ-
ments similar to those reported herein have been observed
for the previously reported compounds (imq)2InCl (Himq )
2-isopropyl-8-mercaptoquinoline) and (pmq)3In (Hpmq )
2-phenyl-8-mercaptoquinoline), respectively.11,18 However,
distortions from the ideal trigonal-bipyramidal geometry are
much greater than those in 3-6, presumably as a result of
the rigid ligand backbones.
(18) Kuz’mina, L. G.; Struchkov, Y. T.; Rokhlina, E. M.; Kravtsov, D. N.
Zh. Strukt. Khim. 1983, 24, 130.
8426 Inorganic Chemistry, Vol. 45, No. 20, 2006

Indium Aminoethanethiolate Complexes
Chart 3
The stability of indium compounds in the presence of
sulfur-containing proteins in vivo is an important factor in
determining the potential utility of indium compounds as
medicinal agents. Therefore, we have studied the reactivity
of our novel indium tris(thiolate) compounds with the
biomolecule L-glutathione, which contains potentially reac-
tive thiol functionality. In these experiments, compound 6
or 7 was added to 4 equiv of L-glutathione in D2O. The
degree of decomposition was determined by monitoring the
1
formation of 4-MeC6H4SH (6) or PrSH (7) by H NMR at
regular time intervals. Both compounds were found to be
quite stable over a 24-h period under these conditions, with
approximately 4% of 6 and 13% of 7 undergoing reaction.
The differing degrees of reactivity, however, demonstrate
the possible influence of a pendant aryl- versus alkylthiolate
group on the in vivo stability of similar InS3N2 complexes
involving tethered aminoethanethiolate ligands.
To determine whether the trigonal-bipyramidal geometry
is the preferred bonding environment for five-coordinate
InS3N2 complexes, it is useful to examine those in which
the amine and thiolate groups are untethered. Structurally
characterized examples include the tris(thiolato)indium-
pyridine adducts (PhS)3In(py)2 (9) and (i-PrS)3In(dmap)2 (10)
[py ) pyridine, dmap ) 4-(dimethylamino)pyridine; Chart
3], which are prepared from the reaction of indium tris-
(thiolate) with excess amine.19 Both five-coordinate systems
show a distorted trigonal-bipyramidal bonding environment
for indium, with the sulfur atoms occupying the equatorial
positions and the nitrogen atoms occupying the axial posi-
tions. Further, the 1:1 adduct (t-BuS)3In(py) (11; Chart 3)
shows a four-coordinate, distorted trigonal-pyramidal ge-
ometry at indium, with the pyridine nitrogen in the apical
position. Indium is 0.43 Å out of the plane generated by the
three basal sulfur atoms [∑(S-In-S) ∼351°]. Interestingly,
no analogous tris(amine) adducts have been reported in the
literature. The structures of compounds 9-11, as well as
3-6, may be rationalized in terms of a simple valence bond
description, in which the amine nitrogen atoms form dative
bonds with the empty p orbital of the covalently bound
indium tris(thiolate) center.
Conclusions
The bicyclic indium bis(thiolate) compounds 3 and 4 were
prepared from metathesis and redox reaction routes, respec-
tively. Further reaction with the appropriate sodium thiolate
salts yields the heteroleptic tris(thiolate) complexes 5-8.
Although the reaction route is general in these cases, the
use of the more reactive indium iodide compound (4) is
required for the preparation of 8, which involves a sterically
bulky thiolate ligand. Compounds 3-8 were spectroscopi-
cally characterized, while X-ray crystallographic data were
also obtained for 3-6. All compounds were found to have
distorted trigonal-bipyramidal geometries at indium, with
similar bond lengths and bond angles in the bicyclic
framework. Through the addition of a third thiolate ligand,
it was shown that the solubility of the resulting product in
organic solvents could be varied, while none of the com-
pounds were found to be soluble in water. 1H NMR studies
of the stability of 6 and 7 against excess L-glutathione in
D2O show both compounds to be quite stable under these
conditions. This work suggests that tethered aminoethanethi-
olate ligands that yield trigonal-bipyramidal InS3N2 bonding
motifs are desirable candidates for the preparation of indium
complexes with high in vivo stability.
Solubility Data. Qualitative observations demonstrate that
substituting the chlorine atom in 3 with various thiolate
ligands results in significant changes in solubility. When 50
mg of product was added to 1 mL of solvent, 3 and 5-7
were found to be completely soluble in methanol. However,
5-7 were also found to be soluble in toluene, while
compound 7 was the only compound completely soluble in
hexanes. This demonstrates that the solubility of the (Me2-
NCH2CH2S)2InSR complex in organic media may be tuned
with the appropriate choice of alkyl- or arylthiolate ligand.
None of these neutral compounds were found to be soluble
in water, however, and preparation of ionic complexes may
be required for solubility in aqueous media.
Experimental Section
General Considerations. Solution 1H and 13C{1H} NMR spectra
were recorded at 23 °C on a JEOL GMX 270-MHz spectrometer
(270.2 and 67.9 MHz, respectively) or a Varian MERCURYplus
200-MHz spectrometer (200.0 and 50.3 MHz, respectively), and
chemical shifts are calibrated to the residual solvent signal. Fourier
transform (FT) IR spectra were recorded as Nujol mulls on a
Mattson Genesis II FT-IR spectrometer in the range of 4000-400
cm-1. Melting points were measured on an Electrothermal MEL-
TEMP melting point apparatus and are uncorrected. Elemental
analyses were performed by Chemisar Laboratories Inc., Guelph,
Ontario, Canada.
Synthetic Procedures. 2-(Dimethylamino)ethanethiol hydro-
chloride (95%), indium(III) chloride, sodium metal, 4-methylben-
zenethiol (98%), 4-methoxybenzenethiol (97%), 1-propanethiol
(99%), 2,6-dimethylbenzenethiol (95%), indium powder (99.99%),
and L-glutathione (98%) were used as received from Aldrich.
Stability Studies. Although compounds 5-8 were pre-
pared with the exclusion of moisture, all compounds are
stable in air for a period of days. Further, 1H NMR analysis
shows that no hydrolysis products are formed on attempting
to dissolve each compound in D2O.
(19) (a) Suh, S.; Hoffman, D. M. Inorg. Chem. 1998, 37, 5823-5826. (b)
Annan, T. A.; Kumar, R.; Mabrouk, H. E.; Tuck, D. G. Polyhedron
1989, 8, 865-871.
Inorganic Chemistry, Vol. 45, No. 20, 2006 8427

Briand et al.
3
Hydrogen peroxide (30% solution in water) and sodium hydroxide
(97%) were used as received from ACP. Diiodine (99.8%) was
used as received from B and A. Reactions were carried out under
an atmosphere of N2 gas, using standard Schlenk techniques unless
otherwise specified. Solvents were dried using an MBraun SPS
column solvent purification system.
12H, SCH2CH2NMe2), 2.64 (t, JH-H ) 6 Hz, 4H, SC2H4NMe2),
2.88 (t, 3JH-H ) 6 Hz, 4H, SC2H4NMe2). 13C{1H} NMR (methanol-
d4): δ 22.99 (SCH2CH2NMe2), 44.11 (SCH2CH2NMe2), 59.27
(SCH2CH2NMe2). FT-IR (cm-1): 534vs, 798vs, 866w, 1018s,
1091s, 1261m. Mp: 201 °C. Anal. Calcd: C, 21.35; H, 4.47; N,
5.89. Found: C, 21.77; H, 4.83; N, 5.89.
The sodium salts NaSR (R ) 4-MeC6H4, 4-MeOC6H4, Pr, and
2,6-Me2C6H3) were prepared by the addition of the appropriate HSR
thiol ligand (0.50 g) to a stoichiometric amount of sodium metal
in methanol (10 mL). After the solvent was refluxed for 2 h, it
was removed in vacuo to yield the sodium thiolates as white
Preparation of (Me2NCH2CH2S)2In(SC6H4-4-Me) (5). A solu-
tion of 3 (0.41 g, 0.68 mmol) and 4-MeC6H4SNa (0.10 g, 0.68
mmol) in toluene (15 mL) was brought to reflux. After 2 h, the
reaction was cooled to 23 °C, a white precipitate was removed by
filtration, and the resulting solution was concentrated in vacuo to
1.5 mL. This concentrated solution was then layered with hexane
(1.5 mL) and kept at -15 °C. After 2 days, the reaction mixture
was filtered to yield colorless crystals of 5 (0.091 g, 0.20 mmol,
30%). 1H NMR (methanol-d4): δ 2.24 (s, 3H, SC6H4Me), 2.30 (s,
1
powders. These were used without further purification. H NMR
data (methanol-d4): R ) 4-MeC6H4, δ 2.15 (s, 3H, SC6H4Me), 6.73
3
3
(d, JH-H ) 8 Hz, 2H, SC6H4Me), 7.23 (d, JH-H ) 7 Hz, 2H,
SC6H4Me); R ) 4-MeOC6H4, δ 3.67 (s, 3H, SC6H4OMe), 6.53 (d,
3JH-H ) 7 Hz, 2H, SC6H4OMe), 7.24 (d, 3JH-H ) 7 Hz, 2H, SC6H4-
OMe); R ) Pr, δ 0.93 (t, 3JH-H ) 7 Hz, 3H, SCH2CH2CH3), 1.54
(m, 3JH-H ) 8 Hz, 2H, SCH2CH2CH3), 2.43 (t, 3JH-H ) 7 Hz, 2H,
SCH2CH2CH3); R ) 2,6-Me2C6H3, δ 2.40 (s, 6H, SC6H3Me2), 6.58
3
12H, SCH2CH2NMe2), 2.48 (t, JH-H ) 5 Hz, 4H, SC2H4NMe2),
3
3
2.73 (t, JH-H ) 6 Hz, 4H, SC2H4NMe2), 6.95 (d, JH-H ) 8 Hz,
2H, SC6H4Me), 7.48 (d, JH-H ) 8 Hz, 2H, SC6H4Me). 13C{1H}
3
NMR (methanol-d4): δ 19.53 (SC6H4Me), 22.79 (SCH2CH2NMe2),
44.04 (SCH2CH2NMe2), 60.60 (SCH2CH2NMe2), 128.76 (SC6H4-
Me), 133.19 (SC6H4Me), 133.67 (SC6H4Me), 134.22 (SC6H4Me).
FT-IR (cm-1): 625w, 666w, 816s, 889m, 951w, 1032s, 1084s,
1163m, 1261m, 1298s. Mp: 142 °C. Anal. Calcd: C, 40.36; H,
6.10; N, 6.28. Found: C, 40.13; H, 6.10; N, 6.66.
3
3
(t, JH-H ) 7 Hz, 1H, SC6H3Me2), 6.84 (d, JH-H ) 7 Hz, 2H,
SC6H3Me2).
(Me2NCH2CH2S)2 was prepared in air using the following
procedure. NaOH (16.94 g, 0.4237 mol) was added to a solution
of 2-(dimethylamino)ethanethiol hydrochloride (10.00 g, 0.07059
mol) in water (40 mL). After the addition of H2O2 (30% in water;
5.34 g, 0.0470 mol), the solution was stirred overnight. The product
was extracted from the solution three times with diethyl ether (3
× 40 mL). The ether was then removed by rotary evaporation to
give a pale-yellow oil. The product was distilled under vacuum to
yield (Me2NCH2CH2S)2 as a colorless oil (5.02 g, 0.0241 mol, 68%).
Preparation of (Me2NCH2CH2S)2InCl (3). Method A. In air,
sodium hydroxide (0.22 g, 5.6 mmol) was added to a solution of
2-(dimethylamino)ethanethiol hydrochloride (0.40 g, 2.8 mmol) in
methanol (10 mL) to form a cloudy white solution. After 1 h, the
mixture was added dropwise to a refluxing slurry of InCl3 (0.21 g,
0.94 mmol) in methanol (10 mL). After 3 h, the reaction mixture
was filtered to remove a white powder and the solvent allowed to
evaporate slowly at 23 °C. After 2 days, colorless crystals of 3
were collected (0.19 g, 0.53 mmol, 57%). FT-IR (cm-1): 538w,
665m, 767s, 892m, 950s, 995s, 1031s, 1103w, 1124m, 1168m,
Preparation of (Me2NCH2CH2S)2In(SC6H4-4-OMe) (6). A
solution of 3 (0.40 g, 0.68 mmol) and 4-MeOC6H4SNa (0.11 g,
0.68 mmol) in toluene (15 mL) was brought to reflux. After 2 h,
the reaction was cooled to 23 °C, a white precipitate was removed
by filtration, and the resulting solution was concentrated in vacuo
to 1.5 mL. This concentrated solution was then layered with hexane
(1.5 mL) and stored at -15°C for 2 days. The reaction mixture
was filtered to yield colorless crystals of 6 (0.16 g, 0.34 mmol,
49%). 1H NMR (methanol-d4): δ 2.30 (s, 12H, SC2H4NMe2), 2.47
3
3
(t, JH-H ) 6 Hz, 4H, SC2H4NMe2), 2.72 (t, JH-H ) 6 Hz, 4H,
3
SC2H4NMe2), 3.73 (s, 3H, SC6H4OMe), 6.74 (d, JH-H ) 7 Hz,
2H, SC6H4OMe), 7.50 (d, JH-H ) 7 Hz, 2H, SC6H4OMe). 13C-
3
{1H} NMR (methanol-d4): δ 22.76 (SCH2CH2NMe2), 44.02 (SCH2-
CH2NMe2), 54.45 (SC6H4OMe), 60.32 (SCH2CH2NMe2), 113.76
(SC6H4OCH3), 128.01 (SC6H4OCH3), 134.42 (SC6H4OCH3), 157.45
(SC6H4OCH3). FT-IR (cm-1): 623m, 665w, 831s, 890w, 950m,
997w, 1034s, 1090m, 1180m, 1236s, 1275s, 1593w. Mp: 108 °C.
Anal. Calcd: C, 38.96; H, 5.89; N, 6.06. Found: C, 39.29; H, 5.91;
N, 6.26.
1
1224m, 1247m, 1299s. H NMR (methanol-d4): δ 2.33 (s, 12H,
SC2H4NMe2), 2.65 (t, 3JH-H ) 6 Hz, 4H, SC2H4NMe2) 2.81 (t, 3JH-H
) 6 Hz, 4H, SC2H4NMe2). 13C{1H} NMR (methanol-d4): δ 22.59
(SCH2CH2NMe2), 43.88 (SCH2CH2NMe2), 60.17 (SCH2CH2NMe2).
Mp: 241 °C. Anal. Calcd for [(Me2NCH2CH2S)2InCl]: C, 26.79;
H, 5.63; N, 7.81. Found: C, 26.81; H, 5.64; N, 7.67.
Preparation of (Me2NCH2CH2S)2In(SPr) (7). A solution of 3
(0.41 g, 0.68 mmol) and PrSNa (0.067 g, 0.68 mmol) in toluene
(10 mL) was brought to reflux. After 2 h, the reaction mixture was
cooled to 23 °C, a white precipitate was removed by filtration, and
the resulting solution was concentrated in vacuo to 1 mL. The
solution was then layered with pentane (2 mL) and stored at -15
°C for 1 day. The reaction mixture was filtered to yield colorless
Method B. Under an atmosphere of N2 gas, 2-(dimethylamino)-
ethanethiol hydrochloride (0.50 g, 3.5 mmol) and sodium metal
(0.16 g, 7.0 mmol) were combined in methanol (10 mL). After the
solution was refluxed for 1 h, it was added dropwise to a refluxing
solution of InCl3 (0.39 g, 1.8 mmol) in methanol (10 mL). After 3
h, the solvent was removed in vacuo to yield a white powder (0.51
g). This material (3‚4NaCl) was used without further purification.
1H NMR (methanol-d4): δ 2.31 (s, 12H, SC2H4NMe2), 2.63 (t, 3JH-H
) 6 Hz, 4H, SC2H4NMe2) 2.81 (t, 3JH-H ) 6 Hz, 4H, SC2H4NMe2).
Preparation of (Me2NCH2CH2S)2InI (4). (Me2NCH2CH2S)2
(1.00 g, 4.81 mmol), In powder (0.55 g, 4.8 mmol), and I2 (0.61 g,
2.4 mmol) were combined in a vessel with toluene (10 mL) to
produce an orange solution. The solution was then refluxed for 7
h and filtered. The solvent was then removed in vacuo to obtain 4
as a pale-yellow powder (1.20 g, 2.67 mmol, 56%). Alternatively,
colorless crystals of 4 were obtained by allowing the reaction
1
crystals of 7 (0.11 g, 0.29 mmol, 42%). H NMR (methanol-d4):
3
3
δ 1.00 (t, JH-H ) 7 Hz, 3H, SCH2CH2CH3), 1.65 (m, JH-H ) 7
Hz, 2H, SCH2CH2CH3), 2.34 (s, 12H, SCH2CH2NMe2), 2.59 (t,
3JH-H ) 6 Hz, 4H, SC2H4NMe2), 2.73 (t, 3JH-H ) 7 Hz, 2H, SCH2-
CH2CH3), 2.77 (t, 3JH-H ) 6 Hz, 4H, SC2H4NMe2). 13C{1H} NMR
(methanol-d4): δ 12.55 (SCH2CH2CH3), 22.75 (SC2H4NMe2), 28.06
(SC2H4CH3), 29.29 (SC2H4CH3), 43.86 (SCH2CH2NMe2), 60.53
(SCH2CH2NMe2). FT-IR (cm-1): 596m, 671w, 764m, 800s, 890m,
953m, 1034s, 1099m, 1259s, 1296s. Mp: 67 °C. Anal. Calcd: C,
33.17; H, 6.83; N, 7.03. Found: C, 33.53; H, 7.04; N, 7.25.
Preparation of (Me2NCH2CH2S)2In(S-2,6-Me2C6H3) (8). A
solution of 4 (0.26 g, 0.58 mmol) and 2,6-Me2C6H3SNa (0.093 g,
0.58 mmol) in toluene (10 mL) was brought to reflux. After 2 h,
1
mixture to sit 1 h at 23 °C. H NMR (methanol-d4): δ 2.36 (s,
8428 Inorganic Chemistry, Vol. 45, No. 20, 2006

Indium Aminoethanethiolate Complexes
the reaction mixture was cooled to 23 °C, a pale-yellow precipitate
was removed by filtration, and the resulting solution was concen-
trated in vacuo to 1.5 mL. The solution was then layered with
hexane (3 mL) and stored at -15 °C. After 1 day, the reaction
mixture was filtered to yield pale-yellow crystals of 8 (0.13 g, 0.29
mmol, 49%). 1H NMR (methanol-d4): δ 2.15 (s, 12H, SCH2-
CH2NMe2), 2.46 (t, 3JH-H ) 6 Hz, 4H, SC2H4NMe2), 2.64 (s, 6H,
S-2,6-Me2C6H3), 2.77 (t, 3JH-H ) 6 Hz, 4H, SC2H4NMe2), 6.90 (t,
were included at geometrically idealized positions (C-H bond
distances 0.95 and 0.99 Å) and were not refined. The isotropic
thermal parameters of the hydrogen atoms were fixed at 1.2 times
that of the preceding carbon atom.
The crystal data for 5 showed signs of twinning: (a) For all of
the “most disagreeable” reflections, Fo was much greater than Fc.
2
(b) K ) Mean[Fo ]/Mean[Fc2] is systematically high for the
reflections with low intensity. (c) There was a high value for wR2
(0.2138) before twin refinement. Using the program ROTAX
(program in WinGX),24 the structure was tested for possible twin
laws. It was determined that twinning occurred around the [0 1 0]
reciprocal lattice direction. The program WinGX was used to prepare
an HKLF5 reflection file for further refinement in SHELXL-97.23
The refinement of the structure was successful, indicating the correct
twin assignment.
The structure for 6 was solved in a noncentrosymmetric space
group Pc21n. Attempts to solve the structure in the centrosymmetric
space group Pnma led to no solution. The refined absolute structure
parameter [0.43(3)] was neither unity nor nil and was used in the
scale parameter in the racemic twin refinement.
3
3JH-H ) 7 Hz, 1H, S-2,6-Me2C6H3), 7.02 (d, JH-H ) 7 Hz, 2H,
S-2,6-Me2C6H3). 13C{1H} NMR (methanol-d4): δ 22.88 (SCH2-
CH2NMe2), 23.33 (S-2,6-Me2C6H3), 43.84 (SCH2CH2NMe2), 60.43
(SCH2CH2NMe2), 124.70 (S-2,6-Me2C6H3), 127.29 (S-2,6-Me2C6H3),
136.35 (S-2,6-Me2C6H3), 142.04 (S-2,6-Me2C6H3). FT-IR (cm-1):
584m, 764m, 802s, 891w, 939w, 1030s, 1093m, 1261m, 1296w.
Mp: 63 °C. Anal. Calcd: C, 41.73; H, 6.36; N, 6.11. Found: C,
42.09; H, 6.06; N, 5.86.
X-ray Structural Analysis. Crystals of 3-6 were isolated from
the reaction mixtures as indicated above. Single crystals of each
compound were coated with Paratone-N oil, mounted using a
CryoLoop (Hampton Research), and frozen in the cold stream of
the goniometer. Data were measured on a Nonius Kappa CCD
4-Circle Kappa FR540C diffractometer using monochromated Mo
KR radiation (λ ) 0.710 73 Å) at -90 and -100 °C, respectively.
Data were collected using æ and/or ω scans.20 Data reduction was
performed with HKL DENZO and SCALEPACK software, which
corrects for beam inhomogeneity, possible crystal decay, and
Lorentz and polarization effects. A multiscan absorption correction
was applied (SCALEPACK).21 Transmission coefficients were
calculated using SHELXL97-2.22 The structures were solved by
direct methods (SIR-97 for 3 and 4; SHELXS-97 for 5 and 6)22 and
refined by full-matrix least squares on F 2 (SHELXL97-2).23 The
non-hydrogen atoms were refined anisotropically. Hydrogen atoms
Stability Studies. Compound 6 or 7 (0.01 g) and 4 mol equiv
of L-glutathione were added to an NMR tube with D2O (1 mL),
1
and the mixture was shaken. A H NMR spectrum was obtained
after 15 min and at regular intervals for 24 h. Percent decomposition
was monitored by comparing integration values of the reprotonated
HSR thiol ligand resonances [for 6, δ 6.78 (d, 2H, HSC6H4OMe),
7.28 (d, 2H, HSC6H4OMe); for 7, δ 0.84 (t, 3H, HSCH2CH2CH3)]
against l-glutathione [δ 4.46 (t, 1H)].
Acknowledgment. We thank the following: Dan Durant
for assistance in collecting NMR data; Dr. Andreas Decken
for preliminary X-ray crystallographic data; and the Research
Corp., the Natural Sciences and Engineering Research
Council of Canada, the New Brunswick Innovation Founda-
tion, the Canadian Foundation for Innovation, and Mount
Allison University for financial support.
(20) COLLECT data collection software; Bruker Nonius BV: Karlsruhe,
Germany, 1998.
(21) Otwinowski, Z.; Minor, W. Macromolecular Crystallography. In HKL
DENZO and SCALEPACK V1.96: Processing of X-ray Diffraction
Data Collected in Oscillation Mode, Methods in Enzymology; Carter,
C. W., Jr., Sweet, R. M., Eds.; Academic Press: San Diego, CA, 1997;
Vol. 276, Part A, pp 307-326.
(22) Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A.; Moliterni,
A. G. G.; Burla, M. C.; Polidori, G.; Camalli, M.; Spagna, R. SIR-97,
A package for crystal structure solution by direct methods and
refinement. J. Appl. Crystallogr. 1999, 32, 115.
(23) Sheldrick, G. M. SHELXL97-2, Program for the Solution of Crystal
Structures; University of Go¨ttingen, Go¨ttingen, Germany, 1997.
(24) WinGX V1.70.01 2005: An Integrated System of Windows Programs
for the Solution, Refinement and Analysis of Single-Crystal X-ray
Diffraction Data: Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837.
ROTAX: Cooper, R. I.; Gould, R. O.; Parsons, S.; Watkin, D. J. J.
Appl. Crystallogr. 2002, 35, 168.
Supporting Information Available: X-ray crystallographic data
for 3-6 in CIF format. This material is available free of charge
via the Internet at http://pubs.acs.org. Crystallographic data for all
structures in this paper have been deposited with the Cambridge
Crystallographic Data Centre, under CCDC 611816 (3), 611817
(4), 611818 (5), and 611819 (6). Copies of this information may
be obtained free of charge from The Director, CCDC, 12 Union
Road, Cambridge CB2 1EZ, U.K. (fax +44-1223-336033; e-mail
deposit@ccdc.cam.ac.uk; web site http://www.ccdc.cam.ac.uk).
IC061132H
Inorganic Chemistry, Vol. 45, No. 20, 2006 8429