Synthesis and characterization of gold(iii) complexes possessing 2,9-dialkylphenanthroline ligands: To bind or not to bind?

Article abstract of DOI:10.1039/b823215f

In an effort to discover potential alternatives to the anti-cancer drug cisplatin, the synthesis of gold(iii) polypyridyl coordination complexes was pursued. Specifically, this report describes the synthesis and characterization of a series of 2,9-dialkyl

Full text of DOI:10.1039/b823215f

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www.rsc.org/dalton | Dalton Transactions
Synthesis and characterization of gold(III) complexes possessing
2,9-dialkylphenanthroline ligands: to bind or not to bind?†
Zachary D. Hudson,a Chinar D. Sanghvi,a Melody A. Rhine,a Julia J. Ng,b Scott D. Bunge,b
Kenneth I. Hardcastle,c Mohammad R. Saadein,a Cora E. MacBethc and Jack F. Eichler*a
Received 24th December 2008, Accepted 10th June 2009
First published as an Advance Article on the web 21st July 2009
DOI: 10.1039/b823215f
In an effort to discover potential alternatives to the anti-cancer drug cisplatin, the synthesis of gold(III)
polypyridyl coordination complexes was pursued. Specifically, this report describes the synthesis and
characterization of a series of 2,9-dialkyl-1,10-phenanthroline (Rphen) gold(III) coordination complexes
(R = n-butyl, sec-butyl, and tert-butyl). Due to the steric hindrance imparted by the alkyl substituents,
these ligands do not react with HAuCl4 to form square-planar gold(III) dichloride complex ions, as is
the case with 1,10-phenanthroline, but instead form salts comprised of [AuCl4]- anions and protonated
2,9-dialkylphenanthroline cations (compounds 1 and 2). In an effort to facilitate direct binding between
the substituted phenanthroline and the gold(III) metal center, reactions were carried out between the
ligand and NaAuCl4 in the presence of a Ag(I) salt. The precipitation of one equivalent of AgCl
afforded the formation of neutral, distorted square-pyramidal gold(III) trichloride complexes
(compounds 3 and 4). Primary or secondary substitutions at the alpha carbon of the alkyl substituent
allow direct metal–ligand coordination, whereas a tertiary substituent inhibits chelation and results
only in the formation of a salt comprised of a protonated phenanthroline cation and a [AuCl2]- anion
(compound 5). Compounds 1–4 have been characterized by 1H NMR, UV/vis, IR spectroscopy, and
X-ray crystallography.
Introduction
Cisplatin (Fig. 1(A)) is often cited as the standard for anti-cancer
metallotherapeutics, and has been successfully implemented in
the treatment of a variety of cancers (e.g., ovarian, testicular, and
head and neck cancers).1 Though it possesses potent anti-cancer
activity, cisplatin has therapeutic drawbacks. Among these is the
development of resistant tumor lines, which presumably arise due
to the increased efficacy of biological reductants and/or cellular
DNA repair mechanisms.2 In addition, because cisplatin’s anti-
cancer activity is afforded by its ability to disrupt DNA replication,
normal tissues that undergo rapid proliferation are often adversely
affected during treatment.3–5
There is an ongoing effort to discover new metal-based drugs
that might alleviate the negative side effects of cisplatin. Gold
therapies, which have been previously used as rheumatoid arthritis
therapies, have recently been recognized as potential anti-cancer
drugs upon the discovery that their administration during arthritis
treatment lowered the risk of several classes of malignancy.6 Gold
Fig. 1 Structures of (A) cisplatin; (B) the square-planar 1,10-phenan-
throline gold(III) dichloride cation;16 (C) 2,9-di-alkyl-1,10-phenanthroline
gold(III) species (R = methyl,13 n-butyl, sec-butyl).
has also been found to enter cells via a unique thiol-shuttle,
potentially providing a more selective mechanism of uptake.7,8
Gold(III) compounds were originally proposed as possible anti-
cancer agents because they are isoelectronic to platinum(II), and
thus might exhibit similar modes of DNA binding.9 However,
even though gold(III) coordination compounds have been found
to interact with DNA, the strength of this interaction is often
variable and has lower affinity than cisplatin.10 In fact, it has
now been shown that the therapeutic effect of gold therapies
may originate within the mitochondria, with cell death possibly
being initiated via the inhibition of the enzyme thioredoxin
reductase.11 Preliminary research has indeed shown that gold(III)
complexes maintain cytotoxicity in cisplatin resistant tumor cell
lines, suggesting a different mechanism of action.12
aDepartment of Chemistry, Division of Natural Science and Mathematics,
Oxford College of Emory University, 100 Hamill Street, Oxford, GA 30054,
USA. E-mail: jack.eichler@emory.edu; Fax: 770-784-8423; Tel: 770-784-
8340
bDepartment of Chemistry, Kent State University, Kent, OH 44242, USA
cDepartment of Chemistry, Emory University, Atlanta, GA 30322, USA
After searching the literature, we found there was a dearth
of structurally characterized gold(III) phenanthroline compounds
(Fig. 1(B)),16 and to our knowledge, there is only one example
of a gold(III) complex with a substituted phenanthroline (phen)
ligand that has been structurally characterized (Fig. 1(C)).13 In
† Electronic supplementary information (ESI) available: Fig. S1: molecular
structures and numbering schemes for compounds 2 and 4; Table S1:
crystal and refinement data for complex 4; Fig. S2: ellipsoid plot of
compounds 1 and 2; Fig. S3: UV/vis spectra of compound 2. CCDC
reference numbers 713225–713229. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/b823215f
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addition, given that phen complexes of other metals have been
found to exhibit anti-cancer activity,14 it was prudent to pursue the
synthesis of new gold(III) complexes possessing substituted phen
ligands. It was decided that the initial ligand targets would be
2,9-dialkylphen (Rphen) derivatives because these ligands are
readily prepared via the synthesis reported by Pallenberg et al.,15
and they have the potential to sterically protect the gold(III) metal
center from biological reductants. Additionally these complexes
should provide an opportunity to probe the nature of DNA
binding (if gold drugs coordinate to DNA in an analogous fashion
to cisplatin, bulky substituents on the 2,9 positions of the phen
ligand should limit DNA binding).
More specifically, given that 2,9-dimethylphen gold(III) trichlo-
ride (Fig. 1(C)) is the only previously reported gold(III) complex
possessing a substituted phen ligand, we sought to prepare anal-
ogous gold(III) phen complexes bearing bulkier alkyl substituents.
In the course of synthesizing these Rphen gold(III) complexes (R =
sec-butyl, n-butyl), it was found that the use of auric acid (HAuCl4)
yielded salts comprised of protonated phen cations ([phenH]+) and
[AuCl4]- anions, and not coordination complexes (Scheme 1(A)).
This result prompted the development of an alternative synthetic
route, and NaAuCl4 was subsequently reacted with the substituted
phen ligands in the presence of silver(I) salts to promote direct
coordination of the substituted phenanthroline. It was found
that this reaction resulted in the formation of one equivalent of
AgCl and a neutral, distorted square pyramidal Rphen gold(III)
trichloride coordination complex (Scheme 1(B)). Attempts to
prepare the t-Buphen congener failed to yield direct coordination
to gold(III) (Scheme 1(C)). Herein, we report the X-ray crystal
structures, full spectroscopic characterization, and preliminary
stability data for both the [AuCl4]- salts (1, 2) and the neutral
distorted square pyramidal complexes (3, 4).
[RphenH][AuCl4] salts; this is in contrast to the successful metal–
ligand chelation reported for unsubstituted phenanthroline.16
The difference in reactivity may be explained both by issues
of steric hindrance introduced by the substitution and by the
increase in nitrogen basicity by the addition of alkyl groups
to the aromatic ligand backbone. Refluxing molar equivalents
of n-Buphen and sec-Buphen with NaAuCl4, along with silver(I)
salts in acetonitrile, yielded neutral Rphen gold(III) trichloride
coordination complexes, [Au(Rphen)Cl3] while the use of the
analogous synthetic procedure with 2,9-di-tert-butyl substituted
ligand yielded the [t-BuphenH][AuCl2] salt (5).
The synthesis of gold(III) salts possessing protonated nitrogen
donor ligands, such as compounds 1 and 2, is not unprecedented.
Cao et al. recently reported the reaction of HAuCl4 with bis(2-
pyridylmethyl)-N-benzylamine (BBPMA), which resulted in a salt
complex of [AuCl4]- and the protonated BBPMA ligand. These
authors were also able to obtain direct coordination between the
ligand and gold(III) metal center by using NaAuCl4 instead of
HAuCl4.17 The synthesis of 2,9-di-methylphen gold(III)trichloride
(Fig. 1(C)),13 a structural analogue of compounds 3 and 4, was
originally carried out using KAuCl4, however these authors did
not require the use of a silver(I) salt to facilitate direct coordination
of the substituted phen ligand. In our laboratory, we were not able
to obtain isolable gold(III) complexes without the use of silver(I)
salts.
In comparison to the free phen ligands, a general downfield
shift occurs for the aromatic and alkyl hydrogens in both the
[RphenH][AuCl4] salts and the neutral [Au(Rphen)Cl3] complexes
(see Fig. 2(C) and the 1H NMR data in the experimental section).
Given the expected downfield shift of the ligand protons upon
coordination to a cationic metal center {[CuCl(sec-Buphen)2]: d 8.73,
8.15, 7.77 (aromatic), 3.01(–CH)]},15 we initially interpreted the
1H NMR data for 1 and 2 as evidence that the Rphen ligands
were directly coordinated to the gold(III) centers. However, after
characterizing compounds 1 and 2 using FT-IR spectroscopy
[1: n = 3178 cm-1 (N–H); 2: n = 3183 cm-1 (N–H)], as well as
elemental analysis (see experimental) and X-ray crystallography
(see Fig. 3(A) and ESI Fig. S1(A)†), we found that the use of
HAuCl4 led only to the formation of the [RphenH][AuCl4] salts.
1
Given these results, we caution against the use of H NMR as a
singular diagnostic of phen coordination to gold(III), especially
if HAuCl4 is used as the gold source. Previous reports have
described the reaction of substituted phen ligands with HAuCl4
and claim that the substituted phen was directly bound to the
1
Au(III) center.18,19 However, this was deduced only by H NMR
studies; without additional structural characterization, it may not
be prudent to make such a conclusion.
The characterization of compounds 1–4 by UV/vis further
demonstrated the difficulty in using spectroscopic data to deter-
mine if coordination of the phen ligand occurred. Comparison of
the UV/vis absorption spectra of compounds 1 and 3 (Fig. 2(A))
and compounds 2 and 4 (Fig. 2(B)) reveal the close similarity of the
absorption properties of the [RphenH][AuCl4] salts and the neutral
[Au(Rphen)Cl3] complexes. The [RphenH][AuCl4] salts (1 and 2)
possess a series of strong absorption maxima at approximately
225–230, 270–275, and 280–285 nm, assigned as intraligand phen
p → p* transitions; and 320 nm, assigned as a Cl–Au ligand-to-
metal charge transfer (LMCT) band (it is noted that the NaAuCl4
starting material exhibits a similar Cl–Au LMCT at approximately
Scheme 1 Reaction schema for the syntheses of (A) [RphenH][AuCl4]
salts (1, 2); (B) the neutral, distorted square pyramidal [Au(Rphen)Cl3]
complexes (3, 4); and (C) the [t-BuphenH][AuCl2] salt (5). (1 and 3, R =
n-butyl; 2 and 4, R = sec-butyl.)
Results and discussion
Synthesis and spectroscopic characterization
A 1 : 1 molar ratio of Rphen [R = n-butyl (n-Buphen), sec-butyl
(
sec-Buphen)] and HAuCl4 was refluxed in methanol, yielding
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Fig.
3
Molecular structures and numbering schemes for (A)
Fig. 2 Spectroscopic data: UV/vis spectra of compounds 1 and 3
(A) and compounds 2 and 4 (B); all compounds were dissolved in a 3 : 1
2-propanol–acetonitrile solvent mixture at a concentration of 5.0 ¥ 10-5 M;
spectra were collected at 20 ◦C; (C) 1H NMR spectra of compounds 2, 4,
and the free sec-Buphen ligand. All spectra were run in CDCl3 solvent at
20 ◦C; residual chloroform resonances are overlaid in red; “a” denotes the
most downfield aromatic sec-Buphen hydrogen (H6 and 13 in Scheme 4) and
“b” denotes the –CH hydrogen from the sec-butyl pendant (H3 and 15 in
Scheme 4).
[
n-BuphenH]+[AuCl4]- (1), (B) [Au(n-Buphen)Cl3] (3), and (C) [t-BuphenH]+-
[AuCl2]- (5). Thermal ellipsoids drawn at 50% probability. Selected bond
◦
˚
lengths (A) and angles ( ) for 1: Au–Cl ◊ ◊ ◊ H–N 2.906, Au(1)–Cl(2)
2.271(3), Au(1)–Cl(3) 2.273(3), Au(1)–Cl(1) 2.275(3), Au(1)–Cl(4)
2.278(3), Cl(2)–Au(1)–Cl(3) 88.85(10), Cl(2)–Au(1)–Cl(1) 90.30(11),
Cl(3)–Au(1)–Cl(1) 178.79(13), Cl(2)–Au(1)–Cl(4) 178.43(12); 3:
Au(1)–N(1) 2.066(9), Au(1)–N(2) 2.597(9), Au(1)–Cl(2) 2.273(3),
Au(1)–Cl(1) 2.291(3), Au(1)–Cl(3) 2.296(3), Au(1)–N(2) 2.597(9),
N(1)–Au(1)–Cl(2)177.7(3), N(1)–Au(1)–Cl(1)89.6(3), Cl(2)–Au(1)–
Cl(3)91.87(13), Cl(1)–Au(1)–Cl(3)174.31(12); and 5: Au–Cl ◊ ◊ ◊ H–N
3.549, Au(1)–Cl(1) 2.258(4), Au(1)–Cl(2) 2.262(4), Cl(1)–Au(1)–Cl(2)
179.50(12) N(1)–Au(1)–Cl(3) 88.6(3), Cl(2)–Au(1)–Cl(1) 89.81(13).
320 nm).16,20 The [Au(Rphen)Cl3] complexes (3 and 4) displayed
absorption maxima that were not clearly distinguishable from
those observed in 1 and 2 (the intraligand transitions were
observed at 225, 270–275, and 280–285 nm; and the LMCT bands
were observed at approximately 320 nm). The difference in the
electronic properties of these two types of compounds is evidenced
by the distinct difference in color between the two classes of
compounds (1–2 are bright yellow; 3–4 are orange), presumed
to be differences in the d–d transitions, though this is not clearly
discernable in the UV/vis absorption spectra.
X-Ray crystal structures†
Though [phenH]+ salts have been structurally characterized,
compounds 1 and 2 appear to be the first examples reported with
the [AuCl4]- anion. Salts with [AuCl4]- have been reported for
other protonated nitrogen donor ligands however, including pro-
tonated bipyridine,21 protonated bis(2-pyridylmethyl)amine,17 and
protonated N-benzyl-C(2-pyridyl)nitrone.22 Analogous to these
structures, compounds 1 and 2 feature square-planar [AuCl4]-
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anions [see Fig. 3(A) (1) and ESI Fig. S1(A) (2)†], and possess
an equal number of [RphenH]+ units within the unit cell (Z = 8 for
1, Z = 2 for 2). However, 1 and 2 are, to our knowledge, the only
examples of[AuCl4]- saltspossessingahydrogenbondbetweenone
of the chloride ligands and the protonated nitrogen donor ligand;
compounds 1 and 2 possess Au–Cl ◊ ◊ ◊ H–N interatomic distances
the protonated [t-BuphenH]+ ligand (Fig. 3(C)); given the bulk of
the tert-butyl groups, this result was not completely unexpected.
The effect of the steric bulk of this phen ligand can be seen by
comparing the Au–Cl ◊ ◊ ◊ H–N hydrogen bonding distance of 5
(3.459 A) to that observed in 1 and 2 (2.906 A and 3.000 A). A
similar complex was reported by Cao et al., in which the [BBPMA–
H2Cl][AuCl4] salt underwent reduction to form the [BBPMA–
H2Cl][AuCl2] salt.17
˚
˚
˚
˚
˚
of 2.906 A and 3.000 A, respectively (see ESI Fig. S2(A) and S2(B)
for depictions of the Au–Cl ◊ ◊ ◊ H–N interactions in compounds
1 and 2, respectively†). According to a review of M–Cl ◊ ◊ ◊ H–N
interactions from the crystallographic database, completed by
Aullo´n et al., the hydrogen bonds in 1 and 2 are characterized as
Stability studies
Given that these gold(III) complexes will be tested for their anti-
cancer properties, preliminary experiments to determine their
stability in physiological buffer were carried out. In parallel exper-
iments, compounds 2 and 4 were dissolved in a 3 : 1 2-propanol–
acetonitrile solvent mixture, and then an aliquot of this solution for
each compound was dissolved in phosphate buffer (0.1 M, pH 7.4)
to make a final gold concentration of 1.0 ¥ 10-5 M. These solutions
were immediately analyzed by UV/vis spectroscopy, and spectra
were then collected hourly over a 24 h period. As seen in Fig. 4
(compound 4) and ESI Fig. S3(A) (compound 2),† there was a
gradual decrease in the absorption maxima of the gold complexes.
After 24 h, an observable, but immeasurable pale yellow precipitate
was present in the cuvette. Given that the hydrolysis of other
gold(III) chloride species in aqueous buffer has been previously
reported,28 this precipitate was assumed to be a gold(III) hydroxide
species ([Au(Rphen)(OH)x(Cl)y]) (see Scheme 2). The formation of
these hydrolysis products appear to be evidenced in the UV/vis
spectra, as the spectra taken after the initial scan indicate the
presence of some intermediate complex, which after complete
precipitation over a 24 h period results in spectra which resemble
those of the initial gold complexes, but at lower concentrations
(see Fig. 4 and ESI Fig. S3(A)†).
˚
intermediate to long (M–Cl ◊ ◊ ◊ H–N distances from 2.52–2.95 A
˚
are classified as intermediate, and 2.95–3.15 A are classified as
long).23
As described above, the use of NaAuCl4 and silver(I) salts in
the synthetic protocol afforded direct coordination of the n-Buphen
and sec-Buphen ligands to gold(III). The coordination environment of
[Au(n-Buphen)Cl3] (3) and [Au(sec-Buphen)Cl3] (4) was determined by
X-ray crystallography to be distorted square pyramidal [range of
bond angles for adjacent atoms in the base of the square pyramid;
88.6–91.87◦ (3); 89.6–90.9◦ (4)], where three chloride ligands and
one of the Rphen nitrogen donors occupy the coordination sites
on the base of the square pyramid, and the remaining Rphen
nitrogen donor lies in the axial position [see Fig. 3(B) (3) and ESI
Fig. S1(B) (4)†]. These compounds are structural analogues of the
methylphen gold(III) trichloride (DMP–gold) previously reported by
Robinson and Sinn (Fig. 1(C)).13 The formation of the distorted
square pyramidal geometry is likely to be caused by the steric
hindrance introduced by the alkyl substituents on the phen ligand.
Structurally characterized gold(III) complexes possessing this
distorted square-pyramidal geometry are rare (only six gold(III)
structures possessing two nitrogen donor ligands and three halide
ligands can be found in the CCDC),24–27 and compounds 3 and
4, along with DMP–gold, represent the only examples bearing
substituted phen ligands. It is noted that a complete crystal
structure was obtained for compound 4, however the structure
could not be refined to the point where more detailed structural
comparisons with 3 and DMP–gold could be made (this was
due to the disorder present in the sec-butyl pendant groups,
which is observed to a lesser extent in the n-butyl substituents
on compound 3). The data that were collected for compound
4 do indicate that it is structurally analogous to 3 and DMP–
gold. The noteworthy feature of these complexes, as previously
reported by Robinson and Sinn, is the elongation of the Au–Naxial
˚
˚
bond [Au–Naxial: 2.594 A; Au–Nequatorial, 2.066 A (3) and Au–Naxial
,
13
˚
˚
2.584 A; Au–Nequatorial, 2.09 A (DMP–gold) ], and the “lean” of
the square pyramid [angle of Au–Naxial axis to the plane of square
pyramid base: 73.2◦, 109.1◦ (3); 73.4◦, 111.1◦ (DMP–gold)13]. This
geometric “lean” is thought to be caused by the electron repulsion
between the filled dz2 orbital and the loan pair of electrons on the
axial nitrogen donor, as well as the steric influence of the phen alkyl
groups. The Au–Cl interatomic distances are in the range expected
Fig. 4 Stability data: UV/vis spectra of compound 4 in phosphate buffer
pH 7.4 over a 24 h period (1.0 ¥ 10-5 M solution, 20 ◦C).
In an effort to corroborate this hypothesis, more concentrated
samples of compound 4 (a dark orange solid) were prepared in
both phosphate buffer and distilled water (5.0 ¥ 10-4 M gold
complex). A pale yellow precipitate formed in both water and
phosphate buffer, though considerably less precipitate formed in
the buffer solution.
The pH of both solutions was measured immediately after the
addition of the gold complex; the pH of the water solution dropped
considerably (the pH after the addition of the gold complex was
3.8), while the pH of the buffer solution, as expected, did not
for square-pyramidal geometry [range of Au–Cl distances: 2.262–
13
˚
˚
2.300 A (3); 2.267–2.2.285 A (DMP–gold) ].
Attempts to synthesize the neutral square-pyramidal gold(III)
complex with the t-Buphen ligand were not successful. In fact,
even when silver(I) salts were used to encourage coordination of
the phen ligand, the only product that could be isolated was a
reduced gold species comprised of a linear [AuCl2]- anion and
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significantly change. The decrease in pH in the gold complex–
water solution seems to support the hypothesis that hydrolysis of
the gold complex is likely to occur in aqueous solution, as the
formation of the hydroxo complex would generate H+ ions (see
Scheme 2). The solid precipitate from both solutions was then
isolated and characterized by IR spectroscopy. The formation of
the hydroxo complex was further confirmed by the presence of an
FT-IR data were collected for the precipitate that formed upon
dissolving compound 4 in water. The precipitate was isolated after
letting a 5 ¥ 10-4 M solution of 4 in water stir at room temperature
overnight. The solid was washed three times with cold diethyl
ether, the diethyl ether washes discarded, and the solid dissolved
in chloroform. The chloroform solution was dried with MgSO4
and filtered. The solid was isolated via removal of the chloroform
in vacuo and then mixed with dry KBr to create a solid pellet.
intense OH stretch in the IR (3442 cm-1). Also of note was the
-1
=
=
observation of C–H stretches at 3069 cm , and C C stretches
at 1594 cm-1 and 1624 cm-1, indicative of the presence of the phen
ligand on the gold hydroxo complex.
X-Ray crystallography†
Compounds 1 and 2
X-Ray crystallography was performed by mounting each crystal
onto a thin glass fiber from a pool of Fluorolube(tm) and
immediately placing it under a liquid nitrogen cooled N2 stream,
on a Bruker AXS diffractometer. The radiation used was graphite
Scheme
formation.
2
Proposed mechanism of gold(III) hydroxo precipitate
˚
monochromatized Mo Ka radiation (l = 0.7107 A). The lattice
parameters were optimized from a least-squares calculation on
carefully centered reflections. Lattice determination, data collec-
tion, structure refinement, scaling, and data reduction were carried
out using APEX2 version 1.0-27 software package.
Even though gold(III)–chloride bonds are not completely inert
in aqueous solution, the fact that the gold–phen binding appears
to be stable may provide an opportunity to extend the in vitro
molecular design of this class of complexes to biological systems.
Additionally, the fact that the gold(III) hydroxo complexes demon-
strated higher solubility in phosphate buffer fosters optimism that
these gold compounds may show promise in future anti-cancer
studies.
Each structure was solved using direct methods. This procedure
yielded the Au atoms, along with a number of the Cl, N, and
C atoms. Subsequent Fourier synthesis yielded the remaining
atom positions. The hydrogen atoms were fixed in positions of
ideal geometry and refined within the XSHELL software. These
idealized hydrogen atoms had their isotropic temperature factors
fixed at 1.2 or 1.5 times the equivalent isotropic U of the C
atoms to which they were bonded. The final refinement of each
compound included anisotropic thermal parameters on all non-
hydrogen atoms.
Experimental
General
The 2,9-dialkylphen ligands (Rphen; where R = n-butyl, sec-
butyl, tert-butyl) were synthesized as described in the literature.15
HAuCl4·3H2O, NaAuCl4·2H2O, silver tetrafluoroborate, silver
trifluoroacetate (Alfa Aesar), and all solvents were used without
further purification. The gold starting materials were weighed
and solvated under a nitrogen atmosphere (either in an inert
atmosphere glovebox or in a nitrogen-purged glovebox) and
subsequently refluxed under normal atmospheric conditions with
the appropriate phen ligand. Aside from eliminating exposure to
direct sunlight, no special handling measures were taken with the
Compounds 3–5
For X-ray crystallography, suitable crystals of 3–5 were coated
with Paratone-N oil, suspended in a small fiber loop and placed
in a cooled nitrogen gas stream at 173 K on a Bruker D8 APEX
II CCD sealed tube diffractometer with graphite monochromated
˚
Cu Ka (1.54178 A) radiation. Data were measured using a series
of combinations of j and w scans with 10 s frame exposures and
0.5◦ frame widths. Data collection, indexing and initial cell
refinements were all carried out using APEX II software.29 Frame
integration and final cell refinements were done using SAINT
software.30 The structure was solved using Direct methods and
difference Fourier techniques (SHELXTL, V6.12).31 Hydrogen
atoms were placed in their expected chemical positions using the
HFIX command and were included in the final cycles of least
squares with isotropic Uij’s related to the atom’s ridden upon.
All non-hydrogen atoms were refined anisotropically. Scattering
factors and anomalous dispersion corrections are taken from the
International Tables for X-ray Crystallography. Structure solution,
refinement, graphics and generation of publication materials were
performed by using SHELXTL, V6.12 software.
1
final gold(III) complexes. H NMR spectra were recorded on a
Varian Mercury 300 MHz spectrophotometer at 20 ◦C; chemical
shifts were referenced to residual solvent peaks. Infrared spectra
were recorded as KBr pellets on a Varian Scimitar 800 Series
FT-IR spectrophotometer, UV/vis spectra were recorded on a
Cary 50 UV/vis spectrophotometer using 1.0 cm quartz cuvettes,
and elemental analyses were completed by Atlantic Microlab Inc.,
Norcross, GA.
Stability studies
The UV/vis spectra of compound 4 were collected in phosphate
buffer pH 7.2 over a 24 h period. A 0.010 g sample of the solid gold
complex was dissolved in 4.00 mL of a 3 : 1 2-propanal–acetonitrile
solvent mixture, yielding a 5.0 ¥ 10-5 M solution; a 7.0 uL
aliquot of this solution was diluted in phosphate buffer to a final
volume of 3.50 mL, which yielded a final gold concentration of
1.0 ¥ 10-5 M. The spectra were collected at 20 ◦C.
Syntheses and characterization
[
n-BuphenH][AuCl4], 1
2,9-Di-n-butyl-1,10-phenanthroline (0.340 g, 1.2 mmol) was dis-
solved in 15 mL of MeOH and added dropwise to HAuCl4·3H2O
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Table 1 Crystal and refinement data for compounds 1–3, 5
Complex
1
2
3
5
Empirical formula
Formula weight
Temperature/K
C20H25AuCl4N2
632.19
160(2)
0.71073
C20H25AuCl4N2
632.19
160(2)
C20H24AuCl3N2
595.73
173(2)
C20H25AuCl2N2
561.29
173(2)
0.71073
˚
Wavelength/A
0.71073
0.71073
Crystal system
Space group
Tetragonal
P4/n
4683.6(10)
8
24.553(3)
24.553(3)
7.7689(12)
90
90
90
1.793
23 975
Triclinic
P1
1111.5(5)
2
9.013(2)
10.472(3)
11.909(3)
92.196(4)
93.497(4)
97.375(4)
1.889
8947
Triclinic
P1
3255.0(3)
6
14.3221(6)
15.3810(7)
15.9327(8)
107.374(4)
102.677(3)
90.992(3)
Orthorhombic
Pnma
2033.0(3)
4
27.523(2)
6.7821(5)
10.8909(9)
90
90
90
1.834
22 152
¯
¯
3
˚
V/A
Z
˚
a/A
˚
b/A
˚
c/A
a/◦
b/◦
g /◦
D
calc/Mg m-3
1.823
22 063
12 705
Reflections collected
Independent reflections
Max., min. transmission
Final R indices [I > 2s(I)]
R indices (all data)
Goodness of fit
4157
3945
2276
0.5519 and 0.1733
R1 = 0.0443, wR2 = 0.1337
R1 = 0.0771, wR2 = 0.1636
1.091
0.4153 and 0.2243
R1 = 0.0321, wR2 = 0.0772
R1 = 0.0547, wR2 = 0.0871
1.036
0.7628 and 0.2151
R1 = 0.0605, wR2 = 0.1257
R1 = 0.1094, wR2 = 0.1488
1.013
0.8644 and 0.3153
R1 = 0.0464, wR2 = 0.0883
R1 = 0.1014, wR2 = 0.1071
1.008
(0.447 g, 1.2 mmol) in 20 mL of MeOH, upon which a deep purple
solution was produced. After refluxing for 1 h at 80 ◦C, the solution
turned dark yellow; the reaction was then refluxed overnight.
Evaporation in vacuo produced a red-orange pasty solid, which
was washed with 20 mL of ether (the ether wash was discarded). A
yellow solid (1) was isolated and then dried under vacuum at 35 ◦C
(0.361 g, 49%). Yellow needles suitable for X-ray diffraction studies
(for crystal and refinement data for compound 1, see Table 1) were
obtained by slow-evaporation from ethanol. Elemental analysis
found: C, 38.27%; H, 3.◦98%; calculated: C, 37.98%; H 3.99%.
see Table 1) were obtained by slow-evaporation from ethanol.
Elemental analysis found: C, 37.99%; H, 3.99%; calculated: C,
37.98%; H, 3.99%. lmax(iPrOH–CH3CN, 20 ◦C)/nm (e, M-1 cm-1)
230 (67 200), 270 (27 500), 280 (25 600) and 320 (7200). IR:
n
max/cm-1 3183 (NH), 3079 (CH), 2963, 2928, 287◦1 (CH), 1619,
1
1602 (conj. CC). H NMR (300 MHz, CDCl3, 20 C) d 8.88 (d,
2H, H7,12), 8.24 (s, 2H, H9,10), 8.06 (d, 2H, H6,13), 3.75 (m,
14.2, 2H, H3,15), 2.02 (m, 2H, H2, 17), 1.96 (m, 2H, H2, 17),
1.60 (d, 6H, H4,16), 1.04 (t, 6H, H1,18) (see Scheme 4 for NMR
numbering scheme).
l
max(iPrOH–CH3CN, 20 C)/nm (e, M-1 cm-1) 224 (59 200), 275
(30 400), 282 (35 200) and 320 (9600). IR: nmax/cm-1 3178 (NH),
1
3073 (CH), 2958, 2930, 2872 (CH), 1624, 1605 (conj. CC). H
NMR (300 MHz, DMSO-d6, 20 ◦C) d 8.85 (d, 2H, H7,12), 8.17 (s,
2H, H9,10), 8.06 (d, 2H, H6,13), 3.26 (m, 4H, H4,15), 1.81 (m, 4H,
H3,16), 1.42 (m, 4H, H2,17), 0.94 (t, 6H, H1,18) (see Scheme 3 for
NMR numbering scheme).
Scheme 4 Numbering scheme for compounds 2 and 4.
[Au(n-Buphen)Cl3], 3
2,9-Di-n-butyl-1,10-phenanthroline (0.265 g, 0.900 mmol) and
NaAuCl4·2H2O (0.365 g, 0.900 mmol) were added to 50 ml of
acetonitrile, upon which a brown solution was produced. This re-
action mixture was refluxed for 1 h, and AgBF4 (0.176 g, 0.9 mmol)
was dissolved in acetonitrile and delivered to the reaction solution.
The final reaction mixture was refluxed overnight, and the
precipitate (AgCl) was filtered through a glass frit covered with
a Celite pad. The filtrate was placed on a rotary evaporator, and
the resulting red-orange residue was dissolved in approximately
20 mL of dichloromethane. This solution was extracted with
20 mL of water; the aqueous layer was discarded, and the organic
layer was dried with MgSO4. The dichloromethane was removed
in vacuo and a red-orange paste was isolated. This crude product
Scheme 3 Numbering scheme for compounds 1 and 3.
[
sec-BuphenH][AuCl4], 2
2,9-Di-sec-butyl-1,10-phenanthroline (0.523 g, 1.8 mmol) and
HAuCl4·3H2O (0.705 g, 1.8 mmol) were reacted in a procedure
analogous to the synthesis of 1, yielding 0.900 g of a reddish-
orange solid, 2 (79.6%). Yellow needles suitable for X-ray diffrac-
tion studies (for crystal and refinement data for compound 2,
7478 | Dalton Trans., 2009, 7473–7480
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©

View Article Online
was washed with a small amount of methanol, leaving behind a
red-orange solid. The methanol wash was discarded and the solid
was dried under vacuum to give 3 (0.313 g, 58%). Orange needles
suitable for X-ray diffraction studies were obtained by slow-
evaporation from dichloromethane (for crystal and refinement
data for compound 3, see Table 1). Mp: 134 ◦C (EtOH). Elemental
analysis found: C, 40.33%; H, 3.99%; calculated: C, 40.30%; H,
4.06%. lmax(iPrOH–CH3CN, 20 ◦C)/nm (e, M-1 cm-1) 225 (57 800),
273 (27 600), 282 (27 200), and 320 (7490) IR: nmax/cm-1 3052 (CH),
2957, 2929, and 2860 (CH), 1619 and 1594 (conj. CC). 1H NMR
(300 MHz, CDCl3, 20 ◦C) d 8.53 (d, 2H, H7,12), 7.98 (s, 2H,
H9,10), 7.80 (d, 2H, H6,13), 3.79 (m, 4H, H4,15), 2.01 (m, 4H,
H3,16), 1.57 (m, 4H, H2,17), 1.03 (t, 6H, H1,18) (see Scheme 3 for
NMR numbering scheme).
a dramatic impact on the type of gold(III) complex that can be
obtained, and in particular have shown that the use of HAuCl4
can lead to the formation of salts comprised of [AuCl4]- anions
and protonated [RphenH]+ ligands (compounds 1 and 2). Finally,
the results of this research seem to indicate that the synthesis
of gold(III) complexes that undergo direct coordination with 2,9-
dialkylphen is limited to ligands that have methyl, 1◦, or 2◦ carbons
on the a-carbon of the alkyl substituent. The successful synthesis
of 3 and 4 may provide access to a class of gold compounds
that can potentially be used to probe the resistance to biological
reductants, as well as the nature of DNA binding; information that
is necessary to determine the efficacy of gold(III) complexes as anti-
cancer therapies. These efforts, in addition to testing compounds
1–4 on existing cancer cell lines, are currently ongoing in our
laboratory.
[Au(sec-Buphen)Cl3], 4
2,9-sec-Butyl-1,10-phenanthroline (0.199 g, 0.681 mmol) and
NaAuCl4·2H2O (0.271 g, 0.681 mmol) were added to 50 mL of
acetonitrile, upon which a deep purple solution was produced.
The addition of silver trifluoroacetate (0.150 g, 0.681 mmol)
produced a cloudy green solution, which developed into a pale
yellow solution after refluxing at 65 ◦C for 6 h. At this point, the
reaction mixture was filtered through a glass frit covered with a
Celite pad and worked up as described for compound 3; a red-
orange solid was isolated (0.371 g, 86%). Orange needles suitable
for X-ray diffraction studies were obtained by slow-evaporation
Acknowledgements
J. F. Eichler gratefully acknowledges the Emory University
Research Council and the Oxford College Research Scholars
Program for funding this research. Z. D. Hudson, C. D. Sanghvi
and M. A. Rhine gratefully acknowledge the Howard Hughes
Medical Institute for supporting their summer research efforts
under grant 52005873. J. J. Ng and S. D. Binge acknowledge
the Ohio Consortium for Undergraduate Research: Research
Experiences to Enhance Learning (REEL) Award for partial
funding of this work. We also thank Dr Shaoxiong Wu and Dr Bing
Wang at the Emory NMR center for their support and assistance.
◦
from dichloromethane. Mp: 137 C (EtOH). Elemental analysis
found: C, 40.42%; H, 4.12%; calculated: C, 40.30%; H, 4.06%.
◦
l
max(iPrOH–CH3CN, 20 C)/nm (e, M-1 cm-1) 225 (59 000), 275
(34 200), 280 (31 700), and 320 (7520). IR: nmax/cm-1 3067 (CH),
2964, 2930, 2871(CH), 1623, 1595(conj. CC). 1H NMR(300MHz,
CDCl3, 20 ◦C) d 8.43 (d, 2H, H7,13), 7.93 (s, 2H, H6,13), 7.83 (d,
2H, H9,10), 4.50 (m, 2H, H3,15), 2.06 (m, 2H, H2), 1.88 (m, 2H,
H17), 1.57 (d, 6H, H4,16), 1.03 (t, 6H, H1,18) (see Scheme 4 for
NMR numbering scheme).
Notes and references
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7480 | Dalton Trans., 2009, 7473–7480
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The Royal Society of Chemistry 2009
©