Heteronuclear NMR Spectroscopic Investigations of Gallium Complexes of Substituted Thiosemicarbazones Including X-Ray Crystal Structure, a New Halogen Exchange Strategy, and 18F Radiolabelling

Article abstract of DOI:10.1071/CH16044

Five thiosemicarbazone ligands have been synthesized, and their coordination chemistry with gallium was investigated. The reaction of these thiosemicarbazones with gallium chloride in alcohol solutions in the presence of a base yielded the corresponding p

Full text of DOI:10.1071/CH16044

CSIRO PUBLISHING
Aust. J. Chem. 2016, 69, 1033–1048
Full Paper
http://dx.doi.org/10.1071/CH16044
Heteronuclear NMR Spectroscopic Investigations of
Gallium Complexes of Substituted Thiosemicarbazones
Including X-Ray Crystal Structure, a New Halogen
Exchange Strategy, and 18F Radiolabelling
A C
,
A
B
T. K. Venkatachalam,
G. K. Pierens, Paul. V. Bernhardt,
A
A
A
A
D. H. R. Stimson, R. Bhalla, L. Lambert, and D. C. Reutens
A
Centre for Advanced Imaging, The University of Queensland, Brisbane,
Queensland 4072, Australia.
B
School of Chemistry and Molecular Biosciences, The University of Queensland,
Brisbane, Queensland 4072, Australia.
C
Corresponding author. Email: t.venkatachalam@uq.edu.au
Five thiosemicarbazone ligands have been synthesized, and their coordination chemistry with gallium was investigated.
The reaction of these thiosemicarbazones with gallium chloride in alcohol solutions in the presence of a base yielded the
corresponding penta-coordinated Ga-Cl metal complexes. In contrast, the reaction of gallium nitrate with the ligands in
the presence of alkoxides resulted in the formation of the corresponding Ga-alkoxides, rather than the anticipated
Ga-nitrate complex. The crystal structures of gallium chloride and gallium methoxide complexes of diphenylthiosemi-
carbazone comprise a planar configuration of the tetradentate-coordinated thiosemicarbazone with Ga3þ ion, with the
chloride or methoxide groups occupying the apical coordination site. The corresponding ethoxido complex was also
prepared in an identical fashion, and NMR analysis confirmed structural similarity to the methoxido complex. Facile
halogen exchange reactions of the gallium chloride complexes were achieved by treatment with silver nitrate, followed by
addition of KF or KI to generate the gallium fluoride and iodide complexes, respectively. This method of exchange using
halogenated inorganic salts aids the preparation of group 13 fluorides, which are notoriously insoluble in organic solvents,
for complexation with organic ligands. All compounds have been fully characterized by NMR, and the X-ray crystal
structures of two of the complexes are reported. Additionally, the positron-emitting isotope 18F was introduced in the
structure of the diphenyl gallium thiosemicarbazone complex.
Manuscript received: 25 January 2016.
Manuscript accepted: 3 March 2016.
Published online: 12 April 2016.
Introduction
explore the potential of exchanging this chloride with other
ligands such as other halogens. Potential applications of
coordination complexes of group 13 metal ions with fluoride
have recently been described. McBride et al. reported the
formation of stable inorganic aluminium complexes with
the radioisotope 18F and highlighted that these provide simple
moieties that can be incorporated in a wide range of bio-
molecules with potential as positron emission tomography
imaging agents.[31–37] Recently, Bhalla et al. have demon-
strated that coordination complexes containing Ga-18F can be
generated from the corresponding chloride complexes by
facile halogen exchange.[38–40]
Here, we describe the preparation and characterization of
several bis-thiosemicarbazone ligands and report the synthesis
of their resulting complexes with Ga3þ, resulting in the forma-
tion of complexes with an N2S2Ga-X core (where X ¼ Cl, I, F,
OMe (methoxy), OEt (ethoxy)). In particular, we demonstrate
that N2S2Ga-Cl complexes can be readily and simply exchanged
with iodide and fluoride.
Thiosemicarbazones are a unique class of versatile compounds
that coordinate various metal ions to form stable complexes
using their S- and N-donor atoms.[1,2] Thiosemicarbazones can
form a ‘masked thiolate’ precursor, which facilitates their ability
to coordinate a variety of 3d transition metal ions.[3–7] CuII and
GaIII complexes with thiosemicarbazones have been prepared in
light of their biological activity, and the coordination of metal
ions has been demonstrated to increase the cytotoxicity of
tridendate thiosemicarbazones.[8–20] Copper complexes of
pyridine derivatives of thiosemicarbazones also show improved
biological activity compared with the parent ligand.[21] The
radio-metal complexes (most notably 64Cu) of these ligands
have been investigated for their applications in molecular
imaging agents.[22–27] Pascu et al.[28–30] have synthesized a
series of 68Ga complexes of bis-thiosemicarbazones to evaluate
their imaging potential and report that the reaction of GaCl3 with
these ligands results in the formation of a square-based pyra-
midal mono-chloride metal complex. This prompted us to
Journal compilation ꢀ CSIRO 2016
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1034
T. K. Venkatachalam et al.
Experimental
2. Yield, 2.4 g. dH (d6-DMSO) 10.20 (2H, br s), 8.39 (2H,
br s), 7.84 (2H, br s), 2.13 (6H, s). dC (d6-DMSO) 178.9, 148.3,
11.6. dN (d6-DMSO) 110.8 (NH2), 168.3 (NH), 317.6 (C=N).
3. Yield, 4.98 g. dH (d6-DMSO) 10.32 (2H, br s), 8.36 (2H,
br s), 7.73 (2H, br s), 2.79 (4H, q, J 7.4), 0.87 (6H, t, J 7.4). dN
(d6-DMSO) 111.0 (NH2), 166.0 (NH), 313.5 (C=N).
4. Yield, 4.5 g. nmax (KBr)/cmꢀ1 3417, 3203, 3149, 2984,
1598, 1506, 1446, 1365, 1289, 1243, 1154, 1085, 1057, 987, 865,
841, 792. dH (d6-DMSO)10.33 (1H, s), 10.20(1H, s), 8.40 (1H, s),
8.39 (1H, s), 7.82 (1H, s), 7.74 (1H, s), 2.84 (2H, q), 2.14 (3H, s),
0.89(3H, t). dC (d6-DMSO)178.9, 178.8, 152.2, 147.3, 16.9, 11.7,
11.0. dN (d6-DMSO) 317.2, 315.7, 167.8, 165.9, 110.8, 110.2.
5. Yield, 6.8 g. nmax (KBr/cmꢀ1 3415, 3226, 3136, 2950,
1584, 1474, 1442, 1240, 1133, 1069, 1005, 922, 906, 865, 828,
763. dH (d6-DMSO) 9.84 (2H, br s), 8.67 (2H, br s), 8.38 (2H,
br s), 7.72 (4H, m), 7.43–7.38 (6H, m). dC (d6-DMSO) 179.1,
140.5, 133.1, 130.2, 128.4, 126.7. dN (d6-DMSO) 167.8, 113.8.
All chemicals were obtained from Sigma-Aldrich and were used
without further purification. NMR spectra were recorded in
dimethyl sulfoxide (d6-DMSO), and the chemical shifts were
referenced to DMSO (proton: 2.5 ppm and carbon: 39.5 ppm).
The NMR data were acquired on a Bruker 900 MHz NMR
spectrometer equipped with a cryoprobe. The proton spectra
were acquired with a sweep width of 18 ppm centred at 7 ppm.
The carbon spectra were acquired with a sweep width of
220 ppm centred at 110 ppm. The COSY experiments were
acquired with a sweep width of 18 ppm using a 908 pulse of 9 ms
with 256 increments. The 13C HSQC spectrum was acquired
with sweep widths of 18 and 160 ppm for proton and carbon,
respectively, and the carbon centred at 80 ppm. HMBC spectral
data were acquired to establish the structures of the compounds
(13C sweep width of 220 ppm). The 15N spectra were acquired
using a sweep width of 400 ppm. The raw data were typically
multiplied by an exponential or shifted sine-squared function
before performing the Fourier transform. The 71Ga NMR
spectrum was acquired on a 500 MHz Bruker NMR machine
with 350 ppm sweep width. Ga (NO3)3 in D2O was used as a
standard at 0 ppm before running the sample spectrum.
Synthesis of Gallium Complexes
Thiosemicarbazone-Gallium Chloride Complex (6)
A suspension of thiosemicarbazone (1.23 g, 5 mmol) in
methanol (40 mL) was added to a round-bottom flask and the
contents were stirred. Sodium methoxide solid (0.540 g,
10 mmol) was introduced, resulting in a yellow solution. After
10 min of stirring, gallium chloride 0.845 g (5 mmol) was added,
resulting in an exothermic reaction and the solution turned to a
deep orange colour. The contents were refluxed for 8 h, and the
mixture was cooled to room temperature. The product, which
precipitated out as an orange solid during the reaction, was filtered
and washed with methanol (1.44 g, 82 %). nmax (KBr)/cmꢀ1 3444,
3402, 3365, 3293, 3171, 1622, 1599, 1580, 1549, 1484, 1465,
1325, 1302, 1243, 1220, 1187, 1144, 1056, 1021, 997, 942, 848,
793. dH (d6-DMSO) 8.00 (1H, br s), 7.97 (1H, s), 2.77 (2H, q), 2.35
(3H, s), 1.08 (3H, t). dC (d6-DMSO) 173.9, 173.6, 148.2, 143.8,
21.0,14.2, 10.0. dN (d6-DMSO) 251.2, 249.5, 103.7, 103.4. m/z
(electron impact (EI)) 351 (Mþ), 315 (M – HCl).
X-Ray Crystal Structure Determination
X-ray quality single crystals were obtained by slow diffusion of
ether into tetrahydrofuran solution. Crystallographic data were
acquired at 190 K on an Oxford Diffraction Gemini CCD
diffractometer employing graphite-monochromated Cu Ka
˚
˚
radiation (1.5418 A) and operating within the range 2 A , 2y
˚
, 125 A. Temperature control was achieved with an Oxford
Cryosystems Desktop Cooler. Data reduction and empirical
absorption corrections (multiscan) were performed with Oxford
Diffraction CrysAlisPro software. The structure was solved
by direct methods with SHELXS and refined by full-matrix
least-squares analysis with SHELXL-97[41] within the WinGX
graphical user interface.[42] All non-H atoms were refined with
anisotropic thermal parameters. The molecular structure dia-
gram was produced with ORTEP-3.[43] The data in CIF format
have been deposited for the gallium chloride and methoxide
complexes, respectively, with deposition numbers CCDC
1410428 and 1410429. The data can be obtained from the
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; Fax: þ44 1223 336033; Email:
deposit@ccdc.cam.ac.uk or from http://www.ccdc.cam.ac.uk/
products/csd/request.
Diphenylthiosemicarbazone Gallium Chloride
Complex (7, C1)
The method as that employed to prepare compound 6 was
used. Yield: 1.98 g, 86 %. nmax (KBr)/cmꢀ1 3447, 3326, 3273,
3067, 1627, 1582, 1521, 1493, 1462, 1428, 1335, 1315, 1288,
1273, 1210, 1166, 1105, 1069, 1051, 1025, 1001, 981, 887, 783.
Table 1. Structures of thiosemicarbazones ligands 1–5
General Synthetic Procedure
Thiosemicarbazone
R1
N
R2
N
Concentrated hydrochloric (2 mL) was added to a flask
containing glyoxal (1.16 g, 20 mmol) and methanol (50 mL).
The mixture was stirred at room temperature to form a homoge-
nous solution. To this mixture, a solution of thiosemicarbazide
(3.6 g, 40 mmol) dissolved in methanol containing 2 N hydro-
chloric acid was added, and the contents stirred at room
temperature for 3 days, resulting in the formation of a white
precipitate. The precipitated thiosemicarbazone was filtered,
washed with methanol, and dried under vacuum.
All thiosemicarbazones 1–5 were synthesized using the
above experimental procedure.
1. Yield, 2.15 g. dH (d6-DMSO) 11.67 (2H, br s), 8.30 (2H, br
s), 7.87 (2H, br s), 7.71 (2H, s). dC (d6-DMSO) 178.1, 140.6. dN
(d6-DMSO) 110.3 (NH2), 175.5 (NH).
NH HN
NH2
H2N
S
S
Compound no.
R1
H
R2
1
2
3
4
5
H
CH3
CH3
CH3CH2
CH3
CH3CH2
CH3CH2
Ph
Ph

Spectroscopic Investigations of Gallium Complexes
1035
dH (d6-DMSO) 8.14 (4H, br s), 7.26 (6H, m), 7.18 (4H, m).
dC (d6-DMSO) 174.8, 142.7, 131.8, 129.5, 129.1, 127.7. dN
(d6-DMSO) 304.5, 253.7, 107.9. m/z (EI) 461 (Mþ).
in an exothermic reaction and the solution turned to a deep orange
colour. The contents were refluxed for 8 h, and the mixture was
cooled to room temperature. The product, which precipitated out
as an orange red solid during the reaction, was filtered and washed
with methanol. (Note: the methoxide complex in d6-DMSO
showed multiple peaks for the elimination of methanol (MeOH)
from the coordinating complex, see X-ray data for further details.)
dH(d6-DMSO)8.0–7.18(10H,m),4.10–4.07(q,MeOH,hydrogen-
bonded), 3.36–3.31 (d, MeO hydrogen-bonded to MeOH), 3.17–
3.16 (3H, d, hydrogen-bonded MeOH). dC (d6-DMSO) 175.9,
143.2, 132.0, 129.5, 128.7, 127.6, 127.5, 127.2, 51.6, 48.6.
Diphenylthiosemicarbazone Gallium Methoxide
Complex (8, C2)
A suspension of thiosemicarbazone (0.445 g, 1.25 mmol) in
methanol (40 mL) was added to a round-bottom flask and the
contents were stirred. Sodium methoxide solid (0.270 g, 5 mmol)
was introduced, resulting in a deep yellow solution. After 10 min
of stirring, gallium nitrate 0.32 g (1.25 mmol) was added, resulting
R1
R2
R1
R2
O
NH2NHCSNH2
EtOH/HCl
N
N
NH HN
O
H2N
NH2
S
S
MeONa
Reflux
MeOH
GaCl3
R1
N
R2
N
N
N
Ga
Cl
NH2
H2N
S
S
R
1 ϭ H, Me, Ph; R2 ϭ H, Me, Et, Ph.
Scheme 1. Synthesis of gallium complexes of thiosemicarbazones with ligands 2–4.
(b)
(a)
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
f1 [ppm]
Fig. 1. 1H NMR spectra of (a) unsymmetrical thiosemicarbazone (ligand 4) and (b) gallium-complexed thiosemicarbazone
(compound 6) in d6-DMSO.

1036
T. K. Venkatachalam et al.
Diphenylthiosemicarbazone Gallium Ethoxide
Complex (9)
30 min, resulting in the formation of an orange solution and
precipitation of silver chloride. The contents were allowed to
settle, and the orange supernatant was transferred to another vial.
To this solution-containing vial was added, with stirring, potas-
sium fluoride (0.0058g, 0.1 mmol), resulting in a deep red
solution. The contents were stirred for 10min at room tempera-
ture, and the solvent was evaporated to obtain an orange-red
residue (0.021 g, 47.7 %). An NMR spectrum of the product
revealed the formation of a fluoride complex. dH (d6-DMSO)
8.07–7.15 (10H, m), 4.10–4.09 (t, MeOH, hydrogen-bonded with
F), 3.17–3.16 (d, MeO hydrogen-bonded). dC (d6-DMSO) 175.6,
141.0, 132.2, 131.9, 129.1, 127.8, 48.7. dF (d6-DMSO) –93.7
(relative to TFA 1 % standard capillary insert standard at 0 ppm).
The method as that employed to prepare compound 8 was
used. dH (d6-DMSO) (note: the ethoxide complex in d6-DMSO
showed multiple peaks for the elimination of ethanol (EtOH)
from the coordinating complex) 7.6–7.0 (10H, m), 4.32 (EtOH,
OH), 3.55 (q, EtOH), 3.44 (q, EtO), 1.24 (t, CH3CH2OH), 1.04
(3H, t, EtO). dC (d6-DMSO) 181.2, 142.8, 141.8, 137.7, 133–
126.0 (multiple peaks), 58.7 (EtO), 56.02 (EtOH), 18.6 (EtO),
14.9 (EtOH).
Halogen Exchange Reactions
Diphenylthiosemicarbazone Gallium Fluoride (10)
Diphenylthiosemicarbazone gallium chloride 7 (0. 0459 g,
0.1 mmol) was suspended in methanol (15 mL) in a 20-mL vial.
The blood red suspension was stirred for 10 min followed by the
addition of silver nitrate (0.017 g, 0.1 mmol), and the contents
were shaken initially for 2 min and then vigorously stirred for
Diphenylthiosemicarbazone Gallium Iodide (11)
The method as that employed to prepare compound 10 was
used except that potassium iodide was used instead. Yield:
0.033 g, 61.0 %. dH (d6-DMSO) 8.07 (br s), 7.15–7.28 (m, Ar),
4.10 (br s, MeO hydrogen-bonded), 3.16 (s, MeO). dC (d6-DMSO)
175.8, 141.2, 131.9, 129.5, 127.8, 48.6.
H3C
N
CH2CH3
Cold Thin Layer Chromatography Determination
of Formation of Ga-F Complex
N
After preparation of the complex using the exchange method,
the Ga-F complex was spotted on a thin layer chromatography
silica gel plate and eluted with 10 % ammonium acetate/MeOH
(1 : 1) and the observed RF value of the product was 0.86. The
chloro compound and the iodo compound of the gallium
complex showed an RF value very similar to that obtained for the
gallium fluoride complex. However, the NMR spectroscopy
showed the 19F NMR signal for the fluoro compound and was
absent for the other two compounds, thus confirming the
formation of the fluoro compound.
NH HN
H2N
NH2
S
S
(Dashed line depicting the asymmetry of ligand 4)
Chart 1.
(b)
(a)
180 170 160 150 140 130 120 110 100
90
80
70
60
50
40
30
20
10
f1 [ppm]
Fig. 2. 13C NMR spectra of (a) unsymmetrical thiosemicarbazone (ligand 4) and (b) gallium-complexed thiosemicarbazone
(compound 6) in d6-DMSO.

Spectroscopic Investigations of Gallium Complexes
1037
Production of Fluorine-18
enriched to .98 % H218O was irradiated with 18 MeV protons
at a beam current of 14 mA for 8 min to produce 4.5 GBq of
fluorine-18. The aqueous [18F] fluoride was transferred from
the cyclotron target to a 10-mL glass-receiving vial located in
No-carrier-added fluorine-18 was manufactured via the
18O (p,n)18F nuclear reaction using a Cycloneꢁ 18 Twin (IBA,
Belgium) dual ion source cyclotron. Pure water (,0.7 mL)
(b)
(a)
10.2 10.0 9.8 9.6 9.4 9.2 9.0 8.8 8.6 8.4 8.2 8.0 7.8 7.6 7.4 7.2 7.0 6.8 6.6
f1 [ppm]
Fig. 3. 1H NMR of (a) diphenylthiosemicarbazone (ligand 5) and (b) gallium-complexed diphenylthiosemicarbazone (compound 7) in
d6-DMSO.
270
265
260
255
250
245
240
235
230
225
f1 [ppm]
Fig. 4. 71Ga NMR spectrum of the diphenylthiosemicarbazone gallium chloride (compound 7) in d6-DMSO.
Ph
N
Ph
N
H3C
N
CH2CH3
N
N
N
N
N
Ga
Cl
Ga
Cl
NH2
NH2
H2N
H2N
S
S
S
S
Chart 2.

1038
T. K. Venkatachalam et al.
Table 2. Crystal data and structure refinement for gallium complexes of diphenylthiosemicarbazone
Identification code
C1
C2
Empirical formula
Formula weight
Temperature [K]
C16H14ClGaN6S2
459.62
C18H21GaN6O2S2
487.25
190(2)
190(2)
˚
Wavelength [A]
1.54180
Triclinic
P 1
1.54184
Crystal system
Space group
Monoclinic
P 21/n
˚
˚
Unit cell dimensions
a ¼ 8.0530(7) A
a ¼ 83.241(8)8
b ¼ 73.961(8)8
g ¼ 69.217(9)8
a ¼ 12.721(2) A
˚
˚
b ¼ 11.2761(11) A
b ¼ 10.1135(9) A
b ¼ 106.71(1)8
˚
˚
c ¼ 11.4160(10) A
c ¼ 17.297(2) A
3
˚
Volume [A ]
931.24(15)
2
2131.5(4)
4
Z
Density (calculated) [Mg mꢀ3
]
1.639
1.518
Absorption coefficient [mmꢀ1
]
5.553
3.830
F(000)
Crystal size [mm3]
464
1000
0.2 ꢁ 0.01 ꢁ 0.01
4.03–62.45
0.4 ꢁ 0.2 ꢁ 0.1
3.84–62.49
Theta range for data collection [8]
Index ranges
–8 # h # 9, –12 # k # 12, –13 # l # 13
6311
–14 # h # 14, –7 # k # 11, –19 # l # 19
9215
Reflections collected
Independent reflections
Completeness to theta ¼ 62.458 [%]
Absorption correction
Max. and min. transmission
Refinement method
2920 (Rint ¼ 0.0758)
98.2
3348 (Rint ¼ 0.0553)
98.4
Semi-empirical from equivalents
1 and 0.80489
Full-matrix least-squares on F2
Semi-empirical from equivalents
1 and 0.47098
Full-matrix least-squares on F2
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices (I . 2s(I))
R indices (all data)
2920/0/235
3348/0/265
1.092
1.055
R1 ¼ 0.0448, wR2 ¼ 0.1092
R1 ¼ 0.0675, wR2 ¼ 0.1482
0.622 and –0.874
R1 ¼ 0.0371, wR2 ¼ 0.0931
R1 ¼ 0.0446, wR2 ¼ 0.0988
0.619 and –0.411
ꢀ3
˚
Largest diff. peak and hole [e A
]
˚
Table 3. Selected bond lengths (A) for diphenyl-
CI1
thiosemicarbazone gallium chloride complex
N6
N5
N2–N3
1.370(7)
2.052(4)
1.348(7)
2.042(5)
2.3080(15)
2.3032(15)
2.2345
C4
N4
C3
N3–Ga1
N4–N5
C2
N4–Ga1
S1–Ga1
S2–Ga1
Cl1–Ga1
S2
Ga1
N3
N2
S1
C1
Table 4. Selected bond angles (8) for diphenyl-
thiosemicarbazone gallium chloride complex
N1
C2–N3–Ga1
N2–N3–Ga1
C3–N4–N5
C3–N4–Ga1
N5–N4–Ga1
C4–N5–N4
C1–S1–Ga1
C4–S2–Ga1
N4–Ga1–N3
N4–Ga1–Cl1
N3–Ga1–Cl1
N4–Ga1–S2
N3–Ga1–S2
Cl1–Ga1–S2
N4–Ga1–S1
N3–Ga1–S1
117.1(4)
121.2(4)
120.4(5)
118.3(4)
121.2(4)
112.7(5)
94.41(19)
94.2(2)
Fig. 5. Single-crystal X-ray structure of diphenylthiosemicarbazone
gallium chloride complex (compound 7).
a hot-cell via a 1/1600 diameter ETFE tubing with a length
of ,20 m under helium pressure. The receiving vial was
measured for radioactive content in a dose calibrator housed
within the hot-cell before delivery into a lead pot. The lead pot
was then manually transferred to a fume cabinet where
aliquots of the aqueous [18F] fluoride were taken for
radiolabelling.
76.48(18)
99.02(14)
99.23(13)
83.04(14)
146.55(14)
110.0(6)
149.84(14)
82.47(13)
Radiolabelling
For the radiolabelling experiments, we initially formed the
nitrate complex in situ and then evaporated the solvent methanol

Spectroscopic Investigations of Gallium Complexes
1039
Fig. 6. Crystal packing diagram of diphenyl gallium thiosemicarbazide chloride (compound 7).
b′
b
a′
4.3
4.2
4.1
4.0
3.9
3.8
3.7
3.6
3.5
3.4
3.3
3.2
3.1
3.0
2.9
f1 [ppm]
Fig. 7. 1H NMR spectrum of diphenylthiosemicarbazone gallium methoxide (compound 8) with a molecule of coordinated methanol.
(Note: only the resonance of the region of interest is shown; peaks labelled as a0 and b0 represent a quartet and a doublet, respectively, for
the hydrogen bonding between methoxide and methanol; peak labelled as b represents the doublet peak in the spectrum.)
and redissolved the residue in dimethyl sulfoxide (we found
previously that the fluoride complex is very stable in dimethyl
sulfoxide solvent). The following quantities of reagents were
used to prepare the nitrate complex.
A 20-mL scintillation vial was charged with compound
7 (10 mg), and methanol (4 mL) was added and the contents
were stirred. To this red suspension was added silver nitrate
(4 mg), and the mixture was shaken for 3 min, followed by
stirring at room temperature for 30 min when an orange yellow
solution was obtained and a white precipitate appeared. The
silver chloride precipitate was allowed to settle (5 min) and two
aliquots of 0.5 mL of the above solution were transferred into
two scintillation vials. The solvent was evaporated under
nitrogen atmosphere to yield a dark red residue, which was
immediately dissolved in dimethyl sulfoxide (0.5 mL) to yield
an orange-red solution.
In the meantime, to a 10-mL vial was added potassium
carbonate (0.7 mg), followed by Kryptofix 222 (1.2 mg).
To this mixture was added acetonitrile (200 mL) and
18F aqueous solution (10 mL; 88 MBq). The vial was sealed
and heated on a hot plate under nitrogen atmosphere
and allowed to dry. To this dry mixture was added, using a
syringe, the gallium nitrate complex (0.5 mL), pre-dissolved
in dimethyl sulfoxide. The contents were stirred and heated
for 3 min at 40–508C resulting in a deep red solution of the
18F complex.

1040
T. K. Venkatachalam et al.
48
49
50
51
52
53
3.45
3.40
3.35
3.30
3.25
3.20
3.15
f2 [ppm]
Fig. 8. HSQC spectrum of diphenylthiosemicarbazone gallium methoxide (compound 8) in d6-DMSO.
Ph
Ph
N
Ph
N
Ph
N
N
MeONa
N
N
MeOH
NH HN
Ga
Ga(NO3)3
NH2
NH2
H2N
H2N
S
S
NO3
S
S
(Intermediate compound)
Ph
N
Ph
N
N
.MeOH
N
Ga
NH2
H2N
S
S
OMe
Scheme 2. Formation of diphenylthiosemicarbazone gallium methoxide (compound 8).
HPLC Conditions for Determination of Radiolabelled
Compound
The eluent used for eluting the radiolabelled compound was a
mixture of acetonitrile and 0.1 % TFA/water (90 : 10). The flow
rate was adjusted to 1 mL minꢀ1 and the injection volume was
20 mL. Under these experimental conditions, the radiolabelled
compound eluted at 15.58 min.
HPLC analysis was performed using a Shimadzu LC 20AD
instrument equipped with a diode ray detector, a quaternary
pump, a thermostatic column compartment, and a radio detector
(Bioscan Flow Count with a pin-diode detector) in conjunction
with LCsolutions software computer-operated system. The
analytical column used was a Zorbax ‘Eclipse Plus C18’
(Agilent) of dimensions of 4.6 mm (diameter) ꢁ 150 mm
(length), 5 m (particle size of column material). The temperature
of the column was maintained at room throughout the analysis.
Determination of Partition Coefficient
To determine the liphophilicity of the molecule, a fresh batch of
the fluoride gallium complex was made using the exchange
method, and it was dissolved in an octanol (20 mL)/water
(20 mL) mixture and was stirred vigorously for 15 min. The

Spectroscopic Investigations of Gallium Complexes
1041
O2
O1
N5
N2
N6
N4
N3
Ga1
S2
N1
S1
Fig. 9. Single-crystal X-ray structure of diphenylthiosemicarbazone
gallium methoxide complex (compound 9). (Note: a single methanol
molecule also co-crystallized in the crystal.)
Fig. 10. Crystal packing diagram of the diphenylthiosemicarbazone
gallium methoxide complex (compound 8; C2).
˚
Table 5. Selected bond lengths (A) for diphenylthio-
semicarbazone gallium methoxide complex (C2)
Stability of Gallium Chloride and Fluoride Complexes
The prepared complexes were weighed (10 mg) and water was
added (pH ¼ 6.4) (10 mL), and the resulting mixture was stirred
for 30 min. The compounds did not go into the solution. To
further test the stability, the compounds were dissolved in
dimethyl sulfoxide and left to stand undisturbed for 3 weeks,
and 1H NMR analysis showed no decomposition, thus demon-
strating the stability of these complexes.
N2–N3
N3–Ga1
N4–N5
N4–Ga1
O1–Ga1
S1–Ga1
S2–Ga1
1.374(3)
2.083(2)
1.366(3)
2.075(2)
1.829(2)
2.2990(8)
2.3168(7)
Results and Discussion
Five thiosemicarbazone ligands have been synthesized by the
reaction of thiosemicarbazide with glyoxal and substituted
diones. All ligands were prepared and have been fully charac-
terized (Table 1).
Table 6. Selected bond angles (8) for diphenylthiosemi-
carbazone gallium methoxide complex (C2)
C2–N3–Ga1
N2–N3–Ga1
C3–N4–N5
C3–N4–Ga1
N5–N4–Ga1
C4–N5–N4
C22–O1–Ga1
C1–S1–Ga1
C4–S2–Ga1
O1–Ga1–N4
O1–Ga1–N3
N4–Ga1–N3
O1–Ga1–S1
N4–Ga1–S1
N3–Ga1–S1
O1–Ga1–S2
N4–Ga1–S2
N3–Ga1–S2
S1–Ga1–S2
116.78(17)
120.89(16)
122.2(2)
Gallium Chloride Complexes
The synthesis of gallium chloride complexes of the thiosemi-
carbazones is summarized in Scheme 1. The synthesis involved
treating the thiosemicarbazone ligands (2–4) with sodium
methoxide, followed by reaction with gallium chloride. All
gallium complexes were obtained in high yield. Surprisingly, we
were unable to form the gallium chloride complex of ligand 1.
The NMR spectra of the methyl-substituted symmetrical
ligand 2 (Table 1) showed the methyl and NH2 resonances as
expected for the structure. The symmetrical diphenylthiosemi-
carbazone ligand displays four distinct singlets corresponding to
the NH and NH2 protons (see Fig. 1) on one side of the
thiosemicarbazone structure as illustrated below (Chart 1).
13C NMR spectra obtained using a 500 MHz instrument
showed only one peak at 178.9 ppm for the C=S carbon.
However, at higher field (900 MHz), the improved resolution
allows us to observe peaks at 178.8 and 178.9 ppm, demon-
strating that we have synthesized an unsymmetrical molecule,
with distinct peaks corresponding to the methyl-substituted arm
and the ethyl-substituted arm of the molecule. Examination of
the 15N spectra using both 15N HSQC and 15N HMBC revealed
chemical shift values at 317.9 and 315.7 ppm, representing the
C=N nitrogens, 167.8 and 165.9 ppm, representing the NH
nitrogen, and peaks at 110.8 and 110.2 ppm, indicating the
presence of the two NH2 groups in the structure of the molecule.
116.27(17)
120.54(17)
113.1(2)
119.90(19)
95.03(9)
94.73(9)
104.13(9)
98.91(9)
76.33(9)
111.92(7)
139.82(7)
81.04(6)
103.51(7)
82.28(6)
152.14(7)
105.21(3)
resulting layers were separated and analyzed using a UV spec-
trometer. The ratio of the UV absorbance at 475 nm for each of
the layers was used to determine the partition coefficient value.
The aqueous solution after storing for 48 h still showed no
significant decomposition, as determined by its UV spectral
characteristics.

1042
T. K. Venkatachalam et al.
b
b′
a
a′
a′
3.5
3.0
2.5
2.0
1.5
1.0
f1 [ppm]
Fig. 11. 1H NMR spectrum of diphenylthiosemicarbazone gallium methoxide (compound 9) in d6-DMSO (only resonances in
the region of interest are shown; peaks labelled a and b represent a quartet and a triplet, respectively, corresponding to ethanol,
whereas peaks labelled a0 and b0 can be ascribed to the ethoxide-coordinated gallium complex). (Note:the multiplicity of the signal
shows a pentet due to hydrogen bond formation between the ethoxide and ethanol.)
10
20
30
40
50
60
4.0
3.5
3.0
2.5
2.0
1.5
1.0
f2 [ppm]
Fig. 12. HSQC spectrum of diphenylthiosemicarbazone gallium ethoxide (compound 9) in d6-DMSO showing the
coordination of a molecule of ethanol (only resonances for the region of interest are shown).
The gallium chloride complex of ligand 4 showed two
15N NMR spectra showed peaks at 251.2 and 249.5 ppm,
corresponding to N=C and peaks at 103.7 and 103.4 ppm,
representing the NH2 protons in the gallium complex. We were
unable to obtain the 15N NMR of the C=N nitrogens despite
several hours of data acquisition. The NMR data provide clear
evidence that the gallium complex showed considerable
singlets very close to each other for the NH2 protons in each
side of the molecule. However, no NH protons of the free ligand
were observed, confirming coordination of gallium to the ligand
as described in Scheme 1. The 13C NMR spectrum showed C–S
signals at 173.9 and 173.6 ppm, respectively (Fig. 2). The

Spectroscopic Investigations of Gallium Complexes
1043
Ph
N
Ph
N
Ph
O
Ph
O
NH2NHCSNH2
EtOH/HCl
NH HN
NH2
H2N
S
S
MeONa
MeOH
GaCl3
Reflux
Ph
N
Ph
N
N
N
Ga
NH2
H2N
S
S
Cl
MeOH/RT/10–15 min
AgNO3
Ph
Ph
N
Ph
N
Ph
N
Filter
N
N
N
N
N
KF (solid)
Ga
F
Ga
NH2
NH2
H2N
H2N
S
S
S
S
NO3
1H ,13C, 19F NMR confirmation of fluorine
KI
NaCl
Ph
N
Ph
Ph
N
Ph
N
N
N
N
N
N
Ga
I
Ga
Cl
NH2
H2N
NH2
S
S
H2N
S
S
Scheme 3. Exchange reactions involving the preparation of fluoro/iodo/chloro diphenylthiosemicarbazone
gallium complexes using silver nitrate in methanol. RT, room temperature.
1 % TFA
0
Ϫ10
Ϫ20
Ϫ30
Ϫ40
Ϫ50
Ϫ60
Ϫ70
Ϫ80
Ϫ90
Ϫ100
1H [ppm]
Fig. 13. 19F NMR spectrum of diphenylthiosemicarbazone gallium fluoride complex (compound 10) after exchange
reaction in DMSO solvent (1 % TFA was used in the capillary as reference standard).

1044
T. K. Venkatachalam et al.
Ph
N
Ph
N
Ph
N
Ph
N
MeOH/RT/10–15 min
AgNO3
N
N
N
N
Ga
Cl
Ga
NH2
H2N
NH2
H2N
S
S
S
S
NO3
KI
Ph
Ph
Ph
N
Ph
N
N
N
AgNO3
N
N
Ga
NO3
N
N
NH2
H2N
S
S
Ga
I
NH2
H2N
S
S
NaCl
Ph
N
Ph
N
N
N
Ga
Cl
NH2
H2N
S
S
Scheme 4. Reversible cycle exchange of halogen in gallium thiosemicarbazone structural core.
Ph
N
Ph
N
Ph
N
Ph
N
AgNO3
MeOH
N
N
N
N
Ga
Cl
Ga
NH2
NH2
H2N
H2N
S
S
S
S
NO3
K2CO3/Kryptofix 222/18F/ACN/H2O
(dry residue)
DMSO
Ph
Ph
N
N
N
N
Ga
18F
Scheme 5. Radiolabelling of gallium-18F thiosemicarbazone complex. ACN, acetonitrile.
NH2
H2N
S
S
difference in their chemical shifts when compared with the
starting thiosemicarbazone, confirming complex formation as
depicted in Scheme 1. Additional evidence for the presence of
gallium in the complex was obtained using 71Ga NMR, which
showed a broad peak at 248.7 ppm after 7 h of NMR data
acquisition.
The proton NMR of diphenyl-substituted thiosemicarbazone
5 (Fig. 3) shows three singlets with an integral ratio of 2 : 2 : 2,
indicating two protons on each of the peaks. The most downfield
broad singlet was assigned to one of the NH2 groups, the next
singlet was assigned to NH group protons, and the final singlet
was assigned to the other NH2 protons. 13C NMR showed the
C–S signal at 179.1 ppm as a singlet, indicative of a symmetrical
compound (without the different chemical shift values observed
in the unsymmetrical compound 4. For this compound,
15N NMR revealed two nitrogens i.e. one corresponding to the
NH group at 167.8 ppm and the other corresponding to the NH2
group at 113.9 ppm. We were unable to detect the signal for the
third nitrogen atom associated with C=N of the phenyl group
attached moiety in the molecule.

Spectroscopic Investigations of Gallium Complexes
1045
80
70
60
50
40
30
20
10
0
0
2.5
5.0
7.5
10.0
12.5
15.0
17.5
20.0
22.5
25.0
[min]
Fig. 14. Radio HPLC of diphenylthiosemicarbazone gallium fluoride (18F).
2000
1750
1500
1250
1000
750
500
250
0
0
2.5
5.0
7.5
10.0
12.5
15.0
17.5
20.0
22.5
25.0
[min]
Fig. 15. HPLC of thiosemicarbazone gallium fluoride complex (UV trace).
1
The H NMR chemical shifts for the diphenylthiosemicar-
bazone gallium chloride complex revealed a broad singlet at
8.14 ppm, corresponding to the NH2 protons followed by two
multiplets at 7.26 and 7.18 ppm, respectively, for the phenyl
protons of the molecule (Fig. 3). These are due to the symmetri-
cal nature of the compound. The 13C NMR spectra showed a
sharp peak at 174.8 ppm, which was assigned to the C–S carbon.
This carbon was shifted upfield by 4 ppm relative to the signal
generated by the staring thiosemicarbazone (179.1 ppm),
demonstrating the coordination of gallium in the structure.
There were five peaks corresponding to the five carbons in the
structure of the molecule. 15N spectra showed three nitrogen
peaks at 107.9 ppm assigned to NH2, 253.7 ppm assigned to
N=C, and the third at 304.5 ppm assigned to the C=N group. The
NH group showed a marked downfield shift in the gallium
complex relative to the starting thiosemicarbazone (253.7 ppm
versus 167.8 ppm). 71Ga NMR was used to confirm the presence
of gallium in the complex. A sharp peak at 248.8 ppm was
observed in the gallium NMR spectrum of the compound in
d6-DMSO (Fig. 4). This chemical shift value is consistent with
previous studies on metallopolymers by Mejia et al.[44] in which
gallium complexes showed a sharp signal at 248 ppm for one
compound and 250 ppm for another compound. Based on the
NMR results, we assign the structures for the gallium complexes
of the unsymmetrical-substituted compound 3 and the diphenyl-
substituted compound 5 as shown in Chart 2.
The crystal parameters, including the size and other physical
characteristics, are shown in Table 2. The gallium ion has a square
pyramidal geometry, and the chloride atom occupies the apex
of the coordination sphere (Fig. 5). The crystal structure showed

1046
T. K. Venkatachalam et al.
that one of the phenyl rings is slightly twisted relative to
the other phenyl ring, and the sulfur atoms of the thiosemicar-
bazone moiety are coordinated. The lengths and angles of
selective bonds are presented in Tables 3 and 4. The Ga–Cl
bond is slightly longer than the Ga–S bond. Cheng et al.[45]
reported the Ga–Cl bond distance in several diphosphane and
diphenylthiosemicarbazone was reacted with gallium nitrate in
the presence of sodium ethoxide in ethanol. The 1H NMR
spectrum of the resultant product in DMSO confirmed forma-
tion of the ethoxide complex with the gallium as two sets of
quartets and triplets were present (see Fig. 11). Ethanol coordi-
nation was also observed with two additional sets of quartets and
triplets. The 13C NMR spectra also confirmed the ethoxide
coordination to gallium along with a molecule of ethanol.
The HSQC spectra (Fig. 12) showed the correlation between
the coordinated ethoxide with a molecule of ethanol.
˚
diarsane complexes to be 2.3585 A, as consistent with the value
obtained in our study. The two amino arms were located in the
opposite direction of the plane of the molecule. The crystal
packing diagram for compound 7 is shown in Fig. 6. The crystal
packing diagram shows absence of p–p stacking of the
phenyl rings in the structure of the gallium complex molecule.
Gallium Fluoride and Iodide Complexes
Attempts to synthesize the gallium fluoride via direct reaction of
the thiosemicarbazone with GaF3ꢂ3H2O proved difficult due to
the poor solubility of the inorganic gallium starting material. As
we had synthesized the gallium chloride complexes, we inves-
tigated the possibility of direct exchange of the Cl with F by
reacting the chloride complex with potassium fluoride. Though
NMR suggested that some exchange had occurred, the incor-
poration of fluoride was low. As a consequence, we developed
an alternative approach where we have been able to use the pre-
formed gallium chloride complexes of our thiosemicarbazone
ligands successfully from the desired fluoride complexes simply
and in high yields. Scheme 3 summarize these reactions.
The first step involves reaction of the chloride complex
with an equimolar quantity of silver nitrate in methanol upon
which the solution immediately changed from red to orange with
precipitation of silver chloride. The solution was filtered and
potassium fluoride was added and stirred at room temperature
for 10 min, yielding a red solution, which was evaporated under
nitrogen to yield an orange red residue. This was dissolved in
d6-dimethyl sulfoxide. The NMR spectrum in d6-DMSO indi-
cated formation of the fluoride complex. The 19F NMR showed a
strong peak indicating complex formation (Fig. 13).
To confirm that the exchange reaction occurring using this
halogen exchange method had broader utility, we formed the
nitrate compound in situ and then successfully regenerated the
chloride complex in moderate yield by the addition of sodium
chloride (instead of potassium fluoride, Scheme 4). Similar
nitrate-mediated exchange reactions yielded the formation of
the iodide derivatives in moderate yield. Thus, we have devel-
oped a method that can facilitate the synthesis of fluoro- and
iodo-complexes from the chloride analogues. This strategy may
be useful as a method of labelling group 13 metals with 18F.
Gallium Alkoxide Complexes
Attempts to isolate the gallium nitrate complexes by reacting the
deprotonated thiosemicarbazone ligands with Ga(NO3)3 in
methanol proved unsuccessful. In fact, this reaction yielded the
Ga-OMe complex. For the diphenyl thiosemicarbazone, the
proton NMR spectrum showed the expected aromatic peaks in
the region of 7.1–8.0 ppm (as observed for the analogous
gallium chloride complex). We also observed a quartet centred
at 4.08 ppm and a doublet centred at 3.165 ppm (Fig. 7). The
quartet is due to the hydrogen bond between the methoxide and
another molecule of methanol. In keeping with this, the methyl
group showed a doublet. The 13C NMR spectrum showed two
peaks at 51.56 and 48.56 ppm, corresponding to the methoxide
and methanol. Furthermore, the 13C NMR indicated the pres-
ence of two types of MeO group in the product. The HSQC
spectra (Fig. 8) revealed a correlation between the coordinated
methoxide and the free methanol, demonstrating the presence of
a molecule of methanol in the solid state. A single-crystal X-ray
diffraction study confirmed the observation of the NMR studies,
showing the presence of a gallium-methoxide complex. The
formation of the gallium-methoxide complex may be explained
by the presence of the sodium methoxide, a base used to
deprotonate the ligand, which may have exchanged with a
nitrate ion of the gallium-nitrate complex initially formed in the
reaction. We propose the following reaction mechanism for the
formation of the methoxide complex (Scheme 2).
The gallium nitrate complex has subsequently been synthe-
sized in the absence of methoxide. NMR studies have demon-
strated that this gallium nitrate complex is less stable in
d6-DMSO.
The X-ray crystal structure of the gallium methoxide com-
plex showed that additional methanol forms hydrogen bonds
with the methoxide in the structure. Hence, two methoxy signals
would be expected in the NMR spectrum and that is consistent
with the results obtained. The crystal parameters are presented in
Table 2. Fig. 9 shows the X-ray crystal structure of the
compound. The bond lengths and angles are shown in Tables
5 and 6, respectively, for this complex.
The crystal packing diagram for the methoxide complex is
shown in Fig. 10. It is evident from the packing diagram that the
methanol coordination with the methoxide of the complex forms
infinite hydrogen bonds in the crystal lattice as expected.
However, a closer look at the packing diagram reveals the
absence of p–p stacking effect in this compound. This observa-
tion is consistent with the results obtained for the chloride
complex C1.
Radiochemistry of the Gallium Chloride Complex
Based on the successful strategy, treatment of the gallium nitrate
formed in situ in methanol medium with 18F/H2O, obtained
directly from the cyclotron, did not furnish the required labelled
compound. Repeated trials did not show any radiolabelling
effects despite changing the temperature or ratio of reactants.
Addition of potassium fluoride in methanol medium also did not
yield the required labelled compound. These unsuccessful
attempts could be rationalized owing to pH changes in the
medium. However, adjustment of the pH with buffers also failed
to yield the required compound. Finally, the radiolabelling of the
thiosemicarbazone gallium chloride complex was performed
following Scheme 5 shown below. In brief, the precursor was
treated with silver nitrate in methanol medium to furnish the
nitrate in situ, followed by the reaction of K18F in dimethyl
sulfoxide to yield finally the Ga-18F thiosemicarbazone com-
plex as a red solution. The complete details of the reaction
Similarly, we have been able to generate the ethoxide
analogue by preparation of the gallium complex using sodium
ethoxide instead of sodium methoxide. In a typical synthesis, the

Spectroscopic Investigations of Gallium Complexes
1047
conditions and the yield are described in the experimental
section.
[3] M. Campbell, Coord. Chem. Rev. 1975, 15, 279. doi:10.1016/S0010-
8545(00)80276-3
[4] T. Lobana, R. Sharma, G. Bawa, S. Khanna, Coord. Chem. Rev. 2009,
253, 977. doi:10.1016/J.CCR.2008.07.004
[5] D. X. West, A. Liberta, S. Padhye, R. Chikate, P. Sonawane, A.
Khumbar, R. Yerande, Coord. Chem. Rev. 1993, 123, 49. doi:10.1016/
0010-8545(93)85052-6
[6] S. Turk, C. Shipman, J. Drach, J. Gen. Virol. 1986, 67, 1625.
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The following HPLC chromatograms show both the hot peak
of18F as wellas the UV trace ofthe complex (Figs 14 and 15). The
retention time ofthe product was 15.7min under ourexperimental
conditions. The complex was stable for prolonged periods of time
under vacuum in a sealed vial (Fig. 14 and Scheme 5).
Thus, we were able to radiolabel the gallium complex of
diphenylthiosemicarbazone chloride with 18F positron emitter
in a short time under less harsh experimental conditions. This
novel strategy may be applicable to introducing radio fluorine
atom in complexes that are resistant to direct fluorination.
Furthermore, it is important to note that the insoluble nature of
group 13 metal fluorides in various organic solvents hampers
the introduction of the fluorine atom directly. However, this
halogen exchange method enables radiofluorination.
The 18F-complex showed a peak at 15.5 min consistent with
the cold fluoride complex. The observed retention time was
similar to that obtained for dimethylthiosemicarbazone gallium
chloride complex,[46] further confirming the formation of the
gallium-18fluoride complex.
[11] B. Booth, K. Agarwal, E. Moore, A. Sartorelli, Cancer Res. 1974, 34,
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Ziolli, I. R. Teixeira, H. Beraldo, Polyhedron 2008, 27, 547.
doi:10.1016/J.POLY.2007.10.008
The partition coefficient was also measured for the cold
fluoro gallium complex using the absorbance at 475 nm in an
octanol/water mixture, yielding a log P value of 1.1. The
complex was stable at room temperature for more than 24 h in
the presence of water. Further work is in progress to optimize
radiolabelling including purification, stability, and in vivo
efficacy to understand the usefulness of this compound as an
imaging agent.
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11.006
Conclusions
Several thiosemicarbazone gallium complexes have been syn-
thesized, and their structural characteristics have been analyzed
using multinuclear NMR techniques. The formation of these
gallium complexes with thiosemicarbazones is further con-
firmed by single-crystal X-ray crystallographic methods.
Diphenylthiosemicarbazone forms gallium chloride/methoxide/
ethoxide/nitrate complexes. We provide evidence that, in the
presence of a base, the methoxide or ethoxide forms the
corresponding gallium-coordinated species, which are stable.
The gallium methoxide and ethoxide complexes are formed
through the intermediate nitrate complex by elimination of
nitrate. The X-ray crystal structure shows that the gallium forms
a penta-coordinated complex with chloride (or methoxide).
Furthermore, we have demonstrated that the ‘chloride ion’ of the
pre-formed gallium chloride complexes of our thiosemicarba-
zone ligands can be readily exchanged with fluoride (or iodide)
via a nitrate-mediated exchange reaction, potentially opening
future opportunities for the formation of inorganic gallium
complexes with the radioisotope 18F that may have potential
application in positron emission topography imaging.
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Acknowledgements
This work was partially supported by an ARC-Linkage grant LP 130100703
(D.R). We thank the colleagues of the Centre for Advanced Imaging for their
help during the course of this investigation.
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