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1. The Aqueous Stabilityof Titanocene Difluoride
Jennifer Niederstadt*, Ahmed Ali, Kantapat Chansaenpak, Mengxi Yang, François P. Gabbai.
Texas A&M Department of Chemistry, 3255 TAMU, College Station Texas 77840
ABSTRACT: In this report we discuss the properties of titanocene difluoride and its ability to be functionalized for the
use in imaging. If titanocene difluoride and its derivatives prove to be stable in aqueous conditions, it could provide a
new platform for 18F/19F isotope exchange pertinent to Positron Emission Tomography.
INTRODUCTION
1Positron Emission Tomography (PET)
requires the use of positron emitting atoms in
biomolecules under study. Fluorine-18 (18F) is an
efficient positron emitter because of its easy preparation
from 18O water and nuclear decay characteristics.
However, because of its short 110-minute half-life, 18F
must be quickly incorporated into biomolecules to
maximize activity. Therefore, the need for a fluoride
captor that can rapidly abstract 18F fluoride as well as
have the versatility to be used in biomolecules has risen.
The approach that has been recently employed
is to use Lewis acidic fluoride binders that are
functionalized with biomolecules and are treated with F-
18 prior to injection. This allows the 18F source to be
rapidly captured and introduced into a target-
functionalized biomolecule enabling highly active in vivo
PET imaging. Previously, we have used cationic boranes
to bind fluorides, but in this study we have chosen
titanocene derivatives. Titanium (IV) is non-toxic, earth-
abundant metal and is well known for its ease of
attraction to halogens. Titanocene has been chosen
because the cyclopentadienyl (Cp) ligands are robust,
and can allow for further derivation and conjugation with
biomolecules.
To start our investigation of Titanocene as a 18F
captor we needed to synthesize, isolate, and test the
stability of titanocene difluoride in aqueous solutions
using buffers over a period of time that would be suitable
for PET imaging. These molecules must be stable to
hydrolysis for this application.
RESULTS AND DISCUSSION
Following a previous report2, we synthesize
titanocene difluoride dissolving sodium fluoride (0.843 g,
0.0200 mol.) in 10.0 mL of water. Then titanocene
dichloride (2.49 g, 0.0100 mol.) is dissolved in 75.0mL of
water. The solutions are added and stirred for 24 hours
at 22.7°. A golden precipitate forms at the bottom of the
red solution. The precipitate is filtered, dried, then
sublimed at 120°C (add vacuum pressure in torr)
yielding a yellow powder. We confirmed synthesis by
NMR observing a sole peak in the 19
F NMR spectrum at
64.8ppm and a sole peak in the 1
H spectrum at 6.48ppm
Figure 1 Lewis structure of Titanocene difluoride
Previously, we report the synthesis and stability
testing of titanocene difluoride in various buffers. We
found titanocene difluoride in pyridine and HEPES to be
unstable. We decide to test the aqueous stability of the
titanocene difluoride and isolate titanocene from an
aqueous solution.
Our first attempt to crystalize the species was to
slowly evaporate acetonitrile from a solution of
titanocene difluoride in 20% acetonitrile in water. (insert
results) In attempt to crystalize the species found in
aqueous solutions, 3 mg of titanocene difluoride is
dissolved in 5 mL of 20% acetonitrile and poured into a
vial. We layered 5 mL of diethyl ether. After a week, only
a white powder is present on top of the layers and no
crystals form indicating our failure to isolate from this
method.
In our next attempt, we add 4.mg of titanocene
difluoride is dissolved in 20% acetonitrile. Solution is
poured into a small vial and then placed inside a larger
vial containing diethyl ether allowing diethyl ether to
slowly effuse into . One week passed to allow sufficient
crystallization and diffusion of ether into the acetonitrile
solution. This also yields white powder..
This appearance of white powder indicates that
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20
40
60
80
0 10 20 30 40 50 60 70 80 90 100
ChemicalShift
Amountof Deuterium Oxide Added (μL)
Chemical Shift of Titanocene Difluoride
in MeCN
2. both methods of crystallization occurred too rapidly,
creating small, imperfect crystals, which cannot be
studied using X-ray diffraction.
1.7 mg of titanocene difluoride is dissolved in
0.7 mL deuterated acetonitrile. Next, D2O is added at 10
μL increments until 100 μL of water has been added.
The chemical shift drops from 70.512 ppm to 44.586ppm
with a steady decline.
Figure 2 Titanocene Difluoride in acetonitrile
Figure 3 Titanocene Difluoride and 0.01 mL water added
Then, to test the saturation of the titanocene,
1.9 mg of titanocene difluoride is dissolved in 0.7 ml of
deuterated acetonitrile. Then D2O is added in 0.1 mL
increments until the amount reaches 0.7 mL. The
chemical shift drops from 72.573 ppm to 17.834 ppm
with a second peak appearing at -78.555 ppm. The
second peak indicates the appearance of dehydrated
free fluoride ions in the solution.
Figure 4 Titanocene Difluoride and 0.1 mL water added
Figure 5 Titanocene Difluoride and 0.7 mL water added
The indication that free fluorine is present leads
us to understand the apparent decomposition of
titanocene in these conditions.
CONCLUSION
Titanocene’s inability to be crystalized properly,
coupled with its rapid decay in the presence of water, we
believe its derivatives using fluoride are not robust
enough for in vivo testing.
REFERENCES
1
Zibo Li, *Kantapat Chansaenpak, Shuanglong Liu, Casey R.
Wade, Peter S. Conti and François P. Gabbaï.
Harvesting 18
F-fluoride ions in w ater via direct 18
F–19
F
isotopic exchange: radiofluorination of zw itterionic
aryltrifluoroborates and in vivo stability studies.
MedChemComm.2012, 3, 1305-1308.
2
Druce, P.M.; Kingston, B.M.; Lappert, M.F.; Spalding,T.R;
Srivastava, R.C. Metallocene Halides. Part I.
Synthesis, Spectra,and Redistribution Equilibria of Di-
π-Cyclopentadienyldihalogeno,-zirconium-(IV), and-
hafnium(IV). J. Chem. Soc. (A), 1969. 0. 2106-2110.
3
Herzog, Axel; Lui, Feng-Quan; Roesky, Herbert W.; Demsar,
Alojz; Keller, Klaus; Noltemeyer, Mathias; Pauer,
Frank. Trimethyltin Fluoride: A New Fluorinating
Reagent for the Preparation of Organometallic
Fluorides. Imtitut fur Anorganische Chemie der
Universitat Gottingen, Tammannstrasse.1990. 13.
1251-1256.
4Jennifer Niederstadt*, Ahmed Ali, Kantapat Chansaenpak,
Mengxi Yang, François P. Gabbai. The Synthesis of
(Bis)cyclopentadienyl-Titanium (IV) Difluoride and its
Stability. 2014.
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ChemicalShift
Amountof Deuterium Oxide added(μL)
Chemical shift of Titanocene Difluoride in
MeCN