Facile calculation of specific rate constants and activation energies of 18F-fluorination reaction using combined processes of coat-capture-elution and microfluidics

Article abstract of DOI:10.1016/j.tet.2011.01.088

Calculation of a specific rate constant (k) and activation energy (E _a) of ¹⁸F-labeling reaction is important to obtain objective data. However, it has never been tried, because short time heating required for the calculation of the

Full text of DOI:10.1016/j.tet.2011.01.088

Tetrahedron 67 (2011) 2427e2433
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Tetrahedron
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Facile calculation of specific rate constants and activation energies
18
of F-fluorination reaction using combined processes of coat-captureeelution
and microfluidics
,
b
,
,
b,
c
,
a
a
,
b
,
,b,c
Bo Yeun Yang a c, Jae Min Jeong a
, Yun-Sang Lee , Dong Soo Lee d, June-Key Chung a
,
*
Myung Chul Lee a
,
b
a Department of Nuclear Medicine, Institute of Radiation Medicine, Seoul National University College of Medicine, 101 Daehangno, Jongno-gu, Seoul 110-744, South Korea
b Department of Radiation Applied Life Science, Seoul National University College of Medicine, Seoul 110-744, South Korea
c Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-744, South Korea
d Department of Molecular Medicine and Biopharmaceutical Sciences, WCU Graduate School of Convergence Science and Technology, Seoul National University, Seoul 151-742,
South Korea
a r t i c l e i n f o
a b s t r a c t
Calculation of a specific rate constant (k) and activation energy (Ea) of 18F-labeling reaction is important
to obtain objective data. However, it has never been tried, because short time heating required for the
calculation of the parameters was difficult. In the present study, we could calculate the parameters using
combination of coat-captureeelution method (Aerts et al.) and microfluidic processes. The Ea values
obtained for Ts-naphthol in acetone, MeCN and t-BuOH were 5.83, 8.98, and 13.54 kcal/mol, respectively,
and for Ms-naphthol in the same solvents were 5.81, 8.16, and 19.34 kcal/mol, respectively. Calculation of
these parameters might be useful for setting up [18F]fluorination procedure and for developing new
precursors.
Article history:
Received 4 December 2010
Received in revised form 27 January 2011
Accepted 27 January 2011
Available online 4 February 2011
Keywords:
Activation energy
Rate constant
Microfluidics
CCE process
18F-labeling
F-18
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
removed to activate [18F]fluoride, and azeotropic evaporation by
heating under reduced pressure with inert gas flow is the most
Positron emission tomography (PET) is an influential modality
for molecular imaging,1 and 18F-labeled agents, such as [18F]FDG are
the most important and widely used probes for PET. And thus the
development of 18F-labeling methods has been always hot issue for
PET, and as the demand for PET increase, it requires more effective
synthesis methods for radio tracers.2
common procedure, which requires time and significant size re-
action vessel. Therefore the evaporation step is the most challenging
process for automation and microfluidics system for 18F-labeling.
Several trials have been reported to exclude the evaporation
step. For example, a special quaternary ammonium solid-phase
resin was developed.5 In this report, 18F is captured on the resin,
water is removed by washing with organic solvent, and then 18F-
labeling is performed on the solid phase system with continuous
flow of precursor solution in organic solvent. However, this method
was suffered with low and fluctuating labeling yields, because the
reaction on a solid phase is significantly slower than the solution-
phase reaction. Another trial was using ionic liquid without evap-
oration step,6 however, this method has problems due to high
viscosity of ionic liquid and residual ionic liquid in the final product.
An electrochemical cell method can exclude evaporation step,
however, it requires specially designed electrochemical cell.7 A la-
beling method by formation of [18F]aluminum fluoride chelate8,9 do
not need evaporation step, because this reaction occurs in aqueous
solution. However, its application field is limited for some special
Most 18F-labeling reactions are nucleophilic substitution using
[
18F]fluoride produced by bombardment of [18O]water with accel-
erated proton.3,4 Generally, [18F]fluoride is captured on an anion
exchange resin and then eluted with base solution such as K2CO3/
Kryptofix 2.2.2 (K222) or tetrabutylammonium bicarbonate (TBAB)
(Fig. 1a). The base solution should contain significant amount of
water to elute ionic bonded [18F]fluoride from the anion resin. And
thus obtained [18F]fluoride is highly solvated with water, which
prevents nucleophilic substitution reaction. So, the water should be
* Corresponding author. Tel.: þ822 2072 3805; fax: þ822 745 7690; e-mail
address: jmjng@snu.ac.kr (J.M. Jeong).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.01.088

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B.Y. Yang et al. / Tetrahedron 67 (2011) 2427e2433
Fig. 1. Comparison of (a) conventional and (b) CCE process (Aerts et al.).13 18F]Fluoride produced by a cyclotron is transported as an aqueous solution in 18O-water. (a) In conventional
[
process, [18F]fluoride in water is captured by a cation exchange resin and then eluted with a base solution in water and organic solvent mixture. The final solution contains [18F]fluoride,
base, organic solvent, and water, and watershould be removedfor thenextlabeling reaction. (b) In CCE process, [18F]fluoride is captured byareverse phase cartridge pre-coated with TBA
and then eluted with an organic solvent together with TBA. The final solution contains [18F]fluoride, base, and organic solvent, and is ready for the next labeling reaction.
molecules, because they label synthons for labeling of ligands but
not ligands themselves, that are similar with silicon-based building
block10 or hydrazone formation method.11 Recently, a method of
using special base solutions in MeCN showed very efficient elution
of the captured [18F]fluoride from the resin and high radiolabeling
yield, and thus is regarded as an important progress in 18F-
labeling.12
In the present study, we tried to calculate k’s and Ea’s of 18F-
labeling reactions by combination of CCE process and microfluidic
system. Generally, 18F-labeling study is just checking the labeling
efficiencies with changing parameters, such as, temperature, sol-
vent, base, time, precursors, and so on, and the derived data are
somewhat subjective. We might have more accurate and objective
data by calculating k’s and Ea’s, which would provide important
information for development of new 18F-labeling methods.
Microfluidic system is called as microfabricated or lab-on-a-chip
system, which is a technology of using microscale fluids and
channels.14 Microfluidic system is developing its field to expand
covering control, detection, and reaction. Application of micro-
fluidics provides several advantages for automated PET radiophar-
maceutical synthesis system, such as low cost, short time processing,
small footprints for analysis, and compact size.14e18 The small size
synthesis chip can be put in a small shielding, and thus small hot cell
space might be enough for installation of synthesis module, which
might facilitate good manufacturing practice (GMP) establishment
in small organizations. All synthesis steps such as radiolabeling,
purification, and analysis, are processed rapidly, and thus resulted in
enhanced radiochemical yield by reducing decayed radioactivity
during synthesis procedure. Some PET agents are already synthe-
sized using microfludic systems.15,16,19
Another important method was developed by Aerts et al.,13
which could be represented as a Coat-CaptureeElution (CCE)
process (Fig. 1b). This method has combined solid-phase and so-
lution-phase system. Solid-phase coat and capture step provides
a simplicity and a solution-phase reaction provides high reaction
yield compare to a solid-phase reaction. The coating step can be
eliminated by using a pre-coated resin during labeling process.
Pre-coating of reverse phase cartridge can be done by passing
aqueous base solution and subsequent washing with water. [18F]
Fluoride is captured on the pre-coated cartridge and then eluted
with organic solvent together with base, which can act as a base
catalyst. The advantages expected from the CCE process are: (1)
the design of automatic synthesis module can be simplified due to
the exclusion of evaporation step, (2) the labeling reaction occurs
in a solution phase, which gives higher reaction yield than a
solid-phase reaction (both of two reacting molecules move in
solution-phase, however, only one reacting molecule can move
in solid-phase), (3) the eluate solution can compose complete
elements for labeling such as [18F]fluoride, base catalyst, pre-
cursor, and organic solvent, by eluting the cartridge using an
organic solvent containing precursor and thus enable to design
a simplified automatic synthesis module, (4) the eluate directly
can be input to a microfluidic system through a single entrance,
which also enables to design a simpler microfluidic system, and
(5) straightforward calculation of specific rate constants (k) and
activation energies (Ea) is made possible because of the short time
reaction in microfluidic system.
2. Results and discussion
2.1. [18F]Fluorination using CCE process
We pre-coated reverse phase cartridges (C18, tC18, C8, and
phenyl) with either TBAB or K222. Aqueous no-carrier-added [18F]
fluoride solution was produced from a cyclotron, and its 1 mL ali-
quot was passed through a pre-coated cartridge and purged with
nitrogen gas (2.84 psi) for 5 min. The [18F]fluoride-captured pre-
coated cartridge was eluted using 1 mL of organic solvents, such as

B.Y. Yang et al. / Tetrahedron 67 (2011) 2427e2433
2429
Fig. 2. Capture efficiencies of 18F activity using two different base solutions from pre-
coated reverse phase cartridges, such as C18, tC18, C8 (n¼27), and phenyl (n¼9).
acetone, methylethylketone (MEK), diethylketone (DEK), cyclo-
hexanone (CHX), t-BuOH, tert-amylalcohol (t-AmOH), MeCN,
dimethylformamide (DMF), and dimethylsulfoxide (DMSO).
Generally the cartridges, especially C8, coated with TBAB cap-
tured [18F]fluoride significantly more efficiently than the cartridges
coated with K222 (Fig. 2). Trifunctional tC18 cartridge20 showed
slightly higher capture efficiency than the original C18 cartridge.
Phenyl cartridge showed the lowest capture efficiency, and the
difference between two base solutions were not significant
(P¼0.60) (Fig. 2).
Captured [18F]fluoride was eluted with various organic solvents.
The adequate solvents for elution were dependent to cartridges and
bases (Fig. 3). Acetone showed the highest elution efficiencies for
C18 and tC18 cartridges coated either with TBAB or with K222.
However, other ketone-containing solvents MEK and DEK were not
efficient for elution in any case. The lower polarities of MEK and
DEK might be less effective to dissolve the polar TBAB or K222 and
might be less effective for elution consequently. A protic solvent
t-BuOH was the most efficient for elution from TBAB coated C8
cartridge, but, was not efficient for K222 coated C8 cartridge in-
terestingly. Both of t-BuOH and MeCN were efficient for either TBAB
or K222 coated tC18 cartridges, however, both of the solvents were
not efficient for K222 coated cartridges (Fig. 3). However, it was
difficult to predict theoretically the best solvent for eluting the
coated cartridges.
Microfluidic [18F]fluorination after CCE process is shown di-
agrammatically (Fig. 4). Two precursors, Ts-naphthol (1) and
Ms-naphthol (3), were synthesized and used for evaluation of
18F-labeling efficiency (Scheme 1). The captured [18F]fluoride and
pre-coated TBAB on a C18 cartridge were eluted by 1 mL of organic
solvents (acetone, MeCN, or t-BuOH) containing 5 mg of each pre-
cursor using a syringe pump. Among the three solvents, acetone
was used because of its efficient recovery of [18F]fluoride using
CCE process, MeCN was used because it is the most frequently used
solvent for 18F-labeling, and t-BuOH was used because of the
reported increased labeling yield of protic solvents.21e23 The
resulting eluate was directly input into a pre-heated microfluidic
Fig. 3. Capture and elution recoveries of 18F from reverse phase cartridges (a) C18, (b)
tC18, and (c) C8 pre-coated with bases (TBAB or K222) using nine different organic
solvents. (n¼3). Recovery¼Capture efficiencyꢀElution efficiencyꢀ100%. Capture effi-
ciency¼Radioactivity captured on cartridge/(Radioactivity captured on car-
tridgeþUncaptured radioactivity). Elution efficiency¼Eluted radioactivity/(Eluted
radioactivityþRadioactivity remaining on cartridge). All checked radioactivities (MBq)
were decay-corrected.
about 80% at 2 min reaction time and decreased after that both at
140 ꢁC (Fig. 5a). In MeCN and t-BuOH, labeling efficiency of 1 in-
creased for 2 min and then the increase rate was slowed down
(Fig. 5c and e). In case of 3, the labeling efficiency reached plateau at
1 min reaction time at 140 ꢁC in all three solvents, however, con-
tinuously increasing labeling efficiency was observed at 120 ꢁC in
all three solvents (Fig. 5b, d, and f). 3 showed about 80% of maxi-
mum labeling efficiencies at 1 min reaction time both in acetone
and MeCN at 140 ꢁC (Fig. 5b and d), however, only about 55% of
maximum efficiency was found in t-BuOH (Fig. 5f). At 120 ꢁC, 3
showed increasing labeling efficiencies as the reaction time in-
crease, however, reached plateau about 70% in MeCN at 4 min
(Fig. 5d).
loop (765
m
m
inner diameterꢀ0.5 m length) made of poly-
etheretherketone polymer-sheathed fused silica (PEEKsil). The
labeled product was collected in a glass vial and fluorination
efficiency was checked by TLC. The reaction time in the loop was
controlled by a flow rate from 0.25 to 4 min (Supplementary data
Table S1).
Generally, the labeling efficiencies of both 1 and 3 increased as
the reaction time and temperature increased (Fig. 5). Both pre-
cursors showed low labeling efficiencies (<10%) at 90 ꢁC in all three
solvents. In acetone, 1 showed maximum labeling efficiency of

2430
B.Y. Yang et al. / Tetrahedron 67 (2011) 2427e2433
r ¼ k ꢀ ½18Fꢃ ꢀ ½Pꢃ
(1)
(2)
½
½
18Fꢃ þ ½Pꢃ
ꢂlnð1 ꢂ FÞ ¼
ꢀ r ꢀ t
18Fꢃ ꢀ ½Pꢃ
ln(1ꢂF)¼ꢂkꢀaꢀt
ꢂ2.303 log(1ꢂF)¼pꢀt
k¼2.303ꢀp/a
a¼[18Fꢂ]þ[P]j[P]
p¼ꢂEa/2.303ꢀR
r¼Radiolabeling rate (mol Lꢂ1 minꢂ1); [18F]¼Concentration of 18Fꢂ
(mol Lꢂ1); [P]¼Concentration of precursor (mol Lꢂ1); t¼Time (min);
F¼Radiochemical yield at time t; k¼Specific rate constant
(L molꢂ1 minꢂ1).
Activation energies (Ea) for fluorination of 1 and 3 could be
derived using k values and Arrhenius equation [Eq. 3]. Ea is the
minimum required energy for reactants to be transformed into
products, and is an important value, because it can represent re-
action rate and be used for supporting experimental results. The log
k values were plotted as a function of time (Fig. 7), and then acti-
vation energy of each compound in each solvent was obtained from
the slope (ꢂEa) of each line (Table 2). The order of Ea values of 18F-
labeling reaction were t-BuOH, MeCN, and acetone representing
the reverse order of reaction rate.
Fig. 4. A diagram of microfluidic 18F-labeling combined with CCE process. [18F]Fluoride
in 1 mL of 18O-water is captured by a C18 cartridge pre-coated with TBA and purged
with 2.84 psi nitrogen gas for 5 min. And then [18F]fluoride and TBA together are
eluted with 1 mL of organic solvent containing 5 mg precursor, and the eluted mixture
is entered into a pre-heated loop directly. The labeled final product is collected in
a glass vial.
O
S
OH
O
O
O
O
S
O
O
S
O
NaH/THF
rt
+
O
O
1
O
S
O
O
S
O
O
S
O
N
0 C
Cl
O
O
HO
OH
+
2
O
S
O
OH
O
O
O
S
O
O
S
O
NaH/THF
0 C
O
O
+
2
3
Scheme 1. Synthesis of precursors.
2.2. Calculation of k and Ea
ꢂEa
k ¼ A ꢀ e
(3)
R ꢂ T
It is well-known that the radioisotope labeling reactions are
pseudo-first order reaction due to the low concentration of radio-
isotope compared to precursor, and thus the reaction rate is de-
pendent only on the concentration of [18F]fluoride because the
concentration change of precursor is negligible [Eq. 1].24,25 In this
model, labeling efficiency graphs could be converted to line graphs
of reaction time versus log(1ꢂF) [Eq. 2] (Fig. 6), of which slopes
represent specific rate constants (ꢂk) of compounds at specific
temperatures (Table 1). The reaction rates were influenced by
temperature as well as reaction solvent. In all given conditions, k
value increased as the temperature increased. When acetone or
MeCN were used as solvents, 3 was better precursor than 1, how-
ever, 1 was better for t-BuOH. The highest k value was found with 3
at 140 ꢁC in acetone, which is the proposed condition for labeling
naphthol with 18F from the results of this experiment.
lnk¼ꢂEa/RꢀTþconstant
A¼Frequency factor or the reaction, constant; Ea¼Activation
energy (kcal molꢂ1); R¼Gas constant (8.31447 J Kꢂ1 molꢂ1);
T¼Absolute temperature.
Above calculations were possible because the measurement of
labeling efficiencies in short time, such as 0.25, 0.5, and 1 min was
possible by application of microfluidic system. In addition, the
simple CCE process can be performed without any special control
device for microfluidic lab-on-a-chip.
Calculation of the activation energies would give new insights
for 18F-labeling chemistry and provide objective data for the re-
actions. Then the obtained parameters might be used for evaluation
of the reactions and be helpful for set up of labeling procedure and
for developing new precursors.

B.Y. Yang et al. / Tetrahedron 67 (2011) 2427e2433
2431
Fig. 5. Labeling efficiencies of 1 and 3 in various solvents at 90, 120, and 140 ꢁC. (a) 1 in acetone, (b) 3 in acetone, (c) 1 in MeCN, (d) 3 in MeCN, (e) 1 in t-BuOH, and (f) 3 in t-BuOH.
3. Conclusion
tetramethylsilane. Fast atomic bombardment (FABþ) ionization
mass spectra were acquired on JEOL, JMS-600 WAzilent 6890 series
spectrometer (JEOL Ltd, Tokyo, Japan) for positive mode. JMS-
LA400 with LFG model has used for 400 MHz NMR to obtain 13C
NMR data (JEOL Ltd, Tokyo, Japan). Infrared spectra were obtained
from KBr pellets on an FT-IR spectrophotometer Nicolet 6700
(Thermo Fisher Scientific, MA, USA). Radio-thin layer chromatog-
raphy (TLC) was counted using a Bio-Scan AR-2000 System imaging
scanner (Bioscan, Inc, WA, USA). 11Plus syringe pump was pur-
chased from Harvard Apparatus (Harvard Apparatus, MA, USA).
C18, tC18 and C8 SepPak solid-phase cartridges were purchased
from Waters (Waters Corporation, MA, USA). Phenyl cartridge,
DiscoveryÒ DSC-Ph SPE Tube was purchased from Supelco (Supelco,
Inc, PA, USA). Thin-layer chromatography (TLC silica gel 60 F254
Aluminum sheets) was purchased from Merck (Merck KGaA,
Darmstadt, Germany). Commercial chemicals were from Sigmae
Aldrich (SigmaeAldrichÒ, MO, USA) and TCI (Tokyo Chemical
Industry Co., Ltc, Tokyo, Japan). Microscale spiral tube was used
Tubing, Spiral-link (Upchurch Scientific, WA, USA).
In this study, [18F]fluorination of two precursors by nucleophilic
substitution reaction was performed successfully using CCE process
with microfluidics system. Capturing and elution of [18F]fluoride on
base-coated reverse phase cartridges showed high efficiencies, and
successive labeling reaction was straightforward and efficient. We
could calculate specific rate constants and activation energies and
found that acetone was the first proposed solvent in this reaction.
This simple and efficient procedure to calculate activation energy
might give a great impact for development of 18F-labeling in-
struments and study of 18F-labeling kinetics.
4. Experimental
4.1. General
[
18F]Fluoride was produced by the 18O(p, n)18F reaction using
18O-enriched (95%) water and a 13-MeV proton beam generated by
a TR-13 cyclotron (Ebco Technologies, Vancouver, Canada). The
produced [18F]fluoride was used after more than 1 h storage.
Electrospray ionization mass spectra (ESI-MS) were acquired on
a Waters 3100 Liquid chromatography-mass spectroscopy (LCeMS)
(Waters Corporation, MA, USA) ESI ion trap spectrometer for pos-
itive and negative ions detection. The samples were diluted 1 to 100
with methanol and injected directly into the source. Chemical shifts
4.2. Synthesis of precursors
4.2.1. 3-(Naphthalene-1-yloxy)propyl 4-methylbenzenesulfonate (Ts-
naphthol) (1). To a solution of 1-naphthol (100 mg, 0.69 mmol) in
4 mL of THF, sodium hydride (68 mg, 1.38 mmol) was added and
stirred for 15 min. 1,3-Bis(Tsoxy)propane (530 mg, 1.38 mmol) was
added to the reaction mixture and stirred for 2 h at room
(d
)
were reported in parts per million downfield from

2432
B.Y. Yang et al. / Tetrahedron 67 (2011) 2427e2433
Fig. 6. Reaction time versus log(1ꢂF) graph. (a) 1 in acetone, (b) 3 in acetone (c) 1 in MeCN, (d) 3 in MeCN, (e) 1 in t-BuOH, and (f) 3 in t-BuOH.
Table 1
calculated for C20H20O4SNa: [MþNa]þ 379.0980, found 379.1039.
Specific rate constants calculated for 18F-labeling of 1 and 3 at 90, 120, and 140 ꢁC in
acetone, MeCN, and t-BuOH
Mp¼51 ꢁC.
Compound
Temperature (ꢁC)
1
3
4.2.2. 1,3-Bis(mesylsoxy)propane (2). Methanesulfonyl chloride
(1 mL, 38.76 mmol) was added to ice-cooled pyridine solution of
1,3-propandiol (1 mL,13.84 mmol) and stirred for 1 h at 0 ꢁC for 1 h.
The reaction mixture was extracted with EtOAc (50 mL), the organic
layer was washed with brine (2ꢀ200 mL), dried over anhydrous
sodium sulfate (w3 g) for 10 min, and concentrated using a rotary
vacuum evaporator at 50 ꢁC. The resulting oil was purified using
a silica gel (w15 g) column chromatography (25:75 EtOAc/n-hex-
ane; Rf¼0.2). Pure product was obtained as a colorless oil after
drying using a rotary vacuum evaporator at 45 ꢁC. Yield¼1.56 g, 1H
140
120
90
140
120
90
Acetone
MeCN
t-BuOH
1.443
1.378
0.932
0.296
0.522
0.608
0.135
0.045
0.006
2.649
1.781
0.864
0.548
0.816
0.214
0.249
0.081
0.001
Values represent specific rate constants k (L/mol min).
temperature. The reaction mixture was extracted with EtOAc
(50 mL), the organic layer was washed with brine (2ꢀ200 mL), dried
over anhydrous sodium sulfate (w3 g) for 10 min, and concentrated
using a rotary vacuum evaporator at 50 ꢁC. The resulting oil was
purified using a silica gel (w40 g) column chromatography (25:75
EtOAc/n-hexane; Rf¼0.4). Pure product was obtained as a bright
yellow powder after drying using a rotary vacuum evaporator at
NMR [300 MHz, CDCl3]:
NMR [400 MHz, CDCl3]:
d
1.77e1.85 (m, 2H), 2.90 (s, 6H), (t, 4H). 13
28.28, 36.59, 65.49. IR (KBr, cmꢂ1): 3053,
C
d
1354, 1174. MS (ESI) m/z calculated for C5H12O6S2: [MþH]þ
233.0154, found 232.9997. MS (ESIþ) m/z calculated for
C5H12O6S2Na: [MþNa]þ 254.9973, found 254.9247.
45 ꢁC. Yield¼0.16 g, 1H NMR [300 MHz, CDCl3]:
d 7.93e7.96 (m, 1H),
7.66e7.68 (m, 1H), 7.50e7.51 (m, 1H),7.41e7.43 (m, 1H), 7.36e7,40
(m, 1H), 7.31e7.33 (m, 2H), 7.26e7.30 (m, 1H), 6.95e6.98 (m, 1H),
6.65e6.68 (m, 1H), 4.35 (t, 2H), 4.09 (t, 2H), 2.62 (s, 3H), 2.25
4.2.3. 3-(Naphthalene-1-yloxy)propyl methanesulfonate (Ms-naph-
thol) (3). To a solution of 1-naphthol (1.10 g, 7.63 mmol) in 4 mL of
THF, sodium hydride (500 mg, 20.83 mmol) was added and stirred
for 30 min. Compound 2 (1.61 g, 6.94 mmol) was added to the re-
action mixture and stirred for 2 h at 0 ꢁC. The reaction mixture was
extracted with EtOAc (100 mL), the organic layer was washed with
(Quintet, 2H). 13C NMR [400 MHz, CDCl3]:
d 21.34, 28.78, 62.80,
66.95, 104.35, 120.36, 121.71, 125.03, 125.75, 126.35, 127.65, 129.62,
144.70,153.99. IR (KBr, cmꢂ1): 2978, 1364,1188, 1173. MS (ESIþ) m/z

B.Y. Yang et al. / Tetrahedron 67 (2011) 2427e2433
2433
with ethanol (3 mL) and deionized water (5 mL) sequentially. The
pre-conditioned cartridge was coated with 1 mL of each prepared
TBAB or K222 solution by passing through the cartridge. After
coating, cartridge was washed with deionized water (5 mL) to
remove the remaining solution. And captured 1 mL of [18F]fluoride,
which was produced from cyclotron. [18F]Fluoride captured car-
tridge was purged with nitrogen gas for 5 min (2.84 psi).
4.4. Determination of labeling efficiency
Labeling efficiency (%) was checked by TLC silica aluminum
sheet and radioactivity was scanner by using a radioTLC scanner.
The eluant was 95% (v/v) MeCN in water. Rf value of [18F]fluoride
was 0.1 and that of [18F]naphthol was 1.0.
Acknowledgements
This work was supported by the NRF (R0A-2008-000-20116-0),
the Converging Research Program funded by MEST (2010K001055),
and Korea Healthcare Technology R&D project funded by MHW
(A070001).
Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2011.01.088. These data include
MOL files and InChIKeys of the most important compounds
described in this article.
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Table 2
Activation energies calculated for 18F-Labeling of 1 and 3 in acetone, MeCN, and t-
BuOH
Solvent
Precursor
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1
3
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Acetone
MeCN
t-BuOH
5.83
8.98
13.54
5.81
8.16
19.34
Values represent activation energies Ea (kcal/mol).
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d 7.83
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1H), 7.44e7.47 (m, 1H), 4.38 (t, 2H), 3.65 (t, 2H), 3.21 (s, 3H), 2.18
(Quintet, 2H). 13C NMR [400 MHz, CDCl3]:
d 29.03, 37.05, 65.32,
66.27, 104.59, 121.70, 125.11, 125.24, 125.74, 126.28, 127.39, 134.34,
154.39. IR (KBr, cmꢂ1): 1359, 1190, 1171. MS (ESIþ) m/z calculated for
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by purging CO2 gas into 40% tetrabutylammonium hydroxide for 6 h,
and then 40% TBAB 0.87 mL, deionized water 2.5 mL, and MeCN
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