Fast and high-yield microreactor syntheses of ortho -substituted [ 18F]Fluoroarenes from reactions of [18F]Fluoride ion with diaryliodonium salts

Article abstract of DOI:10.1021/jo100361d

A microreactor was applied to produce ortho-substituted [ ¹⁸F]fluoroarenes from the reactions of cyclotron-produced [ ¹⁸F]fluoride ion (t_1/2 = 109.7 min) with diaryliodonium salts. The microreactor provided a very convenient means for running sequential reactions rapidly with small amounts of reagents under well-controlled conditions, thereby allowing reaction kinetics to be followed and Arrhenius activation energies (E_a) to be measured. Prepared symmetrical iodonium chlorides (Ar₂I⁺Cl^-) rapidly (<4 min) gave moderate (Ar = 2-MeOC₆H₄, 51%) to high (Ar = Ph or 2-MeC₆H₄, 85%) decay-corrected radiochemical yields (RCYs) of a single radioactive product (Ar¹⁸F). Reaction velocity with respect to Ar group was 2-MeOC₆H₄ < Ph < 2-MeC₆H₄. Activation energies were in the range 18-28 kcal/mol. Prepared unsymmetrical salts (e.g., 2-RC₆H ₄I⁺2′-R′C₆H₄X ^-; X = Cl or OTs) also rapidly gave two products (2-RC ₆H₄¹⁸F and 2-R′C₆H ₄¹⁸F) in generally high total RCYs (79-93%). Selectivity for product [¹⁸F]fluoroarene was controlled by the nature of the ortho substituents. The power of ortho substituents to impart an ortho-effect was in the following order:, 2,6-di-Me > 2,4,6-tri-Me > Br > Me > Et ≈ ⁱPr ? H > OMe. For (2-methyphenyl)(phenyl)iodonium chloride, the time-course of reaction product selectivity was constant and consistent with the operation of the Curtin-Hammett principle. These results will aid in the design of diaryliodonium salt precursors to ¹⁸F- labeled tracers for molecular imaging. This article not subject to U.S. Copyright. Published 2010 by the American Chemical Society.

Full text of DOI:10.1021/jo100361d

pubs.acs.org/joc
Fast and High-Yield Microreactor Syntheses of ortho-Substituted
[18F]Fluoroarenes from Reactions of [18F]Fluoride Ion with
Diaryliodonium Salts
Joong-Hyun Chun,† Shuiyu Lu,† Yong-Sok Lee,‡ and Victor W. Pike*,†
†PET Radiopharmaceutical Sciences Section, Molecular Imaging Branch, National Institute of
Mental Health, Rm. B3 C346A, Building 10, 10 Center Drive, Bethesda, Maryland 20892-1003, and
‡Center for Molecular Modeling, Center for Information Technology, National Institutes of Health,
Bethesda, Maryland 20892
pikev@mail.nih.gov
Received February 25, 2010
A microreactor was applied to produce ortho-substituted [18F]fluoroarenes from the reactions of
cyclotron-produced [18F]fluoride ion (t1/2 = 109.7 min) with diaryliodonium salts. The micro-
reactor provided a very convenient means for running sequential reactions rapidly with small
amounts of reagents under well-controlled conditions, thereby allowing reaction kinetics to be
followed and Arrhenius activation energies (Ea) to be measured. Prepared symmetrical iodonium
chlorides (Ar2IþCl-) rapidly (<4 min) gave moderate (Ar=2-MeOC6H4, 51%) to high (Ar=Ph or
2-MeC6H4, 85%) decay-corrected radiochemical yields (RCYs) of a single radioactive product
(Ar18F). Reaction velocity with respect to Ar group was 2-MeOC6H4 < Ph < 2-MeC6H4.
Activation energies were in the range 18-28 kcal/mol. Prepared unsymmetrical salts (e.g.,
2-RC6H4Iþ20-R0C6H4X-; X = Cl or OTs) also rapidly gave two products (2-RC6H418F and
2-R0C6H418F) in generally high total RCYs (79-93%). Selectivity for product [18F]fluoroarene
was controlled by the nature of the ortho substituents. The power of ortho substituents to impart an
i
ortho-effect was in the following order:, 2,6-di-Me > 2,4,6-tri-Me > Br > Me > Et ≈ Pr . H >
OMe. For (2-methyphenyl)(phenyl)iodonium chloride, the time-course of reaction product
selectivity was constant and consistent with the operation of the Curtin-Hammett principle.
These results will aid in the design of diaryliodonium salt precursors to 18F-labeled tracers for
molecular imaging.
1. Introduction
compound must be high. In practice, this ratio is of the order
of 1(18F):200(19F), and corresponds to specific radioactivi-
ties of the order of 8 Ci/μmol. In PET imaging studies, this
level of specific radioactivity is usually adequate for avoiding
toxic or pharmacological effects and also for establishing
true tracer conditions in which a biochemical target (e.g., a
neurotransmitter receptor) or pathway to be imaged does not
become saturated and obscured with the co-administered
nonradioactive tracer. For fluorine-18 to be at high specific
radioactivity, it must usually be produced as the single-atom
species, [18F]fluoride ion. This is usually achieved by the
Fluorine-18 is a short-lived (t1/2 = 109.7 min) positron
emitter that finds increasing application for labeling tracers
for molecular imaging in animal and human subjects with
positron emission tomography (PET).1 For many of these
applications, the fluorine-18 must be at high specific radio-
activity, meaning that dilution of the radiotracer with non-
radioactive tracer must be low, i.e., the ratio of 18F to 19F
(1) Cai, L. S.; Lu, S. Y.; Pike, V. W. Eur. J. Org. Chem. 2008, 17, 2853–
2873.
3332 J. Org. Chem. 2010, 75, 3332–3338
Published on Web 04/02/2010
DOI: 10.1021/jo100361d
This article not subject to U.S. Copyright. Published 2010 by the American Chemical Society

Chun et al.
JOCArticle
SCHEME 1. Reactions of Diaryliodonium Salts with
[18F]Fluoride Ion
SCHEME 2. Routes Used for the Syntheses of Diaryliodonium
Salts in This Study
18O(p,n)18F reaction on 18O-enriched water, using a moderate-
energy proton beam from a compact cyclotron.2 This is a
highly productive nuclear reaction, capable of generating
multi-Curie levels of fluorine-18.
A major challenge in PET radiotracer development is to
find efficient methods for rapidly incorporating cyclotron-
produced [18F]fluoride ion into organic molecules. This may
be achieved at aliphatic sites and in electron-deficient arenes
by nucleophilic substitution reactions.1 A greater challenge is
the incorporation of [18F]fluoride ion into electron-rich
arenes, for which classical aromatic nucleophilic substitution
is generally a disfavored process, giving low or negligible
yields. The reactions of diaryliodonium salts with [18F]fluo-
ride ion3 (Scheme 1) do not share this limitation and may be
applied to labeling both electron-rich and electron-deficient
arenes with fluorine-18. These reactions have therefore
gained considerable interest.4-6 Notwithstanding, these
reactions exhibit unusual features, and their detailed
mechanisms are not yet well understood. As part of our
ongoing investigations into the scope and nature of these
reactions for PET radiotracer development, we wished to
explore the influence of substituents, particularly ortho
substituents, on reaction rates, energetics and product selec-
tivity under varied but well-controlled conditions. Here, we
show first the utility of a microreactor apparatus for this
radiochemical purpose and second further insights into the
mechanism and outcomes of the radiofluorination reaction.
These findings will assist in future PET radiotracer design
and production.
(Scheme 2). The derivatives of Koser’s reagent were prepared
by treating the appropriate iodoarene diacetate with p-tosic
acid.9 The reactions of Koser’s reagent and derivatives with
(tri(alkyl)stannyl)arenes exhibited excellent regioselectivity
and gave moderate (38%) to high yields (90%). Reactions
with arylboronic acids were regioselective for acids bearing
an o-methyl substituent but not for arylboronic acids bearing
an o-methoxy substituent. Yields were low (20%) to moder-
ate (49%). Direct reactions with mesitylene were effective for
making (mesityl)aryliodonium salts, since with the methyl
substitution pattern, only one positional isomer is possible.
Diaryliodonium tosylates were readily converted into their
corresponding halides in moderate (27%) to high yields
(88%) by metathesis reactions. In each case, metathesis
was readily confirmed by the absence of signals for tosylate
in the 1H NMR spectrum.
2.2. Radiofluorination Reactions within a Microreactor.
The potential advantages of microreactor technology for
PET radiochemistry are increasingly recognized.10,11 In this
study, all radiofluorination reactions were performed in a
commercially available microreactor apparatus (Nanotek;
Advion). The use of this apparatus offers several advantages
over traditional methods of studying radiofluorination reac-
tions, which are usually performed singly with substantial
amounts of nonradioactive precursor (e.g., milligram quan-
tities of precursor for labeling).1,6 As we have recently
shown,11 by use of the microreactor apparatus, a series of
reactions can be performed rapidly with very low fixed
quantities of reagents, under precisely controlled conditions
of temperature, time, and reaction stoichiometry. The whole
microreactor is heated to a controlled temperature, which
can be well above the boiling point of most organic solvents
due to the elevated pressure of the system. Because of the
small internal volume of the microreactor (15.7 μL for 2-m
2. Results and Discussion
2.1. Chemistry. Two main methods were used to prepare
substituted diaryliodonium tosylates, namely, reaction
of Koser’s reagent ([hydroxy(tosyloxy)]iodobenzene; PhI-
(OH)OTs) or an ortho-substituted derivative (RC6H4I(OH)-
OTs) with an arylboronic acid7 or tri(alkyl)stannylarene8
(2) (a) Guillaume, M.; Luxen, A.; Nebeling, B.; Argentini, M.; Clark,
J. C.; Pike, V. W. Appl. Radiat. Isot. 1992, 42, 749–762. (b) Qaim, S. M.; Clark,
J. C.; Crouzel, C.; Guillaume, M.; Helmeke, H. J.; Nebeling, B.; Pike,
€
V. W.; Stocklin, G. In Radiopharmaceuticals for Positron Emission Tomo-
€
graphy; Stocklin, G., Pike, V. W., Eds.; Kluwer Academic Publishers: Dordrecht,
Netherlands, 1993; pp 1-43.
(3) Pike, V. W.; Aigbirhio, F. I. J. Chem. Soc., Chem. Commun. 1995, 21,
2215–2216.
(4) (a) Shah, A.; Pike, V. W.; Widdowson, D. A. J. Chem. Soc., Perkin
Trans. 1 1998, 2043–2046. (b) Gail, R.; Hocke, C.; Coenen, H. H. J. Label.
Compd. Radiopharm. 1997, 40, 50–52. (c) Zhang, M. R.; Kumata, K.; Suzuki,
K. Tetrahedron Lett. 2007, 48, 8632–8635. (d) Pike, V. W.; Aigbirhio, F. I.
J. Label. Compd. Radiopharm. 1995, 37, 120–122.
´ ´
(5) Martın-Santamarıa, S.; Carroll, M. A.; Carroll, C. M.; Carter, C. D.;
Pike, V. W.; Rzepa, H. S.; Widdowson, D. A. Chem. Commun. 2000, 649–
650.
(6) Ross, L.; Ermert, J.; Hocke, C.; Coenen, H. H. J. Am. Chem. Soc.
2007, 129, 8018–8025.
(7) Carroll, M. A.; Pike, V. W.; Widdowson, D. A. Tetrahedron Lett.
2000, 41, 5393–5396.
(8) Pike, V. W.; Butt, F.; Shah, A.; Widdowson, D. A. J. Chem. Soc.,
Perkin Trans 1 1999, 245–248.
(9) (a) Neiland, G.; Karele, B. J. Org. Chem. USSR (Engl. Transl.) 1970,
889; Zh. Org. Khim. 19706, 885. (b) Koser, G. F.; Wettach, R. H. J. Org.
Chem. 1977, 42, 1476–1478.
(10) (a) Lu, S. Y.; Watts, P.; Chin, F. T.; Hong, J.; Musachio, J. L.; Briard,
E.; Pike, V. W. Lab Chip 2004, 4, 523–525. (b) Lee, C. C.; Sui, G. D.; Elizarov,
A.; Shu, C. Y. J.; Shin, Y. S.; Dooley, A. N.; Huang, J.; Daridon, A.; Wyatt,
P.; Stout, D.; Kolb, H. C.; Witte, O. N.; Satyamurthy, N.; Heath, J. R.;
Phelps, M. E.; Quake, S. R.; Tseng, H. R. Science 2005, 310, 1793–1796. (c)
Gillies, J. M.; Prenant, C.; Chimon, G. N.; Smethurst, G. J.; Perrie, W.;
Hamblett, I.; Dekker, B.; Zweit, J. Appl. Radiat. Isot. 2006, 64, 325–332. (d)
Steel, C. J.; O’Brien, A. T.; Luthra, S. K.; Brady, F. J. Label. Compd.
Radiopharm. 2007, 50, 308–311. (e) Lu, S. Y.; Pike, V. W. In PET Chemistry-
The Driving Force in Molecular Imaging; Schubiger, P. A., Lehmann, L., Friebe,
M., Eds.; Springer-Verlag: Heidelberg, 2007; pp 271-287. (f) Audrain, H.
Angew. Chem., Int. Ed. 2007, 46, 1772–1775. (g) Elizarov, A. M. Lab on Chip
2009, 9, 1326–1333.
(11) Lu, S.; Giamis, A. M.; Pike, V. W. Curr. Radiopharmaceuticals 2009,
2, 49–55.
J. Org. Chem. Vol. 75, No. 10, 2010 3333

Chun et al.
JOCArticle
SCHEME 3. Setup of Microfluidic Apparatus for the Study of Radiofluorination Reactions
length; 31.4 μL for 4-m length), entering reactant solutions
rapidly mix under laminar flow and reach the set reactor
temperature. Reaction time simply equates to the residence
time of reactants within the reactor, which is determined by
the flow rates of the reactants. These flow rates were precisely
determined with mechanically driven syringes. Reaction
stoichiometry was controlled by setting the concentration
of reactants in the loaded solutions and also their flow rates
into the reactor.
In this study we performed reactions with [18F]fluoride ion
in either a no-carrier-added state (NCA) (i.e., at high specific
radioactivity) or a carrier-added (CA) state (at low specific
activity). [18F]Fluoride ion was dried in the presence of the
FIGURE 1. Time-course of [18F]fluorobenzene RCY from reac-
tions of [18F]fluoride ion with diphenyliodonium chloride (5 mM) in
DMF-0.25% water in the presence of 0.5 mM KF-K 2.2.2 at 90,
105, and 110 °C (CA) or in DMF in the presence of K2CO3-K 2.2.2
at 90 °C (NCA).
temperatures (Figure 1). At 90 °C NCA [18F]fluoride ion
gave a RCY higher than that of CA [18F]fluoride ion. CA
reactions performed at higher temperatures gave higher
RCYs. Remarkably, an 85% RCY of [18F]fluorobenzene
was produced from [18F]fluoride ion in <3.2 min at 110 °C.
Clearly the presence of a low concentration of water was well
tolerated in these CA reactions.
2.3. Investigation of the ortho-Effect. An intriguing feature
of the reaction of diaryliodonium salts with nucleophiles is
the influence of ortho substitutents, which have been repor-
ted to direct an incoming nucleophile to attack the same ring
as the substituent.12 Here we wished to study this effect more
closely for the reactions of [18F]fluoride ion with ortho-
substituted diaryliodonium salts. We therefore extended
the application of the microreactor to the study of the
NCA radiofluorination of four (2-methylphenyl)(phenyl)-
iodonium salts in different solvents. Each reaction was
studied at various temperatures up to 200 °C for reaction
times up to 4 min. The highest observed RCYs of [18F]fluoro-
arenes are listed in Table 1 with the corresponding reaction
conditions. Each salt gave a higher RCY in DMF than in
acetonitrile containing a low proportion (1.5%) of water, or
for one salt, the tosylate, in anhydrous acetonitrile. The
cryptand (Kryptofix 2.2.2; K 2.2.2), plus base (K2CO3) to
maintain a NCA state or in the presence of a known amount of
potassium fluoride-K 2.2.2 to produce CA reagent. The
generated [18F]fluoride ion complex was then dissolved in the
solvent for reaction. A solution of the diaryliodonium salt was
prepared in the same solvent. These reagent solutions were
loaded into their respective storage loops in the microreactor
apparatus and fed into the reactor at set flow rates (Scheme 3).
Reactions were quenched by diluting the output of the reactor
in water-acetonitrile (1:1 v/v) at room temperature. Recovery
of radioactivity from the reactor was 83 (19%,(mean(SD, n=
13) and 79 ( 16% (mean ( SD, n=20) for CA and NCA
reactions, respectively. There was no discernible dependence of
these values on the nature of the iodonium salt used in the
reaction. Control experiments showed that all of the retained
radioactivity was polar in reverse phase HPLC analysis, con-
sistent with identity as [18F]fluoride ion. Quenched reaction
mixtures were analyzed by reverse phase radio-HPLC. All
reactions gave a simple radioactive product distribution. Thus,
chromatograms showed only unchanged [18F]fluoride ion (at or
near the solvent front), followed either by one peak for a single
[18F]fluoroarene (from a symmetrical diaryliodonium salt) or
two peaks for two [18F]fluoroarenes (from an unsymmetrical
salt). Recovery of radioactive injectate was checked by collection
of all radioactive eluate fractions and separate measurement in a
dose calibrator. Decay-corrected radiochemical yields (RCYs)
were calculated from the radiochromatograms.
Initially, we tested the feasibility of using the microreactor
apparatus for radiofluorination of a diaryliodonium salt, the
reaction of [18F]fluoride ion with diphenyliodonium chloride.
Reactions were performed with NCA [18F]fluoride ion in
DMF or CA [18F]fluoride ion in DMF-0.25% water at set
(12) (a) Yamada, Y.; Kashima, K.; Okawara, M. Bull. Chem. Soc. Jpn.
1974, 47, 3179–3180. (b) Lancer, K. M.; Wiegand, G. H. J. Org. Chem. 1976,
41, 3360–3364. (c) Yamada, Y; Okawara, M. Bull. Chem. Soc. Jpn. 1972, 45,
1860–1863.
3334 J. Org. Chem. Vol. 75, No. 10, 2010

Chun et al.
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TABLE 1. NCA Radiofluorination of (2-Methylphenyl)(phenyl)iodonium Salts in Different Solvents
RCY of [18F]fluoroarenesa (%)
selectivity for
main product
entry
anion
Cl-
solvent
temp (°C)
time (s)
total
[
18F]2-F-toluene
[
18F]F-benzene
1
2
3
4
5
6
7
8
9
MeCN-1.5% H2O
DMF
MeCN-1.5% H2O
DMF
MeCN-1.5% H2O
DMF
MeCN
MeCN-1.5% H2O
DMF
150
150
150
130
160
130
140
150
130
47
157
94
94
75
126
188
94
46
77
26
99
12
48
12
50
98
32
53
18
67
8
33
9
34
66
14
24
8
32
4
15
3
16
32
2.29
2.21
2.25
2.09
2.00
2.54
3.00
2.13
2.06
Br-
I-
OTs-
126
aHighest observed RCYs (the temperature and times are the conditions giving these yields).
TABLE 2. Radiochemical Yields of [18F]Fluoroarenes from the Radiofluorination of ortho-Substituted Diaryliodonium Salts
diaryliodonium salt (ArIþAr0X-) RCY of [18F]fluoroarene (%)
selectivity for
main product
GTs2 - GTs1
(kcal/mol)
entrya
Ar
Ar0
temp (°C)
time (s)
total
Ar18
F
Ar018F
1
2
3
4
5
6
7
8
Ph
2-MeC6H4
2-MeC6H4
Ph
2-MeC6H4
2-MeOC6H4
2-BrC6H4
2-MeC6H4
Ph
2-MeC6H4
Ph
110
140
110
140
140
140
170
170
170
170
130
150
190
190
188
188
188
188
188
188
236
236
236
236
236
236
236
236
85
83
82
66
79
51
86
95
88
74
92
82
82
93
85
83
57
60
75
51
48
52
48
62
59
63
61
68
25
6.5
4
2.28
9.22
18.8
0.63
1.8
2.4
2-MeOC6H4
2-MeOC6H4
2-MeOC6H4
2-MeC6H4
2-EtC6H4
2-iPrC6H4
2-MeC6H4
2-MeC6H4
Ph
38
43
40
11
33
19
21
25
1.26
1.21
1.20
5.56
1.78
3.24
3.00
2.72
0.20
0.17
0.16
1.5
0.46
0.99
1.0
9
2-MeC6H4
10
11
12
13
14
2,6-di-MeC6H3
2,4,6-tri-MeC6H2
2,4,6-tri-MeC6H2
2,6-di-MeC6H3
2-BrC6H4
2,4,6-tri-MeC6H2
Ph
0.92
aEntries 1-6 were performed with CA [18F]fluoride ion and chloride salts in DMF-0.25% water. Entries 7-11 and 14 were performed with NCA
[
18F]fluoride ion and chlorides in DMF. Entries 12 and 13 were performed with NCA [18F]fluoride ion and tosylates in DMF.
bromide and tosylate of (2-methylphenyl)(phenyl)iodonium
effect, since 2-[18F]fluoroanisole was always the least pre-
ferred product (Table 2, entries 4 and 5). From all the
product selectivity values listed in Table 2, it may be deduced
that the power of ortho substituents to impart an ortho-effect
was in the following order: 2,6-di-Me > 2,4,6-tri-Me > Br >
gave almost quantitative incorporation of [18F]fluoride ion
into [18F]fluoroarenes in DMF, whereas incorporations were
significantly lower for the iodide and chloride. Ermert et al.13
have previously observed the similar reactivity of diarylio-
donium tosylate and bromides with [18F]fluoride ion. In all
of our reactions, [18F]2-fluorotoluene was the major radio-
active product and [18F]fluorobenzene the minor radioactive
product. The selectivity for producing [18F]2-fluorotoluene
was quite similar across reactions, ranging from 2.00 to 3.00,
thereby verifying that a methyl substituent confers an ortho-
effect in these reactions.
i
Me > Et ≈ Pr > H > OMe. The selectivity values will be
useful in the rational design of diaryliodonium salt precur-
sors to 18F-labeled tracers.
The ortho-effect has frequently been ascribed to the steric
influence of the o-substituent on the conformation of the
iodonium salt, leading to a preference for the ortho-substi-
tuted aryl ring to rest in the equatorial plane of a trigonal
bipyramidal structure with therefore easy access for attack
by an apically associated nucleophile. Previous studies on the
ortho-effect have only investigated o-alkyl substituents.12
Our results with o-methoxy substituted diaryliodonium salts
show that the ortho-effect is not purely related to substituent
bulk. Rather than substituent bulk, selectivity may be enhan-
ced by the presence of one or more ortho hydrophobic groups
(e.g., methyl), which create a lipophilic microenvironment in
which the incoming [18F]fluoride ion can act as a powerful
nucleophile, by first loosely binding to the hypervalent
iodine atom and then attacking the locally lipophilic ortho-
substituted ring. Opposing (as for OMe) or reinforcing (as
for Br) electronic influences also appear to be important in
determining product selectivity.
In order to further understand the ortho-effect, studies
were extended to a larger range of diaryliodonium salts
bearing a range of ortho substituents. The radiofluorination
of each salt was studied under either CA or NCA conditions
in dry DMF or wet DMF over various temperatures and
times. Maximal observed RCYs, and the corresponding
reaction conditions, are recorded in Table 2. The total RCYs
of [18F]fluoroarenes were impressively high, ranging from
51% to 95%. Yields were lower for salts bearing an o-
methoxy group, with the symmetrical di-o-methoxy substi-
tuted salt giving lowest yield. For unsymmetrical salts,
product selectivities ranged from 1.20 to 18.8 (Table 2).
Surprisingly, an o-methoxy group failed to confer an ortho-
The reliability of the radiofluorination reactions of diphe-
nyliodonium salts have been claimed to be enhanced by
(13) Ermert, J.; Hocke, C.; Ludwig, T.; Gail, R.; Coenen, H. H. J. Label.
Compd. Radiopharm. 2004, 47, 429–441.
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Chun et al.
JOCArticle
addition of a free-radical scavenger, such as TEMPO.14 In this
study, we found that radiofluorination reactions were consis-
tent and reliable in the absence of a free-radical scavenger. In
fact, in a pilot experiment, we found that TEMPO had no
beneficial effect. In general, iodonium salts are well-known to
show photosensitivity15 and indeed much research has been
directed to their use as photoinitiators.16 The microreactor
device used in this study stores and uses the iodonium salt
reagent in the dark, and this may have contributed to the
reliability of the reactions by avoiding radical generation. The
tolerance of these reactions for a low concentration of water is
also striking and is in accord with a previous claim.17 This
tolerance indicates the generally high reactivity of the iodo-
nium salts for reaction with fluoride ion that is in a moderately
hydrated and therefore moderately nucleophilic state.
FIGURE 2. Kinetics of the radiofluorination of bis(o-methylphenyl)-
iodonium chloride in DMF-0.25% H2O to give [18F]2-fluoro-
toluene at different temperatures.
2.4. Kinetics and Energetics of Radiofluorination Reactions.
Examples of the determination of the Arrhenius activation
energies (Ea) for reactions of [18F]fluoride ion are rare, being
confined to isotopic exchange with polyfluoroarenes.18 The
absence of such data may partly derive from the practical
limitations of working with a short-lived radionuclide from a
cyclotron source. The microreactor apparatus afforded an
opportunity to overcome some of these limitations, since
well-controlled reaction conditions could be established for
rapid sequential reactions from the same “stocks” of radio-
active and nonradioactive reagents. In order to gain kinetic
data and derive Ea values, we decided to perform reactions
with CA [18F]fluoride ion (0.5 mM) with a 10-fold molar
excess of diaryliodonium salt (5 mM) in the presence of
Kþ-K 2.2.2. Fluoride ion nucleophilicity is well known to
depend on the state of ion hydration.1,19 Therefore, we
decided to include a small concentration of water (0.25%
v/v) in the reaction medium (DMF) to control the hydration
of the [18F]fluoride ion at a fixed carrier concentration and
hence its nucleophilicity. Six diaryliodonium chlorides were
studied in this manner. Reactions were performed at various
set temperatures for several reaction times up to 188 s.
Figure 2 shows an example of acquired kinetic data, that
from the reaction of CA [18F]fluoride ion with bis(o-methyl-
phenyl)iodonium chloride. The kinetic data were used to
estimate initial reaction velocities, which were then used in
Arrhenius plots to estimate activation energies (e.g., Figure 3).
The Ea values for the reactions of several diaryliodonium
chlorides with CA [18F]fluoride ion in DMF-0.25% water
were estimated to be in the range 18-28 kcal/mol. Activation
energies appeared to increase as first one substituent, either an
o-methyl or o-methoxy group, and then a second was introdu-
ced into the opposite ring of the diaryliodonium salt (Table 3).
The symmetrical o-methoxy substituted salt was estimated to
FIGURE 3. Arrhenius plot for the reaction of [18F]fluoride ion with bis-
(o-methylphenyl)iodoniumchloride (data derivedfrom that inFigure 2).
The solid line is the best fit determined by linear regression and the
dotted lines are the 90% confidence limits (see Experimental Section).
TABLE 3. Arrhenius Activation Energies (Ea) for the Reactions of
Diaryliodonium Chlorides with CA [18F]Fluoride Ion in DMF-0.25%
H2O (in the Presence of Kþ-K 2.2.2)
diaryliodonium chloride
R0
Ea (kcal/mol)
R
R
R0
H
H
H
2-Me
2-Me
2-MeO
H
2-MeO
2-Me
2-MeO
2-Me
2-MeO
20.9 ( 1.6
22.5 ( 2.9
23.5 ( 1.6
25.1 ( 2.6
27.5 ( 2.0
28.0 ( 1.6
20.9 ( 1.6
n.d.
18.3 ( 0.9
n.d.
27.5 ( 2.0
28.0 ( 1.6
have the highest Ea value. Estimates of Ea values for other
reactions of diaryliodonium salts with nucleophiles have been
reported and fall in the range 19-37 kcal/mol. For example, the
decomposition of various substituted diphenyliodonium halides
(halide=Cl-, Br-, orI-) inDMFoccurredwithEa values in the
range 25.5-36.7 kcal/mol.20 Reactions of diphenyliodonium
salts with phenoxide ions in dioxane-water (1:1 v/v) to give
diphenyl ethers have an Ea value of 25.9 kcal/mol.21
(14) (a) Wadsworth, H. J.; Widdowson, D. A.; Wilson, E.; Carroll, M. A. WO
2005/061415, 2005. (b) Carroll, M. A.; Nairne, J.; Smith, G.; Widdowson, D. A.
J. Fluorine Chem. 2007, 128, 127–132.
(15) Irving, H.; Reid, R. W. J. Chem. Soc. 1960, 2078–2081.
(16) (a) Hacker, N. P.; Leff, D. V.; Dektar, J. L. J. Org. Chem. 1991, 56,
2280–2282. (b) Yagci, Y.; Yilmaz, F.; Kiralp, S.; Toppare, L. Macromol.
Chem. Phys. 2005, 206, 1178–1182. (c) He, J. H.; Mendoza, V. S. J. Polym.
Sci. Part A: Polym. Chem. 1996, 34, 2809–2816. (d) He, J. H.; Zhang, J. C.
J. Polym. Sci. Part A: Polym. Chem. 1999, 37, 4521–4527. (e) He, J. H.;
Zhang, J. C. J. Photochem. Photobiol. 1997, 107, 249–252. (f) Padon, K. S.;
Scranton, A. B. J. Polym. Sci. Part A: Polym. Chem. 2000, 38, 2057–2066. (g)
Merritt, E. A.; Oloffsson, B. Angew. Chem., Int. Ed. 2009, 48, 2–21.
(17) Wadsworth, H. J.; Devenish,T. WO 2005/097713 A1, 2005.
(18) Cacace, F.; Speranza, M.; Wolf, A. P.; Macgregor, R. R. J. Fluorine
Chem. 1982, 21, 145–158.
2.5. Selectivities of Reactions; Compliance with the Curtin-
Hammett Principle and Mechanistic Considerations. During
(20) Beringer, F. M.; Mausner, M. J. Am. Chem. Soc. 1958, 80, 4535–4536.
(21) Beringer, F. M.; Gindler, E. M. J. Am. Chem. Soc. 1955, 77, 3203–3207.
(19) Landini, D.; Maia, A.; Rampoldi, A. J. Org. Chem. 1989, 54, 328–332.
3336 J. Org. Chem. Vol. 75, No. 10, 2010

Chun et al.
JOCArticle
SCHEME 4. Suggested Outline Mechanism for the Radiofluor-
ination of an Unsymmetrical Diaryliodonium Salt, through Transi-
tion States TS1 and TS2 To Give Products P1 and P2, Respectively
FIGURE 4. Time-course of the decay-corrected radiochemical yield
(RCY) of [18F]2-fluorotoluene (Δ) and [18F]fluorobenzene (1) and of
the product selectivity (b), from the reaction of CA [18F]fluoride ion
with (2-methylphenyl)(phenyl)iodonium chloride at 110 °C in
DMF-0.25% H2O, in the presence of Kþ-K 2.2.2. Reagents and
Kþ-K 2.2.2 were each initially at 2.5 mM. The dashed line is the line
of linear regression for the product selectivity data.
the accumulation of the data summarized in Table 2, we were
impressed that product selectivities appeared constant for any
particular diaryliodonium salt precursor (small variations oc-
curred more with solvent than with anion; see examples reported
in Table 1). This suggested that reactions might be taking place in
accord with the Curtin-Hammett principle.22 This principle
states that the relative amounts of products formed from two
critical conformations of substrate are completely independent
of the relative populations of the conformations and depend only
upon the difference in the free energy of the transition states,
provided that the rates of reaction are much slower than the rates
of conformational interconversion. The appearance of products
in a constant ratio during the reaction course under set condi-
tions constitutes a test of whether a process that involves one
substrate to give two products complies with the Curtin-
Hammett principle.23 Thus, we set up an experiment with CA
[18F]fluoride ion and (2-methylphenyl)(phenyl)iodonium chlo-
ride as reactants in equimolar proportions in DMF at 110 °Cand
measured the RCYs of the two products with time (Figure 4).
The ratio of products (2.21) was found to be constant over the
measured time course (up to 30% total substrate conversion) in
accord with the Curtin-Hammett principle. The product selec-
tivity was also measured at other temperatures and was essen-
tially invariant. Scrutiny of other data accumulated in this study
revealed very little variation in product selectivity over the time
course of reactions.
Monomeric iodonium cations are expected to be highly
fluxional and able to interconvert through conformations in
which the ligands rapidly interchange equatorial and axial
positions relative to the anion, which is secondarily bonded
to the pivotal hypervalent iodine atom.24 It may be envisaged
that when the anion is an incoming nucleophile it will be able to
attack only the carbon atom in the equatorial ring from an
apical position. Thus, we propose that the radiofluorination of
an unsymmetrical diaryliodonium salt involves attack of
[18F]fluoride ion onto either of two rapidly interconverting
conformers, yielding two transition states that each give a
single radiofluorinated product (Scheme 4). Assuming all of
the radiofluorination reactions follow the Curtin-Hammett
principle, the ratio of radiofluorinated products then depends
solely on the difference in the free energies of the twotransition
states. This difference can be calculated from the product
selectivity value (P1/P2) according to the equation P1/P2 =
e-(G
Ts1 - GTs2
)/RT, whereGTs1 and GTs2 are the free energies of the
transition states 1 and 2, respectively. The values for GTs2
-
GTs1 for the reactions studied here range from 0.16 to 2.4 kcal/
mol (Table 2) and are therefore relatively small compared to
the activation energies for the same reactions (Table 3).
3. Summary
This study demonstrates that microreactor technology can
be excellent for the rigorous and efficient study of radio-
fluorination reactions under well-controlled conditions
using small amounts of material. Furthermore, the reactions
of CA and NCA [18F]fluoride ion with readily synthe-
sized ortho-substituted diaryliodonium salts can produce
[18F]fluoroarenes rapidly and in very high RCYs, even for
salts bearing electron-donating alkyl or methoxy groups.
The powers of individual ortho substituents to impart the
ortho-effect were ranked and showed that this effect is not
due solely to substituent bulk. The activation energies deter-
mined for some of these reactions are within the range
(22) Seeman, J. I. Chem. Rev. 1983, 83, 83–134.
(23) Eliel, E. L.; Wilen, S. H.; Mander, L. N. In Stereochemistry of Carbon
Compounds; Wiley Interscience: New York, 1994; Chapter 10, p 652.
(24) Carroll, M. A.; Martın-Santamarıa, S.; Pike, V. W.; Rzepa, H. S.;
´ ´
Widdowson, D. A. J. Chem. Soc., Perkin Trans. 2 1999, 2707–2714.
J. Org. Chem. Vol. 75, No. 10, 2010 3337

Chun et al.
JOCArticle
estimated for similar reactions of diaryliodonium salts.
Finally, we found evidence that the reactions of [18F]fluoride
ion with unsymmetrical diaryliodonium salts comply with the
Curtin-Hammett principle. These results will aid in our design
of diaryliodonium salts as substrates for producing previously
inaccessible 18F-labeled tracers for molecular imaging.
tions, each solution (10-15 μL) was infused simultaneously into
either the 2-m- or 4-m-length coiled silica glass tube microreactor
of the apparatus at a set flow rate in the range 4-100 μL/min and
preset temperature. The microreactor output was quenched with
MeCN-H2O (1:1 v/v; 1 mL). The radical scavenger, TEMPO
(2,2,6,6-tetramethylpiperidine-1-oxyl), was added to some reac-
tions.14 Amounts of precursor, temperature and flow rates
were varied. Decay-corrected radiochemical yields (RCYs) of
[18F]fluoroarenes were measured by reverse phase radio-HPLC
on a Luna C18 column (250 mm ꢀ 4.6 mm i.d., 10 μm;
Phenomenex, Torrance, CA) eluted at 1.75 mL/min with a
gradient of MeCN-H2O (60:40 v/v) with the percentage of
MeCN increased linearly from 60% to 90% over 7 min.
4.4. Kinetics and Energetics of Radiofluorination Reactions.
Reactions were run between a large molar excess of diaryiodo-
nium salt, relative to fluoride ion, in DMF containing 0.5%
water, in the presence of carrier potassium fluoride and K 2.2.2.
Reaction times were controlled by the rates at which
[18F]fluoride-KF-K 2.2.2 solution and the diaryliodonium
chloride solution were passed through the microreactor. Reac-
tor outputs were quenched by dilution with acetonitrile-water
(1:1 v/v) at room temperature. Reactions were run at a minimum
of six different temperatures each separated by at least 5 °C for
several reaction times ranging up to 188 s. RCYs were deter-
mined by radio-HPLC analysis of reaction products, by com-
paring the integral of the radiochromatogram for each labeled
product with that of unchanged [18F]fluoride ion. Full recovery
of radioactivity from the HPLC system was verified by measure-
ment of all eluted radioactivity in a dose calibrator. With the
program Prism 3.0, RCYs below 20% were plotted against time
(including zero RCY at zero time), and each curve was fitted to a
first-order polynomial. The initial apparent velocities of reac-
tion (V0app, expressed as % RCY/min) were calculated as the
initial slopes of the fitted curves (i.e., as the coefficient of the
second term in the equation of the polynomial fit). ln V0app was
plotted against the inverse of the reaction temperature (1/T,
K-1), and the data fitted to a linear curve with Prism 3.0, which
also provided curves for 90% confidence limits. Arrhenius
activation energies (Ea) were calculated from the fitted slopes,
which equal -Ea/RT (R=gas constant).
4. Experimental Section
Materials, general methods, and details of diaryliodonium
salts syntheses are documented in Supporting Information.
4.1. Production of [18F]Fluoride Ion Reagents.
4.1.1. No-Carrier-Added. Cyclotron-produced no-carrier-
added [18F]fluoride ion (10-200 mCi) in [18O]water (95 atom %,
225-350 μL) was first adsorbed onto a small anion resin
(i.e., MP-1 or QMA) cartridge within the CE module of a
NanoTek apparatus (Advion; Louisville, TN) and then released
with a solution of K2CO3 (0.8 mg; 5 μmol) plus K 2.2.2 (4.5 mg;
11 μmol) in MeCN-H2O (9:1 v/v; 150 μL) into a 5-mL V-vial.
The solution was dried by two cycles of azeotropic evaporation
with acetonitrile (0.45 mL) at 100 °C.
4.1.2. Carrier-added. Cyclotron-produced no-carrier-added
[18F]fluoride ion (120-200 mCi) in [18O]water (225-350 μL)
was dried25 by four cycles of azeotropic evaporation with
acetonitrile (0.65 mL for each addition) at 90 W ꢀ 2 min in a
microwave cavity (type-521; Resonance Instruments Inc., Sko-
kie, IL) housed within a modified Synthia26 module. KF (1 mM)
and K 2.2.2 (1 mM) in 0.5% H2O/DMF (v/v; 400 μL) were
added to the prepared dry 18F--K 2.2.2-Kþ complex and
mixed in a 5-mL V-vial. The solution was then loaded into the
storage loop (255 μL) of the microfluidic apparatus.
4.2. Configuration and Operation of the Microreactor Appa-
ratus. The setup of the LF module used in this work is depicted in
Scheme 3. The microreactor is composed of coiled silica glass
tubing (e.g., length, 4 m; internal diameter, 100 μm; internal
volume, 31.4 μL), housed in a brass ring filled with high-
temperature resistant poly(silicone). The reactor could be
heated and thermostatted to a set temperature. The reactor
may be fed with reagents from storage loops at set flow rates, by
the action of mechanically driven syringes. The reactor may
operate up to pressures of 300 psi, which is monitored.
The apparatus was cleaned by flushing tubes and reactors
with acetonitrile at the beginning of each experimental session
and again at the end. Reagent solutions were loaded into their
respective storage loops from different source vials. To perform
one reaction, 10-20 μL of solution from each loop were infused
(via valve connection from the respective syringe pump f E f
D f C) into the microreactor at a set flow rate and temperature.
A bolus of acetonitrile was then infused from syringe pump 1
(via valve connection from syringe pump 1 f B) to sweep all
reaction mixture out of the microreactor and into the collection
vial via the distribution valve. The volume of the sweeping
solvent just exceeded the aggregate internal volume of the
microreactor and subsequent transfer tubing. Once the source
vials were in place, all operations were programmed to run in
sequence automatically and remotely.
4.5. Test of Curtin-Hammett Principle. Reactions between
CA [18F]fluoride ion (2.5 mM) and (2-methylphenyl)(phenyl)-
iodonium chloride (2.5 mM) in DMF-0.25% water, in the
presence of Kþ-K 2.2.2 (2.5 mM) were performed in the
microfluidic apparatus at 110 °C for various times up to 188 s.
The radiochemical yields of the two radioactive products,
[18F]2-fluorotoluene and [18F]fluorobenzene, were measured,
and the product selectivity for major product, as the ratio of
these two products, was calculated for each reaction time.
Acknowledgment. This research was supported by the
Intramural Research Program (project no. Z01-MH-002793)
of the National Institutes of Health (National Institute of
Mental Health) and also by the NIH Intramural Research
Program through the Center for Information Technology. We
are grateful to the NIH Clinical PET Center for the production
of fluorine-18.
4.3. Radiofluorination Reactions. Dry 18F--K 2.2.2-Kþ
complex (100-150 mCi) was dissolved in reaction solvent
(typically, DMF-0.5% H2O, DMF, or MeCN; 255 μL). A
solution of diaryliodonium salt (10 mM) was prepared in match-
ing solvent. Each of the two solutions (255 μL) was loaded into a
separate storage loop of the microfluidic apparatus. For reac-
Note Added after ASAP Publication. The version published
ASAP April 2, 2010 contained errors in the reported data
due to an error in the computation of microreactor residence
times. Tables 1 and 2, Figures 1-4, and text were corrected in
the version reposted April 22, 2010.
ꢀ
(25) Lazarova, N.; Simeon, F. G.; Musachio, J. L.; Lu, S. Y.; Pike, V. W.
J. Label. Compd. Radiopharm. 2007, 50, 463–465.
(26) Bjurling, P.; Reineck, R.; Westerburg, G.; Gee, A. D.; Sutcliffe, J.;
€
Supporting Information Available: Full experimental and
characterization data for the new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
Langstrom, B. Proceedings of the Sixth Workshop on Targetry and Target
Chemistry; Link, J. M., Ruth, T. J., Eds.; TRIUMF: Vancouver, 1995;
pp 282-284.
3338 J. Org. Chem. Vol. 75, No. 10, 2010