Fluoride-promoted ligand exchange in diaryliodonium salts

Article abstract of DOI:10.1016/j.jfluchem.2010.04.004

Diaryliodonium salts are shown to undergo rapid, fluoride-promoted aryl exchange reactions at room temperature in acetonitrile. Aryl exchange is shown to be exquisitely sensitive to the concentration of fluoride ion in solution; fast exchange is observed as the fluoride concentration approaches a stoichiometric amount at 50 mM substrate concentration. The reaction is slowed, but not halted if benzene is the solvent, indicating that free fluoride ion or a four-coordinate anionic I(III) species may be responsible for the exchange. The fluoride-promoted aryl exchange reaction is general and allows direct measurement of the relative stabilities of diaryliodonium salts featuring different aryl substituents. The aryl exchange reaction may be of practical use for the preparation of hitherto inaccessible diaryliodonium salts, thus it also has implications for labeling radiotracers for molecular imaging with ¹⁸F-fluoride (t_1/2 = 109.7 min).

Full text of DOI:10.1016/j.jfluchem.2010.04.004

Journal of Fluorine Chemistry 131 (2010) 1113–1121
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Fluoride-promoted ligand exchange in diaryliodonium salts
*
Bijia Wang, Ronald L. Cerny, ShriHarsha Uppaluri, Jayson J. Kempinger, Stephen G. DiMagno
Department of Chemistry and Nebraska Center for Materials and Nanoscience, University of Nebraska-Lincoln, Lincoln, NE 68588-0304, USA
A R T I C L E I N F O
A B S T R A C T
Article history:
Diaryliodonium salts are shown to undergo rapid, fluoride-promoted aryl exchange reactions at room
temperature in acetonitrile. Aryl exchange is shown to be exquisitely sensitive to the concentration of
fluoride ion in solution; fast exchange is observed as the fluoride concentration approaches a
stoichiometric amount at 50 mM substrate concentration. The reaction is slowed, but not halted if
benzene is the solvent, indicating that free fluoride ion or a four-coordinate anionic I(III) species may be
responsible for the exchange. The fluoride-promoted aryl exchange reaction is general and allows direct
measurement of the relative stabilities of diaryliodonium salts featuring different aryl substituents. The
aryl exchange reaction may be of practical use for the preparation of hitherto inaccessible
diaryliodonium salts, thus it also has implications for labeling radiotracers for molecular imaging
with 18F-fluoride (t1/2 = 109.7 min).
Received 18 March 2010
Received in revised form 16 April 2010
Accepted 19 April 2010
Available online 27 April 2010
Keywords:
Diaryliodonium salts
Fluorination
Ligand exchange
PET
18F
ß 2010 Elsevier B.V. All rights reserved.
Aryl fluorides
Reductive elimination
1. Introduction
rich 4-methoxyphenyl substituent paired with a relatively
electron-poor aryl substituent, gave surprisingly poor regioselec-
tivity (Fig. 2). Also of interest was that the regioselectivity became
increasingly worse as the reaction progressed. The observation of
the surprisingly better regioselectivity for fluorination of 2, and the
intriguing time course of the regioselectivity of 1 led us to
investigate in detail the reaction of fluoride ion with diaryliodo-
nium salts. These studies led us to discover a remarkably facile,
fluoride-promoted aryl ligand exchange reaction of these com-
pounds.
Positron emission tomography using 18F-labeled radiotracers is
a valuable clinical research and diagnostic technique for human or
animal organ imaging. Although [18F]-2-deoxy-2-fluoro-
D-glucose
is currently the most widely used 18F-fluorinated radiotracer [1–3],
a main focus of recent efforts in radiotracer synthesis has been the
preparation of [18F]-fluorinated aromatic compounds [4–10]. Since
the initial report from Pike in 1995 [11], the radiofluorination of
diaryliodonium salts has garnered attention as
a potential
methodology for late stage introduction of fluorine into diverse
aromatic substrates. This methodology complements typical SNAr-
based approaches by providing a means to fluorinate electron-rich,
as well as problematic electron-poor aromatic rings not easily
accessed by direct substitution (Fig. 1).
To date, electronic substituent effects have provided the best
means to control regioselectivity in diaryliodonium salt decom-
position. It is generally observed that if an unsymmetrically
substituted diaryliodonium salt undergoes thermal decomposition
with 18F-fluoride ion, it is the electron-poor ring that is fluorinated
selectively. During the course of our work with diaryliodonium
salts we observed this trend in regioselectivity, however, we were
also struck by the fact that regioselectivity was not strongly
correlated with the electronic character of the two rings. For
example, the diaryliodonium salt 1, which features an electron-
Aryl transfer from organometallic reagents (Sn, Si, B, Hg, and Li)
[12–20] to monoaryliodine(III) species is commonly used to
prepare diaryliodine(III) compounds. These compounds, in turn,
are used as arylating regents to transfer aryl ligands to organic or
inorganic nucleophiles directly [5,21–29], or in combination with
transition metal catalysis [30–34]. The exchange of aryl ligands on
I(III) centers is in line with the general tendency of these
compounds to engage in reactions typical of organometallic
complexes. Though it has not previously been observed directly,
exchange of aryl ligands among I(III) centers in diaryliodonium
salts has been posited in a few studies. Reutov et al. observed
isotope exchange between diaryliodonium tetrafluoroborates and
[
131I]-labeled aryl iodides at the melting temperatures of the salts
[35]. Reich and Cooperman have shown that 5-aryl-3,7-dimethyl-
5H-dibenziodoles (Fig. 3) exhibit temperature-dependent NMR
spectra [36]. At low temperatures, two methyl groups appear as
singlets at d 2.24 and 2.41 ppm, which coalesce as the temperature
is raised. The line shape changes are reversible and consistent
with degenerate thermal isomerization of the aryl ligand about
* Corresponding author. Tel.: +1 402 472 9895; fax: +1 402 472 9402.
E-mail address: sdimagno1@unl.edu (S.G. DiMagno).
0022-1139/$ – see front matter ß 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2010.04.004

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B. Wang et al. / Journal of Fluorine Chemistry 131 (2010) 1113–1121
Fig. 1. Examples of radiofluorination using diaryliodonium salts [5,11,42]. RCY is the decay-corrected radiochemical yield.
T-shaped iodine. The observation of large negative entropies of
activation and irreproducible rate constants for the isomerization
was interpreted as evidence for an intermolecular ligand exchange
isomerization mechanism (Fig. 3). Although previous reports have
suggested aryl ligand exchange in these compounds, here we show
for the first time that mildly basic ligands, such as fluoride,
promote facile aryl swapping among diaryliodine(III) species at
room temperature.
treatment of the unsymmetrically substituted diaryliodonium salt
1(PF6) with TMAF under the same conditions led to a complex
change in the spectrum (Fig. 5) and an apparent increase in the
number of signals in the aromatic region. Several potential
explanations for this increase in complexity were considered
(Scheme 1), including (1) formation of fluoride bridged syn and
anti dimers, (2) the generation of T-shaped diastereomers with
different aryl groups occupying the axial positions, or (3) fast,
fluoride-promoted aryl ligand exchange resulting in formation of
three distinct diaryliodonium salts.
2. Results and discussion
To test whether the addition of fluoride ion promoted the
formation of bridged dimers, the fluoride salt obtained by
treatment of 1(PF6) with TMAF was further treated with TMS
triflate to generate the I(III) triflates and to remove the fluoride in
the form of TMSF. Even after all traces of fluoride were removed,
the 1H NMR spectrum remained complex and distinct from that of
an independently synthesized 1(OTf). Thus, the formation of
dimers as a possible origin of the observed spectral complexity
could be excluded. To examine whether the addition of fluoride
had promoted formation of two different T-shaped diastereomers,
we independently synthesized 1(OTf), 3(OTf), and 4(OTf) and
subjected them to ES–MS analysis. The pure salt 1(OTf) gave a
single, clean cation peak of m/z = 310.7 (M+ (ꢀOTf)). Similarly,
3(OTf) and 4(OTf) gave cation peaks of m/z = 340.7 and 280.7,
respectively, indicating that these three compounds did not
undergo any exchange reactions during the electrospray ionization
process in the mass spectrometer. In contrast, a preparation of the
triflate salt of 1(OTf) that had been exposed previously to fluoride
ion gave three cation peaks of m/z = 280.7, 310.7, and 340.7,
indicating the presence of three distinct diaryliodonium salts
(Fig. 6). MS–MS analysis of each of these ions indicated that the
principal decomposition product was the corresponding biphenyl
formed by extrusion of iodine. The ES–MS data are consistent with
the formation of three different diaryliodonium compounds upon
treatment of unsymmetrical diaryliodonium salts with fluoride in
solution, and definitively exclude formation of different T-shaped
diastereomers as a possible origin of the complexity observed by
NMR spectroscopy. All data support a remarkably rapid, fluoride-
promoted aryl exchange reaction for unsymmetrically substituted
diaryliodonium salts, and the presence of an equilibrated mixture
of three distinct diaryliodonium fluorides in solution.
Compounds 1–9 (Fig. 4) were prepared by established methods
[16,37–39]. Treatment of the symmetrical diaryliodonium hexa-
fluorophosphates 3(PF6) and 4(PF6) with tetramethylammonium
fluoride (TMAF) in CD3CN gave rise to ion exchange to the
corresponding fluoride salts, 3(F) and 4(F), as was evidenced by the
appearance of a broad singlet in the downfield region of the 19F
NMR spectra (
d
= ꢀ17.9 ppm for 3(F), = ꢀ13.0 ppm for 4(F)) and a
d
concomitant sharpening of the signals for the PF6 anion at
d
= ꢀ72.8 ppm. A general upfield shift of the signals in the aromatic
region was also noted in the 1H NMR spectrum (Fig. 5). In contrast,
Fig. 2. Observed regioselectivity for 1(PF6) (featuring the relatively electron-poor
phenyl substituent) is worse than that of 2(PF6) (featuring relatively electron-rich
3,4-dimethoxyphenyl group): (a) TMAF/CH3CN, evaporation of solvent, addition of
d6-benzene, filtration; (b) 140 8C, 15 min.
We performed a series of control reactions to rule out other
potential origins of the observed aryl exchange reaction. Though
the crystallinity of the PF6 salts is particularly attractive from a

B. Wang et al. / Journal of Fluorine Chemistry 131 (2010) 1113–1121
1115
Fig. 3. Exchange in 5-aryl-3,7-dimethyl-5H-dibenziodoles showing the postulated dimeric transition state [36].
synthetic point of view, diaryliodonium hexafluorophosphates are
never used in radiochemistry studies because their tendency to
liberate 19F-fluoride ion at high temperature results in isotopic
dilution. To investigate whether counterion decomposition was
playing a role in the observed exchange reaction, we investigated
the stability of 1(PF6), 3(PF6) and 4(PF6) in CD3CN. No changes in
the NMR spectra of these compounds were observed, even after the
samples were heated at 80 8C for 24 h. The triflate salts 1(OTf),
3(OTf), and 4(OTf) were also unchanged upon heating in CD3CN.
Treatment of 1(OTf) with 1 equiv. of TMAF in CD3CN also led to
rapid exchange of the aryl ligands, indicating that the weakly
coordinating PF6 and OTf anions behave similarly under these
conditions. Finally, to probe whether TMSOTf played a role in the
exchange reaction, 1(PF6) was treated with tetramethylammo-
nium acetate in CD3CN. Clean ion exchange to 1(OAc) was
observed and the 1H NMR spectrum (Fig. 7) was consistent with a
single unsymmetrically substituted diaryliodonium salt in solu-
tion. Treatment of 1(OAc) with TMSOTf yielded TMSOAc and
1(OTf). The 1H NMR spectrum (Fig. 7) and ES–MS data of 1(OTf)
prepared in this manner were identical to those derived from an
independently prepared sample. All of the control experiments are
consistent with the view that added fluoride promotes the
observed exchange of the aryl ligands on I(III).
Despite the existence of three separate diaryliodonium fluorides
in solution, the 19F NMR spectrum of 1(F) in CD3CN displays one
broad singlet at ꢀ12.3 ppm. This observation is consistent with fast
exchange of fluoride among the three I(III) species. We sought to
slow the exchange rate by removing excess salts, switching to a
nonpolar solvent (d8-toluene) and lowering the temperature, but
under no circumstances could we reach the coalescence tempera-
ture for the exchange. Representative low temperature (ꢀ35, ꢀ60,
and ꢀ80 8C) 19F NMR spectra are shown in Fig. 8.
Fig. 4. Diaryliodonium salts discussed in the work. Throughout the text, the particular counterion of interest (X = PF6, OTf, F) is denoted in parentheses following the
compound number (i.e. 1(PF6)).

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B. Wang et al. / Journal of Fluorine Chemistry 131 (2010) 1113–1121
Fig. 5. 1H NMR spectra in CD3CN of (a) 3(F), (b) 4(F), (c) 1(PF6), (d) 1(PF6) after it was treated with TMAF in CH3CN, desalted with benzene, and dissolved in CD3CN, and (e) a
mixture of 3(F) and 4(F) in CD3CN. Only the aromatic regions are displayed for clarity.
Since radiotracer synthesis using diaryliodonium salts is
typically conducted with nanograms of fluoride ion and a million-
fold excess of potential substrate, we decided to probe the rate of the
aryl exchange process as a function of fluoride ion concentration. As
was seen above, adding 1 equiv. of TMAF to a solution containing
1(PF6) in dry CD3CN allowed the aryl exchange reaction to reach
equilibrium before the first 1H NMR data could be obtained
(approximately 8 min). This rapid equilibration implies a first order
rate constant for the process of at least 1.2 ꢁ 10ꢀ3 sꢀ1. (The simple
kinetic model used to determine this rate constant is ꢀd[Ar1–I–Ar2]/
dt = k([Ar1–I–Ar2] ꢀ [Ar1–I–Ar2]eq) where [Ar1–I–Ar2]eq is the con-
centration of the remaining heterogeneously substituted diarylio-
donium salt once an equilibrium has been established.) In contrast,
when the TMAF concentration was only halved, aryl exchange
became so slow (t1/2 > 24 h) that the rate could not be determined
accurately since it was on the same timescale as room temperature
decomposition processes. With 0.89 equiv. of added TMAF, the
reaction rate was in an intermediate range convenient for
performing a kinetic study by 1H NMR spectroscopy.
dry acetonitrile. (The reaction reached equilibrium in 8 h.) A first
order plot (ln[Ar1–I–Ar2]/[Ar1–I–Ar2]eq vs. t) of these data yielded a
rate constant of 1.15 ꢁ 10ꢀ4 sꢀ1. In a similar study with an only
slightly reduced amount of added TMAF (0.81 equiv.,
a 9%
decrement in [Fꢀ]) the equilibration rate dropped tenfold; the
observed rate constant was 1.06 ꢁ 10ꢀ5 sꢀ1. These observations
suggest that the majority of the fluoride remains bound to the I(III)
center and that a small amount of dissociated fluoride or an anionic
difluorodiaryl I(III) species is responsible for catalyzing the aryl
exchange process. With a substoichiometric amount of added
fluoride, the concentration of dissociated ‘‘free’’ fluoride is low,
leading to a drastic decrease in the rate of aryl group exchange.
These results also suggest that fluoride-promoted aryl exchange
may not be a significant concern under the conditions used
typically for PET radiotracer synthesis where fluoride ion
concentration is very low, and also that this catalyzed exchange
reaction could have synthetic potential.
Recently we found that the fluorination of diaryliodonium salts
could be improved substantially if nonpolar solvents were used
during the thermal decomposition step. Additionally, we found
that the presence of excess salts, even seemingly benign salts such
Fig. 9 shows a set of stacked 1H NMR spectra taken over the
initial 160 min for the reaction of 1(PF6) and 0.89 equiv. of TMAF in
Scheme 1. Possible origins of the additional complexity observed in the 1H NMR spectrum of 1(PF6) after addition of fluoride.

B. Wang et al. / Journal of Fluorine Chemistry 131 (2010) 1113–1121
1117
Fig. 8. 19F NMR spectra of a mixture of 1(F), 3(F) and 4(F) in d8-toluene at various
temperatures.
Similarly, when 1 equiv. of 3(F) was mixed with 1 equiv. of 4(PF6)
in CD3CN solution (to give a total of 0.5 equiv. of fluoride ion), aryl
exchange did not proceed to an observable extent within 24 h.
These results support the conclusion that added tetraalkylammo-
nium salts of weakly coordinating anions do not play a significant
role in the aryl exchange reactions of diaryliodonium salts in
CD3CN.
Fig. 6. ES-MS spectrum of 1(OTf) after it had been treated with TMAF followed by
TMSOTf.
as TMAOTf or TMAPF6, could have a profound and negative impact
upon the amount of fluoroarene produced during this reaction. The
mechanism by which excess salt promotes deleterious side
reactions remains obscure, but a reasonable hypothesis is that
these additional ions serve to balance charge during ligand
exchange reactions, and that ligand exchange reactions are related
to the formation of I(III) species of differing redox potentials.
Accordingly, we investigated whether excess salt, namely the
tetraalkylammonium hexafluorophosphate formed from the ion
exchange reaction, facilitated the aryl ligand exchange process. We
precipitated and isolated 3(F) by treating 3(PF6) with TBAF in THF.
1H and 19F NMR analyses indicated that no TBAPF6 remained in the
sample after this desalting procedure. Compound 4(F) was
desalted by a similar procedure. When 3(F) was mixed with
1 equiv. of 4(F) in acetonitrile, an aryl exchange reaction ensued
which reached equilibrium in less than 10 min (Fig. 5, panel e).
Since one full equivalent of fluoride was present and tetraalk-
ylammonium PF6 was not, this experiment indicates that the
fluoride ion concentration is a much more important determinant
of the aryl exchange rate than the concentration of spectator salts.
To investigate the propensity of aryl ligand exchange to occur
under the high temperature conditions used for aromatic
fluorination, we examined the thermal decomposition of diary-
liodonium salts in the presence of substoichiometric amounts of
TMAF in d6-benzene at 80 8C. In a typical experiment 0.05 mmol of
1(PF6) was dissolved in 0.3 mL of dry acetonitrile and 0.025 mmol
of anhydrous TMAF in 0.3 mL acetonitrile was introduced. The
solvent was removed under reduced pressure, dry d6-benzene was
added to the remaining salts, and the mixture was shaken and
filtered into an NMR tube equipped with a screw top PTFE closure.
1H and 19F NMR revealed that very little, if any aryl exchange
occurred during the sample preparation procedure. The sample
was heated to 80 8C, and the reaction progress was monitored by
NMR spectroscopy. At this temperature both reductive elimination
and aryl exchange were evident. During the course of the reaction
only three decomposition products were formed: fluorobenzene,
iodobenzene and iodoanisole. Importantly, the amount of fluor-
obenzene formed equaled the sum of the amounts of iodobenzene
Fig. 7. Changes observed in the 1H NMR spectrum of 1(PF6) upon treatment with TMAOAc followed by TMSOTf in CD3CN: (a) 1(PF6), (b) 1(OAc), and (c) 1(OTf). The expanded
aromatic regions of the spectra are shown for clarity.

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B. Wang et al. / Journal of Fluorine Chemistry 131 (2010) 1113–1121
substituted diaryliodonium salts remain, 3(F) begins to decompose
to 4-fluoroanisole, albeit at an appreciably slower rate than
fluorobenzene is formed. Thus, the true ‘‘directing group abilities’’
of aryl substituents in diaryliodonium salt fluorination reactions
can only be determined when the fluoride is present at low
concentration and the reaction is monitored to determine which
aryl iodides and which salts are generated during the course of the
functionalization process. Alternatively, the true ability of aryl
ligands on I(III) to direct regioselective functionalization can be
assessed using other nucleophiles that do not promote aryl ligand
exchange. Such nucleophiles include soft, relatively nonbasic
anions such as azide or thiophenoxide [40].
It seems clear from these data that fluoride-promoted aryl
exchange reactions may not play an important role in the
preparation of [18F]-labeled radiotracers because the miniscule
amount of 18F-fluoride added is unlikely to promote aryl ligand
exchange. However, fluoride is not the only anion capable of
promoting aryl swapping in diaryliodonium species; we have
found that other hard bases, including hydroxide, ethoxide, and
phenoxide also promote aryl exchange reactions of diaryliodonium
salts. For example, when an acetonitrile solution of 1(PF6) was
treated with sodium trifluoroethoxide at room temperature, an
immediate ligand exchange reaction occurred. Because of the
increased reactivity of trifluoroethoxide compared to fluoride,
formation of phenyl trifluoroethyl ether was observed (with
excellent selectivity) even at room temperature. As the reaction
progressed, iodobenzene and 4-iodoanisole were produced and the
symmetrical salt 3(OCH2CF3) accumulated. Only after most of the
phenyl-substituted diaryliodonium salts were reduced did 4-(2-
trifluoroethoxy)anisole begin to form. These results mirror exactly
the observations seen for the thermal decomposition of 1(F) at
higher temperature. The alkoxide promoted exchange process may
be responsible, in part, for the fact that hydrolysis reactions of
unsymmetrical diaryliodonium salts are reported to be insensitive
to electronic effects [41]. With these observations in mind, it is
reasonable to consider that use of hydroxide and carbonate bases
in the preparation of 18F-fluoride may give rise to aryl exchange
reactions of diaryliodonium salts during radiochemical syntheses;
thus they should be avoided. Assessments of the ‘‘directing group
abilities’’ of electron-rich arenes may be compromised under such
conditions.
Fig. 9. Stacked 1H NMR spectra (detail showing the p-methoxy region) of 1(PF6) and
0.89 equiv. of TMAF. Elapsed time = 160 min.
and 4-iodoanisole that formed. This observation indicates that
fluorination of benzene occurred by reductive elimination reac-
tions of two different phenyl-substituted iodonium salts (Fig. 10).
It is noteworthy that the regioselectivity for fluorobenzene
formation was perfect; no 4-fluoroanisole was formed under these
substoichiometric conditions (0.5 equiv. of fluoride). Instead, the
symmetrical diaryliodonium salt 3(PF6) accumulated during the
course of the reaction. (An independently prepared sample of
3(PF6) treated 0.5 equiv. of TMAF could only be coaxed to undergo
reductive elimination at appreciable rates at temperatures
significantly higher than 80 8C.) The highly selective formation
of fluorobenzene observed in this case contrasts dramatically with
the results obtained when a full equivalent of fluoride was used
(Fig. 2). Under stoichiometric conditions at 140 8C, a relatively
large amount of 4-fluoroanisole was generated. In addition, the
time course of the reaction 1(PF6) with 1 equiv. of TMAF showed
exceptionally high selectivity for fluorobenzene formation at low
conversion, and only at a much longer reaction time did 4-
fluoroanisole begin to appear. This study makes it clear that aryl
exchange and thermal decomposition are in competition at 80 8C
in benzene, even when substoichiometric amounts of fluoride are
present in solution. If fluoride is still present when no phenyl-
The fluoride-promoted aryl exchange reaction provides a
mechanism by which the relative solution stabilities of various
diaryliodonium salts can be interrogated directly for the first time.
Inspection of Table 1, which lists the relative populations of
symmetrically and unsymmetrically substituted diaryliodonium
salts at equilibrium in benzene, indicates that the unsymmetrically
substituted diaryliodonium salt becomes increasingly more stable
as the electronic disparity between the two rings increases. If two
relatively electron-rich rings are bonded to an I(III) center, as in
Fig. 10. Mechanism for the generation of 4-iodobenzene during the thermal decomposition of 1(F).

B. Wang et al. / Journal of Fluorine Chemistry 131 (2010) 1113–1121
1119
Table 1
Co. and dried under vacuum at 80 8C for 3 days prior to use. All
other reagents were of analytical grade, from Aldrich Chemical
Company. 1H, 13C and 19F NMR spectra were collected and
analyzed in the Instrumentation Center at the University of
Nebraska-Lincoln. 400 MHz (QNP probe) and 500 MHz (CP TXI
Cryoprobe) Bruker NMR spectrometers were used in this study. All
NMR experiments were conducted in tubes sealed with PTFE screw
cap closures to eliminate loss of volatiles. A Q-TOF I tandem mass
spectrometer (Micromass, now Waters) with electrospray ioniza-
tion was used to analyze the samples. Samples were infused in
Equilibrium populations of symmetrically and unsymmetrically substituted
diaryliodonium fluoridesa.
#
Ar1–I–Ar2 (%)
Ar1–I–Ar1 (%)
Ar2–I–Ar2 (%)
1
2
5
6
7
8
9
56
50
22
25
13
<1
18
19
25
22
25
13
<1
18
19
25
74
>98
64
62
50
solution at 5
mL/min by means of a syringe pump. The data were
a
Ratios measured by integration of 1H NMR spectra. Equilibration was
acquired using a mass range of m/z 100–1500. The instrument was
operated at a mass resolution of 5000.
performed treating the corresponding PF6 salts with 1 equiv. of TMAF in
acetonitrile. The solvent was evaporated and the remainder dissolved in d6-
benzene (60 mM total concentration) for NMR analyses.
4.2. General procedure for syntheses of diaryliodonium
hexafluorophosphates
2(F), the observed distribution is simply statistical at equilibrium
in the absence of competing steric effects. In contrast, when
electron-rich and electron-poor aromatic substituents are present,
as in 6(F), the unsymmetrically substituted diaryliodonium salt
predominates. In the case of ortho-methylation of one of the aryl
substituents (as in 7(F) and 8(F)), the additional steric demand in
the vicinity of iodine shifts the equilibrium toward the unsym-
metrically substituted salt, even when other strong electron-
donating substituents are on the ring. These observations are
consistent with an explanation that invokes steric destabilization
of symmetrical diaryliodonium salts bearing ortho-substituents.
Also, it should be noted that while compounds 1–8 feature at least
one electron-rich ring, compound 9 does not. Fluoride-promoted
ligand exchange is also facile for this salt, demonstrating that this
reaction does not require electron-donating substituents on the
arenes.
4.2.1. Method A
In a glove box under N2, 1 mmol of the appropriate 1-
(diacetoxyiodo)arene (322 mg for 1, 352 mg for 3, 390 mg for 5,
347 mg for 6, and 350 mg for 8) was weighed into a glass vial and
1.5 mL of dry acetonitrile was added. A solution of p-toluene-
sulfonic acid monohydrate (190 mg, 1 mmol) in 1.5 mL of dry
acetonitrile was added by syringe. Upon completion of the
addition, anisole (neat, 0.11 mL, 1 mmol) was added and the vial
was sealed and taken out of the glove box. The mixture was
allowed to stir at room temperature for 2 h. Water (10 mL) was
added and the mixture was transferred to a separatory funnel and
extracted (3ꢁ 5 mL) with hexanes. The reserved aqueous layer was
treated with 502 mg (3 mmol) of NaPF6. The white precipitate was
filtered, dried in vacuo, and recrystallized in a mixture of diethyl
ether/dichloromethane to give the purified product.
3. Conclusions
4.2.1.1. Phenyl(4-methoxyphenyl)-iodonium
hexafluorophosphate
8.022 (d,
1(PF6) (78%). [1H] NMR (CD3CN, 400 MHz, 25 8C):
d
In conclusion, we have shown that diaryliodonium species
undergo fluoride-promoted aryl ligand exchange in acetonitrile
and benzene. The data seem to support a mechanism by which a
small amount of dissociated ‘‘free’’ fluoride is responsible for
catalyzing the aryl ligand exchange among I(III) complexes. Aryl
exchange reactions are fast if fluoride is present in nearly
stoichiometric amounts, and become precipitously slower as
fluoride concentration is diminished. Aryl exchange lowers the
apparent regioselectivity of aryl fluoride extrusion from diarylio-
donium fluorides under stoichiometric conditions, but this
problem disappears at low fluoride ion concentration. The
fluoride-promoted aryl exchange reaction is an interesting
mechanistic tool for probing relative solution stabilities of various
diaryliodonium species directly. It is also possible that this reaction
may be useful to prepare novel and currently inaccessible mixed or
symmetrically substituted diaryliodonium salts by inducing aryl
ligand exchange in solutions containing more easily obtained
precursors. The use of such a strategy for diaryliodonium salt
synthesis will be reported separately.
J = 7.6 Hz, 2H, H-20/H-60), 8.011 (d, J = 9.4 Hz, 2H, H-2/H-6), 7.701
(t, J = 7.6 Hz, 1H, H-40), 7.734 (t, J = 7.6 Hz, 2H, H-30/H-50), 7.063 (d,
J = 9.4 Hz, 2H, H-3/H-5), 3.839 (s, 6H, OMe); 13C NMR (CD3CN,
100 MHz, 25 8C)
d
164.77 (C-4), 139.04 (C-2/C-6), 136.22 (C-20/C-
60), 134.27 (C-40), 133.77 (C-30/C-50), 119.58 (C-3/C-5), 115.29 (C-
10), 102.50 (C-1), 57.09 (OMe); 19F NMR (CD3CN, 376 MHz, 25 8C)
d
1
ꢀ72.754 (d, JP–F = 707.7 Hz, PF6ꢀ); HRMS (HRFAB): calcd. for
C
13H12OI [MꢀPF6]+ 310.9925; found 310.9932.
4.2.1.2. Bis(4-methoxyphenyl)iodonium hexafluorophosphate 3(PF6)
(81%). [1H] NMR (CD3CN, 400 MHz, 25 8C):
7.973 (d, J = 9.1 Hz,
4H, H-2/H-20/H-6/H-60), 7.046 (d, J = 9.1 Hz, 4H, H-3/H-30/H-5/H-
d
50), 3.833 (s, 6H, OMe); 13C NMR (CD3CN, 100 MHz, 25 8C)
d 164.61
(C-4/C-40), 138.55 (C-2/C-20/C-6/C-60), 119.42 (C-3/C-30/C-5/C-50),
103.36 (C-1/C-10), 57.06 (OMe); 19F NMR (CD3CN, 376 MHz, 25 8C)
1
d
C
ꢀ72.833 (d, JP–F = 707.3 Hz, PF6ꢀ); HRMS (HRFAB): calcd. for
14H14O2I [MꢀPF6]+ 341.0038; found 341.0036.
4.2.1.3. (3-Trifluoromethylphenyl)(40-methoxyphenyl)-iodonium
hexafluorophosphate 5(PF6) (96%). [1H] NMR (CD3CN, 400 MHz,
4. Experimental
25 8C): d 8.384 (s, 1H, H-2), 8.266 (d, J = 8.1 Hz, 1H, H-6), 8.056 (d,
J = 9.2 Hz, 2H, H-20/H-60), 7.996 (d, J = 8.1 Hz, 1H, H-4), 7.716 (t,
J = 8.1 Hz, 1H, H-5), 7.083 (d, J = 9.2, 2H, H-30/H-50), 3.847 (s, 3H, 40-
4.1. General experimental procedures
OMe); 13C NMR (CD3CN, 100 MHz, 25 8C)
d
164.99 (C-40), 139.99
All reagents were handled under N2. Iodonium salts were
shielded from the light during all operations. Acetonitrile (HPLC
grade, Aldrich) and d6-acetonitrile were distilled from P2O5. d6-
Benzene was distilled under N2 from CaH2. THF was distilled under
N2 from Na/benzophenone. Purified solvents were stored under N2
in Schlenk-style, Teflon-capped storage flasks. Tetramethylammo-
nium fluoride (TMAF) (97%) was obtained from Aldrich Chemical
(C-6), 139.38 (C-20/C-60), 134.44 (C-5), 134.281 (q, J = 33.6 Hz, C-3),
133.08 (q, J = 3.7 Hz, C-2), 133.05 (q, J = 3.7 Hz, C-4), 124.11 (q,
J = 272.8 Hz, CF3), 119.71 (C-30/C-50), 114.83 (C-1), 102.54 (C-10),
57.13 (40-OMe); 19F NMR (CD3CN, 376 MHz, 25 8C)
d
ꢀ63.420 (1JF–
2
1
C = 272.8 Hz, JF–C = 33.6 Hz, CF3), ꢀ72.625 (d, JP–F = 707.1 Hz,
PF6ꢀ); HRMS (HRFAB): calcd. for C14H11OIF3 [MꢀPF6]+ 378.9807;
found 378.9817.

1120
B. Wang et al. / Journal of Fluorine Chemistry 131 (2010) 1113–1121
4.2.1.4. (3-Cyanophenyl)(40-methoxyphenyl)-iodonium hexafluoro-
phosphate 6(PF6) (74%). [1H] NMR (CD3CN, 400 MHz, 25 8C):
4.2.3. Method C
d
In a glove box under N2, 1-(diacetoxyiodo)-4-bromobenzene
8.389 (t, J = 1.6 Hz, 1H, H-2), 8.273 (dd, J1 = 8.2 Hz, J2 = 1.6 Hz, 1H,
H-6), 8.038 (d, J = 9.4 Hz, 2H, H-20/H-60), 8.017 (dd, J1 = 8.2 Hz,
J2 = 1.6 Hz, 1H, H-4), 7.665 (t, J = 8.2 Hz, 1H, H-5), 7.082 (d, J = 9.4,
2H, H-30/H-50), 3.850 (s, 3H, 40-OMe); 13C NMR (CD3CN, 100 MHz,
(401 mg, 1 mmol) was weighed into a glass vial and dry
acetonitrile (3 mL) was added. A solution of p-toluenesulfonic
acid monohydrate (190 mg, 1 mmol) in 3 mL of dry acetonitrile
was added by syringe. Upon completion of the addition,
trimethylstannylbenzene (240 mg, 1 mmol) was added and the
vial was sealed, removed from the glove box, and the mixture was
allowed to stir at room temperature for 2 h. Water (20 mL) was
added and the mixture was transferred to a separatory funnel and
extracted (3ꢁ 5 mL) with hexanes. The reserved aqueous layer was
treated with NaPF6 (502 mg, 3 mmol). The white precipitate was
filtered, dried in vacuo, and recrystallized in a mixture of diethyl
ether/dichloromethane to give phenyl(4-bromophenyl)-iodonium
25 8C)
d
165.04 (C-40), 140.40 (C-6), 139.50 (C-2), 139.47 (C-20/C-
60), 137.79 (C-5), 134.13 (C-4), 119.75 (C-30/C-50), 117.63 (C-3),
116.75 (CN), 114.53 (C-1), 102.56 (C-10), 57.16 (40-OMe); 19F NMR
1
(CD3CN, 376 MHz, 25 8C)
d
ꢀ72.675 (d, JP–F = 707.5 Hz, PF6ꢀ);
HRMS (HRFAB): calcd. for C14H11NOI [MꢀPF6]+ 335.9885; found
335.9876.
4.2.1.5. (2,5-Dimethylphenyl)(40-methoxyphenyl)-iodonium hexa-
fluorophosphate 8(PF6) (62%). [1H] NMR (CD2Cl2, 400 MHz,
9(PF6) (400 mg, 75%). 1H NMR (CD3CN, 400 MHz, 25 8C):
d 8.076 (d,
25 8C):
d
7.88 (d, J = 9.1 Hz, H-20/H-60, 2H), 7.83 (s, H-6, 1H),
J = 7.6 Hz, 2H, H-20/H-60), 7.954 (d, J = 8.8 Hz, 2H, H-2/H-6), 7.740
(t, J = 7.6 Hz, 1H, H-40), 7.708 (d, J = 8.8 Hz, 2H, H-3/H-5), 7.562 (t,
7.41 (s, H-3/H-4, 2H), 7.03 (d, J = 9.1 Hz, H-30/H-50, 2H), 3.85 (s, 40-
OMe, 3H), 2.59 (s, 2-Me, 3H), 2.37 (s, 5-Me, 3H); 13C NMR (CD2Cl2,
100 MHz, 25 8C)
J = 7.6 Hz, 2H, H-30/H-50); 13C NMR (CD3CN, 100 MHz, 25 8C)
d
d
164.2 (C-40), 141.7 (C-2), 138.5 (C-5), 137.8 (C-20/
138.07 (C-2/C-6), 136.60 (C-3/C-5), 136.54 (C-20/C-60), 134.35 (C-
C-60), 137.1 (C-6), 135.4 (C-4), 132.6 (C-3), 119.4 (C-30/C-50), 118.0
(C-1), 98.7 (C-10), 56.5 (40-OMe), 25.3 (2-Me), 20.9 (5-Me); HRMS
(HRFAB): calcd. for C15H16OI [MꢀPF6]+ 339.0246, 340.0279; found
339.0239, 340.0277.
40), 133.68 (C-30/C-50), 128.89 (C-4), 114.48 (C-10), 112.27 (C-1); 19F
1
NMR (CD3CN, 376 MHz, 25 8C)
d
ꢀ72.851 (d, JP–F = 706.0 Hz,
PF6ꢀ); HRMS (HRFAB): calcd. for C12H9BrI [MꢀPF6]+ 358.8932,
360.8912; found 358.8938, 360.8904.
4.2.2. Method B
4.3. Syntheses of diaryliodonium triflates
In a glove box under N2, 1-(diacetoxyiodo)-4-methoxybenzene
(352 mg, 1 mmol) was weighed into a glass vial and 1.5 mL of dry
acetonitrile was added. A solution of p-toluenesulfonic acid
monohydrate (190 mg, 1 mmol) in 1.5 mL of dry acetonitrile
was added by syringe. Upon completion of the addition, 1 equiv. of
the appropriate tributylstannylarene (427 mg for 2, 442 mg for 7)
was added and the vial was sealed and taken out of the glove box.
The mixture was allowed to stir at room temperature for 2 h. Water
(10 mL) was added and the mixture was transferred to a separatory
funnel and extracted (3ꢁ 5 mL) with hexanes. The reserved
aqueous layer was treated with 502 mg (3 mmol) of NaPF6. The
white precipitate was filtered, dried in vacuo, and recrystallized in
a mixture of diethyl ether/dichloromethane to give the purified
product.
4.3.1. Phenyl(4-methoxyphenyl)-iodonium triflate 1(OTf)
To a stirred suspension of diacetoxyiodobenzene (660 mg,
2.05 mmol) in 10 mL dry methylene chloride at 0 8C under N2,
triflic acid (0.36 mL, 4.10 mmol) was added dropwise via syringe.
The mixture was stirred at 0 8C for 5 min and then at room
temperature for 1 h. The resulting clear yellow solution was cooled
to 0 8C and anisole (0.25 mL, 2.30 mmol) was added dropwise via
syringe. The resulting blue colored solution was stirred at 0 8C for
5 min and then at room temperature for 30 min. The volatiles were
removed in vacuo to obtain a dark brown oil which was triturated
with diethyl ether. The solvent was removed in vacuo to obtain an
off white solid which was triturated with diethyl ether. The solid
was collected by filtration and washed with diethyl ether to yield
the product 1(OTf) as a colorless, fine powdery solid (651 mg,
4.2.2.1. (3,4-Dimethoxyphenyl)(40-methoxyphenyl)-iodonium hexa-
70.7%). 1H NMR (500 MHz, CD3CN, 25 8C):
d 8.042 (d, J = 8.5 Hz, 2H,
fluorophosphate 2(PF6) (72%). [1H] NMR (CD3CN, 400 MHz,
H-20/H-60), 8.017 (d, J = 9.1 Hz, 2H, H-2/H-6), 7.690 (t, J = 7.6 Hz,
1H, H-40), 7.524 (t, J = 8.0 Hz, 2H, H-30/H-50), 7.055 (d, J = 9.1 Hz, 2H,
25 8C):
d
7.986 (d, J = 9.1 Hz, 2H, H-20/H-60), 7.647 (dd,
J1 = 8.9 Hz, J2 = 2.2 Hz, 1H, H-6), 7.558 (d, J = 2.2 Hz, 1H, H-2),
7.049 (d, J = 9.1 Hz, 2H, H-30/H-50), 7.022 (d, J = 8.9 Hz, 1H, H-5),
3.845 (s, 3H, 3-OMe), 3.843 (s, 3H, 40-OMe), 3.834 (s, 3H, 4-OMe);
H-3/H-5), 3.835 (s, 3H, OMe). 13C NMR (125 MHz, CD3CN, 25 8C):
d
164.67 (C-4), 139.02 (C-2/C-6), 136.23 (C-20/C-60), 134.14 (C-40),
133.66 (C-30/C-50), 122.37 (q, JC–F = 320.9 Hz, CF3SO3ꢀ), 119.47 (C-
3/C-5), 115.49 (C-10), 102.80 (C-1), 57.06 (OMe). 19F NMR
13C NMR (CD3CN, 100 MHz, 25 8C)
d
164.58 (C-40), 154.62 (C-4),
152.50 (C-3), 138.49 (C-20/C-60), 130.65 (C-6), 119.38 (C-2),
119.13 (C-30/C-50), 115.52 (C-5), 103.37 (C-1), 102.64 (C-10), 57.49
(376 MHz, CD3CN, 25 8C):
d
ꢀ79.29 (s, CF3SO3ꢀ).
(3-OMe), 57.14 (40-OMe), 57.05 (4-OMe); 19F NMR (CD3CN,
4.3.2. Bis(4-methoxyphenyl)iodonium triflate 3(OTf)
1
376 MHz, 25 8C)
(HRFAB): calcd. for
371.0156.
d
ꢀ72.786 (d, JP–F = 705.8 Hz, PF6ꢀ); HRMS
In a flame-dried 25 mL Schlenk flask charged with N2, 1-
(diacetoxyiodo)-4-methoxybenzene (753.0 mg, 2.13 mmol) was
dissolved in 7 mL dry methylene chloride. With stirring, anisole
(0.93 mL, 8.52 mmol) was added by syringe. The solution was
cooled to ꢀ10 8C in a sodium chloride-ice bath. To this solution,
triflic acid (0.21 mL, 2.34 mmol) was added dropwise over the
course of 10 min by syringe. A deep blue color was immediately
observed upon addition. After addition, the solution was allowed
to warm slowly to room temperature overnight. The volatiles were
removed in vacuo to obtain a crude solid. The solid was redissolved
in methylene chloride and precipitated with a 10% solution of ether
in hexanes to yield bis(4-methoxyphenyl)iodonium triflate as a
colorless solid (729.6 mg, 69.5%). 1H NMR (400 MHz, CD3CN,
C
15H16O3I [MꢀPF6]+ 371.0144; found
4.2.2.2. (2-Methyl-4,5-dimethoxyphenyl)(40-methoxyphenyl)-iodo-
nium hexafluorophosphate 7(PF6) (75%). [1H] NMR (CD3CN,
400 MHz, 25 8C):
d
7.939 (d, J = 9.2 Hz, 2H, H-20/H-60), 7.593 (s,
1H, H-6), 7.055 (d, J = 9.2 Hz, 2H, H-30/H-50), 7.026 (s, 1H, H-5),
3.835 (s, 6H, 3/40-OMe), 3.828 (s, 3H, 4-OMe), 2.550 (s, 3H, 2-Me);
13C NMR (CD3CN, 100 MHz, 25 8C)
d
164.45 (C-40), 154.63 (C-4),
150.46 (C-5), 138.28 (C-20/C-60), 136.71 (C-2), 120.59 (C-6),
119.41 (C-30/C-50), 115.28 (C-3), 107.01 (C-1), 102.58 (C-10), 57.51
(3-OMe), 57.14 (40-OMe), 57.04 (4-OMe); 19F NMR (CD3CN,
1
376 MHz, 25 8C)
(HRFAB): calcd. for
385.0313.
d
ꢀ72.735 (d, JP–F = 706.9 Hz, PF6ꢀ); HRMS
25 8C):
J = 8.8 Hz, 2H, H-3/H-30/H-5/H-50), 3.829 (s, 3H, OMe). 13C NMR
(100 MHz, CD3CN, 25 ?C):
164.258 (C-4/C-40), 138.280 (C-2/C-20/
d
7.981 (d, J = 8.8 Hz, 2H, H-2/H-20/H-6/H-60), 7.038 (d,
C
16H18O3I [MꢀPF6]+ 385.0301; found
d

B. Wang et al. / Journal of Fluorine Chemistry 131 (2010) 1113–1121
1121
ꢀ
C-6/C-60), 122.148 (q, J = 320.8 Hz, CF3SO3 ), 119.066 (C-3/C-30/C-
Acknowledgments
5/C-50), 103.383 (C-1/C-10), 56.772 (OMe). 19F NMR (376 MHz,
CD3CN, 25 8C):
d
ꢀ79.249 (s, CF3SO3ꢀ).
We thank the National Science Foundation (CHE 0717562) for
support and the National Institutes of Health (RR016544-01) for
infrastructure to conduct this research.
4.3.3. Diphenyliodonium triflate 4(OTf)
To a stirred suspension of diacetoxyiodobenzene (660 mg,
2.05 mmol) in 10 mL dry methylene chloride at 0 8C under N2,
triflic acid (0.36 mL, 4.10 mmol) was added dropwise via syringe.
The mixture was stirred at 0 8C for 5 min and then at room
temperature for 1 h. The resulting clear yellow solution was cooled
to 0 8C and benzene (0.37 mL, 4.10 mmol) was added dropwise via
syringe. The resulting solution was stirred at 0 8C for 5 min and
then at room temperature for 30 min. The volatiles were removed
in vacuo to obtain a crude brown solid which was triturated with
diethyl ether. The solid was collected by filtration and washed with
diethyl ether to yield the product 4(OTf) as a light brown flaky
crystalline solid (726 mg, 82.4%). 1H NMR (500 MHz, CD3CN,
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7.457 (t, J = 7.5 Hz, 2H, H-4/H-40), 7.299 (t, J = 7.5 Hz, 4H, H-3/H-30/
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7.819 (d, J = 7.5 Hz, 4H, H-2/H-20/H-6/H-60),
d
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To a solution of the appropriate diaryliodonium hexafluoropho-
sphate (0.05 mmol in 0.3 mL of d3-acetonitrile) was slowly added a
solution of TMAF (0.05 mmol) in d3-acetonitile (amount varied).
The resulting solution was mixed well and transferred into an NMR
tube equipped with a Teflon screw cap closure. The progress of the
reaction was monitored by 1H NMR spectroscopy; rates were back
calculated based upon the deconvoluted peak areas.