Crystal Structures of Diaryliodonium Fluorides and Their Implications for Fluorination Mechanisms

Article abstract of DOI:10.1002/chem.201604803

The radiofluorination of diaryliodonium salts is of value for producing radiotracers for positron emission tomography. We report crystal structures for two diaryliodonium fluorides. Whereas diphenyliodonium fluoride (1 a) exists as a tetramer bridged by four fluoride ions, 2-methylphenyl(phenyl)iodonium fluoride (2 a) forms a fluoride-bridged dimer that is further halogen bonded to two other monomers. We discuss the topological relationships between the two and their implications for fluorination in solution. Both radiofluorination and NMR spectroscopy show that thermolysis of 2 a gives 2-fluorotoluene and fluorobenzene in a 2 to 1 ratio that is in good agreement with the ratio observed from the radiofluorination of 2-methylphenyl(phenyl)iodonium chloride (2 b). The constancy of the product ratio affirms that the fluorinations occur via the same two rapidly interconverting transition states whose energy difference dictates chemoselectivity. From quantum chemical studies with density functional theory we attribute the “ortho-effect” to the favorable electrostatic interaction between the incoming fluoride and the o-methyl in the transition state. By utilizing the crystal structures of 1 a and 2 a, the mechanisms of fluoroarene formation from diaryliodonium fluorides in their monomeric, homodimeric, heterodimeric, and tetrameric states were also investigated. We propose that oligomerization energy dictates whether the fluorination occurs through a monomeric or an oligomeric pathway.

Full text of DOI:10.1002/chem.201604803

A Journal of
Accepted Article
Title: Crystal Structures of Diaryliodonium Fluorides and their
Implications for Fluorination Mechanisms
Authors: Yong Sok Lee, Joong-Hyun Chun, Milan Hodošček, and
Victor Pike
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Chemistry - A European Journal
10.1002/chem.201604803
Crystal Structures of Diaryliodonium Fluorides and their Implications for
Fluorination Mechanisms
a
b,d
c
b
Yong-Sok Lee, Joong-Hyun Chun, Milan Hodošček, and Victor W. Pike
a
Center for Molecular Modeling, Office of Intramural Research, Center for Information Technology,
National Institutes of Health, Building 12A, Rm 2049, Bethesda, MD 20892, United States
bMolecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Rm.
B3C346A, 10 Center Drive, Bethesda, MD 20892, United States
c
National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, United
States, and National Institute of Chemistry, Ljubljana, Slovenia
dPresent address: Department of Nuclear Medicine, Yonsei University College of Medicine,
5
0-1 Yonsei-ro, Seodaemun-gu, 03722, South Korea
Abstract: The radiofluorination of diaryliodonium salts is of value for producing radiotracers for positron
emission tomography. We report crystal structures for two diaryliodonium fluorides. Whereas
diphenyliodonium fluoride (1a) exists as a tetramer bridged by four fluoride ions, 2-
methylphenyl(phenyl)iodonium fluoride (2a) forms a fluoride-bridged dimer that is further halogen-
bonded to two other monomers. We discuss the topological relationships between the two and their
implications for fluorination in solution. Both radiofluorination and NMR spectroscopy show that
thermolysis of 2a gives 2-fluorotoluene and fluorobenzene in a 2 to 1 ratio that is in good agreement with
the ratio observed from the radiofluorination of 2-methylphenyl(phenyl)iodonium chloride (2b). The
constancy of the product ratio affirms that the fluorinations occur via the same two rapidly interconverting
transition states whose energy difference dictates chemoselectivity. From quantum chemical studies with
density functional theory we attribute the ‘ortho-effect’ to the favorable electrostatic interaction between
1
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10.1002/chem.201604803
the incoming fluoride and the o-methyl in the transition state. By utilizing the crystal structures of 1a and
a, the mechanisms of fluoroarene formation from diaryliodonium fluorides in their monomeric,
2
homodimeric, heterodimeric, and tetrameric states were also investigated. We propose that
oligomerization energy dictates whether the fluorination occurs through a monomeric or an oligomeric
pathway.
Introduction
Diaryliodonium salts (Ar
2
IX; diaryl- -iodanes) are hypervalent iodine compounds that have found
3
extensive applications in synthetic organic chemistry, including use as arylating agents, oxidizing agents,
and photoinitiators for polymerization.[1] These salts are reactive towards a variety of organic and
inorganic nucleophiles.[2] Of particular interest is their reactivity towards cyclotron-produced
[18
F]fluoride ion (t1/2 = 109.8 min), an important radioisotope for labeling radiotracers used in molecular
[3]
imaging with positron emission tomography (PET), a powerful clinical and biomedical research tool.[4]
1
8
The radiofluorination of diaryliodonium salts is among few metal-free methods that may use [ F]fluoride
ion to radiofluorinate electron-rich or electron-poor arenes at any desired ring position.[5,6] Consequently,
this methodology finds increasing application for direct late-stage labeling of small-molecule
radiotracers[7] and also for the preparation of monofunctionalized [ F]fluoroarenes as synthons for
18
[8]
labeling structurally more complex radiotracers, such as proteins (Figure 1). Prominent examples of
18
[7b]
[18F]4-fluoro-m-
radiotracers prepared directly by this method include [ F]flumazenil,
hydroxyphenethylguanidine,[7d] [18F]FIMX,[7e] and [ F]UCB-H (Figure 1). Mechanistic details on the
radiofluorination of diaryliodonium salts are nonetheless lacking. Improved mechanistic understanding
might be informative on the design of higher-performing diaryliodonium salts as substrates in future PET
radiotracer development.
18
[7i]
2
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Figure 1. Examples of a) radiolabeling synthons and b) prominent PET radiotracers produced directly by the
radiofluorination of diaryliodonium salts.
Diaryliodonium salts are fluxional T-shaped molecules in which aryl rings rapidly switch axial and
equatorial positions in trigonal bipyramidal geometry, a process described as pseudorotation.
Radiofluorination reactions under metal-free conditions are usually presumed to proceed through the
-
general pathway enunciated for reactions of nucleophiles (Nu ) with diaryliodonium salts (Scheme 1),
namely through ligand exchange followed by ligand coupling to either aryl ring with reductive elimination
of aryl iodide.[9] Direct nucleophilic aromatic substitution (S
N
Ar) on an ipso carbon atom has also been
suggested for several nucleophiles,[2a,2d,2f,2i,2m,3] including [ F]fluoride ion.
18
[3]
Clearly, diaryliodonium
3
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salts with identical aryl rings react with nucleophiles to give a single product (ArNu), whereas a salt with
dissimilar aryl rings (ArIAr’X) may give two products (ArNu and Ar’Nu). Generally, however
unsymmetric salts (Ar ≠ Ar’) are much easier to prepare than symmetric salts, and in their synthetic
applications for the arylation of nucleophiles provide for easier product separations from aryl iodide
byproduct.[1a,10] From a radiosynthesis standpoint, an understanding of the mechanistic features that
1
8
control the ratio of the two possible [ F]fluoroarene products is desirable to avoid wastage of radioactivity
and to simplify product purifications.
Scheme 1. General scheme for the reaction between diaryiodonium salts and nucleophiles.
In the absence of a substituent ortho to either carbon bonded to the hypervalent center, diaryliodonium
salts react with nucleophiles to couple the nucleophile to the least electron-rich ring.[1a, 2d,3a,3b,,11] This has
1
8
[3b,11]
been well exemplified for [ F]fluoride ion as nucleophile.
Thus, fluorination chemoselectivity for
aryl(2-thienyl)iodonium bromides has been correlated with the Hammett  constant of the substituent in
the electron-deficient aryl ring.[3b] For halide nucleophiles, o-alkyl substituents frequently promote
preferential ligand coupling to the ortho substituted ring, even when this ring may be more electron-rich
than the partner aryl ring.[3c,12] Again, this has been studied with [ F]fluoride ion as nucleophile.
18
[3c]
Various explanations have been proposed for the ‘ortho effect’ in the reactions of nucleophiles with
diaryliodonium salts. The earliest of these explanations was that the o-methyl group imparted strain in
the transition state of an aromatic nucleophilic substitution reaction, thereby promoting extrusion of the
iodide of the partner aryl group.[12a] Subsequently a steric effect in a trigonal bipyramidal intermediate
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having the nucleophile in apical position was considered responsible. The equatorial position in such an
intermediate was considered to be less crowded than the apical position.[12b] Therefore, in cases where
an o-substituted aryl ring is more bulky than its aryl partner, the o-substituted ring was expected to prefer
the equatorial position and to be more available for ligand coupling.[12b] However, subsequent findings
are not entirely consistent with this mechanistic model. For example Malmgren et al.[2k] found that the
introduction of two o-alkyl groups on the same ring actually inverts chemoselectivity for reactions of
diaryliodonium salts with malonate, a carbon nucleophile, an effect they dubbed an ‘anti ortho effect’.
Also the same diaryliodonium salts treated with a nitrogen nucleophile, namely aniline, failed to show an
ortho effect. In their work Malmgren et al.[2k] found that o-methoxy substituents did not exert ortho
effects. Limited data suggest that this is also true of o-methoxy groups in radiofluorination.[3c]
Clearly, questions remain with respect to understanding the unusual mechanistic influence of
substituents placed in ortho position to the hypervalent iodine atom, especially with regard to control of
chemoselectivity. Computational studies can be of value for understanding experimental findings and for
gaining deeper mechanistic insights. Few computational studies have been performed that are relevant to
the reactions of diaryliodonium salts with nucleophiles.[2k,13] In general, they support the general tandem
ligand exchange-ligand coupling model described in Scheme 1. For example, Malmgren et al.[2k]
performed density functional theory (DFT) calculations and these supported the ligand coupling
mechanism and well predicted the chemoselectivities seen in their experiments on the reactions of various
nucleophiles with diaryliodonium salts. One recent computational study[13d] has found that differences in
partial charge between the ipso carbons of the aryl ligands correlated well with chemoselectivity for meta-
and para-substituted diaryliodonium salt reactions with azide. However, this was not so for ortho-
substituted salts. Another study[13e] concluded from DFT computations that the chemoselectivity of the
1
8
reaction of [ F]fluoride ion with diaryliodonium salts is controlled by transition state energy difference,
as was much earlier suggested based on ab initio and MNDO-d SCF-MO computations on extrusion
reactions of R
2
I-F intermediates generated from disubstituted dialkynyl iodonium salts.[13a] This and a
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subsequent study[13b] strongly alluded to a possible role for salt oligomers that has not received any
subsequent attention, except recently for the radioiodination and astatination of diaryliodonium salts.[2m]
Here we aimed to gain deeper insights into aspects of the mechanism of the radiofluorination of
diaryliodonium salts, including the possible role of oligomers, in order to provide a more rational basis
for further application of this radiolabeling method to the development of new PET radiotracers. A key
question was the structure of diaryliodonium salts in organic solution, because this knowledge is essential
for formulating an understanding of the radiofluorination process, which is typically conducted in a polar
aprotic solvent such as acetonitrile, N,N-dimethylformamide (DMF), or DMSO.[3,5a] In this regard, X-ray
crystallography can provide important clues to solution structure. A few structures of crystalline
diaryliodonium salts have been published and these show the capacity of salts to exist as oligomers
connected by anion bridges.[14] However, to our knowledge the solid-state structure of any example of a
diaryliodonium fluoride (Ar IF), which would be particularly relevant to our interest, has not been
2
reported hitherto. The fluoride ion is special among the halide ions because of the strong electronegativity
of the fluorine atom, its strong propensity to hydrate or, on the contrary, to show high nucleophilicity in
naked form.[5a]
Herein, we report the crystal structures of two diaryliodonium fluorides, 1a and 2a (Figure 2). Based
on these crystal structures, quantum chemical analyses were performed on the fluorides 2a, 3a, 4a, 7 and
8
in monomeric conformation to elucidate the origin of the ‘ortho effect’. We also investigated the
mechanisms for the fluorination for diaryliodonium salts in monomeric, homodimeric, heterodimeric, and
tetrameric states at the level of B3LYP/DGDZVP in order to assess the micro-environmental effect on
the fluorination activation energy (E
a
), as well as the feasibility of fluorination occurring in oligomeric
states.
6
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Figure 2. Diaryliodonium salts discussed and referred to in this study.
Results and Discussion
X-ray structures of diphenyliodonium fluoride and 2-methylphenyl(phenyl)iodonium fluoride
Diphenyliodonium fluoride (1a) and 2-methylphenyl(phenyl)iodonium fluoride (2a) (Figure 1) were
prepared by literature methods. For example, commercially available diphenyliodonium tosylate was first
converted into diphenyliodonium iodide (1d) in aqueous acetonitrile by anion metathesis with potassium
iodide,[3c] followed by reaction with silver(I) oxide and then acidification with 10% aqueous hydrogen
fluoride solution[15] (see Supporting Information). Single crystals of 1a and 2a were then obtained by the
slow evaporation of their acetonitrile solutions in plastic vials.
Unlike the standard halide-bridged dimeric crystal structures of the higher halide salts Ph IX (X = Cl,
2
Br, or I; 1b–1d),[14] the fluoride salt 1a crystallized as a tetrameric structure featuring an eight-membered
ring held together by secondary IF bonds having an average length of 2.545 Å (Figure 3). Isomorphic
IBr[14b] and XeF
[16]
in which (p-
eight-membered rings have also been observed for (p-MeC
6
H
4
)
2
6
I+ and XeF +


MeC form a secondary bond to the respective Br and F species. These crystal
6
H
4
)
2
5
structures, together with the previous characterization of a tetrameric cluster of 2-methylphenyl(2’-
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methoxyphenyl)iodonium chloride (4b) in acetonitrile by LC-MS/MS,[14e] strongly indicate that
tetrameric diaryliodonium fluorides can be stable structures, even in solution. An eight-membered I―F
ring has also been seen in the crystal structure of 2-difluoroiodo-5-tert-butylxylene, which has two
covalent I―F bonds of approximately equal length (average lengths = 2.019 Å and 1.991 Å).[17]
However, in this difluoroiodo compound the average intermolecular IF distance is longer at 2.93 Å; this
is shorter than the sum of van der Waals radii of I and F (3.50 Å) but is 0.38 Å longer than the average
IF distance in 1a (2.545 Å). This comparison clearly indicates that the iodine-fluoride interaction in
diaryliodonium fluorides is secondary bonding,[18] as has been reported also for the iodine-halide
interactions in the crystal structures of 1b–1d[14a] and of (p-MeC
H
4
)
IBr.[14b]
6
2
Figure 3. Crystal structure of 1a together with the two water and two acetonitrile molecules from the crystallization
solvent. Both bond lengths and H-bonding distances are shown in Å. Carbon atoms are shown in green, hydrogen
atoms in white, oxygen atoms in red, iodine atoms in violet, nitrogen atoms in dark blue and fluorine atoms in gray.
Blue distances are IF bonds; red distances are H bonds. Since the unit cell has the center of inversion, only non-
redundant bond distances are shown. The inset gives a formulaic planar view of the structure with water and
acetonitrile molecules omitted.
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Besides the eight-membered IF ring of 1a, the detailed crystal structure shows that each of the four
bridging fluoride ions also forms a hydrogen bond (average FH = 1.90 Å) with one of the two
neighboring water molecules, each of which is also positioned to form a weak hydrogen bond with the
methyl hydrogens of an acetonitrile molecule (Figure 3). The geometry optimization of 1a at the level of
B3LYP/DGDZVP in the gaseous phase gave 2.555 Å as the average IF distance, the same as that seen
in the crystal structure. The experimental and calculated average distances between the ipso carbon of
the aryl ring and the fluoride ion are 3.10 Å and 3.14 Å, respectively. This close correspondence between
the experimental and calculated structures for 1a indicates that the structures of diaryliodonium fluorides
can be investigated adequately at the level of B3LYP/DGDZVP.
The crystal structure of 2a is another tetramer, but of a different kind. The central element is a fluoride-
bridged dimer (Figure 4); its central iodine forms a secondary bond to each of the two bridging fluoride
ions with an average IF distance of 2.655 Å. This structure is notable in that each bridging fluoride ion
has a further secondary bond to the iodine atom of a neighboring monomer (FI = 2.56 Å). The distance
between this iodine and the exocyclic fluoride ion is 2.54 Å, reflecting a weaker polarization of the
exocyclic fluoride ion by two neighboring water molecules, which in turn hydrogen bond with a third
water molecule. This third water molecule also hydrogen bonds with the second bridging fluoride ion of
the dimer. The intricate hydrogen-bonding network in the crystal structure of 2a gives three layers of
square planarity, with the top and bottom layers each having three water molecules and one fluoride ion,
and the middle layer having two iodine centers and two bridging fluoride ions.
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Figure 4. Crystal structure of 2a. Hydrogen bonding interactions for three water molecules above and three water
molecules below the plane of the two iodine and two fluorine atoms are indicated by their respective yellow dashed
lines. Carbon atoms are shown in green, hydrogen atoms in white, oxygen atoms in red, iodine atoms in violet, and
fluorine atoms in gray. Blue distances are I−F bonds; red distances are H bonds; green distance is an exocyclic I−F
bond. All distances are in Å. The unit cell has the center of inversion and thus only non-redundant bond distances
are given. The inset gives a formulaic planar view of the structure without water molecules.
The 2-methyl group in 2a likely prevents the formation of the kind of tetramer seen for 1a (Figure 3).
Nevertheless, structure 2a suggests a possibility for interconversion between the two types of tetramer.
For example, the superposition of the iodine and fluorine atoms of 2a onto 1a indicates that the diaryl
portion of 2a can be fitted easily to that of 1a by a simple translation and rotation (Figure 5). A tetrameric
structure analogous to 1a would then result when both iodine and fluorine atoms of 2a move to their
corresponding atom positions in 1a.
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Figure 5. Overlay of the crystal structures of 1a (dark blue) and 2a (yellow); 2a was superimposed with the best
fit by using the four iodine and four fluorine atoms of 1a as the common docking point. Hydrogen atoms and
solvent molecules are not shown.
Experimental radiofluorination and fluorination
The fluorination of the unsymmetrical diaryliodonium fluoride 2a occurs preferentially at the o-tolyl
18
group. Thus, when 2a and [ F]fluoride ion of high molar activity were heated together in DMF at 180
o
18
18
C for about 4 min, [ F]o-fluorotoluene and [ F]fluorobenzene was formed in 2.1 molar ratio (Scheme
2
; Figure 6). Nearly identical fluoroarene product ratio was seen when 2a was heated in DMSO-d at 100
6
o
19
C (Scheme 1), with the reaction monitored by F NMR spectroscopy. The product NMR spectrum
showed a major peak at δ –117.97 ppm for o-fluorotoluene and a minor peak at δ –113.23 ppm for
fluorobenzene (Figure 7). As expected, a similar experiment on 1a (δ –122.55 ppm) showed
fluorobenzene (δ –113.12 ppm) to be the sole fluoroarene product.
11
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Scheme 2. Radiofluorination and thermolysis of 2a.
Figure 6. Reverse phase radio-HPLC chromatogram of the crude product from the radiofluorination of 2a.
1
9
19
Figure 7. A) F-NMR spectrum for 2a in DMSO-d
6
. B). F NMR spectrum of the crude product from the thermal
o
decomposition of 2a in DMSO-d
o-fluorotoluene.
6
at 100 C for 10 min, showing the two fluoroarene products, fluorobenzene and
Fluorination mechanism in monomeric state
The product ratio (~ 2) from thermolysis of 2a, detected with radiofluorination or F-NMR spectroscopy,
19
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is essentially idential to that reported in the radiofluorinations of 2-methylphenyl(phenyl)iodonium salts
-
-
-
with Cl , Br, I or OTs as anion (2b–2e) in various solvents, including acetonitrile, acetonitrile-1.5%
water, and DMF.[3c] This strongly indicates that the selectivities for the generation of fluorinated arenes
from 2a–2e under many different types of reaction conditions are very similar and are each dictated by
the respective energy difference between the pair of transition states (TSs).
Based on crystal structure, quantum chemical study, and LC-MS evidence,[14e] the dimeric form of 2-
methylphenyl(2’-methoxyphenyl)iodonium chloride (4b) is likely predominant in an organic solvent like
acetonitrile. For diaryliodonium fluorides that may also show a tendency for such dimerization in
solution, dissociation into monomers would be required before the secondary-bonded fluoride ion attacks
an ipso aryl carbon atom. Because monomeric diaryliodonium salts are fluxional T-shaped molecules in
which the two aryl rings may rapidly switch apical and equatorial positions, there are effectively two
ground state (GS) structures.[1b,14e] In the case of a fluorination of a diaryliodonium salt with high molar
1
8
18
activity [ F]fluoride ion (i.e., of a non-fluoride salt precursor that is in vast excess over trace [ F]fluoride
18
-
-
-
ion), the [ F]fluoride ion would first have to undergo ligand exchange with the anion (e.g., X = Cl , Br
-
-
,
I or OTos ) bound to the central iodine atom in either of two rapidly interconverting monomers (Ar
2
IX)
before bonding to an ipso aryl carbon through either of two possible TSs. The energy difference between
these two TSs has been proposed to control the ratio of the two fluoroarene products,[3c] in accord with
the Curtin-Hammett principle.[19]
Figure 8 depicts a reacton path for the fluorination of monomeric 2a in acetonitrile, derived from our
quantum chemical analysis. In this reaction path, the interconversion energy barrier (TSint) between the
two GS conformers is 13.1 kcal/mol, which is substantially lower than the energy barriers for the
formation of fluorobenzene via TS
The ≥ 6 kcal/mol difference between the TSint and the TS
is dictated solely by the energy difference between TS and TS
ratio (o-fluorotoluene/fluorobenzene) at 383.15 K is exp((–GTSB + GTSA)/RT), equalling 3.3, which is in
A
(20.0 kcal/mol) or o-fluorotoluene via TS
or TS assures that the fluorination selectivity
. As an example, the calculated product
B
(19.1 kcal/mol) (Table 1).
A
B
A
B
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1
8
fair agreement with the experimentally observed selectivity (2.3–3.0) for [ F]o-fluorotoluene as the main
product in the radiofluorination of (2-methylphenyl)(phenyl)iodonium salts (2b–2e) in acetonitrile
containing 1.5% water.[3c] Whereas the GS
conformer of 2a is 0.3 kcal/mol more stable than the GS
more stable by 0.9 kcal/mol than the TS .
A
B
conformer, the energetics reverses in the TSs making the TS
B
A
1
8
In the experimental case, the presence of 1.5% water would ensure that the [ F]fluoride ion was fully
hydrated.[20] These waters of hydration would need to be shed during the radiofluorination reaction. This
process was not taken into account in the computed pathway. Nonetheless, computations have shown
how solvated fluoride ion can serve as a good nucleophile despite its very high solvation energy.[20b] The
close agreement between the experimental and computed fluorination selectivities implies that fluoride
ion dehydration had little impact on reaction energetics and outcome. The experimental reaction milieu
+
also included K -K.2.2.2 complex plus carbonate, and likewise their influences appear to have been
negligible.
14
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Figure 8. Reaction path for the thermolysis of monomeric 2a in acetonitrile. Labeled bond distances are shown
in Å. Carbon atoms are shown in green, hydrogen atoms in white, iodine atoms in violet, and fluorine atoms in
yellow. Dashed red lines and numbers are distances between the fluoride ion and the nearest carbon atom ipso to
the iodine atom. TS
A
leads to fluorobenzene and TS to o-fluorotoluene.
B
Table 1. Calculated relative ΔG (kcal/mol) at the level of B3LYP/DGDZVP for thermolysis of diaryliodonium fluorides in
acetonitrile.
Diaryliodonium fluoride
a
Structure
1
0
0
a
2a
0
3a
0
4a
1.1
0
GS
GS
A
B
0.3
0.9
TSInt
13.5
19.8
13.1
20.0
19.1
13.9
20.2
21.9
13.6
20.8
18.6
TS
TS
A
B
a
A B
TS leads to fluorobenzene. TS leads to o-fluorotoluene for 2a and to o-fluoroanisole for 3a and 4a.
Energetics were calculated for 1a at 298.15 K, 2a at 383.15 K, and 3a and 4a at 413.15 K.
Origin of the ortho effect
The spatial positions of the fluoride ion in the TSs of 2a, as shown in Figure 8, provide insight into their
relative stabilities. For example, the fluoride ion in TS is positioned 2.00 Å away from the ipso aryl
B
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carbon as compared to 1.97 Å in TS
A
. Nonetheless, such a difference is too small to explain the widely
observed ‘ortho effect’ imparted by an o-alkyl group in the reaction of diarylodonium salts with various
nucleophiles,[2h,2m,3c,12] wherethis effect may be described as the greater tendency of an o-alkyl group over
an o-hydrogen atom to favor ligand binding at the ipso carbon of the same ring. In order to fully address
the o-methyl effect, quantum chemical calculations were extended to both m-methyl (7) and p-methyl (8)
substituted Ar
2
IFs (Figure 2). The electronic energy of TS
B
is lower than that of TS
A
by 1.0 kcal/mol for
2
a. However, for 7 and 8, the TS
A
becomes more stable than the TS
B
by 0.2 kcal/mol and 1.0 kcal/mol,
respectively. These energy differences are in good agreement with the observed chemoselectivity for 8
favoring the formation of fluorobenzene over p-fluorotoluene by 2 to 1;[3a] no selectivity was observed
for 7.[11b] More importantly, the slight variations of the electronic energy differences between the two
TSs depend upon the position of the methyl group in the arene, which in turn suggests that the origin of
the o-methyl effect on selectivity is electrostatic (rather than solely inductive). To illustrate the
electrostatic origin, both the atomic charge on the methyl group and the distance of this group from the
fluoride were calculated for the TS
fluoride and this group has the atomic polar tensor (APT) derived charge of +0.12. By comparison, the
respective carbons of the m-methyl group in the TS of 7a and the p-methyl group in the TS of 8 are 5.07
Å and 5.84 Å from the fluoride respectively, and both methyl groups have the APT-derived charge of
0.01. This implies a 20-fold higher stability of the o-methyl over the p-methyl; the charge on F does not
change much (see Supporting Information). Whereas the methyl group in any position donates its
electrons to the aryl ring and likely raises the energy of the TS over the TS , at the same time the o-
methyl is better positioned to lower the energy of the TS via direct charge interaction with the incoming
and TS of 2a (Figure S1) further illustrates the local
B
of 2a. The carbon of the o-methyl group is 3.15 Å away from the
B
B
+
B
A
B
fluoride. The electrostatic potential map for the TS
A
B
field on the molecular surfaces.
For the unsymmetrical o-methoxy-substituted fluoride (3a), the GS
A
conformation is more
stable than the GS conformation (fluoride ion nearer to o-anisyl ring) by 0.9 kcal/mol (Table 1 and
B
16
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Chemistry - A European Journal
10.1002/chem.201604803
Figure S1). The bulkiness of the o-methoxy group relative to the o-methyl group along with the high
electron density on the oxygen atom of the former gives rise to a stronger electrostatic repulsion with
the fluoride ion in the GS
B
conformation (Figure S2). Therefore, unlike the o-methyl-substituted case
(21.9 kcal/mol). The calculated
(
2a), the TS (20.2 kcal/mol) is 1.7 kcal/mol more stable than the TS
A
B
fluorobenzene/o-fluoroanisole product ratio at 413.15 K is 0.12, which is also in good agreement with
the observed fluoroarene product ratio of 0.11 in the radiofluorination of (2-
methoxyphenyl)(phenyl)iodonium chloride (3b) in DMF-0.25% water.[3c] Qualitatively, the o-
methoxy group donates electrons to the aryl ring and thus destabilizes the TS
B
relative to the TS , as
A
pointed out in the previous work of Ochiai et. al.[9a] Given that the distance between the fluoride and
the methoxy oxygen atom in the TS
electrostatic interaction between the two atoms. The electrostic potential map for the TS
a further illustrates this (Figure S3). The case of the fluoride substituted with o-methyl on one ring
and with o-methoxy on the other (4a) can be rationalized similarly. The calculated ΔG diffference
between the TS and TS is 2.2 kcal/mol (Figure S4) reflecting the stabilization of TS and
destabilization of TS due to the respective o-methyl and o-methoxy group with resepct to the
B
is only 3.05 Å, the TS
B
is further destabilized by the unfavorable
A
and TS of
B
3
A
B
B
A
unsubstituted aryl ring. This difference is also in good agreement with the observed aryl ring
fluorination selectivity of 4a (2.4 kcal/mol). Our quantum chemical analysis of the effect of an o-
methoxy group thus suggests that the o-anisyl group may serve as a generally effective spectator aryl
group partner in the radiofluorination of diaryliodonium salts, in accord with some of our simple
published examples.[3c] This observation can be put to good use in future PET radiotracer syntheses as a
means to enhance the yield of desired radiotracer over unwanted radiofluorinated byproduct.
GS and TS in homodimeric, heterodimeric, and tetrameric states
Prior studies[3c,13a,13b] have also pointed out that the halogenation selectivity of aryl rings with regard to
diaryliodonium salts in monomeric state is dictated by TS energy differences. However, the possibility
for the fluorination of diaryliodonium salts in dimeric or tetrameric states has not yet been fully explored.
17
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10.1002/chem.201604803
As earlier mentioned, the fluorination mechanism in oligomeric states was first discussed in the work of
Martín-Santamaría et al.,[13b] but with regard to non-aromatic model oligomers, such as (I(CC-CN)(CC-
OMe)F)2, and not with regard to diaryliodonium salts in dimeric or tetrameric state. The present crystal
structures of tetrameric 1a and 2a provide reliable descriptions of the GS conformations that otherwise
might only be guessed at. Accordingly, we were well set to investigate the fluorination of 1a and 2a in
their homodimeric, heterodimeric, and tetrameric states with the aim of assessing the environmental
effects on their thermochemical feasibilities for existence in solution, their activation energies (E
ring selectivities in radiofluorination. In the case of heterodimers, the dimeric structure of Ar
modified to construct the heterodimer (Ar IF)(Ar ICl).
Figure 9A depicts the alternation of the I―F distance from 2.40 Å to 2.78 Å in the dimer of 1a, (Ph
By comparison, the I―Cl distances in the dimer of 1b, (Ph ICl) , are all comparable at 3.11 Å. The
a
s), and
2
IF was
2
2
2
IF) .
2
2
2
monomeric I―F and I―Cl distances were calculated to be significantly shorter at 2.25 Å and 2.86 Å,
respectively. Thus, upon dimerization, the polarization induced by the neighboring monomer lengthens
both the I―F and I―Cl distances. However, the bond length alternation in (Ph
fluoride ion is much less polarized than the chloride ion. Upon heterodimerization of Ph
Table 2, Equation 3), the I―F bond lengthens to 2.53 Å, and the I―Cl bond to 3.18 Å (Figure 9B). In
the homotetramer (Ph IF) (Figure 9C), a slight I―F bond length alternation ranging from 2.47 Å to 2.53
2
IF)
2
reflects that the
2
IF with Ph ICl
2
(
2
4
Å occurs, suggesting that the tetrameric environment smoothes out the I―F bond length alternation seen
in the homodimeric environment.
18
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Figure 9. Structures of GSs and TSs of diphenyliodonium fluoride (1a) in dimeric, heterodimeric and tetrameric
states. All distances are in Å. Carbon atoms are shown in green, hydrogen atoms in white, iodine atoms in violet,
chlorine atoms in red, and fluorine atoms in yellow. The coordinates of these structures are given in the Supporting
Information.
Enthalpies for homodimerization were calculated by subtracting the sum of the enthalpy of each
monomer from that of the dimer at 298.15 K, giving values of –3.4 kcal/mol for the fluoride 1a (Table 2,
Equation 1) and –8.6 kcal/mol for the chloride 1b (Table 2, Equation 2). These values are consistent
with the aforementioned bond length alternation and/or polarization effects. For the formation of the
heterodimer (Ph
kcal/mol (Table 2, Equation 3). The alternative formation of this dimer, through the exchange of the
fluoride ion in potassium fluoride with a chloride ion in the dimer (Ph ICl) , was found to be
thermochemically feasible. For this process (Table 2, Equation 4), the calculated ΔH and ΔG values are
7.9 kcal/mol and –7.1 kcal/mol, respectively. The enthalpy for the tetramerization of 1a was calculated
2
IF)(Ph ICl) from the monomers 1a and 1b, the ΔH value was calculated to be –8.0
2
2
2
–
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10.1002/chem.201604803
to be – 14.7 kcal/mol (Table 2, Equation 5).
Table 2. Calculated ΔH and ΔG for iodonium salt dimer and tetramer formations in the reaction field of acetonitrile at 298.15
K.
ΔH
ΔG
(kcal/mol)
Equation
(
kcal/mol)
1
2
3
4
5
2Ph
2Ph
2
IF  (Ph
ICl  (Ph
2
IF)
2
–3.4
–8.6
–8.0
–7.9
−14.7
5.9
1.4
1.4
–7.1
16.6
2
2
ICl)
2
Ph
(Ph
4Ph
2
IF + Ph
ICl) + KF  (Ph
IF  (Ph IF)
2
ICl  (Ph
2
IF)(Ph
IF)(Ph
2
2
ICl)
ICl) + KCl
2
2
2
2
2
4
Changes in enthalpy (ΔH) clearly favor dimers and tetramers over the respective monomers (Table 2).
However, the calculated ΔG values for dimerization of 1a (5.9 kcal/mol) (Table 2, Equation 1) and 1b
(1.4 kcal/mol) (Table 2, Equation 2), as well as for tetramerization of 1a (16.6 kcal/mol) (Table 2,
Equation 5) do not favor such cluster formation. For the formation of the heterodimer (Ph IF)(Ph ICl)
2
2
from monomers, the ΔG value was also calculated to have a small positive value (1.4 kcal/mol; Table 2,
Equation 3). Such unfavorable ΔGs arise mainly from the the loss of the translational and rotational (TR)
-1
-1
entropy of the two monomers. For example, this is 70 calmol K or 35 R upon dimerization of 1a, based
upon the ideal gas approximation. However, the TR entropy contribution of a monomer to dimerization
in solution is known to be much lower due to its restricted movement. As an example, the experimental
TR entropy contribution to the dimerization of a protein in water was reported to be 5 R ± 4 R as compared
to 50 R from the ideal gas approximation used here.[21] Consequently, the actual ΔG values for
dimerization or tetramerization of 1a are expected to be more favorable than indicated in Table 2. In this
regard, we note that small negative ΔG values of about 3 kcal/mol have been experimentally determined
for the dimerization of 4,4’-dicyclohexyldiphenyliodonium iodide in benzene[2f] and also for (Z)-(β-
bromoalkenyl)-(phenyl)iodonium bromide in chloroform.[22]
Fluorination via monomeric or oligomeric states
The calculated E
a
value for fluorobenzene formation from 1a, taken as the difference in the zero-point
corrected energy between the GS and the TS, steadily increases from 19.8 kcal/mol for the monomer to
20
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10.1002/chem.201604803
2
1.3 kcal/mol for the homodimer, and then to 23.1 kcal/mol for the heterodimer (Table 3). As seen in
Figure 9A for the homodimer, the approach of the incoming fluoride ion to the ipso aryl carbon has to
overcome an extra charge interaction provided by the second central iodine to form fluorobenzene. In the
…
heterodimeric case (Figure 9B), this extra charge interaction is even stronger, because the I F distance at
the TS is 2.71 Å as compared to 2.81 Å for the homodimer (Figure 9A). In addition, the more polarizable
electron cloud of chloride ion is likely to provide a better charge interaction to the central iodine
undergoing thermolysis, resulting in a higher E
heterodimers are likely predominant in the radiofluorination of the chloride 1b, the thermolysis of the
fluoride 1a may involve the formation of homodimers or even homotetramers in solution. The E of the
tetramer is 21.9 kcal/mol, which is 2.1 kcal/mol higher than that of the monomer. The E valuescalculated
(20.9 ± 1.6 kcal/mol)
a
value for fluorobenzene formation. Whereas
a
a
for the monomer, homodimer and tetramer fall in the range of the experimental E
a
measured previously for the high molar activity radiofluorination of 1b in DMF.[3c] Also, the E
(23.1
a
kcal/mol) of the heterodimer is only 0.6 kcal/mol above the range of the experimental value. Thus, this
comparison cannot distinguish clearly whether the major pathway for fluorination of 1a is monomeric
or oligomeric.
E
a
‡
a
Table 3. E (kcal/mol)_and ΔG (kcal/mol) at 298.15 K for the production of fluoroarenes from diaryliodonium salt monomers
and oligomers at the level of B3LYP/DGDZVP in acetonitrile.
a
Salt
c
TS b
Monomer
Homodimer Heterodimer
Tetramer
Experimental
type
‡
‡
‡
‡
#
1
2
2
4
5
6
Substituents
H
E
a
ΔG
E
a
ΔG
E
a
ΔG
E
a
ΔG
E
a
a H
a H
a H
TS
TS
TS
A
A
B
B
B
B
19.8
20.1
18.7
18.7
17.6
20.8
19.8 21.3 20.2 23.1 21.8 21.9 21.5
19.9 21.6 21.0 23.4 22.7
18.9 21.1 20.5 22.0 21.0
20.9 ± 1.6
23.5 ± 1.6
18.3 ± 0.9
25.1 ± 2.6
27.5 ± 2.0
28.0 ± 1.6
2-Me
2-Me
a 2-Me
2-Me
2-OMe TS
2-Me TS
2-OMe TS
20.9
22.0
23.5
2-OMe
a
In diphenyliodonium fluorides for monomer, homodimer and tetramer. Heterodimer is composed of the chloride monomer
plus a fluoride monomer.
b
TS
A
leads to fluorobenzene; TS
B
type leads to o-fluorotoluene product for 4a and 5, and to o-fluoroanisole for 6.
c
From reference [3c].
For 2a, the E
a
s for fluorobenzene formation via TS
A
in monomeric, homodimeric and heterodimeric
environments remain very comparable to those of 1a (Table 3), suggesting that the formation of
21
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Chemistry - A European Journal
10.1002/chem.201604803
fluorobenzene is not affected by the presence of the o-methyl group on the other aryl ring. For o-
fluorotoluene formation via TS , the E increases from 18.7 kcal/mol for the monomer to 21.1 kcal/mol
for the homodimer and then to 22.0 kcal/mol for the heterodimer. The same rationale that was given for
the increase in the E for 1a across oligomers can be invoked to explain this trend. The presence of
the o-methyl group results in TS values that are all lower than for reactions of 2a or 1a through TS s.
B
a
a
B
A
Whereas the E
a
values for 2a are 2.4–3 kcal/mol higher in the dimeric enviroment, their calculated
‡
selectivities based on ΔΔG at 298.15 K still favor the formation of o-fluorotoluene over fluorobenzene.
We have also computationally investigated the formation of o-chlororotoluene via TS
B
(E
a
= 27.1
kcal/mol) and of chlororobenzene via TS (E = 28.4 kcal/mol); the ortho effect is still manifested in
A
a
chlorination in agreement with experiment.[2h] More importantly, these higher calculated E
s (Figure
a
S5) assure that the formation of fluorinated products occurs before the chlorination.
A reaction path for fluorination of 1a/1b was constructed assuming that ΔG for the formation of
Ph IF) or (Ph IF)(Ph ICl) is favorable over their corresponding monomers (Figure 10). In this reaction
path, the more stable dimer is in equilibrium with its monomers, and the interconversion between the two
is much faster than the fluorination itself. For example, the dissociation of (Ph IF) as a function of the
(
2
2
2
2
2
2
inter-iodine distance (Figure S6) indicates that the ΔG at 298.15 K for the two monomers separated by
the I---I distance of 7.5 Å is 9.1 kcal/mol less stable than the dimer separated by a distance of 4.0 Å.
Whereas this value of 9.1 kcal/mol does not represent the TS energy between the dimer and its monomers
in solution, it is substantially lower than the E
a
for fluorination in both monomeric and dimeric 1a. Note
that the TS and TS in Figure 10 represent the TS of fluorination in monomeric and dimeric
M
D
conformations, respectively, and their energy levels are depicted with respect to the GS of dimer (GS
and ΔG ‡
D
);
TS
M
energy level is the sum of the ΔGS
D
M
values of the monomeric 1a.
22
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Figure 10. Reaction path for the fluorination of 1a/1b. The more stable dimer is in equilibrium with its monomers,
and the interconversion between the two is assumed to be much faster than the fluorination itself. The TS and TS
represent the TS of fluorination in monomeric and dimeric conformations, respectively, and their energy levels are
M
D
‡
depicted with respect to the GS of dimer (GS
D
); TS
M
energy level is the sum of the ΔGS
ICl.
D
and ΔG
M
values of the
monomeric 1a. The TS of the heterodimeric conformation does not show Ph
M
2
In the case of (Ph
2
IF)
2
, when the ΔGS is more negative than ̶ 0.4 kcal/mol, the dimeric path to the
D
TS
D
of 20.2 kcal/mol will become a major path for the formation of fluorobenzene rather than the
‡
monomeric path with ΔG
M
of 19.8 kcal/mol. For the fluorination to occur in the heterodimeric or
tetrameric conformation, the dimerization or tetramerization energy then has to be more than 2 kcal/mol
‡
for the heterodimer or 1.7 kcal/mol for the tetramer. This will compensate for the increase in the ΔG in
the heterodimer (21.8 kcal/mol) and the tetramer (21.5 kcal/mol). Nonetheless, the small differences in
‡
the ΔG s values in Table 2 suggests that the fluorination of 1a or 1b likely occur in all conformations
Only when the ΔG for dimerization or tetramerization is more negative than ̶ 4 kcal/mol, will the dimeric
or tetrameric pathway be the major pathway for the fluorination of diaryliodonium salts.
Figure 10 may also explain the discrepancy between the experimental and the calculated E
a
s. For
(20.9 ± 1.6
for the monomer
compound 1a, both the calculated E
a
(19.8 kcal/mol to 23.1 kcal/mol) and the experimental E
a
kcal/mol) are comparable. For the formation of fluorotoluene from 2a, the calculated E
a
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Chemistry - A European Journal
10.1002/chem.201604803
(
18.7 kcal/mol) is also comparable to the experimental E
0.9 kcal/mol).[3c] However, the experimental E
diphenyliodonium chloride 5 (27.5 ± 2.0 kcal/mol) [3c] is substantially higher than the calculated E
a
value for the correspondimg chloride 2b (18.3
±
a
value for the symmetrically o-methyl substituted
a
value,
which ranges from 17.6 kcal/mol for the monomeric conformation to 23.5 kcal/mol for the tetrameric
conformation (Table 3). The experimental E value for the unsymmetrically substituted diaryliodonium
a
chloride 4 (25.1 ± 2.6 kcal; R = o-Me, R΄ = o-OMe) as well as for the symmetrically o-methoxy substituted
diphenyliodonium chloride 6 (28.0 ± 1.6 kcal/mol)[3c] are also higher than the calculated monomer E
a
values that are 20.8 kcal/mol. This inconsistency can be rationalized when the dissociation of a dimer of
a diaryliodonium fluoride (e.g., Figure 9A and Figure 9B) into two monomers is considered. Note that
the ΔG at 298.15 K of the two monomers of 1a separated by the I---I distance at 7.5 Å was calculated
to be 9.1 kcal/mol less stable than the dimer at 4.0 Å. Accordingly, those reactions with the experimenal
a
E value of ~ 27–28 kcal/mol may then arise from a reaction occurring in a concerted manner in which
the dissociation of such dimer is coupled with the fluorination of the monomeric diaryliodonium iodide
with an energy barrier of ~ 20 kcal/mol.
From a practical standpoint, a tendency for simple and complex diaryliodonium salts to adopt
oligomeric states in solution may result in a range of amenabilities to undergo useful radiofluorinations,
dependent on for example bridging anions and solvent. Such dependence has been well observed
experimentally.[3c]
Conclusions
Diaryliodonium fluorides may exist in two types of tetrameric structure. An interconversion pathway
between the two types of structure in solution appears feasible. Both the radiofluorination and thermolysis
of the fluoride 2a give the same fluoroarene product ratio as observed in the radiofluorination of the
corresponding chloride 2b. For this reaction, we constructed a reaction path for monomeric 2a whose TS
energy difference agrees with the experimental product ratio, and thus affirms the previous proposal that
the fluoroarene product selectivity in the fluorination of diaryliodonium salts is dictated by the TS energy
24
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Chemistry - A European Journal
10.1002/chem.201604803
differences. These findings also provide stronger insight into the detailed mechanism of the fluorinations
of diaryliodonium salts, especially with regard to the electrostatic influence of the o-methyl substituent
and spectator ring effects, and this may eventually find application in the design of more effective
precursors for PET radiotracer synthesis. In addition, the fluorination of diaryliodonium salts may occur
in both monomeric and oligomeric states depending upon the magnitude of the energy for salt
dimerization or tetramerization. From this limited study it appears that ring selectivity for fluorination is
quite insensitive to reaction pathway through monomers or oligomers.
Experimental
Quantum Chemistry. Quantum chemical calculations with the density functional theory were carried
out using the B3LYP functional and DGDZVP basis set as implemented in Gaussian 09.[23] The geometry
optimization was carried out in both the gaseous phase and the reaction field of acetonitrile with the
polarizable continuum model together with the UAKS parameter set. To calculate the energy barrier for
the fluorination, reaction paths were constructed by varying a distance between the fluoride and the
respective ipso aryl carbon in the GS in increments of 0.1 Å while relaxing the rest of the structure in the
gaseous phase. The geometries of the TSs were further optimized in the reaction field of acetonitrile and
a single imaginary frequency was obtained for each TS.
19F-NMR spectroscopy. 19F NMR chemical shifts were verified by comparison with authentic samples.
Acknowledgments. This study was supported by the Intramural Research Program of the National
Institutes of Mental Health (NIMH: ZIA-MH002793) and the Center for Information Technology (CIT:
ZIA-CT000265-20) and W. J. Youngs (Chemistry Department, University of Akron) acknowledge the
National Science Foundation (CHE-0116041) and the Ohio Board of Regents for funds used to purchase
the Bruker-Nonius Apex CCD X-ray diffractometer used in this research. The quantum chemical study
utilized PC/LINUX clusters at the Center for Molecular Modeling (CMM) of the NIH
(http://cmm.nih.gov). YS Lee thanks Dr. Sergio Hassan of the CMM/CIT for helpful discussion.
25
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Chemistry - A European Journal
10.1002/chem.201604803
Supporting Information Available: CCDC-776799 (1a) and CCDC-776798 (2a) contain the
supplementary crystallographic data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.ac.uk/data_request/cif. Detailed experimental
procedures, product characterization, and tables of crystallographic data. This material is available free
of charge.
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