Conformational structure and energetics of 2- methylphenyl(2′methoxyphenyl)iodonium chloride: Evidence for solution clusters

Article abstract of DOI:10.1002/chem.201000607

Diaryliodonium salts allow the efficient incorporation of cyclotronproduced [¹⁸F]fluoride ions into electron-rich and electron-deficient arenes to provide potential radiotracers for molecular imaging in vivo with positron emission tomography (P

Full text of DOI:10.1002/chem.201000607

DOI: 10.1002/chem.201000607
Conformational Structure and Energetics of 2-Methylphenyl(2’-
methoxyphenyl)iodonium Chloride: Evidence for Solution Clusters
Yong-Sok Lee,*[a] Milan Hodosˇcˇek,[b] Joong-Hyun Chun,[c] and Victor W. Pike[c]
Abstract: Diaryliodonium salts allow
the efficient incorporation of cyclotron-
produced [18F]fluoride ions into elec-
tron-rich and electron-deficient arenes
to provide potential radiotracers for
molecular imaging in vivo with posi-
tron emission tomography (PET). This
process (ArI+Ar’+18Fꢀ!Ar18F+Ar’I)
is still not well understood mechanisti-
cally. To better understand this and
similar reactions, it would be valuable
to understand the structures of diary-
liodonium salts in organic media,
where the reactions are typically con-
ducted. In this endeavor, the X-ray
structure of a representative iodonium
salt,
A
2-methylphenyl(2’-methoxy-
ACHTUNGTNERiNUNG odonium chloride (1), was de-
likely to undergo fast interconversion
in solution. Also LC–MS of 1 showed
the presence of dimeric and tetrameric
anion-bridged clusters in weak organic
solution. This observation is consistent
with the energetics of 1, both as mono-
meric and dimeric forms in MeCN, cal-
culated at the B3LYP/DGDZVP level.
These evidences of the existence of di-
meric and higher order clusters of 1 in
termined. Our X-ray structure analysis
showed 1 to have the conformational
M–P dimer as the unit cell with hyper-
valent iodine as a stereogenic center in
each conformer. With the ab initio rep-
lica path method we constructed the in-
version path between the two enantio-
mers of 1, thereby revealing two addi-
tional pairs of enantiomers that are
solution are relevant to achieve
a
deeper general understanding of the
mechanism and outcome of reactions
of diaryliodonium salts in organic
media with nucleophiles, such as the
[18F]fluoride ion.
Keywords: cluster compounds
dimerization · iodinium salts · inver-
sion pathways · stereogenic iodine
·
Introduction
Diaryliodonium salts (ArI+ArXꢀ) widely serve as useful re-
agents for arylation and oxidation reactions.[1] They are also
becoming very useful substrates for the preparation of fluo-
rine-18-labeled (t1/2 =109.7 min) fluoroarenes as potential ra-
diotracers for biomedical imaging with positron emission to-
mography (PET).[2] In view of these increasing synthetic ap-
plications, a detailed understanding of the structure of
[a] Dr. Y.-S. Lee
Center for Molecular Modeling
Division of Computational Bioscience
Center for Information Technology, National Institutes of Health
Department of Health and Human Services, Building 12A
Room 2049, Bethesda, MD 20892 (USA)
Fax : (+1)301-402-2867
diarylACTHNURTGNEUiGN odonium salts in organic solution is desirable to assist
E-mail: leeys@mail.nih.gov
in understanding reaction mechanisms and outcomes.
ˇˇ
[b] Dr. M. Hodoscek
National Heart, Lung and Blood Institute
National Institutes of Health
Department of Health and Human Services
Bethesda, MD 20892 (USA)
Previous studies have shown that diaryliodonium salts are
in general fully dissociated in aqueous or polar media,[3] but
have also suggested that they may exist as ion pairs or di-
meric structures in less polar organic solvents.[3,4] Solid-state
structures determined with X-ray crystallography often
and
National Institute of Chemistry, Ljubljana (Slovenia)
prove diaryliodonium salts to be anion-bridged dimers held
[c] Dr. J.-H. Chun, Dr. V. W. Pike
[5]
Molecular Imaging Branch, National Institute of Mental Health
National Institutes of Health
Department of Health and Human Services
Room B3 C346A, Building 10, 10 Center Drive,
Bethesda, MD 20892 (USA)
ꢀ
together by iodine halogen bonds. However, correspond-
ence between solid-state and solution structure has not been
elucidated previously. Here, we present X-ray crystallogra-
phy data on an example of an unsymmetric diaryliodonium
salt, 2-methylphenyl(2’-methoxyphenyl)iodonium chloride
(1). Interestingly, these data unveiled hypervalent iodine as
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000607.
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Chem. Eur. J. 2010, 16, 10418 – 10423

FULL PAPER
a previously unrecognized stereogenic center within a dimer-
ic structure, composed of conformational M and P enantio-
mers (Scheme 1). An immediate consequence of the stereo-
and P enantiomers are located above (7.68) and below
(ꢀ7.68) the plane defined by C1-C8-Cl, respectively, as mea-
sured by their improper dihedral angles I-C1-C8-Cl, and
therefore, show that the hypervalent iodine of 1 is stereo-
genic. A similar observation has been made for the sulfur of
phenyl p-tolyl sulfoxide, which is known to racemize by pyr-
amidal inversion.[8] Aside from the presence of a stereogenic
ꢀ
iodine atom, the structure of 1 resembles those of Ph2I Z
(Z=Cl, Br, or I)[5] in that 1 forms a bridged dimer whose
iodine coordination is square planar. One difference, howev-
er, is that the methoxy and methyl substituents render the
ꢀ
Scheme 1. M and P are conformational enantiomers of 1 and are defined,
respectively, for the negative and positive Cl-I-C8-C9 (f1) dihedral angle.
chloride bridge in 1 longer and more asymmetric (I Cl=
ꢀ
ꢀ
3.101 and 3.028 ꢁ) than in Ph2I Cl (I Cl=3.065, 3.105 ꢁ).
ꢀ
The I Cl bonds in 1 are primarily ionic since their lengths
are about 0.64 ꢁ longer than in solid PhICl2 (2.46 ꢁ).[9] It is
this ionicity that allows the secondary bonds[10] to arise, so
enabling the crystallization of 1 as the Cl-bridged dimer.
In our theoretical study, we first probed the racemization
of 1 in the gas phase. The resulting potential energy surface
(PES) obtained from the RPATH method is shown in
Figure 2; the inset is a graphical representation of the 60
replicas that are superimposed with the best fit by using the
six atoms (C1–C6) of the anisyl group of M1 as the common
docking point. The PES shown in Figure 2 gives three dis-
tinct conformers of M and P, as well as two TSs that are
best described by the rotation around two torsion angles, Cl-
I-C8-C9 (f1) and C8-I-C1-C2 (f2), as shown in Figure 3.
Note that the states shown in Figures 2 and 3 are approxi-
mate since geometry at each replica was minimized with an
added harmonic penalty function. The conformer M2 is
2.2 kcalmolꢀ1 more stable than M1 due to less steric repul-
sion between the two aryl rings, achieved through an equa-
torial rotation of the tolyl group (f2) with respect to the
anisyl group. Further rotation of the tolyl group gives rise to
genic iodine is the possible racemization of 1 in solution. In
the present work, this racemization process was investigated
with quantum chemistry at the B3LYP/DGDZVP level. For
this purpose, we utilized the ab initio replica path (RPATH)
method[6,7] to construct the inversion path for the conform-
ers M and P of 1. This method readily identifies the transi-
tion state (TS) of a chemical reaction or conformational
change of interest without prior knowledge of the TS geom-
etry, as exemplified in our previous study of the inversion of
1,4-benzodiazepines.[7] We also found mass spectrometric
evidence for solution clusters of 1, and therefore, quantum
chemical calculations were carried out to probe the exis-
tence of dimeric 1 in MeCN, choosing the latter as a repre-
sentative organic solvent.
Results and Discussion
X-ray structure and interconversion of the conformational
enantiomers of 1: Our X-ray study found 1 to have the M–P
dimer as the unit cell in
a centrosymmetric crystal
(Figure 1). In particular, the central iodine atoms of the M
Figure 2. PES for the inversion of 1 in the gas phase calculated with the
RPATH method by using 60 replicas. Energy at each point, without zero
point vibration and thermal contribution, is relative to M1. Arrows indi-
cate the approximate states. Inset: Graphical representation of the 60
replicas. Individual structures are superimposed with the best fit by using
the six atoms (C1–C6) of the anisyl group of M1 as the common docking
point.
Figure 1. X-ray crystal structure of dimeric 1, represented in an ORTEP
drawing (50% thermal ellipsoids with hydrogen atoms omitted for clari-
ty). Some bond distances [ꢁ] are indicated. Atoms labeled with A and B
belong to the M and P monomers, respectively.
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Y.-S. Lee et al.
microsecond range, which is too
fast to be investigated with
NMR spectroscopy. In these cir-
cumstances, a theoretical ap-
proach, such as RPATH, seems
the only viable way for studying
the geometry of diaryliodonium
salts and their energetics in or-
ganic solvents.
The superposition of the fully
optimized structures onto the
six atoms (C1–C6) of the anisyl
group of M1 as the common
docking point gives
a visual
representation of each of the
conformer pairs (Figure 4): the
pairs M1 and P1, M2 and P2,
and M3 and P3 are enantio-
mers, whereas TS1 and TS2 are
not. These optimized structures
further provide detailed infor-
mation on the iodine inversion
Figure 3. Conformers of M and P, and of the two TSs. Values in parenthesis indicate the torsion angles, Cl-I-
C8-C9 (f1) and C8-I-C1-C2 (f2); see Scheme 1 for atom numbering.
another conformer M3, which is 1.2 kcalmolꢀ1 more stable
Table 1. Calculated energies and geometrical parameters of the conform-
ers and TSs of 1, as shown in Figure 3, in MeCN at the B3LYP/
DGDZVP level.
ꢀ
than M1. At TS1, the ionic I Cl bond (2.82 ꢁ) is longer than
in M1 (2.75 ꢁ) due to steric repulsion between the tolyl
Structure Energy[a] relative to f1 Cl-I-C8-C9 f2 C8-I-C1-C2 I Cl
ꢀ
ꢀ
group and the Cl atom; this weakening of the I Cl bond in
M1
[o]
[o]
[ꢁ]
TS1 is reflected in the greater energy of 9.0 kcalmolꢀ1 of TS1
relative to M1. Further rotation of f1 yields the conformer
P1, a pseudo enantiomer of M1. Counter-clockwise rotation
of the tolyl ring gives rise to P2 and P3, the respective
pseudo enantiomers of M2 and M3. The energy of TS2 is
1.6 kcalmolꢀ1 lower than that of TS1 due to the Cl atom
being anti to the tolyl methyl group. The calculated energy
barriers within the conformers of M or P are no higher than
2.6 kcalmolꢀ1, indicating that their interconversion at room
temperature likely occurs on a picosecond timescale.
[kcalmolꢀ1
]
M1
M2
M3
TS1
P1
P2
P3
TS2
0
ꢀ70.9
ꢀ77.2
ꢀ76.3
ꢀ2.6
71.0
77.4
76.1
179.2
ꢀ73.2
2.87
2.87
2.86
3.08
2.87
2.87
2.86
3.01
ꢀ0.7
173.6
82.4
ꢀ0.05
9.1 (ꢀ36.6 cmꢀ1
)
87.2
73.3
ꢀ173.7
ꢀ82.6
ꢀ88.0
[b]
[b]
0
ꢀ0.8
ꢀ0.03
9.1 (ꢀ39.4 cmꢀ1
)
[a] Energies include the zero-point correction as well as the enthalpy and
the entropy contribution at 298.15 K. [b] Imaginary torsional–vibrational
mode of the tolyl group.
The geometries of the approximate states in Figure 3 were
further optimized with Gaussian 03 utilizing the polarized
continuum model with the UAKS parameters set in
MeCN.[11] Single imaginary frequencies for the vibrational–
torsional motion of the tolyl group in the direction of M3 or
P1 through TS1 (ꢀ36.6 cmꢀ1) and of P3 or M1 through TS2
(ꢀ39.4 cmꢀ1) were obtained, but none in any other conform-
ers. In terms of energetics (Table 1), M1 and M3 are essen-
tially isoenergetic, whereas M2 is only 0.7 kcalmolꢀ1 more
stable than either of these, due to the attenuated steric re-
pulsion in MeCN. The inclusion of the solvent effect length-
for each enantiomeric pair. Figure 5 shows the microscopic
iodine inversion of M1 to P1 wherein the central iodine
atoms of M1 and P1 are located above (2.08) and below
(ꢀ2.08) the plane of C1-C8-Cl, respectively. These calculated
improper dihedral angles are 5.68 smaller than those found
in the X-ray structure of 1. On the M1–TS1–P1 path, the
iodine of M1 first moves downwards with respect to the C1-
C8-Cl plane until the M3 state is reached; the iodine then
moves upwards to reach TS1, and downwards again to com-
plete the inversion. The P1–TS2–M1 path shows an opposite
movement of the iodine atom, but this is not symmetric to
the M1–TS1–P1 path by inversion, because TS1 and TS2 are
not enantiomers.
ꢀ
ened the ionic bond I Cl in M1 from 2.75 ꢁ in vacuum to
2.87 ꢁ in MeCN, and in TS1 from 2.82 ꢁ in vacuum to
3.08 ꢁ in MeCN. It also rendered TS1 and TS2 isoenergetic
at 9.1 kcalmolꢀ1 higher than M1, suggesting that the inver-
sion of 1 occurs equally well through the enantiomeric TS1
or TS2 (not calculated), as in the case of benzodiazepines.[7]
The energy barrier of 9.1 kcalmolꢀ1 further suggests that the
racemization at room temperature in MeCN occurs in the
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2-Methylphenyl(2’-methoxyphenyl)iodonium Chloride
FULL PAPER
sition
of
the
detected
dimeric
ion,
[(MeO-
C6H4IMeC6H4)2Cl]+ (see the Supporting Information). Simi-
larly, the ion at m/z 708.3 was deduced to be an acetate-
bridged dimer [(MeOC6H4IMeC6H4)2OAc]+ uniquely gener-
ated from an unseen acetate-bridged tetrameric metastable
ion with composition [(MeOC6H4IMeC6H4)4OAc+H]2+ (see
the Supporting Information). Incorporation of OAcꢀ into
the latter must have occurred in the HPLC mobile phase.
These observations directly show the existence of stable di-
meric and tetrameric clusters of 1 even in the weakly organ-
ic HPLC mobile phase. How might such clusters form?
As listed in Table 1, the six conformers of 1 are compara-
ble in energy and thus, all are likely to exist in MeCN at
room temperature. These conformers could then form a
dimer in organic solvent through secondary bonding interac-
tions[10] that were attributed to be the driving force for for-
mation of the dimeric solid-state structure. To investigate
this possibility, quantum chemical calculations were per-
formed on the three pairs of enantiomers. Each dimer was
constructed by manually putting their geometry-optimized
monomers together. Calculations were also performed on an
M1–M1 dimer for comparison. These calculations indicate
that in MeCN the M1–P1 heterodimer is more stable than
M1–M1 and M3–P3 by 1.8 kcalmolꢀ1 and 2.6 kcalmolꢀ1, re-
spectively; the M2–P2 dimer converged to the M3–P3
dimer.
Figure 4. Overlay of the fully geometry-optimized M and P conformers
(green) and transition states (yellow) by using the six atoms (C1–C6) of
the anisyl group of M1 as common docking point. The root mean square
deviation (rmsd) of each fit to M1 is less than 0.07 ꢁ. Each of the pairs
of M1–P1, M2–P2 and M3–P3 is enantiomeric. The Cl atoms of TS1 and
TS2 do not align with those of M or P due to steric repulsion with the
tolyl group. Hydrogen atoms are not shown.
Figure 6 illustrates the energy-minimized structures of
M1–P1 and M1–M1 in MeCN. The dimer M1–P1 closely re-
sembles the X-ray structure shown in Figure 1 as evidenced
Figure 5. Variation of the improper dihedral angle I-C1-C8-Cl along the
reaction path shows the inversion of the iodine atom during racemiza-
tion; the central iodine atom of the M1 and P1 pair is located above
(2.08) and below (ꢀ2.08) the plane of C1-C8-Cl, respectively.
Evidence for clusters of 1 from LC–MS, MS, and energetics
calculations: During the characterization of 1 in MeCN by
LC–MS, we encountered the unexpected finding that re-
versed phase LC operated with water/methanol/acetic acid
as mobile phase gave not a single sharp peak but a broad
multi-peaked elution profile starting from elution near the
solvent front (capacity factor, kꢀꢁ1.0) up to capacity factors
of ꢁ4 (see the Supporting Information). MS of all material
in this broad elution range gave a base peak at m/z 324.9,
corresponding to the monomeric cation of 1, [C14H14OI]+.
Close scrutiny of these spectra also showed a set of low
abundance ions beginning at m/z 684.3 and another set at
m/z 708.3. The former set, according to its isotope [M] and
[M+2] abundance ratio, contained one Cl atom, whereas the
latter did not. The ion m/z 684.3 was deduced to be the Cl-
bridged dimer [(MeOC6H4IMeC6H4)2Cl]+, uniquely generat-
ed from an unseen Cl-bridged tetrameric metastable ion
with composition [(MeOC6H4IMeC6H4)4Cl2+H]2+. High res-
olution mass spectrometry confirmed the elemental compo-
Figure 6. Geometry-optimized dimers M1–P1 and M1–M1 of 1 in MeCN.
In M1–P1, the 2-methyl and 2’-methoxy groups of M1 are pointing out of
the plane, whereas those of P1 are pointing into the plane. In the M1–M1
dimer, all substituents are pointing out of the plane.
by the rmsd of 0.02 ꢁ between the experimental and calcu-
lated bond distances and the less than 38 difference in bond
angles (Table 3 in the Supporting Information). The calcu-
ꢀ
lated I Cl distances (3.09, 3.18 ꢁ) in M1–P1 are longer than
the ones in monomeric M1 or P1 (2.87 ꢁ) but are compara-
ble to those observed in the crystal structure (3.03, 3.10 ꢁ).
When M1 approaches P1 or vice versa, the Mulliken atomic
charge on the iodine atom (+0.38) of M1 forms a strong
charge interaction with the negative charge on the chlorine
atom (ꢀ0.70) of P1 to form another ionic bond with a
length of 3.18 ꢁ. This charge interaction in turn polarizes
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Y.-S. Lee et al.
ꢀ
the I Cl bond of the monomers M1 and P1 as manifested
We are now using the RPATH method to locate the transi-
tion state of such fluorination reactions:
by an increase in length from 2.87 to 3.09 ꢁ. In line with
this bond lengthening, the calculations showed a further po-
larization of the atomic charge on I (+0.44) and Cl (ꢀ0.71)
in the M1–P1 dimer relative to those in the M1 or P1 mono-
mer. Note that these atomic charges are comparable to
other electrostatic potential-derived charges such as
CHelpG.[11]
18Fꢀ
ðArIþAr0ClꢀÞ ArIþAr0Clꢀ
Ar18F=Ar018F þ Ar0I=Ar
!
ꢀꢀ!
2
Conclusion
With the zero-point energy correction and thermal enthal-
py contribution at 298.15 K, the DH for dimerization of M1–
P1 in MeCN, calculated by subtracting the sum of the
energy of each monomer from the energy of the M1–P1
dimer, was ꢀ9.0 kcalmolꢀ1. When the entropy contribution
was included, DG for the dimerization became +2.8 kcal
molꢀ1. This is primarily due to the loss of the translational
and rotational (TR) entropy of the two monomers upon di-
merization, which is 91 calmolꢀ1 Kꢀ1 or about 46R based on
the ideal gas approximation. However, the TR entropy con-
tribution of a solute to dimerization is known to be much
lower in the liquid phase because of hindered movement.
For example, the experimental TR entropy contribution to
the dimerization of a protein in aqueous solution has been
reported to be 5ꢂ4R, as opposed to 50R estimated from
the ideal gas approximation.[12] Assuming the high end of
the TR entropy (i.e., 9R), the DG for the dimerization of
M1 and P1 was estimated to be ꢀ13.1 kcalmolꢀ1 at
298.15 K. The basis set superposition error for M1–P1 for-
mation in the gas phase was only 1.4 kcalmolꢀ1 and thus,
was unlikely to affect the calculated thermochemical stabili-
ty of M1–P1 in MeCN. These results taken together, suggest
that 1 predominantly exists as dimers in MeCN. The thermo-
chemical stability of tetramers has not been considered due
to lack of structural information. Nonetheless, the LC–MS
study indicates the existence of tetramers of 1 in solution.
This might be driven by an increase in entropy of solvent
molecules surrounding the more structurally ordered tet-
ramers. Further experimental and theoretical efforts are
needed to better explain the formation and stability of
higher order clusters.
The determination of the X-ray structure of 1 unveiled hy-
pervalent iodine acting as a stereogenic center. In addition,
with the ab initio RPATH method, we have identified two
additional enantiomers not observed in the crystal structure
of 1, as well as two TSs for the inversion of the enantiomers.
This inversion has
a
calculated energy barrier of
9.1 kcalmolꢀ1 in MeCN, and proceeds with an equatorial ro-
tation of the 2-tolyl group with respect to the 2’-anisyl
group, together with an internal rotation of the 2-tolyl
group. Finally, our quantum chemical calculations suggest
that 1 likely exists as dimers in MeCN because of the strong
secondary bonding interaction between the I and the Cl
atoms of the M and P forms of 1. These calculations appear
consistent with LC–MS observations of clusters of 1 in weak
organic solution. Taken together, these findings now help
our continuing studies of the radiofluorination of iodonium
salts to produce radiotracers for molecular imaging with
PET.
Experimental Section
Synthesis of 1: 2-Methylphenyl(2’-methoxyphenyl)iodonium chloride (1)
was synthesized by treating 2-methoxyphenyl boronic acid with 2-
[hydroxyACTHNUTRGNEUNG
(tosyloxy)iodo]toluene[14] followed by anion metathesis of the
generated diaryliodonium tosylate with ammonium chloride.
X-ray crystallography of 1: Crystals of 1 were grown from MeCN by por-
tionwise addition of water at room temperature. X-ray data were collect-
ed by using a SMART Apex CCD diffractometer (Bruker, Madison, WI,
USA) with graphite-monochromated MoKa radiation (l=0.71073 ꢁ).
¯
Crystal data for 1: C14H14ClIO, Mr =360.60, triclinic, P1, T=100(2) K, a=
7.593(3) ꢁ, b=9.491(4) ꢁ, c=10.383(5) ꢁ, V=697.5(5) ꢁ3, Z=2, m-
A
,
5554 reflections collected, 2764 unique (Rini
=
Besides being more stable than M1–M1 and M3—P3, the
M1–P1 heterodimer has a negligible dipole moment (m=
0.07 D). As a result, the dipole–dipole interaction among
M1–P1 dimers is minimal compared to M1–M1 (m=0.82 D)
or M3–P3 (m=0.37 D). This may explain the formation of
the M1–P1 dimer as a unit cell in a centrosymmetric crystal.
In the case of M1–M1 or M3—P3 dimers (not observed),
the unit cell might require doubling or even quadrupling in
size to minimize the overall dipole moment of the crystal.
The favorable dimerization energy calculated here, fur-
ther indicates that well-known reactions of diaryliodonium
salts similar to 1 with nucleophiles in organic solvents may
require the dissociation of dimers or possibly even tetram-
ers. In the case of the increasingly useful radiofluorination
reactions,[2] such dissociation will likely be necessary to
allow replacement of chloride ions with 18F ions, preceding
attack of the bound fluoride ion onto an aryl carbon atom
to give either of the two possible [18F]fluorarene products.[13]
0.0321), GOF=1.043, final R1A(I>2s(I))=0.0304, wR2 =0.0774. CCDC-
CTHUNGTRENNUNG
710484 (1) contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Quantum chemistry: To investigate the racemization of 1, 60 replicas
were constructed by combining two sets of 30 replicas in a cyclic pathway.
First, 30 replicas were constructed by interpolation between the geome-
try-minimized M and P enantiomers of 1, starting from their X-ray struc-
tures, and then another 30 replicas between P and M. Energy minimiza-
tion, utilizing CHARMM[15] interfaced with GAMESS,[16] was then per-
formed on each replica with an added harmonic penalty function to re-
strain distances in root-mean square space between adjacent replicas
along the reaction pathway in the form:
Nꢀ1
X
1
2
2
Erms
¼
KrmsðRi;iþ1 ꢀ hRiÞ
ð1Þ
i¼1
where N is the number of replicas i along the pathway, Krms is the force
constant (set here to 103 kcalmolꢀ1 A2), and Ri,i+1 and <R> are rmsd
values given by:
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2-Methylphenyl(2’-methoxyphenyl)iodonium Chloride
FULL PAPER
n
n
X
X
2873L; i) S. Telu, J. Chun, F. G. Simꢃon, S. Lu, V. W. Pike, J. La-
belled Compd. Radiopharm. 2009, 52, S4.
[3] a) F. M. Beringer, M. Mausner, J. Am. Chem. Soc. 1958, 80, 4535–
4536; b) Y. Yamada, K. Kashima, M. Okawara, Polym. Lett. Ed.
1976, 14, 65–71.
[4] a) N. P. Hacker, D. V. Leff, J. L. Dektar, J. Org. Chem. 1991, 56,
2280–2282; b) S. Martꢂn-Santamarꢂa, M. A. Carroll, V. W. Pike,
H. S. Rzepa, D. A. Widdowson, J. Chem. Soc. Perkin Trans. 2 2000,
2158–2161.
[5] a) N. W. Alcock, R. M. Countryman, J. Chem. Soc. Dalton Trans.
1977, 217–219; b) N. W. Alcock, R. M. Countryman, J. Chem. Soc.
Dalton Trans. 1987, 193–196; c) H. Li, S. Jiang, Acta Crystallogr.
Sect. E 2006, 63, o83–085; d) C.-Y. Liu, H. Li, A.-G. Meng, Acta
Crystallogr. Sect. E 2007, 63, o3647.
R2i;jþ1
wj ¼
wj½ðxðiÞ ꢀ xjðiþ1ÞÞ þ ðyjðiÞ ꢀ yjðiþ1ÞÞ þ ðzðjiÞ ꢀ zðjiþ1ÞÞ ꢃ
2
2
2
j
j¼1
j¼1
ð2Þ
Nꢀ1
X
hRi ¼ Nꢀ1
Ri;jþ1
i¼1
where n is the total number of replicated atoms j with coordinates (xj(k)
,
yj( ), zj(k)) in replica k, and wj is a suitable input-defined parameter. Ac-
cordingly, the penalty function is proportional to the difference in the
rmsd between the two neighboring structures. In addition, an angle
energy term [Eq. (3)], was included to prevent merging between the ad-
jacent points (force constants Kangle =100 and cosmax=0.95).
Nꢀ1
X
1
2
2
ˇˇ
KangleððR2i;jþ2 ꢀ R2i;jþ1 ꢀ Ri2þ1;jþ2Þ=ð2Ri;jþ1Riþ1;jþ2Þ ꢀ cos maxÞ
[6] H. L Woodcock, M. Hodoscek, P. Sherwood, Y. S. Lee, H. F. Schae-
Eangle
¼
fer III, B. R. Brooks, Theor. Chem. Acc. 2003, 109, 140–148.
i¼1
ˇˇ
[7] Y. S. Lee, V. W. Pike, M. Hodoscek, J. Phys. Chem. A 2008, 112,
ð3Þ
1604–1611.
[8] E. G. Miller, D. R. Rayner, H. T. Thomas, K. Mislow, J. Am. Chem.
Soc. 1968, 90, 4861–4868.
The average restraint energy shown in Equation (1) was less than
0.02 kcalmolꢀ1 per replica after 200 steps of energy minimization. The ab
initio program GAMESS was used for all RPATH calculations at the
B3LYP/DGDZVP level. Further refinement of the approximate TS was
carried out with the TS search algorithm by using the keywords, opt=(ts,
calcfc, noeigentest), as implemented in Gaussian 03 software.[11]
[9] a) E. M. Archer, T. G. D. Van Schalkwyk, Acta Crystallogr. 1953, 6,
88–92; b) J. V. Carey, P. A. Chaloner, P. B. Hitchcock, T. Neugeba-
uer, K. R. Seddon, J. Chem. Res. 1996, 348, 358–359.
[10] a) N. W. Alcock, Adv. Inorg. Chem. 1972, 15, 1–58; b) G. A. Land-
rum, N. Goldberg, R. Hoffman, R. M. Minyaev, New J. Chem. 1998,
22, 883–890.
[11] Gaussian 03, Revision D.01, M. J. Frisch, G. W. Trucks, H. B. Schle-
gel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, J. A. Montgom-
ery, Jr., T. Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S.
Iyengar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani,
N. Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K.
Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda,
O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P. Hratchian,
J. B. Cross, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann,
O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, P. Y.
Ayala, K. Morokuma, G. A. Voth, P. Salvador, J. J. Dannenberg,
V. G. Zakrzewski, S. Dapprich, A. D. Daniels, M. C. Strain, O.
Farkas, D. K. Malick, A. D. Rabuck, K. Raghavachari, J. B. Fores-
man, J. V. Ortiz, Q. Cui, A. G. Baboul, S. Clifford, J. Cioslowski,
B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. L.
Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C Y. Peng, A. Na-
nayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W. Chen,
M. W. Wong, C. Gonzalez, J. A. Pople, Gaussian, Inc., Wallingford
CT, 2004.
Acknowledgements
This work was supported by the Intramural Research Program of the Na-
tional Institutes of Health (NIMH and CIT). We are grateful to Dr. S.
Hassan (CIT) for discussion, and Dr. M. J. Panzner (University of
Akron) for X-ray analysis of 1. The quantum chemical study utilized PC/
LINUX clusters at the Center for Molecular Modeling of the NIH
(http://cit.nih.gov). We are also deeply grateful to Dr. H. U. Shetty
(NIMH) for assistance with LC–MS.
[1] a) P. J. Stang, V. V. Zhdankin, Chem. Rev. 1996, 96, 1123–1178;
b) A. Varvoglis in Hypervalent Iodine in Organic Synthesis, Academ-
ic Press, London, 1997; c) A. Varvoglis, S. Spyroudis, Synlett 1998,
221–232; d) V. V. Zhdankin, P. J. Stang, Chem. Rev. 2002, 102,
2523–2584; e) M. Ochiai, Top. Curr. Chem. 2003, 224, 5–68; f) V. V.
Zhdankin, P. J. Stang, Chem. Rev. 2008, 108, 5299–5358; g) E. A.
Merritt, B. Olofsson, Angew. Chem. 2009, 121, 9214; Angew. Chem.
Int. Ed. 2009, 48, 9052.
[2] a) V. W. Pike, F. I. Aigbirhio, J. Chem. Soc. Chem. Commun. 1995,
2215–2216; b) R. Gail, C. Hocke, H. H. Coenen, J. Labelled
Compd. Radiopharm. 1997, 40, 50–52; c) A. Shah, V. W. Pike, D. A.
Widdowson, J. Chem. Soc. Perkin Trans. 1 1998, 2043–2046; d) S.
Martꢂn-Santamarꢂa, M. A. Carroll, C. M. Carroll, C. D. Carter, V. W.
Pike, H. S. Rzepa, D. A. Widdowson, Chem. Commun. 2000, 649–
650; e) T. L. Ross, J. Emert, C. Hocke, H. H. Coenen, J. Am. Chem.
Soc. 2007, 129, 8018–8025; f) M-R. Zhang, K. Kumata, K. Suzuki,
Tetrahedron Lett. 2007, 48, 8632–8635; g) M. A. Carroll, J. Nairne,
G. Smith, D. A. Widdowson, J. Fluorine Chem. 2007, 128, 127–132;
h) L. Cai, S. Y. Lu, V. W. Pike, Eur. J. Org. Chem. 2008, 2853–
[12] Y. B. Yu, P. L. Privalov, R. S. Hodges, Biophys. J. 2001, 81, 1632–
1642.
[13] J.-H. Chun, S. Y. Lu, Y.-S. Lee, V. W. Pike, J. Org.Chem. 2010, 75,
3332–3338.
[14] M. A. Carroll, V. W. Pike, D. A. Widdowson, Tetrahedron Lett. 2000,
41, 5393–5396.
ˇ
ˇ
[15] K. P. Eurenius, D. C. Chatfield, M. HodoScek, R. R. Brooks, Int. J.
Quantum Chem. 1996, 60, 1189–1200.
[16] M. W. Schmidt, K. K. Baldridge, J. A. Boatz, S. T. Elbert, M. S.
Gordon, J. H. Jensen, S. Koseki, N. Matsunaga, K. A. Nguyen, S. Su,
T. L. Windus, M. Dupuis, J. A. Montgomery, J. Comput. Chem. 1993,
14, 1347–1363.
Received: March 9, 2010
Published online: July 15, 2010
Chem. Eur. J. 2010, 16, 10418 – 10423
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10423