Mechanistic investigations of Cu-catalyzed fluorination of diaryliodonium salts: Elaborating the CuI/CuIII manifold in copper catalysis

Article abstract of DOI:10.1021/om5007903

A combination of experimental and density functional theory (DFT) investigations suggests that the Cu-catalyzed fluorination of unsymmetrical diaryliodonium salts with general structure [Mes(Ar)I]⁺ in N,N′-dimethylformamide proceeds through a Cu^I/Cu^III catalytic cycle. A low concentration of fluoride relative to combined iodonium reagent plus copper ensures that [Mes(Ar)I]⁺ is available as the reactive species for oxidative "Ar⁺" transfer to a Cu^I center containing one or two fluoride ligands. A series of different possible Cu^I active catalysts (containing fluoride, triflate, and DMF ligands) have been evaluated computationally, and all show low-energy pathways to fluorinated products. The oxidation of these Cu^I species by [Mes(Ar)I]⁺ to form cis-Ar(F)Cu^III intermediates is proposed to be rate-limiting in all cases. Ar-F bond-forming reductive elimination from Cu^III is computed to be very facile in all of the systems examined. The conclusions of the DFT experiments are supported by several experimental studies, including tests showing that Cu^I is formed rapidly under the reaction conditions and that the fluoride concentration strongly impacts the reaction yields/selectivities.

Full text of DOI:10.1021/om5007903

Article
pubs.acs.org/Organometallics
Mechanistic Investigations of Cu-Catalyzed Fluorination of
Diaryliodonium Salts: Elaborating the CuI/CuIII Manifold in Copper
Catalysis
Naoko Ichiishi,† Allan J. Canty,*,‡ Brian F. Yates,‡ and Melanie S. Sanford*,†
†Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, United States
‡School of Chemistry, University of Tasmania, Private Bag 75, Hobart, Tasmania 7001, Australia
S
* Supporting Information
ABSTRACT: A combination of experimental and density func-
tional theory (DFT) investigations suggests that the Cu-catalyzed
fluorination of unsymmetrical diaryliodonium salts with general
structure [Mes(Ar)I]+ in N,N′-dimethylformamide proceeds
through a CuI/CuIII catalytic cycle. A low concentration of
fluoride relative to combined iodonium reagent plus copper
ensures that [Mes(Ar)I]+ is available as the reactive species for
oxidative “Ar+” transfer to a CuI center containing one or two fluoride ligands. A series of different possible CuI active catalysts
(containing fluoride, triflate, and DMF ligands) have been evaluated computationally, and all show low-energy pathways to
fluorinated products. The oxidation of these CuI species by [Mes(Ar)I]+ to form cis-Ar(F)CuIII intermediates is proposed to be
rate-limiting in all cases. Ar−F bond-forming reductive elimination from CuIII is computed to be very facile in all of the systems
examined. The conclusions of the DFT experiments are supported by several experimental studies, including tests showing that
CuI is formed rapidly under the reaction conditions and that the fluoride concentration strongly impacts the reaction yields/
selectivities.
CuIII(Ar)(F) intermediate that undergoes reductive elimina-
INTRODUCTION
■
tion8 to liberate the aryl fluoride product.
Diaryliodonium salts1 are widely used as electrophilic arylating
reagents in both metal-free2 and transition-metal-catalyzed
reactions.3 In particular, there has been significant recent
attention to the development of Cu-catalyzed cross-couplings
of diaryliodonium salts with diverse coupling partners,
including phosphonates,3b,e CF3SO2Na,3d fluoride,4 and nitro-
gen3a,c,f and carbon5 nucleophiles. Although a number of
literature reports have probed the mechanisms of metal-free
reactions of diaryliodonium salts with nucleophiles,6 there is
still little known about the detailed mechanism of aryl transfer
from diaryliodonium salts to transition metals such as Cu.7 For
example, the nature of the active Cu catalyst that reacts with the
diaryliodonium salt has not been elucidated in most systems.
Furthermore, the mechanistic origin of the selectivity of aryl
transfer from unsymmetrical IIII reagents to transition metal
centers is poorly understood.1,6
a
Scheme 1. Proposed CuI/III Catalytic Cycle
a
X− = OTf− or F−.
We have recently disclosed the Cu-catalyzed fluorination of
diaryliodonium salts with potassium fluoride.4a In the presence
of 20 mol % of Cu(OTf)2, the unsymmetrical iodonium
reagents [Mes(Ar)I]+ react with high selectivity to generate
Ar−F and Mes−I, regardless of the electronic properties of the
aryl group. This selectivity is complementary to that observed
in the uncatalyzed fluorination of [Mes(Ar)I]+.4a In our original
communication, we proposed that this transformation occurs
through a CuI/III catalytic cycle (Scheme 1) in which the
reaction of a CuI catalyst with [Mes(Ar)I]+ generates a
Herein we describe a detailed investigation of the mechanism
of this Cu-catalyzed fluorination, using a combination of
density functional theory (DFT) calculations and experimental
studies. These investigations provide detailed insights into
many features of the reaction, including (i) the role of the Cu
precatalyst, (ii) possible structures of the active Cu catalyst, (iii)
the impact of changing ratios of reagents and Cu precatalyst,
Received: August 1, 2014
© XXXX American Chemical Society
A
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(iv) the nature of initial interactions between CuI and the
iodonium reagent, and (v) the subsequent sequence of
intermediates leading to Ar−F bond-forming reductive
elimination from CuIII.
RESULTS AND DISCUSSION
■
Oxidation State of the Copper Catalyst. Before
conducting DFT calculations, we sought to gain experimental
insights into the oxidation state of the active Cu species during
this transformation. As shown in Table 1, the CuII salt
Table 1. Cu-Catalyzed Fluorination of [Mes(Ph)I]+ as a
a
Function of Cu Precatalyst and Solvent
Figure 1. PhF formation as a function of time in the reaction of
[Mes(Ph)I]+ with KF catalyzed by Cu(OTf)2 and Cu(OTf)-
(CH3CN)4 in DMF at 60 °C. Conditions: [Mes-I-Ph]BF4 (0.1
mmol, 1 equiv), [Cu] (0.02 mmol, 0.2 equiv), KF (0.11 mmol, 1.1
equiv), DMF (0.1 M), 60 °C. Yields of PhF at each time point were
determined by 19F NMR spectroscopic analysis and represent an
b
◆
●
= Cu(OTf)-
[Cu]
Cu(OTf)2
solvent
yield
PhF:MesF
average of two separate runs.
(CH3CN)4.
= Cu(OTf)2;
DMF
DMF
DMF
DMF
85%
73%
71%
57%
38%
55%
39%
39%
35%
34%
98:2
99:1
Cu(OTf)(MeCN)4
Cu(OTf)(tBuCN)2
Cu(OTf)·benzene
Cu(OTf)2
Table 2. CuI/II Trapping Experiment
96:4
96:4
c
NMP
95:5
c
Cu(OTf)(MeCN)4
Cu(OTf)2
NMP
>99:1
13:87
13:87
14:86
13:87
EtOAc
EtOAc
toluene
toluene
Cu(OTf)(MeCN)4
Cu(OTf)2
Cu(OTf)(MeCN)4
[Cu]
Cu(OTf)2
solvent
λmax
color
a
Conditions: [Mes-I-Ph]BF4 (0.05 mmol, 1 equiv), [Cu] (0.01 mmol,
DMF
540
540
550
na
dark purple solution
dark purple solution
light purple solution
orange precipitate
orange precipitate
0.2 equiv), KF (0.055 mmol, 1.1 equiv), solvent (0.1 M), 60 °C.
b
Combined yield of PhF and MesF as determined by 19F NMR
Cu(OTf)(MeCN)4
Cu(OTf)2
DMF
c
NMP
spectroscopic analysis. NMP = N-methylpyrrolidinone.
Cu(OTf)2
EtOAc
toluene
Cu(OTf)2
na
Cu(OTf)2 and the CuI salts Cu(OTf)(CH3CN)4, Cu(OTf)-
(tBuCN)2, and Cu(OTf)·benzene all afford good yield and high
selectivity in this transformation under the standard conditions
(DMF, 60 °C, 18 h). The lower yield with the CuI precatalysts
is due to competing formation of side products (predominantly
biphenyl, along with traces of mesitylene, benzene, and
diphenyl ether). With both CuII and CuI precatalysts, the
reaction is highly solvent dependent, with the best yields and
selectivities obtained in DMF.9 As shown in Figure 1, the initial
rate of product formation in DMF at 60 °C is slightly faster
with Cu(OTf)(CH3CN)4 than with Cu(OTf)2.
On the basis of the results in Table 1 and Figure 1, we
hypothesized that the two precatalysts might be operating via a
similar CuI active species. In the case of Cu(OTf)2, reduction to
CuI could be occurring in situ, accounting for the slower initial
rate with this precatalyst. Importantly, DMF is well known as a
reductant for transition metals.10,11 To test for this possibility,
we performed CuI trapping experiments, using 2,2′-biquinoline
(biq) as a ligand for colorimetric detection of CuI. Lockhart has
shown that biq has a strong binding affinity for CuI, and the
resulting complexes exhibit a characteristic intense purple color
(λmax = 540 nm).12 Thus, we examined the speciation of
Cu(OTf)2 in the presence of biq in a variety of solvents (Table
2). An intense purple color was observed in DMF and NMP
within 5 min at room temperature in both the presence and
absence of 1.1 equiv of KF, consistent with the formation of
CuI in these solvents. UV−vis spectroscopic analysis of these
purple solutions showed a λmax between 540 and 550 nm,
further consistent with the formation of CuI under these
conditions. In contrast, when Cu(OTf)2 and biq were stirred in
EtOAc or toluene, an orange precipitate was observed. This is
indicative of the CuII complex, [CuII(biq)2]+2.13 However,
treatment of this orange precipitate with DMF at room
temperature resulted in rapid dissolution and a concomitant
color change to intense purple. Overall, these experiments
suggest that DMF promotes the reduction of CuII to CuI at 60
°C. Thus, we conclude that CuI species are available with both
the Cu(OTf)2 and Cu(OTf)(CH3CN)4 precatalysts and, as
discussed below, are likely to be the active catalysts in these
systems.14,15
Preliminary Considerations for Computational Stud-
ies of Copper Triflate Catalyzed Reactions. In our original
communication, we conducted DFT calculations on the
reaction between the symmetrical iodonium cation [Ph2I]+
and the CuI anion [CuF(OTf)]−.4a In the present study, we
have expanded these calculations to examine the unsymmetrical
diaryliodonium reagent [Mes(Ph)I]+.16 In addition, other
possible CuI catalysts, including CuF(DMF)17,18 and
[CuF2]−, have been assessed in detail, following the
consideration of computed thermodynamic data for the
interaction of [Mes(Ph)I]+ and CuI with triflate, fluoride, and
DMF as donor ligands (shown in Table 3). T-shaped and linear
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Table 3. Computation for Reactions of CuI and [Mes(Ph)I]+
with Donor Ligands Present during Cu Catalysis
Table 4. Impact of KF Stoichiometry on Yield and Selectivity
ΔG
ligand exchange at IIII and CuI centers
(kcal/mol)
entry
[Mes(Ph)I]+ + DMF → [Mes(Ph)I(DMF)]+
[Mes(Ph)I]+ + OTf− → Mes(Ph)I(OTf)
[Mes(Ph)I]+ + F− → Mes(Ph)IF
[Cu(DMF)2]+ + OTf− → Cu(OTf)(DMF) + DMF
Cu(OTf)(DMF) + OTf− → [Cu(OTf)2]− + DMF
[Cu(DMF)2]+ + F− → CuF(DMF) + DMF
CuF(DMF) + F− → [CuF2]− + DMF
2.7
1.6
1
2
3
4
5
6
7
8
9
KF (equiv)
yield (PhF)
yield (MesF)
PhF:MesF
−15.7
0.7
0.5
1.0
1.2
1.5
2.0
3.0
37%
83%
74%
25%
10%
9%
<1%
1%
>99:1
99:1
2.0
2%
98:2
−20.7
−16.4
−20.8
−19.1
22%
40%
34%
53:47
20:80
21:79
[Cu(OTf)2]+ + F− → [CuF(OTf)]− + OTf−
[CuF(OTf)]− + F− → [CuF2]− + OTf−
predominate over Cu catalysis. We hypothesized that this
situation could be remedied by slow addition of F− over the
course of the reaction. Indeed, as shown in Scheme 2, the slow
geometries are anticipated for IIII and CuI, respectively. For IIII
species, only data for ligands trans to Ph are presented, as the
alternative isomers with the ligands trans to Mes are marginally
less stable [by 0.7 (DMF) and 0.3 kcal/mol (F−)] or exhibit
identical ΔG (OTf−).
Scheme 2. Slow Addition of TBAF·H2O
The data in entries 1 and 2 show that DMF and triflate are
relatively poor ligands for [Mes(Ph)I]+. In contrast, fluoride
binding to [Mes(Ph)I]+ is highly thermodynamically downhill
(entry 3). Additionally, the complexation of fluoride with a
variety of CuI starting materials is even more thermodynami-
cally favorable (entries 6−9). Assuming that all of the copper is
present as CuI, and noting that the reaction of F− with CuI is
thermodynamically favored over that with [Mes(Ph)I]+
(compare entries 3 and 6−9), an inspection of the ratio of
[Mes(Ph)I]+ to CuI to F− under the catalysis conditions (1 to
0.2 to 1.1, Table 1) shows that there is insufficient F− present
to form an adduct with all of the [Mes(Ph)I]+ reagent. This
deficiency is retained until close to completion of catalysis.
We reasoned that this should be an important factor in
catalysis, as [Mes(Ph)I]+ is a significantly more reactive
electrophile than Mes(Ph)IF. Under conditions where the
resting state of the IIII reagent is Mes(Ph)IF, an extra 15.7 kcal/
mol would need to be added to the ΔG⧧ for Cu catalysis
compared to the analogous reaction with [Mes(Ph)I]+. As a
result, Cu catalysis is expected to be dramatically slower when
[KF] ≥ (2[Cu(OTf)2)] + [Mes(Ph)I]+). To test this proposal
experimentally, we examined the impact of the ratio of [KF] to
([Cu(OTf)2)] + [Mes(Ph)I]+) on catalysis. These studies were
conducted using 20 mol % of Cu(OTf)2 and 1 equiv of
[Mes(Ph)I]+, and the amount of KF was varied from 0.5 to 3.0
equiv relative to the iodonium reagent. Under these conditions,
the iodonium reagent would be fully complexed with fluoride at
1.4 equiv of KF, assuming that all of the KF is soluble. The
extent of Cu catalysis can be estimated based on the ratio of
products PhF:MesF. Under Cu-catalyzed conditions, PhF is
favored by ≥96:4, while the uncatalyzed reaction affords an
approximately 20:80 ratio of PhF:MesF. As shown in Table 4,
selectivity consistent with Cu catalysis was observed up to 1.25
equiv of KF. However, as predicted, significant erosion of
selectivity was observed at 1.5 equiv of KF. Furthermore, with
2.0 or more equiv of KF, the observed selectivity was identical
to that of the uncatalyzed reaction.
addition of 2 equiv of a soluble fluoride source (TBAF·H2O)19
over 7 h resulted in >99:1 selectivity for PhF over MesF (29%
yield).20 For comparison, 18:78 selectivity (and 29% yield)20
was observed when the identical reaction was conducted in a
single pot. These experimental results are fully consistent with
the calculations presented in Table 3.
The computations in Table 3 also illustrate the competitive
nature of DMF and triflate as ligands for CuI (entries 4 and 5).
This prompted us to examine the possibility of three different
CuI complexes as reactants in the oxidation step: [CuF(OTf)]−,
CuF(DMF), and [CuF2]− (Figure 2). Notably, in eq 2 of
Figure 2. Relationship between potential fluorocopper(I) reactants.
Energies ΔG (ΔH) are in kcal/mol.
Figure 2, F− is shown as accessed from Mes(Ph)IF, as there is
no free F− present. Importantly, these data only approximate
the actual speciation in solution due to difficulties in
computation of relative energies when charge separation is
involved (Figure 2, eq 2) and the very high concentration of
DMF present (12.9 M) relative to OTf− and F− (Figure 2, eq
As discussed above, we hypothesize that the dramatic change
in selectivity in the presence of ≥1.5 equiv of F− is due to a
change in the resting state of the diaryliodonium salt from the
cation [Mes(Ph)I]+ to the neutral species Mes(Ph)IF. Under
these conditions, the uncatalyzed reaction is proposed to
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1). Keeping these considerations in mind, pathways from all of
these CuI species are potentially competitive.
The “I···F” interaction in Ia (2.580 Å) is ∼0.4 Å shorter than
the “I···O” interaction in Ib. Ia lies below Ib and essentially at
We have also found that Ar−F bond-forming reductive
elimination is facile from all of the arylcopper(III) species
explored (vide infra). Thus, attempts to ascertain the identity of
the catalytically relevant CuI intermediate(s) rely upon DFT
and experimental examination of the oxidation step. The
general strategy used for exploring oxidation mechanisms is
discussed first, together with computation for the [CuF(OTf)]−
system, as it is more complicated than the others and illustrates
concepts displayed in the other systems. Gaussview structures
for selected intermediates and transition states are shown to
illustrate general features occurring in all cases.
the same level as the reference point “[CuF(OTf)]−
+
[Mes(Ph)I]+”, noting uncertainty associated with ion separa-
tion in this step. Both pathways may be considered competitive,
as they differ by only 1.2 kcal/mol in reaching transition
structures TS_IIa and TS_IIb (with TS_IIb being slightly
favored).
The “I···F” interaction is retained through TS_Ia to TS_IIa,
but the “I···O” interaction ceases after IIb, being replaced by an
“I···Cu” interaction in TS_IIb. The linear geometry at Cu in Ia
and Ib becomes markedly nonlinear in subsequent species. The
developing interaction between [Mes(Ph)I]+ and [CuF-
(OTf)]− is reflected in shorter “Cu···C” distances upon going
from TS_Ia to TS_IIa and from intermediate IIb to TS_IIb.
Consistent with the assignment of “Cu···C” distances as
indicative of bonding in TS_Ia, IIa, TS_Ib, and IIb, the
hydrogen or iodine atoms attached to these carbon atoms are
displaced above the plane of the phenyl ring. The geometries at
Cu for Ia, Ib through to IIa, IIb are linear (Ia, Ib) or
approximately trigonal planar (IIa, IIb), as expected for CuI
species.
General Strategy for Searching for Mechanisms in
Reaction of [CuF(OTf)]− with [Mes(Ph)I]+. Computation of
the oxidation mechanism was guided by our recent DFT study
of aryl transfer from diaryliodonium reagents to palladium(II)
centers.7b,21 In particular, we modeled transition structures
based on the reaction of binuclear [Pd(C∼N)(μ-O2CMe)]2
(C∼N = 3-methyl-2-phenylpyridinyl) with [Ph2I]+. Here, an
initial interaction of [Ph2I]+ with a donor atom of an acetate
22
ligand to give T-shaped IIII is followed by a transition
Both TS_IIa and TS_IIb can be regarded as late transition
states, in view of the very long “I···C(Mes)” distances of 2.769
(TS_IIa) and 2.561 Å (TS_IIb). These can be compared with
2.148 (Ia) and 2.139 Å (Ib) for the initial interaction of the two
molecules. In addition, the “Cu···C(μ-Ph)” distances of 1.967
(TS_IIa) and 1.965 Å (TS_IIb) are only ∼0.05 Å longer than
those in the CuIII products [1.911 (IIIa) and 1.924 Å (IIIb)].
Similarly, the “Cu···I” distance for TS_IIb (2.583 Å) is only
0.03 Å longer than that for coordinated iodomesitylene in the
CuIII product IIIb. Structure TS_IIa is approximately square-
planar at Cu, with the Cu center bearing a Ph ligand, a fluoride
ligand, and a semibidentate triflate group (Cu−O = 2.061, Cu···
O = 2.300 Å).
structure with a four-centered “Pd···(μ-Ph)···I···O” motif (A).
This then leads to “Ph+” transfer to Pd (B) with release of PhI.
Thus, our initial searches for transition structures in Cu-
catalyzed fluorination were modeled on motifs containing “I···
F” (C) or “I···O” interactions (D).
Scheme 3. Transition Structure (A) and Product (B) for the
7b
Arylation of PdII and Model Transition Structures
Explored in the Current Study
Reductive elimination is computed to be facile for both
pathways, occurring directly from IIIa and IIIb with activation
energies of only 4.4 and 4.5 kcal/mol, respectively, to give CuI
products with an η2-bound fluorobenzene ligand.
We also explored mesityl transfer to gain insights into the
experimentally observed selectivity for Ph group fluorination.
We began by searching for transition structures for the reaction
of [Mes(Ph)I]+ with [CuF(OTf)]− that contain a mesityl
bridge in configurations TS_IIa (“I···F”) and TS_IIb (“I···
Cu”). Placement of methyl groups in the 2- and 6-positions of
the bridging aryl group, with the leaving group now as PhI, gave
structures with unfavorable steric interactions in the copper
coordination sphere. Thus, for an analogue of TS_IIa with a
bridging Mes group, there is a methyl “C···O” interaction of
2.83 Å and a methyl “C···F” interaction of 2.36 Å, which are
both much shorter than the corresponding sum of van der
Waals radii (Me + O = 3.52 Å; Me + F = 3.47 Å).23,24
Optimization of this structure led to the transition structure
TS_IIa_Mes (Figure 4). This is analogous to TS_IIa, with
approximate square-planar coordination at Cu, but with a
different orientation of the bridging aryl group. The orientation
of the Mes group is altered in a manner that results in the 2-
and 6-positions being further removed from coordinated
oxygen and fluorine atoms. Also, the “Cu···C···I” angle for
the bridging aryl group is increased from 74.8° in TS_IIa to
87.9° in TS_IIa_Mes. The overall sequence leading to a CuIII
species is very similar to Ia → IIIa. However, analogues of
TS_Ia and IIa display the Mes group interacting with Cu in an
Computation for Ph group transfer from [Mes(Ph)I]+ to
[CuF(OTf)]− resulted in two different transition structures.
The first conforms to motif C (TS_IIa), containing a
semibidentate triflate ligand. The second is based on motif F
(TS_IIb) (Figure 3). Vibrational frequency calculations were
employed to ascertain the structures of their precursors (IIa,
IIb) and to establish the identity of the CuIII products (IIIa,
IIIb). The precursor structures IIa and IIb have strong
interactions between the reactants, illustrated by O−Cu−F
angles of 127.6° and 110.5°, respectively. These results led us to
a search for even earlier transition structures and accompanying
precursors with weaker interactions. These were identified and
supported by intrinsic reaction coordinate (IRC)/vibrational
frequency calculations to be linked to IIa and IIb. Energies in
kcal/mol [ΔG(ΔH)] are presented in Figure 3, although
discussion is confined to considerations of ΔG.
D
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Figure 3. Energy profile for the reaction of [Mes(Ph)I]+ with [CuF(OTf)]−, illustrating oxidative transfer of “Ph+” to give the CuIII complexes IIIa
and IIIb, followed by reductive elimination. The final CuI species is arbitrarily chosen as [Cu(OTf)2]−. Selected interatomic distances and angles are
reported (∑(van der Waals radii): I + O = 3.50 Å; I + F = 3.45 Å; I + Cu = 3.38 Å).23 Energies ΔG (ΔH) are reported in units of kcal/mol.
Gaussview structures are shown for the low-energy pathway.
from this motif to TS_IIa_Mes, which contains an “I···F”
interaction (vide supra).
Reaction of CuF(DMF) with [Mes(Ph)I]+. Following an
analogous approach to that used for [Cu(F)(OTf)]−, a cationic
transition structure TS_IIa_DMF directly analogous to the
neutral triflate species TS_IIa (with an “I···F” interaction) was
identified (Figure 5). Here, DMF is present as a monodentate
O-donor ligand in place of the semibidentate triflate in TS_IIa.
The PhCuIII product IIIa_DMF then undergoes facile reductive
elimination (ΔG⧧ = 3.6 kcal/mol).25 Interestingly, a corre-
sponding transition structure for Mes transfer at CuF(DMF),
explored in a similar manner to that for [CuF(OTf)]−, could
Figure 4. Optimized structures for TS_IIa with a bridging Ph group
and TS_IIa_Mes with a bridging Mes group, oriented to illustrate the
difference in orientation of bridging aryl groups and in “Cu···C···I”
angles.
not be identified.
Reaction of [CuF2]− with [Mes(Ph)I]+. An analogous
approach was used to elucidate the reaction pathways for
[CuF2]−, and the results are shown in Figure 6. Ph and Mes
transfer pathways were identified, and both proceed via “I···F”
interactions analogous to those found for [CuF(OTf)]− in
Figure 3. For mesityl transfer (red pathway), a T-shaped CuIII
intermediate (IIIa′-F_Mes) is formed upon loss of PhI. The
addition of free triflate to this structure would then enable
formation of a transition structure for reductive elimination
from IIIa_F_Mes.
η1 manner, presumably due to unfavorable steric interactions
with the 2,6-methyl groups. An additional 2.6 kcal/mol is
required to access transition structure TS_IIa_Mes compared
with the Ph-bridged analogue. Furthermore, an additional 3.8
kcal/mol is required relative to TS_IIb (see below and
Supporting Information for full details of this sequence). This
is consistent with the high selectivity observed experimentally.
Modeling of a bridging Mes analogue of TS_IIb containing
an “I···Cu” interaction prior to geometry optimization revealed
a short methyl “C···O” interaction (2.47 Å). Attempted
computation for this transition structure led smoothly away
Computation for the Oxidation Step with Variation of
the Aryl Group for the Three CuI Reactants. We next
explored a series of different [Mes(Ar)I]+ reagents in order to
compare the calculated selectivity for oxidative transfer of Ar
versus Mes to CuI to the experimentally observed selectivity as
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contributions for the steric impact of 2,6-Me2 substitution
across the board. For instance, ΔΔG⧧ for XC6H4 transfer
versus Mes transfer is +0.3 and +0.8 kcal/mol for the first two
entries in Table 3 with [CuF2]− (compare columns K and L).
In contrast, the corresponding ΔΔG⧧ values in the [CuF-
(OTf)]− pathways are 3.8 and 3.1 kcal/mol (compare columns
G and I).
For CuF(DMF) (column J), activation energies for all
transfer reactions are higher than the lowest energy pathways
for [CuF(OTf)]− and [CuF2]−, noting the uncertainties in
comparing energy barriers between the three systems.
All of the calculated activation energies in Table 5 (ΔG⧧ =
7.8−14.5 kcal/mol) are lower than those calculated for Ar−F
and Mes−F coupling under Cu-free conditions (15.3−22.2
kcal/mol, vide infra). Thus, it appears that a Cu-catalyzed route
might also account for formation of the minor product (MesF)
under catalysis conditions, rather than this being formed as a
product of Mes(Ph)IF decomposition. It is particularly notable
that low activation energies are computed for both 2,6-
Me2C6H4 and mesityl transfer in the [CuF(OTf)]− and
[CuF2]− systems.
Comparison of Possible Oxidation Pathways. Similar
reaction manifolds are obtained for all three CuI catalysts, and
Figure 7 (related to Figure 2) provides an overview in which
the reference energy is now assigned to the adduct formed
between [CuF2]− and [Mes(Ph)I]+. This is the only pathway
for which the adduct is significantly lower than the reactant
pair. Thus, this adduct could be considered as a resting state.
However, as noted earlier, caution is required in interpretation
because of both the presence of DMF at 12.9 M [which may
lead to the formation of CuF(DMF)] and also the moderate
reliability of DFT when ion separation is involved.
Figure 5. Energy profile for the reaction of [Mes(Ph)I]+ with
CuF(DMF), illustrating oxidative transfer of “Ph+” to give the CuIII
complex IIIa_DMF and subsequent reductive elimination. The final
CuI species is arbitrarily chosen as [Cu(DMF)2]+. Energies ΔG (ΔH)
are in kcal/mol. Gaussview pictures for transition structures are shown.
26
Experiments designed to test the viability of CuF2 as a
a function of Ar group substitution. Table 5 shows the energy
requirement to achieve transition structures from “[CuF-
(OTf)]− + [Mes(Ar)I]+”, “CuF(DMF) + [Mes(Ar)I]+2”,
“[CuF2]− + [Mes(Ar)I]+”, or the relevant precursor adducts
if these are at lower energy than the reactant pair. The
experimental ratio of products (ArF:MesF) is shown, together
with Cu-free ratios (columns 2 and 3). Note that computation
for CuF(DMF) is shown, even though we cannot detect a
pathway for mesityl transfer in this system.
precatalyst show that triflate is not necessary for Cu-promoted
coupling. Specifically, the reaction of 1 equiv of CuF2 with
[Ph(Mes)I]+ at 60 °C in DMF afforded a >99:1 ratio of PhF to
MesF in quantitative yield.27 Although CuF2 has low solubility
in DMF, it is sufficiently soluble to give a relatively weak
positive color test for CuI. Under these conditions, in the
absence of triflate, the reaction likely occurs via either
CuF(DMF) or [CuF2]−.
For [CuF(OTf)]− (columns G−I), the activation energies in
column G are consistently lower (by 1−3 kcal/mol) than those
in columns H and I. Also supportive of transition structure G as
a favored pathway, these transition structures exhibit “I···C”
distances for the departing aryl group (2.764−2.893 Å) that are
shorter than those for H and I (2.936−3.097 Å), suggesting
that G is an earlier transition state than H/I. The data are
consistent with the observed selectivities for coupling products,
where Ar transfer (G) is preferred over Mes transfer (I). For
competition between 2,6-Me2C6H3 and Mes transfer, essen-
tially identical energies are obtained, reflecting the similar steric
and electronic properties of these groups. Notably, as discussed
above, a triangular transition structure analogous to G does not
appear to be feasible for 2,6-substituted arenes.
Overall, the similarities between the reaction barriers for the
three CuI species examined herein suggest that all three
pathways could be competitive. The most favorable one is likely
to depend on the reaction conditions and the speciation of Cu
in solution.
Copper-Free Decomposition of Mes(Ar)IF. Experimen-
tal evidence for the role of copper catalysis rests mainly on the
observation of faster rates and very different product ratios of
ArF:MesF upon the addition of Cu. To explore the difference
in selectivity for ArF and MesF, we also examined C−F bond
formation from Mes(Ar)IF under uncatalyzed conditions. The
Mes(Ar)IF reagents examined are those discussed above for Cu
catalysis. Computation for Mes(Ar)IF followed the approach
documented by De Luthli28 and Olofsson6a for related
̈
The [CuF2]− system displays the same trends as for
[CuF(OTf)]−, showing a competitive process for [Mes(2,6-
Me2C6H3)I]+, and favoring aryl transfer for other [Mes(Ar)I]+
reagents. The p-MeOC6H4 derivative is the lone exception. In
this case, Mes transfer is computed to be favored by 1 kcal/mol,
which is inconsistent with the experimental selectivity.
Although the energy difference is small, it is notable that
computation for the [CuF2]− pathway shows much smaller
unsymmetrical diaryliodine(III) species. An example is shown
in Figure 8, illustrating the transition structure TS_isom for
isomerization of T-shaped isomers of Mes(p-NO2C6H4)IF and
the transition structures for competing aryl−fluoride coupling
pathways.
Computational results are summarized in Table 6, together
with the ratios of products obtained experimentally for Cu-free
fluorination. Curtin−Hammett conditions, in which the
F
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Figure 6. Energy profile for the reaction of [Mes(Ph)I]+ with [CuF2]−, illustrating oxidative transfer to give ArCuIII species IIIa_F and IIIa′_F_Mes,
and subsequent reductive elimination. The final CuI species is arbitrarily chosen as [CuF(OTf)]−. Energies ΔG (ΔH) are in kcal/mol. Gaussview
structures for “Ph+” transfer are shown.
Table 5. Energy Values (kcal/mol) Required to Access Transition Structures for ArF and MesF Coupling from the Reagent
Pairs (“[CuF(OTf)]− + [Mes(Ar)I]+” or “CuF(DMF) + [Mes(Ar)I]+” or “[CuF2]− + [Mes(Ar)I]+”) or Their Respective
Precursor Adducts When These Are at Lower Energy
G
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Table 6. Computed Barriers Compared to Observed
Selectivities for ArF and MesF Coupling upon Uncatalyzed
Decomposition of Mes(Ar)IF
Figure 7. Overview of reaction profile to afford PhCuIII species. The
reference energy is taken as the adduct CuF2·Mes(Ph)I. Energies ΔG
(ΔH) are in kcal/mol.
( 0.2 kcal/mol) for Mes(Ph)IF do not discriminate between
competing pathways. The lack of sensitivity of computation for
the latter two systems does not appear to be a result of the
functional, basis set, or solvent applied here. For example, a
calculation under our computation conditions for a representa-
tive example from the Luthli study,28 (p-MeC6H4)(Ph)IBr,
̈
gives a ΔΔG⧧ of 0.5 kcal/mol, favoring p-MeC6H4Br as
product. This compares well with the reported value of 0.62
kcal/mol (B3LYP, aug-cc-pVDZ, gas phase).28
Reductive Elimination of Aryl Fluorides from ArCuIII
Species. Reductive elimination of PhF and MesF from CuIII is
computed to involve simple triangular motifs in transition
structures with planar four-coordinate geometries at copper
(Figures 3, 5, and 6). The activation energies for these
processes (3.6−7.7 kcal/mol) are substantially lower than for
the oxidation processes in all models examined. As part of a
related catalytic process for Ar−F bond formation, Ribas and
co-workers have computed the activation parameters for C−F
coupling at a five-coordinate CuIII center containing a
tetradentate macrocyclic ligand, [CuIIIF(L-C,N,N′,N″)]+.29
They obtained a ΔG⧧ of 16.2 kcal/mol, which is significantly
higher than in the present systems. This may be the result of
either (i) the extra stability provided by the polydentate ligand
in the Ribas system and/or (ii) the differences between
reductive elimination from four- versus five-coordinate CuIII
centers.
Figure 8. Energy profile and representative Gaussview structures for
interconversion of isomers of Mes(p-NO2C6H4)IF. Energies ΔG
(ΔH) in kcal/mol are referenced to the lower energy isomer (syn-
isom).
CONCLUSIONS
■
Both experimental and DFT results support the feasibility of a
CuI/CuIII catalytic cycle for the reaction of unsymmetrical
diaryliodonium cations with potassium fluoride in DMF using
CuII(OTf)2 as the precatalyst. Several possible reaction
pathways were found, and they exhibit similarities in the
manner in which CuI species interact with [Mes(Ar)I]+ cations.
In all cases, initial CuI·IIII adduct formation involves an
interaction between a donor atom of a ligand on Cu and the
iodine(III) center. This is followed by interaction of the Ar
group with copper, leading, eventually, to transition structures
for rate-limiting Ar transfer (“Cu···(μ-η1-Ar)···I” with an
additional “I···Cu” or “I···F” interaction) to form cis-Ar(F)CuIII.
The CuIII species then undergo facile ArF bond-forming
reductive elimination. The evidence supporting these proposed
pathways is as follows:
energies required for isomerization are significantly lower than
for reductive elimination, were found in all cases. This allows
the reference point for energy to be chosen as that of the more
stable isomer. This was calculated to be the syn-isomer in all
cases except for Mes(p-MeOC6H4)IF. As noted for related
systems,28 the differences in activation energies (ΔΔG⧧ and
ΔΔH⧧) for competing transition structures are relatively small,
but are broadly consistent with the experimental results. For
example, for Mes(3,5-Me2C6H4)IF, the calculated ΔΔH⧧ value
(0.8 kcal/mol) is consistent with the experimental product
distribution. However, ΔΔG⧧ computes as only 0.1 kcal/mol in
this case. Furthermore, the computed ΔΔH⧧ and ΔΔG⧧ values
H
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(1) CuI is detected experimentally when CuII(OTf)2 is added
to DMF, but not in solvents that do not support catalysis.
(2) Experimental and DFT studies suggest that the reactive
IIII species are cations of general structure [Mes(Ph)I]+.
(3) DFT calculations show four low-energy pathways for
oxidative transfer of “Ar+” from [Mes(Ar)I]+ to CuI,
forming cis-Ar(F)CuIII species. These pathways proceed
from [CuF(OTf)]− (2 pathways), CuF(DMF) (1
pathway), and [CuF2]− (1 pathway). All have activation
parameters that are lower than those for decomposition
of Mes(Ar)IF in the absence of Cu.
(4) DFT studies of the highest energy pathway [from
CuF(DMF)] do not show a viable transition structure for
mesityl group transfer. However, pathways commencing
with [CuF(OTf)]− and [CuF2]− enabled comparisons of
the relative energies of Ar versus Mes transfer from
[Mes(Ar)I]+. For the five aryl groups examined,
agreement with experiment is found in all cases
commencing from [CuF(OTf)]− and in four commenc-
ing from [CuF2]−. Notably, with [CuF2]−, smaller ΔΔG⧧
values for Ar versus Mes transfer are observed across the
board, suggesting that this single anomaly may not be
significant.
(d) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299.
(e) Deprez, N. R.; Sanford, M. S. Inorg. Chem. 2007, 46, 1924.
(f) Zhdankin, V. V. Chem. Rev. 2002, 102, 2523.
(2) For examples of metal-free nucleophilic reactions with diary-
liodonium salts, see ref 1 and: (a) Wagner, A. M.; Sanford, M. S. J. Org.
Chem. 2014, 79, 2263. (b) Umierski, N.; Manolikakes, G. Org. Lett.
2013, 15, 188. (c) Jalalian, N.; Ishikawa, E. E.; Silva, L. F.; Olofsson, B.
Org. Lett. 2011, 13, 1552. (d) Laudge, K. P.; Jang, K. S.; Lee, S. Y.; Chi,
D. Y. J. Org. Chem. 2012, 77, 5705. (e) Grushin, V. V.; Kantor, M. M.;
Tolstaya, T. P.; Scherbina, T. M. Izv. Akad. Nauk SSSR, Ser. Khim.
1984, 2338.
(3) For Cu-catalyzed C-heteroatom coupling reactions with Ar2I+,
see: (a) Sokolovs, I.; Lubriks, D.; Suna, E. J. Am. Chem. Soc. 2014, 136,
́
6920. (b) Fananas-Mastral, M.; Feringa, B. L. J. Am. Chem. Soc. 2014,
̃
136, 9894. (c) Lv, T.; Wang, Z.; You, J.; Lan, J.; Gao, G. J. Org. Chem.
2013, 78, 5723. (d) Cullen, S. C.; Shekhar, S.; Nere, N. K. J. Org.
Chem. 2013, 78, 12194. (e) Xu, J.; Zhang, P.; Gao, Y.; Chen, Y.; Tang,
G.; Zhao, Y. J. Org. Chem. 2013, 78, 8176. (f) Vaddula, B.; Leazer, J.;
Varma, R. S. Adv. Syn. Catal. 2012, 354, 986.
(4) (a) Ichiishi, N.; Canty, A. J.; Yates, B. F.; Sanford, M. S. Org. Lett.
2013, 15, 5134. (b) Ichiishi, N.; Brooks, A. F.; Topczewski, J. J.;
Rodnick, M. E.; Sanford, M. S.; Scott, P. J. H. Org. Lett. 2014, 16, 3224.
(5) Cu-catalyzed C−C coupling reactions with Ar2I+: (a) Baralle, A.;
Fensterbank, L.; Goddard, J.-P.; Ollivier, C. Chem.Eur. J. 2013, 19,
10809. (b) Kieffer, M. E.; Chuang, K. V.; Reisman, S. E. J. Am. Chem.
Soc. 2013, 135, 5557. (c) Collins, B. S. L.; Suero, M. G.; Gaunt, M. J.
Angew. Chem., Int. Ed. 2013, 52, 5799. (d) Phipps, R. J.; McMurray, L.;
Ritter, S.; Duong, H. A.; Gaunt, M. J. J. Am. Chem. Soc. 2012, 134,
10773. (e) Zhu, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2012, 134,
10815. (f) Duong, H. A.; Gilligan, R. E.; Cooke, M. L.; Phipps, R. J.;
Gaunt, M. J. Angew. Chem., Int. Ed. 2011, 50, 463. (g) Phipps, R. J.;
Gaunt, M. J. Science 2009, 323, 1593.
(6) (a) Malmgren, J.; Santoro, S.; Jalalian, N.; Himo, F.; Olofsson, B.
Chem.Eur. J. 2013, 19, 10334. (b) Grushin, V. V. Acc. Chem. Res.
1992, 25, 529. (c) Grushin, V. V.; Demkina, I. I.; Tolstaya, T. P. J.
Chem. Soc., Perkin Trans. 2 1992, 505. (d) Chun, J. H.; Lu, S.; Lee, Y.
S.; Pike, V. W. J. Org. Chem. 2010, 75, 3332.
(7) DFT calculations on Cu-catalyzed reactions with diaryliodonium
salts: (a) Chen, B.; Hou, X.-L.; Li, Y.-X.; Wu, Y.-D. J. Am. Chem. Soc.
2011, 133, 7668. DFT calculations on Pd-catalyzed reactions with
diaryliodonium salts: (b) Canty, A. J.; Ariafard, A.; Sanford, M. S.;
Yates, B. F. Organometallics 2013, 32, 544.
Overall, our experimental and DFT studies of this system
illustrate flexibility in the ligand environment that will support a
CuI/III catalytic cycle for ArF coupling. As such, these studies
suggest that there is considerable latitude for the development
of CuI/III-catalyzed aryl−X bond-forming reactions beyond the
immediate successful protocol for Cu(OTf)2-catalyzed fluori-
nation of diaryliodonium salts.3,8,30
ASSOCIATED CONTENT
* Supporting Information
■
S
Complete ref 16, computation for the reaction of [CuF(OTf)]−
with [Mes(Ar)I]+ for mesityl transfer, energy parameters,
Cartesian coordinates and Gaussview diagrams of all optimized
structures, and full details of all experiments. This material is
available free of charge via the Internet at http://pubs.acs.org.
(8) (a) Zhang, H.; Yao, B.; Zhao, L.; Wang, D- X.; Xu, B- Q.; Wang,
M.-X. J. Am. Chem. Soc. 2014, 136, 6326. (b) Casitas, A.; Ribas, X.
Chem. Sci. 2013, 4, 2301. (c) Fier, P. S.; Hartwig, J. F. J. Am. Chem. Soc.
2012, 134, 10795. (d) Casitas, A.; King, A. E.; Parella, T.; Costas, M.;
Stahl, S. S.; Ribas, X. Chem. Sci. 2010, 1, 326. (e) Yao, B.; Wang, D. X.;
Huang, Z. T.; Wang, M. X. Chem. Commun. 2009, 2899.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: Allan.Canty@utas.edu.au (A. J. Canty).
*E-mail: mssanfor@umich.edu (M. S. Sanford).
■
(9) Goodgame, D. M. L.; Goodgame, M.; Canham, G. W. R. Nature
1969, 222, 866.
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
(10) Muzart, J. Tetrahedron 2009, 65, 8313.
(11) For examples of the reduction of CuII with DMF, see:
(a) Malkhasian, A. Y. S.; Finch, M. E.; Nikolovski, B.; Menon, A.;
Kucera, B. E.; Chavez, F. A. Inorg. Chem. 2007, 46, 2950. (b) Teo, J. J.;
Chang, Y.; Zeng, H. C. Langmuir 2006, 22, 7369.
Notes
The authors declare no competing financial interest.
(12) Lockhart, T. P. J. Am. Chem. Soc. 1983, 105, 1940.
ACKNOWLEDGMENTS
(13) Ali, B. F.; Al-Sou’od, K.; Al-Jaar, N.; Nassar, A.; Zaghal, M. H.;
Judeh, Z.; Al-Far, R.; Al-Refai, M.; Ibrahim, M.; Mansi, K.; Al-Obaidi,
K. H. J. Coord. Chem. 2006, 59, 229.
(14) We have also tested running the fluorination process in a
cosolvent of EtOAc/DMF (0.1 M in PhIMes+, 4:1). This afforded 86%
overall yield (98:2 selectivity).
(15) A possible alternative mechanism would be a SET pathway. We
have not conducted an extensive investigation of such processes.
(16) Gaussian 09 was used at the BP86 level for calculations with
N,N-dimethylformamide as solvent and utilizing the quadruple-ξ
valence polarized def2-QZVP basis set on Cu and iodine along with
the corresponding ECP and the 6-311+G(2d,p) basis set on other
atoms. See Supporting Information for full details.
■
We thank the Australian Research Council and the U.S.
National Institutes of Health (GM 073836) for financial
support, and the Australian National Computational Infra-
structure and the University of Tasmania for computing
resources.
REFERENCES
■
(1) For reviews on diaryliodonium salts, see: (a) Yusubov, M. S.;
Maskaev, A. V.; Zhdankin, V. V. Arkivov 2011, 2011, 370. (b) Merritt,
E. A.; Olofsson, B. Angew. Chem., Int. Ed. 2009, 48, 9052. (c) Canty, A.
J.; Rodemann, T.; Ryan, J. H. Adv. Organomet. Chem. 2008, 55, 279.
I
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Article
(17) For literature examples of LnCu(DMF) complexes, see:
(a) Ding, S.; Jiao, N. J. Am. Chem. Soc. 2011, 133, 12374. (b) Ishiguro,
S.-I.; Jeliazkova, B. G.; Ohtaki, H. J. Solution Chem. 1987, 16, 1.
(18) The crystal structure of CuX(PPh3)(DMF) (X = Cl; Br) was
previously reported: Scharfe, S.; Fassler, T. F. Z. Naturforsch. 2012,
̈
676, 564.
(19) TBAF·H2O was selected because it is fully soluble in DMF,
rendering it straightforward to add using a syringe pump.
(20) Significant quantities of biphenyl and phenol were detected as
byproducts, which accounts for the modest yield. This is likely due, at
least in part, to the water in the TBAF·H2O.
(21) For a related study, see: Szabo,
2010, 324, 56.
́
K. J. J. Mol. Catal. A: Chem.
(22) Landrum, G. A.; Goldberg, N.; Hoffmann, R.; Minyaev, R. M.
New J. Chem. 1998, 883.
(23) Bondi, A. J. Phys. Chem. 1964, 68, 441.
(24) Pauling, L. The Nature of the Chemical Bond; Cornell University
Press: Ithaca, NY, 1960; p 262.
(25) For Cu(F)(DMF) as the reactant, an additional pathway via an
analogue of TS_IIb (with an “I···Cu” interaction) was found that
yields PhCuIII(F)(DMF)(IMes). However, we deem this pathway less
likely, as the PhCuIII intermediate has trans-disposed phenyl and fluoro
ligands and thus requires isomerization to allow reductive elimination.
This complex may undergo reversible oxidation, a feature that has
been proposed in other CuI/III-catalyzed reactions (ref 8).
(26) CuF2-mediated aromatic fluorination was reported previously.
Grushin, V. U.S. Patent 7,202,388, 2007.
(27) The use of substoichiometric CuF2 in combination with 0.5−1.1
equiv of KF afforded selectivity favoring MesF. Ongoing investigations
are probing the origins of this result.
(28) De Magalhaes, H. P.; Luthi, H. P.; Togni, A. Org. Lett. 2012, 14,
̃
̈
3830.
(29) Casitas, A.; Canta, M.; Sola,
Chem. Soc. 2011, 133, 19386.
̀
M.; Costas, M.; Ribas, X. J. Am.
(30) For recent reports of related reactions that likely proceed via
similar mechanisms, see: (a) Ye, Y.; Schimler, S.; Hanley, P.; Sanford,
M. S. J. Am. Chem. Soc. 2013, 135, 16292. (b) Ye, Y.; Sanford, M. S. J.
Am. Chem. Soc. 2013, 135, 4648.
J
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