Nucleophilic aryl fluorination and aryl halide exchange mediated by a CuI/CuIII catalytic cycle

Article abstract of DOI:10.1021/ja2058567

Copper-catalyzed halide exchange reactions under very mild reaction conditions are described for the first time using a family of model aryl halide substrates. All combinations of halide exchange (I, Br, Cl, F) are observed using catalytic amounts of Cu

Full text of DOI:10.1021/ja2058567

ARTICLE
pubs.acs.org/JACS
Nucleophilic Aryl Fluorination and Aryl Halide Exchange Mediated by
a CuI/CuIII Catalytic Cycle
Alicia Casitas,† Mercꢀe Canta,† Miquel Solꢀa,†,‡ Miquel Costas,† and Xavi Ribas*,†
†QBIS Research Group, Departament de Química, Universitat de Girona, Campus Montilivi, Girona E-17071, Catalonia, Spain
‡Institut de Química Computacional, Universitat de Girona, Campus Montilivi, Girona, E-17071, Catalonia, Spain
S Supporting Information
b
ABSTRACT: Copper-catalyzed halide exchange reactions under very mild reaction
conditions are described for the first time using a family of model aryl halide substrates.
All combinations of halide exchange (I, Br, Cl, F) are observed using catalytic amounts of
CuI. Strikingly, quantitative fluorination of arylÀX substrates is also achieved catalytically at
room temperature, using common FÀ sources, via the intermediacy of arylÀCuIIIÀX
species. Experimental and computational data support a redox CuI/CuIII catalytic cycle
involving arylÀX oxidative addition at the CuI center, followed by halide exchange and
reductive elimination steps. Additionally, defluorination of the arylÀF model system can be
also achieved with CuI at room temperature operating under a CuI/CuIII redox pair.
’ INTRODUCTION
Transition-metal catalyzed arylÀX fluorination can be envi-
sioned via a three-step catalytic cycle that would involve arylÀX
oxidative addition, followed by X- to F-exchange, and finally
arylÀF reductive elimination (Scheme 1).23
The ability to exchange a given halide in an aryl group for
another halide would enormously facilitate the versatility of many
transition metalcatalyzedcross-couplingreactions.1À5 For instance,
the exchange of less reactive arylÀCl for arylÀBr or arylÀI
bonds would broaden the scope of aryl halide starting materials
for many processes now limited to the most reactive aryl-I.6,7
Only Ni8,9 and Cu-catalyzed2,10 aryl halide exchange processes
have been reported,1 whereas Pd-based systems lack precedent.
Although no generally successful Pd-catalyzed halide exchange
reactions have yet been reported, there has been considerable
success in the development of Pd-mediated direct halogenation
of aromatic rings,11À13 and recently a Pd-catalyzed transforma-
tion of aryl-triflates to arylÀCl and arylÀBr has been reported.14
Special mention is deserved by the halide exchange reactions
that aim to insert a fluorine atom at an aryl group.15À17 Fluorine
forms the strongest single bond to carbon; the combination of its
high electronegativity and small size give rise to the unusual
properties associated with fluorinated organic compounds, that
is, chemical inertness, high thermal stability and high solubility.
At present, up to 30À40% of agrochemicals and 20À30% of
pharmaceuticals contain at least one fluorine atom, which is
usually located at an arene. In light of the importance of fluo-
rinated arenes and the practical limitations of current methods
for their preparation,18À22 the metal-catalyzed conversion of a
nonactivated aryl halide with a nucleophilic fluorine source (i.e.,
an alkali metal fluoride) to yield the corresponding aryl fluoride is
a highly sought and desirable transformation.
Currently, among all transition metals in any oxidation state,
only two Pd-based compounds have been identified as capable of
affording CÀF bond formation via reductive elimination: Ritter’s
pyridyl-sulfonamide PdIV fluoride,24,25 and Buchwald’s phos-
phine PdII fluoride.26 The former was the first example of an
arylÀF reductive elimination from a well-defined arylÀPdIVÀF
species. On the contrary, Buchwald’s compound overcomes the
usual reluctance of arylÀPdIIÀF species to undergo reductive
elimination by using a bulky monodentated phosphine ligand,
which stabilizes a 14-electron tricoordinated arylÀPdIIÀF spe-
cies. The latter undergoes aryl-F reductive elimination using aryl
triflates or bromides and AgF as reactants in 57À85% yield by
thermolysis at ∼100 °C.26 Buchwald’s system stands as the
unique example in the literature that follows the largely sought
catalytic cycle depicted in Scheme 1. On the contrary, electro-
philic fluorinating methodologies (“F+“ reagents)25,27À31 cannot
be used for the displacement of XÀ in nonactivated ArX by FÀ.32
Moreover, a PdII/PdIV catalytic cycle can be considered as
unlikely since intramolecular aryl-X oxidative addition at PdII
finds a single precedent in the literature,33 and no example of the
corresponding intermolecular reaction is known. Ideally, catalytic
nucleophilic aryl fluorination should be a mild (room temperature)
Received: June 23, 2011
Published: October 25, 2011
r
2011 American Chemical Society
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Scheme 1. Transition-Metal Catalyzed ArylÀX Fluorination
Figure 2. Room temperature halide exchange reactions under catalytic
conditions in copper(I).
the slower reactions with 1I, increasing amounts of phen were
needed and also minor amounts of side-product 2, arising from
intramolecular aryl-amine reductive elimination, were observed,
as documented in previous studies.39,40 This reactivity demon-
strates the existence of a reductive elimination/ oxidative addition
CuIII/CuI equilibrium that opened the door to explore a Cu-
catalyzed halide exchange in our L1ÀX systems.
Halide Exchange in ArylÀX Model Substrates (X = Cl, Br, I).
The conceived catalytic strategy for achieving halide exchange
consisted in the addition of a catalytic amount (11 mol %) of a
CuI source ([CuI(CH3CN)4]OTf, OTf = CF3SO3) together
with an excess of the desired halide salt MY (M = Na, Bu4N; Y =
Cl, Br, I) (Figure 2). Oxidative addition reactivity of CuI and
arylÀX species in these systems is precedented.37 Because of
that, we expected initial oxidative addition to proceed forming
arylÀCuIIIÀX species. Subsequent halide exchange, and final arylÀY
reductive elimination should furnish arylÀhalideexchangeproducts.
As envisioned, arylÀI (L1ÀI) exchange to afford arylÀCl
(L1ÀCl) and arylÀBr (L1ÀBr) is achieved in nearly quantitative
yields at room temperature using acetonitrile as solvent, and
Bu4NCl and Bu4NBr, respectively, as halide sources (Table 1,
entries 1 and 4).
Figure 1. ArylÀX reductive elimination promoted by the addition of
1,10-phenathroline to 1X complexes at room temperature.
and rapid process to meet the requirements for late-stage
aromatic fluorination as well as for the preparation of short-lived
18F-radiolabeled molecular probes for positron emission tomo-
graphy (PET).34À36
We have recently described the reductive elimination of
arylÀX from well-defined arylÀCuIIIÀX complexes (X = Cl,
Br, I; Figure 1).37,38 On the basis of these precedents, herein we
report a metal-catalyzed halide exchange from given arylÀX (X =
Cl, Br, I) model substrates to heavier or lighter halogenated aryl
moieties arylÀY (Y = F, Cl, Br, I) in an effective manner under
mild conditions. Furthermore, we show the direct conversion
of aryl chlorides, bromides, and iodides into the corresponding
aryl fluorides, using very mild conditions and simple fluoride
sources such as AgF and KF, under the catalytic cycle depicted
in Scheme 1.
Spectroscopic monitoring experiments provide strong support
that reactions take place via the expected mechanism. In first
place, upon addition of CuI to a solution containing both L1ÀI
and an excess of Bu4NBr or Bu4NCl, an immediate change of
color was evident, and was indicative of halide exchange at the
CuIII center, resulting in the formation of 1Br or 1Cl, respectively.
Gradual fading of the solution color indicated the ongoing
arylÀY reductive elimination, as proved by direct 1H NMR and
ESI-MS analyses of the final crude mixture. The latter observa-
tions agree with a proposal involving arylÀCuIIIÀY species as
resting state, and the arylÀY reductive elimination as the rate-
limiting step. Indeed, the exchange of I to Br using Bu4NBr salt
afforded the L1ÀBr product in a 87% yield (Table 1, entry 4). A
13 mol % content of the arylÀCuIIIÀBr (1Br) resting state
remained in the final crude mixture (determined by 1H NMR)
and accounted for the mass balance of the macrocyclic ligand.
The exchange of arylÀBr and arylÀCl toward the more
reactive arylÀI species could also be accomplished by taking
advantage of the poor solubility of NaX (X = Cl, Br) salts in
acetonitrile. Catalytic halide exchange from L1ÀBr to L1ÀI was
achieved in good yields by using 12 mol % of CuI salt and an
excess of soluble NaI in CH3CN at room temperature (Table 1,
entries 5À6). In this case, yields reach a top limit of 84% because
the final reaction mixture contains a 12% mol content of the
corresponding arylÀCuIIIÀI species (1I). Nevertheless, halide
exchange is clean since only L1ÀI product and a small quantity
’ RESULTS AND DISCUSSION
ArylÀX Reductive Elimination in ArylÀCuIIIÀX Species. In
our previous reports on arylÀCuIIIÀX species 1X (X = Cl, Br, I,
Figure 1), we found that thermolysis was not effective to afford
the aryl-X reductive elimination products. Instead, acid addition
triggered the reaction at room temperature.37,38 We were in-
trigued however, in finding a strategy to avoid the use of an acid
source to trigger the reaction, and we reasoned that should a
reactant-displaced equilibrium between arylÀCuIIIÀX and cor-
responding arylÀX CuI species exist, chemical trapping of the
3 3 3
CuI species could drive reductive elimination. Given the large
affinity of 1,10-phenanthroline (phen) toward CuI to afford
[CuI(phen)2]+, we studied the reaction of a given arylÀCuIIIÀX
species with different equivalents of phen. Quantitative formation
of the arylÀX elimination products (L1ÀX) and [CuI(phen)2]+
species (Figure 1, Supporting Information Table S1) was ob-
served. Reactions were faster for Cl > Br > I, indicating that the
strength of the aryl-X bond formed governed the reactivity. For
1
of remaining starting material (L1ÀBr, <5%) are found by H
NMR in the final reaction mixture after reaction optimization
(Table 1, entry 6).
Catalytic halide exchange from L1ÀCl to L1ÀI is extremely
slow at room temperature and after 96 h only a 36% yield of the
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Table 1. Catalytic Halide Exchange Reactions through ArylÀCuIIIÀHalide Complexes with MY in CD3CN under N2
([CuI(CH3CN)4]OTf as CuI Source)
entry
L1ÀX
L1ÀI
halide salt (MY)
equiv
time (h)
T (°C)
% yield L1ÀYa,b
% starting material
1
Bu4NCl
Bu4NCl
Bu4NCl
Bu4NBr
NaI
5c
1.5
1.5
1.5
40
36
36
2
25
25
25
25
25
25
25
25
40
40
40
50
40
40
25
40
25
96
0
0
2
10c
10d
10e
10f
20g
10h
10i
10j
10k
10l
10l
10m
10m
10n
10n
10i
99
3
0
100
0
4
87
5
L1ÀBr
L1ÀCl
77
12
4
6
NaI
84
7
Bu4NCl
NaI
99
0
8
96
24
24
24
24
24
24
24
24
24
36
53
91
15
31
21
84
78
52
39
89
9
NaI
9
10
11
12
13
14
15
16
17
NaI
56 (17)
57(2)
62(4)
5
NaI
NaI
LiI
Bu4NI
NaBr
NaBr
Bu4NBr
0 (11)
37
38(10)
0
a 1H NMR yield using trimethoxybenzene as internal standard in CD3CN. b Intramolecular CÀN reductive elimination product 2 yield appears in
parentheses for some entries. c Conditions: [L1ÀI] = 9 mM, [CuI] = 1 mM (11 mol %). d Conditions: [L1ÀI] = 9 mM, no addition of copper(I) salt.
e Conditions: [L1ÀI] = 7.6 mM, [CuI] = 1 mM (13 mol %). f Conditions: [L1ÀBr] = 8.6 mM, [CuI] = 1 mM (11 mol %). g Conditions: [L1ÀBr] =
7.6 mM, [CuI] = 0.9 mM (12 mol %). h Conditions: [L1ÀBr] = 9 mM, [CuI] = 1 mM (11 mol %). i Conditions: [L1ÀCl] = 8.5 mM, [CuI] = 0.9 mM
(11 mol %). j Conditions: [L1ÀCl] = 8.5 mM, no addition of copper(I) salt. k Conditions: [L1ÀCl] = 8.5 mM, [CuI] = 1 mM (12 mol %). l Conditions:
[L1ÀCl] = 9 mM, [CuI] = 1 mM (11 mol %), acetone-d6 as solvent. m Conditions: [L1ÀCl] = 9 mM, [CuI] = 1 mM (11 mol %). n Conditions: [L1ÀCl]
= 9 mM, [CuI] = 0.9 mM (10 mol %).
desired product is obtained using 11 mol % of CuI salt and an
excess of soluble NaI in CH3CN (Table 1, entry 8). The reaction
performed at 40 °C (Table 1, entry 10) afforded the L1ÀI
product in moderate yield (56% yield). However, at this tempera-
ture, a competing intramolecular side-reaction involving arylÀ
amine coupling occurs, affording also a 17% of product 2. The
change of CD3CN solvent by acetone-d6 affords L1ÀI in similar
yield (57%) but the contribution of the side reaction is reduced,
and 2 is obtained in only 2% yield (Table 1, entry 11).
On the basis of the previous observations, it can be concluded
that catalytic halide exchange for a given model arylÀX substrate
can be performed by exchanging both toward heavier and also
lighter halides. Copper-catalyzed halide exchange reactions are
favored toward the product with the strongest CÀX bond (CÀCl >
CÀBr > CÀI) when both halide salts (MY and MX) are soluble in
the reaction mixture. In this case, transformation from L1ÀI and
L1ÀBr toward lighter aryl halides is obtained rapidly and in high
Figure 3. Mechanism of copper(I)-catalyzed halide exchange reactions
through arylÀCuIIIÀX complexes as intermediates (X = I, Br, Cl).
yields. On the other hand, the precipitation of the sodium salts out of
the CH3CN solution (Table 1, entries 8À12, 15À17) is key to
understand the catalytic cycle turnover toward heavier halide
products. In line with this, no halide exchange is observed by using
Bu4NBr or Bu4NI as reactants (Table 1, entries 14 and 17,
respectively). This reactivity resembles a previously reported Cu-
catalyzed aromatic Finkelstein reactivity, where arylÀBr subzstrates
were converted to arylÀI products.2
the removed halide) are key to overcome the reversibility of the
arylÀX oxidative addition step.
Fluoride Insertion To Obtain ArylÀF Products. Since cata-
lytic halide exchange mediated by a CuI/CuIII cycle was proven
to be efficient with the combination of any pair of arylÀX and
MY (where X, Y = Cl, Br, I) reagents, we were intrigued by the
possibility to exchange a given arylÀX by fluoride following the
same catalytic cycle (Figure 3 and Scheme 1). We first studied the
stoichiometric reaction of complex arylÀCuIIIÀCl (1Cl) with
AgF and KF as sources of fluoride anions (Figure 4, Table 2). The
reaction was performed in CH3CN at room temperature, and final
reaction mixtures were characterized by 1H NMR and ESI-MS.
A general mechanistic proposal for these catalytic halide ex-
changereactionstaking placeatoursystemsis depictedin Figure3.
In all cases, the resting state is the arylÀCuIIIÀY species, where Y
is the halide (in excess) being inserted. Several parameters influ-
ence the catalytic cycle but most predominantly, the strength of
the arylÀX bond and the low solubility of the MX salt (X being
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To our delight, after reaction optimization, the spectroscopic ana-
lyses provide unequivocal evidence for the formation of arylÀF
product (L1ÀF) (CÀF bond detected by 19F-NMR at À122.5
ppm in DMSO-d6) in up to 91% yield after reaction optimization.
Catalytic fluoride exchange insertion at L1ÀX (X = Cl, Br, I)
turned out to be a more problematic transformation. Silver
fluoride was initially chosen since it gave the best results for stoi-
chiometric reactions. Direct addition of 2 equiv of AgF in CH3CN
to a solution of L1ÀCl and 10 mol % of [CuI(CH3CN)4]OTf
gave L1ÀF product in low yield (40%). That is presumably due
to decomposition of the arylÀCuIIIÀCl initially formed under
the very basic reaction conditions. To address this problem, the
experimental procedure was modified by adding the AgF solution
in a slow dropwise manner. Under these conditions, reaction pro-
ceeded to full conversion of L1ÀCl to a 76% yield of L1ÀF, along
with a 20% yield of the intramolecular arylÀamine coupling side-
product 2 (Figure 5, Table 3). Similar results were obtained by
using L1ÀBr as reactant, affording L1ÀF in 71% yield. On the
contrary, other fluoride sources (Bu4NF, Me4NF or CsF) proved
to be completely inefficient.
that this may be due to the well-established overenhanced
stability of CuI species with ligands bearing tertiary amines in
acetonitrile.43,44 Because of that, a mixture of acetone and
CH3CN was used instead. To our delight, in this solvent mixture
fluoride insertion in L1ÀCl and L1ÀBr was basically quantitative
(>97% yield; Table 3, entries 4 and 7). Nonetheless, the content of
CuI catalyst could be reduced to 5% affording L5ÀF in excellent
yield, although extending the reaction time (Table 3, entry 5).
Fluoride exchange reactions leading to L1ÀF and L5ÀF can be
also accommodated by invoking the mechanistic proposal invol-
ving a CuI/CuIII catalytic cycle. ArylÀX oxidative addition at CuI
(Scheme 1, step 1) to form arylÀCuIIIÀX species is well-known
within these systems.37 The subsequent XÀ to FÀ exchange to
form a putative arylÀCuIIIÀF (Scheme 1, step 2) is not detected
experimentally, and only the final arylÀF product is obtained.
The latter observation suggests a rate-limiting halide to fluoride
exchange followed by a fast reductive elimination step from an
arylÀCuIIIÀF species (Scheme 1, step 3). Consistent with this
scenario, 1H NMR monitoring of the reaction of 1Br with AgF to
form L1ÀF shows the disappearance of 1Br signals to afford the
new L1ÀF compound at room temperature, without the pre-
sence of any other intermediate species (Figure S3).
Effect of Water Content on Halide Exchange Catalysis.
Given the highly hygroscopic character of the halide salts used in
the halide exchange catalysis, we studied the role of water in three
representative halide exchange reactions by performing the reac-
tions under strict anhydrous conditions and adding 10, 50, or 100
equiv of H2O. The copper-catalyzed halide exchange from L1ÀI
to L1ÀCl using Bu4NCl as the halide salt is not affected by the
presence of water (0À100 equiv of H2O) (see Table 1, entry 2,
and Supporting Information Table S2). In the reverse reaction
from L1ÀCl to L1ÀI using 10 equiv of NaI, the reaction is also
not affected by small amounts of water (10 equiv), but yields
decrease when larger amounts are added (50À100 equiv) (see
Table 1, entry 10, and Supporting Information Table S2). The
latter results can be rationalized by the improved solubility of
The high basicity of FÀ is well-documented,15,16,41 and we
suspected that the secondary amines in arylÀCuIIIÀX may be
keen to deprotonation.42 To avoid that, permethylated macro-
cyclic L5ÀX substrates (X = Cl, Br), which are structurally
related to L1ÀCl and L1ÀBr, respectively, were prepared and
studied in the fluoride insertion catalysis. Most rewarding, a quan-
titative formation of arylÀF product, that is, L5ÀF (Figure 5,
Table 3), was accomplished with these systems.
The reactivity of the systems based in permethylated macro-
cylic L5ÀX substrates (X = Cl, Br) exhibits significant differences
with regard to L1ÀX analogues. On one hand, dropwise addition
of the fluoride source was not required for the former, which
suggested that the strong basicity of the fluoride anion directly
affected the secondary amines in the reactions that use L1ÀX. On
the other hand, fluoride insertion at L5ÀX substrates (X = Cl, Br)
failed when reactions were performed in CH3CN. We reasoned
Figure 4. Room temperature nucleophilic fluorination of 1X with MF
salts (M = Ag, K) to afford L1ÀF and CuI (compound 2 is also obtained
in minor quantities).
Figure 5. Catalytic fluorination of arylÀX (X = Cl, Br) substrates at
room temperature.
Table 2. Stoichiometric CÀF Bond Formation through ArylÀCuIIIÀX Complexes with Several Equivalents of MF (M = Ag, K) at
298 K in CH3CN under N2
entry
complex
MF (equiv)
solvent
time (h)
L1ÀF % yielda
2 % yield
1
2
3
4
5
6
7
8
1Cl
AgF (5)
AgF (8)
AgF (12)
KF (5)c
AgF (5)
AgF (5)b
KF (5)c
AgF (5)
CH3CN
CH3CN
CH3CN
8
8
74
91
77
31
84
74
23
76
23
8
8
22
36
14
24
47
22
CH3CN/DMSO-d6 (8:1)
CH3CN
24
4
1Br
CH3CN
1
CH3CN/DMSO-d6 (8:1)
100
1I
CH3CN
3
a NMR yields using 1,3,5-trimethoxybenzene as an internal standard in DMSO-d6 after extractions of copper with NH4OH/MgSO4. b Reaction
performed at 45 °C. c Reactions with KF also afforded a 33% (entry 4) and 27% (entry 7) yield of L1ÀH product.
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Table 3. CuI-Catalyzed CÀF Bond Formation through the Reaction of L1ÀX (X = Cl, Br) Substrates with 2 equiv of AgF at 298 K
(CH3CN, under N2, Light Excluded)
entry
L1ÀX
% mol CuI a
solvent
time (h)
LxÀF % yieldb
2 % yield
1
2
3
4
5
6
7
L1ÀCl
10
0
CH3CN
CH3CN
CH3CN
6
6
76c
20
0
0
L1ÀBr
L5ÀCl
10
10
5
4
71c
98
98
0
21
0
CH3CN/acetone (1:3)
CH3CN/acetone (1:3)
CH3CN/acetone (1:3)
CH3CN: acetone (1:3)
12
24
24
24
0
L5ÀBr
10
97
a As [CuI(CH3CN)4]OTf. b NMR yields using 1,3,5-trimethoxybenzene as an internal standard in DMSO-d6 after extractions of copper with NH4OH/
MgSO4. c Reactions also afforded a 4% (entry 1) and 8% (entry 3) yield of another nonidentified product.
Figure 6. Defluorination of L1ÀF mediated by CuI at room tempera-
ture to afford 1Cl.
NaCl formed upon water addition. Efficient NaCl precipitation is
crucial in order to drive the reaction toward the product with a
weaker CÀX bond. An improved solubility thus reduces the
reaction yields. On the contrary, when the ArÀY bond strength
to be formed is higher that the ArÀX bond broken (i.e., exchange
from L1ÀI to L1ÀCl), the effect of water is not significant.
To address possible effects of water in the fluorination
reactions, we have studied the catalytic fluorination of L1ÀCl
under strictly anhydrous conditions, and also by adding 10 and
50 equiv of H2O (see Table 3, entry 1, and Supporting Informa-
tion Table S2). The yields of fluorinated product L1ÀF show a
progressive decrease as the number of H2O equivalents added
increase (from 75% yield for 0 equiv of H2O added down to 32%
L1ÀF if 50 equiv of H2O are added). Indeed, reactions progress
more slowly and the presence of water triggers a side-reaction
that produces minor amounts of L1ÀH product (<10%). Clearly,
strictly anhydrous conditions are required to obtain the best
yields of fluorination for these systems.45
Defluorination of ArylÀF to ArylÀCl. At this point, we
speculated about the possibility of going a step further and
wondered if arylÀF substrates could be activated by CuI, and
undergo further halide exchange. The combination of equimolar
amounts of CuI and L1ÀF in CH3CN, with the subsequent
addition of excess Bu4NCl, did not afford any fluoride exchange.
However, by changing the solvent to acetone, the same reactants
afforded the formation of a red colored solution, corresponding
to the formation of arylÀCuIIIÀCl (1Cl) (Figure 6) in 75% yield
Figure 7. DFT studies of (a) the L1ÀF reductive elimination reaction
from arylÀCuIIIÀF, and (b) the L1ÀCl reductive elimination from
arylÀCuIIIÀCl (1Cl). Relative Gibbs energy values in acetonitrile
solution are given in kcal molÀ1 and selected bond distances in Å
(one explicit CH3CN molecule (ACN) has been considered in the
calculations; H atoms are omittedfor clarity except forNÀH moieties;see
full calculated reaction pathways in Supporting Information Figure S33).
(estimated by 1H NMR, see Supporting Information Figure S7).
Reaction of 1Cl with phen affords L1ÀCl quantitatively (Figure 1).
The most plausible explanation for this result is that the energy
barrier corresponding to the arylÀF oxidative addition step to
afford arylÀCuIIIÀF is lowered, and rapid formation of arylÀ
CuIIIÀCl (1Cl) upon addition of excess ClÀ is achieved. The low
solubility of the latter in acetone displaces all equilibria toward its
formation. To the best of our knowledge, this is the first example
of aromatic defluorination using a Group 11 metal, since the field
is vastly dominated by reactions mediated by Group 9 and 10
transition metals.17,46
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Computational Studies. DFT computational studies were
performed with the aim of providing a theoretical basis to sup-
port the proposed mechanistic scheme, with special attention to
the CÀF bond forming-cleavage reaction.47 This analysis was
directed at addressing the following specific aspects: (a) the
feasibility and molecular structure of the putative arylÀCuIIIÀF
species; (b) the energetics and viability of the arylÀF reductive
elimination from arylÀCuIIIÀF species; and (c) the energetic
viability of the oxidative addition/reductive elimination connect-
ing “aryl-Cl + CuI”, and arylÀCuIIIÀCl species, as well as the
effect of acetonitrile in these transformations.
relies on a highly elaborated system, we believe these results
might provide inspiration to develop Cu-based fluorinating
technologies with synthetic utility on the basis of mechanistic
understanding.
’ ASSOCIATED CONTENT
S
Supporting Information. Chemical compound full char-
b
acterization; complete description of computational details; full
calculated reaction pathways; XYZ coordinates for all DFT
calculated molecules. This material is available free of charge
via the Internet at http://pubs.acs.org.
(a) The computed molecular structure of arylÀCuIIIÀF
species (1F_ACN) resembles that of the previously crystallographi-
cally characterized arylÀCuIIIÀX family of species (Figure 7a).37
The copper ion adopts a distorted square pyramidal geometry,
and the fluoride anion occupies the axial position, with a CuÀF
distance of 1.915 Å (distance similar to an axial PdIVÀF bond
reported in the literature24). The aryl ligand occupies one of the
equatorial positions and it is in a cis-relative position with respect
to the FÀ. An acetonitrile molecule has a weak interaction
(dCu‑ACN = 4.213 Å) in the empty axial coordination site of the
copper ion.
’ AUTHOR INFORMATION
Corresponding Author
xavi.ribas@udg.edu
’ ACKNOWLEDGMENT
We thank Prof. S. S. Stahl (Univ. of Wisconsin, Madison, WI)
for fruitful comments and for early experiments conducted by
A.C. in Stahl’s lab. We acknowledge financial support from
MICINN of Spain (CTQ2009-08464/BQU to M.C., CTQ2008-
03077/BQU and CTQ2011-23156/BQU to M.S., Consolider-
Ingenio CSD2010-00065, and Ph.D. grant to A.C.), European
Research Council for Project ERC-2011-StG-277801 and the
Catalan DIUE of the Generalitat de Catalunya (2009SGR637 to
M.S., and a Ph.D. grant to M. Canta). X.R., M.C., and M.S. thank
ICREA-Academia awards. We thank STR’s from UdG for techn-
ical support, and we also acknowledge the Centre de Serveis
Científics i Acadꢀemics de Catalunya (CESCA) for partial funding
of computer time.
(b) L1ÀF reductive elimination from 1F_ACN involves the
formation of the arylÀF bond and the formal 2eÀ reduction of
the CuIII center to CuI (step 3 in Scheme 1) to afford the
L1ÀF CuI product. The corresponding transition state (TS)
3 3 3
was found with a small energy barrier (ΔGq = 16.2 kcal molÀ1),
whereas the L1ÀF CuI product was stabilized to a relative
3 3 3
Gibbs energy of À4.1 kcal molÀ1 with respect to the arylÀCuIIIÀ
F species (1F_ACN) (Figure 7a). The latter values are in agree-
ment with a fast and irreversible arylÀF reductive elimination step.
(c) ArylÀCl reductive elimination from 1Cl_ACN was also
studied computationally (Figure 7b), and a much higher barrier
for the arylÀCl reductive elimination step (ΔGq = 26.9 kcal molÀ1
)
was found. Furthermore, the L1ÀCl CuI product remains at
3 3 3
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