Mechanistic and computational studies of oxidatively-induced Aryl-CF 3 bond-formation at Pd: Rational design of room temperature aryl trifluoromethylation

Article abstract of DOI:10.1021/ja201726q

This article describes the rational design of first generation systems for oxidatively induced Aryl-CF₃ bond-forming reductive elimination from Pd^II. Treatment of (dtbpy)Pd^II(Aryl)(CF₃) (dtbpy = di-tert-butylbipyridine) with NFTPT (N-fluoro-1,3,5-trimethylpyridinium triflate) afforded the isolable Pd^IV intermediate (dtbpy)Pd ^IV(Aryl)(CF₃)(F)(OTf). Thermolysis of this complex at 80 °C resulted in Aryl-CF₃ bond-formation. Detailed experimental and computational mechanistic studies have been conducted to gain insights into the key reductive elimination step. Reductive elimination from this Pd^IV species proceeds via pre-equilibrium dissociation of TfO^- followed by Aryl-CF₃ coupling. DFT calculations reveal that the transition state for Aryl-CF₃ bond formation involves the CF₃ acting as an electrophile with the Aryl ligand serving as a nucleophilic coupling partner. These mechanistic considerations along with DFT calculations have facilitated the design of a second generation system utilizing the tmeda (N,N,N′,N′-tetramethylethylenediamine) ligand in place of dtbpy. The tmeda complexes undergo oxidative trifluoromethylation at room temperature.

Full text of DOI:10.1021/ja201726q

ARTICLE
pubs.acs.org/JACS
Mechanistic and Computational Studies of Oxidatively-Induced
ArylꢀCF3 Bond-Formation at Pd: Rational Design of Room
Temperature Aryl Trifluoromethylation
Nicholas D. Ball, J. Brannon Gary, Yingda Ye, and Melanie S. Sanford*
Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, United States
S Supporting Information
b
ABSTRACT: This article describes the rational design of first
generation systems for oxidatively induced ArylꢀCF3 bond-
forming reductive elimination from PdII. Treatment of
(dtbpy)PdII(Aryl)(CF3) (dtbpy = di-tert-butylbipyridine) with
NFTPT (N-fluoro-1,3,5-trimethylpyridinium triflate) afforded
the isolable PdIV intermediate (dtbpy)PdIV(Aryl)(CF3)(F)-
(OTf). Thermolysis of this complex at 80 °C resulted in
ArylꢀCF3 bond-formation. Detailed experimental and compu-
tational mechanistic studies have been conducted to gain
insights into the key reductive elimination step. Reductive
elimination from this PdIV species proceeds via pre-equilibrium dissociation of TfOꢀ followed by ArylꢀCF3 coupling. DFT
calculations reveal that the transition state for ArylꢀCF3 bond formation involves the CF3 acting as an electrophile with the Aryl
ligand serving as a nucleophilic coupling partner. These mechanistic considerations along with DFT calculations have facilitated the
design of a second generation system utilizing the tmeda (N,N,N0,N0-tetramethylethylenediamine) ligand in place of dtbpy. The
tmeda complexes undergo oxidative trifluoromethylation at room temperature.
’ INTRODUCTION
elegantly demonstrated that the sterically large monodentate phos-
phine ligand Brettphos (Brettphos = 2-(dicyclohexylphosphino)-3,6-
dimethoxy-20,40,60-triisopropyl-1,10-biphenyl) promotes stoichio-
metric ArylꢀCF3 coupling from (Brettphos)PdII(Aryl)(CF3) at
80 °C(eq2).15 Remarkably, this latter system was successfully applied
to the catalytic trifluoromethylation of aryl chlorides with Et3SiCF3 at
130ꢀ140 °C.15
The formation of CꢀCF3 bonds is an important transforma-
tion for the construction of pharmaceuticals and agrochemicals.1
Replacing a methyl group with a trifluoromethyl substituent can have
a profound effect on the physical and biological properties of a mole-
cule.2 As a result, there is high demand for versatile synthetic methods
for generating carbonꢀCF3 bonds.3 While there has been significant
progress in the construction of sp3-carbonꢀCF3 linkages,3 there are
comparatively fewer methods for ArylꢀCF3 bond-formation.4ꢀ7
Transition metal-catalyzed cross-coupling between ArylꢀX
and CF3ꢀY would serve as an attractive method for the synthesis of
benzotrifluorides.8ꢀ11 The use of Pd-based catalysts for such trans-
formations is of particular interest because they serve as versatile and
widely used catalysts for a variety of other carbonꢀcarbon bond-
forming reactions.12 However, developments in this area have been
limited by the challenges associated with a key step of the cross-
coupling catalytic cycle, namely ArylꢀCF3 bond-forming reductive
elimination from PdII centers.4,13 The vast majority of known PdII-
(Aryl)(CF3) complexes are inert to ArylꢀCF3 coupling at tempera-
tures as high as 150 °C.24,21
Two strategies have been utilized in the literature to address this
challenge. The first has focused on achieving ArylꢀCF3 bond-forming
reductive elimination from PdII via steric and electronic modification
of the ancillary ligands (L) at (L)nPdII(Aryl)(CF3). For example,
pioneering work by Grushin demonstrated that the Xantphos ligand
(Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) fa-
cilitates high yielding formation of trifluorotoluene from (Xantphos)-
PdII(Ph)(CF3) at 80 °C (eq 1).14 More recently, Buchwald has
Received: February 28, 2011
Published: April 22, 2011
r
2011 American Chemical Society
7577
dx.doi.org/10.1021/ja201726q J. Am. Chem. Soc. 2011, 133, 7577–7584
|

Journal of the American Chemical Society
ARTICLE
While this first approach has provided important break-
throughs, PdII-mediated ArylꢀCF3 bond-forming reactions remain
limited by the requirement for specialized and expensive phosphine
ligands16,17 relatively high reaction temperatures (80ꢀ140 °C), and
the need for expensive Et3SiCF318 in catalytic processes. As a result,
several groups have focused on a second, complementary strategy for
achieving ArylꢀCF3 bond-forming reductive elimination from
Pd.19ꢀ21 This approach hinges on changing the oxidation state,
rather than the ancillary ligand environment, at the metal center. As
shown in eq 3, it was expected that palladium(IV) complexes of
general structure (L)2(X)2PdIV(Aryl)(CF3) (A) would be highly
kinetically and thermodynamically reactive toward ArylꢀCF3 cou-
pling. This hypothesis is predicated on literature reports showing
that PdIV complexes participate in numerous carbon-heteroatom
bond-forming reductive elimination reactions that remain challen-
ging at PdII centers.22,23 A key advantage of this approach would
be that PdIV intermediate A could potentially be accessed
using nucleophilic (CF3ꢀ),24 electrophilic (CF3þ),25 or free-radical
(CF3•)26 based trifluoromethylating reagents.
Table 1. Synthesis of Complexes 1aꢀi
entry
aryl
p-FC6H4
compound
isolated yield
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
70%
54%
63%
51%
58%
32%
49%
47%
42%
p-CNC6H4
p-CF3C6H4
p- PhC(O)C6H4
p-PhC6H4
p-MeOC6H4
p-MeC6H4
C6H5
1g
1h
1i
m-MeC6H4
Two preliminary examples have shown the viability of this
approach. First, Yu and co-workers have elegantly demonstrated
the PdII/IV-catalyzed ligand-directed CꢀH trifluoromethylation with
electrophilic trifluoromethylating reagents (CF3þ reagents).19 Sub-
sequent stoichiometric studies implicated a mechanism involving: (a)
CꢀH activation to form a cyclometalated PdIIꢀAryl intermediate,
(b) oxidation with CF3þ to generate PdIV(Aryl)(CF3), and (c)
ArylꢀCF3 bond-forming reductive elimination from PdIV to release
the product.20
Figure 1. ORTEP drawing of complex 1a. Thermal ellipsoids are drawn at
50% probability, hydrogen atoms are omitted for clarity. Selected bond
lengths (Å): PdꢀC(1) 2.005(3), PdꢀC(25) 2.007(4), PdꢀN(1) 2.107(2),
PdꢀN(2) 2.143(3). Selected bond angles (deg): C(1)ꢀPdꢀC(25)
89.99(13), C(1)ꢀPdꢀN(1) 95.58(11), C(1)ꢀPdꢀN(2) 169.99(11), C-
(25)ꢀPdꢀN(1) 173.92(12), C(25)ꢀPdꢀN(2) 96.67(11).
solution of 1a, and the X-ray crystal structure of this complex is
shown in Figure 1.
In a second example, our group has shown the viability of stoi-
chiometric ArylꢀCF3 bond-forming reductive elimination from PdIV
centers bearing σ-aryl ligands that do not contain chelate directing
groups.21 In this system, the key PdIV intermediate is generated via
oxidation of a preassembled PdII(Aryl)(CF3) species with an N-
fluoropyridinium reagent. We report herein a detailed mechanistic
study of ArylꢀCF3 bond-forming reductive elimination from PdIV in
this latter system. This work provides valuable insights into the in-
fluence of ancillary ligands, the role of each coupling partner, and the
nature of the transition state for this transformation. These mecha-
nistic studies have also allowed us to rationally design the first examples
of room temperature ArylꢀCF3 bond-formation from palladium.
The PdII complexes 1aꢀi are inert toward direct ArylꢀCF3
bond-forming reductive elimination. For example, heating 1a at
130 °C for 72 h produced <5% of 4-fluorobenzotrifluoride (2a), and
the PdII starting material could be recovered in >80% yield (eq 4).
Importantly, similarly low reactivity has been reported in the
literature for other (L∼L)PdII(Aryl)(CF3) complexes (L∼L = di-
phenylphosphinoethane, diphenylphosphinopropane, and diphe-
nylphosphinobenzene).24a,b As discussed above, the only demon-
strated examples of ArylꢀCF3 bond-forming reductive elimination
from PdII require relatively high temperatures (80 °C) and specia-
lized phosphine ligands.14,15
’ RESULTS AND DISCUSSION
Development and Scope of ArylꢀCF3 Coupling at PdIV.
Our studies began with the synthesis of a series of PdIIꢀCF3 com-
plexes of general structure (dtbpy)PdII(Aryl)(CF3) (1aꢀi, dtbpy =
4,40-di-tert-butyl-2,20-bipyridine). These compounds were prepared
by the treatment of (dtbpy)PdII(Aryl)(I) with CsF followed by
TMSCF3 in THF at 23 °C (Table 1). The products were isolated as
yellow solids in 32ꢀ70% yield.21 X-ray quality crystals of 1a were
obtained by vapor diffusion of pentanes into a dichloromethane
We reasoned that the 2eꢀ oxidation of (dtbpy)PdII(Aryl)-
(CF3) would yield a highly reactive PdIV adduct that might undergo
more facile ArylꢀCF3 bond-forming reductive elimination (eq 5, i).
Thus, we examined the reaction of 1a with N-bromosuccinimide
(NBS), N-chlorosuccinimide (NCS), and PhI(OAc)2, which are all
7578
dx.doi.org/10.1021/ja201726q |J. Am. Chem. Soc. 2011, 133, 7577–7584

Journal of the American Chemical Society
ARTICLE
well-known to promote the oxidation of PdII to PdIV.22 As shown in
Table 2, all three oxidants reacted rapidly with 1a in nitrobenzene-d5
at 80 °C. However, the desired trifluoromethylated product was not
obtained; instead, the major organic product contained a nucleophile
derived from the oxidant (Br, Cl, or OAc, respectively). These results
are consistent with the formation of a PdIV intermediate, from which
ArylꢀX (X = OAc, Br, and Cl) bond-forming reductive elimination
is significantly faster than ArylꢀCF3 coupling (eq 5, ii).21
Table 2. Reaction of 1a with Diverse Oxidants (OxidantꢀX)a
In an effort to avoid competing reductive elimination processes, we
next examined the use of electrophilic fluorinating reagents (Fþ
sources). These reagents were selected based on the hypothesis that
fluoride (the X-type ligand introduced to PdIV by Fþ sources) might
undergo slower reductive elimination than CF3.22d,27,28 Gratifyingly,
a variety of different Fþ reagents reacted with 1a to afford modest to
excellent yields of the trifluoromethylated product 2a after 3 h at
80 °C(Table2,entries4ꢀ10). The optimal electrophillic fluorinating
reagent was N-fluoro-1,3,5-trimethylpyridinium triflate (NFTPT),
which provided 2a in 70% yield as determined by 19F NMR
spectroscopy.29 Importantly, <5% of products derived from ArylꢀF
or ArylꢀOTf coupling were observed under these conditions.
This transformation was next applied to complexes 1bꢀi,
which contain sterically and electronically diverse aryl groups. As
shown in Table 3, the yield of trifluoromethylated product was
relatively insensitive to the electronic properties of the arene, and
the reaction proceeded with good results in systems containing
both electron withdrawing [e.g., CN, C(O)Ph] and electron
donating (e.g., CH3, OCH3) para- and meta-substituents.30
At room temperature, the oxidation of 1a by NFTPT produced
a single major intermediate. This species (4) was isolated from
dichloroethane as a yellow solid in 53% yield (eq 6). Analysis of 4 by
19F NMR spectroscopy in MeCN-d3 showed four characteristic
resonances: a doublet at ꢀ30.9 ppm (PdꢀCF3), a singlet at ꢀ79.4
ppm (PdꢀOTf), a multiplet at ꢀ117.1 ppm (PdꢀArF), and a
quartet at ꢀ256.5 ppm (PdꢀF) in a 3:3:1:1 ratio. In nitrobenzene-
d5, broad resonances were observed with similar chemical shifts in the
a Yields were determined by 19F NMR spectroscopy and are an average
of two runs. nd = not detected. b 1a accounted for the remaining mass
balance.
1
same 3:3:1:1 ratio.31 The H NMR spectrum of 4 showed two
diagnostic singlets at 8.47 and 8.40 ppm (3,30 protons of dtbpy) as
well as two singlets at 1.49 and 1.41 ppm (tBu groups of dtbpy).
state structure of 4 shows the octahedral PdIV species (dtbpy)-
Pd(p-FC6H4)(CF3)(F)(OTf). Interestingly, the PdꢀCF3 bond
distance in 4 (2.009(4) Å) is nearly identical to that of the
PdIIꢀCF3 starting material 1a (2.005(3) Å). However, the PdꢀN
bond lengths of 4 (2.038(4) and 2.082(4) Å) are significantly
shorter than those in 1a (2.107(2) and 2.143(3) Å).
Mechanistic Study of ArylꢀCF3 Bond-Forming Reductive
Elimination from PdIV. There are at least three possible path-
ways for ArylꢀCF3 bond-forming reductive elimination from 4,
mechanisms A, B, and C (Figure 3). Mechanism A involves initial
triflate dissociation to form a cationic five-coordinate PdIV
intermediate I and subsequent ArylꢀCF3 bond formation.
X-ray quality crystals were obtained via vapor diffusion of
pentanes into a DCE solution of 4. As shown in Figure 2, the solid
7579
dx.doi.org/10.1021/ja201726q |J. Am. Chem. Soc. 2011, 133, 7577–7584

Journal of the American Chemical Society
ARTICLE
Table 3. NFTPT-Promoted ArylꢀCF3 Coupling at Com-
plexes 1aꢀia
entry
compound
aryl
p-FC6H4
yield arylꢀCF3
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
70%
25%
55%
56%
70%
72%
66%
70%
64%
Figure 3. Three potential mechanisms for ArylꢀCF3 bond formation
from 4.
p-CNC6H4
p-CF3C6H4
p-PhC(O)C6H4
p-PhC6H4
p-MeOC6H4
p-MeC6H4
C6H5
1g
1h
1i
m-MeC6H4
a Yields were determined by 19F NMR spectroscopy and are an average
of two runs.
Figure 4. Plot of initial rate versus 1/[OTf] for reductive elimination
from 4 to form 2a in PhNO2-d5 at 50 °C. y = (1.91 ꢁ 10ꢀ7)x þ 9.98 ꢁ
10ꢀ6; R2 = 0.998.
To confirm that the presence of TfOꢀ was responsible for the
observed effect, this reaction was next examined in the presence of
NBu4PF6, which contains a noncoordinating anion. The use of 1 equiv
of NBu4PF6 under otherwise identical conditions resulted in a >2-fold
increase in the initial rate of reductive elimination to 5.57 ꢁ 10ꢀ5 M
sꢀ1. This result indicates that inibition by NBu4OTf is specifically due
to the TfOꢀ anion. Furthermore, it suggests that enhancing the
polarity of the medium (by adding noncoordinating ions) accelerates
ArylꢀCF3 reductive elimination. Both pieces of data are consistent
with ionic mechanism A operating in this system, as reflected
by the rate expression in eq 7 (derived using the steady state
approximation).36
Figure 2. ORTEP drawing of complex 4. Thermal ellipsoids are drawn
at 50% probability, hydrogen atoms are omitted for clarity. Selected
bond lengths (Å): PdꢀC(1) 2.009(5), PdꢀC(25) 2.018(5), PdꢀN(1)
2.038(4), PdꢀN(15) 2.082(4), PdꢀO(1) 2.226(3). Selected bond angles
(deg): C(19)ꢀPdꢀC(25) 91.09(15), C(19)ꢀPdꢀN(15) 92.18(16),
C(25)ꢀPdꢀN(15) 175.68(17), C(19)ꢀPdꢀF(1) 91.09(15), C(25)ꢀ
PdꢀF(1) 83.31(16), C(19)ꢀPd(1)ꢀO(1) 175.74 (16), C(25)ꢀPd-
(1)ꢀO(1) 95.15 (16).
Mechanism B involves fluoride dissociation, followed by Arylꢀ
CF3 coupling from intermediate II. Mechanism C proceeds via
concerted CꢀCF3 bond-forming reductive elimination. Notably,
there is significant literature precedent for both ionic22e,32,33 and
concerted22e,34 reductive elimination mechanisms from octahe-
dral group 10 metal complexes.
Order in Triflate. The addition of 1 equiv of NBu4OTf to the
thermolysis of 4 in NO2Ph-d5 at 50 °C significantly slowed the
initial rate of formation of 2a (from 2.21 ꢁ 10ꢀ5 M sꢀ1 to 1.35 ꢁ
10ꢀ5 M sꢀ1).35 Furthermore, an excellent linear fit was observed
for a plot of initial rate versus 1/[NBu4OTf] (Figure 4).
Activation Parameters. The initial rate of CꢀCF3 bond-form-
ing reductive elimination from 4 in NO2Ph-d5 was next examined
as a function of temperature. An Eyring plot of the data showed
that ΔHq is þ29.1 ( 0.2 kcal/mol, while ΔSq = þ9.48 ( 0.8 eu.
7580
dx.doi.org/10.1021/ja201726q |J. Am. Chem. Soc. 2011, 133, 7577–7584

Journal of the American Chemical Society
ARTICLE
Table 4. Initial Rates of ArylꢀCF3 Bond-Forming Reductive
Elimination from Complexes 4ꢀ6a
in excellent agreement with the experimental value (þ29.1 ( 0.2
kcal/mol, vide supra).
entry
X
yield arylꢀCF3
initial rate (M sꢀ1) ꢁ 105
1
2
3
CH3
F
93%
45.8
2.21
1.43
As discussed above, we observe experimentally that trifluoro-
methylated products are formed selectively over the correspond-
ing fluorinated compounds. To gain further insights into this
selectivity, we used DFT to examine the transition state for
PhꢀF bond-forming reductive elimination from intermediate 8.
77%
65%b
CF3
a Reactions were run in duplicate and yields were determined by
19F NMR spectroscopy. b 1,4(bistrifluoromethyl)biphenyl formed
in 21% yield.
As shown in eq 8, ΔHq
for PhꢀF coupling is 14.7
298 (DFT)
kcal/mol. As such, this is a higher energy pathway than PhꢀCF3
bond-formation (ΔΔHq298 (DFT) = 1 kcal/mol), consistent with
the experimental results.
The observed entropy of activation indicates a significant increase in
disorder in the transition state for this reductive elimination
reaction. Similar values have been observed for carbon-heteroatom
bond-forming reductive elimination reactions from PdIV that pro-
ceed by ionic mechanisms.22e,23e,37 For example, CꢀOAc reductive
elimination from PdIV complex (phpy)2PdIV(OAc)2 (phpy =
2-phenylpyridine), which is proposed to involve pre-equilibrium
dissociation of an acetate ligand, showed ΔSq of þ4.2 ( 1.2 eu.22e
Electronic Effects. Finally, electronic effects on reductive
elimination were evaluated using PdIV complexes containing
p-fluoro, p-methyl, and p-trifluoromethyl-substituted aryl groups
(complexes 4ꢀ6). Thermolysis of 4, 5, and 6 at 80 °C in NO2Ph-d5
for 3 h afforded the corresponding benzotrifluorides in 77, 93, and
65% yield, respectively (Table 4). The initial rates of reductive
elimination from these complexes at 50 °C in NO2Ph-d5 show that
electron donating substituents accelerate the reaction. For example,
with X = CH3 (5), the initial rate is more than 20 times greater than
with X = F (4). Additionally, when X = CF3 (6), the initial rate is
nearly two times slower than from 4 (Table 4).
While Table 4 clearly shows that electron-donating aryl
substituents accelerate this reaction, it is challenging to definitively
interpret this data in the context of the CꢀCF3 bond-forming event.
Mechanism A is a two-step process involving triflate dissociation
followed by ArylꢀCF3 coupling. Thus, the faster rate with complex
5 may be due to the stronger trans effect of a more electron donating
σ-aryl ligand and/or from a partial positive charge buildup on the
aromatic ring in the transition state for ArylꢀCF3 coupling.
DFT Calculations. We next turned to DFT calculations to
more fully explore the mechanism of ArylꢀCF3 bond formation.
The complex [(bpy)PdIV(Ph)(CF3)(F)(OTf)] (7) (bpy = 2,20-
bipyridyl, eq 8) was employed as a model for 5 (Table 4), and the
CEP-31G(d)38,39 basis set and M0640,41 functional were used along
with a single point solvent correction in nitrobenzene (SMD
solvation model).42 As shown in eq 8, the calculated ΔH298 for
loss of TfOꢀ from 7 in nitrobenzene to form cationic intermediate
[(bpy)PdIV(Ph)(CF3)(F)]þ (8) is 15.0 kcal/mol. Furthermore,
the activation enthalpy (ΔHq298) for PhꢀCF3 bond-forming
reductive elimination from 8 is 13.7 kcal/mol. Thus, we calculate
that mechanism A has an overall ΔHq298 of 28.7 kcal/mol, which is
The calculated charge distribution of intermediate 8 using
Natural Bond Order (NBO) analysis43,44 indicates that the
CF3 carbon carries a significant positive charge (þ1.18), while
the R-carbon of the phenyl ligand bears a charge of þ0.07.45
This charge difference is amplified in the transition state for
CꢀCF3 bond-forming reductive elimination, where the CF3
carbon carries an enhanced positive charge of þ1.24, and the
charge on the Ph carbon decreases to ꢀ0.11. These data imply
that the Ph group is acting as the nucleophile during the bond-
forming event. This is in sharp contrast to other reports of
reductive elimination from PdIV in which the aryl or alkyl
ligand typically serves as the electrophilic coupling
partner.22,23
We next used DFT to determine the transition state enthalpies
(ΔHq298) for ArylꢀCF3 coupling from complexes of general
structure [(bpy)PdIV(p-XC6H4)(CF3)(F)]þ. As expected based
on the NBO analysis, ΔHq298 was smallest with electron donat-
ing para substituents (X) on the aromatic ring, consistent with a
transition state involving nucleophilic attack by the σ-aryl ligand on
the CF3 moiety (Table 5). Furthermore, the ΔHq298 values showed
better correlation with Hammett σþ values for X than the corre-
sponding σ or σꢀ parameters. This implicates significant resonance
effects in the transition state for ArylꢀCF3 coupling.46
Finally, we sought to identify supporting ligands that would lower
the energy barrier for PhꢀCF3 bond-forming reductive elimination
in this system. Literature studies have shown that (tmeda)PdIV-
(CH3)2(Ph)(I) (tmeda = N,N,N0,N0-tetramethylethylenediamine)
is significantly more reactive toward CꢀC bond-forming reductive
elimination than its bipyridine analogue (bpy)PdIV(CH3)2(Ph)-
(I).47 Thus, we hypothesized that using tmeda in place of dtbpy in
our system might impart a similar effect. Consistent with this hy-
pothesis, DFT calculations show that the nitrobenzene solvent-
corrected transition state enthalpy (ΔHq298) for formation of
trifluorotoluene from [(tmeda)PdIV(Ph)(CF3)(F)]þ is 0.8 kcal/
mol lower than that for the analogous bpy complex (12.9 versus
13.7 kcal/mol) (eq 9). Furthermore, ΔH298 for the loss of OTfꢀ
from [(tmeda)PdIV(Ph)(CF3)(F)(OTf)] is >10 kcal/mol lower
than that from 7 (4.2 versus 15 kcal/mol). Thus, the calculated
7581
dx.doi.org/10.1021/ja201726q |J. Am. Chem. Soc. 2011, 133, 7577–7584

Journal of the American Chemical Society
ARTICLE
Table 5. Gas Phase Values of ΔHq298 for CꢀCF3 Bond-
Formation from [(bpy)PdIV(p-XC6H4)(CF3)(F)]þa
Table 6. NFTPT-Promoted PhꢀCF3 Coupling from Com-
plexes 1f, 9, 10, and 11ea
X
ΔHq298 (kcal/mol)
σþ
NMe2
NH2
OH
OMe
SMe
Me
6.89
7.10
7.71
7.86
7.79
9.19
8.41
9.41
9.43
9.23
9.23
ꢀ1.70
ꢀ1.30
ꢀ0.92
ꢀ0.78
ꢀ0.60
ꢀ0.30
ꢀ0.07
0
a Reactions were run in duplicate and yields determined by 19F NMR
spectroscopy.
F
H
CF3
CN
NO2
0.53
Table 7. Reactivity of (tmeda)Pd(Aryl)(CF3) Complexesa
0.71
0.78
a Complexes are calculated using CEP-31G(d)/M06 level of theory.
overall ΔHq298 for reductive elimination from the tmeda complex is
17.1 kcal/mol, suggesting that Aryl-CF3 coupling should proceed at
significantly lower temperatures than from 7.
yield arylꢀCF3
(80 °C)
yield arylꢀCF3
(23 °C)
entry
compound
aryl
1
2
3
4
5
6
7
8
9
11a
11b
11c
11d
11e
11f
p-FC6H4
81%
76%b
60%
92%
94%
90%
95%
85%
90%
78%
52%b
22%
95%
88%
83%
95%
88%
99%
p-CF3C6H4
p-CNC6H4
p-MeOC6H4
C6H5
p-MeC6H4
m-MeC6H4
o-MeC6H4
o-MeOC6H4
11g
11h
11i
a These reactions were conducted at 80 °C for 3 h and at 23 °C for 1 h.
Reactions were run in duplicate and all of the starting material was
consumed. Yields were determined by 19F NMR spectroscopy. b At both
temperatures, trifluorotoluene was formed in 13% yield.
Room Temperature Arene Trifluoromethylation. To assess
the effect of diamine ligands experimentally, a series of
(N∼N)PdII(Ph)(CF3) complexes (9, 10, and 11e) were pre-
pared by the reaction of (N∼N)PdII(Ph)(I) with CsF followed by
TMSCF3 (see Supporting Information for full details).48 Treatment
of 9, 10, and11e with NFTPT under our standard conditions (80 °C
for 3 h in NO2Ph) resulted in clean formation of trifluorotoluene in
modest to excellent yield (Table 6). The readily available and
inexpensive tmeda ligand was particularly effective. Tmeda complex
11e afforded 90% yield of trifluorotoluene at 80 °C (entry 4), and,
most remarkably, provided 83% yield at room temperature (entry 5).
To our knowledge, this is first example of room temperature arene
trifluoromethylation at a Pd center.49
electron donating and electron neutral substituents on the σ-aryl
ligand (for example, Table 7, entries 4ꢀ7). The room tempera-
ture reactions were lower yielding with arenes bearing highly
electron-withdrawing substituents like CF3 and CN (entries 2
and 3), which is consistent with the proposed transition state
(vide supra). Finally, tmeda complexes containing ortho-substi-
tuted aryl groups underwent high yielding room temperature
oxidative trifluoromethylation (entries 8 and 9). In contrast,
these were poorly effective substrates in the dtbpy system, even
at 80 °C.30
’ CONCLUSION
The scope of room temperature oxidative trifluoromethylation
from (tmeda)PdII(Aryl)(CF3) was found to be quite broad.50
These reactions proceeded efficiently and in high yield with
This article describes the rational design of first generation sys-
tems for oxidatively induced ArylꢀCF3 bond forming reductive
7582
dx.doi.org/10.1021/ja201726q |J. Am. Chem. Soc. 2011, 133, 7577–7584

Journal of the American Chemical Society
ARTICLE
elimination from Pd. Experimental mechanistic studies implicate
ArylꢀCF3 coupling from a cationic five-coordinate intermediate,
and DFT suggests that the CF3 ligand serves as the electrophilic
partner during bond formation. Our investigations into the scope
and mechanism of this reaction have facilitated the development
of a second generation ligand system that enables ArylꢀCF3
coupling at room temperature. This work provides a basis for
the design of novel PdII/IV-catalyzed trifluoromethylation reac-
tions of aryl metal species (metal = B, Sn, Si) or simple arene
CꢀH bonds. Efforts in this area are currently underway in our
group and will be reported in due course.
(b) Senecal, T. D.; Parsons, A. T.; Buchwald, S. L. J. Org. Chem. 2011,
76, 1174–1176.
(10) Zhang, C.-P.; Wang, Z.-L.; Chen, Q.-Y; Zhang, C.-T.; Gu, Y.-C.;
Xiao, J.-C. Angew. Chem., Int. Ed. 2011, 50, 1896–1900.
(11) (a) Oishi, M.; Kondo, H.; Amii, H. Chem. Commun. 2009,
1909–1911. (b) Knauber, T.; Arikan, F.; R€oschenthaler, G.; Goossen, L. J.
Chem.—Eur. J. 2011, 17, 2689–2697.
(12) For recent reviews, see: (a) Hassan, J.; Sꢀevignon, M.; Gozzi, C.;
Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359–1470. (b) Beccalli,
E. M.; Broggini, G.; Martinelli, M.; Sottocornola, S. Chem. Rev. 2007,
107, 5318–5365. (c) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q.
Angew. Chem., Int. Ed. 2009, 48, 5094–5115. (d) McGlacken, G. P.;
Bateman, L. M. Chem. Soc. Rev. 2009, 38, 2447–2464. (e) Daugulis, O.;
Do, H.-Q.; Shabashov, D. Acc. Chem. Res. 2009, 42, 1074–1086.
(13) For reviews on [M]ꢀCF3 and [M]ꢀRf (Rf = perfluoroalkyl)
complexes, see: (a) Hughes., R. P. Adv. Organomet. Chem. 1990, 31, 183–267.
(b) Morrison, J. A. Adv. Organomet. Chem. 1993, 35, 211–239.
(14) Grushin, V. V.; Marshall, W. J. J. Am. Chem. Soc. 2006,
128, 12644–12645.
(15) Cho, E. J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.; Watson, D. A.;
Buchwald, S. L. Science 2010, 328, 1679–1681. Pd-catalyzed coupling
between ArI and [ZnꢀCF3]:Kitazume, T.; Ishikawa, N. Chem. Lett.
1982, 137–140.
(16) Current price for Xantphos = $18 122/mol. Determined based
on the largest quantity of Xantphos available from Sigma-Aldrich on
March 17, 2011 (25 g/$783.00).
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental and computa-
b
tional details and spectroscopic data for new compounds. This
material is available free of charge via the Internet at http://pubs.
acs.org.
’ AUTHOR INFORMATION
Corresponding Author
mssanfor@umich.edu
(17) Current price for Brettphos = $99 195/mol. Determined based
on the largest quantity of Brettphos available from Strem Chemicals on
March 17, 2011 (5 g/$924.00).
(18) Price for the largest quantity of TESCF3 available from Sigma-
Aldrich on March 17, 2011: 1 g/$72.90, $13 433/mol. Price for the largest
quantity of TMSCF3 available from Sigma-Aldrich on March 17, 2011:
25 mL/$397.00, $2347/mol.
(19) Wang, X.; Truesdale, L.; Yu, J. Q. J. Am. Chem. Soc. 2010,
132, 3648–3649.
(20) Ye, Y.; Ball, N. D.; Kampf, J. W.; Sanford, M. S. J. Am. Chem. Soc.
2010, 132, 14682–14687.
’ ACKNOWLEDGMENT
We thank the NIH [GM073836 and F31GM089141
(fellowship to N.D.B.)], the National Science Foundation Grad-
uate Research Fellowship and Murrill Memorial Scholarship
(fellowships to J.B.G.) and the Research Corporation Cottrell
Scholar Program for support of this research. Unrestricted
support from Dupont is also gratefully acknowledged. We thank
Paul Lennon and Jim Windak for assistance with mass spectros-
copy as well as Prof. Tom Cundari and Prof. Brian Yates for
valuable discusions on DFT calculations.
(21) Ball, N. D.; Kampf, J. W.; Sanford, M. S. J. Am. Chem. Soc. 2010,
132, 2878–2879.
(22) (a) Dick, A. R.; Kampf, J. W.; Sanford, M. S. J. Am. Chem. Soc.
2005, 127, 12790–12791. (b) Whitfield, S. R.; Sanford, M. S. J. Am.
Chem. Soc. 2007, 129, 15142–15143. (c) Dick, A. R.; Remy, M. S.;
Kampf, J. W.; Sanford, M. S. Organometallics 2007, 26, 1365–1370. (d)
Ball, N. D.; Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 3796–3797. (e)
Racowski, J. M.; Dick, A. R.; Sanford, M. S. J. Am. Chem. Soc. 2009,
131, 10974–10983. (f) Arnold, P. L.; Sanford, M. S.; Pearson, S. M.
J. Am. Chem. Soc. 2009, 131, 13912–13913.
(23) For examples, see: (a) Alsters, P. L.; Engel, P. F.; Hogerheide,
M. P.; Copijn, M.; Spek, A. L.; van Koten, G. Organometallics 1993,
12, 1831–1844. (b) Lagunas, M. C.; Gossage, R. A.; Spek, A. L.; van
Koten, G. Organometallics 1998, 17, 731–741. (c) van Belzen, R.;
Elsevier, C. J.; Dedieu, A.; Veldman, N.; Spek, A. L. Organometallics
2003, 22, 722–736. (d) Canty, A. J.; Denny, M. C.; Patel, J.; Sun, H.;
Skelton, B. W.; White, A. H. J. Organomet. Chem. 2004, 689, 672–677.
(e) Canty, A. J.; Denney, M. C.; Skelton, B. W.; White, A. H. Organo-
metallics 2004, 23, 1122–1131. (f) Yamamoto, Y.; Kuwabara, S.; Matsuo,
S.; Ohno, T.; Nishiyama, H.; Itoh, K. Organometallics 2004,
23, 3898–3906. (g) Kaspi, A. W.; Yahav-Levi, A.; Goldberg, I.; Vigalok,
A. Inorg. Chem. 2008, 47, 5–7. (h) Furuya, T.; Benitez, D.; Tkatchouk,
E.; Strom, A. E.; Tang, P.; Goddard, W. A., III; Ritter, T. J. Am. Chem. Soc.
2010, 132, 3793–3807. (i) Vicente, J.; Arcas, A.; Julia-Hernandez, F.;
Bautista, D. Chem. Commun. 2010, 46, 7253–7255. (j) Williamson, O.;
Zavalij, P. Y.; Zhang, J.; Khaskin, E.; Vedernikov, A. N. J. Am. Chem. Soc.
2010, 132, 14400–14402. (k) Zhao, X.; Dong, V. M. Angew. Chem., Int.
Ed. 2011, 50, 932–934.
’ REFERENCES
(1) Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305–321.
(2) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc.
Rev. 2008, 37, 320–330.
(3) (a) Ma, J. A.; Cahard, D. Chem. Rev. 2004, 104, 6119–6146. (b)
Ma, J. A.; Cahard, D. Chem. Rev. 2008, 108, PR1–PR43. (c) Prakash,
G. K. S.; Chacko, S. Curr. Opin. Drug Discovery Dev. 2008, 11, 793–802.
(d) Shibata, N.; Mizuta, S.; Kawai, H. Tetrahedron: Asymmetry 2008,
19, 2633–2644.
(4) Grushin, V. V. Acc. Chem. Res. 2010, 43, 160–171.
(5) Swarts, F. Bull. Acad. R. Belg. 1892, 24, 415–429.
(6) (a) Henne, A. L.; Whaley, A. M.; Stevenson, J. K. J. Am. Chem.
Soc. 1941, 63, 3478–3479. (b) Furuta, S.; Kuroboshi, M.; Hiyama, T.
Bull. Chem. Soc. Jpn. 1999, 72, 805–819.
(7) Yang, J. J.; Kirchmeier, R. L.; Shreeve, J. M. J. Org. Chem. 1998,
63, 2656–2660.
(8) For examples of Cu-mediated reactions of TMSCF3 with aryl
halides, see: (a) Kobayashi, Y.; Kumadaki, I. Tetrahedron Lett. 1969,
10, 4095–4096. (b) Konderatenko, N. V.; Vechirko, E. P.; Yagupolskii,
L. M. Synthesis 1980, 932–933. (c) Matsui, K.; Tobita, E.; Ando, M.;
Kondo, K. Chem. Lett. 1981, 10, 1719–1720. (d) Suzuki, H.; Yoshida, Y.;
Osuka, A. Chem. Lett. 1982, 11, 135–136. (e) Burton, D. J.; Wiemers,
D. M. J. Am. Chem. Soc. 1985, 107, 5014–5015. (f) Urata, H.; Fuchikami,
T. Tetrahedron Lett. 1991, 32, 91–94. (g) Dubinina, G. G.; Furutachi, H.;
Vicic, D. A. J. Am. Chem. Soc. 2008, 130, 8600–8601. (h) Dubinina,
G. G.; Ogikubo, J.; Vicic, D. A. Organometallics 2008, 27, 6233–6235.
(9) For the Cu-mediated reaction of TMSCF3 with aryl boronic
acids, see: (a) Chu, L.; Qing, F.-L. Org. Lett. 2010, 12, 5060–5063.
(24) (a) Culkin, D. A.; Hartwig, J. F. Organometallics 2004,
23, 3398–3416. (b) Grushin, V. V.; Marshall, W. J. J. Am. Chem. Soc.
2006, 128, 4632–4641. (c) McReynolds, K. A.; Lewis, R. S.; Ackerman,
7583
dx.doi.org/10.1021/ja201726q |J. Am. Chem. Soc. 2011, 133, 7577–7584

Journal of the American Chemical Society
ARTICLE
L. K. G.; Dubinina, G. G.; Brennessel, W. W.; Vicic, D. A. J. Fluorine
Chem. 2010, 131, 1108–1112.
elimination reactions, where solvent ordering around charged species
can have a significant effect. See ref 32a.
(25) (a) Umemoto, T. Chem. Rev. 1996, 96, 1757–1778. (b)
Eisenberger, P.; Gischig, S.; Togni, A. Chem.—Eur. J. 2006, 12, 2579–
2586. (c) Kieltsch, I.; Eisenberger, P.; Stanek, K.; Togni, A. Chimia 2008,
62, 260–263.
(38) Stevens, W. J.; Basch, H.; Krauss, M. J. J. Chem. Phys. 1984,
81, 6026–6033.
(39) Stevens, W. J.; Krauss, M.; Basch, H.; Jasien, P. G. Can. J. Chem.
1992, 70, 612–630.
(26) Stanek, K.; Koller, R.; Togni, A. J. Org. Chem. 2008, 73,
7678–7685.
(40) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215–241.
(41) The M06 functional was selected based its success in DFT
calculations of related late transition metal organometallic complexes.
For examples, see: (a) Sieffert, N.; B€uhl, M. Inorg. Chem. 2009,
48, 4622–4624. (b) Benitez, D.; Tkatchouk, E.; Goddard, W. A., III
Organometallics 2009, 28, 2643–2645. (c) Benitez, D.; Shapiro, N. D.;
Tkatchouk, E.; Wang, Y. M.; Goddard, W. A.; Toste, F. D. Nat. Chem.
2009, 1, 482–486. (d) Ariafard, A.; Hyland, C. J. T.; Canty, A. J.; Sharma,
M.; Brookes, N. J.; Yates, B. F. Inorg. Chem. 2010, 49, 11249–11253.
(42) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B
2009, 113, 6378–6396.
(27) For similar strategies to generate CꢀN or CꢀC bonds using
Fþ sources, see: (a) Mei, T.-S.; Wang, X.; Yu, J.-Q. J. Am. Chem. Soc.
2009, 131, 10806–10807. (b) Sibbald, P. A.; Rosewall, C. F.; Swartz,
R. D.; Michael, F. E. J. Am. Chem. Soc. 2009, 131, 15945–15951.
(28) Engle, K. M.; Mei, T. S.; Wang, X.; Yu, J.-Q. Angew. Chem., Int.
Ed. 2011, 50, 1478–1491.
(29) The yields in Tables 1 and 2 are ∼10% lower than those
reported in our original communication (ref 21), due to a minor error
associated with the quantity of internal standard used for 19F NMR analysis.
The correct yields for these transformations are reported in Table 3.
(30) (dtbpy)PdII(Aryl)(CF3) complexes containing ortho-substi-
tuted aryl ligands reacted with NFTPT to provide very low yields
of the corresponding benzotrifluorides. For example (dtbpy)Pd-
(o-CH3Ph)(CF3) afforded 13% yield of 2-methylbenzotrifluoride.
Interestingly, the major product of this reaction was the corresponding
fluorinated product (2-fluorotoluene, formed in 62% yield).
(31) In MeCN-d3, it is likely that the triflate ligand is replaced by a
solvent molecule.
(32) For examples of mechanisms like A and B for reductive
elimination from PdIV, see: (a) Byers, P. K.; Canty, A. J.; Crespo, M.;
Puddephatt, R. J.; Scott, J. D. Organometallics 1988, 7, 1363–1367. (b)
Ducker-Benfer, C.; van Eldik, R.; Canty, A. J. Organometallics 1994,
13, 2412–2414. (c) Canty, A. J.; Jin, H.; Skelton, B. W.; White, A. H.
Inorg. Chem. 1998, 37, 3975–3981.
(33) For examples of mechanisms similar to A and B for reductive
elimination from PtIV, see: (a) Goldberg, K. I.; Yan, J.; Winter, E. L. J.
Am. Chem. Soc. 1994, 116, 1573–1574. (b) Goldberg, K. I.; Yan, J.;
Breitung, E. M. J. Am. Chem. Soc. 1995, 117, 6889–6896. (c) Williams,
B. S.; Goldberg, K. I. J. Am. Chem. Soc. 2001, 123, 2576–2587. (d)
Vedernikov, A. N.; Binfield, S. A.; Zavalij, P. Y.; Khusnutdinova, J. R. J.
Am. Chem. Soc. 2006, 128, 82–83. (e) Khusnutdinova, J. R.; Zavalij, P. Y.;
Vedernikov, A. N. Organometallics 2007, 26, 3466–3483. (f) Pawlikowski,
A. V.; Getty, A. D.; Goldberg, K. I. J. Am. Chem. Soc. 2007, 129, 10382–
10393. (g) Khusnutdinova, J. R.; Newman, L. L.; Zavalij, P. Y.; Lam, Y.-F.;
Vedernikov, A. N. J. Am. Chem. Soc. 2008, 130, 2174–2175. (h) Smythe,
N. A.; Grice, K. A.; Williams, B. S.; Goldberg, K. I. Organometallics 2009,
28, 277–288.
(43) Glendening, E. D.; Reed, A. E.; Carpenter, J. E.; Weinhold, F.
NBO, version 3.1. See http://www.gaussian.com/g_tech/g_ur/ m_ci-
tation.htm.
(44) For original references of theory, see: (a) Foster, J. P.; Weinhold,
F. J. Am. Chem. Soc. 1980, 102, 7211–7218. (b) Reed, A. E.; Weinhold, F.
J. Chem. Phys. 1983, 78, 4066–4073. (c) Reed, A. E.; Weinstock, R. B.;
Weinhold, F. J. Chem. Phys. 1985, 83, 735–746. (d) Reed, A. E.; Weinhold,
F. J. Chem. Phys. 1985, 83, 1736–1740. (e) Carpenter, J. E. Extension of
Lewis structure concepts to open-shell and excited-state molecular species,
PhD thesis, University of Wisconsin, Madison, WI, 1987. (f) Carpenter,
J. E.; Weinhold, F. J. Mol. Struct. (Theochem) 1988, 46, 41–62. (g) Reed,
A. E.; Curtiss, L. A.; Weinhold, F. Chem. Rev. 1988, 88, 899–926.
(h) Weinhold, F.; Carpenter, J. E. In The Structure of Small Molecules and
Ions; Naaman, R., Vager, Z., Eds.; Plenum: New York, 1988; pp 227ꢀ236.
(45) The ground state structure of the analogous CH3 complex
([(bpy)PdIV(Ph)(CH3)(F)]þ has calculated charges of ꢀ0.58 and
þ0.06 on the CH3 and Ph carbons, respectively.
(46) Assuming a similar entropy component in each transition state,
a Hammett plot of log(kX/kH) versus σþ with rate constants calculated
based on the electronic energies (ΔHq298), provided a reasonably good
linear correlation (Fþ = ꢀ0.79; R2 = 0.84, Figure S8). Much poorer
correlations were observed with σ and σꢀ (F value of ꢀ1.17 and R2 =
0.57; Fꢀ value of ꢀ0.86 and R2 = 0.52).
(47) Markies, B. A.; Canty, A. J.; Boersma, J.; van Koten, G.
Organometallics 1994, 13, 2053–2058.
(48) Complex 11b can also be prepared by reacting (tmeda)PdII(p-
CF3C6H4)(X) (X = acetate or trifluoroacetate) with CsF/TMSCF3 in
THF. This synthetic pathway is potentially useful and relevant for
catalytic applications of these transformations. For example, CꢀH
functionalization reactions often use Pd(OAc)2 or Pd(TFA)2 as cata-
lysts. For examples, see: Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010,
110, 1147–1169.
(34) For examples of mechanisms similar to C for reductive elimina-
tion from PdIV and PtIV, see: (a) Crumpton, D. M.; Goldberg, K. I. J. Am.
Chem. Soc. 2000, 122, 962–963. (b) Crumpton-Bregel, D. M.; Goldberg,
K. I. J. Am. Chem. Soc. 2003, 125, 9442–9456. (c) Arthur, K. L.; Wang, Q. L.;
Bregel, D. M.; Smythe, N. A.; O’Neill, B. A.; Goldberg, K. I.; Moloy, K. G.
Organometallics 2005, 24, 4624–4628. (d) Reference 22e.
(35) We initially examined ArylꢀCF3 bond-forming reductive elim-
ination by monitoring the disappearance of 4and concomitant appearance of
2a over three half-lives. These studies revealed that the rate of product
formation decreases upon higher conversion to product (see Supporting
Information for full details). We hypothesize that this is due to a build-up of
TfOꢀ as the reaction progresses, which then inhibits the first step of
ArylꢀCF3 bond-forming reductive elimination from 4. To avoid this
apparent product inhibition, we used the initial rates method (measuring
the first 10% conversion) for both the order and activation parameter studies.
(36) The addition of 1 equiv of NMe4F to 4 at 23 °C in NO2Ph-d5
produced a complex mixture of PdꢀF and PdꢀCF3 containing products
(as determined by 19F NMR spectroscopy). As a result, it was not
possible to definitively assess the effect of Fꢀ on the rate of reductive
eliminaton from 4.
(49) Vicic has reported that the reaction of (NHC)CuI(CF3) (NHC
= N-heterocyclic carbene) with aryl iodides provides ArylꢀCF3 pro-
ducts at room temperature. The mechanism of the transformation is still
under investigation. See refs 8g and 8h.
(50) For the synthesis of these complexes, see Supporting Information.
(37) The entropy of activation for reductive elimination reactions
from MIV can be highly dependent on both the structure of the MIV
complex and the solvent. This is particularly the case in ionic reductive
7584
dx.doi.org/10.1021/ja201726q |J. Am. Chem. Soc. 2011, 133, 7577–7584