Nucleophile-catalyzed, facile, and highly selective C-H activation of fluoroform with Pd(II)

Article abstract of DOI:10.1021/ja409533s

Exceedingly facile (23 C) and chemoselective H-CF₃ activation with [(dppp)Pd(Ph)(OH)] in the presence of a Lewis base promoter such as n-Bu₃P leads to Pd-CF₃ bond formation in nearly quantitative yield. A combined experimental and computational study points to a new mechanism that involves H-bonding Pd-O(H)···H-CF ₃ and nucleophilic attack of the promoter on the metal, followed by a push-pull-type collapse of the resultant five-coordinate Pd(II) intermediate via a polar transition state.

Full text of DOI:10.1021/ja409533s

Communication
pubs.acs.org/JACS
Nucleophile-Catalyzed, Facile, and Highly Selective C−H Activation
of Fluoroform with Pd(II)
Shin Takemoto and Vladimir V. Grushin*
Institute of Chemical Research of Catalonia (ICIQ), Tarragona 43007, Spain
S
* Supporting Information
Pd(II) center, which readily and cleanly occurs at room
ABSTRACT: Exceedingly facile (23 °C) and chemo-
selective H-CF3 activation with [(dppp)Pd(Ph)(OH)] in
the presence of a Lewis base promoter such as n-Bu3P
leads to Pd-CF3 bond formation in nearly quantitative
yield. A combined experimental and computational study
points to a new mechanism that involves H-bonding Pd-
O(H)···H-CF3 and nucleophilic attack of the promoter on
the metal, followed by a push-pull-type collapse of the
resultant five-coordinate Pd(II) intermediate via a polar
transition state.
temperature and atmospheric pressure to furnish Pd-CF3
complexes in high yield. A combined experimental and
computational study of this new transformation reveals a striking
mechanism that is unprecedented9,15,16 in the chemistry of
fluoroform activation.
For initial studies, we selected [(Ph3P)2Pd2(Ph)2(μ-OH)2]
(1),17 an easily accessible dinuclear complex that readily reacts
with a variety of acids.18 Although even such weak acids as
cyclopentadiene18a and primary amines18d,i are activated by 1,
chloroform only forms a hydrogen bond to the oxygen atoms of 1
without full ionization.17 Therefore, we did not expect 1 to cleave
the C-H bond of CHF3 that is orders of magnitude less acidic
than CHCl3.7 The lack of reaction between 1 and CHF3 in
benzene, THF, and DMF was confirmed. We reasoned that the
reactivity toward fluoroform could be enhanced by adding to 1 a
tertiary phosphine PR3 that would lead to the formation of
mononuclear species19 [(Ph3P)n(R3P)mPd(Ph)OH] (m + n = 2)
bearing a more basic terminal OH ligand.
rifluoromethane (CHF3, fluoroform, HFC-23), a side
Tproduct of the fluoropolymer industry, is a nontoxic and
ozone-friendly gas that nonetheless must be destroyed because of
its high greenhouse effect (>104 that of CO2) and >250-year
atmospheric lifetime.1 Releasing CHF3 waste streams into the
atmosphere may lead to an ecological disaster. The risk of the so-
called “climate bomb” is increasingly high now that the carbon
credit trading program has recently come to an end.2
Incineration of CHF3, a flame retardant, consumes much
energy and results in large amounts of inorganic waste.1 A clearly
preferred alternative to the destruction of CHF3 would be its use
as a feedstock in the production of valuable fluorinated organic
compounds. Fluoroform has long been recognized3,4 as the
cheapest, readily available, and most atom-economical CF3
source for the needs of the pharmaceutical, agrochemical, and
specialty materials industries.5,6 However, chemoselective H-CF3
activation for the synthesis of trifluoromethylated building blocks
and intermediates is highly challenging.
Until very recently, only one way to activate fluoroform, a weak
acid (pKa = 27 in H2O),7 was known, i.e., deprotonation with
strong bases.4 The thus generated CF3− carbanionic species are
notorious for their facile decomposition to difluorocarbene via
fluoride elimination. In 2011, the first reactions of selective
fluoroform activation with transition metal complexes were
reported.8−10 Daugulis et al.8 demonstrated the first zincation of
fluoroform to give Zn-CF3 derivatives in one step. Goldman and
co-workers9 found the first H-CF3 oxidative addition to an Ir(I)
pincer complex. Our group discovered the first direct cupration
of fluoroform10 and demonstrated its synthetic utility.10−14
In spite of the progress made, the highly promising area of
CHF3 activation with transition metals is still in its toddler years.
Finding new transition metal-based systems for selective
fluoroform activation reactions and understanding their
mechanisms is key to further developments in this important
field. Herein we report the first example of H-CF3 activation at a
Screening experiments were performed by adding CHF3 in
excess to a mixture of 1 and a PR3 ligand in DMF and monitoring
the reaction by 19F NMR. Over a dozen of various tertiary
phosphines were tested. In most instances (Ph3P, Cy3P, n-Bu3P,
(o-anisyl)3P, dppm, Xantphos, dippf, and dcypf),20 no reaction
was observed. It was encouraging to find that a few other ligands
(dppb, dpppent, and dppf) did promote CHF3 activation to give
Pd-CF3 species, albeit in only 1−7% yield.20a,21 A slightly higher
yield (15%) was observed with dppe that brought about the
formation of [(dppe)Pd(Ph)(CF3)] (3).22 To our delight,
[(dppp)Pd(Ph)(CF3)] (4)22 was produced in 81% yield from 1
and CHF3 in the presence of dppp (2 equiv per Pd; Scheme 1).
The formation of 4 was also observed in other aprotic dipolar
solvents (DMAC and NMP) but not in media of low polarity
(benzene and THF). The lack of formation of 1,1-difluoro-2-
phenylcyclopropane in a repeat of the reaction in DMF (Scheme
1) in the presence of deliberately added styrene (20 equiv)
suggested that the H-CF3 activation is unlikely mediated by
−
difluorocarbene and, therefore, by CF3 .
Scheme 1. Activation of CHF3 with 1/dppp
Received: September 14, 2013
Published: October 29, 2013
© 2013 American Chemical Society
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Journal of the American Chemical Society
Communication
It was reasonable to propose that the reactive species in the 1/
dppp system was [(dppp)Pd(Ph)(OH)] (5) that would be
formed upon dppp coordination to Pd, followed by chelation and
PPh3 loss. Indeed, it was found that 1 readily underwent ligand
exchange with dppp to give 5 in nearly quantitative yield
(Scheme 2). In a preparative experiment, 5 was isolated in 88%
yield and fully characterized in solution and in the solid state.21
The X-ray structure of 5 (Figure 1) shows the anticipated square-
planar geometry around Pd, with the P-Pd-P angle of 95.2(1)°
being in the expected range, e.g., 93.4(1)° found in 4.22 The Pd-P
bond trans to the OH (2.251(1) Å) is nearly 0.1 Å shorter than
that trans to the Ph ligand (2.344(1) Å), attesting to the immense
difference in the trans influence of these two ligands.
transfer to the Pd atom in 5. Indeed, adding PPh3 to a solution of
5 and fluoroform in DMF triggered instantaneous reaction
producing 4. This observation prompted the question: can PPh3
be replaced by other promoters for the trifluoromethylation of
the Pd center in 5 with fluoroform? As a result of a series of tests,
n-Bu3P was identified as a superior activator. Upon addition of n-
Bu3P (1 equiv) to 5 and CHF3 in DMF, the reaction was
complete within 30 min to give 4 along with a small quantity
(15%) of [(n-Bu3P)2Pd(Ph)(CF3)] (6) in overall 99% yield. In
the course of time, the ratio of 4 to 6 lowered due to ligand
exchange between 4 and the n-Bu3P present in the reaction
solution. However, as the ligand exchange occurred, the total
yield of the Pd-CF3 products (4+6) remained the same. Like the
1/PR3 systems (see above and Scheme 1), the reaction of 5/n-
Bu3P with CHF3 is strongly solvent-dependent. The yields of the
Pd-CF3 products (4 + 6) after 2 h of reaction of 5/n-Bu3P (1:1)
with fluoroform (10 equiv) paralleled the polarity of the medium,
being 99%, 75%, 58%, 8%, and 2% in DMF, NMP, DMAC, THF,
and benzene, respectively.21
Scheme 2. Synthesis of 5 from 1 and dppp
After the H-CF3 bond cleavage leading to 4, the Lewis base
activator is released and therefore, in principle, might be used in
catalytic rather than stoichiometric quantities. This was
confirmed by performing the reaction of 5 with CHF3 in the
presence of 20 and 10 mol % of n-Bu3P and observing the
formation of 4+6 in 100% and 80% total yield, respectively, after
12 h. Unsurprisingly, the Pd-CF3 bond formation was faster in
the presence of larger quantities of n-Bu3P (Figure 2).
Figure 1. ORTEP drawing of [(dppp)Pd(Ph)(OH)] (5) with thermal
ellipsoids drawn at the 50% probability level and all hydrogen atoms
omitted for clarity.
It came as a total surprise when adding fluoroform to a solution
of preisolated pure 5 in DMF resulted in no reaction. Not even
traces of 4 were produced (19F NMR). Importantly, however,
upon addition of CF3H the OH signal (dd, J = 6.7 and 5.3 Hz) in
the 1H NMR spectrum of 5 in THF-d8 shifted upfield by ca. 0.1
ppm. Simultaneously, the upfield doublet (−14.2 ppm JP‑P = 47.3
Hz) in the 31P NMR spectrum shifted downfiled by ca. 1.5 ppm,
whereas the other doublet stayed at its position (17.0 ppm).
Furthermore, 5 was found to promote H/D exchange between
CHF3 and D2O (ca. 8% conversion).21 Evidently, 5 formed a
hydrogen bond to CHF3 in a reversible process (Scheme 3) that
manifested itself in the evolution of the NMR signals from the
hydroxo proton and the P nucleus trans to the OH. The ability of
CHF3 to hydrogen-bond to O-donors has long been
established.23
Figure 2. Yield vs time in the n-Bu3P-catalyzed reaction of 5 with CHF3
(excess) in DMF at 23 °C.
There are two sites in the H-bond complex 5···HCF3 for attack
by a Lewis base, the O-H bond and the 16e d8 Pd(II) center
(Figure 3). Deprotonation of the OH (a) would be favored by
stronger bases and should be less sensitive to the steric bulk of the
base. On the contrary, nucleophilic attack on the more sterically
hindered metal center (b) should require a smaller Lewis base
with a higher affinity for Pd(II). A study of the promoting effect
of various bases (Table 1) provided an unambiguous indication
that the role of the promoter is coordination to the Pd center,
rather than deprotonation of the OH ligand. The strongest effect
was observed for n-Bu3P (Table 1, entry 2), a much more
coordinating yet considerably weaker Brønsted base than Et3N
that did not exhibit any promoting effect (entry 9). More basic
than n-Bu3P yet much bulkier t-Bu3P was almost inactive (entry
3). Being smaller and less basic than Et3N, pyridine was
nonetheless a better promoter (entries 8 and 9), evidently
because of its higher coordinating ability. Finally, poorly basic yet
Scheme 3. Hydrogen Bond Formation between 5 and CHF3
The difference between a solution of 5 generated from 1 and
dppp (2 equiv per Pd; see above) and that of preisolated 5 is
clearly that the former contains free PPh3 and dppp in addition to
5 (Scheme 2) and cleaves the H-CF3 bond to give 4, whereas the
latter does not contain any extra phosphine and fails to cleave the
H-CF3 bond. It therefore became apparent that additional
phosphine was needed for efficient H-CF3 activation and CF3
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Journal of the American Chemical Society
Communication
coordinating chloride and iodide (entries 10 and 11) promoted
the reaction to about the same degree as Ph3P and p-Tol3P.
Figure 3. Two sites in 5···HCF3 for attack by a base :B (a) and a ligand
(nucleophile) :L (b).
Table 1. Lewis Base-Promoted Activation of CHF3 with 5
entry
Lewis base (equiv)
reaction time, h
yield of 4, %21
Figure 4. Computed Gibbs free energy (kcal/mol) profile for PMe3-
mediated reaction of [(dpp)Pd(Ph)(OH)] with CHF3 in DMF.
1
none
24
0.5
24
24
24
24
24
18
5
<1
a
2
n-Bu3P (1)
t-Bu3P (1)
Cy3P (1)
Ph3P (1)
p-Tol3P (1)
dppp (1)
Pyridine (5)
Et3N (10)
PPN Cl (1)
KI (1)
99
3
4
4
41
10
18
76
17
0
5
be viewed as a contact ion pair {[(dpp)Pd(Ph)(Me3P)][HO···
H···CF3]}. Intrinsic reaction coordinate (IRC) calculations from
TS2 in the forward direction and subsequent optimization
established proton migration toward the oxygen atom to yield
{[(dpp)Pd(Ph)(Me3P)][HO-H···CF3]} (S3), an intermediate
with an NBO charge of −0.71 on the CF3 group. The latter is H-
bonded to H2O and has a dative interaction with Pd (Pd···CF3 =
2.994 Å), which leads to PMe3 displacement via TS3 with a low
activation barrier of 2.3 kcal/mol to give the final Pd-CF3 product
(S4), Me3P, and H2O. The computed mechanism (Figure 4)
receives further support from the lack of H-CF3 activation with
6
7
8
9
10
11
18
18
7
13
a
Total yield for 4 and 6 in a 5:1 ratio (1:1 after 24 h).
The above-described data pointed to a push-pull-type
mechanism of Lewis base-induced CHF3 activation with 5. As
shown in Figure 3 (b), the electron density pushed by the
promoting ligand L through the metal to the oxygen atom is
simultaneously pulled from it by the H-bonded CHF3 molecule.
To gain insight into details of this H-CF3 activation, a density
functional theory (DFT) study was performed using [(dpp)Pd-
(Ph)(OH)] (dpp = H2P(CH2)3PH2) and Me3P as simplified
models of 5 and n-Bu3P, respectively.21,24
Cam
́
pora’s25 pincer hydroxides [(PCP)M(OH)] (M = Pd, Ni)
even in the presence of n-Bu3P. Although the terminal OH ligand
in these pincer complexes is highly basic, the stereochemical
rigidity of the (PCP)M framework precludes conformational
changes at the metal center that are required for the reaction to
occur (Figure 4).26
The computed reaction profile is shown in Figure 4. The attack
of Me3P on Pd of the H-bonded adduct S1 gives S2, a five-
coordinate 18e intermediate with the O(H)···HCF3 moiety in
the apical position of the distorted square pyramid. The Pd-O
distance in S2 (2.496 Å) is 0.42 Å longer than in S1 (2.076 Å). An
increase in electron density on the O atom and substantial
polarization of the Pd-OH bond when going from S1 to S2 is
manifested by considerable changes in the computed group
NBO charges for the O(H)···HCF3 (from −0.52 to −0.72) and
OH (from −0.49 to −0.65) units. Intermediate S2 then collapses
with H-CF3 bond cleavage via the rate-determining transition
state TS2 (Figure S5-4). The computed barrier ΔG⧧298K = 21.4
kcal/mol (in DMF) is consistent with the experimentally
observed reaction rates (Figure 2). Furthermore, recomputing
ΔG⧧298K for TS2 in benzene produced the value of 26.7 kcal/mol
that accords with no experimentally observable reaction in this
and other solvents of low polarity at room temperature (see
above). The highly polar nature of TS2 is apparent from its large
dipole moment (19.4 D), as compared to those of S1 (10.4 D)
and S2 (14.0 D), as well as from the large negative NBO charge
on the [HO···H···CF3] group (−0.84) and the long Pd-O
distance (2.749 Å). As the latter is 0.4 Å shorter than the sum of
the van der Waals radii of Pd (1.63 Å) and O (1.52 Å), TS2 may
In conclusion, we have found the first palladation reaction of
fluoroform, leading to Pd-CF3 bond formation in one step. The
reaction employs [(dppp)Pd(Ph)(OH)] (5), a new monomeric
terminal palladium hydroxide, in conjunction with a Lewis base
promoter L. The most efficient L found is n-Bu3P that can be
used for the reaction not only in stoichiometric but also in
catalytic quantities. Our combined experimental and computa-
tional study has identified a remarkable new mechanism of this
H-CF3 activation.27 The reaction occurs due to the cooperative
effect of H-bonding of fluoroform to the OH ligand and
coordination of L to the Pd center, facilitating proton transfer
within the PdO(H)···H-CF3 moiety in a polar transition state.
This nucleophile-assisted push-pull mechanism is distinctly
different from the one that operates in the direct cupration of
fluoroform and involves electrophilic assistance from the alkali
metal cation interacting with fluorines on the CHF3 molecule.15
Considering the exceptional attractiveness of fluoroform as a CF3
source and palladium being one of the very few metals that can
mediate Ar-CF3 bond formation,3,28 the results obtained in the
current work will likely lead to further developments in the area
of aromatic trifluoromethylation.
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Journal of the American Chemical Society
Communication
(13) Lishchynskyi, A.; Novikov, M. A.; Martin, E.; Escudero-Adan
C.; Novak, P.; Grushin, V. V. J. Org. Chem. 2013, 78, DOI: 10.1021/
jo401423h.
(14) Lishchynskyi, A.; Grushin, V. V. J. Am. Chem. Soc. 2013, 135,
12584.
́
, E.
ASSOCIATED CONTENT
* Supporting Information
Full details of synthetic, computational (PDF), and crystallo-
graphic studies (CIF). This material is available free of charge via
the Internet at http://pubs.acs.org.
■
́
S
(15) Konovalov, A. I.; Benet-Buchholz, J.; Martin, E.; Grushin, V. V.
Angew. Chem., Int. Ed. 2013, 52, 11637.
AUTHOR INFORMATION
Corresponding Author
vgrushin@iciq.es
(16) Luo, G.; Luo, Y.; Qu, J. New J. Chem. 2013, 37, 3274.
(17) Grushin, V. V.; Alper, H. Organometallics 1993, 12, 1890.
(18) (a) Grushin, V. V.; Bensimon, C.; Alper, H. Organometallics 1993,
12, 2737. (b) Grushin, V. V.; Bensimon, C.; Alper, H. Organometallics
1995, 14, 3259. (c) Grushin, V. V.; Alper, H. J. Am. Chem. Soc. 1995, 117,
4305. (d) Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 4206.
(e) Ruiz, J.; Rodríguez, V.; Lopez, G.; Chaloner, P. A.; Hitchcock, P. B. J.
́
Organomet. Chem. 1996, 523, 23. (f) Kuznetsov, V. F.; Bensimon, C.;
Facey, G. A.; Grushin, V. V.; Alper, H. Organometallics 1997, 16, 97.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Profs. Juan Cam
gift of pincer complexes and for discussions, Dr. Eddy Martin and
́
pora and Pilar Palma for the generous
́
(g) Ruiz, J.; Rodríguez, V.; Lopez, G.; Chaloner, P. A.; Hitchcock, P. B. J.
Chem. Soc., Dalton Trans. 1997, 4271. (h) Fraser, S. L.; Antipin, M. Yu.;
Khroustalyov, V. N.; Grushin, V. V. J. Am. Chem. Soc. 1997, 119, 4769.
(i) Driver, M. S.; Hartwig, J. F. Organometallics 1997, 16, 5706. (j) Pilon,
M. C.; Grushin, V. V. Organometallics 1998, 17, 1774. (k) Singhal, A.;
Jain, V. K. J. Chem. Res. (S) 1999, 440. (l) Wolkowski, J. P.; Hartwig, J. F.
Angew. Chem., Int. Ed. 2002, 41, 4289. (m) Marshall, W. J.; Grushin, V.
V. Organometallics 2003, 22, 1591. (n) Mann, G.; Shelby, Q.; Roy, A. H.;
Hartwig, J. F. Organometallics 2003, 22, 2775. (o) Carrow, B. P.;
Hartwig, J. F. J. Am. Chem. Soc. 2011, 133, 2116. (p) Wakioka, M.;
Nakamura, Y.; Wang, Q.; Ozawa, F. Organometallics 2012, 31, 4810.
(19) Grushin, V. V.; Alper, H. Organometallics 1996, 15, 5242.
(20) (a) dippf = 1,1′-bis(diisopropylphosphino)ferrocene; dcypf =
1,1′-bis(dicyclohexylphosphino)ferrocene; dpppent = 1,5-bis(diphenyl-
phosphino)pentane. (b) [(Ph3P)2Pd(Ph)(CF3)] and [(Xantphos)
Pd(Ph)(CF3)] have been reported.20c (c) Grushin, V. V.; Marshall, W. J.
J. Am. Chem. Soc. 2006, 128, 12644.
́
Eduardo C. Escudero-Adan for X-ray analysis of 5, and Prof.
Feliu Maseras for valuable comments on the DFT study. The
ICIQ Foundation, The Spanish Government (Grant CTQ2011-
25418), and Osaka Prefecture University (Grant to S.T.) are
thankfully acknowledged for support of this work.
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(26) The low yield of the dppe derivative 3 (see above) might have the
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lack thereof with many monodentate and bidentate ligands explored in
the current work (see above and Table S1).21 A detailed study of the
influence of conformational, steric, and electronic properties of the
supporting ligand on the reaction is the subject of a separate project.
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at as low as 50−80 °C.
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