Synthesis and reductive elimination of arylPd(II) trifluoromethyl complexes: A remarkable concentration effect on chemoselectivity

Article abstract of DOI:10.1039/c6cp07093k

Reductive elimination from Pd(II) aryl trifluoromethyl complexes is a challenging and elusive step which is accompanied by a number of kinetically more favorable side reactions giving rising to a complex mixture. We report herein the synthesis and isolation of several arylPd(II) trifluoromethyl complexes (2a-c) and study their electronic structures, photophysical properties and reductive elimination reactivities. A remarkable concentration effect on chemoselectivity is observed for thermal decomposition of (Xantphos)Pd(II)(Ar)(CF₃) (2c) that favors the formation of Ar-CF₃ at lower concentrations, but gives increasingly more Ar-Ar homocoupling product to a dominant extent as the concentration of 2c increases. This is solid evidence for the involvement of an intermolecular Ar/CF₃ ligand exchange/Ar-Ar reductive elimination mechanism that has been proposed based on DFT computational studies. The interplay between theory and experiment provides valuable insights into the mechanism and kinetics of the key elementary reaction of reductive elimination at Pd(II), and may thus prompt the design of more efficient Pd-mediated nucleophilic trifluoromethylation reactions.

Full text of DOI:10.1039/c6cp07093k

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Synthesis and reductive elimination of arylPd(II)
trifluoromethyl complexes: a remarkable
concentration effect on chemoselectivity†
Cite this: Phys.Chem.Chem.Phys.,
2016, 18, 32664
Received 17th October 2016,
Accepted 15th November 2016
Song-Lin Zhang* and Zhu-Qin Deng
DOI: 10.1039/c6cp07093k
www.rsc.org/pccp
Reductive elimination from Pd(II) aryl trifluoromethyl complexes is a such as Ar–Ar, Ar–F and P–F coupling products are often
challenging and elusive step which is accompanied by a number of observed.4–6 Furthermore, the origins of the byproducts are still
kinetically more favorable side reactions giving rising to a complex elusive and convincing experimental evidence has been scarcely
mixture. We report herein the synthesis and isolation of several disclosed to fully elucidate the kinetics and mechanisms. It is
arylPd(II) trifluoromethyl complexes (2a–c) and study their electronic only in very recent years that limited success has been achieved
structures, photophysical properties and reductive elimination by Buchwald, Grushin and Shoenebeck et al.5 In their reports,
reactivities. A remarkable concentration effect on chemoselectivity the key point for success is the search for an efficient ancillary
is observed for thermal decomposition of (Xantphos)Pd(II)(Ar)(CF3) ligand due to its unique steric and/or electronic properties to
(2c) that favors the formation of Ar–CF3 at lower concentrations, promote the desired Ar–CF3 reductive elimination.
but gives increasingly more Ar–Ar homocoupling product to a
As part of our continuous efforts on trifluoromethylation
dominant extent as the concentration of 2c increases. This is solid reactions, we recently prepared a few key Pd and Cu trifluoro-
evidence for the involvement of an intermolecular Ar/CF3 ligand methyl intermediates and investigated their reactivity properties
exchange/Ar–Ar reductive elimination mechanism that has been in combination with DFT computational studies.7–9 The results
proposed based on DFT computational studies. The interplay between of our DFT study on the rationalization of the difficulties of
theory and experiment provides valuable insights into the mechanism reductive elimination from ArPd(II) CF3 complexes containing an
and kinetics of the key elementary reaction of reductive elimination at ordinary bisphosphine ligand proposed that bimolecular Ph/CF3
Pd(II), and may thus prompt the design of more efficient Pd-mediated ligand exchange and subsequent Ph–Ph reductive elimination
nucleophilic trifluoromethylation reactions.
might be a significant kinetically favorable side pathway for
(ethylenediphosphine)Pd(II)(Ph)(CF3) model complex.10 Furthermore,
Transition metal-mediated trifluoromethylation reactions are a for (Xantphos)Pd(II)(para-CF3-Ph)(CF3) complex, the biomolecular
useful tool for preparing fluorinated compounds widely used in ligand exchange is even exergonic by 4.4 kcal molꢀ1, giving
pharmaceuticals, agrochemicals and organic materials.1 Particularly, (Xantphos)Pd(II)(Ar)2 and (Xantphos)Pd(II)(CF3)2 (Scheme 1).
Pd- and Cu-promoted aromatic trifluoromethylation reactions have Reductive elimination from (Xantphos)Pd(II)(Ar)2 requires only
occupied a dominant position.2,3 It has been generally accepted that a low activation barrier of 8.0 kcal molꢀ1, that is largely lower
reductive elimination from arylPd(II) trifluoromethyl complexes than the activation barrier of 23.2 kcal molꢀ1 required for direct
is a key product-releasing elementary step of the catalytic cycle Ar–CF3 reductive elimination (Scheme 1).11 This would give rise
for Pd-mediated nucleophilic aromatic trifluoromethylation to the decreased formation of the desired Ar–CF3 cross-coupling
reactions. However, reductive elimination of Ar–CF3 from product and the appearance of a significant bisaryl byproduct.
arylPd(II) trifluoromethyl complexes with most ancillary ligands
Inspired by these results, we hypothesized that high concen-
is known to be kinetically unfavorable and several byproducts tration of ArPd(II) CF3 complexes should, in principle, accelerate
bimolecular ligand exchange as a result of statistically greater
probability of intermolecular collision. This should accordingly
promote the formation of bisaryl and simultaneously diminish
the formation of Ar–CF3. Herein, we present, for the first time,
solid experimental evidence proving this hypothesis by the
amazing observation that the concentration dictates the chemo-
selectivity of Ar–CF3 cross-coupling versus Ar–Ar homocoupling.
The Key Laboratory of Food Colloids and Biotechnology, Ministry of Education,
School of Chemical and Material Engineering, Jiangnan University, Wuxi 214122,
Jiangsu Province, China. E-mail: slzhang@jiangnan.edu.cn; Fax: +86-510-85917763;
Tel: +86-510-85917763
† Electronic supplementary information (ESI) available: Experimental details,
spectroscopic characterization data, X-ray crystallographic study, general procedure for
thermal decomposition of 2c and DFT computational details. CCDC 1446596. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6cp07093k It should be emphasized that the concentration effect on the
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respectively. Furthermore, there are fine splittings of the two 19F
signals in 2b–c due to the presence of P–F coupling between the
bisphosphine P atoms and metal-bound CF3. Similarly, this P–F
coupling is also reflected in the 31P NMR spectroscopy for 2b–c,
leading to fine splitting of the 31P signals (for more details on NMR
spectroscopic data, please refer to the ESI†).
The crystal structure of complex 2c can further be obtained
by X-ray crystallographic diffraction analysis.13 As shown by
Fig. 1, complex 2c clearly shows a square planar geometry with
cis-orientation of the CF3 and Ar ligands (Fig. 1) and is in good
agreement with 19F and 31P NMR spectroscopy. The Pd–CF3 and
Pd–Ar bond lengths are 2.066(6) and 2.030(6) Å. The CF3–Pd–Ar
bond angle is only 80.7(3) degrees, which should be attributed
to the large bite angle of Xantphos that forces the approach of
Ar and CF3 ligands.
Scheme 1 Direct reductive elimination versus bimolecular Ar/CF3
exchange/Ar–Ar homocoupling for arylPd(II) trifluoromethyl complexes.
Values in parentheses are relative free energies in toluene in kcal molꢀ1
.
To further understand the electronic structure of complexes
2a–c, UV-vis absorption spectra of 2a–c were determined
(Fig. 2). Complexes 2a–c all exhibit dominant maximum
absorption at ca. 228 nm in the UV region that are attributed
to p–p* transitions of the ancillary ligands. Notably, 2a has two
additional minor yet significant lower-energy absorption bands
at 302 and 314 nm, which are almost negligible for 2b and 2c.
This suggests significant metal-to-ligand charge transfer for 2a
product chemoselectivity for the reductive elimination of aryl
Pd(II) CF3 complexes has never been reported. The interplay
between theory and experiment rationalizes the origins of the
Ar–Ar side products and more importantly adds another important
mechanistic aspect—namely, concentration effect of the substrate
in addition to the ancillary ligand effect—for improving Ar–CF3
reductive elimination from Pd(II). The valuable and convincing
insights into the mechanism and kinetics of the key elementary
reaction of reductive elimination at Pd(II) may thus prompt the
design of more efficient Pd-mediated nucleophilic trifluoro-
methylation reactions.
Complexes 1a–c with the corresponding ligand of bpy, BINAP
and Xantphos were prepared by oxidative addition of para-
trifluoromethylphenyl iodide with Pd(dba)2 in toluene or THF
(Scheme 2).12 Treatment of 1a–c with CF3SiMe3 as the CF3
source in the presence of AgF at room temperature produced
the desired ArPd(II) CF3 complexes 2a–c. After workup and
recrystallization, 2a–c were obtained in isolated yields of 69%,
72% and 67%, respectively (for more details on synthesis and
purification, please refer to the ESI†).
Complexes 1a–c and 2a–c were fully characterized by 1H, 19F,
31P NMR spectroscopy. For instance, 19F NMR spectra of 1a–c
show only one resonance at ca. ꢀ62 ppm, attributed to the
1
atromatic CF3. H NMR spectra are consistent with coordinating
Fig. 1 ORTEP drawing of complex 2c with thermal ellipsoids at 50%
probability. All the hydrogen atoms and solvent molecules are omitted
for clarity. Disorders of fluorine atoms are removed for clarity for the
aromatic CF3 substituent.
bpy, BINAP and Xantphos which are substantially low-field shifted
in the aromatic region compared to the free ligands. For 2a–c,
there are consistently two 19F resonances at ca. ꢀ21 and ꢀ62 ppm,
corresponding to the metal-bound CF3 and aromatic CF3 ligands,
Fig. 2 UV-vis absorption spectra of complexes 2a–c at a concentration
Scheme 2 Synthesis and reactivity of (L)Pd(II)(Ar)(CF3) complexes 2a–c.
of 10ꢀ5 M in CH2Cl2.
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Table 1 Thermal decomposition of complex 2c in benzenea
with backdonation of electron from the Pd center to p*-orbitals
of the bpy ligand.
Emission spectra of 2a–c are shown in Fig. 3. In addition to
the strong emission at ca. 320–330 nm for 2a–c in the UV range,
2c exhibits two significant moderate emissions at 413 and
438 nm, corresponding to visible purple emissions. These two
minor emissions are however absent for 2a and 2b, showing
greater intersystem transition of excited states and the resulting
stronger phosphorescence emission for 2c.
Yieldb
Furthermore, DFT computational studies14,15 were also per-
formed to gain insights into the electronic structures of 2a–c. As
shown in Fig. 4, the HOMO (Highest Occupied Molecular
Orbital) of 2c centers on the Pd 4dz2 orbital (Fig. 4a), while
the LUMO (Lowest Unoccupied Molecular Orbital) is mainly
composed of partial p*-orbitals of Xantphos (Fig. 4b). The
HOMO orbital of 2a is also mainly composed of Pd 4dz2 orbital
(Fig. 4c), but the LUMO is composed of delocalized p* orbitals
across the whole bpy ligand (Fig. 4d). Additionally, the LUMO
and HOMO of 2a are both perpendicular to the molecular
coordinating plane and thus parallel well to each other. This
match of orbital symmetry should allow a better HOMO/LUMO
Entry
Conc. (M)
Xantphos
T (1C)
A%
B%
1
2
3
4
5
6
7
0.1
0.1
0.1
0.1
0.3
0.5
0.7
—
1 eq.
—
1 eq.
—
—
40
40
80
80
80
80
80
26
20
49c
46
65
31
24
Trace
Trace
Trace
Trace
23
32
38
—
8
1.0
—
80
20
45
a
Reaction conditions: 2c, Xantphos (equal to 2c where present), 4,40-
difluorobiphenyl (equal to 2c, internal standard, for entries 1–4),
b
benzene (1 mL), under a N2 atmosphere for 2 hours. Isolated yields
c
using column chromatography. Due to the highly volatile feature of
products A and B, the isolated yields were much lower than the 19F NMR
yields (100% as determined by 19F NMR).
overlap and thus more favorable metal-to-ligand charge transfer,
consistent with the stronger intensity of lower-energy absorption
bands around 300 nm for 2a compared to 2b and 2c.
Reactivity properties of complex 2c were further studied by
thermally heating benzene solution of 2c in an oil bath (Table 1).16,17
As shown by entries 1 and 2, although the conversion was high at
40 1C, the isolated yields of Ar–CF3 and Ar–Ar were low to trace
either in the absence or presence of additional Xantphos. When
the temperature was raised to 80 1C, the conversion reached
100% in 2 h as determined by 19F NMR spectroscopy. The major
product was Ar–CF3 with an isolated yield of 49% which was
caused by the extremely volatile feature of the Ar–CF3 product A
(entries 3 & 4).
Fig. 3 Normalized emission spectra of complexes 2a–c at a concentration
of 10ꢀ6 M in CH2Cl2 with extinction wavelengths of 297, 279 and 279 nm
respectively.
It is remarkable to note that as the concentration of 2c
increases, the isolated yield of the cross-coupling product
Ar–CF3 (A) reaches a maximum value of 65% at 0.3 M and then
gradually decreases (entries 5–8).18 In sharp contrast, the
homocoupling product Ar–Ar (B) increases gradually and signifi-
cantly, up until nearly one-half of the starting Pd(II)(Ar)(CF3) is
converted to Ar–Ar at a high concentration of 1.0 M (entry 8). This
observation is consistent with the proposal of the bimolecular
ligand exchange/Ar–Ar reductive elimination mechanism since at
higher concentrations there is higher probability for bimolecular
ligand exchange, and thus more favorable Ar–Ar homocoupling. As
far as we know, these results provide for the first time compelling
evidence for the involvement of a bimolecular ligand exchange/
Ar–Ar reductive elimination mechanism as a potent side pathway
competing with the intramolecular direct Ar–CF3 reductive elimina-
tion of Pd(II) aryl CF3 complexes. These results are believed to be
highly important and should be well considered during the design of
more efficient nucleophilic aromatic trifluoromethylation reactions.
Fig. 4 HOMO and LUMO of 2a and 2c with an isovalue of 0.03. (a) HOMO
of 2c; (b) LUMO of 2c; (c) HOMO of 2a; (d) LUMO of 2a.
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6 For P–F coupling at Pd and other transition metal centers,
see: (a) O. Blum, F. Frolow and D. Milstein, J. Chem. Soc.,
Chem. Commun., 1991, 258; (b) S. A. Macgregor, D. C. Roe,
W. J. Marshall, K. M. Bloch, V. I. Bakhmutov and V. V.
Grushin, J. Am. Chem. Soc., 2005, 127, 15304; (c) V. V. Grushin
and W. J. Marshall, J. Am. Chem. Soc., 2004, 126, 3068; (d) S. A.
Macgregor, Chem. Soc. Rev., 2007, 36, 67; (e) S. A. Macgregor
and T. Wondimagegn, Organometallics, 2007, 26, 1143;
( f ) S. Erhardt and S. A. Macgregor, J. Am. Chem. Soc., 2008,
130, 15490.
In summary, several Pd(II) aryl trifluoromethyl complexes
2a–c are isolated and fully characterized by 1H, 19F and 31P
NMR spectroscopy, and X-ray crystallography for 2c. Electronic
structure studies of these Pd(II) complexes are presented,
including both UV-vis absorption and emission spectroscopy
and DFT computational studies. Finally, reactivity properties of
2a–c are investigated by thermal heating of their benzene
solution. A remarkable concentration effect on the chemo-
selectivity is observed for 2c, that is the Ar–CF3 cross-coupling
gradually decreases and simultaneously the bisaryl product
increases significantly and steadily as the concentration of 2c
increases. These results provide original and convincing evidence
that a bimolecular ligand exchange mechanism should be
involved in the reductive elimination of Pd(II) aryl trifluoromethyl
complexes, which is consistent with our DFT computational
studies and should be valuable for the rational design of more
efficient nucleophilic trifluoromethylation reactions.
7 S.-L. Zhang, L. Huang and L.-J. Sun, Dalton Trans., 2015,
44, 4613.
8 S.-L. Zhang and W.-F. Bie, Dalton Trans., 2016, 45, 17588.
9 S.-L. Zhang and W.-F. Bie, RSC Adv., 2016, 6, 70902.
10 Computational results showed that bimolecular ligand exchange
is endothermic by 2.9 kcal molꢀ1 for (PH2CH2CH2PH2)-
Pd(Ph)(CF3) and subsequent reductive elimination from
the resulting (PH2CH2CH2PH2)Pd(II)(Ph)2 has an activation
barrier of 12.6 kcal molꢀ1. Please refer to ref. 7 for more
details.
This study was supported by the National Natural Science
Foundation of China (No. 21472068, 21202062) and the Natural
Science Foundation of Jiangsu (No. BK2012108).
11 For aryl Pd(II) trifluoromethyl complexes with other ligands
such as bpy and BINAP ligand, similar results have also
been obtained that bimolecular Ar/CF3 ligand exchange/
Ar–Ar homocoupling are kinetically more favorable compared
to the direct Ar–CF3 reductive elimination. Therefore, this
competing side pathway should probably be a quite common
phenomenon for reductive elimination from aryl Pd(II)
trifluoromethyl complexes. Please refer to ESI for more details.†
Notes and references
1 For organofluorine chemistry and applications, see: (a) P. Kirsch,
Modern Fluoroorganic Chemistry, Wiley-VCH, Weinheim,
Germany, 2004; (b) S. Purser, P. R. Moore, S. Swallow and
V. V. Gouverneur, Chem. Soc. Rev., 2008, 37, 320; (c) Y. Jiang,
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data for complex 2c.
43, 160; (d) T. Furuya, A. S. Kamlet and T. Ritter, Nature, 14 DFT studies were carried out at a level of B97D/SDD-6-311 +
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3 For reviews on copper-mediated trifluoromethylation reactions,
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g(d,p)//B3LYP/Lanl2dz-6-31g* which has been demonstrated
to be a reliable method for treating fluoro-containing Pd
complexes in our previous study after great efforts of evaluating
and comparing various DFT methods as well as high-accuracy
ab initio methods. Please see ref. 7 for more results on this
issue. For more details on computational methods and optimized
structures of stationary points, please refer to the ESI.†
S. Roy, Tetrahedron, 2011, 67, 2161; (c) T. Liu and Q. Shen, Eur. 15 For selected other examples of our recent DFT mechanistic
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Soc., 2006, 128, 4632; (c) For analogous difficult reactions
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J. L. Miller and D. A. Vicic, Organometallics, 2008, 27, 3933.
5 For successful examples of reductive elimination of Ar–CF3 17 Complexes 2a and 2b were less reactive for reductive elimination
from Pd(II) centers, see: (a) E. J. Cho, T. D. Senecal, T. Kinzel, under similar conditions, and the isolated yields were low.
Y. Zhang, D. A. Watson and S. L. Buchwald, Science, 2010, 18 Due to the extremely volatile features of trifluoromethylated
of reaction yields, please refer to the ESI.†
328, 1679; (b) V. V. Grushin and W. J. Marshall, J. Am. Chem.
Soc., 2006, 128, 12644; (c) M. C. Nielsen, K. J. Bonney and
F. Schoenebeck, Angew. Chem., Int. Ed., 2014, 53, 5903.
arene products, the values are all at the lower limit due to
the severe loss of products during vacuum evaporation of the
product solution gathered from column chromatography.
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