Promoting Difficult Carbon–Carbon Couplings: Which Ligand Does Best?

Article abstract of DOI:10.1002/anie.201607089

A Pd complex, cis-[Pd(C₆F₅)₂(THF)₂] (1), is proposed as a useful touchstone for direct and simple experimental measurement of the relative ability of ancillary ligands to induce C?C coupling. Interestingly, 1 is also a good alternative to other precatalysts used to produce Pd⁰L. Complex 1 ranks the coupling ability of some popular ligands in the order P^tBu₃>o-TolPEWO-F≈tBuXPhos>P(C₆F₅)₃≈PhPEWO-F>P(o-Tol)₃≈THF≈tBuBrettPhos?Xantphos≈PhPEWO-H?PPh₃according to their initial coupling rates, whereas their efficiency, depending on competitive hydrolysis, is ranked tBuXPhos≈P^tBu₃≈o-TolPEWO-F>PhPEWO-F>P(C₆F₅)₃?tBuBrettPhos>THF≈P(o-Tol)₃>Xantphos>PhPEWO-H?PPh₃. This “meter” also detects some other possible virtues or complications of ligands such as tBuXPhos or tBuBrettPhos.

Full text of DOI:10.1002/anie.201607089

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International Edition: DOI: 10.1002/anie.201607089
German Edition: DOI: 10.1002/ange.201607089
Cross-Coupling Reactions
Promoting Difficult Carbon–Carbon Couplings: Which Ligand Does
Best?
Estefanꢀa Gioria, Juan del Pozo, Jesffls M. Martꢀnez-Ilarduya, and Pablo Espinet*
Dedicated to Professor Juan ForniØs
Abstract: A Pd complex, cis-[Pd(C6F5)2(THF)2] (1), is
proposed as a useful touchstone for direct and simple
experimental measurement of the relative ability of ancillary
À
ligands to induce C C coupling. Interestingly, 1 is also a good
alternative to other precatalysts used to produce Pd0L. Com-
plex 1 ranks the coupling ability of some popular ligands in the
order
PtBu3 > o-TolPEWO-F ꢀ tBuXPhos > P(C6F5)3 ꢀ
The collection of ligands in Scheme 1, available to us to
check their relative ability to induce reductive elimination,
model the following classes: i) weak ligands facilitating ligand
dissociation to short-living tricoordinated PdII intermediates
PhPEWO-F > P(o-Tol)3 ꢀ THF ꢀ tBuBrettPhos @ Xant-
phos ꢀ PhPEWO-H @ PPh3 according to their initial coupling
rates, whereas their efficiency, depending on competitive
hydrolysis, is ranked tBuXPhos ꢀ PtBu3 ꢀ o-TolPEWO-F >
PhPEWO-F > P(C6F5)3 @ tBuBrettPhos > THF ꢀ P(o-Tol)3 >
Xantphos > PhPEWO-H @ PPh3. This “meter” also detects
some other possible virtues or complications of ligands such as
tBuXPhos or tBuBrettPhos.
P
d-catalyzed cross-coupling reactions involve several steps,
but reductive elimination is most decisive because it is
typically irreversible, and is the driving force pulling forward
the whole catalytic cycle.[1] When the reductive elimination is
slow, competitive side-reactions from the [PdR1R2L2] inter-
mediates formed in the course of the catalytic cycle, such as
homocoupling, b-hydride elimination, hydrolysis, or others,
can dramatically decrease the yield of the desired R1-R2
product. Examples of challenging reductive eliminations are
[2]
[3]
[4]
À
À
À
those forming Ar N, Ar O, or Ar F bonds. The often
facile C C couplings are also difficult when they involve
Scheme 1. Phosphine ligands used in this work.
À
perfluoroaryl[5] or perfluoroalkyl compounds (e.g. CF3).[6,3c]
Along the oxidation step, two electrons of the Pd0 atom
get involved in the formation of two PdII-R bonds [Equa-
tion (1)], which is favored for electron-rich Pd centers. In the
opposite sense, along the reduction process the Pd center
gains electron density. It immediately follows that (for the
same R1 and R2 groups involved) L dissociation, or ancillary
ligands able to withdraw electron density from Pd, should
favor the reductive elimination by lowering the corresponding
activation barrier [Eq. (1)].
(THF, P(C6F5)3); ii) bulky ligands providing low-energy access
to tricoordinated complexes (PtBu3, P(o-Tol)3, tBuXPhos,
tBuBrettPhos, and the previously unreported o-TolPEWO-
F); iii) ligands with electron-withdrawing potential
(PhPEWO-F, o-TolPEWO-F, PhPEWO-H, P(C6F5)3, tBuX-
Phos and tBuBrettPhos); and iv) large bite-angle ligands (e.g.
Xantphos).
A ranking of the relative ability of ligands to induce
reductive elimination should be of help for a more rational
ligand choice in catalysis but it is difficult to measure this
ability in the context of a running catalysis. Here we propose
the use of cis-[PdPf2(THF)2] (Pf = C6F5) (1),[7] as a “meter” on
which the rates and activation energies for the process in
Equation (2) can be measured directly for different ligands.
[*] E. Gioria, Dr. J. del Pozo, Dr. J. M. Martꢀnez-Ilarduya,
Prof. Dr. P. Espinet
IU CINQUIMA/Quꢀmica Inorgꢁnica
Facultad de Ciencias, Universidad de Valladolid
Paseo de Belꢂn, 7, ES47071 (Spain)
E-mail: espinet@qi.uva.es
Supporting information, including experimental details, and the
ORCID identification number(s) for the author(s) of this article can
be found under http://dx.doi.org/10.1002/anie.201607089.
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Complex 1 is convenient for a number of reasons: i) the
two Pf groups to be coupled are already in a cis arrangement
sparing the kinetic interference of an isomerization process;
ii) THF is a very weak ligand for Pd, which is displaced fast by
even fairly weak ligands,[7,8] so THF substitution by ligand in
Scheme 1 can be considered instantaneous compared to
reductive elimination. These two conditions are major
requirements for a valid determination of the coupling rate;
we tried first [PdPf2(COD)] and found that the coupling rate
was often determined by the COD displacement step and not
by the coupling step itself; iii) complex 1 is conveniently easy
to make, handle and store; iv) the coupling reaction is easily
monitored by 19F NMR in protic toluene, where the Fo and Fp
signals of 1 and 2 (also 3) can be precisely integrated; and
v) the Pf-Pf coupling rate is slow compared to conventional
aryls, which facilitates kinetic studies for efficient ligands at
room or not very low temperature. Higher temperature might
be used if interested in ranking less efficient ligands. The
reductive elimination from 1, either spontaneous (for com-
plex 1) or induced by addition of the ligands in Scheme 1, was
studied monitoring the rate of formation of decafluorobi-
phenyl (Pf-Pf, 2). In several cases C6F5H (3) was also detected
[Equation (2)]. It is formed by slow Pd-Pf hydrolysis by
adventitious water in the anhydrous toluene solvent,[9] This
was confirmed using toluene saturated with D2O for the
spontaneous decomposition of 1, which afforded a mixture of
C6F5H and C6F5D (see the Supporting Information for
details).
initial concentrations. The spontaneous coupling and hydrol-
ysis of cis-[PdPf2(THF)2] (1), just discussed, serves as
reference for the different ligands.
All the curves of formation of 2 are regular except for
tBuXPhos where 2 is first formed, and then consumed during
À
the process because the para C F bond of 2 oxidatively adds
to the Pd0(tBuXPhos) formed (Figure 1; see the Supporting
Figure 1. Percentages of Pf-Pf not adding ArI promoted by some
ligands in Scheme 1. The line for THF is kept as shown in Figure 2 for
reference.
Information for details). This complicates the measurement
of coupling rate. Addition of p-FC6H4I prevents this effect by
quickly oxidizing Pd0(tBuXPhos) to non-interfering [PdII-
(C6H4F)I(tBuXPhos)], thus this additive was incorporated
when required.
Adding PPh3 or PMe3 to 1 produces immediately cis-
[PdPf2(PR3)2] (R = Ph, Me),[10] which are indefinitely stable in
solution, indicating a too high coupling activation energy for
measuring it at room temperature.[11] For the rest of the
ligands the results are shown in Table 1, where DGꢀ(Pf-Pf)
The evolution of formation of 2 upon addition of each of
the ligands, in the conditions specified in Table 1, is regular for
all of them (Figure 2). From these experiments the ligands
coupling ability was quantitatively ranked by their DGꢀ
values:
PtBu3 > o-TolPEWO-F ꢀ tBuXPhos > P(C6F5)3 ꢀ
PhPEWO-F > P(o-Tol)3 ꢀ THF ꢀ tBuBrettPhos @ Xant-
phos ꢀ PhPEWO-H @ PPh3.[12]
Table 1: Experimental activation barriers DGꢀ(Pf-Pf) for the reductive
elimination of cis-[PdPf2(THF)2] promoted by different ligands in
Scheme 1, at T=258C (except for entries 1–3, at T=08C), and products
obtained.
Entry
Ligand
DGꢀ(Pf-Pf)
Products[c]
Pf-Pf%:Pf-H%
Time [h][d]
[kcalmolÀ1
]
1
2
3
4
5
6
7
8
9
10
PtBu3
20.7[a]
21.6[a]
21.8[a] [b]
22.3
22.3
23.0
98.0:2.0
97.7:2.3
100:0
95.5:4.5
93.7:6.3
41.6:2.1
48.0:7.2
49.0:0
4
o-TolPEWO-F
tBuXPhos
P(C6F5)3
PhPEWO-F
P(o-Tol)3
1.4
2.6
8
5.6
6
8
8
8
8
THF
23.1
tBuBrettPhos
Xantphos
PhPEWO-H
23.3[b]
24.2
19.1:0
15.3:0.8
24.6
[a] Measurement of initial rates was performed at T=08C for higher
precision. [b] 3 equiv of p-FC6H4I were added. [c] In toluene, at T=258C.
Yields obtained by 19F NMR integration using PhCF3 as internal standard.
[d] After 8 h or times indicated when the reaction is practically finished.
Figure 2. Percentages of Pf (relative to the starting material 1)
obtained as Pf-Pf promoted by ligands in Scheme 1. All at 258C, in
toluene. L:1=2:1.
In addition to ranking their coupling ability, the results of
Equation (2) uncover other interesting aspects of the behav-
ior of the ligands. These are discussed with the help of
Scheme 2, which summarizes the pathways observed to
operate in the reactions 1 + 2L used to build Table 1.
values, as measured from initial reaction rates, are given. The
effect of the comparatively slow competitive formation of
C6F5H on the measurement of DGꢀ(Pf-Pf) values is small
(except perhaps for entry 7) because it hardly affects the
2
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s-donor ligand (hence a weak ligand for PdII, although strong
p*-acceptor from Pd0 at the s* P–C orbitals), so that cis-
[PdPf2(PR3)2] (R = C6F5) easily dissociates phosphine.
Assuming that PhH is formed in both cases from cis-[PdPf2-
(PR3)(OH2)] complexes (entries 1 and 4), the acidity of the
coordinated OH2 in the complex, as well as the percentage of
these molecules in solution, should be higher and more
efficient towards hydrolysis for P(C6F5)3. P(o-Tol)3
(Scheme 2, path v), less donor and less bulky than PtBu3,
and also much less acceptor than P(C6F5)3, affords slower
coupling rate than the other two, and more hydrolysis than
PtBu3.
Overall the formation of PfH is clearly more efficient in
complexes with a strongly withdrawing olefin (o-TolPEWO-F,
2.3% PfH in 1.4 h; PhPEWO-F 6.3% PfH in 5.6 h; Table 1,
entries 2 and 5), than in PhPEWO-H with a less p-acceptor
olefin fragment (entry 10, 0.8% PfH in 8 h). However, this
inconvenience is compensated by their higher coupling rates,
which lead to better Pf-Pf/PfH ratios in the order o-
Scheme 2. Reaction PdII intermediates and final products formed by
reaction of 1 with the different ligands in Table 1.
TolPEWO-F > PhPEWO-F > PhPEWO-H.
Interestingly
PhPEWO-F and PhPEWO-H have practically identical size
and their remarkably different behavior highlights the
enormous effect of the fluorinated aryl ring on the p-acceptor
effect of the PEWO-F olefinic fragment. On the other hand,
o-TolPEWO-F and PhPEWO-F (Scheme 2, path i) share an
identical p-acceptor moiety but have PR2 fragments of very
different size. Consistently, the one with larger substituents
(o-TolPEWO-F) shows a remarkably faster coupling rate.
Quite unexpectedly, considering its structural similarity
with tBuXPhos, tBuBrettPhos proved to be inefficient for
coupling. At variance with tBuXPhos, the course of formation
of 2 with tBuBrettphos in Figure 1 is quite regular but slow,
and using p-FCH4I the profile changes only slightly at later
stages of the reaction (Figure 2). This points clearly to
a different cause of the problem, which can be traced to the
existence of two possible bond isomers for tBuBrettphos: P,O-
bound and P,C-bound (Scheme 3). In fact a very similar P,O-
First of all, the meter complex cis-[PdPf2(THF)2] (1),
which can be easily prepared and handled in THF, decom-
poses slowly but spontaneously when dissolved in non-
coordinating solvents: THF is poorly coordinated to PdII,
and dissociates easily in the absence of external THF,
probably facilitating coupling from a tricoordinated cis-
[PdPf2(THF)] (Scheme 2, pathway iii).[1] Concomitant hydrol-
ysis from adventitious cis-[PdPf2(THF)(OH2)] molecules
compete with Pf-Pf coupling, more favorably in this case
than in any of the others according to Table 1. Since the
reductive elimination has a moderate rate and the presence of
molecules with coordinated water (more acidic) is more
abundant than in the other entries of Table 1 because water
competes with THF, spontaneous decomposition of 1 affords
the highest PfH proportion (Pf-Pf:Pf-H = 48:7.2).
For Xantphos the coupling rate is one of the slowest, but
no PfH is detected. The immediately formed cis-[PdPf2-
(Xantphos)] (Scheme 2, path iv), which gives reductive elim-
ination only very slowly, also prevents thermodynamically
coordination of any OH2, thus blocking formation of PfH.
Although the facilitation of reductive elimination processes
by Xantphos at 808C is well established,[6a,b] this ligand cannot
deal with the Pf-Pf coupling at room temperature, showing
that our coupling-meter complex is a very demanding one for
the ligands.[13]
Very interestingly, the two phosphines PtBu3 and P(C6F5)3
are quite efficient for coupling (Scheme 2, paths v and ii), in
spite of being electronically very different, although slower
coupling and higher percentage of PfH is observed for the
latter. They represent the two possible and apparently
contradictory models that favor coupling by reducing the
activation energy: a) bulky and strongly s donor ligands that
make tricoordinated structures accessible by rising the ground
state energy for four-coordination;[14] and b) poorly s-donor
but strongly p-acceptor ligands that stabilize the TS by
minimizing electronic repulsions in the evolution towards
Pd0.[1] In contrast to the good donor PtBu3, P(C6F5)3 is a poor
Scheme 3. Different coordination behavior of tBuXPhos and tBuBrett-
Phos.
bound complex was found by X-ray diffraction for [Pd(C6H4-
CO2Me-p)(CF3)(CyBrettPhos)], having (determined by DFT
calculations) an activation energy towards reductive elimi-
nation of F3C-C6H4CO2Me-p about 5 kcalmolÀ1 higher than
its putative P,C-bound isomer.[6c]
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The NMR spectra of the PdPf2 complexes are intrinsically
very complex, providing limited structural information, but
the kinetic behavior observed strongly suggests that: i) the
highly efficient tBuXPhos complex (lacking O atoms) must be
P,C-bound; ii) the isomer formed with tBuBrettPhos in
Scheme 3 is the P,O-bound isomer, from which reductive
elimination is occurring slowly; iii) P,O-bound to P,C-bound
isomerization does not occur after long time at room temper-
ature, or it would provoke a sharp increase in coupling rate
that is not observed; iv) the Pd0(tBuBrettPhos) complex
formed upon reduction at room temperature probably
remains P,O-bound since, in contrast with Pd0(tBuXPhos), it
Scheme 5. Synthetic potential of complex 1 as a precursor of the PdoL
catalyst.
À
is not able to activate C F oxidation of the decafluorobi-
phenyl; and v) P,O-bound to P,C-bound isomerization occurs
only upon oxidation with p-IC6H4F, as supported by the cation
X-ray structure of [Pd(C6H4F)(tBuBrettPhos)]2[(m-I)2-
(PdPf2)2] (4; see Scheme 4 and Figure S2 in the Supporting
Buchwaldꢀs precatalysts to form PdL, avoiding the use of base
and formation of indazole or carbazole byproducts,[15,16] and
to Pd2(dba)3, or Pd(CH2TMS)2(COD),4 avoiding the presence
of dibenzilidenacetone (dba), or 1,5-cyclooctadiene (COD) in
the PdL solution. As a matter of fact, 1 can be a general
precursor of PdL with other ligands (as far as they promote
coupling of 1), and we are exploring this reactivity.
In conclusion, complex cis-[PdPf2(THF)2] (1) is a conven-
ient touchstone that only requires the time of monitoring the
formation of the coupling product Pf-Pf (2) to have quick
information on old or newly synthesized ligands. Our protocol
is useful to measure and rank experimentally the ability of
ligands to promote electronically difficult couplings, isolated
from other processes or steps. Moreover, the hydrolysis
product 3 informs of the rate of this competitive unwanted
process. In addition, our system happens to detect some side
reactions with useful meaning: In the case of tBuXPhos, the
consumption of 2 reports on the extremely good performance
of this ligand in the oxidative addition step. On the other
hand, the initially deceptive data of tBuBrettPhos suggest to
use it on a Pd0 and not on a PdII catalyst precursor, in order to
get the more active P,C-isomer from the beginning. This
preference is shown in the coupling reaction experiment in
the presence of p-F(C6H4I), which yields the P,C-bound
isomer of 4 from [Pd0(tBuBrettPhos)].
Scheme 4. Cation and anion structures of the ionic complex [Pd-
(C6H4F)(tBuBrettPhos)]2[(m-I)2(PdPf2)2] (4). See X-ray diffraction struc-
ture in the Supporting Information.
Information), which was crystallized from the mother liquors
of the reaction in entry 8 of Figure 1. Formation of the anion
of 4 from 1 and the bulky iodide, which does not fit on the
crowded cation, consumes half of the initial meter reagent 1,
frustrating further coupling.
Concerning the absence of PfH in reactions with the
ligands tBuXphos and tBuBrettPhos, this result suggests that
the former prevents coordination of water to the P,C-bound
species more efficiently that any of the other ligands helped
by steric hindrance and aryl coordination, while the later,
acting as P,O-chelate, does not offer an available coordination
position to water (a case similar to the P,P-chelate Xantphos).
Overall, particularly considering the undesired competing
hydrolysis, the efficiency for coupling may be ranked tBuX-
Phos ꢀ PtBu3 ꢀ o-TolPEWO-F > PhPEWO-F > P(C6F5)3 @
tBuBrettPhos > THF ꢀ P(o-Tol)3 > Xantphos > PhPEWO-
H @ PPh3. Obviously this preference should not be general-
ized to the whole catalytic cycle because other steps can be
rate determining or fail; to mention just an obvious case, THF
would not keep the catalyst alive through the Pd0 stage.
The behavior of complex 1 as precursor of PdLn deserves
further comment. Complex 1 reacts with one molar equiv-
alent of L = tBuXPhos leading to PdL, decafluorobiphenyl
and THF. As shown in Scheme 5, the reactivity of the Pd0
complex is such that it is oxidized by the decafluorobiphenyl
(usually fairly inert) to give complex 5 (pathway a). This
reaction is prevented in the presence of a better oxidant ArX
(IC6H4F) to give 6 (pathway b). The latter reaction shows that
complex 1 offers an interesting alternative to commercial
The scale of relative DGꢀ(Pf-Pf) values, to which other
ligands may be incorporated in the future, can help for a more
precise understanding of the phenomena associated to
difficult couplings. It is not unreasonable that the ligand
trend observed with this meter could approximately stand for
other kinds of difficult coupling rates, or for easier homo- or
hetero-couplings not measurable because they are too fast.
The new ligands o-TolPEWO-Fand PhPEWO-F, which do
not suffer easy air oxidation, are much faster than PhPEWO-
H, and the former is as fast for the coupling step as the
excellent tBuXPhos or the pyrophoric PtBu3. Other members
of the PEWO-F family are being developed. However, it is
tBuXPhos the one that combines best a fast coupling
performance with an extraordinary capability to give reox-
idative addition with difficult ArX electrophiles.
Crystallographic data for CCDC 1495038 (complex 4) can
be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre.
4
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Chem. Eur. J. 2014, 20, 2040 – 2048; c) T. Kinzel, Y. Zhang, S. L.
Acknowledgements
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This paper is dedicated to Prof. Juan Forniꢁs in recognition of
his long-standing creative contribution to Pd chemistry with
fluoroaryl ligands, including the synthesis of complex 1. Our
research was sponsored by the Spanish MINECO (grant
number CTQ2013-48406-P and CTQ2014-52796-P), and by
the Junta de Castilla y Leꢂn (grant number VA256U13). E.G.
and J.dP. thank FPU grants of the Spanish MECD. We thank
Marconi N. PeÇas-Defrutos and Jose M. Martꢃn-ꢄlvarez for
help with the X-ray structure of [Pd(C6H4F)(tBuBrettPhos)]2-
[(m-I)2(PdPf2)2].
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[9] 6 ppm by Karl Fischer determination (more details are given in
the Supporting Information).
Keywords: cross-coupling mechanisms ·
homogeneous catalysis · palladium catalysis · phosphines ·
reductive elimination
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[12] Note that DGꢀ(Pf-Pf) for the first three ligands in the list was
determined at 08C and for the others at 258C.
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[16] For a recent review see: A. Bruneau, M. Roche, M. Alami, S.
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[5] a) A. C. Albꢁniz, J. A. Casares, in Advances in Organometallic
Chemistry, Vol 62 (Ed.: P. J. Pꢁrez), Academic Press, Elsevier,
Oxford, 2014, pp. 1 – 110; b) M. Ohashi, R. Doi, S. Ogoshi,
Received: July 21, 2016
Revised: August 17, 2016
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Cross-Coupling Reactions
Squeezing cross-coupling products:
Complex cis-[Pd(C6F5)2(THF)2] was used
as a meter to quantify directly the effi-
ciency of ligands to promote reductive
elimination in carbon–carbon bond for-
mation. The ligand could be ranked and
compared to others. The complex is
a good precatalyst for palladium(0) cata-
lytic species PdLn.
E. Gioria, J. del Pozo,
J. M. Martꢁnez-Ilarduya,
P. Espinet*
&&&& — &&&&
Promoting Difficult Carbon–Carbon
Couplings: Which Ligand Does Best?
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!