Unsymmetrical bisphosphines for the amidation of aryl chlorides: A kinetic study

Article abstract of DOI:10.1002/ejoc.201400159

The rate-determining step of the palladium-catalyzed amidation of 4-chlorotoluene with benzamide in the presence of unsymmetrical bisphosphines was investigated. Isostructural [2.2]paracyclophane-derived bisphosphines bearing dicyclohexylphosphino and diarylphosphino moieties were investigated as ligands in the oxidative addition and reductive elimination by kinetic studies. The reductive elimination was accelerated when a bisphosphine ligand was applied that contained an electron-rich phosphine group and a less electron-releasing phosphino moiety. Apart from the reductive elimination, the transmetallation had the largest impact on the palladium-catalyzed amidation of aryl halides. Copyright

Full text of DOI:10.1002/ejoc.201400159

FULL PAPER
DOI: 10.1002/ejoc.201400159
Unsymmetrical Bisphosphines for the Amidation of Aryl Chlorides:
A Kinetic Study
Florian C. Falk,[a] Peter Oechsle,[a] Werner R. Thiel,[b] Constantin-Gabriel Daniliuc,[c] and
Jan Paradies*[a]
Keywords: Ligand design / P ligands / Cross-coupling / Palladium / Amidation / Kinetics
The rate-determining step of the palladium-catalyzed amid-
ation of 4-chlorotoluene with benzamide in the presence of
unsymmetrical bisphosphines was investigated. Isostructural
[2.2]paracyclophane-derived bisphosphines bearing dicyclo-
hexylphosphino and diarylphosphino moieties were investi-
gated as ligands in the oxidative addition and reductive eli-
mination by kinetic studies. The reductive elimination was
accelerated when a bisphosphine ligand was applied that
contained an electron-rich phosphine group and a less elec-
tron-releasing phosphino moiety. Apart from the reductive
elimination, the transmetallation had the largest impact on
the palladium-catalyzed amidation of aryl halides.
steric bulk as well as by bisphosphines (Figure 1).[5e,6k,9]
However, not only is the coordination mode affected by the
presence of a bisphosphine ligand but so is the reductive
elimination. The use of an unsymmetrical substituted bis-
phosphine leads to increased rates for the reductive elimi-
nation, which has also been observed for other catalytic sys-
tems.[10] We used these two features for the design of a new
bisphosphine ligand (GemPhos) bearing one diphenylphos-
phino and one dicyclohexylphosphino moiety (1; see Fig-
ure 2). The catalyst system derived from the rigid
GemPhos-ligand[11] and a palladium source proved to be
highly active in the amidation of sterically demanding cou-
pling partners, such as ortho-substituted and ortho,ortho-di-
substituted aryl chlorides with bulky amides.[12] Astonish-
ingly, the amidation was not catalyzed when electron-rich
4-dicyclohexylphosphino[2.2]paracyclophane[13] was app-
lied as supporting ligand. Consequently, the high activity of
the GemPhos-derived palladium complex results from steric
and electronic features of the second phosphino moiety. In
this report, we provide a detailed rationalization for the ob-
served reactivity based on structural, electronic, and kinetic
information. The electronic modification of the GemPhos
bisphosphines leads to unsymmetrical ligand structures.
Introduction
The formation of C–N bonds via transition metal com-
plexes, especially palladium complexes, is one of the most
versatile methodologies with which to furnish diverse nitro-
gen-containing products spanning applications in agricul-
ture, medicinal chemistry, and materials sciences.[1] The first
C–N cross-coupling reaction using tin-amides reported by
Migita[2] flourished to become an invaluable tool as a result
of the pioneering work of Hartwig[3] and Buchwald.[4] Bis-
phosphines proved particularly suitable as ligands for such
palladium-catalyzed amination reactions.[5] However, in the
past decade electron-rich monophosphines have moved into
focus as suitable ligands for challenging substrates in such
transformations.[6] The amidation of aryl bromides can be
conducted under relatively mild conditions (room temp. to
45 °C).[7] However the amidation of aryl chlorides by
carboxylic amides or sulfonamides is particularly challeng-
ing and higher temperatures are required. Often, very stable
palladium-amide species are formed that only reluctantly
undergo reductive elimination from the κ2N,O coordination
mode, and is frequently accompanied by decomposition.[8]
It was observed that the κ1N coordination mode, which ef-
ficiently channels the intermediate towards product forma-
tion, is stabilized by biaryl monophosphines with high
[a] Institute of Organic Chemistry, Karlsruhe Institute of
Technology (KIT),
Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
E-mail: jan.paradies@kit.edu
www.paradies-group.de
[b] Fachbereich Chemie, Technische Universität Kaiserslautern,
Erwin-Schrödinger-Str. 54, 67663 Kaiserslautern, Germany
[c] Institute of Organic Chemistry, University of Münster,
Corrensstrasse 40, 48149 Münster, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201400159.
Figure 1. Monophosphine- (left) and Xantphos-derived (right) Pd-
amidate complexes.
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F. C. Falk, P. Oechsle, W. R. Thiel, C.-G. Daniliuc, J. Paradies
FULL PAPER
Palladium complexes derived from this ligand display ity. Phosphines 2 and 3 were selected because they exhibit
higher reaction rates in the challenging amidation of aryl either a less electron-donating phosphino group [P(p-CF3-
chlorides, which is a result of fast reductive elimination C6H4)2, 2] or represent an isomeric structure to 1 (pseudo-
from the corresponding amido complexes. The transmetal- ortho isomer 3). The 31P NMR shifts of the three phos-
lation step has a significant influence on the overall reaction phines are summarized in Table 1. The electronic and steric
rate.
features of each phosphine were characterized by 31P NMR
spectroscopy as the bis-selenides (Table 1) and by infrared
spectroscopy of the corresponding rhodium carbonyl com-
plexes (Table 2).[14] The 1J(31P,77Se) NMR coupling con-
stant of phosphine-selenides served as a probe to determine
the electron-releasing character and the hybridization of the
phosphines.[15] The three phosphines 1–3 were converted
into the corresponding bis-selenides 4–6 by treatment with
elemental selenium. Whereas for 1 only one resonance was
observed at δ = –5.9 ppm, the other two bisphosphines ex-
hibit two well-separated 31P NMR signals (Table 1). The
31P NMR resonances of the corresponding selenides are
significantly shifted to lower field compared with the free
phosphines. The increased σ-donor ability of the dicyclo-
hexylphosphino moiety compared with the diarylphosphino
groups is reflected in the decreased P–Se coupling constant
(4: J = 706 Hz; 5: J = 703 Hz, 6: J = 687 Hz) in all three
phosphines. The 1JP,Se of 744 Hz (δ = 32.0 ppm) in 4 is char-
acteristic for diphenylphosphino groups.[15a,15b,15d] The P–
Se coupling constant in the CF3-substituted derivative 5
(1JP,Se = 765 Hz; δ = 31.7 ppm) reflects the increased s-char-
acter of the electron pair in the free phosphine. Thus, the
(4-CF3-C6H4)2P group has less σ-donor ability for metal
coordination compared with a PPh2 group. However, the
PhanePhos-derivative 6 displays smaller P–Se coupling con-
stants (J = 722 Hz for Ph2P=Se and J = 687 Hz for
Cy2P=Se) and reflects higher p-orbital character of the lone
pairs in comparison with 1.
Figure 2. Unsymmetrical bisphosphine derivatives.
Results and Discussion
We initiated our study with the synthesis of a series of
[2.2]paracyclophane-derived bisphosphines 1–3 (see the
Supporting Information for syntheses), which bear electron-
ically differing phosphino units (Figure 2). Phosphine 1 is a
viable ligand for palladium in the amidation of sterically
hindered aryl chlorides and serves as a reference for reactiv-
Table 1. 31P–77Se NMR coupling constants in selenides 4–6.
Phosphines
Phosphinoselenides
31P NMR, δ [ppm]
31P NMR, δ [ppm]
1JP,Se [Hz]
1[a]
2[b]
3
–5.9
4[a]
46.2
32.0
45.0
31.7
41.4
29.3
706
744
703
765
687
722
–5.53
–6.82
1.3
5
6
0.1
Furthermore, the electron-donor ability of the three bis-
phosphines was investigated by IR spectroscopy. Phos-
[a] Data from ref.[10] [b] A through-space P–P coupling constant of
J = 58.5 Hz was observed.
Table 2. 31P NMR shifts and IR-stretching frequencies of the CO in rhodium carbonyl complexes.
Complex
31P NMR δ
[ppm]
1JP,Rh
[Hz]
3JP,P
[Hz]
vCO
[cm–1]
trans-7[a]
cis-7
47.2
23.2
46.4
24.3
46.3
25.1
48.0
23.5
176
119
156
124
153
127
180
117
32
33
32
33
1988[a]
trans-8
cis-8
2001, 1969
[a] Data from ref.[10]
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Amidation of Aryl Chlorides: A Kinetic Study
phines 1 and 2 were quantitatively converted into the corre- Table 3. Selected bond lengths and angles of 10, 11, and 12 from
crystal structure analysis.
sponding rhodium-carbonyl complexes 7 and 8 by reaction
10[a]
11
12
with [Rh(CO)2Cl]2 (9; Table 2). However, the reaction of 3
with the rhodium(I) precursor 9 lead to ill-defined com-
plexes as judged by 31P NMR spectroscopic analysis, and
P1–P2 distance
P1–Pd distance
3.458 Å
3.515 Å
2.294(1) Å
2.291(1) Å
100.1(1)°
311.3°
3.541 Å
2.285(1) Å
2.276(1) Å
98.6(1)°
2.2909(1) Å
2.293(1) Å
100.6(1)°
318.6°
characteristic CO frequencies could not be observed. As ev- P2–Pd distance
idenced by 31P NMR spectroscopic data, complexes 7 and
P1–Pd–P2 angle
Sum of angles PAr2 316.7°
Sum of angles PCy2 319.4°
[a] Data from ref.[10]
8 were formed as 1:1 mixtures of the cis and trans isomers
(Table 2). Only one CO-stretching frequency was found
(1988 cm–1) for cis/trans-7, which was significantly shifted
to lower wavenumbers compared with the symmetrical
GemPhos-derivative (2004 cm–1).[12] For the 2/Rh com-
plexes 8, two absorption bands were found at 2001 and
1969 cm–1. This indicates the formation of two isomeric Rh
complexes in which the fluorinated phosphino group is lo-
cated either trans (high wavenumber) or cis to the CO li-
gand (low wavenumber).
313.4°
326.4°
Kinetic Investigations; Oxidative Addition and Reductive
Elimination
As the next step, we investigated the activity of the [2.2]-
paracylophane-derived phosphines 1–3 as supporting li-
gands in the palladium-catalyzed amidation of 4-chloro-
toluene (13) with benzamide (14; Scheme 1).
Moreover the solid-state structures of the bisphosphine-
Pd complexes 10,[12] 11, and 12 were established (Fig-
ure 3).[16] Generally, the structure analysis revealed that all
three ligands were cis coordinating, and featured very sim-
ilar bite angles of 98° to 100°. The P–P distances were like-
wise in the same region (maximum difference 0.08 Å). Dif-
ferences can be observed in the deviation of the sum of
angles [Σ(ЄRPRЈ)] from 360°, which is indicative of the ste-
ric bulk of the phosphino group. The sums of angles in the
PhanePhos-derivative 12 were significantly larger than
those in the pseudo-geminal isomers 10 and 11, hence
higher steric bulk was apparent compared with the
GemPhos derivatives. The GemPhos-derived palladium
complexes feature comparable sums of angles for the PCy2
and PAr2 moieties (Table 3).
Scheme 1. Palladium-catalyzed amidation of 4-chlorotoluene (13)
with benzamide (14).
The Pd0 precursor [Pd(P(oTol)3)2] (15) served as a suit-
able source for highly active catalysts, which were formed
in situ by treatment with the appropriate bisphos-
phine.[2–4,17] The two GemPhos-derived catalysts 1/15 and
2/15 provided the product 16 in comparable yields (89 and
92%, respectively; Scheme 1). Surprisingly, the most elec-
tron-rich bisphosphine 3 furnished an inactive catalyst
when reacted with 15, which did not undergo oxidative ad-
dition.[18]
Because the two GemPhos ligands were both active in
the amidation reaction, we initiated kinetic investigations
to reveal potential ligand effects. First, we determined the
pseudo-first-order rate constant for the oxidative addition
of the corresponding Pd0 complexes (17 and 18) to 13 to
form the aryl-palladium-chloride complexes 19 and 20 (Fig-
ure 4), by means of 31P NMR spectroscopy.
As expected, the more electron-rich Pd complex 17 dis-
played a significantly higher rate in the oxidative addition
to 13 (krel = k17–pseudo/k18–pseudo = 4Ϯ1) compared with 18.
Figure 3. Molecular structures of (a) [1·Pd(NCMe)2]2+·2[BF4]– (10;
crystallographic data from ref.[10]); (b) [2·PdCl2] (11), and
(c) [3·Pd(NCMe)2]2+·2[BF4]– (12) in the solid state. Hydrogen
atoms, BF4 and solvent molecules are omitted for clarity.
From the solid-state analysis it can be concluded that the However, the catalytic reaction proceeded at 100 °C, so that
GemPhos-ligands have very similar size and bite angle, giv- the oxidative addition should not be rate determining for
ing rise to almost identical molecular structures. Counterin- either catalyst systems. Indeed, when the reaction of 1/
tuitively, the electronic structure of the trifluromethyl- [Pd(P(oTol)3)2] and 2/[Pd(P(oTol)3)2] (0.1 m) with 10 equiv.
phenyl-substituted phosphine 2 suggests considerable elec- 13 was performed at 100 °C, the oxidative addition oc-
tron-donor capacity, as evidenced by NMR and IR analysis curred instantaneously (less than 3 min) and the PdII com-
(Table 1 and Table 2). The CF3-substituted ligand 2 should plexes 19 and 20 were the only observed products.
therefore be an efficient ligand in the palladium-catalyzed
We then investigated the reductive elimination from the
amidation of aryl chlorides.
corresponding palladium aryl amidato complexes 21 and
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F. C. Falk, P. Oechsle, W. R. Thiel, C.-G. Daniliuc, J. Paradies
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Table 4. 31P NMR shifts and P–P coupling constants for 21 and
22.
Complex
31P NMR, δ [ppm]
2JP,P [Hz]
21
26.4, 16.5
18.4, 17.1
26.1, 16.6
17.9, 17.1
27.5
26.3
20.1
17.3
22
Figure 4. Plot af pseudo-first-order kinetics for the oxidative ad-
dition of 4-chlorotoluene (13) at 55Ϯ1 °C (᭺ for 17, k17–pseudo
=
0.04Ϯ0.01 min–1; Δ for 18, k18–pseudo = 0.01Ϯ0.01 min–1). Reac-
tion conditions: 15 (0.025 mmol, 1.0 equiv.), 1 or 2 (0.025 mmol,
1.0 equiv.), PMes3 (internal standard, 0.025 mmol, 1.0 equiv.) were
dissolved in [D6]benzene (0.4 mL) resulting in a 0.6 m solution of
17 or 18. After 5 min, the solution was transferred to an NMR
tube and 4-chlorotoluene (13, 1.25 mmol, 50 equiv.) was added.
The obtained solution was heated to 55Ϯ1 °C and 31P NMR spec-
tra were recorded after the indicated time periods.
22. The amido complexes were prepared according to a
one-pot procedure by the reaction of 1 or 2 with [Pd(P(o-
Tol)3)2] (15) and 4-bromotoluene (23) in tetrahydrofuran
(THF) and subsequent addition of this solution to a solu-
tion of potassium benzamide [formed in situ from benz-
amide (14) and KOtBu in THF] at room temperature
(Scheme 2). The PdII-amidato complexes were formed as
mixtures of diastereomers (1:1 ratio as determined by 31P
NMR spectroscopic analysis). The PdII complexes 21 and
22 were obtained as pure products by recrystallization from
pentane at –35 °C. The 31P NMR spectrum of each PdII-
amidato complex exhibited four resonances corresponding
to the two diastereomers (Table 4).
Figure 5. Reductive elimination of 16 from 21 and 22 at 100 °C (᭺
for 21, k21 = 0.06Ϯ0.01 min–1; Δ for 22, k22 = 0.08Ϯ0.01 min–1).
Reaction conditions: 21 or 22 (0.025 mmol, 1.0 equiv.), P(oTol)3
(0.05 mmol, 2.0 equiv.) and PMes3 (internal standard, 0.025 mmol,
1.0 equiv.) were dissolved in 1,4-dioxane/[D6]benzene (3.5:1,
0.45 mL) and the solution was transferred into an NMR tube. The
solution (0.6 m) was heated to 100 °C and 31P NMR spectra were
recorded after the indicated time periods.
As evident from Figure 5, the reductive elimination of 16
from the pronounced electronically unsymmetrical bisphos-
phine-Pd complex 22 is faster (k22 = 0.08Ϯ0.01 min–1) than
from the more electron-rich bisphosphine-Pd complex 21
(k21 = 0.06Ϯ0.01 min–1) by a factor of krel = 1.3Ϯ0.1. The
reductive elimination requires the highest temperature in
the catalytic cycle and is therefore rate determining. As
judged from the 31P NMR spectra, the cis and trans dia-
stereomers of each of the two complexes 21 and 22 under-
went reductive elimination with the same rate (accumu-
lation or interconversion of one of the isomers was not de-
tected by 31P NMR spectroscopic analysis). Consequently,
the cis and trans diastereomers should have similar transi-
tion-state (TS) energies.[10a,10b] The marginally higher rate
of 22 in the reductive elimination should therefore arise
Scheme 2. One-pot synthesis of PdII-aryl-amidato complexes 21
and 22 (1:1 mixture of diastereomers).
Despite intense efforts, we were not able to enrich one of from a lower activation energy compared with 21. The dif-
the diastereomers for the kinetic investigation. The amidato ferences in transition-state energies ΔΔG‡ can be estimated
complexes 21 and 22 smoothly underwent reductive elimi- from the Arrhenius equation. Taking the approximation of
nation at 100 °C to furnish the amidation product 16 to- similar Arrhenius parameters into account,[19] the differ-
gether with the Pd0 complexes 17 and 18, respectively. The ence in activation energy can be estimated to be 0.2 kcal/
first-order rate plot for this reaction is depicted in Figure 5. mol.
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Amidation of Aryl Chlorides: A Kinetic Study
Figure 6. Energies/enthalpies in kcal/mol for the reductive elimination from (a) 21 and (b) 22.[20]
Quantum chemical calculations were carried out to gain
more detailed insight into the rate-determining reductive
elimination reactions (also see Exp. Sect.); the results are
summarized in Figure 6. All thermodynamic data are re-
lated to the final products. In accordance with our kinetic
data, cis-21 and trans-21 exhibit similar energies/enthalpies
(11.7 vs. 10.3 kcal/mol, see Figure 6, a). The same was
found for the fluorinated system 22 (Figure 6, b), although
the differences in energies/enthalpies increased relative to
the reaction products by 5.2–5.8 kcal/mol compared with
21. A comparison of the TS energies displays similar trends;
the TS of cis-21 and trans-21 as well as cis-22 and trans-22
are similar in energy. However, the TS of the 22 species are
about 5.0–6.1 kcal/mol higher in energy/enthalpy than
those of 21. Consequently 21 and 22 require roughly the
same activation energy to undergo reductive elimination
(e.g., ΔΔE: cis-21: 22.2 kcal/mol; trans-21: 24.4 kcal/mol;
cis-22: 23.8 kcal/mol; trans-22: 24.4 kcal/mol). Taking the
experimental error of 1–2 kcal/mol into account, 21 and 22 ene (13, solid line) and 4-bromotoluene (23, dashed line) with
should have similar rates for the reductive elimination,
which is consistent with our kinetic data.
Figure 7. Reaction profile of the arylation of 14 with 4-chlorotolu-
1 mol-% 1/15 (᭺) or 2/15 (Δ). Reaction conditions: aryl halide 13
or 23 (1.0 equiv.), benzamide (14; 1.2 equiv.), Cs2CO3 (1.4 equiv.),
1,4-dioxane (0.6 m), 100 °C; yields determined by gas chromatog-
raphy using dodecane as internal standard.
Overall Amidation Process; Effect of the Counterion on the
Transmetallation
even at room temperature within 10 min but, as shown ear-
Finally, the overall process for the amidation of aryl hal- lier, the oxidative addition of aryl chlorides occurred readily
ides (X = Br, Cl) with benzamide was investigated (Fig- at 100 °C. Consequently, the transmetallation step must be-
ure 7).
come more relevant to the overall reaction rate. This phe-
In concert with our kinetic investigations, the catalytic nomenon becomes even more pronounced when preformed
amidation of aryl chloride 13 (solid line) was faster with potassium benzamide (24) was used in the catalytic aryl-
the fluorinated phosphine 2 (Δ) as supporting ligand than ation (Figure 8). The catalytic reactions (1 mol-%) of brom-
with 1 (᭺) as a result of the faster reductive elimination. ide 23 or chloride electrophile 13 with potassium benzimide
Somewhat to our surprise, the amidation of 4-bromotolu- (24) as nucleophile produced N-arylbenzamide 16 in higher
ene (23, dashed line) proceeded with a higher rate than with yield (91 and 56%, respectively) within shorter reaction
aryl chlorides (Figure 7). This observation should not be time compared with the Cs2CO3 system (compare Figure 7,
attributed to faster oxidative addition to the aryl bormide.
68 and 41% yield, respectively). This dramatic reactivity in-
The oxidative addition of the Pd0 complexes 1/[Pd(P(o- crease can be understood in terms of the fast salt-metathesis
Tol)3)2] or 2/[Pd(P(oTol)3)2] to bromide 23 proceeds cleanly reaction producing potassium halide and the [κ2P,P-2-κN-
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F. C. Falk, P. Oechsle, W. R. Thiel, C.-G. Daniliuc, J. Paradies
FULL PAPER
imido-μ-4-tolyl]palladium(0) complex (compare Scheme 2,
22) as the product. To shed further light on the effect of the
chloride counterion on the amidation reaction, we con-
ducted further experiments. Aryl triflates are not only
highly reactive electrophiles in the oxidative addition but
also furnish PdII complexes that are weakly coordinated by
the triflate anion. Such highly electrophilic Pd complexes
are rapidly attacked by nucleophiles, leading to transmetal-
lation products. We exploited this reactivity to compare the
amidation reaction between aryl triflate 25 and benzamide
(14) in the absence and presence of chloride ions (Figure 9).
Figure 9. Reaction profile of the arylation of benzamide (14) with
4-tolyl triflate (25) in the absence (dotted line) or presence of am-
monium chloride [Bu4NCl (1.0 equiv.), dotted/dashed line]. Reac-
tion conditions: 4-tolyl triflate (25; 1.0 equiv.), benzamide (14;
1.2 equiv.), Cs2CO3 (1.4 equiv.), 2/[Pd(P(oTol)3)2] (1 mol-%), 1,4-di-
oxane (0.6 m), 100 °C, yields determined by gas chromatography
using dodecane as internal standard.
dition of external chloride sources, this result supports the
conclusion that the transmetallation has more significant
impact on the overall reaction rate than oxidative addition.
Conclusions
Figure 8. Anion dependency in the palladium-catalyzed (1 mol-%
2/[Pd(P(oTol)3)2] Δ) amidation: (a) reaction profile of the amidation
4-chlorotoluene (13, solid line) and 4-bromotoluene (23, dashed
line) with preformed potassium benzamide (24). Reaction condi-
tions: aryl halide 13 or 23 (1.0 equiv.), potassium benzamide
[KHN(C=O)Ph] (1.2 equiv.), 2/[Pd(P(oTol)3)2] (1 mol-%), 1,4-diox-
ane (0.6 m), 100 °C; yields were determined by gas chromatography
using dodecane as internal standard.
We have demonstrated that unsymmetrical bisphosphines
based on the GemPhos-scaffold are efficient ligands for the
amidation of aryl chlorides. Unsymmetrical bisphosphines,
when electronically decoupled, for example through spatial
separation, allow the competing requirements of an efficient
ligand for cross-coupling reactions to be unified: Firstly, an
electron-rich ligand for the efficient oxidative addition and
secondly an electron-deficient ligand for the reductive elimi-
nation. These prerequisites are met by the GemPhos-scaf-
fold featuring both electron-rich and less electron-releasing
phosphino-moieties. The careful design of bisphosphine li-
gands bearing an electron-rich and a less electron-releasing
phosphino moiety will allow higher efficiency to be
achieved in challenging cross-coupling reactions.
The amidation of 25 in the absence of chloride ions pro-
ceeded with comparable efficiency (40% after 4 h; Figure 9)
to that of the amidation of the 4-chlorotoluene (13) with
preformed potassium benzamide (24) (compare Figure 8 so-
lid line after 4 h). However, under these conditions, decom-
position of aryl triflate 25 was observed, resulting in re-
duced yields. In the presence of 1.0 equiv. nBu4Cl (Figure 9
dashed/dotted line) the reaction was efficiently inhibited, re-
sulting in less than 10% yield of the amidation product.
This can be clearly attributed to the exchange of the weakly
coordinating triflate-anion by the strongly coordinating
chloride-anion.[6k] The higher chloride concentration
(0.6 m) makes transmetallation under the same conditions
more challenging, compared with the coupling of aryl
chloride. Such influences have also been observed for
monodentate biaryl phosphine ligands in the Pd-catalyzed
amidation of aryl chlorides.[6k,8] Because the oxidative ad-
Experimental Section
General: Routine monitoring of reactions were performed using sil-
ica gel coated aluminum plates (Merck, silica gel 60, F254), which
were analyzed under UV-light at 254 nm and/or dipped into a solu-
tion of molybdato phosphate (5% phosphor molybdic acid in eth-
anol, dipping solution) and heated with a heat gun. GC analysis
was performed with a Bruker 430-GC. Integrals were referenced to
n-dodecane as internal standard. Solvent mixtures are presented as
volume/volume. Solid materials were powdered. Solvents, reagents
dition of aryl triflate 25 should not be slowed by the ad- and chemicals were purchased from Aldrich, Fluka, ABCR, or
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Amidation of Aryl Chlorides: A Kinetic Study
Acros. THF was distilled from sodium under argon prior to use.
Anhydrous 1,4-dioxane (extra dry over molecular sieves) was pur-
chased from Acros and degassed by freeze-pump-thaw-technique
(3ϫ) and introduced into a glovebox. Cs2CO3 (ReagenPlus) was
purchased from Sigma–Aldrich and weighed out under air. 4-
Chlorotoluene, 4-bromotoluene and n-dodecane were degassed by
freeze-pump-thaw-technique (3ϫ) and introduced in an argon-
filled glovebox. All other solvents, reagents and chemicals were
used as purchased unless stated otherwise. All reactions involving
moisture- or air-sensitive reactants were executed under an argon
atmosphere in oven-dried glassware using standard Schlenk tech-
niques or in an argon-filled glovebox (O2 Ͻ 5 ppm, H2OϽ5 ppm).
Potassium benzimide was prepared by deprotonation of benzimide
with potassium tert-butoxide in anhydrous diethyl ether under an
argon atmosphere and filtration of the product.
X-ray Diffraction: Data sets were collected with a Nonius
KappaCCD diffractometer. Programs used: data collection,
COLLECT;[21a] data reduction Denzo-SMN;[21b] absorption cor-
rection, Denzo;[21c] structure solution SHELXS-97;[21d] structure
refinement SHELXL-97[21e] and graphics, XP.[21f] R values are
given for observed reflections, and wR2 values are given for all re-
flections.
Exceptions and Special Features: For compound 11, two CF3
groups and one dichloromethane molecule were disordered over
two positions in the asymmetrical unit. Several restraints (SIMU,
SADI, SAME, ISOR) were used to improve refinement stability.
Compound 12 presented two disordered BF4 anion groups over
two positions. Several restraints (SIMU, SADI, SAME, ISOR)
were used to improve refinement stability. Two half acetonitrile
molecules that were badly disordered were found in the asymmetri-
cal unit and could not be satisfactorily refined. The program
SQUEEZE[21g] was therefore used to remove mathematically the
effect of the solvent. The quoted formula and derived parameters
do not include the squeezed solvent molecule.
Synthesis of Bisphosphine Selenides. General Procedure: To a solu-
tion of the respective bisphosphine (0.03 mmol, 1.0 equiv.) in de-
gassed CDCl3 (2 mL) was added selenium powder (47 mg,
0.60 mmol, 20 equiv.). The reaction mixture was heated to reflux
for 5 h. After cooling to room temperature, the volume of the mix-
ture was reduced to about 0.5 mL under reduced pressure. The mix-
ture was transferred to a NMR tube with a syringe equipped with
a syringe filter and the bisphosphine selenides were analyzed by
NMR spectroscopy.
[{(p-CF3-C6H4),Cy-GemPhos}PdCl2] (11): A vial was charged with
Pd(NCCH3)2Cl2 (13 mg, 0.050 mmol, 1.0 equiv.) and 2 (36 mg,
0.050 mmol, 1.0 equiv.) and fitted with a crimp cap (rubber sep-
tum), then absolute THF (2 mL) was added and the mixture was
stirred for 2 h at room temperature. The solvent was removed under
reduced pressure and the residue was washed with anhydrous di-
ethyl ether (2ϫ 10 mL) to give the title compound as a slightly-
yellow solid. Crystals suitable for X-ray analysis were obtained
from a saturated solution of 11 in dichloromethane by slow evapo-
ration.
rac-4-Bis(p-trifluoromethylphenyl)phosphino-13-dicyclohexylphos-
phino[2.2]paracyclophane-bisselenide (5): 1H NMR (250 MHz,
CDCl3): δ = 7.99–7.87 (m, 2 H, ArH), 7.57–7.50 (m, 2 H, ArH),
7.34–7.27 (m, 2 H, ArH), 7.27–7.25 (m, 1 H, ArH), 7.20–7.15 (m,
1 H, ArH), 6.94–6.83 (m, 2 H, HPC), 6.80 (d, J = 7.4 Hz, 1 H,
HPC), 6.73–6.68 (m, 2 H, HPC), 6.51 (d, J = 11.2 Hz, 1 H, HPC),
4.51–4.39 (m, 1 H, CH2), 3.60 (d, J = 0.5 Hz, 1 H, CH2), 3.21–2.94
(m, 4 H, CH2), 2.93–2.52 (m, 3 H, CH2, Cy), 2.50–2.35 (m, 1 H,
Cy), 2.32–1.88 (m, 3 H, Cy), 1.86–0.66 (m, 17 H, Cy) ppm. 31P
NMR (101 MHz, CDCl3): δ = 45.00 (d, JP,Se = 703.4 Hz), 31.65 (d,
JP,Se = 765.1 Hz) ppm.
X-ray Crystal Structure Analysis of 11: CCDC-981503; formula
C42H44Cl2P2F6Pd·CH2Cl2;
0.26ϫ0.23ϫ0.06 mm;
19.3661(2) Å, 107.770(1)°; V =
M
=
986.94; yellow crystal;
a
=
13.1687(1), b
=
17.8624(2),
c
=
=
β
=
4338.04(7) Å3; ρcalcd.
1.511 gcm–3; μ = 0.804 mm–1; empirical absorption correction
(0.818Յ TՅ 0.953); Z = 4; monoclinic; space group P21/n (No.
14); λ = 0.71073 Å; T = 223(2) K; ω and φ scans, 26043 reflections
collected (Ϯh, Ϯk, Ϯl), [(sinθ)/λ] = 0.67 Å–1, 7518 independent (Rint
= 0.032) and 6665 observed reflections [IϾ2σ(I)], 589 refined pa-
rameters, R = 0.043, wR2 = 0.112, max. (min.) residual electron
density 1.20 (–0.61)eÅ–3, the hydrogen atoms were calculated and
refined as riding atoms.
4-Diphenylphosphino-12-dicyclohexylphosphino[2.2]paracyclo-
1
phane-bisselenide (6): H NMR (250 MHz, CDCl3): δ = 7.83 (s, 1
H, ArH), 7.78 (d, J = 5.2 Hz, 1 H, ArH), 7.75–7.68 (m, 2 H, ArH),
7.65 (dd, J = 7.8, 1.6 Hz, 1 H, ArH), 7.47–7.28 (m, 6 H, ArH,
HPC), 6.83–6.70 (m, 2 H, HPC), 6.69–6.60 (m, 3 H, HPC), 4.62–4.46
(m, 1 H, CH2), 3.93–3.79 (m, 1 H, CH2), 3.70–3.48 (m, 2 H, CH2),
3.39–3.17 (m, 1 H, CH2), 3.02–2.66 (m, 5 H, CH2, Cy), 2.20–2.05
(m, 1 H, Cy), 1.99–1.62 (m, 8 H, Cy), 1.60–0.96 (m, 9 H, Cy), 0.94–
0.72 (m, 2 H, Cy) ppm. 13C NMR (63 MHz, CDCl3): δ = 146.1,
146.0, 145.7, 145.6, 140.4, 140.1, 139.1, 139.0, 136.9, 136.9, 136.2,
136.2, 135.9, 135.7, 135.3, 134.5, 134.0, 133.8, 133.3, 132.6, 132.4,
132.3, 131.4, 131.4, 130.8, 129.6, 128.4, 128.3, 128.2, 128.1, 126.9,
125.6, 123.5, 42.8, 42.1, 36.6, 35.7, 35.1, 35.0, 35.0, 34.2, 33.5, 29.6,
29.0, 29.0, 28.1, 28.0, 27.7, 27.5, 27.5, 27.3, 27.2, 27.1, 27.0, 26.7,
[(Ph,Cy-PhanePhos)(CH3CN)2Pd][BF4]2 (12): A vial was charged
with Pd(NCPh)2Cl2 (50 mg, 0.13 mmol, 1.0 equiv.) and 3 (77 mg,
0.13 mmol, 1.0 equiv.) and fitted with a crimp cap (rubber septum).
Absolute acetonitrile (3 mL) was added, the mixture was stirred for
30 min at room temperature, then the mixture was transferred to
another vial charged with AgBF4 (57 mg, 0.29 mmol, 2.2 equiv.).
This mixture was stirred for 2 h at room temperature, then filtered
through Celite and the solvent was removed under reduced pres-
sure. The residue was washed with anhydrous diethyl ether
(2ϫ10 mL) to yield the title compound as a yellow solid. Crystals
suitable for X-ray analysis were obtained by diffusion of diethyl
ether into a saturated solution of 12 in acetonitrile.
26.1 ppm. 31P NMR (101 MHz, CDCl3): δ = 41.39 (d, JP,Se
686.6 Hz), 29.29 (d, JP,Se = 721.9 Hz) ppm.
=
[{(p-CF3-C6H4),Cy-GemPhos}Rh(CO)Cl] (8): A vial was charged
with [Rh(CO)2Cl2] (4.6 mg, 0.010 mmol, 0.50 equiv.) and 2 (15 mg,
0.020 mmol, 1.0 equiv.), then CH2Cl2 (0.66 mL) was added and the
orange solution was stirred for 5 min at room temperature. The
solvent was removed under reduced pressure to yield the title com-
pound as an orange solid as two diastereoisomers: 31P NMR
X-ray Crystal Structure Analysis of 12: CCDC-981502; formula
C44H52N2P2B2F8Pd·CH3CN;
0.30ϫ0.17ϫ0.07 mm;
14.6495(2) Å, β = 96.763(1)°; V = 5192.2(1) Å3; ρcalc = 1.269 gcm–3;
0.480 mm–1;
empirical absorption correction
M
=
1032.94; yellow crystal;
a
=
16.8370(2), b 21.1980(2), c =
=
μ
=
(101 MHz, CDCl3): δ = 47.97 (dd, J = 179.8, 33.0 Hz), 23.45 (dd, (0.869ՅTՅ0.967); Z = 4; monoclinic; space group P21/c (No. 14);
J = 117.7, 33.0 Hz) ppm. 31P NMR (101 MHz, CDCl3): δ = 46.33
(dd, J = 153.0, 32.5 Hz), 25.14 (dd, J = 127.2, 32.5 Hz) ppm. FTIR
λ = 0.71073 Å; T = 223(2) K; ω and φ scans, 31410 reflections
collected (Ϯh, Ϯk, Ϯl), [(sinθ)/λ] = 0.59 Å–1, 8998 independent (Rint
= 0.036) and 7837 observed reflections [IϾ2σ(I)], 636 refined pa-
(KBr): ν = 2000.8, 1969.1 cm–1.
˜
Eur. J. Org. Chem. 2014, 3637–3645
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3643

F. C. Falk, P. Oechsle, W. R. Thiel, C.-G. Daniliuc, J. Paradies
vial was charged with Cs2CO3 (456 mg, 1.40 mmol, 1.40 equiv.) and
FULL PAPER
rameters, R = 0.041, wR2 = 0.111, max. (min.) residual electron
density 0.62 (–0.35)eÅ–3, the hydrogen atoms were calculated and either benzamide (14; 145 mg, 1.20 mmol, 1.20 equiv.) or potassium
refined as riding atoms.
benzimide (24; 192 mg, 1.20 mmol, 1.20 equiv.), the respective aryl
(pseudo)halide (1.00 mmol, 1.00 equiv.) and absolute n-dodecane
(0.50 mmol, 0.50 equiv.). In a second vial, bis(tri-ortho-tolylphos-
phine)palladium(0) (15; 7.2 mg, 0.010 mmol, 1 mol-%) and the re-
spective bisphosphine (0.010 mmol, 1 mol-%) were dissolved in ab-
solute 1,4-dioxane (2 mL) and then transferred to the first vial by
using a syringe. The vial containing the reaction mixture was sealed
with a crimp cap (rubber septum), removed from the glovebox and
heated in a preheated vial block to 110 °C. At certain reaction times
(0.5, 1, 2, 4, 6, 8, and 10 h) the vial was cooled in an ice bath
and samples (0.1 mL) were taken under argon by using a syringe.
Afterwards the vial was again heated in the vial block, the samples
were diluted with EtOAc (1 mL), filtered through silica, rinsed with
EtOAc (1 mL), and analyzed by GC. The yield was determined by
using n-dodecane as internal standard.
General Procedure for the Kinetic Investigation of the Oxidative Ad-
dition of Chlorotoluene to Palladium-Gemphos Complexes: In an ar-
gon-filled glovebox, bis(tri-ortho-tolylphosphine)palladium(0) (15;
18 mg, 0.025 mmol, 1.0 equiv.), the respective bisphosphine
(0.025 mmol, 1.0 equiv.), and PMes3 (9.7 mg, 0.025 mmol,
1.0 equiv., internal standard) were dissolved in a 2-mL vial in abso-
lute C6D6 (0.4 mL). The solution was transferred into a NMR tube
by using
a syringe and 4-chlorotoluene (0.15 mL, 157 mg,
1.25 mmol, 50 equiv.) was added. The NMR tube was sealed with
a conventional NMR cap and Teflon tape before it was removed
from the glovebox. The tube was heated to the respective tempera-
ture (55 or 100 °C) for a defined reaction time, then rapidly cooled
to 0 °C in an ice bath and the decrease in the 31P NMR signal of
the Pd0 species was monitored by 31P NMR spectroscopic analysis
and the concentration was calculated by using PMes3 as internal
standard.
DFT Calculations: Quantum chemical calculations on the reductive
elimination reactions starting from compounds cis/trans-21 and
cis/trans-22 were performed with the program Gaussian03W[20]
using the B3LYP gradient corrected exchange-correlation func-
tional[22] in combination with the 6-31G* basis set[23] for C, H, P,
N, O, and F and the Stuttgart RSC 1997 ECP basis set for Pd.[24]
Full geometry optimizations were carried out in C1 symmetry by
using analytical gradient techniques without applying any solvent
model, and the resulting structures were confirmed to be true min-
ima by diagonalization of the analytical Hessian Matrix.
General Procedure for the One-Pot Synthesis of Palladium-
Gemphos-tolyl-amido Complexes 21 and 22: In an argon-filled
glovebox, bis(tri-ortho-tolylphosphine)palladium(0) (15; 36 mg,
0.050 mmol, 1.0 equiv.) and the respective bisphosphine
(0.050 mmol, 1.0 equiv.) were dissolved in absolute THF (1 mL) in
a 2-mL vial. Then 4-bromotoluene (0.012 mL, 17 mg, 0.10 mmol,
2.0 equiv.) was added by using a syringe and the mixture was fil-
tered through a syringe filter into a second vial containing potas-
sium benzimide (24; 9.6 mg, 0.060 mmol, 1.2 equiv.). This reaction
mixture was stirred at room temperature in the glovebox for 2 h,
then filtered through Celite, rinsing with further THF (0.5 mL).
The solvent was removed under reduced pressure and the residue
was dissolved in a minimum amount of absolute CH2Cl2 (0.1 mL)
and pentane (4 mL) was layered over the solution. After 12 h at
–35 °C, a white precipitate formed, which was separated from the
supernatant and washed with cold pentane (1 mL), to give the re-
spective palladium complexes as white solids.
Supporting Information (see footnote on the first page of this arti-
cle): Synthesis and analytical data for 2 and 3; copies of NMR
spectra; kinetic data; X-ray crystallographic data; atom coordinates
from DFT calculations.
Acknowledgments
Financial support by the Deutsche Forschungsgemeinschaft
(DFG) [DFG-funded transregional collaborative research center,
SFB/TRR 88, Cooperative effects in homo- and heterometallic com-
plexes (3MET)] and the Heisenberg Foundation (fellowship to
J. P.) is gratefully acknowledged.
[(Ph,Cy-Gemphos)Pd(p-Tol)(NHCOC6H5)] (21): Two diastereoiso-
mers: 31P NMR (101 MHz, C6D6): δ = 26.4 (d, J = 27.5 Hz), 16.5
(d, J = 27.5 Hz) ppm. 31P NMR (101 MHz, C6D6): δ = 18.4 (d, J
= 26.3 Hz), 17.1 (d, J = 26.3 Hz) ppm.
[{(p-CF3-C6H4),Cy-Gemphos}Pd(p-Tol)(NHCOC6H5)] (22): Two
diastereoisomers: 31P NMR (101 MHz, C6D6): δ = 26.1 (d, J =
20.1 Hz), 16.6 (d, J = 20.1 Hz) ppm. 31P NMR (101 MHz, C6D6):
δ = 17.9 (d, J = 20.3 Hz), 17.1 (d, J = 20.3 Hz) ppm.
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cooled to 0 °C in an ice bath and the decrease of the 31P NMR
signal of the PdII-species was monitored by 31P NMR spectroscopic
analysis; the concentration was calculated by using PMes3 as in-
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 3637–3645

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Received: January 30, 2014
Published Online: May 2, 2014
Eur. J. Org. Chem. 2014, 3637–3645
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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