Oxidative Addition of Water, Alcohols, and Amines in Palladium Catalysis

Article abstract of DOI:10.1002/anie.202008350

The homolytic cleavage of O?H and N?H or weak C?H bonds is a key elementary step in redox catalysis, but is thought to be unfeasible for palladium. In stark contrast, reported here is the room temperature and reversible oxidative addition of water, isopropanol, hexafluoroisopropanol, phenol, and aniline to a palladium(0) complex with a cyclic (alkyl)(amino)carbene (CAAC) and a labile pyridino ligand, as is also the case in popular N-heterocyclic carbene (NHC) palladium(II) precatalysts. The oxidative addition of protic solvents or adventitious water switches the chemoselectivity in catalysis with alkynes through activation of the terminal C?H bond. Most salient, the homolytic activation of alcohols and amines allows atom-efficient, additive-free cross-coupling and transfer hydrogenation under mild reaction conditions with usually unreactive, yet desirable reagents, including esters and bis(pinacolato)diboron.

Full text of DOI:10.1002/anie.202008350

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Accepted Article
Title: Oxidative Addition of Water, Alcohols and Amines in Palladium
Catalysis
Authors: Dominik Munz, Annette Grünwald, and Frank W Heinemann
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10.1002/anie.202008350
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RESEARCH ARTICLE
Oxidative Addition of Water, Alcohols and Amines in Palladium
Catalysis
Annette Grünwald,[b] Frank W. Heinemann,[b] and Dominik Munz*[a],[b]
[a]
Prof. D. Munz
Inorganic Chemistry: Coordination Chemistry
Saarland University
Campus, Geb. C4.1, 66123 Saarbrücken, Germany
Email: dominik.munz@uni-saarland.de
[b]
A. Grünwald, Dr. F. W. Heinemann, and Prof. D. Munz
Department of Chemistry and Pharmacy, General and Inorganic Chemistry
Friedrich-Alexander-Universität Erlangen-Nürnberg
Egerlandstraße 1, 91058 Erlangen, Germany
Supporting information for this article is given via a link at the end of the document.
Abstract: The homolytic cleavage of O‒H and N‒H or weak C‒H
bonds is a key elementary step in redox catalysis, yet thought to be
unfeasible for palladium. In stark contrast, we report the room tem-
perature and reversible oxidative addition of water, isopropanol, he-
xafluoroisopropanol, phenol, and aniline to a palladium(0) complex
with a cyclic (alkyl)(amino)carbene (CAAC) and a labile pyridino li-
gand as is also the case in popular N-heterocyclic carbene (NHC)
palladium(II) pre-catalysts. We elucidate how the oxidative addition
of protic solvents or adventitious water switches the chemoselectivity
in catalysis with alkynes through activation of the terminal C‒H bond.
Most salient, the homolytic activation of alcohols and amines allows
for atom efficient, additive-free cross coupling and transfer hydroge-
nation under mild reaction conditions with usually unreactive, yet de-
sirable reagents including esters and bis(pinacolato)diboron.
The alternative oxidative addition, in case of water referred to as
“water splitting”,[5] produces a palladium(II) hydride from a pa-
lladium(0) precursor (Scheme 1, B). This palladium(II) hydride is
the alleged key intermediate for subsequent redox trans-forma-
tions including the generation of dihydrogen or dehydrogenative
cross coupling.[6] Nevertheless, whereas the intermolecular oxi-
dative addition of strong O‒H and N‒H bonds is known for the
group 9 metals,[7] it remains elusive for the group 10. To the
best of our knowledge, the only exceptions are the 1,2-addition
across activated, nucleophilic alkylidene complexes,[8] a tran-
sient palladium(I) complex with a pincer ligand,[9] and the solvo-
lysis of bis(triisopropylphosphine) platinum(0).[10] Eventually, it is
intriguing to note that protic solvents or co-reagents sometimes
play a pivotal role in palladium catalysis. For example, aqueous
reaction media can lead to exceptional efficient and robust
cross-coupling;[11] similarly, hexafluoroisopropanol (HFIP) emer-
ged as a favorable solvent in C‒H functionalization chemistry.[12]
Nevertheless, the oxidative addition of adventitious water or al-
cohols in general seems to not have been considered in this
context. In fact, water or alcohols instead mediate the reductive
generation of palladium(0) from palladium(II) precursors[13] with
phosphane- or N-heterocyclic carbene (NHC)[14] ligands.
Introduction
The homolytic activation of a bond through oxidative addition is
an important chemical transformation. It is in particular central
to organometallic chemistry, where the insertion of low-valent,
late transition metal complexes into most typically carbon–halo-
gen bonds has revolutionized homogeneous catalysis.[1] The
catalytic valorization of O‒H, N‒H and C‒H bonds is equally im-
portant in catalysis. For instance, the dehydrogenation of alco-
hols or the hydrogen generation from water hold promise to
“cleanly” convert and store energy.[2] In the vast field of molecu-
lar palladium catalysis, it is however common belief that O‒H,
N‒H and weak C‒H bonds are only cleaved heterolytically
through deprotonation with a base. Strong indication for this
redox-neutral mechanism was presented by µ-hydroxo bridged
palladium(II) dimers in Wacker-type oxidation reactions and the
Buchwald-Hartwig amination.[3] These very basic palladium(II)
hydroxo complexes deprotonate anilines to give water and the µ-
anilido bridged palladium(II) dimers (Scheme 1, A).[4]
Results and Discussion
We recently used a palladium(0) complex with an ancillary cyclic
(alkyl)(amino)carbene (CAAC) ligand[15] as a reactive intermedi-
ate.[16] The solid state structure reveals now that 1 is a mononu-
clear, pyridine-coordinate 14-electron complex without interac-
tion of the metal with the pendant imino group (Fig. 1, left).
Figure 1. Complex 1 parallels the alleged palladium(0) intermediate of the
PEPPSITM precatalyst family. Ellipsoids are shown at the 50% probability level,
a second independent molecule of 1 and hydrogen atoms are omitted for
clarity. Selected bond lengths [Å], angles [°] and dihedral angles between
least-square planes [°]: Pd1–C1 1.927(3), Pd1–N3 2.092(3), C1-Pd1-N3
174.6(2), N1-C1-N3-C41 81.1. The second independent molecule shows a
dihedral angle of 47.3° between least-square planes of N4-C42-N6-C82.
Scheme 1. Activation of N‒H or O‒H bonds via either deprotonation (A) or
oxidative addition (B).
1
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Two independent molecules of 1 with different dihedral angles
between least-squares planes, which were calculated through
the five atoms forming the CAAC and the six atoms of the pyri-
dino ligand (81.1° and 47.3°), were found in the unit cell, thus in-
dicating at best weak π-backbonding from the metal to the pyri-
dine ligand. Pyridine-coordinated linear palladium(0) complexes
have previously not been reported to the best of our knowledge.
In fact, dicoordinated, heteroleptic palladium(0) complexes are
very rare and only examples for soft phosphine ligands in combi-
nation with likewise soft NHCs are known.[17] Complex 1 repre-
sents thus an excellent model for the alleged palladium(0) inter-
mediate of the PEPPSITM palladium(II) NHC precatalyst family
(Fig. 1, right), which show outstanding activity in a variety of im-
portant catalytic transformations.[18] Most intriguingly, we rea-
soned that the soft/hard mismatch between the low-valent metal
and the pyridine ligand renders 1 a surrogate for the elusive 12-
electron palladium(0) intermediate in homogeneous catalysis.[19]
Truly, the very broad 1H NMR signals of 1 in perdeuterated ben-
zene suggest a labile pyridino ligand and the potential formation
of aggregates. Stirring solutions of 1 in benzene at room tempe-
rature in the presence of 15 equivalents of water led to a color
change from dark red to yellow, which is indicative for the oxi-
dation to a palladium(II) complex. The conversion of 1 was mo-
nitored by 1H NMR spectroscopic analysis and a singlet at
−5.16 ppm suggested the quantitative formation of a palladium
hydroxo complex. Indeed, the solid-state structure revealed the
formation of the bis-µ-hydroxo bridged dimer dimer2H2O (Fig. 2).
Scheme 2. The equilibrium between 1 and 2H2O is solvent dependent.
Further testing the reversibility of the reaction, we treated
dimer2H2O in tetrahydrofuran with 80 equivalents of deuterated wa-
ter (Fig. S2). Following instantaneous isotopic exchange of the
protons of the bridging hydroxo ligands, we observed as well the
isotopic exchange of the hydrogen atom connected with the for-
mer carbene atom over the course of one week (60 °C: 3 h).
Complex dimer2H2O was treated with hydrogen chloride in order to
unambiguously validate its hydridic reactivity (Scheme 3). Upon
addition of one equivalent of hydrogen chloride, the exchange of
the hydroxo- for a chloro-ligand and the formation of dimer2HCl
was observed. Subsequent addition of another equivalent of hy-
drogen chloride led to the immediate formation of gas bubbles,
which were identified as dihydrogen, as well as the precipitation
of 3, which was isolated in quantitative yield (Fig. S5).
Scheme 3. Complexes 2ROH show the reactivity of palladium hydrides.
For the analogous phenolate complex 2PhOH, stoichiometric
amounts of phenol, dihydrogen and 3 were obtained (see Fig.
S6). Starting from deuterated dimer2D2O gave quantitatively hy-
drogen deuteride HD (Figs. S7, S8). Hydrogenated CAACs em-
bedded in extended π-systems require strong oxidants to be de-
hydrogenated and the addition of acids does not lead to dihydro-
gen generation.[21] Equally note that -hydride elimination is an
established strategy to synthesize Fischer-carbene complexes,
including aza-Fischer carbenes isostructural with CAACs.[22]
Overall, we conclude that dimer2H2O shows the reactivity of a
Figure 2. Solid state structure of dimer2H2O
. Ellipsoids are shown at the 50%
probability level, solvent molecules and hydrogen atoms are omitted for clarity
(except the ones connected to the carbene C atom and the OH group).
Selected bond lengths [Å], angles [°] and dihedral angles [°]: Pd1–Pd2
3.1902(2), Pd1–O1 2.041(2), Pd1–O2 2.195(2), Pd2–O2 2.045(2), Pd2–O1
2.183(2), Pd1–C1 1.989(2), Pd2–C37 1.995(2), Pd1–N2 2.029(2), Pd2–N4
2.027(2), N2-Pd1-C1 82.11(8), N4-Pd2-C37 82.51(8), O1-Pd1-O2 75.08(6),
Pd1-O1-Pd2, 98.05(6), O1-Pd1-C1-N1 71.2(2), O2-Pd2-C37-N3 69.4(2).
palladium hydride and is likely to stand in equilibrium with 2(H)(OH)
In order to further elucidate the water activation mechanism, we
determined a kinetic isotope effect kH2O/D2O of 2.0 (Figs. S9, S10).
This value is consistent with the value of kCH3OH/CH3OD = 2.0 found
for the oxidative addition of methanol to an iridium(I) complex.[7a]
Varying the concentration of water revealed that the reaction
follows a second order rate law in regard to water in tetrahydro-
furan (Fig. 3, bottom left). This is also in agreement with the
mechanism found for this iridium(I) complex, where a reaction
order “higher than one” was reported.[7a] The conversion of 1 in
the presence of 100 equivalents of water follows initially pseudo
first order kinetics, but shows then product inhibition (Fig. 3,
bottom right). This indicates a slower reaction rate due to the
liberation of pyridine (cf. Table 1) and hence dissociation of the
pyridine ligand prior to the rate determining transition state.
.
The formation of a bond between the highly electrophilic pz orbi-
tal of the CAAC ligand and the hydrogen atom derived from wa-
ter is intriguing. It suggests, analogous to the hydride migration
observed upon coordination of free CAACs to aluminum- or bo-
rohydride,[20] the previous formation of the palladium (hydri-
do)(hydroxo) intermediate 2(H)(OH) (Scheme 2). The equilibrium
of the overall reaction turned out to be solvent dependent. Dis-
solving dimer2H2O in pyridine resulted in the clean regeneration of
1 with the concomitant release of one equivalent of water within
six days (see Fig. S1).
2
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HCl
1
1
C6D6
> 1×10−2
ArCCH[e]
C5D5N
π-complex
[a] Relative to 1. [b] Emulsion.[24] [c] Homogeneous. [d] Reaction gives a mix-
ture of products in C6D6 and THF-d8 due to reversible ligand redistribution; the
product was isolated from a reaction in neat isopropanol or aniline, respective-
ly; see Figs. S4, S11–12 for further details. [e] Ar = 4-tert-butylphenyl-.
While no reaction was observed in pyridine, an initial pseudo
first order rate constant of kobs = (8 ± 2)×10−6 s−1 (15 eq. of water)
was determined in tetrahydrofuran. Adding 15 eq. of pyridine
(Table 1) decreased the reaction rate (kobs = (5 ± 1)×10−7 s−1). In
benzene, with both 15 eq. of water, which is an emulsion, or with
2 eq. of water, which is a homogeneous reaction, a faster
reaction (15 eq. in benzene: kobs
=
(6 ± 5)×10−5 s−1, 2 eq. in
benzene: kobs = (2 ± 2)×10−6 s−1, 2 eq. THF: kobs = (9 ± 3)×10−8
s−1) was obtained. We subsequently evaluated the reaction
rates with isopropanol, aniline, phenol, HFIP and hydrogen chlo-
ride and compared them with the common oxidative addition of
chlorobenzene. Following reduced acidity of the protic reagents,
isopropanol (15 eq. in THF: kobs = (9 ± 4)×10−7 s−1) and aniline
(15 eq. in THF: kobs = (5 ± 3)×10−5 s−1) reacted with a slower rate
than phenol (2 eq. in pyridine: kobs = (6 ± 4)×10−4 s−1). The oxi-
dative addition with chlorobenzene (2 eq. PhCl in pyridine:
kobs = (9 ± 3) ×10−4 s−1) proceeded with the same order of magni-
tude as with phenol (2 eq. phenol in pyridine: (6 ± 4)×10−4) and
HFIP (2 eq. HFIP in pyridine: kobs = (2 ± 1)×10−3 s−1). We hence
conclude that O–H oxidative addition of HFIP seems to be a
likely reaction upon generation of palladium(0) in this solvent.
The reaction with hydrogen chloride went to completion before
we could record an NMR spectrum (kobs > 1×10−2 s−1), which is
consistent with previous reports in the literature.[25] Complex
2PhOH shows a monomeric structure in solution, while 2HCl forms
dimers like dimer2H2O according to diffusion NMR measurements
(Table S1). 2PhOH is also a monomer in the solid state with a
rare tricoordinate, T-shaped coordination geometry and hence a
vacant coordination site (Fig. 4).
Figure 3. Top: The conversion of 1 follows initially a pseudo 1st order rate law
followed by product inhibition (48 mmol L−1 1 in THF-d8; 100 eq. H2O); bottom
left: Linearization according to Lineweaver-Burk; bottom right: The activation
of water follows a 2nd order rate law in regard to water. See Figs. S60, S61 for
further details.
The same dissociative substitution mechanism via a formal 12-
electron palladium(0) intermediate has been suggested for the
oxidative addition of aryl halides to palladium(0) bisphosphine
complexes.[23] The reaction rate for the oxidative addition of wa-
ter also showed a strong dependence on the solvent (Table 1).
Table 1. Initial reaction rates for the oxidative addition to 1 in various solvents.
Pseudo 1st order
Equiv.
Reagent
Solvent
rate constant kobs
Reagent[a]
1
[s
]
H2O
H2O
15
15
C5D5N
no reaction
(8 ± 2)×10−6
THF-d8
H2O
+ 15 eq. C5H5N
15
THF-d8
(5 ± 1)×10−7
Figure 4. Solid state structure of 2PhOH. Ellipsoids are shown at the 50% pro-
bability level, solvent molecules, hydrogen atoms except the one connected to
C1 and the hydroxyl group are omitted for clarity. Selected bond lengths [Å],
angles [°] and dihedral angles [°]: Pd1–C1 2.026(2), Pd1–O1 2.0586(8), N2-
Pd1-C1 83.28(4), N2-Pd1-O1 177.08(4), O1-Pd1-C1-N1 66.69(6).
H2O[b]
H2O
15
2
C6D6
(6 ± 5)×10−5
(9 ± 3)×10−8
(2 ± 2)×10−6
(9 ± 4)×10−7
(5 ± 3)×10−5
(6 ± 4)×10−4
(2 ± 1)×10−3
(9 ± 3)×10−4
THF-d8
C6D6
H2O[c]
iPrOH[d]
2
Intriguingly, following the formation of 2PhOH in deuterated
15
15
2
THF-d8
THF-d8
C5D5N
C5D5N
C5D5N
1
pyridine by H NMR spectroscopic analysis (Fig. 5, Figs. S13,
[d]
PhNH2
S14) revealed a signal of low intensity at −14.93 ppm (≈ 20%
relative to 2PhOH at 10% conversion). This signal, which is in the
common range for palladium hydrides,[26] disappeared over the
course of the reaction. An analogous signal (−13.72 ppm in
THF-d8) was observed in the reaction with aniline (see Fig. S15),
but not with water.
PhOH
HFIP
PhCl
2
2
3
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Figure 5. A palladium hydrido complex is the intermediate for the formation of
2PhOH from 1. Integration is given in relation to reaction product 2PhOH
prior to addition of phenol; green, 10% conversion; red, 35% conversion, pink,
55% conversion; yellow, 100% conversion. See Figs. S13–15 for the entire
spectra and the reaction with aniline.
; blue,
Scheme 4. Water catalyzes the oxidative addition of 4-tert-butylphenyl acety-
lene and solid state structures of 4 and 2HCCAr
. Ellipsoids are shown at the
50% probability level, solvent molecules and hydrogen atoms are omitted for
clarity, except for 4: connected to C37 and 2HCCAr: connected to C1. Selected
bond lengths [Å], angles [°] and dihedral angles [°] 4: Pd1–N2 2.258(4), Pd1–
C1 1.987(4), Pd1–C38 2.050(4), Pd1–C37 1.999(4), C1-Pd1-N2 76.0(2), C38-
Pd1-C37 36.7(2); 2HCCAr Pd1–C1 2.018(2), Pd1–N2 2.050(2), Pd1–C37
1.987(2), C1-Pd1-N2 82.63(7), C37-Pd1-C1 98.17(8), C37-Pd1-N2 172.63(8).
We suggest that these signals relate to the fleeting
intermediates 2(H)(OPh) and 2(H)(HNPh), respectively (vide infra).[26]
Eventually, despite the comparably high acidity of terminal
acetylenes, the reaction with 4-tert-butylphenylacetylene did not
give the oxidative addition product, but instead the π-complex 4
(Scheme 4, left). However, the reaction of dimer2H2O with 4-tert-
butylphenyl acetylene (Scheme 4, right) afforded cleanly 2HCCAr
in analogy to Hartwig’s deprotonation of anilines (cf. Scheme
1).[4] This reaction sequence reveals that water mediates the
formal oxidative addition of a weak C‒H bond.
We modeled the reactions in silico in order to further elucidate
the mechanism (Scheme 5, black).[27] The first elementary step
is the substitution of the pyridino- by an aqua ligand (G =
+29 kJ mol−1; G‡ = +62 kJ mol−1). Subsequent oxidative addi-
tion to 1H2O involving two molecules of water (G‡ = +108 kJ
mol−1) is the rate determining transition state. The (hydri-
do)(hydroxo) complex 2(H)(OH) (G = +20 kJ mol−1) was predicted
to be kinetically unstable and to give 2H2O (G = −6 kJ mol−1;
G‡ = +99 kJ mol−1) via migration of the hydride to the carbene.
Numerous further reaction pathways (Scheme 5, Figs. S67,
S68), including oxidative addition involving only one molecule of
water (G‡ = +121 kJ mol−1), an assisting molecule of pyridine
(G‡ = +114 kJ mol−1) and two molecules of water in an 1,2-
addition mechanism across the carbene‒metal bond (G‡ =
+131 kJ mol−1) are less favorable. Eventually, note that the di-
merization 2H2O further shifts the equilibrium towards the product
side (Fig. S69). The calculations confirm (Fig. S70) that the re-
action proceeds with a lower barrier in benzene (G‡ = +106
kJ mol−1; G = −3 kJ mol−1) than in tetrahydrofuran (G‡ = +108
kJ mol−1; G = −6 kJ mol−1, vide supra). Contrarily, it is pre-
dicted to proceed endergonic (G‡ = +25 kJ mol−1) in pyridine
with a very high activation energy (G‡ = +139 kJ mol−1). The
computational results for the oxidative addition of phenol
(Scheme 5, purple) are likewise in excellent agreement with the
experiment.
Scheme 5. Most favorable[28] reaction profile for the activation of water (black) and phenol (purple) in tetrahydrofuran (PBE0-D3BJ(THF)/def2-TZVPP//PBE0-
D3BJ/def2-SVP). For aniline, other solvents (pyridine, benzene), and further details, see Figs. S62–71 and Tables S9–12.
4
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They corroborate (I.) a very fast reaction at room temperature
and (II.) the spectroscopic capture of the fleeting (hydri-
do)(phenolato) intermediate 2(H)(OPh) (G = −16 kJ mol−1; G‡ =
+89 kJ mol−1 and +58 kJ mol−1, respectively). In further agree-
ment with the experiment a fairly similar barrier of G‡ = +70 kJ
mol−1 is calculated for the oxidative addition of chlorobenzene
(G = −127 kJ mol−1; Fig. S77). A closer look at the structural
parameters of the rate determining transition state ts1H2O–2(H)(OH)
suggests that the hemilabile imino ligand[29] provides only mo-
derate stabilization to the transition state (Pd–N: 2.46 Å; Fig. 6)
and rather “traps” the final oxidative addition product through
coordination to give a square planar palladium(II) complex.[30]
The calculations confirm that direct dihydrogen generation from
2(HCl)+ is not feasible (G‡ = +139 kJ mol−1). Contrarily, the -
hydride elimination to give 2(H)(HCl)+ is very facile (G‡ = +84 kJ
mol−1 G = +2 kJ mol−1) even at room temperature. The subse-
quent dihydrogen release proceeds essentially barrierless
(G‡ = +7 kJ mol−1 G = −44 kJ mol−1). We again conclude that
the intermediate palladium hydride is key for the dihydrogen
generation.
Encouraged by the facile and reversible oxidative addition of va-
rious reagents to 1, we evaluated a series of desirable catalytic
transformations: In order to demonstrate reversible hydride
transfer as required for reduction chemistry and hydrogen sto-
rage, we studied the transfer hydrogenation of acetophenone in
isopropanol (Scheme 7). This reaction, which typically requires
the addition of co-reagents such as a base, is of course very
well established for the group 9 metals. It proceeds there via
metal hydrides, but examples for group 10 elements are scar-
ce.[31] Indeed, complex 1 readily catalyzed the reduction of ace-
tophenone under mild reaction conditions (0.5 mol% 1, 65 °C,
6 h: 75%; 22 h: 90% conversion) without the addition of further
co-reagents, whereas no conversion was obtained in blind reac-
tions (a) without complex 1, (b) with only the ligand or (c) in
Figure 6. Structural parameters of the rate determining transition state ts1H2O
2(H)(OH). Calculated bond lengths are given in [Å].
–
1
presence of 5 mol% NaOH. Intriguingly, the H NMR spectros-
copic analysis revealed that 2iPrOH is the resting state of the cata-
lyst (Fig. S36).
This suggests that the oxidative addition of water should
proceed with slightly slower kinetics for “conventional” NHCs
and CAACs. Hence and in order to quantify the effect of the
hemilabile imino group on the kinetics, the related transition
states for the NHC with two diisopropylphenyl substituents (IPr)
as well as a CAAC with two methyl groups adjacent to the
carbene atom (CAACMe) were calculated. The reaction barrier
for the water activation in tetrahydrofuran was predicted to be
G‡ = +128 kJ mol−1 (G‡ = +121 kJ mol−1 in benzene) for the
NHC and G‡ = +126 kJ mol−1 (G‡ = +119 kJ mol−1 in benzene)
for the CAAC complex (see Figs. S72, S73). These values
suggest that the activation of water by the PEPPSITM system
might require gentle heating or a higher water concentration at
room temperature. Eventually, we validated the mechanism for
the formation of dihydrogen after the addition of acids, i.e. the
protonation of dimer2HCl (Scheme 6).
Scheme 7. Catalytic transfer hydrogenation of acetophenone in isopropanol.
For further details see Table S2 and Figs. S35–37.
Amides are typically synthesized from activated carboxylic acid
derivatives or in the presence of an over-stoichiometric amount
of a strong base.[32] The cross coupling of esters with amines is
challenging and was only realized for palladium and nickel NHC
complexes under harsh reaction conditions (Pd: 3 mol% cat.,
1.5 eq. K2CO3, 110 °C, 16 h; Pd-PEPPSI[33] and [Pd(IPr)(acac)
Cl][34] similar conditions; Ni: 15 mol% cat., 1.25 eq. Al(OtBu)3,
60 °C, 12 h).[35] Just recently, a protocol using milder conditions
(Pd: 1 mol% cat., 2 eq. Cs2CO3, 40 °C, 4 h) was found.[36] We
hypothesized that the facile oxidative addition of the N‒H bond
of aniline should allow for the amidation of an ester under mild
conditions even without additives. Indeed, we observed the
formation of N-phenylacetamide 5 in 85% crude yield after 48 h
reaction time at only 66 °C (1 h: 33%; 24 h: 80%; Table 2).
Table 2. Catalytic cross coupling of ester with aniline. For further related
catalytic results, see Tables S3–6 and Figs. S38, S39.
Reaction Time [h]
Modification
Crude Yield
(Isolated Yield) [%]
Scheme 6. Dihydrogen evolution with acids proceeds in tetrahydrofuran via a
palladium hydride (PBE0-D3BJ(THF)/def2-TZVPP//PBE0-D3BJ/def2-SVP).
See Figs. S74, S75 for less favorable isomers of 3+ and transition states.
5
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RESEARCH ARTICLE
shuts down the palladium(0) pathway, mediates the formation of
1
-
-
-
33
2HCCAr and consequently switches the chemoselectivity.
24
80
48
85 (84)
97 (96)
24 + 24
Addition of 0.3 eq. KOtBu
after 24 h
24 h
absence of 1
0
No conversion was observed in the absence of 1. Of course,
this reaction also showed product inhibition due to the liberation
of phenol and subsequent oxidative addition to 1. Accordingly,
the equilibrium of the reaction could be further shifted by
addition of 0.3 eq. of potassium tert-butoxide (KOtBu), i.e. de-
protonation of 0.3 eq. of phenol (97% crude yield). The direct
formation of mixed borate esters from alcohols and bis(pina-
colato)diboron (B2Pin2) is equally challenging, because it
involves the oxidative addition of either a strong O‒H or B‒B
bond.[37] However, metal alkoxides react readily with B2Pin2.[38]
Indeed, 0.5 mol% of 1 allowed for the unprecedented and
quantitative conversion of B2Pin2 and phenol, aniline, tert-buta-
nol, tert-butylamine, n-octanol and n-octylamine to dihydrogen
and the respective (amino-)borates 6ER. All reactions proceeded
at room temperature, with e.g. 20% conversion for phenol within
1 h, and achieved quantitative conversion at 50 °C within less
than 2.5 h (Table 3, Figs. S40–53). Of course, no turnover was
obtained in the absence of 1 or the presence of the ligand only.
Scheme 8. A: Catalytic dimerization (head to head, E) of terminal acetylene
under dry conditions. B: Catalytic polymerization of terminal acetylene.
Conclusion
We report the facile oxidative addition of N‒H and O‒H bonds,
including water and aniline, to a palladium(0) complex to give re-
active palladium(II) hydrides. The bond activation proceeds via
a cyclic transition state featuring two substrate molecules and
parallels mechanistically an intramolecular deprotonation.
These reactions are reversible at room temperature with rate
constants similar to the oxidative addition of chlorobenzene.
The investigated complex, a surrogate of the elusive 12-electron
intermediate in palladium catalysis, resembles the alleged active
species of pervasive N-heterocyclic carbene (NHC) palladium(II)
precatalysts. The introduction of a hemilabile imino group allows
to trap otherwise transient intermediates and hence suggests
that the homolytic activation of strong N‒H and O‒H bonds
might be as well of relevance for other palladium catalytic sys-
tems with more common ligands. The catalytic transfer hydro-
genation of secondary alcohols illustrates additive-free and re-
versible hydrogen transfer chemistry. Indeed, the complex also
catalyzes the challenging direct borylation of alcohols and
amines with bis(pinacolato)diboron under release of dihydrogen
and the cross coupling of an ester with aniline. All these reac-
tions proceed under mild reaction conditions and without the
addition of co-reagents such as a base. Eventually, we elucida-
te the effect of protic solvents or reagents on the functionali-
zation of a terminal alkyne. We find that water catalyzes the
formal oxidative addition of the terminal C‒H bond, which then
switches the chemoselectivity from hydroalkynylation to alkyne
polymerization.
Table 3. Catalytic borylation of alcohols and amines by B2Pin2.
Time
[h]
Temp.
[°C]
Crude Yield
[%]
E
R
O
Ph
1.5
2.5
1
50
50
50
50
rt
> 99
> 99
> 99
> 99
> 99
> 99
NH
O
Ph
tBu
NH
O
tBu
1
n-oct.
n-oct.
1
Overall, this work discloses the oxidative addition of O‒H and
N‒H bonds as a synthetic strategy in palladium chemistry, illus-
trates cyclic (alkyl)(amino)carbene (CAAC) ligand cooperativity
with a hydrogen atom, outlines how to achieve efficient catalysis
in absence of additives, and describes the non-innocence of ad-
ventitious water for the activation of a weak C‒H bond.
NH
1
rt
We eventually explored the catalytic valorization of 4-tert-butyl-
phenyl acetylene in order to expose the oxidative addition of ad-
ventitious water in palladium catalysis. Palladium(II) catalysts
with a vacant coordination site polymerize terminal alkynes,[39]
whereas Pd0/PdII catalytic cycles were proposed for the dimer-
ization to enynes.[40] Indeed, 1 catalyzes the selfhydroalkynyla-
tion to dimer 7 in 78% crude yield (isolated yield: 65%) under
dry conditions (Scheme 8, A; Figs. S54–56). Conversely, using
the same reaction conditions except for the addition of varying
amounts of water (1 – 100 equivalents) gave quantitatively
trans-cisoidal poly(arylacetylene) 8 (Scheme 8, B; Figs. S57–58
and Table S7). Catalytic amounts of either dimer2H2O or 2HCCAr
afforded the polymer as well. Apparently, and as supported by
the computations (Fig. S76), the oxidative addition of water
Acknowledgements
We thank the Fonds der Chemischen Industrie (Liebig fellowship
for D.M.) as well as the Bavarian Equal Opportunities Sponsor-
ship – Realization of Equal Opportunities for Women in Re-
search and Teaching (A.G.) for financial support. We thank the
RRZ Erlangen for computational resources. Support by K.
Meyer is gratefully acknowledged. We also thank Ro. Dorta, S.
Harder, M. Driess as well as S. Schneider for helpful discussions.
6
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10.1002/anie.202008350
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RESEARCH ARTICLE
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Conflict of interest
The authors declare no conflict of interest.
Keywords: bond activation • hydride • oxidative addition •
palladium • hydrogen • catalysis • cross coupling • aniline • N-
heterocyclic carbene NHC• DFT
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7
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RESEARCH ARTICLE
Entry for the Table of Contents
The oxidative addition of OH, NH and weak CH bonds to a palladium(0) complex is facile, allows for additive-free catalysis and
suggests non-innocence of adventitious water in palladium catalysis.
Institute and/or researcher Twitter usernames: @MunzDominik
8
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