Mechanistic Studies of Palladium-Catalyzed Aminocarbonylation of Aryl Chlorides with Carbon Monoxide and Ammonia

Article abstract of DOI:10.1021/jacs.8b04073

Mechanistic information on a reliable, palladium-catalyzed aminocarbonylation of aryl chlorides with ammonia is reported. The reaction occurs with ethylene complex 1 as catalyst, and mechanistic information was gained by isolation of catalytic intermediates and kinetic measurements, including the first mechanistic data on the oxidative addition of aryl chloride to a palladium(0) complex in the presence of CO. Arylpalladium and phenacylpalladium halide intermediates were synthesized, and kinetic measurements of the formation and reactions of these intermediates were undertaken to determine the mechanism of the oxidative addition of aryl bromides and chlorides to a Pd(0) dicarbonyl compound in the presence of CO and the mechanism of the reaction of ammonia with a Pd(II) phenacyl complex to form benzamide. The oxidative addition of aryl chlorides and aryl bromides was determined to occur with rate-limiting reaction of the haloarene with a three-coordinate Pd(0) species bearing a bidentate phosphine and one CO ligand. A primary ¹³C kinetic isotope effect suggested that this step involves cleavage of the carbon-halogen bond. Our data show that the formation of benzamide from the reaction of phenacylpalladium halide complexes with ammonia occurs by a pathway involving reversible displacement of chloride from a phenacylpalladium chloride complex by ammonia, deprotonation of the bound ammonia to form a phenacylpalladium amido complex, and reductive elimination to form the C-N bond. Consistent with this mechanism, the reaction of an aryl palladium amido complex with CO formed the corresponding primary benzamide. A catalyst deactivation pathway involving the formation of a Pd(I) dimer also was elucidated.

Full text of DOI:10.1021/jacs.8b04073

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Article
Mechanistic Studies of Palladium-Catalyzed Aminocarbonylation
of Aryl Chlorides with Carbon Monoxide and Ammonia
Justin Y. Wang, Alexandra E. Strom, and John F. Hartwig
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b04073 • Publication Date (Web): 31 May 2018
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Mechanistic Studies of Palladium-Catalyzed Aminocarbonylation of Aryl Chlorides with Carbon
Monoxide and Ammonia
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Justin Y. Wang,† Alexandra E. Strom,† and John F. Hartwig†‡
†Department of Chemistry, University of California, Berkeley, California 94720, United States
‡Chemical Sciences Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, CA 94720,
USA
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Abstract
Mechanistic information on a reliable, palladium-catalyzed aminocarbonylation of aryl chlorides
with ammonia is reported. The reaction occurs with ethylene complex 1 as catalyst, and mechanistic
information was gained by isolation of catalytic intermediates and kinetic measurements, including the
first mechanistic data on the oxidative addition of aryl chloride to a palladium(0) complex in the presence
of CO. Arylpalladium and phenacylpalladium halide intermediates were synthesized and kinetic
measurements of the formation and reactions of these intermediates were undertaken to determine the
mechanism of the oxidative addition of aryl bromides and chlorides to a Pd(0) dicarbonyl compound in
the presence of CO and the mechanism of the reaction of ammonia with a Pd(II) phenacyl complex to
form benzamide. The oxidative addition of aryl chlorides and aryl bromides was determined to occur with
rate-limiting reaction of the haloarene with a three-coordinate Pd(0) species bearing a bidentate phosphine
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and one CO ligand. A primary C kinetic isotope effect suggested that this step involves cleavage of the
carbon-halogen bond. Our data show that the formation of benzamide from the reaction of
phenacylpalladium halide complexes with ammonia occurs by a pathway involving reversible
displacement of chloride from a phenacylpalladium chloride complex, deprotonation of the bound
ammonia to form a phenacylpalladium amido complex, and reductive elimination to form the C-N bond.
Consistent with this mechanism, the reaction of an aryl palladium amido complex with CO formed the
corresponding primary benzamide. A catalyst deactivation pathway involving the formation of a Pd(I)
dimer was also elucidated.
Introduction
Palladium-catalyzed carbonylation reactions of aryl halides and pseudohalides furnish aromatic
ketones,1 aldehydes,2 amides,3 esters,4 and other carboxylic acid derivatives.5 These processes have been
used in industry to create pharmaceuticals, agrochemicals, and dyes.6 For example, lazabemide, a
monoamine oxidase B inhibitor, was prepared in one-step by the palladium-catalyzed aminocarbonylation
of 2,5-dichloropyridine.7 An intermediate in the synthesis of a GPIIb/IIa receptor antagonist was also
synthesized by palladium-catalyzed aminocarbonylation of a highly functionalized aryl iodide on a 40 kg
scale.8 Finally, the reductive carbonylation of aryl halides with a palladium catalyst has been conducted
industrially on a >100 kg scale.9
Despite the broad scope and utility of palladium-catalyzed carbonylations of aryl halides, most of
the steps of these reactions are poorly defined (Figure 1).10 The migratory insertion of CO into square
planar arylpalladium halide complexes is fast and has been proposed to occur via a five-coordinate
intermediate,11 but few studies on the mechanism for oxidative addition of aryl halides in the presence of
CO have been reported,10b few studies on the reactions of amines with acylpalladium complexes have
been published,12 and no examples of the reactions of ammonia with acylpalladium complexes have been
described. Pd(0) carbonyl complexes have been proposed as intermediates when reactions are conducted
in the presence of carbon monoxide, but often, such compounds containing ligands used for these
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carbonylation reactions have not been isolated, and examples of the reactions of Pd(0) carbonyl
complexes with aryl halides are limited.13, 14 The mechanism of oxidative addition of aryl halides in the
presence of CO has been proposed to be distinct from the mechanism of oxidative addition of the same
aryl halide during palladium-catalyzed coupling in the absence of CO. This difference results from the
unproductive equilibria between active Pd(0) complexes lacking CO and inactive Pd(0) carbonyl adducts
or clusters.10a, 13a Although bidentate phosphines often have been used as ancillary ligands to discourage
aggregation of Pd(0) compounds, monomeric Pd(0) complexes of these ligands in the presence of CO can
contain one or two CO ligands, and they can associate to form bimetallic dimers containing a bridging CO
moiety.15 It is unclear which of these compounds undergo oxidative addition of the aryl halide. In one of
the few studies on the oxidative additions of aryl halides to Pd(0)-carbonyl complexes, Grushin conducted
the oxidative addition of aryl iodides to (Xantphos)Pd(CO)210b to form a phenacyl Pd(II) iodide complex.
However, experimental studies to reveal the Pd(0) species that reacts with the aryl halide were not
reported; the mechanism of this oxidative addition was only explored computationally.
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Figure 1. Simplified catalytic cycle for the aminocarbonylation of aryl halides with Pd and ammonia.
Data on the mechanism of the catalytic carbonylation of aryl chlorides and data on the oxidative
addition of aryl chlorides to Pd(0) in the presence of CO are particularly scarce.6a Catalytic carbonylations
of aryl chlorides are attractive because aryl chlorides are more commercially available and less expensive
than other aryl halides.16 However, the oxidative addition of aryl chlorides to Pd(0) in the presence of CO
and the overall carbonylation of aryl chlorides is likely to be slow because the oxidative addition of aryl
chlorides occurs most rapidly with low-coordinate, electron-rich Pd(0) species and the binding of CO
makes the electron density lower and the coordination number higher than those in homoleptic Pd(0)
phosphine complexes.6a, 17 Indeed, many methods for the carbonylation of aryl or heteroaryl chlorides
require high temperatures (≥ 100 °C),13a, 18 presumably to cause dissociation of CO from Pd(0) or
separation of Pd(0) carbonyl clusters. Thus, an improved understanding of the identity of the palladium
complex that reacts with the aryl chloride could enable the discovery of new carbonylations and catalysts
that induce milder carbonylations of aryl chlorides.
In addition to the ambiguity about the mechanism of the oxidative addition of aryl halides to
Pd(0) in the presence of CO, the mechanism of the reaction of acylpalladium complexes with
nucleophiles is unclear. The mechanism of the reaction of phenacylpalladium complexes with alcohols to
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generate phenyl esters has been examined,19 but few studies of the analogous reactions with amines have
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been conducted.12,
Alcohols are typically more acidic than amines; therefore, alkoxides can be
generated in situ during catalysis under basic conditions, and either the alcohol or the alkoxide could
serve as coupling partners. In contrast, anionic amides are unlikely to be generated. Moreover, the
coordinating ability and nucleophilicity of alcohols and alkoxides is much different from that of amines,
leading to differences between the mechanism for the reaction of acyl complexes with oxygen-based
nucleophiles and the mechanism for reactions with nitrogen-based nucleophiles. For example, the
formation of phenyl esters from trans-(PPh3)2Pd(COPh)I was suggested by Yamamoto to involve
displacement of PPh3 by an alcohol.20 Upon deprotonation of the bound alcohol and extrusion of iodide,
(PPh3)Pd(COPh)(OR) underwent reductive elimination of an ester. In contrast, the formation of
benzamide was proposed to occur by substitution of iodide from trans-(PPh2Me)2Pd(Ar)I by CO to
generate a cationic Pd(II) carbonyl species, nucleophilic attack of amine on the bound CO, deprotonation
of the ammonium nitrogen to form an arylpalladium carbamoyl complex, and reductive elimination of
benzamide by formation of a carbon-carbon bond.13b The difference between the mechanisms proposed to
be followed with an alcohol and amine and the required displacement of phosphine and iodide for these
paths make it even less clear how the aminocarbonylation of an aryl chloride with a catalyst containing a
bidentate ligand and ammonia as nucleophile would occur (Figure 1).
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The synthesis of primary benzamides by palladium-catalyzed carbonylation of aryl halides with
ammonia is one of the least explored versions of carbonylative couplings.18e, 21 Palladium-catalyzed
carbonylation reactions to form primary benzamides are typically conducted with ammonia surrogates,
followed by deprotection.22 While procedures involving ammonia or ammonium salts to generate primary
benzamides exist, they are limited in number.23 Reactions to form primary amides with ammonia may be
particularly difficult to achieve, due to the low nucleophilicity of ammonia,24 the slow reductive
elimination from Pd(II) complexes containing unsubstituted amido groups (i.e. -NH2),25 and the tendency
of ammonia to poison transition metal catalysts.26 Thus, the challenge of achieving the
aminocarbonylation of aryl halides directly with ammonia prompted us to identify a system that catalyzes
the aminocarbonylation of aryl halides with ammonia as the nucleophile.
Herein, we report the aminocarbonylation of aryl chlorides with ammonia to form primary
benzamides catalyzed by a Pd(0) complex of 1,3-(dicyclohexylphosphino)propane (DCPP) and describe
detailed mechanistic studies of the reaction. A series of intermediates in the catalytic cycle were prepared
independently and demonstrated to be competent reaction intermediates. Aryl chlorides and bromides
were shown to react with a three-coordinate Pd(0) complex bearing a bidentate phosphine and a carbonyl
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ligand generated by dissociation of CO from the more stable dicarbonyl complex. A primary C kinetic
isotope effect and a Hammett analysis of the effect of the electronic properties of aryl chlorides showed
that the reaction of the chloroarene with the palladium complex is irreversible, involves cleavage of the
carbon-halogen bond, and occurs by the same concerted, non-ionic C–Cl cleavage as occurs for oxidative
addition of aryl halides to lower-coordinate Pd(0) species. Our data show that benzamide forms from the
resulting phenacylpalladium chloride intermediate by an inner-sphere pathway during which ammonia
displaces chloride from a phenacylpalladium chloride complex to generate a cationic Pd(II) ammine
complex. This ammine complex undergoes deprotonation to furnish a phenacyl Pd(II) amido complex,
which reductively eliminates benzamide. Overall, the rate-limiting step of the aminocarbonylation of aryl
chlorides with ammonia was found to be the oxidative addition of an aryl chloride to Pd(0). Finally, a
catalyst deactivation pathway involving the protonation of a dicarbonyl Pd(0) complex ligated by DCPP
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with NH4Cl to produce a cationic, dimeric Pd(I) complex was revealed. Thus, our studies provide a rare
experimental foundation for deducing the full mechanism of a palladium-catalyzed carbonylation process
and provides the first data on the individual steps for valuable carbonylations of aryl chlorides with
ammonia.
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Results and Discussion
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Identification of a Reaction System for Studies on the Mechanism of Aminocarbonylation of Aryl
Chlorides with Ammonia.
Table 1. Effect of reaction conditions on the aminocarbonylation of p-chlorotoluene.a
NH3 Source
Entry
[Pd] (mol%)
(DCPP)Pd(OAc)2 (2)
Pd(OAc)2, (2.5)
Pd(OAc)2, (2.5)
1 (2.5)
L (mol%)
Solvent T (°C) Yield (%)c
(equiv)
1b
2
-
DCPP·2HBF4 (5)
DCPP (5)
-
NH4Cl (1.1) NMP
120
120
120
110
0
NH3 (4)
NH3 (4)
NH3 (4)
DMSO
DMSO
DMSO
50
80
91
3
4
aReaction conditions: p-chlorotoluene (0.4 mmol), CO (450 Torr), K2CO3 (3 equiv), 0.5 mL solvent, 24 h,
25 mL Schlenk bomb. b760 Torr of CO. cDetermined by NMR spectroscopy.
We chose to study the mechanism of palladium-catalyzed carbonylative couplings of
chloroarenes with ammonia as the nucleophile because of the simplicity of these reagents and the
synthetic value of the formation of primary benzamides. However, identifying a suitable system for
mechanistic studies was not straightforward. Buchwald published aminocarbonylations of aryl halides
with primary and secondary amines catalyzed by Pd(OAc)2 and DCPP (1,3-
bis(dicyclohexylphosphino)propane), but they showed that these reactions occur by
phenoxycarbonylation of the aryl halide with the phenoxide base to form phenyl esters, which
subsequently react with amines to form amides. Thus, the catalytic process was not an
aminocarbonylation, and the insolubility of the phenoxide base would complicate mechanistic studies.
Beller published the aminocarbonylations of aryl bromides with ammonia, but the analogous reactions of
aryl chlorides, particularly those of electron-neutral aryl chlorides, occurred in low yield.18e, 21 Barnard
published the most striking system for the aminocarbonylation of chloroarenes with ammonium chloride
in a review. The reaction was reported to occur with 1 bar of CO at 100-120 °C with a catalyst generated
from Pd(OAc)2 and DCPP.23a The scope of the reaction in the review was limited to two examples of aryl
chlorides, but the work by Buchwald suggested that (DCPP)Pd(0) complexes could catalyze the
carbonylation of electron-rich and electron-poor aryl chlorides in the presence of 1 atm of CO.3c DCPP is
similar to the 1,3-bis(diisopropyphosphino)propane ligand in some of the earliest publications by Milstein
on palladium-catalyzed alkoxy and amino carbonylations of aryl chlorides with CO.13a
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Thus, we conducted studies to assess the scope of the aminocarbonylation of chloroarenes with
ammonia catalyzed by DCPP complexes of palladium. We conducted initial studies on the reaction of p-
chlorotoluene in the presence of ammonia or ammonium salts and low pressures of CO (Table 1)
published by Barnard. The conditions for reactions of ammonium chloride did not form p-toluamide
(Table 1, entry 1) in our hands, but reactions with gaseous ammonia afforded a measurable yield of the
benzamide (entry 2). Reactions with a catalyst generated from the free base of DCPP (entry 3) formed p-
toluamide in higher yields than those initiated with the HBF4 salt of DCPP (entry 2). Ultimately, we
found that reactions catalyzed by the ethylene complex 1 shown in Scheme 1 occurred in a high 91%
yield (entry 4), even at 110 °C instead of 120 °C, with 450 Torr of CO.
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Scheme 1. Synthesis of (DCPP)Pd(C2H4) (1) from Pd[P(tBu)3]2.
Ethylene complex 1 was synthesized by bubbling ethylene through a solution of Pd[P(tBu3)]2 and
DCPP. Complex 1 was characterized by NMR spectroscopy, elemental analysis, and X-ray
crystallography (see Supporting Information). We used complex 1 as a catalyst precursor because Bunel
and Pörschke previously showed that the addition of CO to structurally analogous Pd ethylene complexes
bearing bidentate phosphines rapidly formed (bisphosphine)Pd(CO)2 complexes.27 By starting with the
ethylene complex, the carbonylation reactions would occur without induction periods that could result
from reduction of Pd(II) to Pd(0).
A summary of our assessment of the scope of the aminocarbonylation is shown in Table 1. With
2.5 mol% of ethylene complex 1 as a precatalyst, 450 Torr of CO, and 4 equiv of ammonia,
chlorobenzene (2a) formed benzamide (3a) in 83% yield. Electronically deactivated aryl chlorides 2b-d
underwent the aminocarbonylation process in good yields (75-89%). The sterically hindered and electron-
rich aryl chloride 2e underwent carbonylation, in a lower, but acceptable, yield of 62%. Reactions with
electron-poor aryl chlorides 2f-j afforded the corresponding benzamides 3f-j in 60-100% yields, showing
the compatibility of the reaction with a bulky ester (2h), cyano group (2i), and extended π systems (2j).
Reactions with the heteroaryl chlorides 3-chloropyridine (2k) and 2-chlorothiophene (2i) generated the
corresponding heteroaromatic benzamides 3k and 3l in 77% yield and 69% yield, respectively. Thus,
complex 1 catalyzes the aminocarbonylation of a broad set of aryl chlorides with ammonia, and
mechanistic studies on this system, therefore, would involve a system that is synthetically valuable.
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Table 2. Scope of palladium-catalyzed aminocarbonylation of aryl chlorides with ammonia.a
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aReactions were performed in a 25 mL Schlenk vessel on a 0.4 mmol scale in 0.5 mL of solvent, and
yields are reported as isolated yields.
Identification of Pd(0) Carbonyl Adducts
To initiate our studies on the mechanism of the aminocarbonylation of chloroarenes with
ammonia, we prepared the Pd(0) carbonyl compound ligated by DCPP. The stable carbonyl complex that
would be present in the catalytic system was generated by the addition of 1000 Torr of CO to ethylene
complex 1. The dicarbonyl compound (DCPP)Pd(CO)2 (4) was generated within 5 minutes in 98% yield.
The 31P NMR spectrum consisted of a singlet resonance at 20.8 ppm, and the 13C NMR spectrum
consisted of a broad resonance at 196.7 ppm for a carbonyl ligand. To determine the number and bonding
mode of CO ligands bound to 4 under conditions relevant to the catalytic process, we measured solution-
phase IR spectra of the (DCPP)Pd(0) carbonyl compound generated from 1 under 760 Torr of CO in a
mixture of DMSO and toluene (1:1 v/v).28 Two C–O stretches were observed at 1993 and 1949 cm-1 (see
Supporting Information), which is consistent with the formulation of the Pd(0) species as a tetrahedral
complex with C2v symmetry containing two terminal carbonyl ligands. The solid-state structure of Pd(0)
complex 4 was determined by X-ray crystallography (Figure 2). In the solid state, this complex displays a
distorted tetrahedral geometry in which the propyl backbone of DCPP constrains the P1-Pd1-P2 angle to
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98.84(3)° and the C1-Pd1-C2 angle is 110.98(6)°. The C1–O1 and C2–O2 bond distances (1.132(5) and
1.147(5) Å, respectively) are indicative of metal-to-ligand π-backbonding and are similar to those of other
previously reported mononuclear Pd(0) complexes containing terminal CO ligands.10b, 27a, 29 Dicarbonyl
compound 4, as a solid or in solution, is only briefly stable in the absence of CO.
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Scheme 2. Synthesis of (DCPP)Pd(CO)2 (4) from ethylene complex 1.
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aYield determined by 31P NMR spectroscopy with PMes3 as an internal standard.
To evaluate if dicarbonyl 4 remains intact at elevated temperatures, solution-IR spectra were
obtained at 75 °C under 760 Torr of CO in a variable temperature IR cell. Two stretches at 1993 and 1949
cm-1 were detected, indicating that the Pd(0) complex retains both carbonyl ligands at elevated
temperatures. To determine if the speciation of (DCPP)Pd(0) carbonyl compounds is dependent on CO
pressure, the headspace of a solution of 4 was briefly flushed with nitrogen. The solution-IR spectrum of
an aliquot of this solution contained the same two C–O stretches at 1993 and 1949 cm-1 at room
temperature and stretches at 1994 and 1948 cm-1 at 75 °C (see Supporting Information). Thus, at both one
atmosphere of CO and low pressures of CO, dicarbonyl compound 4 was the sole carbonyl compound
observed.
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Figure 2. Solid state structure of (DCPP)Pd(CO)2 (4) with ellipsoids set at 1:1. Selected bond lengths (Å):
P1-Pd1 2.3799(6), Pd1-C1 1.961(4), Pd1-C2 1.944(4), C1-O1 1.132(5), C2-O2 1.147(5). Selected bond
angles (°): P1-Pd-P2 98.84(3), C1-Pd1-P1 110.98(6), C1-Pd1-P2 110.98(6), C1-Pd1-C2 113.83(16).
Figure 3: Variable temperature 13C and 31P NMR spectra of 4 under 600 Torr of 13CO in toluene-d8.
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To complement the IR spectral data, NMR spectra of dicarbonyl compound 4 were obtained with
600 Torr of 13CO in toluene-d8 (Figure 3). Unfortunately, 31P-13C coupling between bound 13CO and
DCPP was not detected in either 13C or 31P NMR spectra; thus, the number of bound carbonyl ligands to 4
could not be determined by the multiplicity of the resonances observed in the 13C or 31P NMR spectra.30 A
broad resonance at 197 ppm was observed in the 13C NMR spectrum of (DCPP)Pd(CO)2 in toluene-d8 at
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room temperature, and the resonance for unbound CO was absent, indicating rapid exchange between
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bound and unbound CO. The C NMR spectrum at -40 °C contained a sharper resonance at 197 ppm,
and signal consistent with unbound 13CO was observed at 184 ppm at -80 °C. Even at these temperatures,
31P-13C coupling was not observed in either the 13C or 31P NMR spectra. Due to the absence of
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phosphorus-carbon coupling, the number of CO ligands bound to 4 was determined by quantitative C
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13
NMR spectroscopy with CO and an internal C enriched integration standard, 4-phenylanisole. At -40
°C with 1000 Torr of 13CO, the number of CO ligands per palladium was determined to be 2.0. This value
is consistent with the structure of dicarbonyl complex 4.31, 32
Thus, IR and NMR spectroscopy along with X-ray crystallography showed that ethylene complex
1 is converted quantitatively to dicarbonyl complex 4 in the presence of CO. These methods also showed
that complex 4 retains both CO ligands at elevated temperatures and under reduced pressures of CO.
Therefore, we employed (DCPP)Pd(C2H4) (1) as a precursor to (DCPP)Pd(CO)2 (4) for kinetic studies
(vide infra).
Synthesis and Reactivity of Pd(II) Intermediates
To determine if Pd(II) aryl and phenacyl halide complexes bearing DCPP were catalytic
intermediates, we synthesized (DCPP)Pd(II) aryl halide complexes 5a-j and (DCPP)Pd(II) phenacyl
halide complexes 6a-j. Pd(II) aryl halide complexes (5a-j) ligated by DCPP were synthesized by the
reaction of Pd(PtBu3)2 and an aryl halide in the presence of DCPP (Scheme 3). Phenacylpalladium
chloride complexes 6a-b and 6e-f were obtained from the reaction of Pd(PPh3)4 with an acid chloride and
subsequent ligand exchange with DCPP (Scheme 4a), whereas phenacylpalladium halide complexes 6g-i
(Scheme 4b) were generated by carbonylation of (DCPP)Pd(II) aryl halide complexes. Phenacylpalladium
halide complexes (6c and 6d) were also obtained by the reaction of dicarbonyl complex 4 (generated in
situ from 1 and CO) with an aryl chloride or bromide in the presence of CO (Scheme 4c), demonstrating
that 4 or compounds generated from 4 are capable of oxidative addition of aryl chlorides and bromides.
Pd(II) phenacyl complexes 6a-i are stable in solution and as solids and in the presence or absence of CO;
they also do not undergo decarbonylation under vacuum at room temperature.
Scheme 3. Synthesis of Pd(II) aryl halide complexes.
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In contrast to complexes 6a-i, phenacyl Pd(II) compound 6j is only stable in solution in the
presence of a CO atmosphere. Our attempts to isolate this compound resulted in the formation of
decarbonylation product 5j. Thus, characterization of 6j was performed in situ by NMR spectroscopy
under CO. After warming a solution of ethylene compound 1 and 1.5 equiv of 2-methoxy-4-fluoro-
bromobenzene to 80 °C under 800 Torr of CO for 2.5 h, phenacylpalladium complex 6j formed in 53%
yield, and arylpalladium complex 5j formed in 8% yield (Scheme 5). Reaction for an additional 24 h at
room temperature did not fully convert 5j to 6j.
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Scheme 4. Synthesis of Pd(II)phenacyl complexes by oxidative addition or carbonylation.
The reaction of phenacyl complex 6a with excess ammonia in the presence of a soluble and
hindered base, DBU, formed the corresponding primary benzamide in high yield (Scheme 6), indicating
that these acyl complexes are chemically competent to be intermediates in the palladium-catalyzed
aminocarbonylation reactions. Thus, by studying a series of stoichiometric reactions of palladium
complexes, we have provided strong evidence that compounds 5a-j and 6a-j are catalytic intermediates in
palladium-catalyzed aminocarbonylation of aryl chlorides with ammonia.
Scheme 5. Synthesis of Pd(II) phenacyl bromide complex 6j via oxidative addition of the corresponding
aryl halide to in situ generated (DCPP)Pd(CO)2 in the presence of CO.
aYield was determined by 1H NMR spectroscopy with trimethoxybenzene as an internal standard.
Scheme 6. Pd(II) phenacyl chloride compound 6a reductively eliminates in the presence of ammonia to
form a primary benzamide.
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aYield was determined by 1H NMR spectroscopy with trimethoxybenzene as an internal standard.
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The Mechanism of Oxidative Addition of Aryl Chlorides to (DCPP)Pd(CO)2
Scheme 7. Determination of pseudo-first order rate constants kobs from the oxidative addition of 3,5-
difluorochlorobenzene to (DCPP)Pd(CO)2.
The rate constants for the oxidative addition of 3,5-difluorochlorbenzene to (DCPP)Pd(CO)2 (4)
were measured by monitoring the appearance of the sum of the concentrations of arylpalladium halide
complex 5e and phenacylpalladium halide complex 6e under pseudo-first order conditions of excess
haloarene at 100 °C in a mixture of DMSO and toluene (1:1 v/v) (Scheme 7). Because dicarbonyl
compound 4 is stable for only short times in the absence of CO, complex 4 was generated in situ from
ethylene complex 1 prior to rate measurements.33 The dependence of the rate of oxidative addition on CO
pressure was determined to be inverse first order, based on the linear relationship between 1/kobs and CO
pressure (Figure 4a). The dependence of the rate on the concentration of 3,5-difluorochlorobenzene was
determined to be first order based on the linear relationship between 1/kobs and 1/[ArCl] (Figure 4b).
1800
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(b)
(a)
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y = 1.19x + 7.09
R² = 0.991
y = 427x - 31.1
R² = 0.989
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4
1/[ArCl] (M-1)
pCO (Torr)
Figure 4. Dependence of the observed rate constant (kobs) on (a) the pressure of CO (250-1500 Torr) with
ArCl = 0.27 M and (b) the concentration ArCl (0.27-0.68 M) with pCO = 1000 Torr for the oxidative
addition of 3,5-difluoro-chlorobenzene to (DCPP)Pd(CO)2 (28 mM) in 1:1 v/v DMSO and toluene at 85
°C.
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The observation of a first order dependence on the concentration of aryl chloride and an inverse
first order dependence on the pressure of CO is consistent with the mechanisms of oxidative addition
depicted in Figure 5. Path A involves reaction of the arene with the neutral three-coordinate species to
cleave the carbon-halogen bond and form a five-coordinate intermediate that undergoes rapid insertion of
CO into the metal-aryl bond. This mechanism would be the simplest one that is consistent with our data.
However, two alternative pathways are also consistent with the reaction orders. Path B involves the
reaction of an aryl chloride with (κ2-DCPP)Pd(CO) after dissociation of one of the phosphino groups of
the DCPP ligand in (κ2-DCPP)Pd(CO) to form (κ1-DCPP)Pd(CO), followed by oxidative addition. Path C
involves rate-limiting displacement of the CO ligand in (κ2-DCPP)Pd(CO) by the haloarene to form (κ2-
DCPP)Pd(ArX). Carbon-halogen bond cleavage would then occur in this arene complex to form a four-
coordinate, arylpalladium halide complex that would insert CO to form the phenacylpalladium halide
species. Paths B and C occur without formation of a five-coordinate addition product from a neutral,
three-coordinate Pd(0) complex.
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We differentiated between these oxidative addition pathways for reactions of aryl chlorides to
(DCPP)Pd(CO) by a combination of 13C kinetic isotope effects (vide infra) and calculations by DFT (see
Supporting Information). Our computational studies strongly suggested that the reaction did not occur by
Path B involving partial dissociation of the bisphosphine ligand. The overall barrier for the oxidative
addition of an aryl chloride to (κ1-DCPP)Pd(CO) was computed to be 15 kcal/mol higher than the
experimental barrier at standard state conditions, and it was calculated to be 12 kcal/mol higher than the
experimental barrier at the temperature and concentrations of the reaction.34 This high barrier for reaction
by path B is consistent with the importance of chelating ligands to observe the carbonylation of aryl
chlorides.3c, 13a, 18b, c In contrast, the difference in energy between the highest-energy transition state – the
transition state for oxidative addition of an aryl chloride – via path A and the computed energy of the
experimentally determined resting state (DCPP)Pd(CO)2 at concentrations close to those of the catalytic
reaction was higher than the experimentally measured barrier by only 4 kcal/mol. The computed barrier
for reaction by path C is ambiguous because we were unable to locate a transition state for the ligand
substitution process, but this computed barrier is likely several kcal/mol lower than the experimental
barrier based on the ground-state energies and transition state for oxidative addition to the (DCPP)Pd
fragment. Although the transition state for carbon-chlorine bond cleavage was located for path C, this
bond cleavage event cannot be rate limiting because our kinetic data show an inverse first order
dependence on pressure of CO. Thus, computation did not clearly show whether the reaction occurs by
path A or C.
13
Instead, reaction by path A or C was distinguished by measuring the C kinetic isotope effect
(KIE) of the reaction of an aryl chloride with the Pd(0) dicarbonyl complex 4. Path A involves irreversible
reaction of the haloarene, followed by carbon-halogen bond cleavage. This addition could occur with or
without initial, reversible formation of an arene complex, but cleavage of the carbon-halogen bond would
occur in the irreversible step. Therefore, this pathway would be expected to occur with a primary kinetic
isotope effect at the carbon ipso to chlorine. In contrast, reaction by pathway C involves irreversible
displacement of CO to form an arene complex; because the irreversible step of the arene does not involve
cleavage of the carbon-chlorine bond, this pathway would not give rise to a primary 13C KIE at the carbon
ipso to chlorine. Thus, the presence or absence of a primary 13C KIE at the carbon ipso to chlorine would
distinguish between these pathways.
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Figure 5. Proposed oxidative addition mechanisms of aryl halides to dicarbonyl compound 4.
Measurement of a 13C KIE for the Oxidative Addition of 4-chloro-N-methylbenzamide to
(DCPP)Pd(CO)2
Scheme 8. Determination of 13C KIE of the oxidative addition of 4-chloro-N-methylbenzamide to 4.
13
The C KIE for the oxidative addition reaction of an aryl chloride to dicarbonyl 4 was obtained
by the NMR spectroscopic method pioneered by Singleton.35 A primary 13C KIE of 1.013(6) was
measured at the carbon ipso to chlorine for the oxidative addition of 4-chloro-N-methylbenzamide to
complex 4 (Scheme 8). The 13C KIEs at the carbonyl carbon was 0.993(8) and for the carbon atoms ortho,
meta and para to chlorine were 0.994(5), 0.998(5), and 0.992(8), respectively. 4-Chloro-N-
methylbenzamide was chosen as the substrate in this study for its ease of isolation and the carbon of the
N-methyl group was used at the standard. This 13C KIE indicates that C-Cl bond cleavage is irreversible.
Thus, our data are inconsistent with reaction by path C and are consistent with oxidative addition of the
aryl chloride to a three-coordinate Pd(0) complex (path A, Figure 5).36 Oxidative addition of an aryl
chloride to a neutral, three-coordinate Pd(0) complex has not been documented previously. It is possible
that the transition state for this oxidative addition reaction could involve concomitant dissociation of CO
from (DCPP)Pd(CO) and cleavage of a C-Cl bond to avoid formation of a five-coordinate product.
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Hammett Analysis of the Oxidative Addition of Aryl Chlorides to (DCPP)Pd(CO)2
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1.20
CF3
0.90
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(CO)NHMe
0.30
F
-0.4
-0.2
0.2
0.4
0.6
H
Me
-0.3
-0.6
y = 1.74x + 7.74×10-3
OMe
R² = 0.988
σp
Figure 6. Hammett plot of the oxidative addition of para-substituted aryl chlorides (0.56 M) to
(DCPP)Pd(CO)2 (28 mM) with pCO = 750 Torr in DMSO-d6/toluene-d8 (1:1 v/v) at 100 °C.
Because our data indicate that the oxidative addition of aryl chlorides to dicarbonyl 4 may occur
via a three-coordinate Pd(0) center bearing a bidentate ligand, we investigated whether this unusual
oxidative addition of an aryl chloride proceeds by a concerted cleavage of the C-Cl bond or by a stepwise
SNAr-type mechanism. The oxidative addition of aryl halides to Pd(0) compounds bearing bidentate
ligands have been proposed in prior publications to occur by an SNAr type process on the basis of
computational findings and a Hammett analysis of the electronic effects of aryl halides on oxidative
addition to L2Pd(0) species.37 In contrast, the accepted mechanism for oxidative addition of aryl halides to
Pd(0) complexes containing one or two dative ligands is a concerted cleavage of the carbon-halogen bond
of the aryl halide.38
To gain additional insight into the oxidative addition of aryl chlorides to dicarbonyl complex 4,
the electronic effects of the aryl group on the rate of the reaction were measured. A linear correlation
between the σ parameter and the rate of oxidative addition was observed with a ρ value of 1.74 (Figure
6).39 This ρ value indicates negative charge build-up at the carbon ipso to chlorine during the transition
state of oxidative addition of aryl chlorides to 4. A similar ρ value of 1.7 was measured by Yamamoto in
the double carbonylation of aryl bromides with Pd(PPh2Me)2Cl2.13b In addition, the ρ value of 1.74
obtained from our Hammett analysis is comparable to ρ values of oxidative addition of aryl iodides (ρ =
2) and triflates (ρ = 2.55) to Pd(PPh3)4, which are proposed to occur via concerted cleavage of the carbon-
halogen or carbon-triflate bond.38 Conversely, the oxidative addition of 2-bromo and 2-chloropyridines
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with substituents in the 5 position to Pd(PPh3)4 exhibit larger ρ values (4.4 and 4.3, respectively), and the
oxidative addition of these heteroaryl halides have been proposed to occur by an SNAr type process.40
Thus, on the basis of our Hammett analysis, a ρ value of 1.74 is inconsistent with oxidative addition by an
SNAr mechanism.
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In addition, the 13C KIE measured for the oxidative addition of an aryl chloride to dicarbonyl 4 is
distinct from 13C KIE values reported for SNAr reactions. The 13C KIE values for the SNAr reaction of the
chlorine in atrazine with hydroxide are between 1.03–1.04.41 Thus, based on our 13C KIE measurements,
kinetic studies, and a Hammett analysis, we conclude that the C-Cl bond cleavage by reaction with
(DCPP)Pd(CO) occurs by a concerted process, not by an SNAr-type reaction.
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Mechanism of Oxidative Addition of Aryl Bromides to (DCPP)Pd(CO)2
Scheme 9. Determination of pseudo-first order rate constants kobs from the oxidative addition of 2-
methoxy-4-fluoro-bromobenzene to (DCPP)Pd(CO)2.
Because the carbonylative functionalization of aryl chlorides by Pd(0) in the presence of CO is
less common than the analogous functionalization of aryl bromides and iodides, we performed
mechanistic studies on the oxidative addition of aryl bromides to (DCPP)Pd(CO)2. This study would
reveal whether the mechanism of oxidative addition of aryl bromides to 4 differs from the mechanism of
the reaction of aryl chlorides. The dependence of the rate of oxidative addition on the concentration of
aryl bromide and on the pressure of CO was determined for reactions in a mixture of DMSO and toluene
(1:1 v/v) under pseudo-first order conditions. Ethylene complex 1 served as a precursor to dicarbonyl
compound 4, and the sterically hindered and electronically deactivated aryl bromide 2-methoxy-4-fluoro-
bromobenzene was selected for this study because oxidative addition of this substrate occurs at elevated
temperatures with rates that are convenient to measure. The observed rate exhibited an inverse first order
dependence on the pressure of CO (Figure 7a) and a first order dependence on the concentration of aryl
bromide (Figure 7b). As such, these experiments suggest that aryl bromides and aryl chlorides react by
similar pathways under these reaction conditions, wherein the haloarene reacts irreversibly with
(DCPP)Pd(CO) to cleave the carbon-halogen bond. These results also agree with the computational
studies performed by Grushin on the oxidative addition of aryl iodides to (Xantphos)Pd(CO)2 discussed in
the introduction.
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y = 0.680x + 75.7
R² = 0.996
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R² = 1.00
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ArBr (M)
pCO (Torr)
Figure 7. Dependence of the observed rate constant (kobs) on (a) the pressure of CO (250-1500 Torr) with
ArBr = 0.27 M at 75 °C and (b) the concentration of ArBr (0.27-0.68 M) with pCO = 1000 Torr at 70 °C
for the oxidative addition of 2-methoxy-4-fluoro-bromobenzene to (DCPP)Pd(CO)2 (28 mM) in DMSO
and toluene (1:1 v/v).
Potential Mechanisms for the Formation of Benzamide from a Phenacylpalladium Chloride
Intermediate
Scheme 10. Reaction to assess whether phenacylpalladium complex 6a reductively eliminates 4-
fluorobenzoyl chloride.
The formation of benzamide from phenacylpalladium chloride complexes ligated by DCPP could
occur by reductive elimination of benzoyl chloride, followed by reaction of this acid chloride with
ammonia and base, or it could occur by direct reaction of ammonia and base with the phenacylpalladium
chloride complex. Although most mechanisms proposed for carbonylative couplings of aryl halides
involve reaction of the nucleophile with an acylpalladium halide complex, phenacylpalladium chloride
complexes have been reported recently to undergo reductive elimination to generate benzoyl chloride as
part of a catalytic synthesis of benzoyl chlorides from aryl halides, CO and chloride salts5c, 10c, 42 This
synthesis of benzoyl chlorides occurs with palladium catalysts containing bulky, monophosphine ligands,
not bidentate phosphines like those in our current study. Nevertheless, we conducted experiments to test
whether this reductive elimination occurs in the catalytic aminocarbonylation. To do so, DCPP-ligated
phenacyl complex 6a was heated at 80 °C for 2.5 h in the presence of 20 equiv of 4-iodobenzotrifluoride
and 760 torr of CO (Scheme 10). This temperature and time corresponds to those at which 6a reacts with
ammonia and DBU to form 4-fluorobenzamide (Scheme 6). If 6a reductively eliminated 4-fluorobenzoyl
chloride, the iodoarene would trap the Pd(0) resulting from the reductive elimination. Under these
19
conditions, 4-fluorobenzoyl chloride was not detected by F NMR spectroscopy. Thus, we conclude that
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the reductive elimination of benzoyl chloride is not a likely pathway in the formation of benzamide from
DCPP-ligated phenacyl complexes, and we conducted detailed studies to distinguish between pathways
for the formation of benzamide by reaction of ammonia and base with the phenacylpalladium complex
(Figure 8).
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Figure 8. Proposed mechanisms for the formation of benzamide from (DCPP)Pd(II) phenacyl chloride
complexes with ammonia and base.
Four potential pathways for formation of benzamide from phenacyl compound 6a are shown in
Figure 8. Path A occurs by reversible exchange of chloride by ammonia, deprotonation of the coordinated
amine to form a Pd(II) acyl amido species, and reductive elimination to generate a primary benzamide.
The exchange of amine for chloride could occur by any of the known pathways for ligand substitution on
square-planar compounds. Path A is reminiscent of the inner-sphere reductive elimination of esters from
acyl Pd(II) aryloxy complexes or the reaction of cationic acyl palladium(II) complexes with alcohols.19
Path B involves an outer-sphere attack of ammonia at the carbonyl group of compound 6a, followed by
deprotonation of the resulting intermediate. Subsequent collapse of the anionic intermediate and loss of
chloride produces the products of reductive elimination. Such pathways involving outer-sphere attack on
an acyl group have been discussed for palladium-catalyzed alkoxycarbonylation reactions under basic
conditions.4b, 43 Paths C and D involve displacement of chloride by either DMSO or CO to generate a
cationic Pd(II) species. This cationic Pd(II) species could be more prone to nucleophilic attack by
ammonia than a neutral compound. Path C involves displacement of chloride by DMSO or CO and
subsequent displacement of the bound DMSO or CO by ammonia. The reductive elimination products
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would then be generated by deprotonation and reductive elimination. Path C is equivalent to Path A if the
first two steps are fully reversible before deprotonation of the bound amine. Path D is the outer sphere
variant of path C, in which ammonia attacks the acyl carbonyl group of a cationic Pd(II)-DMSO or Pd(II)-
CO complex. After deprotonation and collapse of the resulting anionic intermediate, Pd(0) and a primary
benzamide are generated.
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Paths A, C, and D can be differentiated from path B by the order in chloride. Paths A, C, and D
would be inverse first order in chloride, whereas path B would be zero order in chloride. The order of the
reaction in chloride and ammonia for path A would be the same as that for paths C and D, except that
reaction by path D would be first order in DMSO or CO and reaction by path C would be first order in
DMSO and CO at low amounts of DMSO or CO and zero order at high amounts of DMSO or CO. To
elucidate the mechanism by which the phenacyl complex reacts with ammonia, we measured the
dependence of the rate of formation of benzamide from acyl complex 6a on the concentration of
ammonia, chloride, base, DMSO, and pressure of CO (Scheme 11).
Determination of the Mechanism for the Formation of Benzamide
Scheme 11. Determination of initial rates and pseudo-first order rate constants for the formation of 4-
fluorobenzamide from Pd(II) phenacyl chloride compound 6a.
The rate of formation of benzamide from compound 6a was determined by obtaining pseudo-first
31
order rate constants from the decay of 6a by P NMR spectroscopy (Scheme 11) with 10-30 equiv of
ammonia. All experiments were performed under 750 Torr of CO to capture the Pd(0) generated from
reductive elimination as (DCPP)Pd(CO)2 and were conducted with DBU as base. DBU was chosen as a
substitute for K2CO3 to create homogeneous reaction conditions. Because DBU is a hindered base, it does
not act as a nucleophile and generate side products.
The rate of formation of benzamide was determined to be first order in ammonia (Figure 9a) and
inverse first order in N(n-butyl)4Cl (Figure 9b, black trace). The inverse first order dependence on the
concentration of N(n-butyl)4Cl, a soluble source of chloride, is consistent with reaction by paths A, C, and
D. The reaction of 6a with ammonia was approximately zero order in N(n-butyl)4PF6 (Figure 9b, red
trace), indicating that the inverse first order dependence on added chloride did not result from a salt effect
or increase of solvent polarity from the salt.44
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0.25 0.5 0.75
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1.25
0
250 500 750 1000 1250
pNH3 (Torr)
[N(n-butyl)4X](M)
Figure 9. Dependence of the observed rate constant (kobs) on pNH3 (392-1177 Torr, 10-30 equiv) with
pCO = 750 Torr and [DBU] = 0.34 M (a) and on [N(n-butyl)4Cl] (0.34-1.0 M, black trace) or [N(n-
butyl)4PF6] (0.34-1.0 M, red trace) with pCO = 750 Torr, [DBU] = 0.34 M, and pNH3 = 785 Torr (20
equiv) (b) for the rate of formation of 4-fluorobenzamide from 6a (34 mM) in 1:1 v/v DMSO and toluene
at 35 °C. The pressure of CO is the pressure added to a J. Young tube at -196 °C.
The dependence of the reaction rate on the concentration of DBU was found to be first order at
low concentrations of DBU and zero order at high concentrations of DBU. The reaction of 6a with
ammonia and 10-30 equiv (0.342-1.03 M) of DBU occurred with an approximately zero-order
dependence on the concentration of DBU (Figure 9a). When initial rates were measured with 1-5 equiv of
DBU (0.0342 M to 0.171 M), the rate of formation of benzamide was first order in DBU (Figure 10b).
These results indicate that deprotonation is the rate limiting step at low concentrations of base and that
attack of 6a by ammonia is rate limiting at high concentrations of base. To explore the effects of base on
reaction rate further, we determined the order of the reaction in base in the presence of 10 equiv of N(n-
butyl)4Cl (0.342 M). A first-order dependence of the rate on base was observed under these conditions
(Figure 10c).
3
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2400
2000
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(c)
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y = 653x + 177
R² = 0.999
y = 0.226x + 1.03
R² = 0.983
y = 32.4x - 0.197
R² = 0.983
0
0.2 0.4 0.6 0.8
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0.05 0.1 0.15 0.2
0
1
2
3
1/[DBU](M-1)
[DBU] (M)
[DBU] (M)
Figure 10. Dependence of the observed rate constant (kobs) on [DBU] (0.34-1.0 M) with pCO = 750 Torr
and pNH3= 392 Torr (10 equiv) at 35 °C for the rate of formation of 4-fluorobenzamide from 6a (34 mM)
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in DMSO and toluene (1:1 v/v) (a). Dependence of the initial rate on [DBU] (0.034-0.17 M) with pCO =
750 Torr and pNH3 = 588 Torr (15 equiv) at 60 °C for the rate of formation of 4-fluorobenzamide from 6a
(34 mM) in DMSO and toluene (1:1 v/v) (b). Dependence of the observed rate constant (kobs) on [DBU]
(0.34-1.0 M) with pCO = 750 Torr, pNH3= 392 Torr (10 equiv), and [N(n-butyl)4Cl] = 0.34 M at 35 °C
for the formation of p-fluorobenzamide from 6a (34 mM) in DMSO and toluene (1:1 v/v) (c). The
pressure of CO is the pressure added to a J. Young tube at -196 °C.
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R² = 0.993
0
0.25 0.5 0.75
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250 500 750 1000 1250
[DMSO] (M)
pCO (Torr)
Figure 11. Dependence of the observed rate constant (kobs) on (a) the concentration of DMSO (0.0-1.0 M)
with pCO = 750 Torr, [DBU] = 0.34 M, and pNH3 = 785 Torr (20 equiv) at 65 °C and (b) the pressure of
CO (250-1000 Torr) with [DBU] = 0.34 M and pNH3 = 785 Torr (20 equiv) at 65 °C for the rate of
formation of p-fluorobenzamide from 6a (34 mM) in 1,2-difluorobenzene. The pressure of CO is the
pressure added to a J. Young tube at -196 °C or at -95 °C.
The first order behavior in DBU at low concentrations of DBU and zero order behavior in DBU
at high concentrations of DBU is consistent with paths A, C, and D. Therefore, to differentiate between
paths A, C, and D, the effect of the concentration of DMSO (0.0-1.0 M, 0-30 equiv) and the pressure of
CO (250-1000 Torr) on the rate of formation of benzamide was measured in 1,2-difluorobenzene, a polar
but non-coordinating solvent.45 A positive, fractional order in DMSO was observed (Figure 11a). This
non-integer order in DMSO is likely due to an increase in polarity of the reaction mixture at higher
concentrations of DMSO, which would lead to a higher concentration of ammonia. The lack of a clear
first-order dependence on the concentration of DMSO is inconsistent with path D and is consistent with
path A or path C with the first two steps fully reversible. A zero-order dependence of kobs on the pressure
of CO was observed (Figure 11b). This absence of a first order dependence on the pressure of CO is
inconsistent with path D and also is consistent with path A or path C with the first two steps fully
reversible. At the same time, the formation of benzamide occurs in the absence of added DMSO (Figure
11a), and the addition of DMSO does not significantly alter the rate of formation of benzamide. Thus, it is
unlikely that DMSO additive or solvent assists the exchange of ammonia for chloride. Given the lack of
dependence on high concentrations of DMSO, the relatively hard property of cationic Pd(II), the known
direct substitution of chloride by nitrogen Lewis bases,46 and lack of dependence of the rate on CO, it is
unlikely that CO assists the exchange of ammonia for chloride. Thus, we favor the reaction by a version
of path A in the presence or absence of DMSO or CO in the system. Our kinetic data on the formation of
benzamide from 6a are all consistent with ligand substitution of chloride by ammonia, most likely by
associative ligand substitution, followed by deprotonation of coordinated ammonia and reductive
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elimination from the resulting phenacylpalladium(II) amido species to obtain Pd(0) and a primary
benzamide.
6
7
Formation of Benzamide from an Aryl Pd(II) Amido Complex
8
9
Scheme 12. Synthesis of Pd(II) aryl amido complex 7 and subsequent reactivity with CO.
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aYields were obtained by 19F NMR spectroscopy with OTf- as an internal standard.
Decarbonylation of phenacyl Pd(II) halide species to the corresponding arylpalladium(II) halide
species can occur during the catalytic process.47 Such arylpalladium(II) halide intermediates were
observed during our mechanistic studies of the oxidative addition of electron-poor aryl halides and of
ortho-substituted aryl halides in the presence of CO. These complexes could result from reversible
migratory insertion or slow migratory insertion of CO. Thus, ammonia could react with an
arylpalladium(II) halide complex to form an arylpalladium(II) amido complex prior to migratory insertion
of CO, to form aniline by reductive elimination as a side product, or to form a phenacylpalladium amido
or arylpalladium carbamoyl complex by insertion of CO into the palladium-aryl or palladium-amido bond
and subsequent formation of the organic amide.48
To explore the potential intermediacy of arylpalladium amido complexes, arylpalladium amido
complex 7 was synthesized as shown in Scheme 12. Abstraction of chloride from 5a with AgOTf in the
1
presence of ammonia and subsequent deprotonation with KHMDS formed 7. H–15N HSQC and 15N
DEPT experiments confirmed the presence of a mononuclear Pd-NH2 amido species (see Supporting
Information). Amido complex 7 slowly degrades in THF at room temperature. The onset of this
decomposition can be detected by 31P NMR spectroscopy after approximately 1.5 hours at room
temperature. However, attempts to isolate 7 as a solid by crystallization led to rapid decomposition. Thus,
compound 7 was prepared in situ and was reacted with 1000 Torr of CO at 80 °C. After one hour, p-
fluorobenzamide formed in 99% yield and compound 7 was fully consumed. The sole compound
observed by 31P NMR spectroscopy was dicarbonyl complex 4. (Scheme 12). p-Fluoroaniline was not
19
observed by F NMR spectroscopy. These data imply that reductive elimination from a phenacyl Pd(II)
amido complex or an aryl Pd(II) carbamoyl complex to generate the corresponding primary benzamide is
faster than reductive elimination from an aryl Pd(II)amido complex to form aniline.
Identification of the Catalyst Resting State
To identify the major palladium complex in the catalytic reaction, the aminocarbonylation of 4-
chlorofluorobenzene was monitored by 31P NMR spectroscopy (Figure 12). Because dicarbonyl 4 is
poorly soluble in DMSO alone, leading to weak signals, the catalytic reaction was monitored in a mixture
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of DMSO and toluene (1:1 v/v) to maintain the solubility of the palladium complexes. After 14 h at 100
°C, at which point 54% conversion of starting material occurred, the P NMR spectrum consisted of a
singlet at 20.3 ppm, which corresponds to dicarbonyl 4, along with a second resonance at 15.6 ppm
(Figure 12a). After 14 h at the lower temperature of 80 °C, at which point 10% conversion of starting
material occurred, the 31P NMR spectrum contained only the resonance at 20.3 ppm for 4 (Figure 12b).
31
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Figure 12. Room temperature 31P NMR spectra of a catalytic reaction at partial conversion conducted at
100 (a) and 80 °C (b) after 14 h in DMSO and toluene (1:1 v/v) and of Pd(I) dimer 8a in CDCl3 at room
a
temperature (c). Conversion was determined with 19F NMR spectroscopy with 4-fluorotoluene as an
internal standard.
The second compound corresponding to the resonance at 15.6 ppm in Figure 12a is the dinuclear
hydride complex 8a in Scheme 13. This complex was prepared independently in 32% isolated yield by
31
the addition of ammonium chloride to complex 4 at 100 °C for 45 min in the presence of CO. The P
1
NMR spectrum of 8a at room temperature consists of a singlet at 15.6 ppm, and the H NMR spectrum
contains a quintet at –5.28 ppm for the bridging hydride. Similar cationic Pd(I) dimers have been
synthesized previously and proposed to be resting states in palladium-catalyzed alkoxycarbonylation
reactions or have been isolated as by-products of palladium-catalyzed synthesis of hydrogen peroxide
from carbon monoxide, oxygen, and water.49 We hypothesized that this hydride complex forms in the
catalytic cycle by protonation of dicarbonyl complex 4.
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Figure 13. Solid state structure of Pd(I) dimer 8b with ellipsoids set at 30% and selected hydrogen atoms
omitted for clarity. Selected bond lengths (Å): Pd1-Pd2 2.749(1), Pd1-C1 2.09(1), Pd2-C1 2.02(2), C1-O1
1.15(2). Selected bond angles (°): P2-Pd1-P1 97.74(13), Pd1-C1-Pd2 83.9(6), P3-Pd2-P4 98.09(13).
Single crystals of 8b, an analog of 8a containing a tetrafluoroborate counterion, was obtained by
addition of HBF4 etherate to (DCPP)Pd(CO)2, which was generated in situ from 4 and CO, and
1
crystallization from a solution of THF and toluene (1.5:1 v/v). (Scheme 13). The H and 31P NMR
spectrum of 8b is identical to that of compound 8a. The solid-state structure of complex 8b consists of a
dinuclear structure with two palladium centers that adopt distorted square-planar geometries. This
geometry has been observed for other crystallographically characterized Pd(I) dimers bearing two
bidentate ligands and a bridging carbonyl and hydride ligand.49a, 50 The Pd-Pd distance is 2.749(1) Å,
which is consistent with a metal-metal bond (Figure 13). In this structure, the two phosphorus atoms on
each palladium are inequivalent, but a single 31P NMR resonance is observed in solution at room
temperature.
This equivalence of the phosphines in solution arises from a rapid, dynamic process, rather than a
different structure in the solid state and in solution. Cooling 8b to –99 °C in THF-d8 caused the quintet of
1
the bridging hydride in the H NMR spectrum to partially coalesce to become a more complex, broad
multiplet. Similarly, the 31P NMR resonance of 8b at –99 °C in THF-d8 broadens and exhibits a
multiplicity that is more complex than a singlet (see Supporting Information). The NMR spectra recorded
of 8b at –99 °C indicate that a dynamic process approaches but is not slower than the NMR timescale at –
99 °C. In addition, due to the complexity of the spectra of 8b at –99 °C, we were unable to determine the
nature of the dynamic process leading to the equivalence of the phosphorus atoms of 8b in solution at
room temperature. This equivalence of the two phosphorus atoms has been previously reported for
structurally analogous cationic Pd(I) dimers.49c, 51 A rapid dissociation and association of either the
bridging carbonyl or bridging hydride from one of the Pd atoms has been proposed as the cause for the
equivalence of the phosphorus atoms at room temperature.51
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Scheme 13. Synthesis of Pd(I) dimers 8a and 8b.
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The reactivity of Pd(I) dimer 8a was studied to assess its relevance to the mechanism of the
catalytic aminocarbonylation. Compound 8a was treated with an excess of DBU in the presence of 760
Torr of CO in DMSO at 100 °C. Over the course of 16 h, complex 8a slowly reduced to dicarbonyl
compound 4. After this time, only 56% of 8a converted to 4, which precipitated as colorless crystals,
along with Pd black (Scheme 14). Because the generation of 4 from 8a is slower than the catalytic
process, the formation of 8a is a catalyst deactivation pathway, and we propose that 4 is the catalyst
resting state.
Scheme 14. Reduction of Pd(I)dimer 8a to Pd dicarbonyl complex 4 in the presence of CO and base.
aYield was determined with PMes3 as an internal standard.
Identification of the Rate Limiting Step of the Catalytic Reaction
Based on our kinetic studies and identification of the major palladium complexes present in the
catalytic reaction, the rate limiting step of the catalytic cycle is the oxidative addition of an aryl chloride
to dicarbonyl compound 4. In addition, the rate of the reduction of dimer 8a to dicarbonyl 4 will affect the
observed rate of the catalytic process. To identify the rate-determining step of the catalytic cycle, a time
course of the reaction was measured with varying amounts of CO and ammonia (Figure 14).
Qualitatively, the rate of the reaction conducted with 900 Torr of CO was less than the reaction conducted
with 450 Torr of CO. This smaller rate is consistent with rate-limiting oxidative addition because
dissociation of CO from compound 4 occurs prior to oxidative addition. The decrease in rate at higher
concentrations of CO is inconsistent with rate-limiting reduction of 8a to 4, which would be expected to
exhibit either zero or positive orders in CO pressure. Although doubling the amount of ammonia from 3
to 6 equiv increases the reaction rate slightly, the small size of that effect is inconsistent with rate-limiting
formation of benzamide from reaction of the phenacyl complex with ammonia. We attribute this slight
enhancement in rate to an increase in overall basicity of the reaction medium, which inhibits the
formation of the inactive dimer 8a. Thus, these data are consistent with oxidative addition as the rate-
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limiting step in the catalytic aminocarbonylation of aryl chlorides, as predicted from studies of the
individual steps.
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Standard Conditions
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Double CO
Double Ammonia
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Time (min)
Figure 14. Time course of the palladium-catalyzed aminocarbonylation of 4-chlorobenzotrifluoride with
varying amounts of CO and ammonia. aYields were determined by GC.
Conclusion
The lack of studies on the oxidative addition and the formation of benzamide during the
palladium-catalyzed aminocarbonylation of aryl chlorides has made the catalytic cycle of this process
ambiguous. Our kinetic studies of the oxidative addition of the aryl halide and the formation of
benzamide from a phenacylpalladium complex during the palladium-catalyzed aminocarbonylation of
aryl chlorides with ammonia, as well as determination of the catalyst resting state and deactivation
pathways, establish an experimental basis for the elementary steps that constitute the catalytic cycle of
palladium-catalyzed aminocarbonylation. Our results indicate that the aminocarbonylation of aryl
chlorides catalyzed by DCPP-ligated Pd(0) occurs by the mechanism summarized in Figure 15.
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Figure 15. Proposed mechanism for palladium-catalyzed aminocarbonylation of aryl chlorides with
ammonia.
The oxidative addition of a chloroarene and bromoarene to (DCPP)Pd(CO)2 (4) was first-order in
the concentration of aryl halide and inverse first-order in the pressure of CO, indicating that the haloarene
reacts with a three-coordinate Pd complex bearing DCPP and one CO ligand (Figure 5, Path A). A
primary 13C KIE of 1.013(6) was measured for the carbon ipso to chlorine for the oxidative addition of 4-
chloro-N-methylbenzamide to 4 and a ρ value of 1.74 was obtained from a Hammett analysis of the effect
of the electronic properties of the arene on the rate of oxidative addition. Together, these data are
consistent with irreversible C–Cl bond cleavage during the reaction of the Pd(0) species with the
13
haloarene by a concerted pathway, rather than an SNAr type pathway. In addition, our C KIE study
discounts the possibility of irreversible ligand substitution of CO from (DCPP)Pd(CO) with an aryl
chloride, wherein oxidative addition occurs at a two-coordinate (DCPP)Pd(0) complex, and implies that
the oxidative addition of an aryl chloride occurs at a Pd(0) complex bearing DCPP and one CO ligand.
Thus, we propose that the oxidative addition of aryl chlorides occurs at (DCPP)Pd(CO) by a concerted C–
Cl bond cleavage event.
The rate of formation of benzamide from Pd(II) phenacyl compound 8a was first order in
ammonia and inverse order in chloride. A non-integer, positive order in the concentration of DMSO and
pressure of CO was observed when the reaction was conducted in a non-coordinating solvent. These data
are consistent with a mechanism for reaction of phenacyl compound 6a with ammonia that involves an
inner sphere displacement of chloride by ammonia to form a cationic Pd(II) ammine complex as an
intermediate (Figure 8, Path A). The rate of formation of benzamide was zero order in base at high
concentrations of base and first order in base at low concentrations of base. These reaction orders imply
that the rate-limiting step of benzamide formation is deprotonation at low concentrations of base and
formation of an ammine complex at high concentrations of base. Moreover, the formation of benzamide
does not occur directly from a cationic ammine intermediate. Instead, deprotonation generates an acyl
Pd(II) amido species, which reductively eliminates to generate benzamide.
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The rate limiting step of the overall catalytic reaction with an aryl chloride was determined by
studying the dependence of the rate of the catalytic reaction on the pressure of ammonia and CO. Changes
to the pressure of ammonia did not affect the rate of the reaction significantly, whereas reactions at higher
pressures of CO were slower than those at lower pressures of CO. Because the oxidative addition of an
aryl chloride to 4 is inverse order in CO, the rate limiting step of the catalytic reaction is oxidative
addition. The resting state of the catalytic reaction was determined to be dicarbonyl compound 4, which is
consistent with the observed dependence of the rate on CO pressure. A Pd(I) hydride dimer 8a was also
present in the catalytic system. This complex slowly reduces to dicarbonyl 4 in the presence of CO and
base, and this slow rate of reentry into the catalytic cycle leads to the partial accumulation of this complex
and reduction of the rate of the reaction. Future efforts in this area will be directed toward the
development of palladium-catalyzed carbonylations that occur with additional classes of organic
electrophiles.
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Acknowledgements. The authors acknowledge the NIH for support of this work (5R37-GM055382), the
Small Molecule X-ray Crystallography Facility (S10-RR027172), the Central California 900 MHz NMR
Facility (NIH-GM68933), the Molecular Graphics and Computation Facility (NIH-S10OD023532), and
the Catalysis Facility of Lawrence Berkeley National Laboratory, which is supported by the Director,
Office of Science, of the US Department of Energy under contract no. DE-AC02-05CH11231. The
authors thank Dr. Antonio DiPasquale for X-ray crystallographic analyses and Dr. Hasan Celik and Dr.
Jeffrey G. Pelton for assistance with NMR spectroscopy. The authors also acknowledge Dr. Jessica L.
Klinkenberg and Huy Nguyen for preliminary experimental work. J.Y.W. thanks Dr. Sophie I. Arlow, Dr.
D. Matthew Peacock, and Dr. York Schramm for insightful discussions.
Supporting Information Available. Experimental procedures, characterization, X-ray data, and
computational details. This material is available free of charge via the internet at http://pubs.acs.org.
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Bunel also observed the absence of 31P-13C coupling in (DIPP)Pd(13CO) (DIPP = 1,3-
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32.
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Even with 1000 Torr of 13CO at –40 °C, phosphorus-carbon coupling was still not detected.
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