Mechanistic Study of the Role of Substrate Steric Effects and Aniline Inhibition on the Bis(trineopentylphosphine)palladium(0)-Catalyzed Arylation of Aniline Derivatives

Article abstract of DOI:10.1021/acscatal.7b00024

The mechanism of the bis(trineopentylphosphine)palladium(0) (Pd(PNp₃)₂)-catalyzed coupling of aryl halides and aniline derivatives was studied in an effort to understand the role of substrate steric effects on the reaction. Prior studies had shown that the rate of Pd/PNp₃-catalyzed coupling of aryl bromides and aniline derivatives was largely unaffected by substrate steric demand. The oxidative addition of aryl bromides to Pd(PNp₃)₂ is found to follow first-order kinetics with a rate that is independent of both ligand and aryl halide concentration. Thus, the rate limiting step for oxidative addition of aryl bromides is irreversible ligand dissociation. In the case of aryl chlorides, the oxidative addition rate has a first-order dependence on [ArCl] and an inverse dependence on [PNp₃], indicating a mechanism involving reversible dissociation of the ligand followed by rate limiting oxidative addition. This difference in aryl halide effect was also found for the catalytic coupling reaction. Aryl bromide steric demand does not affect the coupling rate with hindered anilines, whereas the coupling rate of aryl chlorides is negatively affected by substrate steric demand. These results suggest that oxidative addition is rate limiting in the catalytic reaction for aryl chlorides but that oxidative addition is not rate limiting for aryl bromides. Aniline was found to give coupling rates significantly slower than those of 2,6-diisopropylaniline for both aryl bromides and chlorides. Aniline promotes the decomposition of the [(PNp₃)Pd(Ar)(μ-X)]₂ catalytic intermediate to a catalytically inactive palladacycle ([(κ²-P,C-Np₂PCH₂C(Me₂)CH₂)Pd(μ-X)]₂) through C-H activation of a neopentyl group and elimination of arene. These studies show that the ability of the Pd/PNp₃ catalyst system to tolerate steric demand in aryl bromides stems from the fact that the rate limiting step of the catalytic cycle is independent of the concentration and steric demand of aryl bromides. A catalyst deactivation pathway involving ligand metalation was identified that is promoted by unhindered aniline derivatives.

Full text of DOI:10.1021/acscatal.7b00024

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Article
Mechanistic Study of the Role of Substrate Steric Effects and
Aniline Inhibition on the Bis(trineopentylphosphine)palladium(0)-
Catalyzed Arylation of Aniline Derivatives
Huaiyuan Hu, Fengrui Qu, Deidra L. Gerlach, and Kevin H. Shaughnessy
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b00024 • Publication Date (Web): 23 Feb 2017
Downloaded from http://pubs.acs.org on February 23, 2017
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Mechanistic Study of the Role of Substrate Steric
Effects and Aniline Inhibition on the
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Bis(trineopentylphosphine)palladium(0)ꢀCatalyzed
Arylation of Aniline Derivatives
Huaiyuan Hu, Fengrui Qu, Deidra L. Gerlach, and Kevin H. Shaughnessy*
Department of Chemistry, The University of Alabama, Box 870336, Tuscaloosa, AL 35487ꢀ
0336
Abstract: The mechanism of the bis(trineopentylphosphine)palladium(0) (Pd(PNp ) )ꢀcatalyzed
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coupling of aryl halides and aniline derivatives was studied in an effort to understand the role of
substrate steric effects on the reaction. Prior studies had shown that the rate of Pd/PNp3ꢀ
catalyzed coupling of aryl bromides and aniline derivatives was largely unaffected by substrate
steric demand. The oxidative addition of aryl bromides to Pd(PNp ) is found to follow first
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order kinetics with a rate that is independent of both ligand and aryl halide concentration. Thus,
the rate limiting step for oxidative addition of aryl bromides is irreversible ligand dissociation. In
the case of aryl chlorides, the oxidative addition rate has a first order dependence on [ArCl] and
an inverse dependence on [PNp ] indicating a mechanism involving reversible dissociation of
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ligand followed by rate limiting oxidative addition. This difference in aryl halide effect was also
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found for the catalytic coupling reaction. Aryl bromide steric demand does not affect the
coupling rate with hindered anilines, whereas the coupling rate of aryl chlorides is negatively
affected by substrate steric demand. These results suggest that oxidative addition is rate limiting
in the catalytic reaction for aryl chlorides, but that oxidative addition is not rate limiting for aryl
bromides. Aniline was found to give significantly slower coupling rates than 2,6ꢀ
diisopropylaniline for both aryl bromides and chlorides. Aniline promotes the decomposition of
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the [(PNp )Pd(Ar)(µꢀX)] catalytic intermediate to a catalytically inactive palladacycle ([(κ ꢀ
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P,CꢀNp PCH C(Me )CH )Pd(µꢀX)] ) through CꢀH activation of a neopentyl group and
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elimination of arene. These studies show that the ability of the Pd/PNp catalyst system to
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tolerate steric demand in aryl bromides stems from the fact that the rate limiting step of the
catalytic cycle is independent of the concentration and steric demand of aryl bromides. A catalyst
deactivation pathway involving ligand metallation has been identified that is promoted by
unhindered aniline derivatives.
KEYWORDS:
amination, oxidative addition, kinetics, mechanistic study, palladium,
palladacycle, phosphine
Introduction
Aryl amines are common motifs in pharmaceuticals, agricultural chemicals, and electronic
materials. Metalꢀcatalyzed amine arylations have become widely used synthetic methods in both
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academic and industrial labs. These methods date back over 100 years to Ullman's initial report
of the coupling of aryl halides with amines mediated by copper. Copperꢀcatalyzed methods
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continue to be widely used for C–N bond formation. Beginning with the seminal work of
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Buchwald and Hartwig, palladiumꢀcatalyzed amine arylation has been developed into a
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powerful method for the synthesis of carbonꢀnitrogen bonds. Much of the development of these
catalyst systems has focused on the identification of more effective ligands to promote the
catalytic process. Current classes of privileged ligands include sterically demanding
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trialkylphosphines,
2ꢀbiarylphosphines,
Nꢀheterocyclic
carbenes,
and
chelating
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alkylphosphines.
Our group has shown that neopentylphosphines, such as di(tertꢀbutyl)ꢀneopentylphosphine ((t-
Bu) PNp) and trineopentylphosphine (PNp ) afford effective catalysts for a variety of C–C and
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C–N coupling reactions. The neopentyl substituent provides additional conformational
flexibility compared to other sterically demanding substituents, such as tꢀbutyl or 1ꢀadamantyl.
Depending on the conformation, the neopentyl group can have a relatively large or small steric
impact. Conformationally flexible ligands have shown promise for coupling of challenging
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sterically demanding substrates.
The catalyst derived from Pd (dba)
and
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trineopentylphosphine displays high catalytic efficiency for the coupling of a wide scope of
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sterically demanding aryl bromides and chlorides with sterically hindered aniline derivatives. In
contrast, the catalysts derived from the more rigid (t-Bu) PNp or P(tꢀBu) are much less active
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for the coupling of diꢀorthoꢀsubstituted aryl halides with hindered aryl amines. More
interestingly, the Pd (dba) /PNp system showed limited sensitivity to the steric demand of the
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substrates based on both isolated yields and reaction rate. In some cases, more sterically hindered
substrates gave faster reaction rates than less hindered examples (Scheme 1).
Scheme 1. Pd (dba) /PNp ꢀcatalyzed coupling of aryl bromides and aniline derivatives.
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In order to better understand the effect of sterically demanding substrates on the Pd/PNp3
catalyst system, we sought to explore the mechanism in more detail. Mechanistic studies of BꢀH
amination systems have generally supported a mechanism involving formation of a
coordinatively unsaturated active species followed by a sequence of oxidative addition,
replacement of the halide with the amide nucleophile, and reductive elimination (Scheme 2). In
the case of sterically demanding, monodentate ligands, the active species is proposed to be a
monoligated complex (LPd(0)). The oxidative addition product may form an off cycle halideꢀ
bridged dimer with these ligands.
Scheme 2. General mechanism for palladiumꢀcatalyzed amination
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Detailed mechanistic studies have been performed on several BꢀH catalyst systems. The
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Hartwig, Blackmond, and Buchwald groups carefully studied the Pd/BINAP catalyst system.
The consensus mechanism involves reversible ligand dissociation from Pd(BINAP) to provide
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the coordinatively unsaturated Pd(BINAP) species that undergoes rate limiting oxidative addition
of the aryl bromide (Scheme 2, L = BINAP). Reaction with amine and base affords a palladium
amide species, which undergoes reductive elimination to provide the product and regenerate the
active Pd(BINAP) species.
The Buchwald group has performed computational and experimental studies on palladium/2ꢀ
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biphenylphosphine catalyst systems. Based on these studies, a similar mechanism beginning
with a monophosphineꢀpalladium complex was proposed. The reaction is proposed to involve
rotation of the palladium from interacting with the ligand arene group to orienting away from the
arene upon amine coordination. Reaction progress kinetic analysis (RPKA) of the coupling of
aryl halides with sterically demanding primary amines catalyzed by CPhos (2ꢀ((2',6'ꢀ
bis(dimethylamino)biphenyl)diphenylphosphine) gave different rate limiting steps depending on
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the aryl halide substrates. For aryl chlorides, oxidative addition appears to be rate limiting,
whereas for aryl bromides the reductive elimination is the likely rate limiting step.
Organ has studied the mechanism of amination using PEPPSI precatalysts and weak bases,
such as Cs CO . In the case of alkyl amines, deprotonation of the palladiumꢀbound amine by the
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heterogeneous weak base is the rate determining step.
This step is sensitive to the electronic
nature of the aryl halide and aryl amine, both of which affect the pK of the palladiumꢀbound
a
amine. With more acidic aniline complexes, deprotonation is faster and reductive elimination is
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thought to be rate determining.
Mechanistic studies of trialkylphosphine catalyst systems are most relevant to the
trineopentylphosphine system. The oxidative addition of aryl halides to PdL complexes (L =
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P(tꢀBu) , (1ꢀAd)P(tꢀBu) , CyP(tꢀBu) , and PCy ) was found to depend on the nature of the ligand
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and the halide leaving group. For aryl bromides, the mechanism appears to involve two
competing rate limiting ligand displacement steps prior to oxidative addition: irreversible ligand
dissociation and irreversible associative displacement of the ligand by the aryl bromide. The
associative mechanism is the major pathway with the less hindered tricyclohexylphosphine
ligand, whereas the dissociative pathway becomes competitive with more hindered ligands. The
participation of an associative pathway is supported by computational studies showing this as an
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energetically favorable pathway. In contrast, oxidative addition of aryl chlorides involves
reversible dissociation of a ligand followed by rate limiting oxidative addition with no evidence
of a competing associative pathway. Analysis of the full catalytic mechanism using Pd(P(tꢀBu)3)2
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showed that the reaction rate depended on base identity, but not the amine. Hartwig proposed
competing mechanisms involving rate limiting oxidative addition to both Pd(P(tꢀBu) ) and [((tꢀ
3
–
Bu) P)Pd(OR)] species.
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The majority of these experimental and computational studies have focused on simple aryl
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halides. Organ has explored the effect of substrate electronic properties,
but there has been
limited work on the mechanistic impact of substrate steric properties. In light of the steric
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tolerance seen in the Pd (dba) /PNp catalyst system, we were interested to explore the
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mechanism of this reaction in more detail. We hypothesized that the conformational flexibility of
trineopentylphosphine was responsible for the tolerance of steric bulk in these reactions.
Trineopentylphosphine is capable of adopting very sterically demanding conformations with
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significantly larger cone angles than P(tꢀBu)3. Unlike, P(tꢀBu) , PNp exhibits significant
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conformational flexibility allowing it to facilitate the coupling of sterically demanding substrates.
We sought to better understand the mechanism for this system and how substrate steric demand
affects the reaction.
Results
Oxidative addition of aryl halides to Pd(PNp ) . In our report of the Pd/PNp ꢀcatalyzed
3 2
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amination reaction, the catalyst was generated in situ from Pd (dba) and PNp . Given the
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complexity of the Pd (dba) system, we chose to use the well defined Pd(PNp ) complex (1) to
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3 2
study of the mechanism of the oxidative addition reaction. We have previously reported that
Pd(PNp ) reacts cleanly with unhindered or monoꢀorthoꢀsubstituted aryl bromides to cleanly
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afford halideꢀbridged [(Np P)Pd(Ar)(µꢀBr)] complexes 3a and 3b (eq 1).
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In the case of 2ꢀbromoꢀmꢀxylene (2c), the oxidative addition occurs to afford 3c as observed by
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P NMR spectroscopy, but the product undergoes decomposition by CꢀH activation of the ligand
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to afford palladacycle 4 and arene (Scheme 3). Our group has recently reported the synthesis of
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palladacycles derived from (tꢀBu) PNp ([(κ ꢀP,CꢀtꢀBu PCH C(Me )CH )Pd(µꢀBr)] and [(κ ꢀ
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P,CꢀtꢀBu PCH C(Me )CH )Pt(µꢀOAc)] , but the complexes were not structurally
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characterized. The acetate bridged dimer is an active catalyst for the crossꢀcoupling of aryl
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acetylenes with propargyl alcohols. Metallacyclic complexes of platinum ([(κ ꢀP,Cꢀtꢀ
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2
Bu PCH C(Me )CH )Pt(µꢀCl)] )
and iridium ((κ ꢀP,CꢀtꢀBu PCH C(Me )CH )IrCl(P(tꢀ
2 2 2 2
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Bu) Np) derived from (tꢀBu) PNp have been structurally characterized. Dahlenburg reported a
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PNp ꢀderived iridium metallacycle, but the complex was not structurally characterized.
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Scheme 3. Attempted oxidative addition of 2ꢀbromoꢀmꢀxylene to Pd(PNp3)2
Complex 4 was isolated and Xꢀray quality crystals were obtained by recrystallization from
pentane (Figure 1). The complex adopts a butterfly structure with a 126° angle between the two
palladium square planes. The palladacycle has a constrained PꢀPdꢀC angle (82.7°, 82.8°). This
value is similar to other reported fiveꢀmembered ring palladacycles derived from
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alkylphosphines. Due to the steric strain, the PꢀCꢀC angles of the neopentyl groups are large
(123.8–125.0°). The neopentyl substituents are positioned above and below the palladium square
planes with relatively small PdꢀPꢀCꢀC dihedral angles (28.4–53.9°).
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Figure 1. ORTEP diagram of complex 4 (ellipsoids drawn at the 50% probability level).
Hydrogen atoms are omitted for clarity. Selected bond lengths (Å): Pd1ꢀBr1, 2.5914(5); Pd1ꢀP1,
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.240(1); Pd1ꢀBr2, 2.5357(5); Pd1ꢀC1, 2.033(4); Pd2ꢀBr1, 2.5268(5); Pd2ꢀBr2, 2.5952(5); Pd2ꢀ
P2, 2.234(1); Pd2ꢀC16, 2.046(4); P1ꢀC3, 1.822(4). Selected bond angles (deg): Br1ꢀPd1ꢀBr2,
5.14(2); Br1ꢀPd2ꢀBr2, 85.24(2); C1ꢀPd1ꢀP1, 82.7(1); Br1ꢀPd1ꢀP1, 103.91(3); Br2ꢀPd1ꢀC1,
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88.4(1); Pd1ꢀC1ꢀC2, 118.3(3); C1ꢀC2ꢀC3, 108.6(4); P1ꢀC2ꢀC3, 109.4(3); Pd1ꢀP1ꢀC3, 104.9(2);
P1ꢀC6ꢀC7, 124.8(4) P1ꢀC11ꢀC12, 125.0(3); Pd1ꢀP1ꢀC6ꢀC7, ꢀ45.4(5); Pd1ꢀP1ꢀC11ꢀC12, ꢀ28.4(5);
Pd2ꢀP2ꢀC21ꢀC22, 45.0(4); Pd2ꢀP2ꢀC26ꢀC27, 53.9(4).
The observation of 3c during the oxidative addition to Pd(PNp ) suggested the compound
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could be formed, but that it was not thermally stable. Complex 3c can be prepared by the
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reaction of 2ꢀbromoꢀmꢀxylene (2c) with (COD)Pd(CH TMS) and PNp in pentane at room
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temperature (eq 2). Under these conditions, complex 3c is stable and can be isolated. Xꢀray
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similar structure to previously reported complexes 3a and 3b (Figure 2).
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Figure 2. ORTEP diagram of complex 3c (ellipsoids drawn at the 50% probability level).
Hydrogen atoms are omitted for clarity. Selected bond lengths (Å): Br1ꢀPd1, 2.5814(4); Br1ꢀ
Pd1, 2.5060(3); Pd1ꢀP1, 2.2710(3); Pd1ꢀC1 2.009(1); Br1ꢀPd1ꢀBr1, 85.68(1). Selected bond
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angles (deg): Br1ꢀPd1ꢀP1, 97.49(1); P1ꢀPd1ꢀC1, 91.31(4); C1ꢀPd1ꢀBr1, 85.52(4); Pd1ꢀP1ꢀC9,
1
12.80(4); Pd1ꢀP1ꢀC19, 115.11(4); Pd1ꢀP1ꢀC14, 115.71(4); Pd1ꢀBr1ꢀPd1, 94.32(1); C10ꢀC9ꢀP1,
28.7(1); C20ꢀC19ꢀP1, 125.57(9); C15ꢀC14ꢀP1, 126.5(1); Pd1ꢀP1ꢀC9ꢀC10, 163.9(1); Pd1ꢀP1ꢀ
1
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C14ꢀC15, 49.9(1); Pd1ꢀP1ꢀC19ꢀC20, 60.9(1).
Oxidative addition of aryl halides to PdL can be envisioned to proceed by three main
2
mechanisms: dissociative ligand loss followed by oxidative addition (path A), direct oxidative
addition to the L Pd species (path B), or associative displacement of the ligand by aryl halide
2
1
6a
followed by oxidative addition (Scheme 4). Prior experimental and computational studies have
16a,17a
shown that path B is unlikely with sterically demanding ligands,
although it may be
1
6c
possible in the case of PCy3.
Both paths A and C have a potentially reversible ligand
displacement followed by the oxidative addition step. In path A, a reversible ligand dissociation
followed by rate limiting oxidative addition would result in a rate expression with an inverse
dependence on ligand concentration and a nonꢀlinear dependence on aryl halide. The inverse of
this rate expression would depend linearly on [L] and inversely on [ArX] with the same nonꢀzero
yꢀintercept if 1/kobs is plotted versus 1/[ArX] or [L]. If ligand dissociation is rate limiting and
irreversible, then the rate expression would be a simple first order dependence on [PdL ] with no
2
dependence on [L] or [ArX]. The associative pathway (path C) requires a first order dependence
on [ArX] in all cases. If oxidative addition were rate limiting, there would be an inverse
dependence on [L]. Conversely, if associative ligand substitution were rate limiting, there would
be no ligand concentration dependence. Thus the mechanism can be ascertained by analysis of
the effect of aryl halide and ligand concentration on the rate of the reaction.
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Scheme 4. Possible Mechanism for the Oxidative Addition of ArX to Pd(PNp3)2.
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The rate of the reaction of Pd(PNp ) (7.9 mM) with aryl bromides 2a, 2b, and 2c was
3
2
determined under pseudoꢀfirst order conditions over the aryl bromide concentration range of 150
3
1
to 310 mM in toluene at 60 °C. Reaction progress was followed by P NMR spectroscopy by
observing the decrease in the concentration of Pd(PNp ) . Pd(PNp ) , dimeric complexes 3a-b,
3
2
3 2
and free PNp were the only phosphorus containing products observable for 2a and 2b (Figure
3
S59, Supporting Information). In the case of 2c, the oxidative addition product is converted to
palladacycle 4 after formation (Scheme 3). Formation of complex 4 is irreversible under these
conditions. In addition, complex 4 does not react with aryl halides. Therefore, conversion of 3c
to 4 does not affect the rate of Pd(PNp ) consumption in the reaction with 2c. Oxidative addition
3
2
products 3a-c give broad spectra at the reaction temperature due to isomerization between
stereoisomeric forms, which makes accurate integration difficult. Therefore, the decrease in the
concentration of Pd(PNp ) was used to determine the reaction rate. Plotting ln[Pd(PNp ) ]
3
2
3 2
versus time afforded linear plots indicating that the reactions were first order in palladium (see
Supporting Information). At 0.15 mM 1ꢀbromoꢀ4ꢀtertꢀbutylbenzene (2a), the observed rate
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constant was 1.11 x 10 s . Changing the concentration of 2a over a factor of 2 had no effect on
the reaction rate (Figure 3, Table S2, Supporting Information) indicating a zero order
dependence on [ArBr]. Oxidative addition of 2b and 2c to Pd(PNp ) were also zero order in
3
2
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ꢀ4 ꢀ1
[
ArBr] and gave a similar rate constant (1.05 ± 0.07 x 10 s ) to that observed with 2a. The lack
of dependence of the reaction rate on the concentration and identity of the aryl bromide shows
that the aryl bromide is not involved in the rate determining step of the oxidative addition
reaction.
Figure 3. Plot of aryl bromide concentration vs. first order rate constant for the oxidative
addition of 2a (red square), 2b (blue diamond), and 2c (green triangle) to 1.
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The effect of added ligand on the oxidative addition was then studied. The oxidative
addition of 2a (80 mM) to Pd(PNp ) (7.9 mM) was carried out in the presence of 2, 4, 6, and 10
3 2
equivalents of PNp (16 to 79 mM) at 60 °C. The reactions in the presence of additional PNp3
3
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proceeded in the same fashion as those run in the absence of added ligand. The decay of
Pd(PNp ) was linear with no evidence of an induction period. At all concentrations of excess
3
2
PNp tested, the observed rate constant was the same within experimental error (0.86 ± 0.02 X
3
ꢀ
4 ꢀ1
1
0 s , Figure 4). Thus, the reaction is also zero order in [PNp ].
3
Figure 4. Plot of excess PNp concentration vs. first order rate constant for the oxidative
3
addition of 2a (10 mM) to 1.
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The zero order dependence of both [ArBr] and [PNp ] on the rate of the oxidative addition
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reaction is only consistent with a mechanism involving rate limiting irreversible ligand
dissociation followed by oxidative addition (Path A, Scheme 4). Therefore, the observed rate
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ꢀ4 ꢀ1
constant 1.0 ± 0.15 X 10 s corresponds to k , the ligand dissociation rate constant. Other
1
sterically demanding trialkylphosphines, such as P(tꢀBu) , (1ꢀAd)P(tꢀBu) , CyP(tꢀBu) , and PCy
3
3
2
2
all undergo oxidative addition by mechanisms that involve reaction of the aryl halide directly
1
6a,16c
with PdL as a competitive mechanistic pathway.
Of the systems studied to date, only Qꢀ
2
phosꢀtol (1ꢀdi(tertꢀbutyl)phosphinoꢀ1',2',3',4',5'ꢀpenta(4ꢀtolyl)ferrocene) undergoes oxidative
16b
addition by rate limiting irreversible ligand dissociation.
Trineopentylphosphine has a smaller
ꢀ4
ꢀ1
16b
dissociation rate constant than that reported for Qꢀphosꢀtol (6 X 10 s at 50 °C).
Similar kinetic studies were conducted on the oxidative addition of aryl chlorides to
Pd(PNp ) . In the absence of excess PNp , 4ꢀchlorotoluene (2d), 2ꢀchlorotoluene (2e), and 2ꢀ
3
2
3
chloroꢀmꢀxylene (2f) were reacted with Pd(PNp ) under pseudoꢀfirst order conditions at 70 °C
3 2
(
eq 3). The plot of ln[Pd(PNp ) ] vs. time gave a linear relationship indicating these reactions
3 2
were first order in palladium (see Supporting Information). Plotting kobs vs. [ArCl] showed that
the reaction rate had a positive, but nonꢀlinear, dependence on [ArCl] (Figure 5). In addition, the
rate of the reaction depended on the identity of the aryl chloride with the reaction occurring
faster with less hindered aryl chlorides (2d > 2e > 2f). The oxidative addition of 4ꢀchlorotoluene
(2d) was then performed in the presence of excess PNp . Plotting kobs vs. [PNp ] provides a
3
3
negative dependence of the rate on [PNp ] (Figure 6).
3
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Figure 5. Plot of aryl chloride concentration vs. first order rate constant for the oxidative
addition of 2d (red square), 2e (blue diamond), and 2f (green triangle) to 1.
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Figure 6. Plot of excess PNp concentration vs. first order rate constant for the oxidative
3
addition of 2d (10 mM) to 1.
The results in Figures 5 and 6 show that aryl chlorides react by a different mechanism than is
observed for aryl bromides. The inverse ligand dependence is consistent with a reversible ligand
loss, as opposed to the irreversible ligand dissociation seen for aryl bromides. Both the reversible
dissociative displacement mechanism (path A) and reversible associative ligand substitution
(path C) are consistent with a positive dependence on [ArCl] and a negative dependence on
[
PNp ]. Path C would be expected to have a linear dependence on [ArCl], however. Plotting
3
1
/kobs vs. 1/[ArCl] and [PNp ] allows the two mechanisms to be further distinguished (Scheme
3
4). The reversible associative displacement mechanism (path A) should provide linear plots for
both 1/kobs vs. 1/[ArCl] and 1/kobs vs. [L] with both plots giving the same nonꢀzero yꢀintercept.
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The dissociative mechanism (path C) would also give linear plots for 1/kobs vs. 1/[ArCl] and
1/kobs vs. [L]. In this case, the 1/kobs vs. 1/[ArCl] plot would have a yꢀintercept of zero, whereas
the 1/kobs vs. [L] plot would have a nonꢀzero yꢀintercept.
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A plot of 1/kobs and 1/[ArCl] provides a linear plot for 2d, 2e, and 2f with a nonꢀzero yꢀ
intercept (Figure 7). The yꢀintercepts for 2d and 2e are identical (4,800 s), whereas a higher
value (6,600 s) is obtained with 2f. The nonꢀzero yꢀintercept is consistent with reversible ligand
dissociation prior to rate limiting oxidative addition as the major pathway. A plot of 1/kobs vs.
[PNp ] shows a positive correlation that appears to deviate from linearity at higher ligand
3
2
concentration (R = 0.977, Figure 8). Linear regression provides a yꢀintercept of 13,800 s, which
is a factor of 2ꢀ3 larger than those obtained from the aryl chloride plots.
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Figure 7. Plot of [ArCl] concentration vs. kobs for the oxidative addition of 2d (red square), 2e
2
(
blue diamond), and 2f (green triangle) to 1. Black lines show linear regression (R > 0.99)
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Figure 8. Correlation of the Inverse of Observed Rate Constant (1/k ) and the Concentration of
obs
PNp Ligand in Excess of 4ꢀChlorotoluene ([Pd(PNp ) ] : [4ꢀChlorotoluene] = 1: 10 ). ( linear fit:
3
3 2
3
4
2
y = 1.04*10 x + 1.39*10 , R = 0.977)
Although the yꢀintercept of the plots obtained in these experiments are not identical, they fall
within a relatively narrow range. Significantly, the plot of 1/kobs vs. 1/[ArCl] has a nonꢀzero yꢀ
intercept, which would exclude the associative pathway (Path C). The average yꢀintercept values
for the three aryl chlorides (Figure 7) provides a ligand dissociation rate constant (k , Scheme 4)
1
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of 1.8 X 10 s at 70 °C. This values is approximately twice that obtained for k from the
1
ꢀ4
ꢀ1
oxidative addition of aryl bromides at 60 °C (1 X 10 s ), which is consistent with the higher
temperature. The fact that the values for the ligand dissociation rate constants (k ) obtained with
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aryl bromides and chlorides are comparable provides strong support for both processes involving
ligand dissociation as a first step. The rate of this step should be independent of the aryl halide,
whereas an associative ligand substitution would be dependent on the nature of the aryl halide.
The evidence indicates that oxidative addition of aryl chlorides proceeds by a reversible
dissociation of ligand followed by rate limiting oxidative addition (Path A, Scheme 4). This is
the same mechanism seen for the oxidative addition of aryl chlorides with other bulky
1
6a,16b
trialkylphosphines.
The reaction of aryl bromides and chlorides both involve dissociative
loss of PNp . In the case of the more reactive aryl bromide, oxidative addition occurs rapidly and
3
the ligand dissociation is rate limiting. With the less reactive aryl chloride, the oxidative addition
is rate limiting and ligand dissociation is reversible.
Reaction of aryl halide complexes with aniline. The next step in the standard mechanism is
the coordination of the amine nucleophile to the arylpalladium complex (Scheme 2). The fourꢀ
2
5
coordinate amine complex has been characterized for complexes of triꢀ(oꢀtolylphosphine),
12b,12c
SPhos, and XPhos.
Analogous complexes of sterically demanding trialkylphosphines have
not been reported. Dimeric aryl halide complexes 3a and 3b were reacted with aniline and 2,6ꢀ
diisopropylaniline in an effort to generate the amine adducts (6, Scheme 5). Treatment of 3a or
31
3
b with 20 equivalents of aniline or 2,6ꢀdiisopropylaniline resulted in no change in the P NMR
spectrum at room temperature after 20 minutes. Heating of the reaction at 60 °C resulted in slow
formation of palladacycle 4 and loss of arene. Coordination of aniline is not thermodynamically
favored for dimeric complexes 3a and 3b. Aniline complexation to [(SPhos)PdPh(µꢀCl)] has
2
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been observed spectroscopically.
The relative binding constant for aniline is three orders of
magnitude less than that of morpholine, however.
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Scheme 5. Reaction of aniline derivatives with Pd(II)ꢀaryl complexes 3a-b
We hypothesized that aniline coordinates in an unfavorable equilibrium with the arylpalladium
complex (3) followed by a thermodynamically favored deprotonation to give the palladium
amide intermediate that undergoes irreversible reductive elimination. Deprotonation of the
relatively acidic palladium bound amine by the strong base should be strongly favored
thermodynamically and would likely occur with a high rate. Buchwald observed that the
competitive reaction of (Sꢀphos)Pd(Ph)Cl with dibutylamine and aniline resulted in no
12c
observable binding of aniline.
Upon introduction of base, only diphenylamine was formed,
however. These results suggest that the aniline complex is formed as a minor component at
equilibrium, but undergoes conversion to product much faster than the more abundant
dibutylamine complex.
To test this hypothesis, a solution of complex 3b was generated by reacting Pd(PNp ) (7.7
3
2
mM) with 2ꢀbromotoluene (77 mM) in toluene at 80 °C (Scheme 6). The reaction was followed
3
1
by P NMR spectroscopy and reached completion after 35 minutes. After the consumption of
Pd(PNp ) was complete, 2,6ꢀdiisopropylaniline (5b, 18.5 mM) and NaOꢀtꢀBu (30.8 mM) were
3
2
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added to the NMR tube and the reaction was monitored by P NMR spectroscopy. In less than
five minutes, complex 3b and the free PNp were completely converted to Pd(PNp ) with
3
3 2
formation of the diaryl amine product (Scheme 6). Individually, aniline shows no observable
reaction with 3a and NaOtꢀBu decomposes complex 3. In combination, aniline and NaOtꢀBu
cleanly react with 3b to give Pd(PNp ) and the diaryl amine product. This process happens
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significantly faster than the formation of aryl palladium dimer 3b from 1.
Scheme 6. Reaction of arylpalladium complex 3b with aniline and NaOtꢀBu
The possibility of alkoxide coordination to palladium prior to amine coordination has been
18
proposed for some systems. To explore this possibility, complex 3a was reacted with an excess
NaOꢀtꢀBu (10 equivalents). The reaction resulted in consumption of 3a and formation of multiple
uncharacterized, nonꢀpalladacycle phosphorusꢀcontaining products in the NMR spectrum. In the
presence of both aniline and base, complex 3b cleanly turns over the catalytic cycle to give
Pd(PNp ) (Scheme 6). This result suggests that the reaction of aniline and base with the
3
2
arylpalladium intermediate to turn over the catalytic cycle is much faster than the decomposition
of 3b by tertꢀbutoxide.
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Full Catalytic Reaction Profile. The reaction profile for the full catalytic reaction was
analyzed for the coupling of aryl bromides and aryl chlorides with anilines catalyzed by
Pd(PNp ) (eq 4). The reaction of 1ꢀbromoꢀ4ꢀtertꢀbutylbenzene (2a) or 2ꢀbromoꢀmꢀxylene (2c)
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
with 2,6ꢀdiisopropylaniline (5b) occurred at nearly identical rates to give complete conversion in
approximately 50 minutes at 60 °C (Figure 9). Aniline (5a) gives significantly slower conversion
rates than 2,6ꢀdiisopropylaniline, however. In addition, 2a reacted faster with aniline than the
more hindered 2c. Only 50% conversion was observed after six hours when aniline was reacted
with 2c, compared to complete conversion of 2a in less than 4 hours. All aryl bromide and
aniline combinations show an induction period early in the reaction prior to achieving maximum
conversion rate.
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9
1
1
1
1
1
1
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1
1
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0
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 9. Reaction profile for the Pd(PNp ) ꢀcatalyzed coupling of 2a and 5a (red square, solid
3 2
line), 2a and 5b (red square, dotted line), 2c and 5a (green triangle, solid line), and 2c and 5b
(green triangle, dotted line). Product yields determined by GC.
The same analysis was done on the coupling of 4ꢀchlorotoluene (2d) and 2ꢀchloroꢀmꢀxylene
(2f) with aniline (5a) and 2,6ꢀdiisopropylaniline (5b) at 70 °C (eq 5). The amination occurred at
a higher rate with 4ꢀchorotoluene than 2ꢀchloroꢀmꢀxylene whether the aryl amine was aniline or
2,6ꢀdiisopropylaniline (Figure 10). Similar to the reaction with aryl bromides, aniline was
arylated at a much slower rate than the more sterically demanding 2,6ꢀdiisopropylaniline. In
contrast to aryl bromides, no induction period is observed for the coupling of aryl chlorides with
aniline derivatives.
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ACS Catalysis
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Figure 10. Reaction profile for the Pd(PNp ) ꢀcatalyzed coupling of 2d and 5a (red square, solid
3
2
line), 2d and 5b (red square, dotted line), 2f and 5a (green triangle, solid line), and 2f and 5b
(green triangle, dotted line). Product yields determined by GC.
With the hindered 2,6ꢀdiisopropylaniline (5b), the results are consistent with the oxidative
addition studies. Aryl bromides have little effect on the rate of the catalytic reaction, whereas
more hindered aryl chlorides are coupled at slower rates than unhindered aryl chlorides. These
results are consistent with the fact that rate of oxidative addition is independent of the aryl
bromide, but depends on the aryl chloride. In contrast, the rate of coupling of both aryl bromides
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9
1
1
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1
1
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6
and chlorides with aniline is strongly dependent on the steric demand of the aryl halide. In
addition, aniline (5a) causes a significant inhibition of the coupling reaction. Another noteworthy
point is that an induction period is observed in the coupling of aryl bromides. No induction
period is seen in the oxidative addition of aryl bromides, however.
0
1
2
3
4
5
6
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8
9
0
1
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9
0
1
2
3
4
5
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7
8
9
0
Substrate competition studies. In order to gain more insight into the effect of substrate steric
hindrance on the coupling reaction, competition experiments in which two aryl halides were
coupled in the same reaction were performed. Competition studies were performed by reacting
aniline or 2,6ꢀdiisopropylaniline (1 equiv) with a mixture of aryl halides (3 equiv each) in the
presence of Pd(PNp ) (0.01 equiv) and NaOtꢀBu (1.5 equiv) in toluene at 90 °C (eq 6). The
3
2
reactions were analyzed by GC, which allowed the quantity of both residual aryl halides and both
diaryl amine products to be determined (Table 1). In the coupling of 1ꢀbromoꢀ4ꢀtertꢀ
butylbenzene (2a) and 2ꢀbromoꢀmꢀxylene (2c) with aniline (5a), the aniline was completely
consumed to give a 64:36 ratio of products 7aa and 7ca favoring coupling of the less hindered
aryl bromides (2a). The preference for 2a is slightly stronger in the case of the more hindered
aniline (5b, 68:32 7ab:7cb). Independent rate measurements of 2a and 2c reacting with 5b show
little difference in rate, presumably because the oxidative addition step is not rate determining.
When the two aryl bromides are both present, the relative reaction rates for the oxidative addition
2
a and 2c to Pd(PNp ) can be observed. As expected, the less hindered aryl bromide reacts faster
3
in the oxidative addition step.
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Table 1. Product ratios for competitive coupling of aryl halide mixtures with aniline derivatives.
1
2
3
1
3
2
3
Ar X/Ar X Ar NH
Ar NHAr
Ar NHAr
2
a
a
yield (%)
64 (7aa)
68 (7ab)
68 (7da)
yield (%)
36 (7ca)
32 (7cb)
32 (7ca)
37 (7cb)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2a/2c
2a/2c
2d/2f
2d/2f
5a
5b
5a
5b
72 (7db)
a
Product yields determined by GC analysis
The coupling of an excess of aryl chlorides (2d and 2f) with a limiting amount of aniline or
2,6ꢀdiisopropyl aniline at 90 °C resulted in complete consumption of aniline to give a mixture of
diaryl products (Table 1). The product ratio for the mixture of 4ꢀchlorotoluene (2d) and 2ꢀchloroꢀ
mꢀxylene (2f) favored the 2dꢀderived product by a slightly higher ratio (68:32 7da:7ca) than was
seen with aryl bromides. As was seen with the aryl bromides, the less hindered aryl chloride was
favored by a slightly higher ratio with the more hindered aniline 5b (73:27 7db:7cb). The
product selectivity appears to be primarily determined by the preference for the Pd(PNp ) active
3
species to oxidatively add the less hindered aryl halide. This preference is not strongly affected
by the halide identity.
Because of the fast rate of the reaction of aniline and base with aryl halide dimers, the kinetics
of this portion of the catalytic cycle could not be studied independently. To probe this portion of
the mechanism, we performed a competition experiment using a limiting amount of an aryl
halide (2a-f) with an excess of a mixture of aniline (5a) and 2,6ꢀdiisopropyl aniline (5b) or 2ꢀ
toluidine (5c) and 5b (eq 7). The resulting products were analyzed by GC and reported in Table
2. In each case, only the secondary amines derived from the lessꢀhindered aniline (5a or 5c) were
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9
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detected at the end of the reactions with no products derived from 5b observed. These results
contrast with the rate profiles for individual aniline derivatives, which show that aniline 5a gives
much slower rates than does the more hindered 5b (Figures 9 and 10). Another observation from
these studies was that the 2,6ꢀdisubstituted aryl halides (2c and 2f) gave incomplete conversion
in the presence of aniline (2a), whereas the less hindered aryl halides were completely
consumed. Complete conversion is seen for the coupling of 2c and 2f with the mixture of more
hindered aryl amines (5c and 5b).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 2. Product ratios for competitive coupling of aryl halides with aniline mixtures.
1
2
3
1
2
1
3
Ar X Ar NH Ar NH
2
Ar NHAr
Ar NHAr
2
/
a
a
yield (%)
yield (%)
0 (7ab)
0 (7bb)
0 (7cb)
0 (7ab)
0 (7bb)
0 (7cb)
0 (7db)
0 (7eb)
0 (7cb)
0 (7db)
2
a
5a/5b
5a/5b
5a/5b
5c/5b
5c/5b
5c/5b
5a/5b
5a/5b
5a/5b
5c/5b
100 (7aa)
100 (7ba)
49 (7ca)
2
b
2
c
2
a
100 (7ac)
100 (7bc)
100 (7cc)
100 (7da)
100 (7ea)
52 (7ca)
2
b
2
c
2
d
2
e
2
f
2
d
100 (7dc)
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2
e
5c/5b
5c/5b
100 (7bc)
100 (7cc)
0 (7bb)
0 (7cb)
2
f
a
Product yields determined by GC analysis
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4. Aniline inhibition
The nature of the inhibitory effect of aniline on these reactions was not immediately apparent.
Stoichiometric studies showed that the reaction of the oxidative addition product 3 with aniline
in the presence of base is fast relative to oxidative addition. Thus, it is not clear what kinetic role
aniline would play in the catalytic cycle. We first considered whether aniline has an effect on the
rate of oxidative addition, perhaps by coordinating to the Pd(PNp ) species and inhibiting the
3
oxidative addition step. The oxidative addition of 2a (20 equiv) to Pd(PNp ) was carried out in
3
2
the presence of aniline or 2,6ꢀdiisopropylaniline (30 equiv) at 60 °C for 6 hours (eq 8). The rate
of consumption of Pd(PNp ) was observed to be slightly faster in the presence of anilines 5a or
3
2
5
b than in their absence (Table 3). Palladacycle 4 was formed in the presence of 5a or 5b with a
corresponding decrease in the oxidative addition yield, however. Palladacycle 4 does not form in
the absence of aryl amine under these conditions. Complex 4 was formed in larger amounts in
the presence of aniline (5a) than with the more hindered 5b.
Table 3. Product distribution for oxidative addition of 2a to Pd(PNp ) in the presence of aniline
3
2
a
a
a
aniline
none
1 (%)
3a (%)
4 (%)
14
86
0
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