Development of new palladium catalysts for the alkoxycarbonylation of aryl chlorides

Article abstract of DOI:10.1016/S0022-328X(01)01293-1

The alkoxycarbonylation of different aryl chlorides was studied. Studies of the butoxycarbonylation of 4-chlorobenzotrifluoride and chlorobenzene using chelating ferrocenylphosphines reveal the advantages of these ligands compared to the well-known tricyc

Full text of DOI:10.1016/S0022-328X(01)01293-1

Journal of Organometallic Chemistry 641 (2002) 30–40
www.elsevier.com/locate/jorganchem
Development of new palladium catalysts for the
alkoxycarbonylation of aryl chlorides
Wolfgang Ma¨gerlein a, Adriano F. Indolese b, Matthias Beller a,*
a Institut fu¨r Organische Katalyseforschung (IfOK) an der Uni6ersita¨t Rostock e.V., Buchbinderstraße 5-6, D-18055 Rostock, Germany
b Sol6ias AG, WRO-1055.622, Klybeckstraße 191, CH-4002 Basel, Switzerland
Received 2 May 2001; accepted 7 August 2001
Abstract
The alkoxycarbonylation of different aryl chlorides was studied. Studies of the butoxycarbonylation of 4-chlorobenzotrifluoride
and chlorobenzene using chelating ferrocenylphosphines reveal the advantages of these ligands compared to the well-known
tricyclohexylphosphine (PCy3). (1-{2-(Dicyclohexylphosphino)ferrocenyl}ethyldicyclohexylphosphine (4) was shown to give the
most active palladium catalyst system. The usefulness of this catalyst is demonstrated in the alkoxycarbonylation of various aryl
chlorides. Optimized carbonylation conditions were realized by a statistical design of three critical reaction parameters. © 2002
Elsevier Science B.V. All rights reserved.
Keywords: Carbonylation; Palladium; Ferrocenyl phosphines; Aryl chlorides; Homogeneous catalysis; Benzoic acids
1. Introduction
cleophiles a variety of acids, esters, amides, aldehydes,
ketones and other carboxylic acid derivatives are acces-
sible [2] (Scheme 1).
An especially interesting class of starting materials
for the refinement of aryl halides are aryl chlorides,
owing to their low cost and commercial availability
with a variety of substitution patterns. These substrates,
however, usually display a lower reactivity compared to
the corresponding bromides and iodides. Therefore,
special catalyst systems, which facilitate the oxidative
Palladium-catalyzed CꢀC and CꢀX (X=N, O, S)
coupling reactions of aryl halides constitute powerful
methods in synthetic organic chemistry [1]. The palla-
dium-catalyzed carbonylation of aryl halides (or halide
equivalents) is an especially valuable tool for the selec-
tive introduction of a carboxylic group into aromatic
frameworks. By reacting the respective aryl substrate
with carbon monoxide and ubiquitously available nu-
Scheme 1. Carbonylation of aryl-X derivatives.
* Corresponding author. Tel.: +49-381-466930; fax: +49-381-4669324.
E-mail address: matthias.beller@ifok.uni-rostock.de (M. Beller).
0022-328X/02/$ - see front matter © 2002 Elsevier Science B.V. All rights reserved.
PII: S0022-328X(01)01293-1

W. Ma¨gerlein et al. / Journal of Organometallic Chemistry 641 (2002) 30–40
31
addition of the aryl chlorides are required for efficient
activation [3].
Again product yields were comparably low (20%) and
the high temperature required for the reaction makes
the incorporation of sensitive functional groups into the
substrate impossible [9]. Aminocarbonylation employ-
ing a palladium catalyst based on 1,2-bis(diphenylphos-
phino)ethane in the presence of sodium iodide proceeds
under mild conditions with high yields. In general, the
scope of aryl chloride substrates was restricted to elec-
tron-deficient (i.e. activated) derivatives [10]. Lately, we
demonstrated that palladium salts in the presence of
dppb or dppf are efficient catalysts for the carbonyla-
tion of heteroaryl chlorides [11]. However, these cata-
lysts only work efficiently with activated aryl chloride
substrates.
Very recently we discovered that a catalyst system
consisting of palladium and a ferrocenylphosphine en-
ables the carbonylation of electron-deficient, electroni-
cally neutral and electron-rich aryl chlorides in good to
excellent yield [12]. This represents a substantial im-
provement in efficiency, utility and practicability of this
interesting coupling reaction. Critical to the success of
this method is the use of cyclohexyl-substituted, biden-
tate ferrocenyl phosphine ligands along with sodium
carbonate as a base. After an initial communication
[12], we describe here a full account of our work on the
development of this new catalyst.
Significant progress has been made very recently in
the activation of aryl chlorides for coupling reactions
such as the Heck olefination [4], and the Suzuki aryla-
tion [5], using palladium catalyst systems modified with
sterically demanding, basic, monodentate phosphine or
carbene ligands.
With regard to the importance of benzoic acid
derivatives, it is surprising that the efficient carbonyla-
tion of aryl chlorides is still a challenging problem.
Clearly, the carbonylation of aryl chlorides is more
difficult compared to other CꢀC coupling reactions due
to the presence of a large excess of p-accepting carbon
monoxide ligand. Carbon monoxide bound to the metal
center reduces the activity of the palladium complex
towards oxidative addition. Moreover, clustering and
agglomeration of Pd atoms is facile in the presence of
CO [6], leading to non-active palladium species. Until
recently, only the discovery by Milstein and coworkers
[7], who introduced palladium complexes containing the
highly basic 1,3-bis(di-iso-propylphosphino)propane
ligand, provided a more general solution to the car-
bonylation of aryl chlorides. The drawbacks of this
catalyst system, however, are the difficulty in synthesis
and the high sensitivity of this pyrophoric phosphine
along with the comparatively low turnover numbers of
the catalyst (1 mol% of palladium). Other catalyst
systems known in the literature for the carbonylation of
aryl chlorides suffer from additional disadvantages. Tri-
cyclohexylphosphine (PCy3) has been most often em-
ployed as a ligand for the palladium-catalyzed hydroxy-
or methoxycarbonylation of chloroarenes. Unfortu-
nately, the reported yields of the carbonylation prod-
ucts were always below 30% [8]. In another approach,
aryl chlorides were reacted using a heterogeneous Pd/C
catalyst at high temperatures (200 °C) within 50 h.
2. Results and discussion
2.1. Preliminary carbonylation experiments with
tricyclohexylphosphine as the ligand
In initial studies to develop more efficient carbonyla-
tion catalysts we examined the butoxycarbonylation of
aryl chlorides in the presence of the PCy3 ligand (Table
1). Aryl chloride substrates 4-chloroacetophenone
Table 1
Carbonylation of aryl chlorides in the presence of PCy3 as the ligand a
Entry
Aryl chloride (R)
Base
CO-pressure (bar)
Yield (%) b
1
4-COCH3
4-COCH3
4-COCH3
4-CF3
4-CF3
4-CF3
NaOAc
NaOAc
NEt3
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
15
15
15
15
25
3
80
25
14
56
24
38
6
2 c
3
4
5
6
7 d
8
H
15
15
4-OCH3
B5
a Aryl chloride (7 mmol), 14 ml n-butanol.
b Determined by GC using diethyleneglycol di-n-butylether as an internal standard.
c 130 °C.
d 15 h.

32
W. Ma¨gerlein et al. / Journal of Organometallic Chemistry 641 (2002) 30–40
Furthermore, the respective benzoic acids were iden-
tified in small amount as by-products (B10%).
Catalyst systems based on the PCy3 ligand (at rea-
sonable temperatures and Pd concentrations) are ap-
parently restricted to the conversion of chloroarenes
activated by electron-withdrawing groups.
In order to overcome this problem we sought ligands
leading to more efficient palladium catalysts, thus per-
mitting the reaction of aryl chlorides independent of
their electronic nature under milder reaction conditions
(temperature, CO pressure, Pd concentration). During
the course of our ligand studies, Pd in the presence of
bidentate phosphines with ferrocenyl moiety as the
ligand backbone showed considerable carbonylation ac-
tivity (Scheme 2).
Scheme 2. Ferrocenyl phosphine ligands for aryl chloride carbonyla-
tion.
In the past enantiomerically pure ligands 1–4 of the
Josiphos type [16] were employed very successfully in
asymmetric catalytic processes, e.g. hydrogenations
[17]. Contrary to most other electron-rich phosphines
1–5 are comparatively stable and can be handled under
air in solid form.
(highly activated aryl chloride), 4-chlorobenzotrifl-
uoride (slightly activated aryl chloride), chlorobenzene
(non-activated aryl chloride) and 4-chloroanisole (deac-
tivated aryl chloride) were chosen. PCy3 was employed
because this is the most common ligand previously
reported for aryl chloride carbonylations. We thought
the results would give a good impression about the
current status of aryl chloride alkoxycarbonylation in
the presence of a standard ligand.
2.2. Test system 4-chlorobenzotrifluoride/Josiphos:
e6aluation of critical reaction parameters
When employing the activated substrate (4-
chloroacetophenone) we observed an 80% yield of n-
butyl 4-acetylbenzoate in the presence of 0.5 mol%
PdCl2(PhCN)2, PCy3 and three equivalents of NaOAc
(145 °C, 15 bar CO, 24 h, entry 1, Table 1). Based on
our previous model studies of carbonylation reactions
[13], we employed an excess of phosphine ligand (P/
Pd=14) in order to activate the palladium catalyst by
displacing CO ligands from the metal center [14].
A temperature of about 145 °C seems to be a lower
limit for the activity of the Pd/PCy3-catalyst since the
ester yield decreases to 25% when the temperature is
lowered to 130 °C (entry 2, Table 1). The use of NEt3
instead of NaOAc as the base leads to a dramatic drop
in the catalyst efficiency (entry 3, Table 1). In general,
we found that amines are inferior to inorganic bases for
aryl chloride carbonylation [15].
With the less-activated substrate (4-chlorobenzotrifl-
uoride) a yield of only 56% of the n-butyl ester was
observed, which is significantly lower compared to 4-
chloroacetophenone (cf. entries 1 and 4, Table 1). CO
pressures above or below 15 bar (entries 5 and 6, Table
1) had a negative effect on the catalyst productivity.
Electron-neutral/electron-rich substrates (chloroben-
zene and 4-chloroanisole, entries 7 and 8, Table 1)
essentially fail to react under the same conditions.
In addition to the desired products, considerable
amounts of n-butyl acetate were formed in all experi-
ments where NaOAc was used as the base (e.g. entry 2:
73%, entry 4: 41%). Interestingly, the yield of n-butyl
acetate is directly proportional to the product yield.
The reaction of 4-chlorobenzotrifluoride with CO
and n-butanol in the presence of a PdCl2(PhCN)2/
Josiphos (1) catalyst under similar conditions compared
to the PCy3 ligand (i.e. 0.5 mol% Pd, P/Pd=14, 3
equivalents NaOAc, 145 °C, 14 bar CO) leads to n-bu-
tyl 4-trifluoromethylbenzoate in 67% yield after 15 h
(cf. 56% yield after 24 h with PCy3). This promising
result encouraged us to establish optimal conditions for
the reaction. Based on our results [13] as well as those
of other groups [18], the most important reaction
parameters (temperature: 130, 145, 160 °C; CO pres-
sure: 3, 14, 25 bar; P/Pd-ratio: 2, 8, 14) were varied
using a statistical approach. Clearly, these variables are
not independent of each other, i.e. a change of one
variable may be different at two different values of
another variable. It is possible to reduce the necessary
33=27 experiments to 15 by virtue of statistical calcu-
lations, without losing any essential information [19]
(Table 2).
The results in Table 2 show that in all cases the yield
of n-butyl 4-trifluoromethylbenzoate is lower than the
conversion. This difference in yield is explained by the
formation of 4-trifluoromethylbenzoic acid which is
formed along with considerable amounts of n-butyl
acetate (vide infra). Since no other side-products (e.g.
through dehalogenation, aryl-aryl-coupling, etc.) were
obtained, the conversion instead of the product yield is
the measure for the carbonylation activity of the cata-
lyst system. The time/conversion plot of the reaction
and the fact that no palladium metal forms indicate
that the catalyst is still active after 15 h.

W. Ma¨gerlein et al. / Journal of Organometallic Chemistry 641 (2002) 30–40
33
Table 2
Butoxycarbonylation of 4-chlorobenzotrifluoride in the presence of Josiphos (1) as the ligand; systematic variation of the reaction parameters
temperature, pressure, P/Pd ratio
Entry
T (°C)
p (bar)
P/Pd
Conversion (%) a
Yield of ester (%) a
Selectivity (%) b
1
2
3
4
5
6
130
130
130
130
130
145
145
145
145
145
160
160
160
160
160
144.3
3
3
25
25
14
3
14
25
14
14
3
2
14
2
14
8
8
8
8
2
14
2
14
2
14
8
14
70
75
39
39
52
97
91 (89)
90
73
98
84
99
85
99
93
100
61
65
29
30
46
74
73 (72)
68
61
67
64
72
68
52
35
78
87
87
74
77
88
76
80 (81)
76
84
68
76
73
80
53
38
78
7 c
8
9
10
11
12
13
14
15
16
3
25
25
14
3
The difference in conversion and product yield is made up of 4-trifluoromethylbenzoic acid: 7 mmol 4-chlorobenzotrifluoride, 14 ml n-butanol.
a Determined by GC using diethyleneglycol di-n-butylether as an internal standard.
b Selectivity=ester yield/conversion.
c Results of a reproduction experiment in brackets.
The results indicate that 145 °C is a reasonable
temperature for both activity and selectivity of the
catalyst with the conversions essentially above 90% and
yields of around 70% (entries 6–8, 10, Table 2). At
130 °C the change of CO pressure exerts a much
stronger influence on the conversions and yields than
the P/Pd ratio (cf. entries 1–4, Table 2). Thus, at 3 bar
CO conversions and yields of about 70% are virtually
not affected by the concentration of 1 (entries 1 and 2,
Table 2). In contrast at 145 °C the decrease in catalyst
efficiency upon raising the CO pressure is much less
pronounced, as demonstrated by entries 6–8 (Table 2).
Instead of which the P/Pd ratio influences the conver-
sion much more (cf. entries 7, 9 and 10, Table 2). At 3
bar CO and with P/Pd=8 (entry 6, Table 2) the
conversion is essentially quantitative (76% selectivity).
Repetition of the experiment in entry 7 underlines the
very good reproducibility of the system (73 vs. 72%
yield of n-butyl 4-trifluoromethylbenzoate). At 160 °C
the general tendencies with regard to the influence of
CO pressure and P/Pd ratio are the same as those at
145 °C. At this high temperature, the carbonylation
activity (conversion) of the catalyst is generally higher,
but the selectivity becomes worse (entries 11–15, Table
2). From these results an optimum set of values within
the limits of the variables was calculated. Applying the
calculated conditions (T=144 °C, p=3 bar, P/Pd=
14) lead to a further improved conversion of 100% and
a product yield of 78% (entry 16, Table 2). This demon-
strates clearly the feasibility of a statistical reaction
design for palladium-catalyzed carbonylation reactions.
This nice tool for optimizing catalytic reactions should
be used more often, since a significant reduction of
experiments and therefore time and consumables is
possible.
Scheme 3. Proposed mechanism for the formation of 4-trifluoro-
methylbenzoic acid and n-butyl acetate under carbonylation condi-
tions.

34
W. Ma¨gerlein et al. / Journal of Organometallic Chemistry 641 (2002) 30–40
As mentioned above, in all experiments where NaOAc
was used as the base the concomitant formation of the
respective 4-trifluoromethylbenzoic acid and n-butyl ace-
tate was observed. Interestingly, the yields of these
by-products are related and increase with increasing
temperature. The formation of 4-trifluoromethylbenzoic
acid and n-butyl acetate is explained by the following
reactions sequences (Scheme 3).
Additive
Conversion Yield of
Selectivity
(%)
(%)
ester (%)
–
93
96
35
77
38
80
Molecular
sieves
,
(4 A)
A successful carbonylation reaction of the aryl chlo-
ride formally gives an equimolar amount of HCl (Eq. (1),
Scheme 3). The intermediate HPd(L)Cl-complexes react
with NaOAc to give NaCl and HOAc and thus an
amount of HOAc equivalent to the aryl chloride conver-
sion is formed (Eq. (2), Scheme 3). In the presence of a
large excess of alcohol, esterification with n-bu-
tanol takes place to give n-butyl acetate and H2O
(amount equal to the conversion).
It has to be pointed out, that the formation of the
by-products is also conceivable via nucleophilic attack of
the acetate ion on the acyl palladium intermediate with
concomitant formation of the mixed 4-trifluoromethyl-
benzoic acid–acetic acid anhydride and subsequent alco-
holysis. However, this mechanism alone cannot account
for the observed amounts of n-butyl acetate above 100%.
Due to the better leaving group ability of benzoate
compared to acetate, partial hydrolysis of n-butyl 4-tri-
fluoromethylbenzoate is observed under the reaction
conditions (Eq. (4), Scheme 3). The resulting 4-trifl-
uoromethylbenzoic acid and NaOAc yield HOAc since
the pKa of the substituted benzoic acid is lower than that
of acetic acid (Eq. (5), Scheme 3). Esterification of
butanol analogous to Eq. (3) (Scheme 3) leads to the
formation of an additional amount of n-butyl acetate.
Thus, the maximum amount of n-butyl acetate produced
equals two times the conversion of aryl chloride minus
the yield of benzoic acid ester.
The experimental results obtained are in good agree-
ment with the proposed mechanism for the formation of
the by-products. The observed yields of n-butyl acetate
at 160 °C correlate well with the calculated maximum
yields [Table 2, entry 13: 105% (observed) vs. 102%
(calculated) or entry 15: 153% (observed) vs. 151%
(calculated)]. At lower temperatures (130 °C) the esterifi-
cation of acetic acid (and the formation of water) occurs
to a lower extent compared to at 160 °C. Therefore, the
yields of n-butyl 4-trifluoromethylbenzoate are higher
and the observed yields of n-butyl acetate (13–43%) are
below the respective maximum values (49–87%; entries
1–5, Table 2). In a control-carbonylation experiment in
the absence of the aryl chloride (14 ml n-butanol, 21
mmol NaOAc, 0.5 mol% PdCl2(PhCN)2 and 7 mol%
PCy3 at 130 °C and 15 bar CO), but in the presence of
HOAc (7 mmol) the formation of n-butyl acetate (79%
after 24 h) was observed. This indicates that the esterifi-
cation shown in Eq. (3) (Scheme 3) indeed takes place
under the conditions of carbonylation catalysis.
2.3. Butoxycarbonylation of non-acti6ated aryl
chlorides in the presence of ferrocenyl ligands
Since both high conversion and yield was achieved for
the carbonylation of 4-chlorobenzotrifluoride in the
presence of the PdCl2(PhCN)2/Josiphos (1) catalyst
(Table 2), we were interested in the performance of this
type of catalyst with non-activated aryl chlorides. First,
the palladium-catalyzed carbonylation of chlorobenzene
was studied in the presence of 1. Next, other 1,2-disub-
stituted ferrocenyl ligands (2–4) and 1,1%-disubstituted
ferrocenyl phosphines 5 and 6 were employed in this
reaction. For all the experiments the previously opti-
mized conditions of temperature (145 °C), CO pressure
(3 bar) and P/Pd ratio (8) were applied. In addition
,
molecular sieves (4 A) were added in order to restrict the
formation of benzoic acid.
Table 3 gives a summary of the results obtained. When
chlorobenzene is reacted in the presence of the Josiphos
ligand 1, 59% conversion is seen and n-butyl benzoate is
formed in 49% yield (entry 1, Table 3). Although
conversion and product yield are significantly lower
compared to the reaction with 4-chlorobenzotrifluoride,
the catalyst turnover number (TON=98) and turnover
frequency (TOF=6.5 h−1) are similar to the best results
reported for the alkoxycarbonylation of chlorobenzene
[7]. A catalyst based on ligand 2, which possesses an
‘inverse’ structure compared to Josiphos 1 and no
strongly basic trialkylphosphine subunit, leads to a
significantly lower conversion/yield (cf. entries 1 and 2,
Table 3). Ligand 3 with a di-tert-butylphosphino moiety
gives a similar conversion to 2, with a much lower
selectivity of only 27%, despite molecular sieves being
employed (entry 3, Table 3). If both phosphorus atoms
are substituted with cyclohexyl groups in the ligand
(1-{2-(dicyclohexylphosphino)ferrocenyl}ethyl-dicyclo-
hexylphosphine) (4), an efficient conversion of
chlorobenzene (78%) with a yield of almost 70% of
According to Scheme 3, a water-removing agent
should lead to an increased selectivity for the product
(n-butyl 4-trifluoromethylbenzoate). Therefore, the ex-
periment with the worst selectivity (entry 15, Table 2) was
,
performed in the presence of molecular sieves (4 A, ca.
3 g). As expected the yield of the product increased
dramatically (77 vs. 35%):

W. Ma¨gerlein et al. / Journal of Organometallic Chemistry 641 (2002) 30–40
35
Table 3
(\99%). Although the reaction time for the carbonyla-
tion experiments was in general 16 h, an examination of
the time/conversion behavior of the reaction at 1 bar
CO revealed that the reaction had essentially proceeded
to completion after 5–6 h, indicating the much higher
carbonylation activity of the catalyst in the presence of
Na2CO3. At lower catalyst loadings, i.e. only 0.05 mol%
of PdCl2(PhCN)2 [20], the conversion of the substrate is
still 100%, however, the selectivity is somewhat lower
(yield 78%; TON=1560). This is the highest turnover
number that we are aware of for the carbonylation of
chlorobenzene [21]. The new carbonylation protocol is
also useful for aryl chlorides other than chlorobenzene,
especially electron rich, i.e. deactivated substrates. The
results are depicted in Table 4.
Butoxycarbonylation of chlorobenzene at 145 °C in the presence of
0.5 mol% PdCl2(PhCN)2 and bidentate ferrocenyl phosphine ligandsa
A quantitative conversion of the aryl chloride was
observed in all the reactions examined [22]. 2-Chloro-
fluorobenzene and 4-chlorotoluene, which with respect
to their p-electron density and steric bulk resemble
chlorobenzene, reacted to afford the respective substi-
tuted benzoic acid esters in high yield (98–100%) (en-
tries 1, 2, Table 4). The catalyst is also active for
heterocyclic chloride substrates, as indicated by entry 3
(Table 4). 3-Chloropyridine is converted to the nicotinic
ester in 72% yield (GC). With the electron rich and
bulkier 2-chloroanisole, the desired product is formed
in almost quantitative yield (95%) (entry 4, Table 4).
The respective o-methoxybenzoic acid is not observed.
In contrast, the butoxycarbonylation of the isomeric
3-chloroanisole proceeds with a significantly lower
product selectivity of 80%. Here, m-methoxybenzoic
acid is formed in 15% isolated yield (entry 5, Table 4).
In addition ethyl (4-chlorophenyl)acetate was employed
as a substrate. No side reactions occurred at the ben-
zylic methylene group, although transesterification of
the ethyl ester takes place and n-butyl (4-butoxycar-
bonylphenyl)acetate is formed in 80% yield (entry 6,
Table 4). Additionally, a mixture of the diacid and
(4-butoxycarbonylphenyl)acetic acid were isolated as
by-products in 13% total yield.
The difference in conversion and product yield is due to the forma-
tion of benzoic acid.
n-butyl benzoate is achieved in the presence of only 0.5
mol% Pd catalyst (entry 4, Table 3).
If the structure of the cyclohexylphosphino ferro-
cenyl ligand is changed from a 1,2- to a 1,1%-disubstitu-
tion (ligand 5), a lower catalyst activity is observed (cf.
entries 4 and 5, Table 3). In this case the conversion
drops to 62% with only 31% of the product being
formed. The catalyst based on the phenylphosphine
ligand 6 is much less efficient than the other systems
PdCl2(PhCN)2/1–5, presumably due to the reduced nu-
cleophilicity of the catalytically active palladium
species.
Further improvement of the carbonylation of
chlorobenzene is possible by using Na2CO3 as base at
low CO pressures of 1 or 3 bar. Here, the carbonylation
of chlorobenzene in the presence of ligand 4 proceeds
quantitatively (100%) with extremely high selectivities
3. Conclusions
In conclusions, we have examined the palladium-cat-
alyzed alkoxycarbonylation reaction of activated and
deactivated aryl chlorides with regard to the influence
of critical reaction parameters, product selectivity, and
the performance of various catalyst ligands. Our inves-
tigations resulted in the development of a new efficient
catalyst system based on cyclohexyl-substituted ferro-
cenylphosphine ligands for the carbonylation of aryl
chlorides. A considerable advantage is that these lig-
ands are air stable and commercially available. With
the PdCl2(PhCN)2/4 catalyst (0.5 mol% Pd) in the
presence of sodium carbonate as a base, chlorobenzene
was converted to n-butyl benzoate in an essentially

36
W. Ma¨gerlein et al. / Journal of Organometallic Chemistry 641 (2002) 30–40
Table 4
Butoxycarbonylation of various aryl chloridesa
quantitative yield within 16 h (130–145 °C). The CO
pressure can be as low as 1 bar. A turnover number of
almost 1600 was observed at catalyst loading of only
0.05 mol%, underlining the high productivity of the
catalyst system. The observed catalyst productivity for
the carbonylation of chlorobenzene is more than one
order of magnitude higher compared to other known
palladium catalysts. This result is noteworthy if one
considers that catalyst costs are of special importance
for aryl chloride activation, otherwise the use of these
starting materials is not advantageous. The applicabil-
ity of the carbonylation protocol to other aryl chloride
substrates is demonstrated. Furthermore, it is shown
that statistical reaction design is a useful tool for the
optimization of carbonylation catalysts.
4. Experimental
4.1. General
All reactions were carried out under an Ar atmo-
sphere. A 100 ml stainless steel autoclave (no. 4593
from Parr Co.) equipped with a magnet-driven pro-
peller stirrer was used in all of the carbonylation exper-
iments. Experiments with CO pressures above 1 bar
were conducted under non-isobaric conditions. Experi-
ments with a CO pressure at 1 bar were conducted
under isobaric conditions. In this case the pressure was
kept constant by using a pressure regulator and a CO
reservoir. The course of the reaction was followed by
measuring the decrease of the CO pressure in the

W. Ma¨gerlein et al. / Journal of Organometallic Chemistry 641 (2002) 30–40
37
reservoir. The CO gas (purity 99.97%) used was pur-
chased from Aga Gas GmbH, Berlin (Germany).
Commercially obtained materials were used as re-
ceived without further purification. Anhydrous n-bu-
tanol was purchased from Aldrich Chemical Co.
Anhydrous DMF and anhydrous dioxane were pur-
chased from Fluka Chemical Co. 2-Pentanol (Aldrich
closed, heated to temperature of 145 °C and pressur-
ized with 1 bar CO from a CO reservoir which was
connected to the autoclave with a pressure regulator
providing a constant pressure during the reaction. For
experiments at higher CO pressures the autoclave was
not connected to the CO reservoir (non-isobaric condi-
tions). After 16 h and subsequent cooling to room
temperature, the yellow–orange reaction mixture was
diluted with CH2Cl2 (70 ml) and poured into a separat-
ing funnel. The mixture was washed with water (70 ml)
and the aqueous layer was extracted with CH2Cl2 (2×
20 ml). The combined organic layers were dried over
anhydrous MgSO4, filtered and concentrated in vacuo.
The crude material was purified by column chromatog-
raphy (silica gel, mixtures of EtOAc–hexanes as
eluent).
,
Chemical Co.) was dried over molecular sieves (4 A).
All of these solvents, as well as distilled water (if used
as a reagent), were additionally saturated with Ar. Aryl
chlorides were purchased from Aldrich Chemical Co.
except for chlorobenzene which was purchased from
Fluka Chemical Co., and ethyl(4-chlorophenyl)acetate
which was prepared according to a literature procedure
[23]. Et3N (Fluka Chemical Co.) and di-n-propylamine
(Aldrich Chemical Co.) were dried over molecular
,
sieves (4 A) and saturated with Ar. Anhydrous AcONa
In order to isolate benzoic acids, formed either as
by-products or as the main product (in the case of
water as nucleophile), the pH of the aqueous layer was
adjusted to a pH of 0 by dropwise addition of concen-
trated HCl. The mixture was then extracted with Et2O
(3×50 ml). The combined organic layers were dried
over anhydrous MgSO4, filtered and concentrated in
vacuo to afford the acids as white solids.
and Na2CO3 were purchased from Fluka Chemical Co.
PCy3 and 1,1%-bis(diphenylphosphino)ferrocene (6) were
purchased from Strem Chemical Co. 1,1%-Bis(dicyclo-
hexylphosphino)ferrocene (5) [24] was prepared accord-
ing to the literature procedure. Bis(benzonitrile)-
dichloropalladium(II) was prepared according to the
literature procedure [25]. 1-{2-(Diphenylphosphino)-
ferrocenyl}ethyl-dicyclohexylphosphine (1), 1-{2-(dicy-
clohexyl-phosphino)ferrocenyl}ethyl-diphenylphosphine
(2), 1-{2-(diphenylphosphino)ferrocenyl}-ethyl-di-tert-
butylphosphine (3), and 1-{2-(dicyclohexylphosphino)-
ferrocenyl}ethyl-dicyclohexylphosphine (4) (all as race-
mates) were prepared by Solvias AG, Basel (Switzer-
land) and used as received. Diethyleneglycol di-n-
butylether (internal GC standard) was purchased from
Fluka Chemical Co.
4.2.1. n-Butyl benzoate
The reaction of chlorobenzene (788 mg, 7 mmol) was
effected using the general procedure to afford 1.060 g
(5.95 mmol, 85%) of the title compound as a colorless
oil. Rf=0.69 (EtOAc–hexane 1:5); 1H-NMR (400.1
MHz, CDCl3, 297 K): l 8.04 (m, 2H), 7.55 (m, 1H),
3
7.43 (m, 2H), 4.33 (t, 2H, J(H,H)=6.6 Hz), 1.76 (tt,
3
3
2H, J(H,H)=7.1, 6.6 Hz), 1.48 (qt, 2H, J(H,H)=
1H- and 13C{1H}-NMR spectra were recorded in a
Bruker ARX 400 spectrometer. Chemical shifts (l) are
given in parts per million and refer to residual solvent
as the internal standard. IR spectra were recorded in a
Nicolet Magna 550 spectrometer. Gas chromatography
was performed in a Hewlett–Packard HP 6890 chro-
matograph with a HP5 column.
7.4, 7.1 Hz), 0.98 (t, 3H, J(H,H)=7.4 Hz); 13C{1H}-
3
NMR (100.6 MHz, CDCl3, 297 K): l 166.7, 132.7,
130.5, 129.5, 128.3, 64.8, 30.7, 19.2, 13.7; IR (KBr,
cm−1): 2960, 1719, 1452, 1315, 1275, 1111, 710. Anal.
Calc. for C11H14O2: C, 74.12; H, 7.92. Found: C, 73.95;
H, 7.90%.
4.2.2. n-Butyl 4-trifluoromethylbenzoate
4.2. General procedure for the carbonylation of aryl
chlorides [26]
The reaction of 4-chlorobenzotrifluoride (1.264 g, 7
mmol) was effected using the general procedure, how-
ever, with NaOAc (1.723 g, 21 mmol) as the base and
Josiphos 1 (83.2 mg, 0.140 mmol) as the ligand at 14
bar CO and 160 °C (15 h) to afford 1.051 g (4.27
mmol, 61%) of the title compound as a colorless oil
along with 4-trifluoromethylbenzoic acid (199.6 mg,
1.05 mmol, 15%; analytical data, vide infra) as a by-
product. Rf=0.67 (EtOAc–hexane 1:10); 1H-NMR
(400.1 MHz, CDCl3, 297 K): l 8.07 (m, 2H), 7.61 (m,
2H), 4.28 (t, 2H, 3J(H,H)=6.6 Hz), 1.69 (tt, 2H,
An oven-dried Schlenk flask was evacuated and filled
with Ar (three cycles), then charged with the aryl
chloride (7 mmol), n-butanol (14 ml) or another nucle-
ophile/solvent, PdCl2(PhCN)2 (13.4 mg, 0.035 mmol,
0.5 mol%), and ligand 4 (84.9 mg, 0.140 mmol, 2 mol%)
to give an orange solution. Sodium carbonate (2.226 g,
,
21 mmol, three equivalents) and molecular sieves (4 A,
ca. 3 g) were added to the autoclave. After evacuating
and filling the autoclave with Ar (three cycles), the
reaction mixture was transferred from the Schlenk flask
into the autoclave by means of a PVC-tube (¥:2 mm)
under a positive pressure of Ar. The autoclave was
3
3J(H,H)=7.1, 6.6 Hz), 1.40 (qt, 2H, J(H,H)=7.4, 7.1
Hz), 0.90 (t, 3H, 3J(H,H)=7.4 Hz, 3H, CH3); 13C{1H}-
NMR (100.6 MHz, CDCl3, 297 K): l 165.4, 134.3 (q,
3
2J(C,F)=32.4 Hz), 133.7, 129.9, 125.3 (q, J(C,F)=

38
W. Ma¨gerlein et al. / Journal of Organometallic Chemistry 641 (2002) 30–40
1
3.8 Hz), 123.6 (q, J(C,F)=272.8 Hz), 65.4, 30.7, 19.2,
13.7; IR (KBr, cm−1): 2964, 1727, 1327, 1279, 1169,
1132, 1067, 864, 776, 705. Anal. Calc. for C12H13F3O2:
C, 58.54; H, 5.32. Found: C, 58.79; H, 5.15%.
(400.1 MHz, CDCl3, 297 K): l 9.11 (s, 1H), 8.65 (m,
1H), 8.17 (m, 1H), 7.27 (m, 1H), 4.24 (m, 2H), 1.64 (m,
2H), 1.36 (m, 2H), 0.86 (m, 3H); 13C{1H}-NMR (100.6
MHz, CDCl3, 297 K): l 164.9, 153.0, 150.6, 136.7,
126.1, 123.0, 65.0, 30.4, 18.9, 13.4); IR (KBr, cm−1):
3423, 2961, 1724, 1591, 1466, 1284, 741, 703. Anal.
Calc. for C10H13NO2: C, 67.02; H, 7.31; N, 7.82.
Found: C, 66.81; H, 7.38; N, 7.89%.
4.2.3. 4-Trifluoromethylbenzoic acid
White solid, m.p. 220 °C. 1H-NMR (400.1 MHz,
CDCl3, 297 K): l 8.10 (m, 2H), 7.69 (m, 2H);
13C{1H}-NMR (100.6 MHz, CDCl3, 297 K): l 167.3,
134.0 (q, 2J(C,F)=32.4 Hz), 133.7, 129.9, 125.0 (q,
4.2.7. n-Butyl 2-methoxybenzoate
3J(C,F)=3.8 Hz), 123.5 (q, J(C,F)=272.8 Hz), 65.4,
The reaction of 2-chloroanisole (998 mg, 7 mmol)
was effected using the general procedure to afford 1.327
g (6.37 mmol, 91%) of the title compound as a colorless
oil. Rf=0.17 (EtOAc–hexane 1:20); 1H-NMR (400.1
1
30.7, 19.2, 13.7; IR (KBr, cm−1): 2995, 1700, 1316,
1289, 1172, 1144, 1063, 863, 780. Anal. Calc. for
C8H5F3O2: C, 50.54; H, 2.65. Found: C, 51.16; H,
2.82%.
3
MHz, CDCl3, 297 K): l 7.77 (dd, 1H, J(H,H)=7.9
4
3
Hz, J(H,H)=1.8 Hz), 7.43 (ddd, 1H, J(H,H)=8.4,
4
4.2.4. n-Butyl 2-fluorobenzoate
7.4 Hz, J(H,H)=1.8 Hz), 6.95 (m, 2H), 4.28 (t, 2H,
The reaction of 2-chlorofluorobenzene (914 mg, 7
mmol) was effected using the general procedure to
afford 1.044 g (5.32 mmol, 76%) of the title compound
as a light-yellow oil along with 2-fluorobenzoic acid (49
mg, 0.35 mmol, 5%; analytical data, vide infra) as a
3J(H,H)=6.6 Hz), 3.87 (s, 3H), 1.72 (tt, 2H,
3J(H,H)=7.1, 6.6 Hz), 1.46 (qt, 2H, J(H,H)=7.4, 7.1
3
Hz), 0.95 (t, 3H, 3J(H,H)=7.4 Hz); 13C{1H}-NMR
(100.6 MHz, CDCl3, 297 K): l 166.2, 159.0, 133.2,
131.4, 120.4, 120.0, 111.9, 64.5, 55.8, 30.6, 19.1, 13.6;
IR (KBr, cm−1): 2959, 1727, 1465, 1301, 1253, 1082,
757. Anal. Calc. for C12H16O3: C, 69.21; H, 7.74.
Found: C, 69.33; H, 7.58%.
1
by-product. Rf=0.51 (EtOAc–hexane 1:15); H-NMR
(400.1 MHz, CDCl3, 297 K):
l 7.92 (td, 1H,
3J(H,H)=8.0 Hz, 4J(H,H)=1.7 Hz), 7.49 (m, 1H),
7.18 (t, 1H, 3J(H,H)=8.0 Hz), 7.11 (dd, 1H,
3J(H,F)=10.8 Hz, 3J(H,H)=8.0 Hz), 4.32 (t, 2H,
4.2.8. n-Butyl 3-methoxybenzoate
3J(H,H)=6.6 Hz), 1.73 (tt, 2H, J(H,H)=7.1, 6.6 Hz),
The reaction of 3-chloroanisole (998 mg, 7 mmol)
was effected using the general procedure to afford 991
mg (4.76 mmol, 68%) of the title compound as a
light-yellow oil along with 3-methoxybenzoic acid (160
mg, 1.05 mmol, 15%; analytical data, vide infra) as a
by-product. Rf=0.65 (EtOAc–hexane 1:5); 1H-NMR
3
1.46 (qt, 2H, 3J(H,H)=7.4, 7.1 Hz), 0.96 (t, 3H,
3J(H,H)=7.4 Hz); 13C{1H}-NMR (100.6 MHz,
3
CDCl3, 297 K): l 164.4 (d, J(C,F)=3.7 Hz), 161.8 (d,
1J(C,F)=259.6 Hz), 134.2 (d, J(C,F)=9.0 Hz), 131.9,
3
123.8 (d, 4J(C,F)=3.8 Hz), 119.0 (d, 2J(C,F)=9.6
2
Hz), 116.8 (d, J(C,F)=22.6 Hz), 65.1, 30.6, 19.1, 13.6.
Anal. Calc. for C11H13FO2: C, 67.32; H, 6.68. Found:
C, 67.59; H, 6.59%.
(400.1 MHz, CDCl3, 297 K): l 7.77 (dd, 1H,
4
3J(H,H)=7.9 Hz, J(H,H)=1.8 Hz), 7.43 (ddd, 1H,
3J(H,H)=8.4, 7.4 Hz, 4J(H,H)=1.8 Hz), 6.95 (m,
3
2H), 4.28 (t, 2H, J(H,H)=6.6 Hz), 3.87 (s, 3H), 1.72
4.2.5. 2-Fluorobenzoic acid
(tt, 2H, 3J(H,H)=7.1, 6.6 Hz), 1.46 (qt, 2H,
White solid, m.p. 122–123 °C. 1H-NMR (400.1
3J(H,H)=7.4, 7.1 Hz), 0.95 (t, 3H, J(H,H)=7.4 Hz);
3
3
MHz, CDCl3, 297 K): l 7.97 (td, 1H, J(H,H)=8.0
13C{1H}-NMR (100.6 MHz, CDCl3, 297 K): l 166.2,
159.0, 133.2, 131.4, 120.4, 120.0, 111.9, 64.5, 55.8, 30.6,
19.1, 13.6; IR (KBr, cm−1): 2959, 1727, 1465, 1301,
1253, 1082, 757. Anal. Calc. for C12H16O3: C, 69.21; H,
7.74. Found: C, 68.96; H, 7.88%.
Hz, 4J(H,H)=1.8 Hz), 7.62 (m, 1H), 7.29 (td, 1H,
3J(H,H)=8.0 Hz, J(H,H)=1.0 Hz), 7.23 (ddd, 1H,
4
3J(H,F)=11.1 Hz, 3J(H,H)=8.0 Hz, 4J(H,H)=1.0
Hz); 13C{1H}-NMR (100.6 MHz, CDCl3, 297 K): l
3
1
167.8 (d, J(C,F)=2.8 Hz), 163.7 (d, J(C,F)=257.8
Hz), 136.1 (d, 3J(C,F)=8.9 Hz), 133.6, 125.5, (d,
4.2.9. 3-Methoxybenzoic acid
4J(C,F)=4.0 Hz), 120.7 (d, J(C,F)=10.0 Hz), 118.1
White solid, m.p. 104–105 °C. 1H-NMR (400.1
2
(d, J(C,F)=22.3 Hz); IR (KBr, cm−1): 3016, 2879,
MHz, CDCl3, 297 K): l 7.72 (dt, 1H, J(H,H)=8.0
2
3
1697, 1615, 1466, 1308, 753. Anal. Calc. for C7H5FO2:
C, 60.01; H, 3.60. Found: C, 60.37; H, 3.73%.
Hz, 4J(H,H)=1.1 Hz), 7.63 (dd, 1H, 4J(H,H)=2.6, 1.1
Hz), 7.39 (t, 1H, 3J(H,H)=8.0 Hz), 7.16 (ddd, 1H,
4
3J(H,H)=8.0 Hz, J(H,H)=2.6, 1.1 Hz), 3.87 (s, 3H);
4.2.6. n-Butyl nicotinate
13C{1H}-NMR (100.6 MHz, CDCl3, 297 K): l 171.4,
159.6, 130.5, 129.5, 122.7, 120.5, 114.4, 55.5; IR (KBr,
cm−1): 2961, 1694, 1466, 1311, 1291, 1044, 755. Anal.
Calc. for C8H8O3: C, 63.14; H, 5.30. Found: C, 63.57;
H, 5.45%.
The reaction of 3-chloropyridine (795 mg, 7 mmol)
was effected using the general procedure to afford 841
mg (4.69 mmol, 67%) of the title compound as a
1
colorless oil. Rf=0.23 (EtOAc–hexane 1:5); H-NMR

W. Ma¨gerlein et al. / Journal of Organometallic Chemistry 641 (2002) 30–40
39
4.2.14. (4-Butoxycarbonylphenyl)acetic acid
4.2.10. n-Butyl 4-methylbenzoate
1H-NMR (400.1 MHz, CD3OD, 297 K): l 8.00 (m,
2H), 7.42 (m, 2H), 5.10 (s, br., 2H), 4.34 (t, 2H,
3J(H,H)=6.6 Hz), 3.72 (s, 2H), 1.78 (tt, 2H,
The reaction of 4-chlorotoluene (886 mg, 7 mmol)
was effected using the general procedure to afford 1.077
g (5.6 mmol, 80%) of the title compound as a
light-yellow oil along with 4-methylbenzoic acid (76
mg, 0.56 mmol, 8%; analytical data, vide infra) as a
3
3J(H,H)=7.1, 6.6 Hz), 1.51 (qt, 2H, J(H,H)=7.4, 7.1
Hz), 1.02 (t, 3H, 3J(H,H)=7.4 Hz); 13C{1H}-NMR
(100.6 MHz, CD3OD, 297 K): l 175.0, 168.3, 141.7,
131.2, 130.9, 130.5, 66.2, 42.0, 32.2, 20.6, 14.4.
1
by-product. Rf=0.59 (EtOAc–hexane 1:15); H-NMR
(400.1 MHz, CDCl3, 297 K): l 7.93 (m, 2H), 7.22 (m,
3
2H), 4.31 (t, 2H, J(H,H)=6.6 Hz), 2.40 (s, 3H), 1.75
(tt, 2H, 3J(H,H)=7.1, 6.6 Hz), 1.47 (qt, 2H,
3J(H,H)=7.4, 7.1 Hz), 0.98 (t, 3H, J(H,H)=7.4 Hz);
3
Acknowledgements
13C{1H}-NMR (100.6 MHz, CDCl3, 297 K): l 166.7,
143.3, 129.5, 128.9, 127.7, 64.6, 30.7, 21.5, 19.2, 13.7;
IR (KBr, cm−1): 2960, 1719, 1458, 1310, 1275, 1107,
754. Anal. Calc. for C12H16O2: C, 74.97; H, 8.39.
Found: C, 74.79; H, 8.40%.
We gratefully acknowledge the financial support
from Solvias AG, Basel (Switzerland) and from the
State of Mecklenburg-West Pomerania. Drs H.-U.
Blaser, M. Studer, A. Schnyder, F. Spindler (all Solvias
AG) are thanked for helpful discussions. We thank Mrs
M. Heyken (IfOK) for her excellent technical assistance
and Dr C. Fischer, K. Kortus, S. Buchholz (all IfOK)
for their analytical services. Dr J. Krauter (Degussa
AG) is thanked for his advise and help with the statisti-
cal design of reaction parameters. Dr M.J. Hateley
(IfOK) is thanked for helpful comments on this
manuscript.
4.2.11. 4-Methylbenzoic acid
White solid, m.p. 179–180 °C. 1H-NMR (400.1
3
MHz, CD3OD, 297 K): l 7.93 (d, 2H, J(H,H)=8.2
Hz), 7.28 (d, 2H, 3J(H,H)=8.2 Hz), 2.41 (s, 3H);
13C{1H}-NMR (100.6 MHz, CD3OD, 297 K): l 170.3,
145.2, 131.1, 130.4, 129.3, 21.9; IR (KBr, cm−1): 2977,
2549, 1677, 1419, 1286, 1184, 756. Anal. Calc. for
C11H13FO2: C, 67.32; H, 6.68. Found: C, 67.59; H,
6.59%.
References
4.2.12. n-Butyl (4-butoxycarbonylphenyl)acetate
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The reaction of ethyl (4-chlorophenyl)acetate (1.391
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afford 1.392 g (4.76 mmol, 68%) of the title compound
as a light-yellow oil along with a mixture of (4-carboxy-
phenyl)acetic acid and (4-butoxycarbonylphenyl)acetic
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1
hexane 1:5); H-NMR (400.1 MHz, CDCl3, 297 K): l
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3
3J(H,H)=8.3 Hz), 4.31 (t, 2H, J(H,H)=6.6 Hz), 4.09
3
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3
3J(H,H)=7.1, 6.6 Hz), 1.59 (tt, 2H, J(H,H)=7.1, 6.7
3
Hz), 1.47 (qt, 2H, J(H,H)=7.4, 7.1 Hz), 1.33 (qt, 2H,
3
3J(H,H)=7.4, 7.1 Hz), 0.97 (t, 3H, J(H,H)=7.4 Hz),
3
0.90 (t, 3H, J(H,H)=7.4 Hz); 13C{1H}-NMR (100.6
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129.3, 129.2, 64.9, 64.7, 41.3, 30.7, 30.5, 19.2, 19.0, 13.7,
13.6; IR (KBr, cm−1): 2960, 1736, 1720, 1613, 1466,
1418, 1277, 1106, 740. Anal. Calc. for C17H24O4: C,
69.84; H, 8.27. Found: C, 69.85; H, 8.33%.
[3] The low reactivity of aryl chlorides in palladium-catalyzed cou-
pling reactions is generally ascribed to their reluctance to un-
dergo oxidative addition to the catalytically active Pd(0) species.
The oxidative addition step is accelerated if electron-deficient
aryl chlorides are employed and/or the electron density at the
Pd(0) metal center is increased, e.g. by the use of basic phosphine
ligands. For an excellent recent review see: V.V. Grushin, H.
Alper, in: S. Murai (Ed.), Topics in Organometallic Chemistry,
vol. 3, Springer, Berlin, 1999, p. 193.
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4.2.13. (4-Carboxyphenyl)acetic acid
1
[27] H-NMR (400.1 MHz, CD3OD, 297 K): l 8.00
(m, 2H), 7.42 (m, 2H), 5.10 (s, br., 2H), 3.72 (s, 2H);
13C{1H}-NMR (100.6 MHz, CD3OD, 297 K): l 175.1,
170.0, 141.9, 131.2, 130.9, 130.8, 42.0.

40
W. Ma¨gerlein et al. / Journal of Organometallic Chemistry 641 (2002) 30–40
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(g) W.A. Herrmann, C. Broßmer, K. Ofele, C.-P. Reisinger, T.
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carbonylation reactions has shown that, for a given Pd concen-
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8
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acetate), approximately 10 h (2-chloroanisole), and approxi-
mately 15 h (2-chlorofluorobenzene, 3-chloropyridine). The fact
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aryl chloride is not the rate determining step under the applied
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of these by-products is given.
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