Process for preparing aryl-substituted aliphatic carboxylic acids and their alkyl esters

A new process for preparing aryl substituted aliphatic carboxylic acids or then alkyl esters is provided. A 1-aryl substituted olefin is reacted with carbon monoxide in the presence of water or an alcohol at a temperature between about 25.degree. C. and about 200.degree. C. An excess of several moles of water or alcohol is preferred. An acid such as hydrochloric acid may also be added. As catalyst, a mixture of a palladium compound and a copper compound with at least one acid-stable ligand are present.

TECHNICAL FIELD 
This invention relates to a process for preparing aryl-substituted 
aliphatic carboxylic acids or the esters thereof. 
BACKGROUND OF THE INVENTION 
Among the processes known for preparing 2-(4-isobutylphenyl)propionic acid 
or esters thereof is that of Shimizu et al. (U.S. Pat. No. 4,694,100, 
issued September, 1987), who teach the reaction of p-isobutylstyrene with 
carbon monoxide and water or alcohol in the presence of a palladium 
catalyst and a mineral acid, e.g., HCl. This patent also teaches the 
alternative reaction of p-isobutylstyrene with carbon monoxide and 
hydrogen in the presence of a metal complex carbonyl catalyst to produce 
2-(4-isobutylphenyl)propionaldehyde, which is then oxidized to produce the 
desired product. The preparation of the starting material for this 
reaction is disclosed as the reaction of isobutylbenzene with acetaldehyde 
in the presence of sulfuric acid, producing 
1,1-bis(4-isobutylphenyl)ethane, which is then catalytically cracked to 
produce p-isobutylstyrene and isobutylbenzene. 
Another process for preparing ibuprofen is that of European Patent 
Application 284,310 (Hoechst Celanese, published September, 1988), which 
teaches that ibuprofen can be prepared by carbonylating 
1-(4-isobutylphenyl)ethanol with carbon monoxide in an acidic aqueous 
medium and in the presence of a palladium compound/phosphine complex and 
dissociated hydrogen and halide ions, which are preferably derived from a 
hydrogen halide. This process has the disadvantage of starting with 
1-(4-isobutylphenyl)ehtanol), a compound which is not economical to make 
by known processes. 
Gardano et al. (U.S. Pat. No. 4,536,595, issued August, 1985) teach the 
preparation of alkaline salts of certain alphaarylpropionic acids by 
reaction with carbon monoxide, at substantially ambient temperature and 
pressure conditions, of the corresponding arylethyl secondary halide in an 
anhydrous alcoholic solvent in the presence of alkaline hydroxides and, as 
catalyst, a salt of cobalt hydrocarbonyl. 
Alper et al. in J. Chem. Soc. Chem. Comm., 1983, 1270-1271, discloses the 
alkenes can react with carbon monoxide, water, hydrochloric acid and a 
mixture of palladium and copper to produce the hydrocarboxylated product, 
branched chain carboxylic acid. Oxygen is necessary to succeed in the 
reaction. Subsequently, Alper et al. have disclosed similar catalyst 
systems, but employing a chiral ligand, as being successful in asymmetric 
hydrocarboxylation reactions. See Alper et al., PCT Application, WO 91 
03,452 and J. Am. Chem. Soc., 112, 2803-2804 (1990). 
Another process for preparing ibuprofen is that of Japanese Patent 
Application (Kokai) No. 59-10,545 (Mitsubishi Petrochemical, published 
January, 1984), which teaches that ibuprofen can be prepared by reacting 
p-isobutylstyrene with carbon monoxide and water or alcohol in the 
presence of a palladium (II) catalyst and a peroxide, e.g., cumyl 
hydroperoxide. 
THE INVENTION 
In the following specification, the meaning of the substituent groups is as 
follows: alkyl means straight or branched chain alkyl having 1 to 20 
carbon atoms and includes, for example, methyl, ethyl, propyl, isopropyl, 
butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, 
neopentyl, hexyl, heptyl, octyl, 2-ethylhexyl, 1,1,3,3-tetramethylbutyl, 
nonyl, decyl, dodecyl, tetradecyl, hexadecyl, octadecyl and eicosyl; 
cycloalkyl means cyclic alkyl having 3 to 7 carbon atoms and includes 
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; 
substituted aryl means phenyl or naphthyl substituted by at least one 
substituent selected from the group consisting of halogen (chlorine, 
bromine, fluorine or iodine), amino, nitro, hydroxy, alkyl, alkoxy which 
means straight or branched chain alkoxy having 1 to 10 carbon atoms, and 
includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 
isobutoxy, secondary butoxy, tertiary butoxy, pentyloxy, isopentyloxy, 
hexyloxy, heptyloxy, octyloxy, nonyloxy and decyloxy, aryloxy including 
phenoxy and phenoxy substituted with halo, alkyl, alkoxy and the like, 
haloalkyl which means straight or branched chain alkyl having 1 to 8 
carbon atoms which is substituted by at least one halogen, and includes, 
for example, chloromethyl, bromomethyl, fluoromethyl, iodomethyl, 
2-chloroethyl, 2-bromoethyl, 2-flouoroethyl, 3-chloropropyl, 
3-bromopropyl, 3-fluoropropyl, 4-chlorobutyl, 4-fluorobutyl, 
dichloromethyl, dibromomethyl, difluoromethyl, diiodomethyl, 
2,2-dichloroethyl, 2,2-diibromoethyl, 2,2-difluoroethyl, 
3,3-difluoropropyl, 4,4-dichlorobutyl, 4,4-difluorobutyl, trichloromethyl, 
trifluoromethyl, 2,2,2-trifluoroethyl, 2,3,3-trifluoropropyl, 
1,1,2,2-tetrafluoroethyl and 2,2,3,3-tetrafluoropropyl; 
alkyl-substituted cycloalkyl means that the cycloalkyl moiety is cyclic 
alkyl having 3 to 7 carbon atoms and the alkyl moiety is straight or 
branched chain alkyl having 1 to 8 carbon atoms, and includes, for 
example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, 
cyclohexylmethyl, cycloheptylmethyl, 2-cyclopropylethyl, 
2-cyclopentylethyl, 2-cyclohexylethyl, 3-cyclopropylpropyl, 
3-cyclopentylpropyl, 3-cyclohexylpropyl, 4-cyclopropylbutyl, 
4-cyclopentylbutyl, 4-cyclohexylbutyl, 6-cyclopropylhexyl and 
6-cyclohexylhexyl; 
alkylthio means a divalent sulfur with alkyl occupying one of the valencies 
and includes the groups methylthio, ethylthio, propylthio, butylthio, 
pentylthio, hexylthio, octylthio and the like; 
heteroaryl means 5 to 10 membered nono- or fused-heteroaromatic ring which 
has at least one heteroatom selected from the group consisting of 
nitrogen, oxygen and sulfur, and includes, for example, 2-furyl, 3-furyl, 
2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazolyl, 
imidazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzimidazolyl, quinolyl, 
oxazolyl, thiazolyl and indolyl; 
substituted heteroaryl means 5 to 10 membered mono- or fused-heteroaromatic 
ring which has at least one heteroaromatic ring which has at least one 
heteroatom selected from the group consisting of nitrogen, oxygen and 
sulfur and which is substituted by at least one substituent selected from 
the group consisting of halogen, amino, nitro, hydroxy, alkyl, alkoxy and 
haloalkyl on the above-mentioned heteroaromatic nucleus; 
alkanoyl means alkanoyl having 2 to 18 carbon atoms and includes, for 
example, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl, 
hexanoyl, octanoyl, lauroyl and stearoyl; 
aroyl means benzoyl or naphthoyl; 
substituted aroyl means benzoyl or naphthoyl substituted by at least one 
substituent selected from the group consisting of halogen, amino, nitro, 
hydroxy, alkyl, alkoxy and haloalkyl on the benzene or naphthalene ring; 
heteroarylcarbonyl means that the heteroaryl moiety is 5 to 10 membered 
mono- or fused-heteroaromatic ring having at least one heteroatom selected 
from the group consisting of nitrogen, oxygen and sulfur as mentioned 
above, and includes, for example, furoyl, thinoyl, nicotinoyl, 
isonicotinoyl, pyrazolylcarbonyl, imidazolylcarbonyl, pyrimidinylcarbonyl 
and benzimidazolylcarbonyl; 
substituted heteroarylcarbonyl means the abovementioned heteroarylcarbonyl 
which is substituted by at least one substituent selected from the group 
consisting of halogen, amino, nitro, hydroxy, alkoxy and haloalkyl on the 
heteroaryl nucleus; and includes, for example, 
2-oxo-1,3-dioxolan-4-ylmethyl, 2-oxo-1,3-dioxan-5-yl. 
The present invention embraces any salts, racemates and individual optical 
isomers thereof of the compounds of the following formula (I) having a 
chiral carbon atom. 
##STR1## 
where Ar, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are subsequently defined. 
The salts of the compounds of formula (I) include pharmaceutically 
acceptable salts such as inorganic acid addition salts (e.g. 
hydrochloride, hydrobromide, sulfate, nitrate or phosphate), organic acid 
addition salts (e.g. acetate, tartrate, citrate, fumarate, maleate, 
mandelate, oxalate, salicylate, hybenzate, fendizoate, methanesulfonate or 
p-toluenesulfonate), metallic salts (e.g. sodium salt, potassium salt, 
calcium salt, magnesium salt or aluminum salt), salts with bases (e.g. 
salt with triethylamine, diethanolamine, ammonium, guanidine, hydrazine, 
quinine or cinchonin) or salts with amino acids (e.g. salt with lysine or 
glutamine). 
In accordance with the present invention, aryl-substituted aliphatic 
carboxylic acids or esters thereof are prepared by carbonylating an 
olefinic compound with carbon monoxide in a neutral or acidic medium 
containing at least 1 mol of water or of a C.sub.1 to about C.sub.8 linear 
or branched aliphatic alcohol per mol of olefinic compound at a 
temperature of between about 25.degree. C. and about 200.degree. C. and a 
carbon monoxide pressure of at least about one atmosphere in the presence 
of a mixture of (i) a palladium compound in which the palladium has a 
valence of 0-2 and (ii) a copper compound having a valence of 1 or 2 and 
at least one acid-stable ligand. 
The olefinic compound which is carbonylated in the practice of this 
invention has the formula: 
##STR2## 
where Ar is unsubstituted or substituted aryl and R.sub.2, R.sub.3 and 
R.sub.4 are hydrogen, alkyl, cycloalkyl, substituted or unsubstituted 
aryl, alkoxy, alkylthio, substituted or unsubstituted heteroaryl, 
alkanoyl, substituted or unsubstituted aroyl, substituted or unsubstituted 
heteroarylcarbonyl, trifluoromethyl or halo. 
Preferably, in the compounds of formula II, Ar is unsubstituted or 
substituted aryl, R.sub.2, R.sub.3 and R.sub.4 are hydrogen, C.sub.1 to 
C.sub.2 alkyl, substituted or unsubstituted phenyl or trifluoromethyl. 
Most preferably Ar is phenyl substituted with alkyl or naphthyl substituted 
with alkoxy, R.sub.2, R.sub.3 and R.sub.4 and are hydrogen, methyl or 
trifluoromethyl. 
The carbonylation of the compound of formula II is conducted at a 
temperature between about 25.degree. C. and about 200.degree. C., 
preferably about 25.degree.-100.degree. C., and most preferably about 
40.degree.-80.degree. C.. Higher temperatures can also be used. It has 
been found that a small advantage in yield is obtained by gradually 
increasing the temperature within the preferred ranges during the course 
of the reaction. 
The partial pressure of carbon monoxide in the reaction vessel is at least 
about 1 atmosphere (14.7 psig) at ambient temperature (or the temperature 
at which the vessel is charged). Any higher pressures of carbon monoxide 
can be used up to the pressure limits of the reaction apparatus. A 
pressure up to about 3000 psig is convenient in the process. More 
preferred is a pressure from about 300 to about 3000 psig at the reaction 
temperature, and most preferred is a pressure from about 400 to about 800 
psig. 
The carbonylation is conducted in the presence of at least about one mol of 
water or of an aliphatic alcohol per mol of the compound of formula II; 
however, an excess is preferred in order to assist in driving the reaction 
to completion. Although there is no real upper limit to the amount of 
water or alcohol except that imposed by practicality (e.g. the size of the 
reaction vessel), an amount up to about 100 mols per mol of the compounds 
of formula II is useful in the process. Further, controlling the amount of 
water or alcohol used in the process of this invention is advantageous in 
terms of producing the highest yields. Therefore, an amount from about 2 
to about 50 mols of water or of alcohol per mol of the compounds of 
formula II is preferred, and an amount from about 3 to about 24 mols of 
water or alcohol per mol of the such olefinic compound is most preferred. 
With the use of water, the free carboxylic acid of formula I is obtained; 
with an alcohol, the product is an carboxylic acid ester (where R.sub. 1 
is alkyl). These compounds have the following formula: 
##STR3## 
where R.sub.1 is hydrogen or alkyl and Ar, R.sub.2, R.sub.3 and R.sub.4 
are as previously defined. 
Any alcohol which produces an ester of the carboxylic acid may be used in 
the practice of this invention. In a preferred embodiment, the lower 
aliphatic alcohols, are used. Examples of the alcohols to be used in this 
embodiment include methyl alcohol, ethyl alcohol, n-propyl alcohol, 
isopropyl alcohol, n-, iso- sec-, and tert-butyl alcohols, the pentyl 
alcohols, the hexyl alcohols, etc. Methyl alcohol is highly preferred, and 
ethyl alcohol is most highly preferred. Other alcohols, glycols, or 
aromatic hydroxy compounds may also be used. 
In a preferred embodiment of this invention, the carbonylation reaction is 
initiated under neutral conditions, i.e., with no added acid. It can also 
be performed in the presence of an added acid. When acids are added, such 
acids include sulfuric acid, phosphoric acid, sulfonic acids, or acetic or 
halo- substituted acetic acids. A hydrogen halide acid such as 
hydrochloric or hydrobromic acid is preferred. The hydrogen halide may be 
added as a gas phase or as a liquid phase (in the form of an alcoholic or 
aqueous solution); in another preferred embodiment it is added as an 
aqueous solution. Any aqueous concentrations may be used. Hydrochloric 
acid is particularly preferred, at a concentration up to about 10%; more 
highly preferred is a concentration from about 10% to about 30%. The 
amount of acid added is such as to provide up to about 40 mols of hydrogen 
ion per mol of olefinic compounds of formula II; more preferred is an 
amount to provide up to about 10 mols of hydrogen ion per mol of olefinic 
compound; the most preferred amount provides up to about 4 mols of 
hydrogen ion per mol of the compounds of formula II. 
The carbonylation process of this invention is conducted in the presence of 
a reaction-promoting quantity of i) a mixture of a palladium compound in 
which the palladium has a valence of 0-2 and ii) a copper compound, with 
at least one acid-stable ligand. Ligands which may be used include 
monodentate or multidentate electron-donating substances such as those 
containing elements P, N, 0 and the like, and those containing multiple 
bonds such as olefinic compounds. Examples of such acid-stable ligands are 
trihydrocarbylphosphines, including trialkyl- and triarylphosphines, such 
as tri-n-butyl-, tricyclohexyl-, and triphenylphosphine; lower alkyl and 
aryl nitriles, such as benzonitrile and n-propionitrile; ligands 
containing pi-electrons, such as an allyl compound or 1,5-cyclooctadiene; 
piperidine, piperazine, trichlorostannate(II), and acetylacetonate; and 
the like. In one embodiment, the palladium and copper are added as a 
pre-formed complex of palladium(II) chloride or bromide, copper(II) 
chloride or bromide and carbon monoxide or any other similar complex. In a 
preferred embodiment, active catalytic species are formed in situ by the 
addition to the reaction mixture of the individual components, i.e., a 
ligand, a copper compound, and a palladium compound such as the inorganic 
salts of palladium(II) and copper(II) such as the chlorides, bromides, 
nitrates, sulfates, or acetates. In the most preferred embodiment, 
triphenylphosphine, copper(II) chloride, and palladium(II) chloride are 
used and are added individually or together, either simultaneously or 
sequentially. 
The amount of copper and palladium compounds preferably employed is such as 
to provide from about 4 to about 8000 mols of the compound of formula II 
per mol of the mixture of metal salts; more preferred is an amount to 
provide from about 10 to about 4000 mols of olefinic compound per mol of 
the salts mixture; the most preferred amounts provide from about 20 to 
2000 mols of the compounds of formula II per mol of the metal salt 
mixture. The process of this invention is conducted in the presence of at 
least one mol of ligand per mol of the mixture of metal salts. More 
preferably about 2 to about 40 mols of ligand per mol of the mixed salts 
are present, and most preferably about 2 to about 20 mols of ligand per 
mol of mixed salts are used. 
The presence of a solvent is not required in the process of this invention, 
although it may be desirable in some circumstances. Those solvents which 
can be used include one or more of the following: ketones, for example, 
acetone, methyl ethyl ketone, diethyl ketone, methyl-n-propyl ketone, 
acetophenone, and the like; linear, poly and cyclic ethers, for example, 
diethyl ether, di-n-propyl ether, di-n-butyl ether, ethyl-n-propyl ether, 
glyme (the dimethyl ether of ethylene glycol), diglyme (the dimethyl ether 
of diethylene glycol), tetrahydrofuran, dioxane, 1,3-dioxolane, and 
similar compounds; and aromatic hydrocarbons, for example, toluene, ethyl 
benzene, xylenes, and similar compounds. Alcohols are also suitable as 
solvents, for example, methanol, ethanol, 1-propanol, 2-propanol, isomers 
of butanol, isomers of pentanol, etc. Acids and esters may also be used, 
such as formic or acetic acid or ethyl acetate, etc. When an ester or an 
alcohol is used as solvent, the product is either the corresponding ester 
of the carboxylic acid (if no water is present in the reaction) or a 
mixture of the ester and the carboxylic acid itself (if water is present). 
Most highly preferred are ethers, especially tetrahydrofuran. When 
solvents are used, the amount can be up to about 100 mL per gram of the 
compounds of formula II, but the process is most advantageously conducted 
in the presence of about 1 to 30 mL per gram of the compound of formula 
II. 
In those embodiments of this invention in which an ester of ibuprofen is 
produced, the ester is converted to the acid by conventional methods of 
hydrolysis.

The following examples are given to illustrate the process of this 
invention and are not intended as a limitation thereof. 
EXAMPLE 1 
A) Carbon monoxide (15 ml/min) was bubbled through THF (15 mL) for 10 
minutes. PdCl.sub.2 (0.029 g, 0.16 mmol) and CuCl.sub.2 (0.050 g, 0.37 
mmol) were added. The mixture was stirred at room temperature for 3-5 
hours. During this period, PdCl.sub.2 and CuCl.sub.2 were dissolved and a 
yellow solid was formed. This yellow compound can be directly used as 
catalyst or it can be isolate by filtering and drying under CO atmosphere. 
Reference: D. Zargarian and H. Alper, Organometallics 1991, 10, 2914. 
B) The [PdCl.sub.2 /CuCl.sub.2 /CO] complex was freshly prepared as 
described above. To this catalyst (0.16 mmol) was added a solution of 
triphenylphosphine (0.13 g, 0.50 mmol), 4-isobutylstyrene (1.28 g, 8.0 
mmol), H.sub.2 O (1 mL) and THF (15 mL). The mixture was transferred to a 
100-mL Hastelloy B autoclave via syringe and the autoclave was then purged 
with CO (3.times.500 psig). The reactor was pressurized with CO (500 psig) 
and was agitated at 50.degree. C. overnight (18 h). GC analysis of an 
aliquote found that the reaction mixture contained 96% of ibuprofen. The 
reactor was cooled to room temperature and CO pressure was released. 
Ibuprofen can be isolated as the following typical work-up procedure. 
Distilled H.sub.2 O was added and the product was extracted with hexane. 
The combined hexane extracts was dried (MgSO.sub.4) and was then 
concentrated by rotary evaporation. The resulting residue was taken with 
1N NaOH and was extracted with ether. The aqueous solution was acidified 
with concentrated HCl. Extraction with ether, drying (Na.sub.2 SO.sub.4), 
and evaporation afforded 2-(4-isobutylphenyl)propionic acid (ibuprofen) 
(1.56 g, 95% yield) as a white solid. 
EXAMPLE 2 
The [PdCl.sub.2 /CuCl.sub.2 /CO] complex was freshly prepared as described 
above. To this catalyst (0.16 mmol) was added a solution of 
triphenylphosphine (0.13 g, 0.50 mmol), 4-isobutylstyrene (1.28 g, 8.0 
mmol), MeOH (1 mL) and THF (15 mL). The mixture was transferred to a 
100-mL Hastelloy B autoclave via syringe and the autoclave was then purged 
with CO (3.times.500 psig). The reactor was pressurized with CO (500 psig) 
and was agitated at 50.degree. C. overnight (18 h). GC analysis of an 
aliquote found that reaction gave a 96:4 mixture of methyl (b 
2-(4-isobutylphenylpropionate and methyl 3-(4-isobutylphenyl)propionate in 
97% conversion. 
EXAMPLE 3 
PdCl.sub.2 (0.029 g, 0.16 mmol) and CuCl.sub.2 (0.050 g, 0.37 mmol) were 
charged into an autoclave (Hastelloy B, 100 mL). The autoclave was purged 
with CO and a solution of triphenylphosphine (0.13 g, 0.50 mmol), 
4-isobutylstyrene (1.28 g, 8.0 mmol), H.sub.2 O (1 mL) and THF (30 mL) was 
added. The autoclave was again purged with CO and was then filled with CO 
(500 psig). The autoclave was agitated at 50.degree. C. overnight. The 
reactor was cooled to room temperature and CO pressure was released. GC 
analysis found that the reaction mixture contained 96% of ibuprofen. 
EXAMPLE 4 
The [PdCl.sub.2 /CuCl.sub.2 /CO] complex was freshly prepared as described 
above. Ph.sub.3 P (0.13 g, 0.50 mmol) was added and the mixture was 
transferred to an autoclave (Hastelloy B, 100-mL). A solution of 
4-methoxystyrene (1.07 g, 8.0 mmol), H.sub.2 O (1 mL), and THF (15 mL) was 
then added via syringe. The autoclave was purged with CO (2.times.500 
psig) and was then pressurized with CO (500 psig). After stirring at 
50.degree. C. for 16 hours, the reactor was cooled to room temperature and 
CO pressure was released. Standard workup afforded 
2-(4-methoxyphenyl)propionic acid (1.42 g, 99% yield) Mp=52-55.degree. C. 
(without further purification). 
EXAMPLE 5 
The [PdCl.sub.2 /CuCl.sub.2 /CO] complex was freshly prepared as described 
above. To this catalyst (0.16 mmol) was added a solution of 
triphenylphosphine (0.13 g, 0.50 mmol). The mixture was transferred to an 
autoclave (Hastelloy B, 100-mL). A solution of 1-decene (1.12 g, 8.0 
mmol), H.sub.2 O (1 mL), and THF (15 mL) was then added via syringe. The 
autoclave was purged with CO (2.times.500 psig) and was then pressurized 
with CO (500 psig). The reactor was agitated at 50.degree. C. overnight. 
GC analysis of an aliquote showed a 1:1 mixture of 2-methyldecanoic acid 
and n-undecanoic acid in 70% conversion. The reactor was cooled to room 
temperature and CO pressure was released. Standard workup yielded 
undecanoic acid (1.0 g, 68% yield) as an oil. 
EXAMPLE 6 
Pd (PPh.sub.3).sub.4 (0.092 g, 0.08 mmol) and CuCl.sub.2 (0.024 g, 0.18 
mmol) were charged into an autoclave (Hastelloy B, 100 mL). 
Isobutylstyrene (0.71 g, 4.4 mmol), THF (30 mL) and H.sub.2 O (1 mL) were 
added via syringe. the autoclave was purged With CO (3.times.500 psig) and 
was then filled with CO (500 psig). After stirring at 50.degree. C. for 19 
hours, the autoclave was cooled at room temperature and CO pressure was 
released. GC analysis indicated ibuprofen in 86% conversion. 
It is obvious that many variations may be made in the products and 
processes set forth above without departing from the spirit and scope of 
this invention. 
TABLE 
______________________________________ 
A Comparison of the Rates of 
the Catalytic Hydrocarboxylation of IBS 
% Conversion of 
Substrate to Product 
Catalyst 2 h 4 h 6 h 8 h 10 h 
______________________________________ 
[PdCl.sub.2 /CuCl.sub.2 /CO] complex 
27 50 70 84 95 
(Preformed) 
PdCl.sub.2 /CuCl.sub.2 complex (In situ) 
20 38 52 69 84 
PdCl.sub.2 /CuCl.sub.2 /10% HCl 
36 72 100 
PdCl.sub.2 /10% HCl 
8 20 34 45 56 
PdCl.sub.2 3 9 11 16 19 
______________________________________ 
Conditions: 
P.sub.co = 500 psig 
Temperature = 50.degree. C. 
Ligand = Ph.sub.3 P (3 equiv) 
Solvent = THF/H.sub.2 O (30:1) 
Substrate/catalyst = 50