Regioselective Carboxylation of Phenols with Carbon Dioxide

Article abstract of DOI:10.1246/bcsj.76.2191

A few novel methods were developed for the regioselective preparation of p-hydroxybenzoic acid (pHBA) and its amino derivative by means of the Kolbe-Schmitt reaction. Thus, the carboxylation of tetraalkylammonium phenoxide at 125°C under the CO₂ pressure of 5.0 MPa in the presence of K₂CO₃ gave pHBA in a maximum yield of 56% with the regioselectivity of 97-100%. The carboxylation of potassium phenoxide (PhOK) at 230°C under the CO₂ pressure of 0.5 MPa also gave pHBA regioselectively in a 39% yield, together with unaltered phenol (61%) Under such conditions, the potassium salt of salicylic acid (SA) once formed was transformed into pHBA. Heat treatment of the dipotassium salt of ¹³C labeled SA indicated that the transformation occurs via two pathways, i.e., the intramolecular rearrangement of the salicylate (66%) and the decarboxylation of the salicylate followed by the recarboxylation of the resulting PhOK (34%). Furthermore, the carboxylation of cesium m-aminophenoxide and 5-amino-1-naphthoxide with CO₂ gave regioselectively 4-hydroxyanthranilic and 8-amino-4-hydroxy-1-naphthoic acids, respectively, in good yields. This is a simple one-pot reaction giving these industrially useful acids with good yields.

Full text of DOI:10.1246/bcsj.76.2191

Ó 2003 The Chemical Society of Japan
Bull. Chem. Soc. Jpn., 76, 2191–2195 (2003) 2191
Regioselective Carboxylation of Phenols with Carbon Dioxide
#
ꢀ
Mohammad Abdur Rahim, Yoshihisa Matsui, Takanori Matsuyama,y and Yoshio Kosugiy;
Department of Life Science and Biotechnology, Faculty of Life and Environmental Science, Shimane University,
Matsue 690-8504
yAdvanced Organic Material Chemistry, Faculty of Science and Engineering, Shimane University, Matsue 690-8504
Received June 4, 2003; E-mail: yosihisa@life.shimane-u.ac.jp
A few novel methods were developed for the regioselective preparation of p-hydroxybenzoic acid (pHBA) and its
amino derivative by means of the Kolbe–Schmitt reaction. Thus, the carboxylation of tetraalkylammonium phenoxide at
125 ꢁC under the CO2 pressure of 5.0 MPa in the presence of K2CO3 gave pHBA in a maximum yield of 56% with the
regioselectivity of 97–100%. The carboxylation of potassium phenoxide (PhOK) at 230 ꢁC under the CO2 pressure of 0.5
MPa also gave pHBA regioselectively in a 39% yield, together with unaltered phenol (61%). Under such conditions, the
potassium salt of salicylic acid (SA) once formed was transformed into pHBA. Heat treatment of the dipotassium salt of
13C labeled SA indicated that the transformation occurs via two pathways, i.e., the intramolecular rearrangement of the
salicylate (66%) and the decarboxylation of the salicylate followed by the recarboxylation of the resulting PhOK (34%).
Furthermore, the carboxylation of cesium m-aminophenoxide and 5-amino-1-naphthoxide with CO2 gave regioselectively
4-hydroxyanthranilic and 8-amino-4-hydroxy-1-naphthoic acids, respectively, in good yields. This is a simple one-pot
reaction giving these industrially useful acids with good yields.
The most convenient and popular method for the preparation
of aromatic hydroxycarboxylic acids is the carboxylation of al-
kali metal phenoxides (PhOM) with carbon dioxide (CO2). The
reaction is known as the Kolbe–Schmitt reaction and has been
used for over a century.1 It has been thought for a long time1
of PhOM, by CO2. Tetraalkylammonium ions (R4Nþ) have
larger ionic radii (0.347, 0.400, 0.452, and 0.494 nm for
Me4Nþ, Et4Nþ, Pr4Nþ, and Bu4Nþ, respectively4b) than alkali
metal ions and will effectively interfere with the attack of CO2
at the ortho positions of PhONR4 to give selectively pHBA.
Second, we describe the carboxylation of PhOK at high temper-
ature and low CO2 pressure, at which mono- (SAK1) and dipo-
tassium salicylates (SAK2) are transformed into potassium salts
of pHBA.5,6 The mechanism of the transformation is also dis-
cussed on the basis of experiments with 13C-labeled SAK2. Fi-
nally, we describe the regioselective carboxylation of cesium
m-aminophenoxide and 5-amino-1-naphthoxide with CO2 to
give industrially useful 4-hydroxyanthranilic acid and 8-ami-
no-4-hydroxy-1-naphthoic acid, respectively.
that the reaction proceeds via a complex (PhOM CO2) com-
ꢂ
posed of PhOM and CO2. However, recent mechanistic stud-
ies2 have revealed that the reaction proceeds by a direct attack
of CO2 on the benzene ring. The attack occurs on electron-rich
ortho and para positions to give salicylic acid (SA) and p-hy-
droxybenzoic acid (pHBA). It is favorable for the industrial
production that the attack occurs reigoselectively on the para
position, since pHBA and 6-hydroxy-2-naphthoic acid
(2H6NA) prepared from phenol and 2-naphthol, respectively,
are key compounds for totally aromatic liquid-crystal
polymers. We recently found3 that cesium phenoxide and 2-
naphthoxide give pHBA and 2H6NA, respectively, in much
higher yields than the widely used methods with sodium or po-
tassium phenoxide and 2-naphthoxide. The prominently selec-
tive carboxylation is ascribed to the large ionic radius (0.169
nm4a) of cesium, which interferes with the direct attack of
CO2 at the ortho positions of the phenoxide and naphthoxide.
Sodium and potassium are too small in ionic radii (0.095 and
0.133 nm, respectively4a) to interfere effectively with the
CO2 attack at the ortho positions.
Experimental
Reagents. Phenol, m-aminophenol, and alkali metal hydrox-
ides (NaOH, KOH, and CsOH H2O) were purchased from Kanto
ꢂ
Chemical Co. 5-Amino-1-naphthol, carbonates (Na2CO3 and
K2CO3), and sulfate (K2SO4) were supplied by Wako Pure Chem-
ical Industries. Tetramethyl- (Me4NOH), tetraethyl- (Et4NOH),
tetrapropyl- (Pr4NOH), and tetrabutylammonium hydroxides
(Bu4NOH) were purchased from Aldrich Chemical Co. These
chemicals were of guaranteed grade and were used without further
purification. CO2 of purity more than 99.9% and nitrogen were
supplied by Sanin Sanso Co. 13C-enriched CO2 (more than
99%) was supplied by ISOTEC INC (Miamisburg, Ohio, USA).
Preparation of PhONR4. Me4NOH (0.8 mL of 25 wt % aque-
ous solution, 2.3 mmol) and phenol (0.2 g, 2.1 mmol) were added
to 50 mL of water and stirred for 2–3 min. When necessary, an ad-
ditive (K2CO3, Na2CO3, or K2SO4) was mixed together. The so-
lution was concentrated on a rotary evaporator at 45 ꢁC. The con-
centrated solution was lyophilized in a flask at <10 Pa for 30–40 h
The present paper describes some experiments directed to-
ward other methods for the regioselective preparation of pHBA
by the Kolbe–Schmitt reaction. First, we describe the carbox-
ylation of tetraalkylammonium phenoxides (PhONR4), in place
# Shimane Institute for Industrial Technology, Research-Business
Park, Hokuryo-cho, Matsue 690-0816
Published on the web November 15, 2003; DOI 10.1246/bcsj.76.2191

2192 Bull. Chem. Soc. Jpn., 76, No. 11 (2003)
Carboxylation of Phenols with CO2
to give tetramethylammonium phenoxide (PhONMe4). PhONEt4,
PhONPr4, and PhONBu4 were prepared similarly by mixing phe-
nol (0.2 g, 2.1 mmol) with Et4NOH (1.0 mL of 35 wt % aqueous
solution, 2.3 mmol), Pr4NOH (2.1 mL of 20 wt % aqueous solu-
tion, 2.3 mmol), and Bu4NOH (1.5 mL of 40 wt % aqueous solu-
tion, 2.3 mmol), respectively.
Preparation of PhOM. Phenol (5.00 g, 53.2 mmol) was dis-
solved in a 100 mL of aqueous solution containing 10% excess al-
kali metal hydroxides. Water was removed on a rotary evaporator
at 80 ꢁC, followed by vacuum drying at 180 ꢁC for 3 h. The pre-
pared phenoxides were ground to fine powders in a dry box under
dry nitrogen stream.
General Reactions and Analyses. The prepared PhONR4 or
PhOM was placed in an autoclave (200 mL) and CO2 of a requisite
pressure was introduced after flushing with nitrogen. The auto-
clave was heated quickly to the reaction temperature and main-
tained there for a requisite reaction time. The reaction mixture
in the autoclave was then cooled in a water bath and next dissolved
in a small amount of aqueous methanol. The solution was acidified
(pH 3–4) with the addition of dilute HCl and analyzed by high-per-
formance liquid chromatography (HPLC) with a column (ODS col-
umn 150 ꢃ 4:6ꢀ mm) on a Shimadzu LC-10 AD chromatograph.
1H NMR spectra were taken in CDCl3 using tetramethylsilane as
pHBA were low (7–27%), and significant amounts of unaltered
phenol were recovered (72–93%). We could not increase the
yield of pHBA by changing reaction time, temperature, or
the mole ratio of the hydroxide to phenol. The only effective
method we found was the addition of K2CO3 to the reactant.
Thus, the carboxylation of PhONMe4 (2.12 mmol) in the pres-
ence of K2CO3 (1 g, 7.22 mmol) gave pHBA in a 56% yield,
together with a small amount of alkyl esters of pHBA, and
the recovery of unaltered phenol decreased to 37%. The regio-
selectivity for pHBA was virtually unchanged (97%). The im-
proving effect of K2CO3 was also found in the other PhONR4,
though the yields (30–35%) of pHBA were significantly less
than that in the case of PhONMe4 (Scheme 1). The addition
of K2SO4, in place of K2CO3, to the reactant showed no im-
proving effect, whereas Na2CO3 showed an improving effect
similar to that of K2CO3. It is not clear why K2CO3 shows such
an improving effect. We can rule out the possibility that
K2CO3 contributed to increasing the surface area of the reactant
in contact with CO2, since K2SO4 showed no such effect. A
possible explanation is as follows: The reactant phenol is
monobasic acid, whereas the product pHBA is dibasic acid.
Since the carboxyl group is stronger in acidity than phenol,
the carboxyl group of pHBA formed will react with neighbor-
ing PhONR4 to give the carboxylate ion and inactive phenol. If
K2CO3 is present in the neighborhood of pHBA, the carboxyl
group is neutralized by K2CO3, and the phenoxide is not con-
sumed for the neutralization of the carboxyl group. There
was a fear that a cation-exchange reaction occurs between
PhONR4 and K2CO3 to form PhOK, of which the regioselectiv-
ity for pHBA is considerably lower than PhONR4. However,
the regioselectivity was unchanged by the addition of K2CO3,
indicating that the effect of the cation-exchange reaction is mi-
an internal standard on
a JEOL JNM-A400 (400 MHz)
spectrometer. Mass spectra were obtained at 70 eV on a Hitachi
M-80B spectrometer. All the products were known and were iden-
tified by comparing the retention times in HPLC, 1H NMR spectra,
and mass spectra with those of the authentic samples.
Results and Discussion
Carboxylation of PhONR4. PhONR4 was subjected to car-
boxylation under conditions employed in the usual Kolbe–
Schmitt reaction. The results are summarized in Table 1. Re-
ꢁ
action temperature (125 C) was somewhat lower than usual
(150 ꢁC), since it seemed that PhONR4 was labile and decom-
ꢁ
posed to give brownish products at 150 C. Interestingly, the
regioselectivity of the carboxylation for pHBA was very high,
i.e., 96% for PhONMe4 and PhONEt4, and virtually 100% for
PhONPr4 and PhONBu4. It is evident that these cations are
large enough in size to interfere with the attack of CO2 on
the ortho positions of the phenoxide. However, the yields of
Scheme 1. Regioselective preparation of pHBA by the
Kolbe–Schmitt reaction of PhONR4.
Table 1. Products in the Carboxylation of PhONR4 (2.1 mol)aÞ with CO2 (5.0 MPa) in a 200 mL Autoclave
Reaction condition
Recov.
phenol
/%
YieldbÞ
/%
Selectivity
for
pHBAdÞ
Entry
R
Additive
mmol
Temp.
/ꢁC
Time
/h
SA
1.0
2 ꢄ 0
0.6
0:5 ꢄ 0:1
3.9
0:5 ꢄ 0
0
pHBA
4HIPA
EstercÞ
1
2
3
Me
Me
Me
Et
None
K2CO3 (7.22)
K2SO4 (7.22)
None
125
125
125
125
150
125
125
125
125
125
2
2
2
5
2
2
2
2
5
5
71.9
37 ꢄ 5
90.6
85 ꢄ 2
84.6
64 ꢄ 1
92.8
67 ꢄ 1
89 ꢄ 3
56 ꢄ 1
26.5
56 ꢄ 4
8.6
0.5
3 ꢄ 1
0
0
96
97 ꢄ 1
93
96 ꢄ 1
74
99 ꢄ 1
100
>99
>99
100
1:4 ꢄ 0:2
0
0
0
4
14 ꢄ 2
11.3
30 ꢄ 1
7.1
trace
trace
trace
0
5
6
7
Et
Et
Pr
None
K2CO3 (7.22)
None
1:0 ꢄ 0:1
0
8
9
10
Pr
Bu
Bu
K2CO3 (7.22)
None
K2CO3 (7.22)
trace
trace
0
30 ꢄ 1
11 ꢄ 3
35 ꢄ 1
0
0
0
3:1 ꢄ 0:9
trace
10 ꢄ 1
a) PhONR4 was prepared under conditions of [R4NOH]/[PhOH] = 1.1–1.5. b) The mean and standard error are shown for duplicated or
triplicated runs. c) The corresponding alkyl para-hydroxybenzoates. d) The selectivity was calculated based on the yields of pHBA and
the corresponding ester, but 4HIPA was not included.

M. A. Rahim et al.
Bull. Chem. Soc. Jpn., 76, No. 11 (2003) 2193
Table 2. Products in the Reactions of PhOK (3.78 mmol), SAK1 (2.84 mmol), SAK2 (2.33 mmol), pHBAK1 (2.84
mmol), and pHBAK2 (2.33 mmol) under High (5.0 MPa) or Low (0.5 MPa) CO2 Pressure for 1 h in a 200 mL
Autoclave
Reaction condition
CO2 Temp.
Yield
/%
Entry
Reactant
/MPa
/ꢁC
phenol
SA
pHBA
4HIPA
1
2
3
4
5
6
7
8
9
10
PhOK
PhOK
SAK1
SAK2
SAK1
SAK2
pHBAK1
pHBAK2
pHBAK1
pHBAK2
0.5
5.0
0.5
0.5
5.0
5.0
0.5
0.5
5.0
5.0
230
230
200
200
200
200
200
200
200
200
61.1
17.0
34.2
55.0
17.4
1.3
35.2
4.0
45.3
1.1
0.0
54.5
24.6
6.9
74.2
62.1
2.0
0.0
4.7
1.9
38.8
2.1
trace
26.0
0.8
1.0
8.6
13.9
1.0
trace
1.7
40.6
34.7
trace
22.8
60.9
96.0
48.5
95.6
1.3
nor, if any. The R4Nþ and PhOꢅ ions have large polarizability,
and belong to soft acid and base classes, respectively.7 On the
other hand, Kþ and CO32ꢅ belong to hard acid and base classes,
respectively. Thus, the soft PhOꢅ ion prefers to associate with
the soft R4Nþ ion, rather than with the hard Kþ ion.7
These data show that low CO2 pressure is advantageous for
the regioselective preparation of pHBA. Table 2 also contains
experimental data in the case of pHBA. The mono- and dipo-
tassium salts of pHBA were treated under the same conditions
as the salicylates. The dipotassium salt of pHBA was stable,
and the recovery of pHBA after treatment was 96%, irrespec-
tive of applied CO2 pressure. The monopotassium salt was less
stable, and the recovery decreased to 49–61%. The main prod-
uct was phenol (35–45%), and small amounts of SA and 4HIPA
were involved. The results indicate that the potassium salts of
pHBA are thermodynamically more stable than those of SA. In
order to clarify the pathways in the transformation of the sa-
Carboxylation of PhOK at High Temperature and Low
Pressure. It is known5,6 that mono- (SAK1) and dipotassium
salicylates (SAK2) are rapidly converted to the salts of pHBA
at high temperature above 200 ꢁC and low pressure. Thus, it is
anticipated that the carboxylation of PhOK at high temperature
and low CO2 pressure will give regioselectively pHBA, since
the salicylate once formed is converted to pHBA ꢁduring
reaction. In fact, the carboxylation of PhOK at 230 C and
CO2 pressure of 0.5 MPa gave exclusively pHBA in a yield
of 34–39% (Table 2), though the recovery of unaltered phenol
was significantly high (61–65%). Only minor amounts of SA
(less than 0.7%) and 4-hydroxyisophthalic acid (4HIPA, less
than 0.1%) were found in the reaction mixture. This result
was in sharp contrast to the carboxylation at higher CO2 pres-
sure of 5.0 MPa: The recovery of phenol was only 17%, and SA
and 4HIPA were the main products (55 and 26%, respectively).
The yield of pHBA was only 2%. It is evident that the salicylate
once formed by the direct attack of CO2 on the ortho positions
of the phenoxide is transformed into the potassium salt of
pHBA at low CO2 pressure of 0.5 MPa. The activation volume
of the salicylate for transformation into pHBA may be so large
that the reaction is unlikely to occur at high CO2 pressure. In
order to confirm this assumption, SAK1 and SAK2 were treated
at 200 ꢁC for 1 h under the CO2 pressures of 0.5 and 5.0 MPa
(Table 2). The recovery of unaltered SA was 25% for SAK1
and only 7% for SAK2 under the CO2 pressure of 0.5 MPa,
whereas the values were 74% for SAK1 and 62% for SAK2 un-
der the CO2 pressure of 5.0 MPa, indicating that the salicylates
are reactive at low CO2 pressure and relatively stable at high
CO2 pressure. SAK1 and SAK2 gave pHBA in 41% and
35% yields, respectively, together with significant amounts of
phenol (28–34%) formed by decarboxylation, after the treat-
ment under the CO2 pressure of 0.5 MPa. On the other hand,
the treatment at the high CO2 pressure of 5.0 MPa gave only
a trace amount of pHBA for SAK1 and a significant amount
(23%) of pHBA for SAK2, together with 4HIPA (9–14%).
ꢀ
licylate into the salt of pHBA, we prepared SA (SA ) labeled
at the carboxyl group with 13C,2g and the dipotassium salt of
ꢀ
SA was subjected to heat treatment under the same conditions
as described above. The reaction products were esterified to
give methyl p-hydroxybenzoate (MepHBA) and analyzed by
GC/MS as previously reported.2g The relative peak intensities
of m=z 152 and m=z 153 were 100 and ca. 203, respectively, for
MepHBA produced by heat treatment under the CO2 pressure
of 0.5 MPa. Virtually the same result was obtained for MepH-
BA given by treatment under the CO2 pressure of 5.0 MPa.
Considering the natural abundance of 13C (1.1% for each C),
we evaluated that ca. 66% of pHBA is transformed by the in-
tramolecular rearrangement from the salicylate.8 The rest
(34%) of pHBA will be produced via the decarboxylation of
the salicylate, followed by recarboxylation at the para position
of the phenoxide (Scheme 2).
Scheme 2. Two pathways from dipotassium salt of SA to that
of pHBA.

2194 Bull. Chem. Soc. Jpn., 76, No. 11 (2003)
Carboxylation of Phenols with CO2
Table 3. Products in the Carboxylation of Alkali Metal Salts of Aminophenols with CO2 (5.0 MPa) in a 100 mL Au-
toclave
Reaction condition
Yield
/%
Entry
1
Phenols
Alkali
metal
CO2
Temp.
/ꢁC
Time
/h
/MPa
o-COOHaÞ
p-COOHbÞ
m-Aminophenol
Na
K
Cs
Na
K
5
5
5
5
5
5
200
200
250
160
230
190
1
1
1
3
5
10
80.0
80.0
5.9
53.5
72.1
7.2
0
0
50.6
0
0
43.9
2
5-Amino-1-naphthol
Cs
a) ortho-Carboxylated products, i.e., p-aminosalicylic acid for m-aminophenol and 5-amino-1-hydroxy-2-naphtho-
ic acid for 5-amino-1-naphthol. b) para-Carboxylated products, i.e., 4-hydroxyanthranilic acid for m-aminophenol
and 8-amino-4-hydroxy-1-naphthoic acid for 5-amino-1-naphthol.
Scheme 3. Regioselective carboxylations of cesium salts of aminophenols.
Carboxylations of Cesium Salts of Aminophenols. We re-
cently found3 that cesium phenoxide and 2-naphthoxide give
pHBA and 2H6NA, respectively, in much higher yields than
the widely used methods with sodium or potassium phenoxide
and 2-naphthoxide. The selective carboxylation is ascribed to
the large ionic radius of cesium, which interferes with the direct
attack of CO2 at the ortho positions of the phenoxide and
naphthoxide. In the present work, we extended the method to
the regioselective preparation of industrially useful 4-hydroxy-
anthranilic and 8-amino-4-hydroxy-1-naphthoic acids from
m-aminophenol and 5-amino-1-naphthol, respectively. Ac-
cording to reports,9 m-aminophenol gives only p-aminosalicyl-
ic acid by the ordinary Kolbe–Schmitt reaction with sodium or
potassium salts, but not 4-hydroxyanthranilic acid at all. Thus,
we investigated an effect of alkali metal ion on product compo-
sition after the carboxylation of m-aminophenoxide (Table 3).
The carboxylation of sodium or potassium salt of m-aminophe-
nol under the CO2 pressure of 5.0 MPa gave only p-aminosali-
cylic acid in a 80% yield. In sharp contrast, the cesium salt
gave selectively 4-hydroxyanthranilic acid in a 51% yield, to-
gether with a small amount (6%) of p-aminosalicylic acid
(Scheme 3). This is the simplest one-pot reaction giving the
best yield among a number of synthetic methods10 for 4-hy-
droxyanthranilic acid. We also examined an effect of alkali
metal ion on the product composition after the carboxylation
of 5-amino-1-naphtoxide (Table 3). Upon carboxylating the
cesium salt, we obtained 8-amino-4-hydroxy-1-naphthoic acid
in a good yield (44%), together with 5-amino-1-hydroxy-2-
naphthoic acid as a minor product (7%). On the other hand,
the sodium and potassium salts gave only 5-amino-1-hy-
droxy-2-naphthoic acid (54 and 72% yields, respectively).
The markedly regioselective para-carboxylation of the cesium
aminophenoxides will be attributed to the large ionic radius of
the cesium ion, which interferes with the direct attack of CO2 at
the ortho positions of the aminophenoxides.
A part of the experimental work was assisted by Takeshi
Aoki and Masaru Yamasaki. Financial supports by Sumitomo
Chemical Industry and San-In Kensetsu Kougyou Co. are
gratefully acknowledged.
References
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2
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Bull. Chem. Soc. Jpn., 76, No. 11 (2003) 2195
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and unlabeled MepHBA are 209 (¼ 194 þ 15) and 109
(¼ 100 þ 9), respectively, and the the relative amounts of labeled
and unlabeled MepHBA are 66% [¼ 100 ꢃ 209=ð209 þ 109Þ] and
34%, respectively.
3 M. A. Rahim, Y. Matsui, and Y. Kosugi, Bull. Chem. Soc.
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In this calculation, we assumed that the incorporation of
13CO2 into pHBA via the decarboxylation–recarboxylation path-
way was negligible, since the amount of 13CO2 released from the
ꢀ
dipotassium salt of SA was far less than that of added CO2. Based
on the natural abundance of 13C, we estimated the relative amounts
of labeled and unlabeled MepHBA from the GC/MS data as fol-