Mild, single-pot hydrocarboxylation of gaseous alkanes to carboxylic acids in metal-free and copper-promoted aqueous systems

Article abstract of DOI:10.1002/chem.201000352

A direct, selective and highly efficient method has been developed for the hydrocarboxylation of C_n gaseous alkanes into C_n+1 carboxylic acids, in aqueous acid-solvent-free medium at low temperatures. The approach is based on a metal-free or copper-promoted reaction of ethane, propane or n-butane with carbon monoxide and water, in a H₂O/MeCN medium at 50-60 °C, in the presence of potassium peroxodisulfate. The effects of various reaction parameters, such as the absence or presence of a copper promoter, solvent composition, temperature, time, CO and alkane pressure, were studied. A free radical mechanism was confirmed by radical trap experiments involving acyl radical formation, oxidation and subsequent hydroxylation by water. Remarkable yields (based on alkane) of carboxylic acids in the 34- 41% range were achieved even in the metal-free systems, although in the presence of a tetracopper(II) triethanolaminate derived promoter they reach superior values of 58 and 87% for the hydrocarboxylations of propane and nbutane, respectively; in these cases, branched isobutyric and 2-methylbutyric acids were the predominant products. From a green perspective, important features of the present alkane hydrocarboxylations include the exceptional metal-free, mild and acid-solvent- free reaction conditions, the operation in aqueous medium with a rare hydroxylating role of water, with high selectivities, and yields of carboxylic acids. Taken together, these conditions correspond to the mildest and the most efficient method so far reported for the oxidative functionalisation of gaseous alkanes.

Full text of DOI:10.1002/chem.201000352

FULL PAPER
DOI: 10.1002/chem.201000352
Mild, Single-Pot Hydrocarboxylation of Gaseous Alkanes to Carboxylic
Acids in Metal-Free and Copper-Promoted Aqueous Systems
[
a]
Marina V. Kirillova, Alexander M. Kirillov, and Armando J. L. Pombeiro*
Abstract: A direct, selective and highly
efficient method has been developed
for the hydrocarboxylation of Cn gas-
eous alkanes into Cn+1 carboxylic acids,
in aqueous acid-solvent-free medium at
low temperatures. The approach is
based on a metal-free or copper-pro-
moted reaction of ethane, propane or
n-butane with carbon monoxide and
firmed by radical trap experiments in-
volving acyl radical formation, oxida-
tion and subsequent hydroxylation by
water. Remarkable yields (based on
alkane) of carboxylic acids in the 34–
41% range were achieved even in the
metal-free systems, although in the
presence of a tetracopper(II) triethano-
laminate derived promoter they reach
superior values of 58 and 87% for the
hydrocarboxylations of propane and n-
butane, respectively; in these cases,
branched isobutyric and 2-methylbuty-
ric acids were the predominant prod-
ucts. From a green perspective, impor-
tant features of the present alkane hy-
drocarboxylations include the excep-
tional metal-free, mild and acid-sol-
vent-free reaction conditions, the
operation in aqueous medium with a
rare hydroxylating role of water, with
high selectivities, and yields of carbox-
ylic acids. Taken together, these condi-
tions correspond to the mildest and the
most efficient method so far reported
for the oxidative functionalisation of
gaseous alkanes.
water, in a H O/MeCN medium at 50–
2
608C, in the presence of potassium per-
oxodisulfate. The effects of various re-
action parameters, such as the absence
or presence of a copper promoter, sol-
vent composition, temperature, time,
CO and alkane pressure, were studied.
A free radical mechanism was con-
Keywords: alkanes · CꢀH activa-
tion · carboxylation · carboxylic
acids · copper
Introduction
In spite of the sweeping development of green chemistry
in recent years, its application to alkane-based processes is
rather limited, which is primarily due to the unreactive
[4]
As the main components of natural gas, light alkanes are
abundant and potentially cheap carbon raw materials for
character of the CꢀH and CꢀC bonds in alkanes. Thus, in
[1]
[1,3]
added value organic chemicals. However, the high inert-
ness of gaseous alkanes prevents their broad application in
the direct syntheses of oxygenated products, and therefore,
they are mainly used as fossil fuels or, under drastic condi-
tions involving power-consuming processes (cracking, dehy-
drogenation and reforming), converted into olefins that are
most cases,
the implementation of relatively mild and se-
lective transformations of light alkanes requires the pres-
ence of metal catalysts (commonly bearing precious metals),
and the use of strongly acidic reaction media, typically con-
[
5,6]
[7]
centrated trifluoroacetic
or sulfuric acid, or a super-
[8]
acid. Therefore, from a green perspective, there is a strong
demand for potential metal-free, acid-solvent-free and/or
aqueous medium alternatives
[
1,2]
[9]
common intermediates in large-tonnage organic synthesis.
Hence, the search for single-pot, mild and environmentally
benign methods of oxidative functionalisation of alkanes
[10]
of single-pot alkane func-
tionalisation, which are topics of high significance that still
remain very poorly developed.
[
1,3]
constitutes a challenging problem of modern chemistry.
Among the useful organic molecules that can be obtained
directly from gaseous alkanes, low aliphatic C –C carboxylic
3
5
acids are important commodity chemicals that are in in-
creasing demand and are used in a wide variety of applica-
tions. Their large-scale production is mainly based on the
[
a] Dr. M. V. Kirillova, Dr. A. M. Kirillov, Prof. A. J. L. Pombeiro
Centro de Quꢀmica Estrutural, Complexo I
Instituto Superior Tꢁcnico, TU Lisbon
Av. Rovisco Pais, 1049-001, Lisbon (Portugal)
Fax : (+351)218464455
[2]
carbonylation of ethylene, oxidation of propanal or naphtha
(
for propionic acid), liquid-phase oxidation of butyralde-
E-mail: pombeiro@ist.utl.pt
hydes (for butyric acids), and carbonylation of olefins or al-
Chem. Eur. J. 2010, 16, 9485 – 9493
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9485

[
2]
cohols (for C acids). However, there are still a number of
in the absence (metal-free process) or in the presence of a
copper promoter (copper-promoted process) (Scheme 1).
Hence, ethane was directly converted into propionic acid,
5
general limitations of those methods from both environmen-
tal and cost perspectives, including: 1) the common use of
raw materials that are considerably more expensive than al-
kanes and require prior production; 2) the required multi-
stage transformations, and the need for harsh reaction con-
ditions and expensive metal catalysts; and 3) the low prod-
uct yields and/or poor selectivity and complex workup.
In pursuit of our general line of research on various
metal-catalysed oxidative transformations of alkanes under
Scheme 1. Hydrocarboxylation of C
n
alkanes to the corresponding Cn+1
carboxylic acids in H O/MeCN medium.
2
[
6,11,12]
mild conditions,
we have preliminarily communicat-
[
12a]
ACHTUNGTRENNUNGe d
a novel, efficient and cleaner route for the selective
and single-pot synthesis of carboxylic acids from alkanes,
which has been further extended to a detailed investigation
propane into isobutyric (major product) and butyric acids,
and n-butane was transformed into 2-methylbutyric (major
product) and valeric acids. Surprisingly, these mild and se-
lective transformations of inert alkanes proceed rather effi-
ciently in metal-free systems, wherein a crucial role is
[12b]
of cycloalkanes.
This route is based on the hydrocarboxy-
lation reaction of an alkane with carbon monoxide and
water in the presence of peroxodisulfate oxidant. In contrast
[5,6]
ꢀ
to state-of-the-art alkane carboxylation methods,
the
played by the active radical sulfate SO C (known as an
4
14]
[
present approach does not require absolute trifluoroacetic
acid (TFA) as a solvent, and proceeds efficiently in aqueous
active single electron-transfer oxidant),
generated upon
thermolysis of peroxodisulfate. It should be stressed that the
metal-free carboxylations also proceed with the same effi-
ciency in a Teflon reactor, thus confirming that the reactions
are not promoted by the reactor metal wall.
acid-solvent-free medium (H O/MeCN mixed solvent), at
2
mild temperatures (50–608C) and even in the absence of
any metal catalyst.
Hence, the general objective of the current study was the
detailed investigation and optimisation of the hydrocarboxy-
Since the effectiveness of various metal-free oxidative
transformations can be improved by the presence of a metal
[9,12]
lation of C gaseous alkanes (ethane, propane and n-butane)
promoter (or metal catalyst),
racopper(II) triethanolaminate
[OꢁCu {N(CH CH O) } (BOH) ][BF ] (1) for this purpose.
we used hydrosoluble tet-
n
to the corresponding Cn+1 carboxylic acids, by studying the
influence of a variety of experimental conditions (i.e., the
absence or presence of a metal promoter, solvent composi-
tion, temperature, time, and relative amounts of substrate
and carbon monoxide). Although the method we are report-
ing still has some environmental limitations, its significance
in a green context with respect to prior work on alkane car-
derivative
A
H
U
G
R
N
N
A
H
U
G
R
N
U
ACHTUNGTRENNUNG
4
4
2
2
3
4
4 2
This promoter has previously been shown to display the
[12]
highest efficiency in such alkane carboxylations,
and is
also a remarkable catalyst for the oxidation of cycloalkanes
[15]
and benzyl alcohols.
Selected results obtained for the
metal-free and copper-promoted hydrocarboxylation of gas-
eous alkanes are given in Table 1, and briefly discussed
below.
[
5,6,13]
boxylations
eral
and on mild alkane transformations in gen-
[
1,3,7]
consists of the following features: 1) the use of an
aqueous acid-solvent-free medium; 2) the possibility of oper-
ating under metal-free conditions; 3) the very mild tempera-
tures; 4) the rather high efficiency and selectivity, and 5) the
useful application of water as a
The metal-free hydrocarboxylation of ethane (Table 1,
entry 1) leads to the formation of propionic acid in 34%
yield (all yield values in this paper are rounded off and are
relevant reagent that provides
Table 1. Metal-free versus copper-promoted hydrocarboxylation of gaseous alkanes to carboxylic acids in
H O/MeCN medium.
2
the main source of the OH
group in the carboxylic acid
product.
[a]
[
b]
Entry Alkane
Carboxylic acid
product
Total yield [%] (bond selectivity)
[c]
Metal free
Copper promoted
[
d]
[d]
1
2
33.7
17.1
Results and Discussion
[
e]
[e]
41.0 (18/28=1:21) 58.3 (18/28=1:28)
Metal-free versus copper-pro-
moted hydrocarboxylation of
alkanes: The hydrocarboxyla-
tions of gaseous alkanes were
[
d]
[e]
3
34.1 (18/28=1:24) 86.7 (18/28=1:35)
[
a] Selected results (for more assays, see Tables 2, 3 and 4), major product is indicated first; reaction conditions
undertaken in stainless steel au- (unless stated otherwise): p
toclaves by treating an alkane respectively; p(CO)=10.0 atm; K
ACHTUNGTRENNUNG
(alkane)=1.0, 1.0 and 0.75 atm (1 atm=0.266 mmol) for C H , C H and n-C H ,
2
6
3
8
4
10
2
S
2
O
8
=1.5, 1.0 and 1.0 mmol for reactions with C
O (3 mL)/MeCN (3 mL); 508C (for n-C 10) or 608C (for C and C
13.0 mL capacity). [b] Total yield (moles of all carboxylic acids/100 moles of alkane) determined by GC analy-
2
H
6
, C
3 8 4
H and n-C H10, re-
spectively; H
2
4
H
2
H
6
3 8
H ); 6 h in an autoclave
with CO, water and potassium
peroxodisulfate at low tempera-
ture (typically 50–608C) in neu-
(
sis; whenever applicable, selectivity parameters are indicated in brackets: 18/28 stand for bond selectivity, with
respect to the relative normalised reactivities of hydrogen atoms at primary and secondary carbon atoms of al-
2
tral H O/MeCN medium, either kanes. [c] In the presence of compound 1 (4.0 mmol). [d] 17 h. [e] H O (2 mL)/MeCN (4 mL).
2
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Chem. Eur. J. 2010, 16, 9485 – 9493

Hydrocarboxylation of Alkanes to Carboxylic Acids
FULL PAPER
[13c]
H O/CO/air system.
2
However, all these processes exhibit-
ed low efficiencies in terms of carboxylic acid yields, which
[13]
did not exceed 0.4% relatively to the alkane.
More data on alkane hydrocarboxylations, including the
effects of solvent composition, temperature, time, and CO
and alkane pressures, are summarised in Tables 2, 3 and 4
and Figure 1, and are discussed below, particularly regarding
the reactions with propane as a model substrate.
Hydrocarboxylation of ethane to propionic acid: Due to the
presence of only primary carbon atoms, ethane appears to
be the least reactive alkane towards hydrocarboxylation,
apart from methane, for which the attempted conversion to
acetic acid has so far been unsuccessful. Hence, typical
yields of propionic acid after 6 h reaction time lie in the 8–
1
0% range (Table 2, entries 1–3) when using 10 atm of
based on alkane). In the corresponding copper-containing
system, the yield drops to approximately half, which points
to an eventual inhibiting effect of compound 1 in the hydro-
carboxylation of ethane, conceivably due to competitive
ethane oxidation reactions that only occur in the presence
of the metal catalyst. In fact, the yields of oxidation prod-
ucts (alcohols and ketones) in the hydrocarboxylation of cy-
[
a]
Table 2. Hydrocarboxylation of ethane to propionic acid.
Entry
p
A
H
U
G
R
N
U
G
2
H
6
)
p(CO)
[atm]
t
Solvent H
2
O/
K
2
S
2
O
8
Propionic
[b]
A
H
U
G
R
N
U
G
A
H
U
G
R
N
U
G
[h] MeCN [mL]
ACHTUNGTRENNGNU[ mmol] acid [%]
1
2
3
4
5
6
7
8
9
10
10
10
10
10
10
5
3
1
10
30
30
20
20
20
20
30
10
10
20
6
6
6
6
6
6
6
17
17
6
3:3
3:3
3:3
2:4
4:2
6:0 (or 0:6)
2:4
3:3
3:3
3.0
1.5
2.0
2.0
2.0
2.0
1.5
1.5
1.5
2.0
8.0
9.4
[c]
9.7 (9.9)
4.7 (6.2)
0.9 (6.4)
0
[
[
c]
c]
[12b]
clohexane are increased in the presence of 1.
In contrast to studies with ethane, the promoting role of 1
was evident in the reactions with propane and n-butane; in
these cases, the yields of the corresponding carboxylic acids
of 58 and 87%, respectively (Table 1, entries 2 and 3), were
higher than those obtained in the metal-free hydrocarboxy-
lation (41 and 34%, respectively).
2.0
5.0
17.1 (33.7)
5.3
[
c]
[
d]
10
3:3
[a] Reaction conditions (unless stated otherwise): 608C, in an autoclave
13.0 mL capacity), in the presence of compound 1 (4.0 mmol). [b] Yield
moles of propionic acids/100 moles of ethane) of propionic acid deter-
(
(
The reactivities of the hydrogen atoms at secondary
carbon centres in propane and n-butane are dominant, lead-
ing to the formation of isobutyric and 2-methylbutyric acids
as the main products, respectively. This is more pronounced
in the copper-promoted systems than in the metal-free ver-
sions, as exemplified by the higher bond selectivity parame-
ters (18/28) of 1:35 versus 1:24, respectively, in the hydrocar-
boxylation of n-butane (entry 3). The bond selectivity pa-
rameter 18/28 refers to the normalised (for the relative
number of hydrogen atoms) reactivities of hydrogen atoms
at primary and secondary carbon atoms of the alkanes.
Furthermore, a very high selectivity towards the forma-
tion of carboxylic acids, under both metal-free and Cu-pro-
moted systems, was observed for all the alkanes tested; gen-
eration of alcohols and ketones as byproducts of partial
alkane oxidations did not exceed 1% of the overall yield.
The achieved yields of carboxylic acids (34–87%) are re-
markable, considering the high degree of inertness of gas-
eous alkanes, the very mild reaction conditions, the use of
aqueous medium and the possibility of operating in metal-
free systems. In this regard, it should be mentioned that
some transformations of gaseous alkanes into carboxylic
mined by GC analysis. [c] Yield in brackets was obtained in the absence
of compound 1 (metal-free system). [d] Ca[V{ON
mmol) was used instead of 1.
2 2 2
ACHTUNGTRENNU(NG CH COO) } ] (4.0
ethane, 20–30 atm of CO and the optimal H O/MeCN
2
(3 mL/3 mL) solvent composition. The reaction does not
occur either in only water or acetonitrile (Table 2, entry 6),
and is also less efficient in the presence of an excess of
either of the solvents (entries 5 and 4). Higher yields of pro-
pionic acid (up to 34%) can be attained by lowering the
ethane pressure to 1 atm and by prolonging the reaction
time to 17 h (Table 2, entry 9).
As mentioned above, better yields of propionic acid are
typically observed in the metal-free systems; compound 1
produces an inhibiting effect, depending on the reaction
conditions (Table 2, entries 3–5, 9). It should be noted that
inhibition behaviour is also displayed by Ca[V{ON-
AHCTUNGTRNNEUG( CH COO) } ] (Table 2, entry 10), which is one of the most
2 2 2
efficient catalysts for ethane carboxylation in TFA medi-
[6a]
um.
Propionic acid appears to be the only product of the
ethane hydrocarboxylation, since neither the partial oxida-
tion of ethane, nor the conversion of acetonitrile into acetic
acid, were detected. The acetonitrile solvent was inert to-
wards carboxylation under the reaction conditions, since no
[13]
acids in water have previously been reported, including:
[13a]
[13b]
1) metal-free
and Rh-catalysed
carbonylations of
methane and ethane in H O/CO/K S O (or O ) systems,
2
2
2
8
2
and 2) vanadium-catalysed carboxylations of methane in the
Chem. Eur. J. 2010, 16, 9485 – 9493
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9487

A. J. L. Pombeiro et al.
propionic acid formation was observed upon repeating the
reaction in the absence of ethane (blank test).
The solvent composition was a very important reaction
parameter in the hydrocarboxylation of propane (Fig-
ure 1a). Unfortunately, the reaction did not proceed appre-
ciably (1% products yield) in only water, which would be
the ideal solvent from both environmental and cost perspec-
Hydrocarboxylation of propane to butyric acids: The hydro-
carboxylation of propane proceeded more efficiently than
that of ethane, leading to substantial yields of butyric acids,
both in the metal-free and copper-promoted processes
[4a,d,10,16]
tives.
Neither could butyric acids be obtained when
using acetonitrile as the sole solvent (Figure 1a). However,
(
overall yields up to 41 and 58%, respectively). Isobutyric
the mixed H O/MeCN solvent appears to be remarkably
2
acid was always the predominant product, with the yields of
butyric acid typically being one order of magnitude lower.
The reactions were dependent on a variety of experimental
factors, which are shown in Figure 1 and Table 3.
suitable; use of this solvent system led to 32 and 30% over-
all yields of butyric acids, for p CAHTUNGTRNEUNG( C H )=5 atm and p(CO)=
3 8
30 atm, in the Cu-promoted systems at the optimal 1:2 and
1:1 H O/MeCN volumetric ratios, respectively (Figure 1a,
2
Table 3, entries 9 and 5). When the reaction was undertaken
with a double excess of water
relative to acetonitrile, the cor-
responding yield fell to 11%. In
the metal-free systems, the
overall yields of butyric acids
were similar (12–14%) at dif-
ferent solvent compositions (2:1
to 1:2 H O/MeCN range). The
2
two solvents play essential func-
tions: acetonitrile dissolves the
organic species, whereas water
is required to solubilise the per-
oxodisulfate oxidant and, most
importantly, to provide the
main source of the hydroxyl
group for the carboxylic acid
product. For the first time, this
remarkable carboxylating role
of water was recently confirmed
by us on the basis of experi-
1
8
[12a]
ments with H2 O.
Although the mixed H O/
2
MeCN solvent system can be
easily recycled and is far green-
er and cheaper than the abso-
lute trifluoroacetic acid, which
is used as the conventional sol-
vent for the alkane carboxyla-
[5,6]
tions,
the presence of aceto-
nitrile still constitutes a draw-
back from an environmental
perspective.
However,
one
should mention that various
water/organic solvent mixtures
are typically less noxious than
[17]
the pure organic solvents.
Replacement of acetonitrile
with acetone has been attempt-
ed in the propane hydrocarbox-
Figure 1. Effects of a) solvent composition, b) temperature, c) reaction time, and pressures of d) carbon mon- ylation, but resulted in
a
oxide and e) propane on the yields of isobutyric (light green/blue coloured) and butyric (dark green/blue col-
modest overall yield of 10
3 8
oured) acids in the hydrocarboxylation of C H . Green (right) and blue (left) bars correspond to the metal-
free and copper-promoted processes, respectively. Typical reaction conditions (except for the varying parame-
ter) are those given in Table 3, entry 5 for diagrams (a)–(d); entries 1, 9, 12, 14 (Cu promoted) or 2, 4, 11, 14
versus 30% for the H O/MeCN
2
system (Table 3, entry 15 vs. 5).
(
metal free) for diagram (e).
Moreover, the use of H O/
2
9488
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Chem. Eur. J. 2010, 16, 9485 – 9493

Hydrocarboxylation of Alkanes to Carboxylic Acids
FULL PAPER
[
a]
Table 3. Copper-promoted and metal-free hydrocarboxylation of propane to butyric acids.
the copper-promoted system,
Bond selectivity the overall yield of butyric
[
b]
Entry
p
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(C
3
H
8
)
p(CO)
[atm]
t
H
[mL]
2
O/MeCN
Carboxylic acid yield [%]
[
c]
A[ atm]
C
H
T
U
N
G
T
R
E
N
N
U
N
G
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
[h]
Isobutyric
Butyric
Total
18/28
acids gradually increased from
13 to 37% on extending the re-
action time from 2 to 15 h.
1
2
3
4
5
6
7
8
9
7
7
5
5
5
5
5
5
5
5
3
3
3
1
5
5
5
30
20
10
20
30
40
30
30
30
30
20
30
10
10
30
30
20
6
6
6
6
6
2:4
3:3
3:3
3:3
3:3
3:3
3:3
3:3
2:4
4:2
3:3
2:4
2:4
2:4
3:3
3:3
3:3
20.2
1.5
21.7
1:40
A
H
U
G
R
N
U
G
A
H
U
G
R
N
U
G
A
H
U
G
R
N
U
G
ACHTUNGTRNENUNG( 1:22)
11.8 (14.3)
20.2 (15.5)
26.6 (12.7)
26.4 (7.3)
28.5
32.0 (12.7)
27.5 (10.4)
10.6 (13.1)
1.5 (3.7)
1.6 (3.3)
3.3 (1.8)
3.3 (1.4)
4.0
4.7 (2.0)
4.2 (1.9)
0 (1.5)
13.3 (18.0)
21.8 (18.8)
29.9 (14.5)
29.6 (8.7)
32.5
36.7 (14.7)
31.7 (12.3)
10.6 (14.6)
1:24 (1:12)
1:38 (1:14)
1:24 (1:21)
1:24 (1:16)
1:21
1:20 (1:19)
1:20 (1:16)
– (1:26)
Although alkane carboxyla-
tions in TFA are known to pro-
ceed even in the absence of CO
(with TFA acting then as the
6
10
15
6
6
6
6
6
6
6
[6]
carbonylating agent ), the hy-
drocarboxylation of propane in
10
11
12
13
14
15
16
17
H O/MeCN medium does not
A
H
U
G
R
N
U
G
A
H
U
G
R
N
U
G
A
H
U
G
R
N
U
G
A
H
U
T
E
N
N
(1:26)
2
34.2
27.6
52.7 (35.8)
9.0
20.4
3.8
3.1
5.6 (5.2)
1.2
3.2
38.0
30.7
1:27
1:27
proceed to any extent unless
CO is added, because no other
carbonylating reagent is pres-
ent. Carbon monoxide is typi-
cally introduced into the reac-
tion mixture in some excess rel-
[
[
[
[
[
d]
d]
e]
f]
58.3 (41.0)
10.2
1:28 (1:21)
1:23
6
6
23.4
1:19
(–)
g]
A
H
U
G
R
N
U
G
A
H
U
G
R
N
U
G
A
H
U
G
R
N
U
G
[
a] Yield and bond selectivity values in brackets correspond to metal-free systems; selected results (additional
assays are given in Figure 1); reaction conditions (unless stated otherwise): K
toclave (13.0 mL capacity), in the presence of compound 1 (8.0 mmol). [b] Yield (moles of carboxylic acid/ the highest product yields. As
2 2 8
S O
=1.5 mmol, 608C, in an au- ative to propane to generate
1
00 moles of propane) determined by GC analysis. [c] Bond selectivity parameter 18/28 corresponds to the rel-
ative normalised reactivities of hydrogen atoms at primary and secondary carbon atoms in propane. [d] Com-
pound 1 (4.0 mmol), K =1.0 mmol. [e] Acetone (3 mL) was used instead of MeCN. [f] Ca[V{ON-
(CH COO) ] (8.0 mmol) was used instead of 1. [g] Reaction performed in the presence of CBrCl (1.0 mmol)
for the reaction time, changes
in the CO pressure affect the
metal-free and copper-promot-
2 2 8
S O
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
2
2
}
2
3
leading to the formation of 2-bromopropane (12.2%) and 1-bromopropane (4.9%) as the only observed prod- ed hydrocarboxylations differ-
ucts.
ently (Figure 1d). Thus, for the
metal-free reaction, the highest
overall yield of 23% was ach-
EtOH or H O/CHCl solvent compositions resulted in the
ieved at low CO pressure (5 atm); higher pressures led to a
reduction in yield. In the Cu-promoted process, an increase
of p(CO) led to a gradual increase in yield, reaching the op-
timal value of 30% at 30 atm of CO. Although replacing
2
3
formation of only traces of isobutyric acid. The poor results
obtained when using acetone or ethanol as the second com-
ponent of the solvent mixture can be associated with their
increased reactivity (compared to MeCN) towards oxida-
tion, which can compete with the carboxylation reaction.
The unsuitability of chloroform in the reaction can be due
to solubility problems (heterogeneous system) and its radi-
cal trap behaviour (see the discussion of experiments with
CO with CO as an alternative carboxylating agent would
2
be very desirable from an environmental viewpoint, all such
attempts have so far been unsuccessful.
Propane pressure also has a considerable influence on the
reaction (Figure 1e) as it determines the amount of sub-
strate in the reaction mixture. Hence, a clear trend of yield
growth on lowering the propane pressure can be detected in
both metal-free and Cu-promoted processes. The highest
yields of butyric acids of 41 and 58%, respectively, were
CBrCl below).
3
As can be seen from Figure 1b, the temperature is also an
important reaction parameter. Hence, for the Cu-promoted
system, the overall yield of butyric acids (14%) obtained at
408C can be considered rather high, taking into account the
thus achieved at p ACHTUNGTNERNUG( C H ) of 1 atm. Nevertheless, the product
3 8
inertness of this gaseous alkane. However, the hydrocarbox-
ylation is more efficient with a slight increase in the temper-
ature, attaining the optimal yield values at 608C. Interesting-
ly, the metal-free system requires about 108C higher temper-
atures to reach activities similar to that of the Cu-promoted
system. Thus, only traces of isobutyric acid are formed at
yields were also significant at elevated pressures of propane
(Table 3).
The observed bond selectivity parameter 18/28 is indica-
tive of the predominant reactivity of the methylene over the
methyl protons in propane (and is suggestive of a radical
mechanism); this is also dependent on a variety of reaction
factors and, in particular, on the presence of the copper pro-
moter (Table 3). The typical 18/28 parameter values lie in
the 1:20 to 1:28 range for the Cu-promoted systems, whereas
they are generally about one-third smaller in the metal-free
reactions (i.e., 18/28 ratio of 1:12 to 1:19). Such a difference
in bond selectivity suggests that compound 1 not only pro-
motes the hydrocarboxylation, but also affects the mechanis-
tic pathway and the product distribution pattern.
4
8
08C in the metal-free reaction, whereas an overall yield of
% is observed at 508C, which increases to 23% at the opti-
mal temperature of 708C (Figure 1b). Further increases in
temperature led to a gradual drop in yield as a result of
[12a,14]
thermal decomposition of the peroxodisulfate.
The accumulation of products was already observed after
h of reaction (Figure 1c). However, in a metal-free system,
2
a slightly longer reaction time of 4 h was typically required
to achieve the optimum value (16%) of overall yield, which
remained almost invariable beyond this time. In contrast, in
For comparison, we also tested Ca[V{ON
ACHTUNGTRNENU(G CH COO) } ]
2 2 2
as a promoter; this resulted in a slightly inferior yield and
Chem. Eur. J. 2010, 16, 9485 – 9493
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9489

A. J. L. Pombeiro et al.
selectivity (23%, 18/28=1:19) than when the reaction was
performed in the presence of compound 1 (30%, 18/28=
even higher yield of 87% could be obtained after 6 h, pro-
viding the reaction was performed in a solvent composed of
a double excess of acetonitrile over water (Table 4, entry 9).
In contrast, a much lower yield (28%) was obtained with a
2:1 water/acetonitrile volumetric ratio (Table 4, entry 10).
Attempts to replace 1 with the vanadium-containing com-
1
:24) (Table 3, entry 16 vs. 5). Interestingly, the bond selec-
tivities given above are significantly higher (18/28 ratio 1:3
to 1:7) than those obtained in the V-catalysed carboxylation
[6d]
of propane in TFA. Moreover, the latter reaction generat-
ed a considerable amount (up to 8%) of acetic acid through
CꢀC bond cleavage and oxidation processes; such side reac-
pound, Ca[V{ON CAHTUNGTRNEUN(G CH COO) } ], resulted in yields almost
2 2 2
identical to those obtained in the metal-free system
(Table 4, entries 12 and 2). Although the tetracopper(II)
complex 1 exhibits a significant promoting effect on butane
hydrocarboxylation, its substitution for a simple copper salt,
tions were not observed under the conditions developed in
the present work.
Hydrocarboxylation of n-butane to 2-methylbutyric and va-
leric acids: In general, the hydrocarboxylation of n-butane
exhibits features similar to those observed in the case of
propane and, thus, is not discussed in much detail. Butane
hydrocarboxylation at the secondary carbon atoms is even
more preferable, as attested to by the superior bond selec-
tivity 18/28, which lies in the 1:33 to 1:54 and 1:17 to 1:24
ranges for the Cu-promoted and metal-free systems, respec-
tively (Table 4). Hence, 2-methylbutyric acid is always the
predominant product, whereas the amount of valeric acid
formed is relatively minor, not exceeding 3.6% yield
Cu ACHTUNGTNERGUN( NO ) ·2.5H O, resulted in a strong inhibiting effect,
3 2 2
leading to an overall product yield of only 14% versus 25%
in the metal-free system (Table 4, entries 11 and 2). This fact
indicates the particular relevance of the N,O-ligands and
their intricate arrangement in 1. Apart from the high activi-
ty of 1, the application of this compound as the preferable
metal promoter is also favoured by its solubility in water, its
high stability and its facile self-assembly synthesis in aque-
ous medium from readily available and relatively inexpen-
[15a,b]
sive chemicals.
However, further exploration of alkane
hydrocarboxylations cannot be limited to use of the promot-
(
Table 4, entry 9). Considerable amounts of products can be
er 1, and other water-soluble transition-metal com-
[11a,c,18]
obtained even in the metal-free systems (Table 4, entries 2
and 8), although the Cu-promoted reactions always resulted
in superior yields. The effect of CO pressure was studied
(
5
effect of time was investigated (Table 4, entries 2 and 6–8), a
considerable accumulation of products was found to occur
after 6 h of reaction (entry 2), although the highest yields of
A
H
U
G
R
N
U
G
should also be tested.
[6]
Table 4, entries 1–5), revealing a maximum overall yield of
1% at a p(CO) of 15 atm (Table 4, entry 2). When the
on the carboxylation of alkanes, both in TFA and in H O/
2
[12]
MeCN media, supports a free radical mechanism. Hence,
based on literature and experimental data, tests with radical
1
8
traps and O-labelled water and on theoretical calcula-
[12a]
A
H
U
G
R
N
U
G
the simplified mechanism presented in Scheme 2 is
3
1
4 (metal free) and 80% (Cu promoted) were attained after
7 h (entry 8). However, in the Cu-promoted system, an
proposed for metal-free and Cu-promoted hydrocarboxyla-
tion of gaseous alkanes. The first step involves the genera-
tion of a free alkyl radical RC,
which is formed through hydro-
Table 4. Copper-promoted and metal-free hydrocarboxylation of n-butane to 2-methylbutyric and valeric
acids.
gen-atom abstraction from an
alkane by the sulfate radical
[
a]
[
b]
Entry
p(CO)
[atm]
t
Carboxylic acid yield [%]
Bond selectivity
18/28
ꢀ
SO4C (reaction 1). The latter is
[c]
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
[h]
2-Methylbutyric
Valeric
Total
derived from the thermolytic
and copper-promoted (when in
the presence of 1) decomposi-
1
2
3
4
5
6
7
8
9
1
1
1
1
5
10
15
20
30
10
10
10
10
10
10
10
10
6
6
6
6
6
2
4
17
6
6
14.3
43.8 (23.6)
48.9
39.8
4.9
1.3 (0)
10.9 (9.3)
77.8 (32.1)
83.1 (14.3)
26.8
0.4
1.7 (1.7)
1.9
1.6
0.2
0 (0)
0.5 (0.8)
2.4 (2.0)
3.6 (0.9)
0.9
14.7
45.5 (25.3)
50.8
41.5
5.1
1.3 (0)
11.4 (10.1)
80.2 (34.1)
86.7 (15.2)
27.7
1:54
1:39 (1:21)
1:39
1:37
1:37
[6a–c,13a,14a]
tion of K S O .
It is
2
2
8
important to mention that
almost quantitative transforma-
tion of potassium peroxodisul-
fate into KHSO4 (reaction 1)
takes place in the hydrocarbox-
ylation reactions. In fact, upon
cooling the reaction mixtures,
this salt crystallises and can be
easily separated by filtration;
–
1:33 (1:17)
1:49 (1:24)
1:35 (1:24)
1:45
1:15
1:13
[
d]
[
[
[
[
e]
0
1
2
3
f]
6
6
6
12.9
21.2
3.3 (2.8)
1.3
2.4
0.1 (0.1)
14.2
23.6
3.3 (2.9)
g]
h]
1:50 (1:42)
[
a] Yield and bond selectivity values in brackets correspond to metal-free systems; reaction conditions (unless
stated otherwise): p(C 10)=0.75 atm (1.0 atm=0.266 mmol), K =1.0 mmol, H O (3 mL)/MeCN (3 mL),
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
4
H
2
S
2
O
8
2
5
08C, in an autoclave (13.0 mL capacity), in the presence of compound 1 (4.0 mmol). [b] Yield (moles of car- this salt can potentially be re-
boxylic acid/100 moles of n-butane) determined by GC analysis. [c] Bond selectivity parameter 18/28 corre- converted into K S O through
2
2
8
sponds to the relative normalised reactivities of hydrogen atoms at primary and secondary carbon atoms in n-
butane. [d] H O (2 mL)/MeCN (4 mL). [e] H O (4 mL)/MeCN (2 mL). [f] Cu(NO ꢃ2.5H O (4.0 mmol) was
used instead of 1. [g] Ca[V{ON(CH(CH )COO) ] (4.0 mmol) was used instead of 1. [h] Reaction performed
in the presence of CBrCl (1.0 mmol) leading to the formation of 2-bromobutane [20.1% (Cu promoted) and
0.0% (metal-free)] and 1-bromobutane [1.0% (Cu promoted) and 0.5% (metal free)].
established
processes.
The involvement of alkyl rad-
icals was supported by perform-
electrochemical
2
2
A
H
U
T
E
N
N
3
)
2
2
[19]
A
H
U
G
R
N
N
3
2 2
}
3
1
9490
www.chemeurj.org
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 9485 – 9493

Hydrocarboxylation of Alkanes to Carboxylic Acids
FULL PAPER
Nevertheless, a less favourable route, in which the forma-
tion of the carboxylic acid may occur through the mixed an-
hydride RC(O)OSO H should also be mentioned. This an-
3
hydride can be generated by protonation of the acyl sulfate
ꢀ
+
ꢀ
by HSO4 or by coupling of RCO with HSO , and would
4
undergo intramolecular hydrogen transfer with elimination
[12a]
of SO , thus leading to the carboxylic acid product.
3
Conclusion
The present study shows that even the most inert hydrocar-
bons (i.e., alkanes) can be selectively and efficiently trans-
formed into useful organic products under mild and relative-
ly environmentally benign conditions, thus extending a
green chemistry approach to alkane-based processes. Hence,
ethane, propane and n-butane are converted into propionic,
isobutyric and 2-methylbutyric acids, respectively, as the
main products, through single-pot aqueous medium hydro-
carboxylation with carbon monoxide, water and potassium
peroxodisulfate, representing the mildest and the most effi-
cient method so far reported for the oxidative functionalisa-
tion of gaseous alkanes.
The hydrocarboxylations have been optimised by studying
the effects of a variety of reaction parameters, allowing re-
markably high overall yields (based on alkane) of carboxylic
acids, namely, 34% of propionic acid, 58% of butyric acids,
and 87% of 2-methylbutyric and valeric acids in the reac-
tions with ethane, propane and n-butane, respectively, to be
achieved. A significant promoting effect of the water-soluble
tetracopper(II) complex 1 was observed in the hydrocarbox-
ylations of propane and n-butane, although this compound
was found to inhibit the reaction with ethane. Moreover, dif-
ferent bond selectivities have been observed in the metal-
free and Cu-promoted reactions, possibly indicating the in-
volvement of distinct steps in the reaction mechanisms. A
free radical mechanism is confirmed by tests with a radical
trap.
Scheme 2. Proposed simplified mechanism for the hydrocarboxylation of
gaseous alkanes in H O/MeCN medium.
2
ing the hydrocarboxylations in the presence of CBrCl as a
3
C-centred radical trap. Under these conditions, full suppres-
sion of carboxylic acid formation was observed in the metal-
free reaction with propane (Table 3, entry 17 vs. 4), with the
appearance of 2-bromopropane (12%) and 1-bromopropane
(
5%) products (entry 17). Similar behaviour was observed
in the hydrocarboxylation of n-butane, in which the overall
carboxylic acid yields declined from 25 and 46% (metal-free
and Cu-promoted systems, respectively) to 3% in the pres-
ence of CBrCl (Table 4, entry 2 vs. 13). In this case, 2-bro-
3
mobutane was formed as the major product with a yield of
either 20 (Cu promoted) or 10% (metal free), whilst the
yields of 1-bromobutane did not exceed 1%.
Subsequent carbonylation of the alkyl radical by CO gives
an acyl radical RCOC (Scheme 2, reaction 2) that, upon oxi-
2ꢀ
ꢀ
dation by S O8 , forms the acyl sulfate RC(O)OSO3 (reac-
2
tion 3). Hydrolysis of the latter by water (Scheme 2, reac-
[12a]
tion 4) results in the carboxylic acid product.
Although the present method still has some environmen-
tal limitations (particularly in terms of requiring the use of
acetonitrile as a solvent component and peroxodisulfate as
an oxidant), it bears a number of remarkably green features
An alternative pathway (Scheme 2, reaction 5) can take
place in the copper-promoted process in which 1 can act as
an oxidant of the acyl radical (reaction 5). This route in-
II
I
volves the Cu /Cu redox couple, and requires K S O to re-
in comparison with most of the state-of-the-art meth-
2
2
8
II
[1,3,5–9,13]
generate the Cu form (Scheme 2, reaction 5’). In this
regard, it is worthwhile mentioning that Cu is particularly
effective in the oxidation of C-centred radicals.
cation RCO thus formed, is hydrolysed, furnishing the car-
boxylic acid product (Scheme 2, reaction 6). This last reac-
ods
of light-alkane functionalisation. Those features
II
include the exceptional possibility of operating under metal-
free conditions at very mild temperatures, in aqueous acid-
solvent-free medium and using water as a relevant reagent.
The approach also leads to high selectivities and product
yields.
[14a]
The acyl
+
tion occurs through the protonated carboxylic acid
+
RC(OH)2 (formed by nucleophilic attack of H O on
This work contributes to the development of environmen-
tally viable alkane functionalisations, however, an in-depth
screening of the following improvements should still be un-
dertaken: 1) substitution of K S O for a cheaper and clean-
2
+
RCO ), which is deprotonated by water, as supported by
theoretical calculations on the corresponding ethyl spe-
[
12a]
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
cies.
reflected in both the metal-free (3!4) and Cu-promoted
5!6) pathways, as confirmed by us in the course of ex-
periments with H O, which resulted in the formation of
Hence, the important hydroxylating role of water is
2
2
8
er oxidant (e.g., air, O or H O ), 2) development of an or-
2
2
2
[12a]
(
ganic-solvent-free reaction medium or replacement of aceto-
nitrile with a less harmful solvent (e.g., bioethanol), and
18
2
18
RCO OH as the main product.
3) use of CO as a desirable chemical feedstock that can be
2
Chem. Eur. J. 2010, 16, 9485 – 9493
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9491

A. J. L. Pombeiro et al.
used as the carboxylating agent instead of CO. Studies that
address these and other issues are in progress in our labora-
tory.
Plotkin, Industrial Organic Chemicals, 2nd ed., Wiley, New York,
2
004.
[
3] For reviews, see: a) G. B. Shulꢅpin, Mini-rev. Org. Chem. 2009, 6, 95;
b) M. M. Dꢀas-Requejo, P. J. Pꢁrez, Chem. Rev. 2008, 108, 3379;
c) L. Que, Jr., W. B. Tolman, Nature 2008, 455, 333; d) J. A. Labing-
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50; g) R. H. Crabtree, J. Organomet. Chem. 2004, 689, 4083; h) M.
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General methods: All chemicals were obtained from commercial sources
[20]
[
15a]
and used as received. Compound 1
and the other tested promoters
[
4] a) Organic Reactions in Water (Ed.: U. M. Lindstrom), Blackwell,
New York, 2007; b) R. A. Sheldon, I. Arends, U. Hanefeld, Green
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were prepared according to published procedures. GC analyses were per-
formed with a Fisons Instruments GC 8000 series gas chromatograph
with a DB WAX (J&W) capillary column (30 mꢃ0.25 mmꢃ0.25 mm;
helium carrier gas) and by using Jasco–Borwin v.1.50 software. In some
1
cases, carboxylation products were also identified by GC–MS, H and
1
3
1
C{ H}NMR spectroscopy techniques by using a Trio 2000 Fisons spec-
trometer with a coupled Carlo Erba (Auto/HRGC/MS) gas chromato-
graph, and a Varian UNITY 300 NMR spectrometer, respectively.
[5] a) C. Jia, T. Kitamura, Y. Fujiwara, Acc. Chem. Res. 2001, 34, 633;
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6] a) M. V. Kirillova, M. L. Kuznetsov, J. A. L. da Silva, M. F. C. Gue-
des da Silva, J. J. R. Frafflsto da Silva, A. J. L. Pombeiro, Chem. Eur.
J. 2008, 14, 1828; b) M. V. Kirillova, J. A. L. da Silva, J. J. R. Frafflsto
da Silva, A. J. L. Pombeiro, Appl. Catal. A 2007, 332, 159; c) M. V.
Kirillova, M. L. Kuznetsov, P. M. Reis, J. A. L. da Silva, J. J. R.
Frafflsto da Silva, A. J. L. Pombeiro, J. Am. Chem. Soc. 2007, 129,
Alkane hydrocarboxylations: In a typical experiment, the reaction mix-
tures were prepared as follows: K
4
6
2
S
2
O
8
(1.00–2.00 mmol), H
.0 mL) and MeCN (2.0–4.0 mL) (typical total solvent volume was
.0 mL) were added to the metal promoter (optional; 0.0–16.0 mmol, typi-
2
O (2.0–
cally 4.0 mmol) contained in a 13.0 mL stainless steel autoclave, equipped
with a Teflon-coated magnetic stirring bar. The autoclave was closed and
flushed with N three times to remove the air, and pressurised with gas-
2
1
0531; d) M. V. Kirillova, J. A. L. da Silva, J. J. R. Frafflsto da Silva,
eous alkane (0.75–10.0 atm; typically 10.0, 5.0 or 0.75 atm of ethane, pro-
pane or n-butane, respectively) and CO (5–40 atm; typically 20 atm). The
reaction mixture was stirred for 1–20 h (typically 6 h) at 25–808C (typi-
cally 50 or 608C) using a magnetic stirrer and an oil bath, whereupon it
was cooled in an ice bath, degassed, opened and transferred to a flask.
Diethyl ether (9.0–11.0 mL) and cycloheptanone (90 mL; GC internal
standard) were added. The obtained mixture was vigorously stirred for
A. F. Palavra, A. J. L. Pombeiro, Adv. Synth. Catal. 2007, 349, 1765;
e) M. V. Kirillova, A. M. Kirillov, P. M. Reis, J. A. L. Silva, J. J. R.
Frafflsto da Silva, A. J. L. Pombeiro, J. Catal. 2007, 248, 130; f) A. M.
Kirillov, M. Haukka, M. V. Kirillova, A. J. L. Pombeiro, Adv. Synth.
Catal. 2005, 347, 1435; g) P. M. Reis, J. A. L. Silva, A. F. Palavra,
J. J. R. Frafflsto da Silva, T. Kitamura, Y. Fujiwara, A. J. L. Pombeiro,
Angew. Chem. 2003, 115, 845; Angew. Chem. Int. Ed. 2003, 42, 821.
1
0 min, and the organic layer was analysed by GC, revealing the forma-
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Pombeiro, Dalton Trans. 2009, 2109; b) R. R. Fernandes, M. V. Kiril-
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tion of carboxylic acids as the dominant products. In some cases (typi-
cally at low CO pressures), the presence of alcohols and ketones as by-
products of partial alkane oxidation was also detected, however, their
overall yields did not exceed 1%.
Additional experiments were performed under the typical reaction condi-
tions in the presence of the carbon-centred radical trap CBrCl , revealing
3
the suppression of carboxylic acid formation, either in the presence or in
the absence of the metal promoter.
Blank tests indicated that the metal-free hydrocarboxylations proceed
with similar efficacy in a Teflon reactor, thus confirming that the reac-
tions were not promoted by the reactor metal wall. In addition, no gener-
ation of acetic or propionic acids from the acetonitrile solvent was detect-
ed when the reactions were repeated in the absence of the alkane.
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Acknowledgements
This work was supported by the Foundation for Science and Technology
FCT), Portugal, through its PPCDT (FEDER funded) and “Science
007” programs.
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Received: February 9, 2010
Published online: May 7, 2010
Chem. Eur. J. 2010, 16, 9485 – 9493
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9493