Ketonic decarboxylation catalysed by weak bases and its application to an optically pure substrate

Article abstract of DOI:10.1002/ejoc.200300778

Ketonic decarboxylation is a very old reaction that transforms two carboxylic acids into a ketone or a dicarboxylic acid into a cyclic ketone, in particular adipic acid into cyclopentanone. Herein it is reported that catalytic amounts of weak bases such as sodium carbonate can carry out this reaction selectively. This is in accordance with a mechanism involving decarboxylation and nucleophilic attack at a second carboxyl group. The reaction can be employed in asymmetric syntheses since the stereogenic centres in the β-positions retain their stereochemistry. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200300778

FULL PAPER
Ketonic Decarboxylation Catalysed by Weak Bases and Its Application to an
Optically Pure Substrate
Michael Renz*[a] and Avelino Corma[a]
Keywords: Asymmetric synthesis / Base catalysis / Carboxylic acids / Cyclopentanone / Ketonic Decarboxylation
Ketonic decarboxylation is a very old reaction that transforms
two carboxylic acids into a ketone or a dicarboxylic acid into
a cyclic ketone, in particular adipic acid into cyclopentanone.
Herein it is reported that catalytic amounts of weak bases
such as sodium carbonate can carry out this reaction select-
ively. This is in accordance with a mechanism involving de-
carboxylation and nucleophilic attack at a second carboxyl
group. The reaction can be employed in asymmetric syn-
theses since the stereogenic centres in the β-positions retain
their stereochemistry.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
tion.[10] In the patent literature a multitude of metals as
their oxides, hydroxides, phosphates, other salts, or combi-
nations of these have been proposed as catalysts for carry-
ing out the reaction at high temperatures (300Ϫ450
°C).[3,11Ϫ15] Metal salts of adipic acid such as calcium, lead,
or thorium salts are less useful for the production of cyclo-
pentanone since they only give 43%, 35%, and 15% yields,
respectively.[16]
Cyclopentanone is a valuable fine chemical with in-
creased demand in recent years since it is the starting mate-
rial for many fragrances or pharmaceuticals and is also used
as a special solvent for the synthesis of polycarbonates.[1] It
can be produced from adipic acid in a dry distillation at
elevated temperatures (300Ϫ450 °C) by ketonic decar-
boxylation [Equation (1)]. This transformation of adipic
acid into cyclopentanone is very interesting from an econ-
omic point of view since adipic acid is a cheap bulk chemi-
cal that is often obtained as a by-product in oxidation reac-
tions of cyclohexane derivatives.
(2)
(1)
The cyclopentanones used in the fragrance industry are
often highly substituted ones.[17] Whereas the introduction
of substituents in the α-position to the carbonyl group is
relatively easy, the possibilities for the β-position are quite
limited. Furthermore, the organoleptic properties depend
not only on the position of the substituent but also on the
absolute stereochemical configuration. One alternative en-
try to substituted cyclopentanones may be the cyclization
of the corresponding adipic acid derivatives. Therefore, it
would be interesting to know if these β-substituents disturb
the cyclization under the normal reaction conditions and if
a stereogenic centre in the β-position maintains its stereo-
chemistry during the ketonic decarboxylation [Equa-
tion (2)].
Although ketonic decarboxylation has been known for
more than 140 years (dry distillation of calcium acetate to
produce acetone),[2] the mechanism is still under dis-
cussion.[3] This might be the reason why so many different
catalysts have been proposed as promoters for this reaction.
In general, thorium oxide is recommended as catalyst for
the ketonic decarboxylation.[4] In the special case of adipic
acid, the decarboxylation has also been carried out in pres-
ence of catalytic amounts of barium hydroxide,[5,6] potass-
ium fluoride (reacting as base),[7] or without any additive at
all.[8,9] More recently, iron oxide has been identified as the
origin of the catalytic activity of graphite for this reac-
In the present article we show that the transformation
of adipic acid into cyclopentanone can be carried out with
catalytic amounts of an environmentally friendly weak base.
Moreover, we will show that this reaction system allows the
production of asymmetric precursors of interest in the
fragrance industry.
[a]
´
´
Instituto de Tecnologıa Quımica, UPV-CSIC, Universidad
´
Politecnica de Valencia
Avda. de los Naranjos s/n, 46022 Valencia, Spain
Fax: (internat.): ϩ 34-96-387-7809
E-mail: mrenz@itq.upv.es
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200300778
Eur. J. Org. Chem. 2004, 2036Ϫ2039

Ketonic Decarboxylation Catalysed by Weak Bases
FULL PAPER
Results and Discussion
time. In 320 min an accumulated yield of 90% in cyclo-
pentanone was achieved.
For comparison purposes, we first carried out the dry
When the weak base Na2CO3 is used instead of NaOH,
distillation of adipic acid without introduction of any addi- exactly the same trends are observed, and even small
tive. Thus, 10 g of acid were placed in a round-bottomed amounts of salt increase the initial rate of the reaction.
flask fitted with a short Vigreux column and connected to Upon increasing the quantity of Na2CO3, the initial rate
a distillation apparatus. The flask was heated to 350 °C increases further, although the yield starts to decrease (Fig-
(heating mantle temperature) and, after a period of 30 to ure 2). The sodium carbonate reacts with adipic acid to
35 min, a biphasic mixture of two colourless liquids — form carbonic acid and sodium adipate, and the thermo-
cyclopentanone and water — started to distil. The progress dynamic equilibrium is shifted towards sodium adipate
of the reaction was followed by the quantification of the upon decomposition of carbonic acid into water and car-
liberated CO2. Indeed, from Figure 1 it can be seen that the bon dioxide. This demonstrates clearly that no strong base
acid is converted into cyclopentanone and after 3.5 h a 90% is necessary to initiate the reaction. In order to show that
yield of carbon dioxide was obtained with a sticky black the increase of the initial rate is not influenced by the nature
residue remaining in the distillation flask. The yield of of the base but depends instead on its quantity, several car-
cyclopentanone obtained as distillate at the end of the reac- bonates and hydroxides of alkali and alkaline-earth metals
tion is always 5Ϫ10% lower than the yield of carbon diox- were tested as additives. In Table 1 it can be seen that they
ide. When only 1.8 mol % of sodium hydroxide was added perform similarly from a kinetic point of view. No special
to the acid before heating, the reaction time was reduced contribution was detected, for example, for barium cations,
by half and the yield was slightly improved (Figure 1). The which have been proposed as reaction promoters. Conse-
purity of cyclopentanone was determined by GC analysis quently, the choice of additive should only be influenced by
1
and H NMR spectroscopy and was found to be 99% or the cost of the metal salt, its potential environmental im-
higher in all cases. The reaction rate can be enhanced suc- pact, and disposal facilities. Furthermore, it should be
cessively by adding increasing amounts of base. However, noted that with catalytic amounts of calcium hydroxide
with more than 3.3 mol % the yield started to decrease and (0.05 equiv.) an 84% yield of cyclopentanone is obtained
was significantly lower when carrying out the reaction in whereas distillation of calcium adipate itself only provides
the presence of 21 mol % of sodium hydroxide. This is prob- 43%, as mentioned above.
ably due to the formation of disodium adipate, which is not
transformed into cyclopentanone. This result is in agree-
ment with published results indicating that sodium salts, in
general, give poor results for the ketonic decarboxylation[3]
and that salts of adipic acid give low yields, as already men-
tioned above. The residue, in this case a white-brownish
solid, can be re-used and employed instead of the base, i.e.
a new batch of adipic acid can be added and the cyclopenta-
none obtained in a shorter reaction time. For example, 10 g
of adipic acid were added to 0.5 g of NaOH (0.18 equiv.)
and the mixture distilled as above. Six more 10 g portions
of adipic acid were added successively and distilled each
Figure 2. Yield of carbon dioxide and cyclopentanone and the in-
itial rate for the dry distillation of adipic acid in the presence of
different amounts of Na2CO3
Table 1. Yield of carbon dioxide and cyclopentanone and the initial
rate for the dry distillation of adipic acid in presence of different
bases
Entry Base (equiv.)
Initial rate
(mmol/min) (%)
Yield CO2 Yield ketone
(%)
1
2
3
4
5
6
Li2CO3 (0.05)
NaOH (0.10)
K2CO3 (0.05)
Mg(OH)2 (0.05) 1.46
Ca(OH)2 (0.05) 1.51
Ba(OH)2 (0.05) 1.45
1.39
1.50
1.55
90.4
91.2
91.4
94.1
91.0
91.5
83.8
84.3
86.1
84.5
84.2
90.0
Figure 1. Conversion of adipic acid to cyclopentanone in the pres-
ence of different amounts of NaOH obtained by quantification of
the evolved CO2; time measurement was started when the reaction
temperature was reached
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M. Renz, A. Corma
FULL PAPER
These findings are in accordance with the mechanism
proposed by Rand et al. and depicted in Scheme 1.[7] In a
first step one of the two acid functionalities is deprotonated
and decarboxylated at elevated temperatures. The corre-
sponding carbanion then attacks the second carboxyl group
and cyclopentanone is formed by elimination of a hydroxide
anion. The base is thereby regenerated and immediately de-
protonates a new substrate molecule. Decarboxylation and
nucleophilic attack may be concerted (as depicted) to avoid
the formation of an unstable carbanion. The simultaneous
coordination of the two carboxylic groups to one metal cen-
tre, which has also been proposed as a possible reaction
step,[3] is not supported by our results, since we observe that
all metal cations, despite their higher or lower tendency to
coordinate two acid groups, give the same results. We can
therefore conclude that this reaction does not require any
specific base. For the deprotonation of the carboxylic acid,
a carbonate or any other material that may be protonated
temporarily (e.g. glassware) can act as catalyst for this reac-
tion. The radical mechanism that has been proposed for
other cases[18] cannot be expected to occur when simple alk-
ali or alkaline-earth cations are involved.
Table 2. Yield of carbon dioxide and cyclopentanone derivative for
the dry distillation of β-substituted adipic acid in the presence of
5 mol % of sodium carbonate
Entry Substrate
Yield CO2 Yield ketone ee[a]
(%)
(%)
(%)
1
2
3
(Ϯ)-3-methyladipic acid
(ϩ)-3-methyladipic acid
(Ϯ)-3-tert-butyladipic acid 89
86
95
87
72
83
Ϫ
100
Ϫ
[a]
Enantiomeric excess.
Figure 3. GC analysis on a chiral column of the products (3-meth-
ylcyclopentanone) obtained from (Ϯ)-3-methyladipic acid (left
chromatogram) and from (ϩ)-3-methyladipic acid (right chromato-
gram)
Conclusion
Scheme 1. Proposed mechanism for the ketonic decarboxylation of
adipic acid to give cyclopentanone involving deprotonation, decar-
boxylation and nucleophilic attack
Ketonic decarboxylation can be carried out in the pres-
ence of catalytic amounts of environmentally friendly
weakly basic catalysts such as Na2CO3. The stereogenic
centres in the β-position maintain their stereochemistry and
the reaction can be employed in asymmetric synthesis.
In order to check if ketonic decarboxylation can be used
in asymmetric synthesis, we first submitted racemic 3-meth-
yl- and 3-tert-butyladipic acid to the dry distillation in the
presence of 5 mol % of sodium carbonate. From Table 2 it
can be seen that both cyclopentanone derivatives are ob-
tained in the same way as the unsubstituted one (entries 1
and 3). When optically pure (ϩ)-3-methyladipic acid was
employed, the yield of carbon dioxide was in the same
range as before but the yield of the ketone dropped to only
72% (Table 2, entry 2). This is probably due to the lower
quantity (only one third) of starting material used. Under
these conditions, the amount of substance lost in the vol-
ume of the apparatus becomes more important with respect
Experimental Section
General Remarks: All products were identified by GC-MS on an
Agilent Technologies 6890N Network GC System coupled with an
Agilent 5973 Network Mass Selective Detector and by NMR spec-
troscopy on a Bruker spectrometer at a frequency of 300 MHz for
1H spectra and at a frequency of 75 MHz for 13C spectra. The two
enantiomers of 3-methylcyclopentanone were separated on a Fi-
sons Instruments GC 8035 equipped with an ALPHA DEX 120
column from Supelco (30 m, 0.25 mm, 0.25 µm film) at 70 °C iso-
therm. Adipic acid (99% purity), (Ϯ)-3-methyladipic acid (99%),
(R)-(ϩ)-3-methyladipic acid (96%), and (Ϯ)-3-tert-butyladipic acid
to the whole amount. However, the obtained product, 3- (99%) were purchased from Acros Organics. The products cyclo-
pentanone, (Ϯ)-3-methylcyclopentanone, and (R)-3-methylcyclo-
pentanone are commercially available.
methylcyclopentanone, was optically pure as demonstrated
by GC analysis with a chiral column (Figure 3). This indi-
cates that we can follow an easier synthesis strategy for ob-
taining chiral cyclopentanone derivatives, in which substitu-
ents in the β-position to the carbonyl group can be intro-
duced before cyclization.
General Procedure: The dry distillation was carried out in a 50 mL
round-bottomed flask fitted with a 10-cm Vigreux column connec-
ted to a microdistillation apparatus and the gas outlet was connec-
ted to a gas burette. The flask was heated with a hemispherical
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Eur. J. Org. Chem. 2004, 2036Ϫ2039

Ketonic Decarboxylation Catalysed by Weak Bases
FULL PAPER
heating mantle and the reaction time was started when 350 °C reac-
tion temperature had been reached (after ca. 25 min). Adipic acid
(10.0 g, 68.4 mmol) was placed in the flask together with a mag-
netic stirring bar and the corresponding amount of base. The heat-
ing was started and the progress of the reaction was followed by
measuring the gas evolution. When no gas was produced anymore,
the reaction was stopped, the two phases separated and the organic
layer analysed by GC analysis, GC-MS and NMR spectroscopy.
The purity of the cyclopentanone was in all cases higher than 99%.
Traces of unchanged adipic acid could be detected by 1H NMR
spectroscopy.
45 min no gas was produced anymore and the reaction was
stopped. The two phases were separated and the organic one
(7. 23 g, 51.6 mmol, 83%) analysed by GC analysis, GC-MS, and
NMR spectroscopy. The purity of the (Ϯ)-3-tert-butylcyclopenta-
none was higher than 99%.
Acknowledgments
The authors thank ACEDESA and CICYT (MAT2003Ϫ07945-
C02Ϫ01) for financing this work. M. R. is grateful to the Spanish
´
Ministry of Science and Technology for a ‘‘Ramon y Cajal’’ Fel-
lowship.
In the case of the re-use of the residue, adipic acid (10.0 g,
68.4 mmol) was placed in the flask together with NaOH (496 mg,
12.4 mmol) and distilled until gas production ceased. A new 10.0-
g portion of adipic acid was placed in the flask and the distillation
continued. Over seven cycles 36.4 g (90%) of cyclopentanone was
obtained as a colourless liquid from 70.0 g of adipic acid.
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(Ϯ)-3-methyladipic acid (10.0 g, 62.4 mmol) was placed in the flask
together with a magnetic stirring bar and Na2CO3 (325 mg,
3.07 mmol). The heating was started and the progress of the reac-
tion was followed by measuring the gas evolution. After 45 min no
gas was produced anymore and the reaction was stopped. The two
phases were separated and the organic one (5.33 g, 54.3 mmol,
87%) analysed by GC analysis, GC-MS, and NMR spectroscopy.
The purity of the (Ϯ)-3-methylcyclopentanone was higher than
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(ϩ)-3-methyladipic acid (3.0 g, 18.7 mmol) was placed in the flask
together with a magnetic stirring bar and Na2CO3 (100 mg,
0.943 mmol). The heating was started and the progress of the reac-
tion was followed by measuring the gas evolution. After 25 min no
gas was produced anymore and the reaction was stopped. The two
phases were separated and the organic one (1.33 g, 13.5 mmol,
72%) analysed by GC analysis, GC-MS, and NMR spectroscopy.
The purity of the (R)-3-methylcyclopentanone was higher than
99%. Only one enantiomer could be detected by GC analysis on a
chiral ALPHA DEX column.
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the flask together with a magnetic stirring bar and Na2CO3
(325 mg, 3.07 mmol). The heating was started and the progress of
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[19]
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Received December 12, 2003
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