Sustainable Process for Production of Azelaic Acid Through Oxidative Cleavage of Oleic Acid

Article abstract of DOI:10.1007/s11746-015-2727-z

This work describes two sustainable methods for production and purification of azelaic acid (AA) to replace the current process of ozonolysis of oleic acid (OA). The first proceeds in two steps, coupling smooth oxidation of OA to 9,10-dihydroxystearic acid (DSA) with subsequent oxidative cleavage by sodium hypochlorite. An alternative methodology is also proposed, using a chemocatalytic system consisting of H₂O₂/H₂WO₄ for direct oxidative cleavage of the double bond of OA at 373 K. A convenient technique for separation and purification of azelaic acid is also proposed.

Full text of DOI:10.1007/s11746-015-2727-z

J Am Oil Chem Soc (2015) 92:1701–1707
DOI 10.1007/s11746-015-2727-z
ORIGINAL PAPER
Sustainable Process for Production of Azelaic Acid Through
Oxidative Cleavage of Oleic Acid
Vincenzo Benessere1,2 · Maria E. Cucciolito1,2 · Augusta De Santis1 ·
Martino Di Serio1,2 · Roberto Esposito1,2 · Francesco Ruffo1,2 · Rosa Turco1,2
Received: 24 April 2015 / Revised: 24 September 2015 / Accepted: 24 September 2015 / Published online: 12 October 2015
© AOCS 2015
Abstract This work describes two sustainable meth-
ods for production and purification of azelaic acid (AA)
to replace the current process of ozonolysis of oleic acid
(OA). The first proceeds in two steps, coupling smooth
oxidation of OA to 9,10-dihydroxystearic acid (DSA) with
subsequent oxidative cleavage by sodium hypochlorite. An
alternative methodology is also proposed, using a chem-
ocatalytic system consisting of H2O2/H2WO4 for direct oxi-
dative cleavage of the double bond of OA at 373 K. A con-
venient technique for separation and purification of azelaic
acid is also proposed.
relevant role. They can be transformed into methyl esters
for production of biodiesel or functionalized to produce sur-
factants, plasticizers, monomers, and new solvents [2, 3].
These include cis-9-octadecenoic acid (oleic acid, OA in
Scheme 1), which is a very interesting raw material, since
it is renewable, inexpensive, and available in different geo-
graphical areas.
Its most common transformations are epoxidation,
hydroxylation, and oxidative cleavage of the double bond.
The latter reaction is particularly interesting because it
selectively produces azelaic acid (AA) and pelargonic acid
(PA) (Scheme 1).
Keywords Oleic acid · Azelaic acid · Pelargonic acid ·
Hydrogen peroxide · Tungstic acid · Sodium hypochlorite
Azelaic acid has important applications in textiles (poly-
esters and polyamides) and pharmaceuticals (antiacne).
Industrially, oxidative cleavage of the double bond is car-
ried out by ozonolysis [4]. However, use of ozone and
molecular oxygen at high temperatures represents a serious
drawback of this process, since these oxidants present com-
bustion hazards. It is therefore required to find new pro-
cesses that meet the standards of sustainability.
A valid alternative is hydrogen peroxide, because it is
capable of oxidizing with excellent atom economy and is
safer than gaseous reactants [5]. Many of the known strat-
egies couple H2O2 with catalytic systems such as RuO2,
Na3PO4{[WO(O2)2]}, H2WO4/Co(OAc)2, and Re2O7 [6–
16]. These synthetic routes (path i of Scheme 1) typically
include a first step of dihydroxylation that gives 9,10-dihy-
droxystearic acid (DSA). In a second step (ii) a new cata-
lyst is introduced, either in the same reaction environment
[14] or on the purified diol [15], for oxidative cleavage of
the CH(OH)–CH(OH) bond.
Introduction
Among the wide variety of biomass materials, fats and
oils play an important role as they have competitive cost,
are available in different geographical areas, and display
functional groups suitable for many industrial applications
[1, 2]. Their most abundant components are fatty acids
(FA), i.e., monocarboxylic acids with an aliphatic chain,
mostly present in the form of free acids or as ester deriva-
tives of glycerol. Among these, long-chain fractions play a
* Francesco Ruffo
ruffo@unina.it
1
Dipartimento di Scienze Chimiche, Università di Napoli
Recently, an efficient one-pot strategy (iii in Scheme 1)
was proposed with a catalyst based on the quaternary
ammonium salt Q3{PO4[WO(O2)2]4} [17]. Even in this
case, there are some disadvantages, namely high catalyst
“Federico II”, Complesso Universitario di Monte S.Angelo,
via Cintia, 80126 Naples, Italy
2
Consorzio Interuniversitario di Reattività Chimica e Catalisi
(CIRCC), Bari, Italy
1 3

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J Am Oil Chem Soc (2015) 92:1701–1707
Scheme 1 Oxidative cleavage
of oleic acid (OA)
O
OH
OA
(i) ox, cat
OH
O
OH
(iii) ox, cat
OH
DSA
(ii) ox, cat
O
O
O
HO
HO
OH
AA
PA
loading (7 % in moles based on W), use of phase-trans-
fer agents, and addition of hydrochloric acid for product
recovery. Very efficient systems based on gold catalysts
have also recently been described, although some doubts
can be raised due to the high cost of this noble metal [18].
Therefore, many efforts have been made to find a success-
ful strategy for production of azelaic acid. This was also
demonstrated by the launch in 2014 of the industrial Mat-
rica process, which does not use ozone in the vegetable oil
oxidative scission reaction. The present work fits into this
context and aims to identify new processes for oxidation
of oleic acid that do not require organic solvents or phase-
transfer agents, and use low catalyst loading. A clean proto-
col for isolation of azelaic acid is also proposed.
All samples [25 mg mixture dissolved in 500 µL
tetrahydrofuran (THF)] were derivatized with N,O-
bis(trimethylsilyl)trifluoroacetamide (BSTFA, 300 µL).
n-Undecane was added as internal standard (1 % v/v) to
5 mL hexane.
1H nuclear magnetic resonance (NMR) spectra were
recorded in CDCl3 at 400 MHz.
Oxidative Cleavage in Two Steps
In a 250-mL round-bottom flask equipped with a con-
denser, tungstic acid (0.040 g, 0.160 mmol) was suspended
in aqueous solution of H2O2 (60 % w/w, 1.36 g, 24 mmol),
and the system was stirred at 343 K. Oleic acid (5.1 mL,
16 mmol) was added as soon as complete dissolution of
tungstic acid was observed. After 2 h, the mixture was
allowed to cool down to room temperature and NaOCl
(4.5 % active Cl2, 150 mL, 95.4 mmol) was added. The sys-
tem was stirred at room temperature for 2 h, and pH was
then adjusted to 1 using aqueous hydrochloric acid solu-
tion (37 % w/w). The reaction mixture was extracted with
ethyl acetate (4 × 200 mL). The combined organic layers
were dried with anhydrous sodium sulfate and evaporated
under reduced pressure. The products were analyzed by
1H NMR without further purification of the crude mate-
rial and through GC after derivatization (tr AA = 11 min,
tr PA = 4.2 min).
Materials and Methods
General
Solvents, oleic acid (90 %), and the other reagents were
purchased from Sigma Aldrich. Aqueous hydrogen per-
oxide (aqueous solution 60 %) was supplied by Solvay
(Rosignano, Italy).
The collected samples were quantified by gas chroma-
tography (GC) on a PerkinElmer instrument coupled to a
flame ionization detector (FID), equipped with a Perki-
nElmer Elite series 5 capillary column (0.10 µm, 0.32 mm
ID, 15 m). The carrier gas was helium at pressure of
1.72 bar at the head of the column. The injector tempera-
ture was 423 K, and the detector temperature was 523 K.
The oven temperature was held at 313 K for 1 min, then
ramped to 453 K at 7 K/min and kept for 1 min, finally
being increased to 503 K at 7 K/min and kept for 4 min.
Procedure for Obtaining a Fraction Enriched in the
Intermediate Peroxo Species (PS)
In a 250-mL round-bottom flask equipped with a con-
denser, tungstic acid (0.040 g, 0.160 mmol) was suspended
in aqueous solution of H2O2 (60 % w/w, 1.36 g, 24 mmol)
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J Am Oil Chem Soc (2015) 92:1701–1707
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Fig. 1 1H NMR spectrum of the peroxo species (PS)-rich fraction (in CDCl3)
and the system was stirred at 343 K. Oleic acid (5.1 mL,
16 mmol) was added as soon as complete dissolution of
tungstic acid was observed. After 2 h, the mixture was
allowed to cool down to room temperature. The oily resi-
due was melted, and hexane was added. After cooling at
273 K, the resulting white solid was filtered (mainly DSA),
and washed with hexane. The solvents were removed
under vacuum from the mother liquor, and hexane was
added at 273 K to the resulting oily residue. The resulting
white solid was again filtered (mainly DSA), and washed
with hexane. The solvents were removed under vacuum
from the mother liquor, affording a fraction enriched in PS
(90 % according to the NMR spectrum reported in Fig. 1).
Caution: evaporation of solutions which may contain
hydrogen peroxide or peroxo species at a rotary evapora-
tor represents a serious safety risk and can cause explo-
sion and destruction of equipment. The peroxides value
was 550 mmol O2/kg (NFT 60-220).
was allowed to cool down to room temperature and cool
water (50 mL) was added. The reaction mixture was
extracted with hot ethyl acetate (4 × 100 mL). The com-
bined organic layers were dried with anhydrous sodium
sulfate and evaporated under reduced pressure. The prod-
ucts were analyzed by H NMR without further purifica-
tion of the crude material and by GC after derivatization
(tr AA = 11 min, tr PA = 4.2 min, tr DSA = 20 min).
1
Separation and Purification of Azelaic Acid (Single
Step)
The reaction mixture was extracted with cool water
(100 mL) and then with hot ethyl acetate (3 × 200 mL).
The volume of the organic phase was reduced under vac-
uum and extracted with hot water (3 × 50 mL). On cool-
ing the aqueous phase, a white precipitate of azelaic acid
formed, which was collected, washed with cool water, and
1
dried (isolated yield 60 %). The H NMR spectrum of iso-
Oxidative Cleavage in a Single Step
lated AA is given in Fig. 2.
In a 250-mL round-bottom flask equipped with a con-
denser, tungstic acid (0.283 g, 1.13 mmol) was sus-
pended in aqueous solution of H2O2 (60 % w/w, 51.2 g,
904 mmol) and the system was stirred at 343 K. Oleic
acid (36.3 mL, 113 mmol) was added as soon as complete
dissolution of tungstic acid was observed. The reaction
mixture was stirred under reflux. After 8 h, the mixture
Results and Discussion
General Strategies
Two different strategies (a and b) were identified, as sum-
marized in Scheme 2.
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J Am Oil Chem Soc (2015) 92:1701–1707
Fig. 2 1H NMR spectrum in CDCl3 of isolated azelaic acid (AA)
assessed by 1H NMR spectroscopy. Identification and
quantification of the products were carried out via GC anal-
ysis of the reaction mixtures.
OA
(a)
(b)
(i)
(iii)
DSA
AA + PA
Oxidative Cleavage in Two Steps (a)
(ii)
AA + PA
The process was conducted in a single batch, and screening
was performed as reported in Table 1.
(i) H2WO4, H2O2, 343 K; (ii) NaOCl, RT; (iii) H2WO4, H2O2, reflux
The spectrum of a typical reaction mixture (i) revealed
that DSA was not the only oxidation product, as three diag-
nostic signals appeared in the region of the protons gemi-
nal to oxygenated functions. The signals were associated
to three different species, which, also on the basis of GC,
mass spectroscopy, and number of peroxides (550 mmol
O2/kg, NFT 60–220), were identified as DSA (δ 3.4), its
parent epoxide EPOXY (δ 2.8), and PS (δ 3.7). The latter
is an intermediate peroxo species (Fig. 3) whose formation
has been mentioned in literature [16].
A fraction largely enriched in PS was also isolated,
and its proton spectrum is reported in Fig. 1. The signal
at δ 88.0 in the carbon spectrum confirms this assignment.
Other relevant signals are at δ 77.2 (–CHOH–) and 179.4
(C=O). However, the presence of byproducts was not a
drawback because subsequent cleavage of the σ–C–C bond
(ii) easily occurred upon addition of NaOCl.
Scheme 2 Strategies for oxidative cleavage of oleic acid (OA)
The first procedure (a) involves a smooth and relatively
fast oxidation of oleic acid to 9,10-dihydroxystearic acid
(i) using commercially available H2WO4 as the only cata-
lytic ingredient and H2O2 (60 % v/v). It should be noted
that this concentration is higher than that usually adopted in
oxidation reactions (up to 35 %). This step is followed by
oxidative cleavage with a stoichiometric amount of NaOCl
at room temperature (ii), which implies energy savings in
terms of both cost and emissions. In fact, these experimen-
tal conditions are considered advantageous according to the
criteria of the EcoScale, which is a semiquantitative tool to
assess the impact of chemical synthesis [19].
In the alternative approach (b) the synthesis takes place
in one step (iii). The two-phase system does not require
addition of further solvents, and it operates in reflux con-
ditions. In both cases, the conversion was preliminarily
Using an OA/H2O2 ratio of 1/1.5, complete conver-
sion of OA was achieved within 60 min (entries 1 and 2).
Increasing the amount of oxidant (entries 3 and 4) was
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J Am Oil Chem Soc (2015) 92:1701–1707
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Table 1 Conversion of oleic
acid (OA) at 343 K (first step)
Entry OA/H2WO4 OA/H2O2 OA conversion (%)a EPOXY (%)a,b DSA (%)a,b PS (%)a,b t (min)
1
2
3
4
5
6
7
100/1
100/1
100/1
100/1
200/1
400/1
1600/1
1/1.5
1/1.5
1/2
90
4
7
1.1
45 1.0
52 1.1
47 1.0
45 1.0
40 1.0
40 1.0
40 1.0
10 1.1
30
60
120c
240c
60
>99
>99
>99
80
−
−
−
7
16
43
45
15
20
20
2
4
5
2
2
2
1/4
1/1.5
1/1.5
1/1.5
4
1.1
2
>99
>99
−
10
120
>240
a
Evaluated by 1H NMR spectroscopy. Values are averages of three runs. Errors reported as standard devia-
tions
b
Other minor oxidation products are present but have not been identified
c
Time to completion
O
O
OH
EPOXY
OOH
O
OH
O
OH
OH
OH
OOH
PS
Fig. 3 Structures of EPOXY and peroxo species (PS)
found to be detrimental to the reaction, plausibly due to the
resulting dilution of the catalyst.
appreciable amounts of the desired carboxylic acids, but
only formation of DSA (entry 1 of Table 2).
Variation of the catalyst loading was attempted to iden-
tify the lowest substrate/catalyst ratio capable of promoting
the reaction within a reasonable reaction time (entries 5–7).
It is evident that excessive reduction of the amount of cata-
lyst (1600/1, entry 7) resulted in an extended reaction time.
Instead, a loading of 400/1 (entry 6) was found convenient,
as complete conversion of OA was achieved in only 2 h.
Regarding the subsequent oxidation with NaOCl, it should
be stressed that the feasibility of this process has already
been described on isolated DSA [20]. In the present work,
the reaction was carried out with a NaOCl:OA molar ratio
of 6:1, and was followed by monitoring the disappearance
of the signals at δ 2.8–3.7. Complete conversion of DSA,
PS, and EPOXY occurred within 2 h at room temperature,
and AA was obtained in maximum yield of 54 % start-
ing from the conditions of entry 4, as quantified by gas
chromatography.
A run performed without any tungstic acid indicated that
the presence of a catalytic ingredient is required (entry 2).
Under reflux, however, conversion of oleic acid into pelar-
gonic and azelaic acid was already significant within 4 h
(entry 3). The system was then refined by tuning the sub-
strate/catalyst and substrate/oxidant ratios, the modality of
addition of the oxidant, and the reaction time. Increasing
the catalyst loading was not beneficial for the performance
of the catalyst (entry 3 versus 4). The yields of AA and PA,
in fact, did not exhibit any appreciable changes. There-
fore, a substrate/catalyst ratio of 100/1 was considered as
a fair compromise between an acceptable reaction rate and
minimization of the catalyst loading. It should be noted that
this level of concentration is sevenfold lower (based on W
atoms) than that proposed in a recent study based on phos-
photungstic acid [17]. Translated to mass, this means that
our system uses a catalyst loading about 10 times lower
for the same amount of oleic acid (taking into account the
additional mass derived from phase-transfer agents [17]).
Subsequently, the effect of varying the amount of oxi-
dant was evaluated, assuming that the high temperature
could degrade the hydrogen peroxide. Actually, the data
reported in entries 5–7 suggest that the yield of azelaic acid
Oxidative Cleavage in a Single Step (b)
In the single step (iii in Scheme 2), the OA/H2O2/H2WO4
ratio was set at 100/400/1 as initial conditions. A first gen-
eral consideration is that, at 343 K, the reaction did not give
1 3

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J Am Oil Chem Soc (2015) 92:1701–1707
Table 2 Results of oxidative
cleavage of oleic acid (OA) in a
single step (at 373 K)
Entry
t (h)
OA/H2WO4
OA/H2O2
DSA (%)a,b
90
PA (%)a,b
AA (%)a,b
1c
2
4
4
4
4
4
4
4
8
8
8
100/1
–
1/4
¼
2
–
–
20 1.0
26 1.1
5.0 0.2
4.0 0.2
–
14 1.0
10 1.1
43 1.3
3
100/1
50/1
100/1
50/1
100/1
50/1
100/1
100/1
¼
36
2
4
¼
24 1.3
41
64
72
72
43
64
91
2
3
4
4
2
2
2
5
1/8
1/8
1/(4 + 4)
¼
52
44
33
3
2
2
6
7
1.0 0.1
3.0 0.2
5.0 0.4
–
8
26 1.4
55 1.2
69 1.5
9
1/4
1/8
10
a
As chromatography yields. Values are averages of three runs. Errors reported as standard deviations
Other minor oxidation products are present but have not been identified
At 343 K
b
c
increases with the amount of oxidant. The effects of the
modality of addition of H2O2 were also taken into account.
Therefore, a test was conducted in which eight equivalents
of hydrogen peroxide were added in two steps at an interval
of 2 h. The increase in yield of AA up to 72 % indicates
that the addition of the “new” hydrogen peroxide enhances
the performance of the system.
reaction
mixture
extraction
hot water, AcOEt
Finally, the increase in product yield on doubling the
reaction time was determined (entries 8–10). After 8 h of
reaction, an excellent yield of AA (91 %) was obtained by
using the conditions described in entry 10. After the opti-
mization of the reaction conditions, a convenient methodol-
ogy for isolation and purification of azelaic acid was also
developed (Fig. 4). This was inspired by classical methods
of extraction [21], previously used for separation of dicar-
boxylic from monocarboxylic acids [22], and also applied in
the specific case of the azelaic and pelargonic couple [23].
The reaction was quenched by adding cold water to
the reaction mixture, and the resulting suspension was
extracted with hot ethyl acetate (AcOEt). The aqueous
phase contained the catalyst and the residual H2O2, while
the organic phase captured the crude reaction products.
After evaporation under vacuum of the organic solvent,
white suspension was obtained, which was extracted with
boiling water. On cooling, azelaic acid crystallized into
aqueous
phase
organic
phase
evaporation AcOEt
extraction hot water
aqueous
organic
phase
phase
crystallization
AA
Fig. 4 Flowchart for isolation of azelaic acid (AA)
1
white microcrystals. H NMR confirmed a high degree of
product purity (Fig. 2). It should be noted that this conveni-
ent procedure for isolation of azelaic acid was found less
feasible when applied to the crude reaction mixture of the
oxidative cleavage in two steps (a).
(OA). The first method couples a system based on H2O2/
H2WO4 with subsequent addition of sodium hypochlorite.
It has the advantage of mild reaction conditions, but it has
not been possible to obtain AA in yields higher than 51 %.
The second approach requires the same catalytic ingredi-
ent as the first procedure and is capable of producing AA
at 373 K with an unprecedented chromatographic yield of
91 %. Neither of these methods uses phase-transfer agents,
and they both employ low catalyst loading. Furthermore,
Conclusions
The present work aims to identify methodologies for sus-
tainable production of azelaic acid (AA) from oleic acid
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J Am Oil Chem Soc (2015) 92:1701–1707
1707
10. Song HY, Chen J, Tong J (2005) Study on synthesis of azelaic
acid by catalytic oxidation using phase transfer catalyst. Huaxue
Shiji 27:65–67
tungstic acid has a more favorable ecotoxicological profile
than phosphotungstic acid. A convenient method for puri-
fication of the product has also been highlighted. Future
developments will focus on further optimization of the iso-
lation procedures and recovery of the catalytic ingredients.
11. Santacesaria E, Sorrentino A, Rainone F, Di Serio M, Speranza F
(2000) Oxidative cleavage of the double bond of monoenic fatty
chains in two steps: a new promising route to azelaic acid and
other industrial products. Ind Eng Chem Res 39:2766–2771
12. Haimov A, Cohen H, Neumann R (2004) Alkylated polyethyl-
eneimine/polyoxometalate synzymes as catalysts for the oxida-
tion of hydrophobic substrates in water with hydrogen peroxide.
J Am Chem Soc 126:11762–11763
Acknowledgments The authors warmly thank Prof. Thierry
Ollevier (Université Laval, Canada) for helpful discussions. The
authors thank MIUR (Progetto Rebiochem—Cluster 2012) for finan-
cial support. The authors also thank Solvay (Rosignano, Italy) for a
generous loan of hydrogen peroxide (60 % v/v).
13. Santacesaria E, Ambrosio M, Sorrentino A, Tesser R, Di Serio
M (2003) Double bond oxidative cleavage of monoenic fatty
chains. Catal Today 79–80:59–65
14. Oakley MA, Woodward S, Coupland K, Parker D, Temple-Heald
C (1999) Practical dihydroxylation and C–C cleavage of unsatu-
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