Two-step continuous flow synthesis of α-terpineol

Article abstract of DOI:10.1016/j.tetlet.2021.153318

α-Terpineol is a naturally occurring monoterpene present in essential oils, of high value on the market as it is widely used as flavoring in the cosmetics and food industry. This study aims to produce α-terpineol by two different synthetic strategies, using both batch and continuous flow systems, focusing on the optimization of the process, improving the reaction conversion and selectivity. The first strategy adopted was a one-stage hydration reaction of (+)-α-pinene by an aqueous solution of chloroacetic acid (molar ratio 1:1 between pinene and the acid) in continuous flow conditions. This reaction was carried out at 80 °C with a residence time of 15 min, obtaining good conversion (72%) and selectivity (76%), and productivity of 0.53 kg.day^?1. The second strategy accomplished was a two-step cascade reaction with (+)-limonene as starting material, where the first step is a chemospecific double bond addition using trifluoroacetic acid, and the second step is the basic hydrolysis of the ester promoted by a solution of sodium hydroxide (2.25 M) in methanol (1:1). This reaction was adapted to a continuous flow condition, where all steps involved a residence time of 40 min, at 25 °C, with no quenching between steps required, with 97% conversion, 81% selectivity and up to 0.14 kg.day^?1.

Full text of DOI:10.1016/j.tetlet.2021.153318

Tetrahedron Letters 80 (2021) 153318
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Two-step continuous flow synthesis of a-terpineol
Beatriz L.C. de Carvalho, Anderson R. Aguillon, Raquel A.C. Leão, Rodrigo O.M.A. de Souza
Biocatalysis and Organic Synthesis Group, Chemistry Institute, Federal University of Rio de Janeiro, 21941-909 Rio de Janeiro, RJ, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
a
-Terpineol is a naturally occurring monoterpene present in essential oils, of high value on the market as
Received 7 July 2021
Revised 4 August 2021
Accepted 7 August 2021
Available online 13 August 2021
it is widely used as flavoring in the cosmetics and food industry. This study aims to produce -terpineol
by two different synthetic strategies, using both batch and continuous flow systems, focusing on the opti-
mization of the process, improving the reaction conversion and selectivity. The first strategy adopted was
a one-stage hydration reaction of (+)-a-pinene by an aqueous solution of chloroacetic acid (molar ratio
a
1:1 between pinene and the acid) in continuous flow conditions. This reaction was carried out at 80 °C
with a residence time of 15 min, obtaining good conversion (72%) and selectivity (76%), and productivity
of 0.53 kg.dayÀ1. The second strategy accomplished was a two-step cascade reaction with (+)-limonene as
starting material, where the first step is a chemospecific double bond addition using trifluoroacetic acid,
and the second step is the basic hydrolysis of the ester promoted by a solution of sodium hydroxide
(2.25 M) in methanol (1:1). This reaction was adapted to a continuous flow condition, where all steps
involved a residence time of 40 min, at 25 °C, with no quenching between steps required, with 97% con-
Keywords:
Continuous flow
a-terpineol
Cascade reactions
version, 81% selectivity and up to 0.14 kg.dayÀ1
.
Ó 2021 Elsevier Ltd. All rights reserved.
Introduction
and (+)-a-pinene and oxygenated terpenes as starting materials
under acidic conditions (Scheme1) [4,9–13]. However, a compara-
Over the decades, flavors and fragrances sector have been grow-
ing in all its applications and nowadays they represent a multi-bil-
lionaire global market. The growing global industrialization has led
to the massive production of processed food, beverages, personal
care products, detergents, cleaning products and soaps, which
show the industry’s necessity to produce scented or flavored prod-
ucts. Thereby, such a high demand for natural products in this par-
ticular area could be seen as a disadvantage because of the
fluctuating prices of raw materials. To outline the problem and
continue expanding the market, scientific innovations are needed
to deliver synthetic fragrances and flavors [1–3].
tive and systematic study of different catalysts under mild reaction
conditions for the production
literature.
a-terpineol has not been reported in
In this context, the development of chemoselective synthesis of
-terpineol has, as main challenge, to avoid degradation and iso-
a
merization products which current leads to low yield and selectiv-
ities [14].
The adoption of continuous flow technology for the synthesis of
natural product on safer and more efficient conditions has become
popular. Providing better control on reaction parameters such as
mixing, mass and heat transfer and on-line purification, down-
stream processing help minimize solvent usage, waste and manual
handling [15–17]. In this context, our research group [16,18–21]
have been involved in the development of flow chemistry method-
ologies for organic synthesis and biocatalysis [15,16] and herein
we report the evaluation of continuous flow technology for the
a-Terpineol is a high-value naturally occurring monoterpene
present in essential oils widely used as a flavoring aromatic sub-
stance. Likewise, it is also used as an anti-fungal agent, as a disin-
fectant in cleaning commodities [4], as a fine chemical building
block [5], and has antibacterial [6] and antitumoral activities
[7,8]. Consequently, there is an intense search for more effective
synthesis of -terpineol starting from readily available (+)-limo-
a
synthetic ways to obtain
a-terpineol [4,9]. The use of the terpene
nene and (+)-a-pinene [10,22,23].
as a chemical platform has been already investigated, and many
new catalytic processes were reported affording the target com-
pound via chemical [8] or biochemical [9] catalytic conversion.
Results and discussion
Thus, different methods to produce
described in the literature, using both monoterpenes (+)-limonene
a-terpineol have been
We began our work evaluating batch reactions already
described in literature for a-terpineol synthesis starting from read-
https://doi.org/10.1016/j.tetlet.2021.153318
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

Beatriz L.C. de Carvalho, A.R. Aguillon, Raquel A.C. Leão et al.
Tetrahedron Letters 80 (2021) 153318
and the acid was 1:1. The best batch conditions were adapted to
continuous flow systems.
After this initial assessment we decided to translated batch pro-
tocol to continuous flow conditions connecting two syringe pumps
(A:
a-pinene and B: 7.51 M chloroacetic acid aqueous solution)
through a T-mixer into a mixing zone (PBR filled with glass wool)
and a reaction zone at temperatures between 70 and 90 °C. It is
important to highlight that it was necessary an implementation
of a homemade static mixer, before tubular reactor mixer, as mix-
ing intensification strategies, increasing the homogeneity of the
reaction medium and avoiding the presence of hotspots. Flow rates
were adjusted in order to have a 1:1 mixture of reagents, according
to the desired residence time. Results are found on Table 1, and all
conversion values were analyzed by a GC/MS considering the sub-
strate, (+)-a-pinene, consumption.
Under the conditions outlined in Table 1, first experiments at
70 °C have shown that long residence time (60 min) led to lower
selectivity towards the desired product (entries 1 and 3, Table 1).
At this point, 30 min (entry 2, Table 1) residence time already gave
us moderate conversion (60%) with high selectivity (81%) and
increasing reaction temperature to 80 and 90 °C, keeping residence
time on 15 min, allowed a slight increase on reaction conversion
with similar selectivity (entries 5 and 7, respectively, Table 1).
Scheme 1. Different starting materials for a-terpineol synthesis.
Under the best conditions found for
a-terpineol synthesis (entry
5, Table 1) a space–time-yield of 0.53 Kg. dayÀ1 can be obtained
(based on conversion values, selectivity and pinene flow). The
results highlight that the replacement of conventional batch to
flow reactor allowed decreasing both reaction time.
ily available monoterpenes (+)-
a-pinene and (+)-limonene. The
reaction studied for -terpineol synthesis starting from (+)-a-
a
pinene was reproduced according to Román-Aguirre et al [4]
(23 M chloroacetic acid aqueous solution, 73 mmol substrate, 4 h
at 70 °C) leading to the desired product with 58% of selectivity. Fur-
ther optimization of reaction parameters (reaction time, tempera-
ture, catalyst concentration) leaded us to a slight reduction on
reaction time (3 h) with an increase on selectivity (67%) without
yield reduction, at 70 °C using a 27 mol. LÀ1 chloroacetic acid stock
solution (supporting information, Table S1).
As a second strategy we decided to evaluate the approach of
starting from (+)-limonene for
requires a two-step methodology consisted in an oxidation reac-
tion mediated by trifluoroacetic acid leading to trifluoroacetyl-
a-terpineol synthesis, which
a-
terpineol, an unstable intermediate, which proceeded to the next
step with the crude mass, followed by hydrolysis of this intermedi-
ate ester. We have used the work of Mattos et al [24] as a starting
point where the reaction was performed at room temperature for
1 h in cyclohexane. It was performed a previous optimization in
batch conditions evaluating the conversion and selectivity values
in function of reaction time (supporting information, Table S2).
These results showed that after 30 min of reaction time no further
enhancement on conversion and selectivity values were observed.
Moreover, other experiments evaluating molar ratio condition of
The best condition was found, using (+)-a-pinene (10 mmol),
chloroacetic acid in water (7.51 mol/L) at 70 °C for 3 h, with a con-
version value of 84% and selectivity of 67% (supporting informa-
tion, entry 1, Table S1). From the batch reaction studies we
learned that: the reaction showed sensibility to temperature, we
could reduce in one hour the reaction time described by Román-
Aguirre et al [4], and the best molar ratio between the substrate
Table 1
Results on continuous flow protocol using (+)-a-pinene as substrate.
Entry
T (°C)
Res. time (min)
Conv. (%) SD*
Select. (%) SD*
1
2
3
4
5
6
7
70
70
80
80
80
90
90
60
30
60
30
15
30
15
48 1.63
60 0.94
68 10.96
73 5.79
72 2.45
84 1.63
72 4.19
65 0.94
81 5.91
57 2.45
71 0.82
76 1.25
75 2.16
76 1.70
Reaction using a-pinene 98%, chloroacetic acid aqueous solution (7.51 M). *All conversion and selectivity values were determined by GC/MS considering the substrate, (+)-a-
pinene, consumption. Values were measured in triplicate; the medium value is reported, as well as the standard deviation (SD).
2

Beatriz L.C. de Carvalho, A.R. Aguillon, Raquel A.C. Leão et al.
Tetrahedron Letters 80 (2021) 153318
Table 2
(+)-Limonene in the synthesis of trifluoroacetyl-a-terpineol.
Entry
Molar ratio ((+)-limonene:acid)
Conv. (%)*
Select. (%)*
1
2
3
4
1:1
1:1.2
1:2
88
90
81
93
87
90
75
80
1:1 (no solvent)
Reaction using (+)-limonene (10 mmol) and CF3CO2H 10 mmol (1:1), at room temperature, for 30 min. *All conversion and selectivity values were determined by a GC/MS
considering the substrate, (+)-limonene, consumption.
(+)-limonene and trifluoroacetic acid were also tested on batch
condition (Table 2).
(Scheme 2). Therefore, the methanolic sodium hydroxide solution
was added directly to the reaction media after the first step reac-
tion time and samples were taken to follow product formation.
After 40 min of total reaction time, the conversion was maximum
(97%) and with excellent selectivity (93%).
It is well-established that this methodology for the conversion
of (+)-limonene into a-terpineol occurs with retention of the abso-
In our experiments a small decrease on selectivity was detected
when 1:2 M ratio (limonene: trifluoroacetic acid) was used (entry
3, Table 2). It is important to highlight that with the aim of finding
a better condition to continuous flow process, we decided to eval-
uate a solvent free reaction, giving excellent conversions and good
selectivity’s (entry 4, Table 2). Considering these preliminary
results, this reactional condition has become a very interesting
protocol for process intensification. Therefore, a study monitoring
the reaction time on solvent-free condition allowed us to observe
that after only 5 min 93% of conversion was already achieved with
very good selectivity, 89% (supporting information, Table S3).
As mentioned before, in order to access at the desired product,
we need to run a two-step reaction. Since the ester intermediate is
very unstable in acidic media, a cascade batch process is needed to
fully understand the potential of this solvent-free approach
lute configuration without loss of optical activity [24]. As the main
goal of this work is the evaluation of flow system for the synthesis
of
a-terpineol, so we did not evaluated the optical purity of the a-
terpineol obtained.
From these results, we decided to move forward in order to
translate batch protocol to a continuous flow cascade process.
Firstly, the reaction first step was study in flow conditions (sup-
porting information, Table S4) and later on, the second step was
assembled. The complete continuous flow setup is shown on
Scheme 3 and it is composed of three syringe pumps, two mixing
Scheme 2. Two-step cascade batch reaction of the a-terpineol synthesis.
Scheme 3. Cascade continuous flow setup for the synthesis of a-terpineol.
3

Beatriz L.C. de Carvalho, A.R. Aguillon, Raquel A.C. Leão et al.
Tetrahedron Letters 80 (2021) 153318
zones and two reaction zones, both at room temperature. Resi-
dence time was also adjusted in order to fit equipment require-
ments. The conversion and selectivity values were determined by
GC/MS considering the substrate (+)-limonene consumption. Those
values were measured in triplicate so we could obtain standard
deviation values.
Appendix A. Supplementary material
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153318.
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The continuous flow cascade system starting from (+)-limonene
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Residence time on the first step had a small change compared to
the optimization protocol in order to have a flow rate where we
could meet the second step requirements of residence time. For
the second reaction, mixing is a crucial step, so we decided to have
an extended residence time in order to accomplish the hydrolysis
reaction. Space time yield obtained for this cascade process is
0.14 kg.dayÀ1 (based on conversion values, selectivity and limo-
nene flow), lower than the one obtained for the continuous flow
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(Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado
do Rio e Janeiro – FAPERJ) for financial support. This study was
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All experimental information is in the supporting information.
4