Methyl Perillate as a Highly Functionalized Natural Starting Material for Terephthalic Acid

Article abstract of DOI:10.1002/open.201700178

Renewable commodity chemicals can be generated from plant materials. Often abundant materials such as sugars are used for this purpose. However, these lack appropriate functionalities and, therefore, they require extensive chemical modifications before they can be used as commodity chemicals. The plant kingdom is capable of producing an almost endless variety of compounds, including compounds with highly appropriate functionalities, but these are often not available in high quantities. It has been demonstrated that it is possible to produce functionalized plant compounds on a large scale by fermentation in microorganisms. This opens up the potential to exploit plant compounds that are less abundant, but functionally resemble commodity chemicals more closely. To elaborate this concept, we demonstrate the suitability of a highly functionalized plant compound, methyl perillate, as a precursor for the commodity chemical terephthalic acid.

Full text of DOI:10.1002/open.201700178

DOI: 10.1002/open.201700178
Methyl Perillate as a Highly Functionalized Natural
Starting Material for Terephthalic Acid
Esmer Jongedijk,[b] Frits van der Klis,[c] Rozemarijn de Zwart,[c] Daan S. van Es,[c] and Jules Beekwilder*[a]
Renewable commodity chemicals can be generated from plant
materials. Often abundant materials such as sugars are used
for this purpose. However, these lack appropriate functionali-
ties and, therefore, they require extensive chemical modifica-
tions before they can be used as commodity chemicals. The
plant kingdom is capable of producing an almost endless vari-
ety of compounds, including compounds with highly appropri-
ate functionalities, but these are often not available in high
quantities. It has been demonstrated that it is possible to pro-
duce functionalized plant compounds on a large scale by fer-
mentation in microorganisms. This opens up the potential to
exploit plant compounds that are less abundant, but function-
ally resemble commodity chemicals more closely. To elaborate
this concept, we demonstrate the suitability of a highly func-
tionalized plant compound, methyl perillate, as a precursor for
the commodity chemical terephthalic acid.
up to 6008C and high pressure.[2] Methyl perillate (MPA), on
the other hand, carries an unsaturated six-membered ring, is
functionalized at the para position, and has an acid group at
the C7 position. MPA is a monoterpenoid, which occurs in the
plant species Salvia dorisiana (see Figure S1 and Table S1 in
the Supporting Information). Terpenoids such as artemisinic
acid and farnesene are produced with high yields through mi-
crobial fermentation,[4] using metabolic engineering of micro-
organisms upon the introduction of plant metabolic pathways.
Though this has not yet been achieved for MPA, its precursors
limonene and perillic acid (PA) can be obtained by using mi-
crobial systems.[5] Therefore, when compared to glucose
(Table 1) and other bio-based precursors (Table S2), MPA could
be considered as a highly functionalized precursor for TA
synthesis.
A mild conversion of MPA to TA was designed (Scheme 1),
using dehydrogenation and oxidation reactions, and subse-
quently tested.
Global material demands inspire research towards bio-based
building blocks. For instance, terephthalic acid (TA) is currently
produced from petrochemical sources by oxidation of para-
xylene (pX).[1] Global TA demand is expected to reach 65million
tons in 2018, predominantly for the production of polyethy-
lene terephthalate (PET).[2] One approach for the bio-based
supply of TA is to use sugars or polysaccharides as starting ma-
terials, which are abundantly available from biomass.[3] Howev-
er, the structural similarity between sugars and TA is limited
and, therefore, a considerable number of harsh synthesis steps
are needed for TA production (Table 1).
First, MPA was synthesized from commercially available
(À)-perillaldehyde as the starting material, using silver oxide as
a catalyst, providing PA in reasonable isolated yield (Scheme 1,
reaction a) (66% yield, 94% pure) (see Figure S2 and
These steps include solubilizing sugars, hydrodeoxygenation
of the sugar ring, dehydrogenation to produce a mixture of ar-
omatics, separation of pX, and oxidation, with temperatures
[a] Dr. J. Beekwilder
Wageningen Plant Research
PO box 16, 6700AA Wageningen (The Netherlands)
E-mail: jules.beekwilder@wur.nl
[b] E. Jongedijk
Laboratory of Plant Physiology, Wageningen University
6708PB Wageningen (The Netherlands)
[c] F. v. d. Klis, R. d. Zwart, Dr. D. S. v. Es
Wageningen Food and Biobased Research
6708 WG Wageningen (The Netherlands)
Supporting Information and the ORCID identification number(s) for the
author(s) of this article can be found under https://doi.org/10.1002/
open.201700178.
ꢀ 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
This is an open access article under the terms of the Creative Commons
Attribution-NonCommercial-NoDerivs License, which permits use and
distribution in any medium, provided the original work is properly cited,
the use is non-commercial and no modifications or adaptations are
made.
Scheme 1. Synthesis of terephthalic acid from methylperillate, as developed
in this study.
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Table 1. Comparison of sugars and methyl perillate as precursors for TA.
Compound
sugars
Functional group(s)
–oxygenated ring
Reactions needed
Natural source
–solubilization
–biomass (sugars)
–hydrodeoxygenation
–oxidation (100–6008C, 0.1–83 bar)[3]
methyl perillate
–oxygenated ring
–acid group
–dehydrogenation
–oxidation
–essential oil (Perilla, Salvia)
or fermentation
–functionalized p-position
Table S3).[6] The resulting PA was methylated to MPA by esterifi-
cation in excess methanol with catalytic p-toluene sulfonic acid
(Scheme 1, reaction b). During methylation, a by-product was
formed, 8-methoxy-methyl perillate (MMPA). Short reaction
times ensured minimal MMPA formation, and it could be readi-
ly separated from MPA (see Figures S3 and S4). Nearly pure
MPA (3.0 g, 48% yield, 96% pure) was used as the starting ma-
terial for the synthesis of TA.
Three procedures were considered for the dehydrogenation
of MPA to methyl cumic acid (MCA). A dehydrogenation proce-
dure using ethylene diamine and metallic sodium has been re-
ported for the dehydrogenation of limonene.[7] We could re-
produce these results; however, this procedure consumes met-
allic sodium and was, therefore, considered not fully sustaina-
ble. Another procedure, using zeolite NaY as a catalyst, yielded
a mixture of isomers, with only 25% of MCA; this procedure
was, therefore, not considered.[8] The third procedure, a hetero-
genic catalytic procedure using a solid-supported Pd catalyst
for hydrogenation was followed,[9] involving sequential catalyt-
ic double-bond isomerization, hydrogenation, and dehydro-
genation. Acetone was used as a hydrogen acceptor[10] to steer
the reaction towards complete ring dehydrogenation. Initially,
limonene was used as a testing substrate. When a Pd/C cata-
lyst was used, formation of dehydrogenated product p-cymene
was observed only when the reaction was performed at 1508C
(20 h); whereas, at 1008C (20 h), no conversion of limonene
could be observed. Changing the support material of the cata-
lyst to alumina (5% Pd/Al2O3) resulted in a somewhat reduced
yield at 1508C, but it had a strongly improved reactivity and
selectivity towards the desired product (80%, Table S4) at
1258C and 1008C for 20 h. At 1258C, the reaction time could
be reduced to 1 h for full conversion of limonene and compa-
rable, even superior, yields of p-cymene (see Figure S5 and
Table S5). Also, these shorter reaction times significantly re-
duced the formation of acetone-related by-products diacetone
alcohol and mesityl oxide. Thus, a short dehydrogenation pro-
cedure for limonene-like substances was developed, which op-
erates efficiently at mild temperature.
Figure 1. Methyl cumate, the product of dehydrogenation from MP. GC-MS
chromatograms of dehydrogenation product and MCA reference compound.
Side products related to acetone are detected; the side product of PA meth-
ylation (MMPA) is still present, and some other side products are visible; a li-
brary-hit of their identity is indicated in the chromatogram.
hydrogenation. Isopropanol (iPrOH) and water are formed by
transfer hydrogenation and aldol–addition reactions, respec-
tively. However, no hydrolyzed or trans-esterified forms of MPA
or MCA were detected in the end product.
Use of highly functionalized starting materials such as MPA
provide benefits by reducing the number of synthetic steps.
This is the case for the oxidation to form TA. Previous studies
have shown that oxidation of the isopropyl group at position 4
can be readily achieved, but oxidation of the methyl group at
position 7 of limonene and its dehydrogenation product p-
cymene is more difficult and needs an extra step.[11] In MPA
and MCA, the 7 position is already occupied by a carboxyl
group. Therefore, oxidation to form the end product TA can be
achieved by an efficient single oxidation step (Scheme 1,
reaction d).
Using the developed procedure (1258C, 1 h, 5% Pd/Al2O3),
MPA was efficiently converted to MCA (see Figures 1 and S6). A
plausible reaction mechanism involves sequential isomerization
and dehydrogenation (Scheme S1),[9] in which transfer hydro-
genation to acetone pulls the equilibria towards the fully dehy-
drogenated product MCA. The ratio of MCA to MPA was 1:0.17
(85% conversion). The end product contained similar acetone
aldol addition products to those detected in the limonene de-
Two oxidation methods were tested to convert intermediate
MCA to TA. First, oxidation with KMnO4 was tested,[12] but
yielded only 12% TA. Second, a procedure for the oxidation
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with nitric acid was tested. Aromatic isopropyl groups can be
efficiently oxidized to the corresponding carboxylic acid group
by nitric acid.[7,13] Under aqueous nitric acid conditions, the
methyl ester group of MCA is rapidly hydrolyzed, yielding the
free cumic acid (CA) in situ. Oxidation of CA using 65% nitric
acid resulted in full conversion and 89% isolated yield (24 h
reflux, non-optimized; Figure S7). The product contained 70%
TA (Figure S7) and a single side-product was identified as 1,1-
dinitroethyl benzoic acid by using NMR, LC-MS, and IR analyses
(Figure S7).[14] It is known that 1,1-dinitroethyl benzoic acid is
also converted to TA by heating in 30% nitric acid at 1808C.[14b]
This protocol improves earlier described nitric acid oxidation
yields starting from benzene (42% yield of TA)[15] and p-cymene
(51% yield of p-toluic acid).[16] These results show that it is pos-
sible to oxidize MCA to TA in a single step with good yield.
In conclusion, we have demonstrated the applicability of
two mild catalytic steps to convert the natural monoterpenoid
MPA to the commodity chemical TA. By employing palladium-
catalyzed dehydrogenation, short and mild conditions can be
deployed, which offer advantages in terms of sustainability
and yield. Subsequently, oxidation using nitric acid is efficient
in producing TA with high yield and high purity. Our work
clearly outlines the advantages of selecting highly functional-
ized molecules as starting materials to produce commodity
materials such as TA (Figure 2). This approach anticipates the
ability of the fermentation industry to produce functionalized
terpenoid compounds at affordable prices. The fermentative
production of complex functionalized molecules such as farne-
sene, which is positioned as a jet-fuel, indicates that this is a re-
alistic scenario. Therefore, the identification of compounds that
carry appropriate functionalization and the development of
sustainable procedures to convert them into bio-based build-
ing blocks may have high potential for future applications.
Keywords: bio-based commodity chemicals · methyl perillate ·
monoterpene · natural functionalization · terephthalic acid
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Conflict of Interest
The authors declare no conflict of interest.
Received: November 7, 2017
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