Zeolite catalyzed highly selective synthesis of 2-methoxy-6-acetylnaphthalene by Friedel-Crafts acylation of 2-methoxynaphthalene in acetic acid reaction media

Article abstract of DOI:10.1016/j.molcata.2016.11.012

Zeolite catalyzed Friedel-Crafts acetylation of 2-methoxynaphthalene to produce 2-methoxy-6-acetylnaphthalene with high selectivity and conversion has been a challenging task, because the obtained compound is a key intermediate for an anti-inflammatory agent, Naproxen. However, no satisfactory results have been obtained with zeolite catalysts, and harmful solvents have been used to gain a high selectivity together with a high conversion. Here, we report the synthesis of 2-methoxy-6-acetylnaphthalene from 2-methoxynaphthalene with a high selectivity and a high conversion under an unprecedented simple reaction system; acetic anhydride as an acetylating agent, acetic acid as a solvent, and proton-type zeolite catalysts with low acidity. Among the examined zeolites, a proton-type H-MOR (SiO₂/Al₂O₃ = 200) with a low acid content shows a conversion of 82% and an 86% selectivity for 2-methoxy-6-acetylnaphthalene. Further, detailed control experiments using H-MOR catalyst in acetic acid solvent were carried out to propose a plausible reaction mechanism.

Full text of DOI:10.1016/j.molcata.2016.11.012

Accepted Manuscript
Title: Zeolite Catalyzed Highly Selective Synthesis of
2-Methoxy-6-acetylnaphthalene by Friedel-Crafts Acylation
of 2-Methoxynaphthalene in Acetic Acid Reaction Media
Author: Tomoyoshi Yamazaki Makoto Makihara Kenichi
Komura
PII:
S1381-1169(16)30486-1
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.molcata.2016.11.012
MOLCAA 10109
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Journal of Molecular Catalysis A: Chemical
Received date:
Revised date:
Accepted date:
13-5-2016
7-11-2016
7-11-2016
Please cite this article as: Tomoyoshi Yamazaki, Makoto Makihara, Kenichi
Komura, Zeolite Catalyzed Highly Selective Synthesis of 2-Methoxy-6-
acetylnaphthalene by Friedel-Crafts Acylation of 2-Methoxynaphthalene in
Acetic Acid Reaction Media, Journal of Molecular Catalysis A: Chemical
http://dx.doi.org/10.1016/j.molcata.2016.11.012
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Zeolite
Catalyzed
Highly
Selective
Synthesis
of
2-Methoxy-6-acetylnaphthalene by Friedel-Crafts Acylation
of 2-Methoxynaphthalene in Acetic Acid Reaction Media
Tomoyoshi YAMAZAKI, Makoto MAKIHARA, and Kenichi KOMURA*
Department of Materials Science and Technology, Faculty of Engineering, Gifu
University, Gifu city, 501-1193, Japan.
*To whom corresponding author; K. KOMURA
E-mail; kkomura@gifu-u.ac.jp, Tel; +81-58-293-2600
Highlights



Very high selectivity for 2-methoxy-6-acetylnaphthalene together with a high
conversion of 2-methoxynaphthalene was achieved by using proton-type mordenite
High silica zeolites with 12-membered ring pore showed a high activity for this
acylation reaction
Detailed control experiments were carried out to propose a plausible reaction
mechanism
Abstract
Zeolite catalyzed Friedel-Crafts acetylation of 2-methoxynaphthalene to produce
2-methoxy-6-acetylnaphthalene with high selectivity and conversion has been a
challenging task, because the obtained compound is a key intermediate for an

anti-inflammatory agent, Naproxen. However, no satisfactory results have been
obtained with zeolite catalysts, and harmful solvents have been used to gain a high
selectivity together with a high conversion. Here, we report the synthesis of
2-methoxy-6-acetylnaphthalene from 2-methoxynaphthalene with a high selectivity and
a high conversion under an unprecedented simple reaction system; acetic anhydride as
an acetylating agent, acetic acid as a solvent, and proton-type zeolite catalysts with low
acidity. Among the examined zeolites, a proton-type H-MOR (SiO2/Al2O3 = 200) with a
low acid content shows a conversion of 82% and an 86% selectivity for
2-methoxy-6-acetylnaphthalene. Further, detailed control experiments using H-MOR
catalyst in acetic acid solvent were carried out to propose a plausible reaction
mechanism.
Keyword: Friedel-Crafts acetylation, zeolite, acetic acid, 2-methoxynaphthalene,
shape-selectivity
1. INTRODUCTION
Friedel–Crafts acetylation, an efficient method for preparing acetylated aromatics,
has been widely used in both laboratory-scale synthesis and practical production of
chemicals. The resulting acetylated aromatics are important substances that are widely
used for manufacturing products such as pharmaceuticals, agrochemicals, flavors and
fragrances. Generally, the acetylation reaction can be adequately promoted by a
Lewis-acid catalyst such as HF, BF3 and AlCl3. However, because there is a growing
demand for the development of environmentally benign chemical processes, the use of
alternative catalysts, such as solid-acid catalysts, has attracted attention. In particular,
zeolite-catalyzed reactions of anisole to give 4-acetylanisole have been investigated by

many researchers, and the highly regioselective synthesis of this isomer has been
attributed to the shape-selectivity of the zeolite catalysts [1–3].
2-Methoxy-6-acetylnaphthalene (2,6-ACMN; 1) shown in Scheme 1 is a key
intermediate used in the synthesis of the anti-inflammatory agent, Naproxen,
[(2S)-2-(6-methoxy-2-naphthyl)propanoic acid]. In 1999, Heinichen and Höldrich
reported the acetylation of 2-methoxynaphthalene (2-MN) catalyzed by H-BEA zeolite
in sulfolane as a solvent to give a 54% conversion of 2-MN with a 49% selectivity for 1
[4]. In 2000, Lee et al. comprehensively explored the acetylation of 2-MN by using
acetic anhydride (Ac2O) in the presence of H-Y, H-MOR, and H-BEA zeolite catalysts
in 1,2-dichloroethane solvent. The reaction over H-MOR (SiO2/Al2O3 = 8.0) resulted in
a 60% conversion of 2-MN with a low selectivity for 1 (8.4%), and it was also claimed
that 1-acetyl-2-methoxynaphthalene (1,2-ACMN; 2) was formed at the external surface
of the zeolite [5]. A mechanism for the reaction on H-BEA zeolite in nitrobenzene as a
reaction medium has been proposed by Fromentin et al. [6]. Some researchers have
claimed that in acetylation reactions of 2-MN by zeolite catalysts, the formed
1,2-ACMN (2) reverts to the starting substance 2-MN [6–8]. Approaches to the
reactions over H-BEA zeolite by using microwave irradiation have been recently
reported by Bai et al. [9], whereas Blanco et al. used a modified heteropoly acid catalyst
[10]. However, no satisfactory synthesis of the isomer 1 has been accomplished by the
acetylation of 2-MN. A kinetic study of the acetylation of 2-MN over dealuminated
H-Y zeolite revealed that the reaction proceeds by an Eley–Rideal mechanism, and the
formation of 1,8-ACMN and the deacetylated compound have been also discussed [11].
In 2008, Schster and Höldrich introduced a reaction catalyzed by a Nafion/silica hybrid
catalyst in sulfolane and toluene solvents that showed a high conversion and a high

selectivity for 1 with small amounts of 1,7-ACMN accompanied. However, reactions on
ion-exchanged BEA zeolites such Fe3+-exchanged BEA in sulfolane gave low
conversions and low selectivities [12]. Many investigators have explored
zeolite-catalyzed acylation reactions of 2-MN; however, the reactions require harmful
solvents such as nitrobenzene, 1,2-dichloroethane, and sulfolane to achieve a high
conversion of 2-MN and a high selectivity for 1.
In another approach, Gunnewegh et al. used the mesoporous silica [Al]MCM-41 to
achieve a 42% conversion of 2-MN and a 96% selectivity for 2 in 1,2-dichloroethane or
nitrobenzene as solvents [13]. Reactions with mesoporous silica or ion-exchanged clay
as catalysts did not give satisfactory results, and the reactions were carried out in
nitrobenzene or 1,2-dichloroethane as solvents [14]. An examination of numerous
reports on the acetylation of 2-NM over zeolite catalysts strongly suggests that the
acetylation of 2-MN generally occurs in a kinetically controlled manner at the
1-position, leading to 2, whereas the acetylation at the 6-position gives 1 as the
thermodynamically more stable product that could be formed in a shape-selective
manner [5,15].
Because there was no satisfactory established method for the selective synthesis of 1
from 2-MN by a zeolite-catalyzed Friedel–Crafts acylation, we attempted to overcome
this problem on the basis of the following concepts: (i) the use of a zeolite catalyst, (ii)
the use of Ac2O or acetic acid (AcOH) as the acylating agent, and (iii) the use of an
appropriate solvent. The last is a critical factor, because the progress of the Friedel–
Crafts acylation is severely dependent on the combination of catalyst and solvent that is
used. Furthermore, the reaction must be green and environmentally benign, and it must
not require harmful or hazardous solvents, such as nitrobenzene, 1,2-dichloroethane,

and sulfolane, as used previously. Therefore, the development of an alternative reaction
system is a challenging and urgent task in constructing a green chemical process [16].
Here, we report the development of a Friedel–Crafts acylation of 2-MN by Ac2O in
an acetic acid medium over zeolite catalysts that proceeds with a high conversion
together with a high selectivity. We present reaction profiles based on the control
experiments over an H-MOR (SiO2/Al2O3 = 200) catalyst in acetic acid and propose a
plausible mechanism of this catalytic reaction.
Scheme 1
2. EXPERIMENTAL
2.1. Characterization
Powder X-ray diffraction (XRD) was measured by a Shimadzu XRD-6000
diffractometer with CuK radiation (=1.5418 Å). Elemental analyses were performed
using a X-ray Fluorescence Spectroscopy (XRF) (Bruker S8 Tiger). Nitrogen adsorption
and desorption isotherm measurements were carried out on a Belsorp 28SA apparatus
(Bel, Japan). Solid-state 29Si magic angle spinning (MAS) NMR and 27Al NMR spectra
were recorded at ambient temperature by using a 4-mm diameter zirconia rotor at a
spinning rate of 6 kHz (ECA-500 NMR spectrometer, JEOL). The ratios of SiO2/Al2O3
in MOR (200) is almost the limit of measurement, and MOR(200) was allowed to
adsorb NH3 using an ammonia water (NH3 aq.) for enhancement of the intensity.
Thermal gravimetric and differential thermal analyses (TG-DTA) were carried out by
using a Shimadzu DTG-50 analyser at a ramping rate of 10 °C/min under an air stream.
The crystal size and morphology were measured by a field emission scanning electron

microscopy (FE-SEM) (S-4800; Hitachi High-Technologies, Japan). The products were
analyzed by a Shimadzu Gas Chromatograph GC-18 with FID (Column: Ultra-1
capillary column; Agilent Technologies, U.S.A.).
2.2. Materials
2-Methoxynaphthalene and 2-methoxy-6-acetylnaphthalene were purchased from
Tokyo Chemical Industry, Co., LTD. Acetic anhydride and acetic acid and other
solvents were purchased from Nacalai Chemicals. All of used zeolites are commercially
available; BEA(25) was purchased from Zeolyst, other zeolites such as LTL(6)
(TSZ-500HOA, Tosoh), FER(17) (TSZ-720KOA), H-Y(5.6), H-Y(300) (USY
HSZ-390HUA),
H-MOR
(TSZ-600HOA,
HSZ-630HOA,
TSZ-650HOA,
HSZ-690HOA) and H-ZSM-5(190), H-ZSM-5(70) (HSZ-860NHA and HSZ-870NHA)
were purchased from Tohsoh. NaY(200) was purchased from JGC Catalysts and
Chemicals and protonated before use. H-BEA zeolites (SiO2/Al2O3 = 150 and 200) were
hydrothermally synthesized by the HF method [17]. MAPO-5 (MgO/Al2O3=0.1) and
ZAPO-36 (ZnO/Al2O3=0.1) were prepared according to our recent reports [18,19].
Zeolite catalysts were used after calcination at 600 °C for 4 h. The numbers in
parentheses are SiO2/Al2O3 ratio.
2.3. Reaction
The typical reaction procedure; the prescribed amount of 2-MN (2.0 mmol), an
acetylating agent (acetic anhydride, 20 mmol) and zeolite catalyst (0.50 g) were
suspended in AcOH (10 mL), and then the resulting mixture was stirred at 150oC. After
cooling to room temperature, a small portion of the reaction solution was filtrated and
an aliquot was analysed by GC to determine the product yield and selectivity for each
isomer.

2.4. Analysis of the occluded organic molecules in the zeolite
The catalyst well-dried at 90oC was put in a Teflon beaker, and suspended in cold
water. Then, HF solution (55%) was added dropwise slowly to resolve the zeolite.
Resulting mixture was transferred to a separatory funnel, and organic compounds were
extracted with CHCl3 (20 ml×2). The organic layer was washed with brine and dried
with Na2SO4, and then, evaporated to dryness. Obtained solid including the extracted
products were resolved in EtOAc and analysed by GC. Only 1 was detected, which
means that the reaction occurs in a completely shape-selective manner in the H-MOR
zeolite with straight 12MR pore.
3. RESULTS AND DISCUSSIONS
3.1. Screening of the reaction conditions
We carried out a preliminary screening of acetylation of 2-MN with Ac2O in the
presence of several representative zeolite catalysts (Table 1). In Ac2O, no catalytic
activity was observed in the absence of a catalyst (Table 1, entry 1), and homogeneous
AlCl3 gave 2 in only 10% yield (entry 2). With the zeolite catalysts used, low
conversions of 2-MN to give 2 as the major product were observed (entries 3–7).
However, slightly greater selectivities for 1 were found with H-Y and H-MOR zeolites
as catalysts (entries 4 and 7).
Table 1
Figure 1 shows the results of acetylation of 2-MN in AcOH solvent with Ac2O as an
acylating agent and various catalysts. The conventional homogeneous Lewis acid

catalyst AlCl3 gave 2 in only 34% yield (A in Fig. 1). Siliceous mesoporous silica,
which is an efficient amidation catalyst [20], showed no catalytic activity (B in Fig. 1).
H-Y(15), H-BEA(25), and H-MOR(25) zeolites showed low conversion of 2-MN.
H-BEA(25) gave exclusively 2 in 13% yield. H-MOR(25) showed a slightly higher
selectivity for 1 but only 17% conversion of 2-MN was achieved (C, D, and E in Fig.
1). Amazingly, using H-MOR(200) with low acidity gave 82% conversion of 2-MN,
and the desired isomer 1 was obtained as the major product with 86% selectivity (F in
Fig. 1). It is clear that H-MOR(200) is the best catalyst for the selective production of 1.
The reaction gave the two isomers 1 and 2 with no by-products, such as 1,8-ACMN.
Furthermore, this reaction produced the acetylated products and AcOH from Ac2O.
AcOH is a widely used raw material in the chemical industry, suggesting that this
reaction system has marked advantages because the AcOH formed can be reused as
Ac2O after dehydration process, leading to establishment of a cyclic chemical process in
accordance with a concept in green sustainable chemistry.
Figure 1
3.2. Screening of other high-silica zeolite catalysts
Using H-MOR (SiO2/Al2O3 = 200) with low acidity produced the desired isomer 1
with high selectivity and high conversion of 2-MN under very simple reaction
conditions. H-MOR zeolite is known to be a highly selective catalyst for alkylation
reactions of biaromatics because a shape-selectivity can be induced by its straight pore
channels (7.0 Å × 6.5 Å) [21]. The high selectivity for 1 also indicates that the reaction

must occur in the straight pore channels of H-MOR by a sufficiently shape-selective
manner.
Table 2 shows the results of the Friedel–Crafts acylation reactions of 2-MN using
several high-silica zeolites under the same reaction conditions as described above.
Details of the characterization (powder XRD charts, N2-adsorption isotherms, and SEM
images) of the catalysts used are given in the Supporting Information.
Montmorillonite clay gave 11% conversion of 2-MN and 8% selectivity for 1 (Table
2, entry 1). Metaloaluminophosphate zeolites containing a straight pore with 12MR,
such as MAPO-5 (AFI topology, entry 2) and ZAPO-36 (ATS topology, entry 3),
showed high selectivities for 1 of 92% and 90%, respectively. However, conversion of
2-MN on MAPO-5 was only 5%, and that on ZAPO-36 was 38% (entries 2 and 3). The
well-known zeolite catalyst H-ZSM-5 (MFI topology), which has three-dimensional
pores with 10MR, showed no reaction in spite of a larger content of acid sites (entries 4
and 5). This result indicates that the pores of H-ZSM-5 do not allow entry of 2-MN for
catalysis and the reaction does not occur even at the external acid sites. High conversion
of 2-MN (68%) and high selectivity for 1 (78%) were achieved on H-BEA(200) with
the three-dimensional 12MR zeolite (*BEA topology, entry 6) and a slightly higher
conversion of 2-MN was achieved on the H-BEA(150) catalyst, albeit with a lower
selectivity for 1 (entry 7). These results suggest that H-BEA is also a promising catalyst
for the reaction. The reaction catalyzed by H-Y(200) with three-dimensional 12MR
pores (FAU topology) proceeded with a moderate conversion of 2-MN (57%).
However, the undesired isomer 2 was predominantly formed with 91% selectivity (entry
6), indicating that a shape-selective reaction does not occur in pores of H-Y zeolite
because of the size of its supercage (entry 8). H-MOR(110) with higher acidity showed

a moderate conversion of 2-MN (55%) and gave the highest selectivity for 1 (90%,
entry 9). H-MOR(300) with fewer acid sites than H-MOR(110) showed moderate
conversion of 2-MN (57%) and selectivity for 1 (73%, entry 11). The best results were
obtained with H-MOR(200) zeolite: conversion of 2-MN of 82% and selectivity for 1 of
86% (entry 10). The reaction in nitrobenzene solvent with H-MOR(200) gave 61%
conversion of 2-MN and the selectivity for 1 was 54% (entry 12). These results indicate
that H-BEA(150) (entry 7) and H-MOR(200) (entry 10) are good catalysts for this
acylation reaction, giving the highest conversion of 2-MN and the highest selectivity for
1. Therefore, the acetylation reaction using zeolites requires the presence of a pore
structure with 12MR and low acidity.
Table 2
3.3. Reaction profile and catalyst reusability
The reaction profile of the acylation of 2-MN is shown in Figure 2. Initially, the
reaction slowly proceeds, showing 53% conversion of 2-MN after 6 h, albeit with high
selectivity for 1 (79%). The profile then shows an increase in the conversion of 2-MN to
82% after 48 h. The selectivity for 1 remains fairly constant at about 80% up to 96 h,
and a slight enhancement of the conversion of 2-MN is observed at 96 h. The reaction
profile suggests that the reaction would achieve approximate equilibrium after 48 h.
Furthermore, the only organic compound occluded in the pores of H-MOR catalyst after
the reaction was 1, and no other isomers (2 and others) were detected by GC analysis.
This result indicates that the reaction occurring in the pores of the zeolite catalyst

practices almost perfect discrimination between the isomers, giving only the slimmest
isomer 1 (see Section 2.4).
Figure 2
Reusability and recyclability are important advantages of zeolite catalysts. After the
first reaction, TG–DTA analysis of the well-dried catalyst showed about 8% weight
loss, which can be assigned to occluded organic molecules during the reaction (see
Supporting Information). The catalyst was reactivated by calcination at 600 °C for 6 h
under flowing air, and then reused under the same reaction conditions. The results are
shown in Figure 3. Unfortunately, the conversion of 2-MN decreased to 53% on the first
reuse and to 50% on the second reuse. However, the selectivity for 1 remained high
after the first (91%) and second reuse (93%). After the third reuse, conversion of 2-MN
decreased to about 30%, but the selectivity for 1 increased to about 98%. This can be
attributed to the use of acetic acid at high temperature because the Brønsted active sites
of zeolites are often damaged by steam in even weakly acidic media
Figure 3
To identify the reason for the loss of catalytic activity, we analyzed the fresh
H-MOR(200) catalyst and the H-MOR(200) catalyst after being used five times. In the
powder-XRD charts of both catalysts, there are no significant differences in the peak
patterns and intensities (Supporting Information). However, the nitrogen-adsorption
isotherms show a decrease in both the surface area and pore volume after the catalyst

was used five times: the surface area decreases from 519 to 417 m2/g and the pore
volume decreases from 0.274 to 0.236 mL/g (Supporting Information). Therefore, it
seems that repeated reactions under acidic conditions caused collapse of the zeolite
catalyst, which is confirmed by SEM images (Supporting Information). XRF
measurements reveal a decrease in the Al content of the H-MOR catalyst (fresh catalyst
SiO2/Al2O3 = 200, five times reused SiO2/Al2O3 = 270). These results clearly indicate
that leaching of Al and collapse of the pore occurred in the catalyst used five times.
Solid-state magic-angle spinning (MAS) 29Si and 27Al NMR studies were also
performed for both H-MOR catalysts (Supporting Information). Because of the low
amount of Al in the catalyst, NH3 was absorbed on the catalyst used five times to
27
enhance the sensitivity [22]. In Al MAS NMR, both samples show only a sharp peak
at −57 ppm, corresponding to tetrahedral coordinated species, and no octahedral
29
coordinated species at 0 ppm are observed. In the Si MAS NMR spectra, two broad
peaks at −112 and −115 ppm, associated with Q4 silicon, are observed for both samples.
29
However, the Si MAS NMR spectrum of the H-MOR catalyst used five times has a
shoulder peak at −113 ppm, which implies that repetitive use of the catalyst creates a
new environment, such as an amorphous aluminosilicate and a new T-site as a result of
leaching of aluminum (see Supporting Information).
4. REACTION CHARACTERISTICS
To elucidate the reaction mechanism, we performed control experiments under
certain reaction conditions and determined the detailed product distributions. The
following conditions were used for all of the control experiments: H-MOR(200) as the
catalyst, AcOH as the solvent, a temperature of 150 °C, and a reaction time of 48 h.

4.1. Effect of Ac2O on the reactions of 1 and 2
Reactions of 1 or 2 with H-MOR(200) in AcOH were carried out to estimate the
stability of the products in our reaction medium. No reaction of 1 was observed (figure
not shown), although a remarkable decrease in the amount of 2 was observed after 48 h
with formation of 1 in 23% yield and 2-MN in 60% yield (Figure 4). This clearly shows
that 2 readily reverts to 2-MN and is subsequently converted to 1 in the presence of
H-MOR(200). This result confirms that migration of acetyl group of 2 can occur in the
absence of Ac2O [5].
Deacetylation of 1 did not occur in the presence of a stoichiometric amount of Ac2O
(figure not shown). However, the reaction profile of an equimolar mixture of 2 and
Ac2O shows a slight decrease in the concentration of 2 (about 20%) and formation of
about 10% of 1 and a trace amount of 2-MN after 48 h, as shown in Figure 5. This result
shows that deacetylation of 2 to 2-MN is suppressed in the presence of Ac2O, and that
2-MN reacts with the acyl cation in the straight pores of H-MOR(200) to give
thermodynamically stable 1 [6].
Figure 4 and Figure 5
4.2. Effect of 2-MN on the reactions of 1 and 2
Reactions of equal amounts of 2-MN and 1 or 2 in the absence of Ac2O were
performed to estimate the affinity and/or interactions of the products with 2-MN. In the
reaction of 2-MN with 2, a considerable conversion of 2 to 2-MN was observed, and no
other products (such as 1) were detected (see Supporting Information). This shows that
rapid conversion of 2 to 2-MN occurs whereas the acyl cation does not react with 2-MN

to give 1 probably because sufficient acyl cations do not exist in the zeolite pores; the
acyl cations cannot be formed from the eliminated AcOH and solvent. In contrast, no
remarkable change in the product distribution is observed for mixtures of 2-MN and 1
(see Supporting Information). These results conflict with the results shown in Fig. 4,
indicating that promotion of the reaction to give 1 requires a sufficient amount of Ac2O.
Next, we investigated the interactions of 2-MN, 1 or 2, and Ac2O over H-MOR
(200) in AcOH under conditions close to the standard reaction conditions. In the
reaction of 1 (Figure 6), 2-MN is consumed, accompanied with an increase in the
amount of 1 and formation of a trace amount of 2. This result obviously reflects the
reaction occurring in standard reaction media. In the reaction of 2 (Figure 7), there is an
obvious decrease in the amount of 2-MN and a marked increase in the amount of 1.
However, there is no marked decrease in the amount of 2, indicating that the acyl
cations in the acid sites of the zeolite predominately react with 2-MN to produce 1 and
deacetylation of 2 does not significantly occur in the presence of Ac2O, as shown in Fig.
5.
Figure 6 and Figure 7
4.3. Plausible reaction mechanism
The zeolite-catalyzed Friedel–Crafts acylation reaction usually proceeds via an
intermediate -complex, which forms by electrophilic addition of 2-MN to an acyl
cation activated at the acid site and this active cation often enhances migration of an
acetyl group (protiodeacetylation) [6,23]. In general, the reaction smoothly proceeds
with zeolites as solid acid catalysts. Generally, migration and/or deacetylation of 1 at

the acid sites, particularly at the external acid sites, could promote the formation of
2-MN but a low selectivity for 1. However, it may be fairly presumed that in our system
a high selectivity for 1 can be achieved because of the low acidity of the zeolites used.
The undesirable reaction of 1 to 2-MN at the external acid sites can be negligible, and
product 1 was found to be very stable as shown by the above control experiments. In the
straight pores of H-MOR(200), 2-MN predominately gives 2,6-ACMN (1) by a
shape-selective manner. Thus, the reversible reaction of 1 to 2-MN can be ignored in
our reaction system. We also found that remarkable deacetylation of 2 occurred in the
absence of Ac2O, whereas deacetylation of 2 was suppressed in the presence of a large
amount of Ac2O. From these findings from the control experiments, in the presence of
Ac2O, deacetylation of 2 would be suppressed for a low acid amount of zeolite,
particularly at the external acid sites covered by Ac2O (strong adsorption of Ac2O), and
it is also difficult for product 2 to enter the straight channels of H-MOR(200) zeolite
because of its molecular size. Therefore, considerable deacetylation of 2 is not observed
in the presence of a large amount of Ac2O, as shown in Fig. 5, and there is no
significant decrease in 2 during the reaction, even at equilibrium. However, Kim et al.
claimed that migration of 2 to 1 occurs under hard reaction conditions [5]. Consumption
of a large amount of Ac2O, which is activated to form an acyl cation with release of
AcOH at the acid sites of the catalyst, is also a considerable driving force for the
reaction; that is, the formation of 1 or 2 by the instantaneous reaction of 2-MN with an
acyl cation would be a critical step, and released acetic acid is thermodynamically stable
and has a low energy compared with the cationic intermediates.
From these findings, we have deduced the reaction mechanism, as shown in Fig. 8.
The acylating agent Ac2O is activated at a Brønsted acid site of the zeolite to form an

acyl cation species with release of AcOH in an irreversible reaction, because the
temperature is too low to produce Ac2O from the released AcOH or AcOH as solvent.
The resulting acyl cation immediately reacts with 2-MN by electrophilic substitution at
an electron-rich position of the substrate. 2,6-ACMN (1) is predominantly formed by a
shape-selective manner in the zeolite pores, while 1,2-ACMN (2) is directly formed via
a -complex intermediate [6]. From the results of the occluded compound analysis
(Section 2.4), it can be inferred that formation of 2 mainly occurs at the external acid
sites. The reaction of 2-MN with the activated acyl cation at the acid site to give 2
should be reversible, because suppression of deacetylation was observed and some
2-MN was detected with a large amount of Ac2O. However, the desired isomer 1 does
not undergo migration of acetyl group and/or deacetylation under the reaction
conditions, indicating that the backward reaction of 1 to 2-MN with release of AcOH
would be forbidden, while the product 2 reacts with a proton at the acid site to give
2-MN. However, suppression of deacetylation of 2 can be seen in Figs. 2 and 7 because
of presence of a large amount of Ac2O. After the reaction of 2-MN yielding 1 and 2, a
Brønsted acid site regenerates for next reaction of 2-MN.
Figure 8
5. CONCLUSION
Ecofriendly Friedel–Crafts acetylation of 2-MN over zeolite catalysts was
examined, and it was found that using Ac2O as an acetylating agent, H-MOR zeolite
with low acidity as a catalyst, and acetic acid as a solvent produced the desired isomer
2,6-ACMN (1) with a high selectivity (86%) and a high conversion of 2-MN (82%).

H-BEA with 12MR pores also showed a fairly good conversion and selectivity for 1.
The H-MOR(200) catalyst can be reused and recycled, although the conversion
decreased after the third use due to collapse of the catalyst. Based on detailed control
experiments with the H-MOR (200) catalyst in AcOH solvent, we propose a plausible
mechanism for this acylation reaction. We believe that we could improve our catalytic
system to give perfect selectivity for 1 with 100% conversion of 2-MN. Further research
of this reaction is ongoing.
ACKNOWLEDGMENT
This work partially is supported by JSPS KAKENHI Grant Number 15K05586.
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Figure captions
Fig.1. Results of Friedel-Crafts acylation of 2-MN in acetic acid solvent. (A; AlCl3,
B; MCM-41, C; H-Y (15), D; H-BEA (25), E; H-MOR (25), F; H-MOR (200)).
Fig.2. Reaction profile of acylation of 2-MN over H-MOR (200) catalyst at 150°C
using Ac2O in acetic acid. (●; conversion, ■; yield of 1, ▲; yield of 2).
Fig.3. Reuse and recycle experiment of H-MOR (200) catalyst of acetylation of
2-MN. Reaction conditions; Ac2O/2-MN (10 mmol), 0.5 g (H-MOR (200)) 150°C
for 48h.
Fig.4. Reaction profile of 1,2-ACMN (2) in the presence of H-MOR (200) in AcOH
at 150°C (▲; 1,2-ACMN (2), ■; 2,6-ACMN (1), ♦; 2-MN).
Fig.5. Reaction profile of 1,2-ACMN (2) and Ac2O in the presence of H-MOR (200)
in AcOH at 150°C (▲; 1,2-ACMN (2), ■; 2,6-ACMN (1), ♦; 2-MN).
Fig.6. Reaction profile of 2,6-ACMN (1), 2-MN and Ac2O in the presence of H-MOR
(200) in AcOH at 150°C (▲; 1,2-ACMN (2), ■; 2,6-ACMN (1), ♦; 2-MN).
Fig.7. Reaction profile of 1,2-ACMN (2), 2-MN and Ac2O in the presence of H-MOR
(200) in AcOH at 150°C (▲; 1,2-ACMN (2), ■; 2,6-ACMN (1), ♦; 2-MN).
Fig.8. Plausible reaction mechanism.

Fig. 1
100
80
60
2,6-ACMN
1,2-ACMN
40
20
0
A
B
C
D
E
F

Fig. 2
100
80
100
80
2,6-ACMN
1,2-ACMN
60
40
20
0
60
40
20
0
0
25
50
time (h)
75
100

Fig. 3
100
80
2,6-ACMN
1,2-ACMN
60
40
20
0
5th
fresh 1st 2nd 3rd 4th

Fig. 4.
100
80
60
40
20
0
1,2-AC-MN (2)
2-MN
2,6-ACMN (1)
0
12
24
time (h)
36
48

Fig. 5.
100
80
60
40
20
0
1,2-AC-MN (2)
2,6-ACMN (1)
2-MN
0
12
24
36
48
time (h)

Fig. 6.
100
80
60
40
20
0
2,6-ACMN (1)
2-MN
1,2-AC-MN (2)
0
12
24
time (h)
36
48

Fig.7.
100
80
60
40
20
0
1,2-AC-MN (2)
2,6-ACMN (1)
2-MN
0
12
24
time (h)
36
48

Fig. 8.

Scheme
Scheme 1. Friedel-Crafts acylation of 2-methoxynaphthalene over zeolite catalyst.