Development of highly efficient Friedel-Crafts alkylations with alcohols using heterogeneous catalysts under continuous-flow conditions

Article abstract of DOI:10.1039/d1ra04005g

The development of Friedel-Crafts alkylations with alcohols under continuous-flow conditions using heterogeneous catalysts is reported. The reactivities and durabilities of the examined catalysts were systematically investigated, which showed that montmorillonite clay is the best catalyst for these reactions. A high turnover frequency of 9.0 × 10²h^?1was recorded under continuous-flow conditions, and the continuous operation was successfully maintained over one week.

Full text of DOI:10.1039/d1ra04005g

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Development of highly efficient Friedel–Crafts
alkylations with alcohols using heterogeneous
catalysts under continuous-flow conditions†
Cite this: RSC Adv., 2021, 11, 24424
a
a
a
a
Koichiro Masuda, * Yukiko Okamoto, Shun-ya Onozawa, Nagatoshi Koumura
ab
and Shu Kobayashi
*
¯
The development of Friedel–Crafts alkylations with alcohols under continuous-flow conditions using
heterogeneous catalysts is reported. The reactivities and durabilities of the examined catalysts were
systematically investigated, which showed that montmorillonite clay is the best catalyst for these
Received 23rd May 2021
Accepted 5th July 2021
DOI: 10.1039/d1ra04005g
2
ꢁ1
reactions. A high turnover frequency of 9.0 ꢀ 10
h was recorded under continuous-flow conditions,
rsc.li/rsc-advances
and the continuous operation was successfully maintained over one week.
5
Efficient and high-throughput synthetic methods are in high Supported iron oxide,
a uorinated polymer-supported
6
demand for the ideal continuous production of ne chemicals. Brønsted acid, and hydroxyl-functionalised sulfonic acid
Continuous-ow syntheses, especially using packed bed reac- silica were used as xed bed catalysts to achieve continuous-
7
tors, offer green and sustainable methods that yield desired ow reactions with considerably high turnover frequencies
1
materials as sole products, and the development of highly (TOFs).
active and durable heterogeneous catalysts is an important task
in this research area.
In this study, we systematically evaluated a series of hetero-
geneous acid catalysts for Friedel–Cras alkylations with alco-
Aromatic alkylations, in particular, the Friedel–Cras alkyl- hols and the excellent catalytic activities of layered
2
ation, are among the most employed organic reactions, with aluminosilicates.
classical processes using alkyl halides and aromatic
The reaction of benzyl alcohol (1a) with p-xylene was chosen
compounds in the presence of acids as promoters. Alkyl halides as the model system (Scheme 1). Under acidic conditions, 1a
are to be avoided from the viewpoint of green and sustainable provided Friedel–Cras product 2a and dimeric ether 3a;
chemistry, as these substrates yield hydrogen halides as further reaction of 3a furnished 2a. Self-oligomerisation of 1a,
coproducts, which are not only corrosive but also autocatalytic, initiated by overalkylation of any aromatic ring, but mainly
8
boosting reactivity and oen resulting in uncontrollable those in 2a, is a possible side reaction of this system, as
9
reactions.
conrmed by the strong uorescence of polybenzyl structures.
2
b
Alcohols are environmentally benign alternatives. While Therefore, catalysts were evaluated and discussed using the
the methylation of toluene with methanol is a well-known conversion of 1a in relation to selectivity for 2a and 3a. The
industrial reaction, within the process window of ne chem- catalysts and their conditions are summarised in Table 1.
icals, Friedel–Cras alkylations with alcohols suffer from low Column size, catalyst loading, and ow rate were varied to
reactivities and catalyst deactivation. Alcoholic hydroxyl groups
and water, the coproduct of the reaction, can destroy catalytic
activity and even hydrolyse catalysts to inert structures. Recent
3
water-tolerant Lewis acid and heterogeneous acid catalyst
developments have enabled the catalytic conversions of acti-
4
vated alcohols (and aldehydes) with solvent amounts of arenes.
a
Interdisciplinary Research Center for Catalytic Chemistry, National Institute of
Advanced Industrial Science and Technology (AIST), 1-1-1 Higashi, Tsukuba, Ibaraki
3
05-8565, Japan. E-mail: koichiro-masuda@aist.go.jp; shu_kobayashi@chem.s.
u-tokyo.ac.jp
b
Department of Chemistry, School of Science, The University of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
†
Electronic supplementary information (ESI) available. See DOI:
0.1039/d1ra04005g
Scheme 1 Acid-catalysed reactions of benzyl alcohol (1a) in p-xylene.
1
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a
Table 1 Evaluation of heterogeneous acid catalysts
ꢁ
1
b
ꢁ1
c
Entry
Catalyst
Column (mm)
Flow rate (mL min
)
Reaction scale
WHSV (h
)
Average selectivity
1
2
3
4
5
6
7
H-Y zeolite (501.5 mg)
H-beta zeolite (537.7 mg)
Naon/silica (338.9 mg)
ø5 ꢀ L50
ø5 ꢀ L50
ø5 ꢀ L50
ø5 ꢀ L50
ø5 ꢀ L50
ø3 ꢀ L50
ø3 ꢀ L50
0.05
0.05
0.05
0.25
0.10
1.00
1.00
10 mmol (50 mL)
10 mmol (50 mL)
10 mmol (50 mL)
20 mmol (100 mL)
20 mmol (100 mL)
20 mmol (100 mL)
20 mmol (100 mL)
0.13
0.12
0.19
0.24
2.7
83
82
90
85
85
77
76
2
Sulf. ZrO (1349 mg)
d
Mont. K10 (47.5 mg)
d
Bentonite (18.7 mg)
69
78
d
H-mont. (16.6 mg)
a
Procedure: each catalyst was packed into a glass column for an EYELA MCR-1000 column-type ow reactor and pre-treated with p-xylene at the
designed ow rate until all inside air has been ejected. A solution of 1a in p-xylene (0.2 M, 10 or 20 mmol scale with 0.04 M pentadecane as the
ꢂ
internal standard) was pumped into the column heated at 120 C, and the obtained mixture was fractionated into test tubes for analysis.
b
c
Average selectivity over whole fraction collected toward 2a and 3a, calculated as (2a + 2 ꢀ 3a)/(conversion of 1a). The catalyst was diluted
d
with celite (1/9). WHSV describes the relative substrate mass feed speed to the catalyst, and dened as follows: WHSV ¼ [ow rate
ꢁ
1
ꢁ1
ꢁ1
(mL min )] ꢀ [Conc. (g L )] ꢀ 60 (min h )/Wcatalyst
.
achieve optimal conditions. It is necessary that the whole of H-beta decreased more rapidly than that of H-Y, showing
catalyst in the column is effective for easier comparison of the good linearity in the semi-log plot.
1
0
catalyst performance. The results in reactors of varying size
Naon-H has been reported to be a good catalyst for this
12
under various conditions are summarised by weight hourly reaction under batch conditions. The low reactivity reported
space velocity (WHSV) and substrate/catalyst weight ratio (S/C). under ow conditions was assumed to be due to the small
6
The progress of each ow reaction, initially obtained as surface area of the commercial Naon NR50 solid; therefore, we
13
conversion-time data, is plotted against S/C ratio for normal- immobilised Naon DE521 dispersion on silica gel and then
isation, as shown in Fig. 1. applied it to the reaction, which led to high selectivity and more-
Zeolites have been reportedly used in Friedel–Cras alkyl- stable catalytic activity than those observed for the zeolites
ation chemistry with benzyl alcohols under batch con- (entry 3; right green). Sulfated zirconia is also known to be
4b,11
14
ditions.
Among various structures, H-Y and H-beta zeolites a strong heterogeneous Brønsted acid; this material was found
were chosen as typical acid catalysts in this study. While H-Y to be a good catalyst for this reaction, with stable reactivity and
ꢁ
1
15
showed moderate reactivity at a ow rate of 0.05 mL min
,
selectivity observed (entry 4, purple). Metal-exchanged clays or
16
H-beta recorded full conversion at the beginning (Table 1, acidied ones have been reported to be good catalysts for the
entries 1 and 2; blue and red in Fig. 1). Interestingly, the activity activation of benzyl alcohols under batch conditions; we found
that commercial montmorillonite K10 was highly efficient for
this reaction (entry 5, turquoise). This clay catalyst required
dilution with celite to avoid column stacking, despite its
considerably high reactivity. Moreover, bentonite freshly acti-
vated with 1 M sulfuric acid at room temperature (a raw clay
mineral containing montmorillonite as the main component
provided by Fujilm Wako Chemicals) showed excellent activity
(entry 6, orange). It should be noted that an experiment was
conducted with a more than 25-times larger WHSV, a reduced
column volume of 36%, and a 10-times faster ow rate owing to
the extremely high catalytic activity of this clay. Interestingly,
while a signicant drop in activity was observed using
commercial montmorillonite K10, house-acidied natural clay
maintained its catalytic efficiency even aer processing large
amounts of substrate. The differences between the two clays
Fig. 1 Evaluation of heterogeneous acid catalysts. The results are prompted us to conduct further investigations. Puried mont-
given as conversion vs. S/C plots; semi-log forms were employed due morillonite (Kunipia F, provided by Kunimine Industry), acidi-
to wide variations on the S/C axis. S/C is given as the integration of

ed under the same conditions as the bentonite catalyst,
WHSV over time, with the value calculated as follows, assuming
constant flow rate: S/C ¼ WHSV ꢀ t.
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exhibited excellent productivity and durability (entry 7, deep
blue).
16
In a previous report, montmorillonite was activated with
dilute HCl, whereas commercial K10 used sulfuric acid as the
activating reagent. However, our trials showed that aqueous
HCl treatment resulted in slightly lower catalytic activity than
sulfuric acid (Table 2, entry 1; purple plot in Fig. 2). Interest-
ingly, concentrated HCl (35%) provided a higher conversion
and better catalyst stability (entry 2, turquoise). In order to
observe clear catalyst differences, montmorillonites treated
with concentrated HCl and 1 M HCl were re-examined under
further accelerated conditions (entries 3 and 4, orange and deep
blue). A ten-fold-diluted catalyst column was employed at
a slower ow rate to ensure that the experiment was conducted
in the higher turnover region without reaction scale-up. The
concentrated-HCl-treated catalyst showed a slower drop in
catalyst activity, which indicates that conc. HCl treatment is
optimal for catalyst preparation (entry 4). Under these condi-
Fig. 2 Fine-tuning montmorillonite under accelerated conditions.
within 1 h in benzene; the formation of polybenzyl seems to be
a problem. We assume that the less reactive benzene is unable
to compete with the overalkylation of any alkylated product,
resulting in uncontrollable polymerisation that clogged the
reactor. A similar tendency was observed for toluene; the
desired product 2c was obtained, however, yield and selectivity
were not comparable with those of p-xylene, and the column
pressure gradually increased during the ow reaction. More
nucleophilic anisole, as solvent, provided good reactivity, with
the desired product 2d obtained in good yield without any
clogging observed. These monosubstituted aromatics gave para-
and ortho-substituted products, with slightly p-favoured
tendencies, presumably due to steric hindrance.
tions, the reaction provided a turnover number (TON) of 1.09 ꢀ
4
1
0 for a 20 mmol-scale experiment, with a turnover frequency
2
ꢁ1
(
TOF) of 9.0 ꢀ 10 h at the initial stage of the ow reaction.
With this catalyst in hand, standard synthetic conditions were
established by reducing the WHSV to 6.8 (ø5 ꢀ 50 mm column
ꢁ1
with 1/9 catalyst dilution, 0.25 mL min ), which achieved full
conversion with minimal amounts of intermediate 3a detected
(
see ESI† for details). These synthetic conditions delivered
ꢁ
1
a TON of 491 and a TOF of 76.7 h based on conversion, with
2
h
ꢁ
1
.28 mmol h productivity of the desired product and a 456 g
ꢁ1
ꢁ3
dm space time yield (STY). All fractions were collected,
with the desired product isolated in 63% yield.
Monosubstituted benzyl alcohols were next investigated
using p-xylene as the solvent. The position of the substituent
affected the reactivity; o- and m-methylbenzyl alcohols gave the
desired products 2e and 2f in moderate yields, while p-methyl-
benzyl alcohol afforded the desired 2g in a slightly higher yield.
This difference is attributable to the steric hindrance of the
The scope and limitations of the reaction were investigated
under the established synthetic conditions (Scheme 2). The
reaction was initially examined with benzyl alcohol as the
substrate in benzene, toluene, and anisole as solvents. The
desired products 2c and 2d were obtained successfully in
toluene and anisole, while column clogging was observed
a
Table 2 Fine-tuning montmorillonite under accelerated conditions
Catalyst loading
(mg)
ꢁ
1
ꢁ1
b
Entry
Table 1, entry 7)
1
2
3
4
Acid treatment
SO (1 M)
HCl (1 M)
HCl (conc.)
HCl (1 M)
HCl (conc.)
Cat/celite
Flow rate (mL min
)
WHSV (h
)
Average selectivity
(
H
2
4
1/9
1/9
1/9
1/99
1/99
16.6
16.4
16.1
1.92
3.36
1.0
1.0
1.0
0.1
0.25
78
79
81
68
97
76%
75%
77%
73%
70%
a
Procedure: the catalyst was mixed with Celite® and packed into a glass column for an EYELA MCR-1000 column-type ow reactor and pre-treated
with p-xylene at the designed ow rate until all inside air had been ejected. A solution of 1a in p-xylene (0.2 M, 20 mmol scale with 0.04 M
ꢂ
pentadecane as the internal standard) was pumped into a column heated at 120 C, and the obtained mixture was fractionated into test tubes
b
for analysis. Average selectivity toward 2a and 3a, calculated as (2a + 2 ꢀ 3a)/(conversion of 1a).
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a
ꢁ1
b
Scheme 2 Substrate scope. Reactions were conducted according to the general procedure (see ESI†) unless otherwise noted. 0.1 mL min . A
c
d
e
ꢂ
f
ø5 ꢀ 100 (mm) column was used. Dodecane was used as the internal standard. A ø10 ꢀ 50 (mm) column was used. 160 C. 0.1 M, 10 mmol
g
scale. A ø10 ꢀ 100 (mm) column was used.
product; 2e and 2f are less sterically hindered than 2g (Scheme GC conditions. 1-Adamantanol, reportedly a good aliphatic
7
2
, indicated as positions 1–3 in the structures). Therefore, 2e substrate, was found to be troublesome in our case, with rapid
and 2f are more prone to overreacting with the substrate, which catalyst deactivation observed, especially at high temperatures;
reduces their yields. Indeed, an increase in column pressure the desired 2k was isolated in only 26% yield aer optimising
was observed at the end of the ow reaction involving o-meth-
ylbenzyl alcohol (1e), suggesting that this substrate has a higher
tendency to polymerise. The reaction of the more electron-
donating p-methoxybenzyl alcohol suffered from clogging, and
the desired product 2h was not obtained. On the other hand, the
electron-withdrawing p-chlorobenzyl alcohol reacted success-
fully, albeit with slightly lower reactivity, and required a smaller
WHSV for reaction completion. The desired product 2i was
obtained in high yield without any drop in reactivity or column
clogging observed.
Several aliphatic alcohols were found to react under slightly
modied conditions. Cyclohexanol provided the desired
product 2j in good yield at higher temperatures and longer
retention times, presumably via dehydrated cyclohexene as an Fig. 3 Long-term operation with p-chlorobenzyl alcohol (1i). The
reaction was conducted with a ø10 ꢀ 100 mm column at a flow rate of
intermediate. Conversion was not determined for this
substrate, due to overlap with the solvent peak under standard
ꢁ
1
0
.2 mL min . A total of 60.1 g of substrate was processed with this
column at a catalyst loading of 187 mg.
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the reaction conditions. Neopentyl alcohol gave no isolable
amount of the desired product, which is presumably due to the
instability of the primary carbocation intermediate.
Notes and references
1 (a) M. B. Plutschack, B. Pieber, K. Gilmore and
P. H. Seeberger, Chem. Rev., 2017, 117, 11796; (b)
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To demonstrate the power of our continuous-ow reaction,
p-chlorobenzyl alcohol was employed under long-term opera-
tion conditions (Fig. 3), which were slightly modied for
stability. The desired product 2i was obtained in excellent yield
without any loss of reactivity over one week (¼ 168 h), with an
3
overall TON of 2.6 ꢀ 10 recorded. All reaction fractions were
combined and distilled to obtain pure 2i in 93% yield (91.2 g).
In conclusion, a highly active and durable catalyst suitable
for continuous ow synthesis was successfully developed for
Friedel–Cras alkylations using alcohols. Systematically inves-
tigating catalysts under continuous-ow conditions revealed
clear differences in activity and durability, and identied acti-
vated montmorillonite clay as the best catalyst for these reac-
tions. Alkylated products were obtained in moderate-to-high
yields with some amounts of polymeric by-products, which
could be controlled by adjusting the electronic properties of
both the electrophile and nucleophile. p-Chlorobenzyl alcohol
was employed in a long-term process, with the desired 2i
produced almost quantitatively and isolated in 93% yield.
Further studies into this continuous-ow chemistry are
currently underway.
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Author contributions
3
07.
KM contributed to conceptualising the project, evaluating the
catalysts, and manuscript writing. YO investigated substrate
scope and optimised the conditions. SO was involved in study
conceptualisation. NK supervised the team and SK adminis-
tered the entire project.
1
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Acknowledgements
1
This work was partially supported by the New Energy and
Industrial Technology Development Organization.
24428 | RSC Adv., 2021, 11, 24424–24428
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