Rate Acceleration of Solid-Liquid Phase-Transfer Catalysis by Rotor-Stator Homogenizer

Article abstract of DOI:10.1002/adsc.201600425

A rotor-stator homogenizer was found to be an effective mixing tool that accelerated solid-liquid phase-transfer reactions. In the asymmetric alkylation under phase-transfer conditions using the homogenizer, a considerably high turnover frequency was observed. (Figure presented.).

Full text of DOI:10.1002/adsc.201600425

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DOI: 10.1002/adsc.201600425
Rate Acceleration of Solid-Liquid Phase-Transfer Catalysis by
Rotor-Stator Homogenizer
Taichi Kano,a Yusuke Aota,a and Keiji Maruokaa,*
a
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
E-mail: maruoka@kuchem.kyoto-u.ac.jp
Received: April 24, 2016; Revised: May 25, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600425.
Abstract: A rotor-stator homogenizer was found to
be an effective mixing tool that accelerated solid-
liquid phase-transfer reactions. In the asymmetric
alkylation under phase-transfer conditions using the
homogenizer, a considerably high turnover frequen-
cy was observed.
shown in Figure 1, the homogenizer consists of
a rotor within a stationary stator. Due to the high ro-
tational speed, the medium to be processed is drawn
axially into the mixing head and then forced radially
through the slots in the rotor-stator arrangement. The
high speed and minimal gap between the rotor and
stator produces extremely strong shear forces which
result in reduction of the particle size, and vigorous
mixing. Because these features of the rotor-stator ho-
mogenizer seem to be well-suited for phase-transfer
reactions using solid bases, we were interested in ap-
plication of the rotor-stator homogenizer to solid-
liquid phase-transfer catalysis.
Keywords: alkylation; homogenizer; organic cataly-
sis; phase-transfer catalysis
Phase-transfer catalysis represents one of the most
We first focused our attention on the benzylation of
practical synthetic methodologies given its operation- tert-butyl glycinate-benzophenone Schiff base under
al simplicity and mild reaction conditions that enable phase-transfer conditions (Table 1).[8] When the reac-
applications both in academic research and industrial tion mixture with solid KOH as base was vigorously
processes.[1] The phase-transfer reactions are com- stirred by the homogenizer in the presence of
monly carried out using a magnetic or mechanical stir- 10 mol% of tetrahexylammonium bromide (THAB),
rer. Vigorous stirring enlarges the interfacial contact the desired benzylation product was obtained in high
area between the two phases, and therefore is usually yield (94%) after only 40 seconds (entry 1). In
necessary to attain a sufficient reaction rate.[1b] In this marked contrast, however, the attempted reaction
respect, ultrasonic irradiation is also recognized as an under standard conditions using 50% KOH aqueous
effective mixing method both in liquid-liquid and solution with a magnetic stirrer resulted in formation
solid-liquid phase-transfer reactions.[2–6] Liquid-liquid of the product in only 3% yield with the recovery of
phase-transfer reactions benefit from the use of ultra-
sound because sonication produces fine emulsions,
which greatly increase the interfacial area.[4–6] The
rate acceleration by ultrasonic irradiation in solid-
liquid phase-transfer reactions can be ascribed to
a combination of fragmentation of solids and efficient
mixing, enabling better mass transfer.[2,3] However,
mechanical stirring should be used simultaneously
during sonication in some cases[4] and also there is
considerable difficulty in controlling the reaction tem-
perature.[6]
We describe herein our studies on the application
of a rotor-stator homogenizer in synthetically useful
solid-liquid phase-transfer reactions. The rotor-stator
homogenizer has been commonly used to disrupt bio-
logical samples such as plant and animal tissues.[7] As Figure 1. The rotor-stator homogenizer.
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Table 1. Comparison of mixing performance in the phase-
transfer-catalyzed alkylation.[a]
Scheme 2. Phase-transfer-catalyzed Darzens condensation of
2-chloroacetophenone with benzaldehyde.
Entry
Mixing method
Base
Yield [%][b]
1
2
3
4
5
6
homogenizer[c]
KOH
50% aq. KOH
KOH
50% aq. KOH
KOH
50% aq. KOH
94
80
31
3
6
24
homogenizer[c]
magnetic stirrer[d]
magnetic stirrer[d]
ultrasonic wave[e]
ultrasonic wave[e]
[a]
The reaction of tert-butyl glycinate-benzophenone Schiff
base (1.0 mmol) with benzyl bromide (1.2 mmol) was car-
ried out in the presence of THAB (0.10 mmol) in toluene
(5.0 mL) and either solid KOH (5.0 mmol, ground by
pestle and mortar) or 50% KOH aqueous solution
(280 mL) at 08C.
Determined by H NMR.
25000 rpm.
1350 rpm.
Scheme 3. Phase-transfer-catalyzed cyclopropanation of sty-
rene with chloroform.
[b]
[c]
[d]
[e]
1
Ultrasonic cleaner (Branson 2510J-MT, 100 W, 42 kHz).
Scheme 4. Phase-transfer-catalyzed alkyne isomerization to
allene.
the starting materials (entry 4). Additionally, the reac-
tion using either solid KOH or 50% KOH aqueous
solution gave the desired product in low yields under and the desired products were obtained in moderate
ultrasonic irradiation (entries 5 and 6), and the ad- to good yields within short reaction times (5–8 min).
vantage of using the homogenizer in solid-liquid
phase-transfer catalysis was clearly demonstrated.
We then carried out the asymmetric alkylation of
tert-butyl glycinate-benzophenone Schiff base using
A similar tendency was also observed in the conju- chiral phase-transfer catalyst (S)-1 under homogeniza-
gate addition of tert-butyl glycinate-benzophenone tion conditions (Scheme 5).[3,13] We have previously
Schiff base to methyl acrylate using solid K2CO3 as reported that the similar reaction using 50% KOH
base and 20 mol% of tetrabutylammonium bromide aqueous solution as base with magnetic stirring re-
(TBAB) and 10 mol% of CsCl as catalysts.[9] While quired long reaction times (2–12 h) for completion.[13b]
the desired conjugate adduct was obtained in 54% In contrast, use of solid KOH and the homogenizer
yield under homogenization conditions, the yield was
significantly diminished with magnetic stirring under
identical reaction conditions, as shown in Scheme 1.
Encouraged by these results, we further examined
several solid-liquid phase-transfer reactions such as
Darzens condensation, cyclopropanation and alkyne
isomerization using the homogenizer as shown in
Scheme 2, Scheme 3 and Scheme 4.[10–12] In all cases
tested, a remarkable rate acceleration was observed
Scheme 1. Phase-transfer-catalyzed conjugate addition of
tert-butyl glycinate-benzophenone Schiff base to methyl ac-
rylate.
Scheme 5. Phase-transfer-catalyzed asymmetric alkylation of
tert-butyl glycinate-benzophenone Schiff base with benzyl
bromide.
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resulted in considerable rate enhancement and the the rotor-stator homogenizer instead of a standard
desired benzylation product was obtained in good magnetic stirrer. We believe that the rotor-stator ho-
yield and enantioselectivity after mixing for only mogenizer used mainly in biological studies would be
5 min. The present reaction was performed at a very a powerful and reliable tool for organic synthesis in
low catalyst loading and was completed in a quite biphasic systems such as the solid-liquid phase-trans-
short time, thus resulting in a much higher turnover fer reactions.
frequency (TOF=21360 hÀ1) compared to that of the
reactions using
a magnetic stirrer (TOF=162–
980 hÀ1).[13b]
Experimental Section
To demonstrate the practical utility of the present
method using the homogenizer, a preparative scale Typical Procedure
experiment was performed. Accordingly, 1.55 g of 2-
To a mixture of 2-chloroacetophenone (1.55 g, 10.0 mmol),
chloroacetophenone was subjected to the Darzens
condensation and gave 1.88 g of the corresponding
product in 84% yield (Scheme 6).
tetrahexylammonium bromide (870 mg, 2.00 mmol) and lith-
ium hydroxide monohydrate (1.68 g, 40.0 mmol) in toluene
(4.0 mL) was added benzaldehyde (1.22 mL, 12.0 mmol) at
room temperature. The mixture was stirred by the homoge-
nizer (25000 rpm) in a water bath at the same temperature.
After stirring for 20 min, the reaction mixture was filtered
through Celite with EtOAc as eluent. The filtrate was con-
centrated to afford a residual oil. The residue was purified
by column chromatography on silica gel (eluting with
hexane/EtOAc=10/1) to afford the product; yield: 1.88 g
(8.40 mmol, 84%).
Scheme 6. Gram-scale synthesis using the homogenizer.
In solid-liquid phase-transfer catalysis, the particle
size of solid base correlates with its effective surface
area and therefore the reaction rate. We measured
the particle size of K2CO3 to explain the drastic rate
enhancement in the phase-transfer reactions using the
homogenizer and the observed SEM images are
shown in Figure 2. The particle size of unprocessed
K2CO3 was found to range approximately from
200 mm to 800 mm (Figure 2, left). While pestle and
mortal grinding resulted in a broad size distribution
including a large proportion of coarse particles
(Figure 2, middle), treatment of K2CO3 with the ho-
mogenizer for 30 seconds in toluene gave a very fine
dispersion of particles (<5 mm) (Figure 2, right).
Based on these observations, we propose that the
solid-liquid phase-transfer catalysis using the homoge-
nizer is accelerated as a consequence of the increased
effective surface area of solid base in addition to the
high speed mixing.
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Re-
search from MEXT, Japan. We thank Prof. Hideki Yamochi
(Kyoto University) for taking SEM images.
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Rate Acceleration of Solid-Liquid Phase-Transfer Catalysis
by Rotor-Stator Homogenizer
5
Adv. Synth. Catal. 2016, 358, 1 – 5
Taichi Kano, Yusuke Aota, Keiji Maruoka*
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