Phase-transfer catalysis: Mixing effects in continuous-flow liquid/liquid O-and S-Alkylation processes

Article abstract of DOI:10.1055/s-0033-1339839

This article describes detailed studies on the importance of mixing effects in the O- and S-alkylation of selected phenol and thiophenol substrates. Direct comparison between various continuous-flow reactors and a batch microwave reactor demonstrates the

Full text of DOI:10.1055/s-0033-1339839

LETTER
▌2393
letter
Phase-Transfer Catalysis: Mixing Effects in Continuous-Flow Liquid/Liquid
O- and S-Alkylation Processes
Mixing Effects in Phase-Transfer-Catalyzed O- and S-Alkylations
Benedikt Reichart, C. Oliver Kappe,* Toma N. Glasnov*
Christian Doppler Laboratory for Flow Chemistry (CDLFC) and Institute of Chemistry, University of Graz, Heinrichstrasse 28, 8010 Graz,
Austria
Fax +43(316)3809840; E-mail: toma.glasnov@uni-graz.at; E-mail: oliver.kappe@uni-graz.at
Received: 05.08.2013; Accepted after revision: 22.08.2013
Abstract: This article describes detailed studies on the importance
of mixing effects in the O- and S-alkylation of selected phenol and
thiophenol substrates. Direct comparison between various continu-
ous-flow reactors and a batch microwave reactor demonstrates the
excellent mixing properties of the flow devices, which improve the
reaction outcome.
Key words: O- and S-alkylation, phase-transfer catalysis, ethers,
continuous-flow, mixing
The general concept of using liquid-liquid biphasic condi-
tions for the synthesis of different O- and S-alkylated
ethers is a well-established technique in phase-transfer
catalysis1 and one of the most widely used synthetic meth-
ods for the alkylation of phenols2–4 and thiophenols.5–7
Undoubtedly the main benefits are the use of inexpensive
inorganic bases and the ease of purification of the prod-
ucts via simple phase separation and solvent removal.
Toma N. Glasnov received his Ph.D. (2007) from the University of
Graz, Austria, under the supervision of Professor C. Oliver Kappe
working on microwave-assisted organic synthesis. After a short-term
stay at Evotec Ltd. (UK), he returned to Graz to continue his research
as a post-doctoral fellow at the Christina Doppler Laboratory for
Microwave Chemistry for the next five years. As of the beginning of
2013 he is an Assistant Professor at the same Institute and the leader
of the Christian Doppler Laboratory for Flow Chemistry. His current
research interests are in the area of process intensification of chemical
reactions, applying microwave or continuous-flow approaches. Addi-
tional research fields include the preparation and scaffold decoration
of biologically active heterocycles, transition-metal-catalyzed reac-
tions and the synthetic applications of enamines.
It is important to emphasize that at least two steps are in-
volved in the catalytic sequence of each phase-transfer re-
action. The initial step is the net rate of anion delivery in
an active form into the phase of reaction, commonly the
organic phase. Subsequently the ‘organic phase displace-
ment reaction step’ will take place and result in the desired
product. A valuable phase-transfer-catalyzed process tra-
ditionally requires high reaction rates in both steps and the
overall reactivity reaches a steady state level when the
‘transfer step’ and the ‘intrinsic organic reaction step’ are
equal.1,8
yields and short reaction times.9 Regardless of aforemen-
tioned advantages, there are only a few publications deal-
ing with liquid-liquid biphasic reactions in microreactor
devices.2–6,10–13 In a recent study by Kobayashi’s group in-
volving the tetrabutylammonium bromide (TBAB) cata-
lyzed alkylation of a β-ketoester, an increase in yield from
49% (batch) to 75% (glass micromixer) was promoted by
using a suitable microreactor.10
Employing microreactor systems for liquid-liquid bipha-
sic reactions in organic synthesis offers attractive benefits,
including maximization of both mass transfer rate and re-
action rate via a significant increase of interfacial area
generated by the intense mixing and segmented flow in
continuous-flow (CF) devices. When organic and aqueous
phases, with high interfacial tension, are mixed via a T-
piece a segmented flow-type pattern is created and thus a
large specific interfacial area is formed. Additionally, us-
ing the fact that within each formed segment the interac-
tion of the liquid with the channel walls will create a fluid
vortex and as a result continuously refreshes the interface
between the two phases, efficient liquid-liquid biphasic
phase-transfer processes can be performed with high
Herein, we present a study on the mixing efficiency of
three different types of continuous-flow devices in the O-
and S-benzyl ether formation employing two model sub-
strates, 4-tert-butylphenol and 2,4,6-trimethylthiophenol
(see Scheme 1). For the initial optimization and a direct
comparison, microwave (MW) batch experiments are also
described.
As a good starting point for our studies the phase-transfer-
catalyzed benzylation of 4-tert-butylphenol was consid-
ered as an appropriate model reaction.2,3 In general, the
use of TBAB assures consistently good results in various
SYNLETT 2013, 24, 2393–2396
Advanced online publication: 13.09.2013
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6
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5
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1
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1
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3
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DOI: 10.1055/s-0033-1339839; Art ID: ST-2013-B0752-L
© Georg Thieme Verlag Stuttgart · New York

2394
B. Reichart et al.
LETTER
Next, we focused our attention toward transferring the
MW reaction conditions into a flow process, aiming to
further enhance the reaction profile. Compared to conven-
tional batch reactors, lab-scale flow equipment with
small-diameter channels or capillaries offers enhanced
heat and mass transfer and allows safer operation of reac-
tions in an extended range of temperatures and/or pres-
sures.15 Rapid mixing and excellent heat transfer
performance can be easily maintained at higher produc-
tion scale as well.15a,16 Three different types of continu-
ous-flow reactor setups were tested: a stainless steel coil
reactor, a packed bed reactor (filled with stainless steel
beads) and a glass chip microreactor (see Figure 1). All of
them were connected with a lab-scale continuous-flow
system (Syrris ASIA)17 equipped with two syringe pumps,
two sample loops (5 mL volume each) and a back pressure
regulator (for a detailed description of the reactor setup
and experimental details see the Supporting Information).
Following the ‘microwave-to-flow’ paradigm,18 the al-
ready optimized MW conditions were directly translated
into a continuous-flow protocol, assuring identical reac-
tion conditions. To our satisfaction, all three different
flow setups performed excellently, resulting in more than
93% conversion (Table 1, entries 6–8) as compared to the
77% conversion in the MW experiments, thus confirming
the superior mixing properties of the continuous-flow
equipment. For ease of experimentation, the stainless steel
beads (60–125 μm) filled reactor was used in several fur-
ther experiments. Unfortunately, all attempts to decrease
the amount of TBAB resulted in a decreased conversion
similar to the batch MW experiments. Nevertheless, the
benzyl ether formation while using only 2.5 mol% or 1
mol% of PTC was considerably higher as compared to the
identical batch MW reaction (Table 1, entry 3 vs. entry 9
and entry 4 vs. entry 10). Higher temperatures resulted in
increased amounts of unidentified side products in both
MW and CF experiments.
OH
BnBr (1.2 equiv)
TBAB (5 mol%)
O
CH2Cl2–H2O, 70 °C, 10 min
BnBr (1.2 equiv)
TBAB (0.2 mol%)
SH
S
CH2Cl2–H2O, 70 °C, 2 min
Scheme 1 Formation of O- and S-benzyl ethers
phase-transfer-catalyzed reactions.1 Therefore we decided
to use TBAB as a standard phase-transfer catalyst (PTC)
for the O- and S-alkylation reactions. For the initial batch
experiments a small-scale sealed-vessel microwave reac-
tor (Biotage Initiator 8)14 was used (see Table 1, entries 1–
5). In a control experiment, omitting TBAB, benzyl bro-
mide, sodium hydroxide and 4-tert-butylphenol were
mixed with a water–dichloromethane (1:1, 4 mL) mixture
(Table 1, entry 1), leading to only 5% conversion (HPLC,
 = 215 nm) after processing, thereby demonstrating the
importance of the PTC for the process. In contrast to the
control experiment, using 5 mol% of TBAB led to a 78%
conversion to the expected product, while the use of less
TBAB (2.5 mol%) led to a decreased conversion of 39%
(Table 1, entries 2 and 3). Interestingly, increasing the re-
action temperature to 120 °C and concomitantly reducing
the amount of PTC to only 0.2 mol%, a 76% conversion
of 4-tert-butylphenol into the corresponding benzyl ether
could still be achieved (Table 1, entry 5). Apparently, in-
creasing the reaction temperature to some extent allows a
reduction of the PTC while maintaining good conversion.
For our investigations under continuous-flow we decided
to use 5 mol% of TBAB, 70 °C reaction temperature and
10 minutes of reaction (residence) time as optimal reac-
tion conditions.
Table 1 Phase-Transfer O-Alkylation of 4-tert-Butylphenol
Entrya
Methodb
Temp (°C)
Time (min)
TBAB (mol%) Product (%)c Side products (%)c
1
2
MW
70
70
10
10
10
5
0
5
78
39
19
76
94
94
93
58
50
1
1
1
1
9
1
1
1
1
5
MW
5
3
MW
70
2.5
1
4
MW
90
5
MW
120
70
10
10
10
10
10
5
0.2
5
6
coil
7
chip
70
5
8
packed bed microreactor
packed bed microreactor
packed bed microreactor
70
5
9
70
2.5
1
10
90
a All results are mean values of at least triplicate experiments.
b For detailed information see the Supporting Information.
c HPLC conversions measured at λ = 215 nm.
Synlett 2013, 24, 2393–2396
© Georg Thieme Verlag Stuttgart · New York

LETTER
Mixing Effects in Phase-Transfer-Catalyzed O- and S-Alkylations
2395
Table 2 Phase-Transfer S-Alkylation of 2,4,6-Trimethylbenzene-
thiol
Entrya Methodb,c
Temp Time TBAB Product
(°C) (min) (mol%) (%)d
1
2
MW
70 10
100 10
70 10
0
7
23
MW
0
3
MW
5
100
26
Figure 1 Different continuous-flow setups, using (a) packed bed mi-
croreactor (filled with stainless steel beads), (b) stainless steel coil or
(c) static glass mixer
4
MW
70
70
70
70
70
90
70
2
2
2
2
2
2
2
0.2
0.2
0.2
0.2
0.1
0.1
0
5
coil
82
6
chip
91
Next, we turned our attention to the S-alkylation of 2,4,6-
trimethylthiophenol. As thiophenols tend to be more reac-
tive compared to phenols, we also expected to find a high-
er sensitivity to the changes in the reaction conditions,
related to the amount of PTC as well as to the mixing pro-
files in MW batch and CF reactions. Starting traditionally
with the MW batch optimization, several control experi-
ments in the absence of a PTC were performed (Table 2,
entries 1 and 2). Working at 70 °C and after 10 minutes re-
action time, only 7% of the corresponding thioether was
observed (HPLC, λ = 215 nm). At 100 °C, however, the
reaction proceeded further to 23% conversion, even in the
absence of TBAB. Applying the previously optimized
conditions for the O-alkylation and just altering the base
from sodium hydroxide to potassium carbonate resulted in
a quantitative transformation (Table 2, entry 3).19 Interest-
ingly, no side product formation was observed in this
case. Reducing both the reaction time (2 min) and the
amount of PTC (0.2 mol%) resulted in only 26% conver-
sion in the MW batch experiment (Table 1, entry 4). To
our surprise, transferring the conditions into the CF equip-
ment resulted in >82% of benzyl thioether. Notably, the
specific mixing characteristics in the three different mi-
croreactors did influence the outcome of S-alkylation in
contrast to the previously performed O-alkylation. At this
point the packed bed microreactor flow experiment per-
formed superior (100% conversion; Table 2, entry 7)
compared to the stainless steel coil and glass chip reactors
(82% and 91%, respectively; Table 2, entries 5 and 6) un-
der otherwise identical conditions. Reducing the amount
of TBAB to 0.1 mol%, while keeping the temperature
constant, produced a slight drop to 97% of conversion.
This could be avoided by increasing the temperature to 90
°C (Table 2, entries 8 and 9). The ‘soft’ 1,3,5-trimethyl-
thiophenoxide anions seem to be more reactive and were
able to cross the liquid-liquid interfacial barrier into the
organic phase more easily as compared to the ‘hard’ 4-
tert-butylphenoxide anions. We strongly believe that this,
in conjunction with the intense mixing and high interfacial
areas created by the stainless steel bead filled CF reactor,
caused the gain in efficiency and reaction rate. This effect
can also be utilized to run the S-alkylation completely
without the addition of any TBAB (Table 2, entries 10–
12).
7
packed bed microreactor
packed bed microreactor
packed bed microreactor
packed bed microreactor
packed bed microreactor
packed bed microreactor
100
96
8
9
100
20
10
11
12
70 10
0
57
100 10
0
84
a All results are mean values of at least triplicate experiments.
b CAUTION: malodorous smell can cause nausea and unconscious-
ness.
c For detailed information see the Supporting Information.
d HPLC conversions measured at λ = 215 nm.
In conclusion, we have demonstrated the advantages of
using continuous-flow technology in the O- and S-alkyl-
ations of phenols and thiphenols. The simple concept of
using efficient mixing and high interfacial areas in phase-
transfer-catalyzed liquid-liquid reactions resulted in sig-
nificant rate enhancements with drastic decrease in the
amount of used PTC under continuous-flow conditions.
Acknowledgment
This work was supported by a grant from the Christian Doppler Re-
search Society (CDG).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
References and Notes
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2393–2396

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LETTER
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(19) Synthesis of 1,3,5-Trimethyl-2-[(phenylmethyl)thio]-
benzene:
A: Batch Microwave Conditions: Into a 5-mL microwave
Pyrex process vial equipped with a magnetic stir bar organic
stock solution A (2 mL; 0.2 M 2,4,6-trimethylthiophenol and
0.24 M benzyl bromide in CH2Cl2) and aq stock solution D
[2 mL; 0.6 M K2CO3 and 0–2 mM (0–1 mol%) TBAB] were
placed. The vial was sealed with a Teflon septum fitted in an
aluminum crimp top and heated in the microwave reactor for
1–10 min (fixed hold time) at 70–100 °C (3–18 bar). After
cooling to 45 °C, the reaction mixture was immediately
quenched with 2 M aq HCl to reach pH <2. After 2 min of
vigorous stirring the aqueous phase was separated via
syringe and 10 μL aliquots of the organic phase were
subjected to HPLC analysis (λ = 215 nm). 1,3,5-Trimethyl-
2-[(phenylmethyl)thio]benzene was isolated by phase
separation from the basic aqueous phase, followed by H2O
extraction (3 ×). The obtained organic phases were
combined, dried over MgSO4, filtrated and concentrated
under vacuum to provide the S-benzyl ether (88 mg, 91%
yield, yellowish plates); mp 35–36 °C (lit.3: mp 36 °C). MS
(APCI, –): m/z = 242.1 [M+], 241.1 [M+ – 1], 151.1 [M+ –
91]. 1H NMR (300 MHz, CDCl3): δ = 2.28 (s, 3 H), 2.37 (s,
6 H), 3.78 (s, 2 H), 6.92 (s, 2 H), 7.08–7.11 (m, 2 H), 7.22–
7.25 (m, 3 H).
B: Continuous Flow Conditions: For details please see the
provided Supporting Information.
Synlett 2013, 24, 2393–2396
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