Highly selective Friedel-Crafts monoalkylation using micromixing

Article abstract of DOI:10.1039/b211433j

Highly selective Friedel-Crafts monoalkylation of aromatic compounds with N-acyliminium ions has been achieved by efficient 1:1 mixing using a multilamination-type micromixer.

Full text of DOI:10.1039/b211433j

Highly selective Friedel–Crafts monoalkylation using micromixing†
Seiji Suga, Aiichiro Nagaki and Jun-icih Yoshida*
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto
University, Sakyo-ku, Kyoto 606-8501, Japan. E-mail: yoshida@sbchem.kyoto-u.ac.jp;
Fax: +81-75-753-5911; Tel: +81-75-753-5651
Received (in Cambridge, UK) 19th November 2002, Accepted 6th December 2002
First published as an Advance Article on the web 20th December 2002
Highly selective Friedel–Crafts monoalkylation of aromatic
compounds with N-acyliminium ions has been achieved by
efficient 1+1 mixing using a multilamination-type micro-
mixer.
consisting of the lamellae of the two fluids is generated by
means of the slit-shaped interdigital channel. Then, the
lamellated flow leaves the device perpendicular to the direction
of the feed flows. The reaction of the N-acyliminium ion 2 with
aromatic compound 3 using the micromixer was carried out as
follows. The solutions of 2 (produced from 1.2 equiv. of 1)11
and 3 were introduced to the mixer by syringe pumping
technique (flow rate: 5.0 mL min21) at 278 °C and the product
solution that left from the device was immediately quenched
with triethylamine in order to avoid further reactions.12 To our
surprise, the monoalkylation product 4 was obtained in
excellent selectivity, and the amount of dialkylation product 5
was extremely small (4+5 = 96+4, total yield 96%). A T-shaped
tube mixer (f = 500 mm) was also examined, but the selectivity
was essentially the same as the batch reactor.
Microreactors (miniaturized chemical reactors)1are expected to
make a revolutionary change in chemical synthesis2 from both
academic and industrial viewpoints.3 With the advancement of
microfabrication technology, development of new synthetic
methodologies based upon the inherent features that exist at the
micrometer scale is strongly needed. It is generally expected
that extremely fast and exothermic reactions can be conducted
in a highly controlled manner in micro-structured reactors by
virtue of the advantages of efficient mixing and heat transfer.
Thus, we have examined the reaction of N-acyliminium ion
pools,4 which has been developed by our group as a highly
reactive species toward various nucleophiles, using a micro-
structured device. We chose Friedel–Crafts type alkylation
reactions of aromatic compounds5 because the use of a
conventional macro-scale batch reactor usually leads to the
formation of significant amounts of polyalkylation products
together with a desired monoalkylation product.6 We envi-
sioned that efficient 1+1 mixing using a micro-scale mixer7
would facilitate the selective formation of a monoalylation
product.8
N-Acyliminium ion 2 is generated by the anodic oxidation9 of
carbamate 1 having a silyl group as an electroauxiliary10 in
CH2Cl2 and is stable in the absence of a nucleophile as shown
in Scheme 1.
Prior to using a micromixer, the reaction using a conventional
batch reactor was examined. The addition of 2 (produced from
1.2 equiv. of 1)11 to aromatic compound 3 resulted in the
formation of an essentially 1+1 mixture of monoalkylation
product 4 and dialkylation product 5 (Scheme 2). The reverse
addition and the simultaneous addition of the solution of 2 and
that of 3 to a batch reactor also gave essentially the same results.
These observations indicated that it is quite difficult to avoid
dialkylation using a conventional batch reactor presumably
because of inefficient mixing.
Scheme 2
To effect the desired efficient 1+1 mixing for monoalkyla-
tion, we used a multilamination-type micromixer produced by
IMM (Institut für Mikrotechnik Mainz GmbH) as shown in Fig.
1. In this micromixer the fluids to be mixed are introduced into
the mixing element as two counter-flows and the fluids stream
into an interdigital channel (channel width = 25 mm) configura-
tion. In the next stage, a periodical flow configuration
Scheme 1
† Electronic supplementary information (ESI) available: experimental
section. See http://www.rsc.org/suppdata/cc/b2/b211433j/
Fig. 1 Schematic diagram of mixing using an IMM micromixer (channel
width = 25 mm).
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This journal is © The Royal Society of Chemistry 2003

The amount of 2 is crucial for the selectivity. The use of 1.2
equiv. of precursor 1 gave the best results.11 The use of 2.0 and
2.5 equiv. of 1 resulted in the formation of significant amount of
5 (4+5 = 79+21 and 67+33, respectively). Probably surplus 2
further reacted with 4 to give 5. The reaction temperature was
also found to be an important factor governing the selectivity.
With the increase of the temperature, the yield of 4 decreased
dramatically, whereas the yield of 5 increased as depicted in
Fig. 2. It is reasonable to consider that the present Friedel–
Crafts type alkylation using the extremely reactive N-acylimin-
ium ion seems to be very exothermic and that it is difficult to
control the reaction temperature by using a conventional macro-
scale reactor. In the case of a micromixer, however, precise
control of the temperature could be achieved by virtue of high
surface to volume ratio of micro-scale reactors.
The dramatic effect of the micromixing is generally observed
for the alkylation of other aromatic compounds with N-
acyliminium ion 2. The reaction of 2 with thiophene in the
micromixer took place smoothly to give the monoalkylation
product 6 exclusively, while the reaction in the batch reactor
gave significant amount of dialkylation product 7 as shown in
Scheme 3. A similar tendency was also observed for the reaction
of furan and N-methylpyrrole.13
The sequential alkylation reactions with two different
alkylating agents were also achieved. The first alkylation was
carried out with N-acyliminium ion 2 using the micromixer to
obtain the monoalkylation product 6 (X = S), which was
directly subjected to the second alkylation with a different N-
acyliminium ion 8 in a batch reactor to obtain dialkylation
product 9 (Scheme 4).
Therefore, the present method provides a simple and
straightforward method for the selective introduction of two
different alkyl groups on an aromatic ring.
Scheme 4
potential for using micromixing to effect chemical transforma-
tions that are difficult using more conventional chemical
methods. It is hoped that numerous reactions of this type can be
exploited in order to open new opportunities of chemical
synthesis in ‘micro-world’.
Notes and references
1 Ed. W. Ehrfeld, Microreaction Technology, Springer, Berlin, 1998; Eds.
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H. Warrington in Automated Synthetic Methods for Speciality Chem-
icals, ed. W. Hoyle, Royal Society of Chemistry, 1999, p. 26; W.
Ehrfeld, V. Hessel and H. Löwe, Microreactors, Wiley-VCH, Wein-
heim, 2000; K. F. Jensen, Chem. Eng. Sci., 2001, 56, 293.
2 H. Salimi-Moosavi, T. Tang and D. J. Harrison, J. Am. Chem. Soc.,
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In summary, micromixing provides a solution to Friedel–
Crafts polyalkylation problem that complicates the conven-
tional reactions. The present observations nicely illustrate the
3 Reviews: For example: S. H. DeWitt, Curr. Opin. Chem. Biol., 1999, 3,
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Fig. 2 Temperature effect of the reaction of 2 with 3.
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11 The yield of 2 based on 1 is estimated as ca. 80% as judged by the yield
of the reaction of 2 with excess allyltrimethylsilane, which is a highly
reactive carbon nucleophile. Therefore, 1.2 equiv. of 1 was used. In
these mixing experiments a 0.05 M solution of 2 (based on 1) in CH2Cl2
and a 0.042 M solution of 3 in CH2Cl2 at 278 °C were quickly
transferred to syringes which were kept cool with dry ice and
immediately introduced to a micromixer cooled at 278 °C. Decomposi-
tion of 2 was thus avoided.
12 The separate reaction of 2 with triethylamine gave rather inactive
species that did not give the allylated product upon treatment with
allyltrimethylsilane, although the details are not clear at present.
Triethylamine might also suppress the acid-promoted decomposition of
the product.
13 A mixture of 2- and 3-substituted product (ca. 2+1) was obtained in the
reaction of N-methylpyrrole. In cases of thiophene and furan 2-substi-
tuted products were obtained selectively.
Scheme 3
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