L. Yasmin et al. / Tetrahedron Letters 55 (2014) 2246–2248
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contrast with the confined mode which is not residence time
dependent. In the confined mode of VFD processing, as the
10 mm diameter tube containing a finite volume of liquid rotates,
a dynamic thin fluid film forms on the wall of the tube where there
is intense shear, at least for tilt angles h > 0°. The average thickness
of the fluid film depends on the processing parameters, including
rotational speed, h and the volume of the liquid.25 The present
work focuses on using the confined mode of operation of the
VFD to promote Diels–Alder reactions involving anthracenes and
maleimides, establishing the ability to effect the reactions in media
with a high mole fraction of water, without the need for catalysts,
and with relatively short reaction times.
Scheme 1. Diels–Alder reaction for optimizing the VFD operating parameters.
Initially, our efforts were directed at the typical cycloaddition
reaction between 9-hydroxymethylanthracene (1a) and N-phenyl-
maleimide (2a) in water. For reasons of cost, safety, and environ-
Table 1
Reaction conditions for preparing cycloadduct 3a
Entry
Temp
Time
Solvent
Reaction
modea
Conversion
(%)
mental concerns, water is
a desirable solvent for chemical
(°C)
(min)
reactions, and the study of organic reactions in aqueous solvent
has an intriguing history.27 The pioneering work of Breslow et al.
established that Diels–Alder reactions proceed faster (as high as
700-fold) and have a higher endo/exo selectivity in water than in
organic solvents.10 The small size and high polarity of water mole-
cules, as well as the three-dimensional hydrogen bonded network
system of bulk water, provide some unique properties which in-
clude a large cohesive energy density, high surface tension, and a
hydrophobic effect.28 These unique properties are believed to be
responsible for the rate and selectivity enhancements of Diels–Al-
der reactions. The main difficulty of the above reaction was the low
solubility of the anthracene in water, which was addressed by the
addition of a suitable alcohol as a co-solvent, ca. 10%. The effect of
addition of different alcohols has been studied extensively by Blok-
zijl et al.29,30 They reported that a number of Diels–Alder reactions
show an increase in rate upon addition of small amounts (a few
mol %) of suitable alcohols. This trend has been explained by
assuming an enhancement of hydrophobic interactions in such
media. The alcohol molecules are expected to promote the water
structure, which in turn favors the entropic contribution of hydro-
phobic interactions.31 Breslow et al. also studied the reaction be-
tween substituted 9-hydroxymethyl-anthracene and maleimides
in alcohol–water mixtures, establishing that a small amount of
an alcohol co-solvent does not interfere with the ability of water
to solvate ionic transition states (activated complexes), but that
the co-solvent is recruited to help solvate the hydrophobic por-
tions. The induced solubility perturbations reflect the solvation of
the reactants by the co-solvent. Overall, they successfully corre-
lated the rate constant with the solubility of the starting materials
for each Diels–Alder reaction. From these relations the change in
solvent accessible surfaces between initial state and activated
complex was estimated.31 Fujita et al.15 described the same reac-
tion of 1a and 2a using a self-assembled coordination cage which
decreased the entropic cost of the reaction. Unfortunately, using
either a batch or control experiment at 90 °C for 5 h in water, re-
sulted in incomplete reaction with only trace amounts of product
formed.15
1
2
3
4
5
6
90
50
50
50
60
50
60
10
20
30
10
30
H2O
VFD
VFD
VFD
VFD
VFD
Batch
0
67
78
91
70
15
H2O/EtOHb
H2O/EtOHb
H2O/EtOHb
H2O/EtOHb
H2O/EtOHb
a
VFD is in the confined mode, at 45° tilt angle, and 7000 rpm.
10% ethanol in water.
b
resulted in almost 67% conversion into the cycloadduct 3a (deter-
mined by 1H NMR spectroscopy). The reaction time was then in-
creased from 10 min to 30 min (entries 3 and 4) and the percent
conversion into product gradually increased up to 91%. When the
reaction temperature was increased from 50 °C to 60 °C for
10 min, we observed only a slight increase in conversion 70% to
3a (entry 5). As a control, we conducted the best replicated reac-
tion conditions (entry 4) in a batch mode process and interestingly,
only a very low conversion was observed (entry 6). It is noteworthy
that in every case we produced only the central 9,10-cycloadduct,
with no evidence for any terminal 1,4-cycloadduct.
Inside the reaction tube of the VFD both centrifugal and gravi-
tational forces are active at the 45° tilt angle. According to fluid
dynamics, Stewartson/Ekman layers are formed in the thin films
created at this angle.18 The intense shear layers in dynamic thin
film accelerate the Diels–Alder reaction which results in higher
yields of 3a. The choice of rotating speed of the VFD is also impor-
tant for promoting this reaction. In previous studies,25 we reported
that a higher speed favors the progress of organic reactions, but
interestingly, here we found changing the speed had little effect
on the reaction outcome (Fig. 1). Indeed for a tilt angle of 45° the
yield increases as speed increases, to almost quantitative conver-
sion at 5000 rpm, with then a slight reduction for even higher
speeds. This discontinuity is becoming evident for a number of
applications of the VFD, including a discontinuity for the simple
dimerization of cyclopentadiene, although this is in the absence
of any solvent.25 Clearly this is a special phenomenon which war-
rants a detailed understanding of the fluid dynamics and will fea-
ture in a separate study.
Use of the VFD to prepare 3a from the starting materials 1a and
2a was investigated (Scheme 1). A 10 mm diameter glass tube with
a cap was used to carry out the reaction in the confined mode. The
reaction parameters of speed and tilt angle for VFD were fixed at
7000 rpm and 45°, respectively, which were optimized processing
parameters for previous studies on the use of the VFD in organic
reactions.25 Experimentally, the substrates 1a and 2a were mixed
together in water or water with a small mole fraction of ethanol,
and the temperature and reaction time were varied to optimize
the conversion. We first took both reactants 1a and 2a in water
in the VFD at 50 °C for 1 h. However, this resulted in incomplete
formation of 3a (Table 1, entry 1). On the other hand, a 9:1
water/ethanol solvent system at 50 °C for 10 min (entry 2),
After establishing the optimized results for 9-hydroxymethyl-
anthracene and N-phenylmaleimide, the scope of the Diels–Alder
reactions for different 9-substituted anthracenes and different N-
substituted maleimides was investigated (Scheme 2 and Table 2).
Overall the results showed that there was high conversion into
the expected 9,10-cycloadducts 3b-i, except for 9-carboxylic acid
anthracene 3j. It may be the presence of the electron-withdrawing
carboxylic acid moiety on the anthracene ring that inhibits this
reaction.
In summary, we have developed a highly efficient and more be-
nign methodology using a high mole fraction aqueous medium
with ethanol in a microfluidic platform for Diels–Alder reactions,
Yasmin, Lyzu
