Effect of reaction parameters on the synthesis of 5-arylidene barbituric acid derivatives in ball mills

Article abstract of DOI:10.1021/op5003787

The influence of crucial reaction parameters on Knoevenagel condensation in planetary ball mills was investigated. Rotation frequency (ν_rot), milling ball diameter (d_MB), milling ball filling degree (φ_MB), and beaker size

Full text of DOI:10.1021/op5003787

Article
pubs.acs.org/OPRD
Effect of Reaction Parameters on the Synthesis of 5‑Arylidene
Barbituric Acid Derivatives in Ball Mills
Robert Schmidt,† Christine F. Burmeister,‡ Matej Balaz,§ Arno Kwade,‡ and Achim Stolle*,†
́
̌
†Institute for Technical Chemistry and Environmental Chemistry (ITUC), Friedrich-Schiller University Jena, Lessingstraße 12,
D-07747 Jena, Germany
‡Institute for Particle Technology (IPAT), Technical University Braunschweig, Volkmaroder Straße 5, D-38104 Braunschweig,
Germany
§Institute of Geotechnics, Slovak Academy of Sciences, Watsonova 45, 04001 Kosi
̌
ce, Slovac Republic
S
* Supporting Information
ABSTRACT: The influence of crucial reaction parameters on Knoevenagel condensation in planetary ball mills was investigated.
Rotation frequency (νrot), milling ball diameter (dMB), milling ball filling degree (ΦMB), and beaker size had obvious influences on
yield. It was found that higher νrot, lower dMB, milling beakers with larger diameter, and a ΦMB of ∼0.3 are advantageous for the
reaction. Furthermore, the influence of the type of mill was investigated, including reactions performed in different planetary and
mixer ball mills, in a stirred media mill, and with a mortar mill. Comparisons with the other solvent-free synthetic routes showed
that ball milling is an effective way of performing the reaction with low energy intensity.
Scheme 1. Generic Reaction Scheme of the Knoevenagel
Condensation
INTRODUCTION
■
The use of mechanical stress for the accomplishment of
mechanochemical reactions is now an established field of
research represented by a huge number of reactions in different
fields of organic, inorganic, and organometallic chemistry and
materials science.1 In all cases, mechanical stress is provided to
the reactants, whereby the energy input can be realized in
different ways. The easiest but imprecise way is to use a mortar
and pestle.2 Results that are more reliable can be obtained with
different types of ball mills, such as planetary (PBMs) or mixer
ball mills (MBMs). The results of organic reactions in ball mills
are subject to several influencing parameters, especially the
influence of rotation frequency (νrot), milling time (t), and
number of milling balls (nMB).3 Although a large number of
synthesis protocols have been published, parameters such as the
3c,d,4
milling ball diameter (dMB
)
and beaker size5 have received
To investigate the influence of different milling and grinding
apparatuses, three different types of PBMs, an MBM, a stirred
media mill (SMM), an MM, and a mortar and pestle were used.
The main differences between the PBMs are the diameter of
less attention. Furthermore, comparative studies on reactions in
different types of mills are rare.2,6 However, the kind of mill
utilized can strongly influence the outcome of a reaction. For
example, Schneider et al. investigated the Suzuki−Miyaura
reaction in two types of PBMs and one MBM.2 The reaction
proceeded well in the PBMs at 300 min−1, whereas in the MBM
at the same frequency only low yields were observed. Wang and
co-workers investigated pinacol couplings in an MBM and a
mortar mill (MM).6a Although mechanical energy is supplied in
both mill types, higher yields of the pinacol coupling product
were obtained in an MM.
We have recently investigated the influence of several
reaction parameters on the yield of a Knoevenagel
condensation of vanillin (1a) and barbituric acid (2a) (Scheme
1) in a planetary ball mill aiming to close this knowledge gap,5
including questions regarding the influence of beaker size,
geometry, and the way the mechanical energy is provided. To
this end, Knoevenagel condensation was performed using
various tools for allocating mechanical stress.
the main disc (dMD), the speed ratio (r), the maximal νrot,max
,
the maximal volume of the milling beaker (VMV,max), and the
number of milling beakers (nMV) that can be applied (Table 1).
PBM P7 offers the application of two milling beakers, and in
PBM P5 four milling beakers can be utilized, in contrast to
PBM P6 in which only one milling beaker can be installed. The
used MBM offers two positions for milling beakers whereby
their maximal volume is limited to 50 mL. The maximal
oscillation frequency (νosc,max) is 1800 min−1 (≙ f = 30 Hz).
Several reaction parameters were investigated and will be
discussed for the different types of ball mills. The reactions
performed by milling were compared to other solvent-free
Received: December 3, 2014
Published: February 19, 2015
© 2015 American Chemical Society
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minimum reaction time was observed at 650 min−1. For
experiments with 20 mm milling balls, t97% was decreased by a
factor of 4 when νrot was increased from 450 to 650 min−1.
Influence of Milling Ball Diameter (dMB). Milling balls are
available in a large number of different diameters ranging from
0.20 to 30 mm. The question is what size is best for organic
reactions in ball mills. The size of the milling balls is directly
correlated to the energy input, as larger milling balls refer to a
larger mass of single balls, leading to higher kinetic and stress
energy.10 If the number of milling balls is constant, using
smaller milling balls leads to decreased impact energy, and
lower yields are observed.3c,d However, at a constant milling
ball filling degree (ΦMB), a smaller dMB is equivalent to a larger
number of milling balls (nMB). This leads to an increased
chance for collision of the milling balls expressed by an
increased number of stress events and, in the end, a higher
yield.11 The results in Figure 2a show that at a constant milling
ball filling degree, smaller milling balls accelerate the reaction.
Quantitative yields for 30 mm milling balls were achieved after
40 min; this milling time could be reduced to 25 and 20 min
using 20 and 10 mm milling balls, respectively. The results
confirm that smaller milling balls are favorable over larger
milling balls and should be used for this type of reaction. In
Figure 2b, the dependence of the stress frequency (SF) and
stress energy (SE) from dMB is shown. SF is defined as the
number of stress events per second, and SE is the energy that is
supplied at each stress event.12 Larger milling balls lead to
higher SE but concurrently decrease the SF. In this case, the
increase in SE was less than the decrease in SF (e.g., the SF for
30 mm milling balls is ∼70-times lower than that of 10 mm
milling balls, whereas the SE is only 45-times higher). This
suggests that the stress energy of a single collision plays a minor
role, and that the process is mainly affected by the stress
frequency.
Influence of the Milling Ball Filling Degree (ΦMB). As
mentioned earlier, aside from the application of smaller milling
balls, the stress frequency can be increased by using a larger
number of milling balls. The milling ball filling degree
represents the volume of the milling balls relative to the beaker
volume. This important parameter influences not only the
stress frequency but also the trajectories of the milling balls to
affect the yield and the amount of heat dissipated by
friction.3a,c,10,13 Fang et al. investigated the influence of ΦMB
on temperature in a lysis mill and observed that the
temperature was maximum when 60% of the tube was filled
with milling balls.14 Visualized in Figure 3a, the results showed
that ΦMB is an important parameter in Knoevenagel
condensation in PBMs. Independent of the dMB, a minimum
for the milling time of approximately 0.25 ≤ ΦMB ≤ 0.3 was
observed in which a broader minimum could be identified for
the 10 mm balls. ΦMB that was either higher or lower than this
range led to decreased yields, and the milling time had to be
increased to reach similar conversion levels. If ΦMB was less
than optimal, the energy provided was reduced due to a lower
number of milling balls. This led to a reduced stress frequency,
and as the amount of substrate was constant, less energy was
transferred to the substrate (Figure 3b). On the other hand, ball
movement is hindered at high ΦMB values, meaning that the
milling balls have less acceleration and therefore the energy
input is reduced.15 The manufacturer advises that in 250 mL
milling beakers the recommended number of milling balls are
50 × 10 mm, 15 × 20 mm, and 6 × 30 mm balls, corresponding
to ΦMB of 0.1, 0.25, and 0.34, respectively.16 For the 20 and 30
Table 1. Specifications of the Planetary (PBM) and Mixer
Ball Mills (MBM) Utilized
dMD
[mm]
νmax
VMV,max
[mL]
type of ball mill
ra
[min−1
]
nMV
PBM P5
250
1:−2.19
1:−1.82
1:−2
400
500
500
80
4
1
2
2
PBM P6
121.6
140
650
b
PBM P7
1100
MBM MM400
1800
50
a
Defined as the ratio of the rotation speed of the pot to the revolution
b
speed of the main disk. The maximal value of νrot is dependent on
dMB
.
methods, whereas gentle grinding processes were supported by
means of classical or microwave-assisted heating.
RESULTS AND DISCUSSION
■
Reaction in PBM Pulverisette 6 (PBM P6). The influence
of several reaction parameters on the yield of the Knoevenagel
condensation of 1a with 2a was investigated in PBM P6. The
primary parameters chosen for this study are the rotation
frequency (νrot), milling ball filling degree (ΦMB), milling ball
diameter (dMB), and the size of the milling beakers.
Φ
MB was defined as the volumetric ratio of the overall milling
ball volume (VMB) to the total volume of the milling beaker
(VMV).
∑ VMB
VMV
ΦMB
=
(1)
Influence of the Rotation Frequency (νrot). The first
parameter that was investigated in PBM P6 was the rotation
frequency. This parameter directly influences the kinetic energy
of the milling balls and consequently the stress energy that is
transferred to the substrate. Furthermore, the temperature in
the milling beaker is increased due to friction.8 This is why νrot
was described to be the most important factor other than
reaction time for reactions in ball mills.3d In general, higher νrot
leads to higher yields, which has been confirmed for several
organic reactions.3d,e,6b,9 The results for the model reaction of
1a and 2a are presented in Figure 1. Whereas full conversion
was not observed within 60 min at 450 min−1, increasing νrot
led to a gradual decrease in the milling time to achieve
quantitative yields (t97%, hereafter defined as the time when the
yield is ≥97%), and full conversion could be already achieved at
550 min−1 after 30 min with 20 mm milling balls. The
Figure 1. Influence of νrot on t97%. Conditions: PBM P6, 250 mL steel
beaker, ZrO2-balls, ΦMB = 0.25, dMB = 20 mm, 100 mmol 1a, and 100
mmol 2a. Milling time t97% = time to reach yield ≥97%. At 450 min−1,
full conversion was not observed after 60 min.
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Figure 2. Influence of dMB on the yield of the model reaction (a) and the stress conditions (b). Conditions: PBM P6, 250 mL steel beaker, ZrO2-
balls, νrot = 650 min−1, ΦMB = 0.42 for dMB = 10 and 20 mm, ΦMB = 0.45 for dMB = 30 mm, 100 mmol 1a, and 100 mmol 2a.
Figure 3. Influence of ΦMB on t97% (a) and the stress conditions (b). Conditions: PBM P6, 250 mL steel beaker, ZrO2-balls, νrot = 650 min−1, 100
mmol 1a, and 100 mmol 2a. dMB = 10 mm in (b).
mm milling balls, these values are in accordance with the
observed minimums. For the 10 mm milling balls, the
manufacturers advice does not match with the optimal value
found here for the model reaction and would result in reduced
yields.
Influence of Beaker Size. Although a large number of
organic reactions have been performed in PBMs, the influence
of the beaker volume has not been investigated.2,17 However,
the geometry of the milling beakers influences the energy input
as shown by Mio and co-workers in milling experiments of
gibbsite powder.18 To investigate the influence of the beaker
size and geometry on the Knoevenagel condensation, we
performed the model reaction in five different milling beakers
in which the volume (VMV), inner diameter (dMV), and height
(hMV) of the beaker were varied. As can be seen in Table 2, with
increasing beaker volume, t97% decreases significantly with a
constant ΦMB and grinding stock filling degree ΦGS, which is
defined as the ratio of the bulk volume of the substrates and
V
mL beaker after 1 h, full conversion was achieved after 30 and
18 min in 250 and 500 mL beakers, respectively. Thus, VMV is
not the only parameter of importance, dMV and hMV also
influence yield. By keeping dMV constant and changing hMV, we
found that taller beakers led to slightly better results. Varying
MV.5 While no quantitative yields could be achieved in an 80
d
MV at a constant hMV showed that t97% decreases from 30 to 18
min when the diameter was increased from 75 to 100 mm.
An explanation of the results is that changes in diameter and/
or height lead to changes in the number of milling balls and
therefore to changes in the SF (eqs 2 and 3).11a In addition, the
energy input can be influenced by the curvature of the base of
the beaker, which differs among the equipment examined.8
nMB ∝ dM2 V and nMB ∝ hMV
(2)
SF ∝ nMB
(3)
Table 2. Influence of Beaker Size on Time to Reach
a
Quantitative Conversion (t97%
)
The kinetic energy of the milling balls is dependent on dMV
.
Ekin is given by the mass of a single milling ball (mMB), the
revolution radius (R), and the square of the angular velocity of
the revolution (Ω).10,18
SE
[10−4
J]
VMV
dMV
hMV
t97%
n1a and n2a hMV/
[mL] [mm] [mm] [min]
[mmol]
dMV
SF [s−1
]
80
65
75
24
69
80
45
69
>60
30
32
100
132
132
200
0.37
0.92
1.07
0.45
0.69
1.00
1.69
1.75
2.29
2.26
73252
227012
312022
279640
452894
1
Ekin
=
mMBv2 = mMBRΩ2dMB
250
330
330
500
(4)
(5)
2
75
30
100
100
25
Ekin ∝ SE
18
Therefore, if dMV changes, Ekin and ultimately the stress
energy (SE) will be influenced. Furthermore, discrete element
method (DEM) simulations show that milling beakers with the
a
Conditions: PBM P6, steel beaker, ZrO2-balls, ΦMB = 0.30, ΦGS
0.30, dMB = 10 mm, and νrot = 550 min−1.
=
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a
same volume but larger diameters have bulk changes in their
packing and higher velocities (see Supporting Information).
Figure 4 illustrates the dependence of the specific power on the
Table 3. Substrate Screening of the Model Reaction
entry
substrate 1
substrate 2
product 3
yield [%]
1
1a
1b
1c
1d
1e
1f
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
3a
3b
3c
3d
3e
3f
>97
>97
>97
82
2
3
4
5
85
6
>97
>97
>97
>97
>97
>97
>97
7
1a
1b
1c
1d
1e
1f
3g
3h
3i
8
9
10
11
12
3j
3k
3l
a
Conditions: PBM P6, 250 mL steel beaker, ZrO2-balls, ΦMB = 0.30,
dMB = 10 mm, νrot = 650 min−1, t = 20 min, 100 mmol 1, and 100
mmol 2.
Figure 4. Dependence of specific power on the geometry of the
milling beaker. Conditions: PBM P6, steel beakers of different
geometries (see Table 2), ZrO2-balls, ΦMB = 0.30, dMB = 10 mm, and
νrot = 550 min−1.
balls tended to be advantageous relative to larger ones.
Visualized in Figure 6a, the milling time to achieve quantitative
yields at a constant νrot was always lower for 2 than 5 mm balls,
except at 1000 min−1 where the reaction was completed within
10 min in both cases due to the high energy input. Regarding
ΦMB (Figure 6b), the results also indicate an optimum similar
to that in PBM P6, but the optimal value was slightly shifted to
a lower ΦMB of ∼0.2.
hMV/dMV ratio. The highest specific power is seen at 0.7 and
leads to the shortest reaction times. At a constant diameter and
different heights, the higher power is calculated for larger values
of hMV due to a higher SF. The SE is roughly the same when
dMV is equal.
Scope of the Reaction. The investigated model reaction was
successfully performed in PBMs with quantitative yields. Thus,
further cleanup is not necessary as the reaction proceeds
without side products. Figure 5 illustrates this finding by
The maximal νrot in PBM P5 is limited to 400 min−1, which is
considerably below the νrot in PBM P6 in which no quantitative
yields were obtained within 60 min at 450 min−1. Observing the
influence of the rotation frequency in PBM P5, we found that at
νrot = 300 min−1 after a milling time of 60 min, a yield of 15%
could be achieved (Figure 7). At 350 min−1, quantitative yield
was observed after 60 min, and at 400 min−1, the reaction was
completed after 30 min of milling time.
1
comparing the H NMR spectra of a commercially available
sample and the product obtained by ball milling in a PBM.
Comparison of Different Types of Ball Mills. Upon the
three investigated PBMs being compared, it is evident that the
reaction is transferable from one type of PBM to another.
Similar results for t97% were achieved, especially when νrot was
adjusted to the milling system. Figure 8 compares the results at
different values of νrot. In PBM P5, quantitative yields were
achieved after 30 min at 400 min−1. This corresponds to results
at 550 min−1 in P6 and 800 min−1 in PBM P7. Scholl et al.
reported similar results for the synthesis of Ti5Si3 in PBMs P5
and P6.6e The reason that comparable results can be obtained
at lower νrot in P5 is the higher diameter of the main disc
leading to increased energy input. Furthermore, the speed ratio
(r) is different and may influence the energy input as well.
Whereas Mio et al. reported that the specific impact energy and
ball motion depend on r, Rosenkranz and co-workers did not
observe a change in ball motion.7,13 The reaction in PBM P7
requires a comparably higher νrot due to the lower kinetic
energy based on the smaller inner diameter of the milling
beakers. Similar results and trends were observed with respect
to the influence of the investigated parameters νrot, dMB, and
1
Figure 5. Comparison of H NMR spectra of a commercial and ball
mill product 3a. (A) Sample obtained by ball milling and (B) the
commercial sample.
To enlarge the scope of reaction, we performed the
Knoevenagel condensation with several solid aldehydes and
barbituric acid (2a) with its 1,3-dimethyl derivative (2b) as the
CH acidic compound (Scheme 1). As one can see in Table 3,
quantitative yields were achieved in almost all cases. Only the
reactions of 2a with 1d or 1e had lower yields at 82 and 85%,
respectively.
Reactions in PBM P5 and P7. To investigate the influence
of the type of mill, the model reaction was performed in PBM
ΦMB.
Reactions in a Mixer Ball Mill (MBM). In MBMs, ball
movement is caused by horizontal or vertical oscillation of the
milling beakers, and therefore the trajectories of the milling
balls are different from those in PBMs (Figure 9). The energy is
mainly provided by impact and friction when the milling balls
collide into one another and with the cap of the milling beaker.
P5 and P7. The following results show the influence of νrot, dMB
,
and ΦMB for reactions in PBM P7. In general, similar behaviour
as in PBM P6 was observed.5 Figure 6 shows that the milling
time can be reduced by a factor 12 if νrot is increased from 600
to 1000 min−1. Furthermore, as in PBM P6, smaller milling
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Figure 6. Influence of νrot, dMB (a), and ΦMB (b) on t97% in PBM P7. Conditions: PBM P7, 45 mL steel beaker, and ZrO2-balls with (a) ΦMB = 0.26
and (b) νrot = 800 min−1, dMB = 10 mm, 20 mmol 1a, and 20 mmol 2a.
Figure 7. Influence of νrot on the model reaction in PBM P5.
Conditions: PBM P5, 250 mL steel beakers, ZrO2-balls, ΦMB = 0.29,
dMB = 10 mm, 100 mmol 1a, and 100 mmol 2a.
Figure 9. Schematic movement and construction of an MBM milling
beaker.
Figure 8. Dependence of t97% on νrot in three different PBMs.
Conditions for PBM P5 and P6: 250 mL steel beakers, ZrO2-balls,
Φ
MB = 0.29, dMB = 10 mm, 100 mmol 1a, and 100 mmol 2a. For PBM
P7: 45 mL steel beakers, ZrO2-balls, ΦMB = 0.21, dMB = 10 mm, 20
Figure 10. Influence of t and dMB on yield in an MBM. Conditions:
MBM MM400, 35 mL steel beaker, ZrO2-balls, ΦMB = 0.30, νosc = 30
Hz, 14 mmol 1a, and 14 mmol 2a.
mmol 1a, and 20 mmol 2a.
For reactions in MBMs, the same parameters as in PBMs are
important. The influence of the oscillation frequency (νosc) was
discussed for several reactions in the literature, indicating that
higher frequencies are beneficial as shown for PBMs.2,3b,f
However, the influence of other parameters, such as dMB and
and the yield increased slower with milling time. Analagous to
the reactions observed in PBMs, smaller milling balls
accelerated the reaction in the MBMs due to an increased
number of stress events.
In PBMs, the milling ball filling degree was revealed to be a
crucial parameter that strongly influenced the outcome of the
reaction. Therefore, reactions with different ΦMB were
performed in MBMs. As seen in Figure 11, at ΦMB = 0.06,
only low yields were achieved, and no full conversion was
observed after 60 min. Upon ΦMB being increased to 0.18, the
reaction was highly accelerated and quantitative yields could be
achieved within 40 min. At ΦMB = 0.3, t97% could be further
reduced, indicating that in the area of ΦMB = 0.06−0.3 higher
values for ΦMB are preferable. Handling of ΦMB > 0.3 was
difficult due to the geometry of the milling beakers (Figure 9).
Φ
MB, have rarely been analyzed for reactions in MBMs.3b,19 To
investigate the influence of reaction parameters on the model
reaction, we performed a Knoevenagel condensation of 1a with
2a in an MBM MM400 at 30 Hz with horizontal oscillation.
Figure 10 shows the influences of dMB and milling time.
Higher yields were observed at extended milling times.
Regarding dMB at a constant ΦMB, 5 mm milling balls led to
high yields within 30 min, and quantitative yields were observed
after 35 min of milling. In contrast, 10 mm milling balls yielded
the condensation product in quantitative amounts after 40 min,
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step for scaling up because SMMs can be equipped with
grinding chambers with volumes of several liters.
Reaction in a Mortar Mill (MM). Manual grinding by
mortar and pestle is a common way to deliver mechanical
energy to substrates and has been used for miscellaneous
organic reactions.21 However, this method has some disadvan-
tages, including safety aspects due to the open reaction system
and problems regarding scaling up the reaction. A significant
disadvantage is that the energy input is strongly dependent on
the strength and endurance of the experimenter such that
reproducibility and long reaction times are problematic. The
energy provided by mortar and pestle is generated by friction
and, in contrast to ball mills, impact is not a factor.
Performing the Knoevenagel reaction with mortar and pestle
showed only 11% conversion after 1 h of grinding. In additional
to the low yield, hand grinding for such long times is not very
practical. A way of avoiding some of the disadvantages of using
mortar and pestle is the application of a mortar mill (MM).6a
This automated version of hand grinding with a mortar and
pestle affords more reproducible results; the acting force can be
adjusted and is operator independent. As shown in Table 4, in
Figure 11. Influence of ΦMB in an MBM. Conditions: MBM MM400,
35 mL steel beaker, ZrO2-balls, dMB = 10 mm, νosc = 30 Hz, 14 mmol
1a, and 14 mmol 2a.
Part of the volume is located in the cap of the beaker. The
results of the reaction with ΦMB = 0.45 showed that because of
the reduced space for acceleration only low yields could be
achieved.
In MBMs and PBMs, t97% is in the same range for both types
of ball mills (see Figure 1). A transfer from PBM to MBM is
possible, and similar dMB and ΦMB effects are observed. In
contrast to the horizontal MBM shown above, MBMs can also
be operated with vertical oscillating milling beakers. In a vertical
a
Table 4. Comparison of Hand and MM Grinding
n1a and n2a [mmol] grinding time [min] yield [%]
manual grinding
MM
10
50
60
60
11
19
33
9
MBM Pulverisette 23 (15 mL steel beaker, 5 steel balls, dMB
=
10 mm), the condensation reaction of 1a and 2a was examined
at three operating frequencies. With νosc = 50 s−1, a yield of
80% was observed after a milling time of 60 min. For reactions
executed at 40 and 30 s−1, low yields of 10 and 8%, respectively,
were detected.
120
60
MM
100
120
13
a
Conditions: MM Pulverisette 2, mortar and pestle made of ZrO2, 200
Reaction in a Stirred Media Mill (SMM). Stirred media
mills are used for a broad scope of applications, especially for
fine and ultrafine grinding of materials. This type of mill
consists of a stationary grinding chamber and a rotating agitator
that hits and accelerates the milling balls.20 Two reactions were
performed with different setups. In the first experiment, the
stirrer speed was set to 500 min−1, but after 1 h of milling, only
low yields were observed. Therefore, in the second experiment,
the stirrer speed was increased in two steps to 1000 min−1 (5
min at 500 min−1, 5 min at 750 min−1, and then continuous
milling at 1000 min−1). In both cases, handling of the mixture
was difficult as the substrates partially stuck at the wall of the
grinding chamber over the course of the reaction, causing the
mixing efficiency to be reduced. However, high yields were
observed after 30 min (Figure 12). The successful transfer of
the reaction from a PBM to a stirred media mill is an important
N tangential force, and 100 N downforce.
an MM Pulverisette 2, 19% of product could be gained after 60
min, which could be increased to 33% after 120 min. By
doubling the initial amount of substrate, the yields decreased to
9 and 13% after 60 and 120 min, respectively. The advantage of
an MM compared to manual grinding with mortar and pestle is
evident. Higher yields could be achieved, and at the same yield,
the reaction could be scaled up by a factor of 10. However,
compared to reactions in PBMs and MBMs, no quantitative
conversion could be obtained in the examined time range;
reaction times had to be considerable longer to achieve
comparable yields. Thus, the energy provided is apparently not
enough to reach full conversion.
Grinding Reactions Supported by Thermal Heating
and Microwave Irradiation. Grinding reactions supported by
thermal heating (thermal-assisted grinding = TAG) were
performed in a water bath at 45 and 75 °C using a rotary
evaporator as the reactor. Mixing of the reactants was ensured
by rotating a round-bottom flask containing 2 mm glass milling
balls at 100 min−1.22 An additional reaction was performed in a
Rotaprep microwave reactor (microwave-assisted grinding =
MAG) with a rotating vessel and 220 g glass balls. In this case, 5
mL of water was added to the reaction mixture because the
reaction mixture could not be heated by microwave irradiation
without it. Samples were taken after 5 and 10 min of irradiation
at 800 W at a constant temperature of 75 °C.
The results are summarized in Table 5. The reaction in a
water bath at 45 °C only yielded 5% after 1 h. Increasing the
temperature to 75 °C led to a strong increase in the yield to
75%. Reactions initiated by microwave heating led to an
inhomogeneous product, probably due to inhomogeneous
Figure 12. Reaction of 1a and 2a in an SMM. Conditions: 500 mL
steel beaker, steel balls, dMB = 2 mm, ΦMB = 0.60, 200 mmol 1a, and
200 mmol 2a. Squares: stirrer speed = 500 min−1. Circles: stirrer speed
= 5 min at 500 min−1, 5 min at 750 min−1, and then 1000 min−1.
432
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Article
“fresh” surfaces by particle size reduction, and direct energy
input by impact and friction.1d,24
Table 5. Grinding Reactions Supported by Thermal Heating
(TAG) and Microwave Irradiation (MAG)
Comparison of Methods. Table 7 offers a comparison of
the investigated methods, in which it is seen that reactions in
ball mills lead to the highest yields in short reaction times. The
reactions with a mortar and pestle and MM do not yield
quantitative product even after reaction times of 1 and 2 h.
Better results could be achieved by TAG and MAG. The
reaction time for the TAG-process was 60 min, whereas the
microwave-assisted reaction was as fast as reactions in PBMs P6
and P7 at optimized conditions. Aside from the reaction yield,
the energy intensity is also of interest.2,25 The lowest E value
was calculated for the MAG-process. However, one has to
consider that in this case the addition of water was necessary.
Comparing the reactions in ball mills, reactions in PBMs were
slightly less energy intensive than reactions in an MBM. The
highest energy intensities were observed for the reaction in an
MM and by TAG. These reactions required 16-fold more
energy than that of the reaction in PBM P6.
Regarding the scale of the reaction, the lowest amount of
substrate could be treated using a mortar and pestle as well as
in MBMs. To scale up the reaction, PBMs and SMMs are the
best choices. Figure 13 illustrates the scale of the reactions in
the investigated PBMs. Scaling up was achieved by utilizing a
larger volume and number of milling beakers (e.g., PBM P5).
Thus, scaling up from PBM P7 with one 45 mL beaker (Figure
13, P7 (45; 1)) to PBM P5 with four 250 mL beakers (250; 4)
was successful by a scaling factor of 20. For the reactions in
PBM P6 with 250 and 500 mL beakers, the initial amounts of
100 and 200 mmol could be doubled without a negative effect
on the yield or t97%.5 Similarly, the grinding stock filling degree
temperature [°C]
time [min]
yield [%]
a
a
TAG
45
15
30
60
15
30
60
5
1
4
5
TAG
75
75
37
38
75
82
90
b
MAG
10
a
Conditions: rotary evaporator with water bath, 250 mL round-
bottom flask, 75 g glass balls, νrot = 100 min−1, dMB = 2 mm, 40 mmol
b
1a, and 40 mmol 2a (ΦMB = 0.098, ΦGS = 0.12). Conditions:
Rotaprep microwave reactor, 2000 mL vessel, 220 g glass balls, dMB = 2
mm, 800 W, νrot = 25 min−1, 100 mmol 1a, and 100 mmol 2a (ΦMB
0.035, ΦGS = 0.04).
=
water distribution (see Supporting Information). Nevertheless,
yields of 90% could be achieved after 10 min.
Influence of Reaction Temperature. The results of the
reactions in the water bath strongly indicate that the reaction is
temperature dependent. During ball milling, the reaction
temperature raises due to friction and heat dissipation.8 In
PBMs, direct control of the temperature is impossible. Only by
pausing the milling cycle for a considerable amount of time to
allow the milling vessels to cool down is an imprecise control of
heat flux possible. Therefore, the influence of the temperature
during ball milling was investigated. The reactions were
performed in an MBM with custom-made double-walled
stainless steel vessels (8 mL) that allow for temperature
adjustment by circulating a heated fluid through the system.23
Reactions were performed with optimal conditions, as found in
MBM with standard stainless steel beakers (Table 6). The
Φ
GS could be increased from 0.3 to 0.6. Thus, further scaling in
P5 with a scaling factor of 80 should be possible by utilizing 500
mL beakers.
Table 6. Influence of the Reaction Temperature on
Knoevenagel Condensation in an MBM
a
CONCLUSIONS
■
The Knoevenagel condensation proceeded quantitatively in
different kinds of PBMs as well as in an MBM at a comparable
time upon adjusting ν. The reaction could be scaled up in
PBMs by a factor of 20. Inducing mechanical energy by
grinding with a mortar and pestle or in an MM resulted in quite
lower yields. Under microwave irradiation, high yields could be
achieved, but the addition of water was essential. Also, good
yields were achieved under solvent-free conditions with TAG
using a water bath, but the reaction time was much longer than
that of ball milling. In comparison to the other investigated
methods, the results confirm that ball milling is a powerful
technique for organic reactions that is fast, solvent-free, and
requires low energy intensity.
thermostat
temperature [°C]
internal beaker
temperature [°C]
yield after 5
min [%]
yield after 20
min [%]
b
40
50
60
70
75
80
38.7
48.6
57.5
67.0
73.1
78.0
4
9
16
30
82
97
97
b
12
11
37
76
88
a
Conditions: MBM MM301, 8 mL double-walled steel beaker, ZrO2-
balls, ΦMB = 0.3, dMB = 5 mm, νosc = 30 Hz, 3.2 mmol 1a, and 3.2
b
mmol 2a. After 10 min.
The influence of crucial parameters was investigated for
different types of ball mills. It was shown that the rotation
frequency (νrot), the milling ball filling degree (ΦMB), the
milling ball diameter (dMB), and the beaker size all have a
strong influence on the yield. On the basis of these results,
some general strategies and conclusions for performing organic
reactions in planetary ball mills can be drawn. The application
of smaller milling balls is preferable over larger ones, and a
milling ball filling degree of 0.3 is optimal. Under these
conditions, the rotation frequency and the grinding stock filling
degree can be optimized, allowing for subsequent scaling up by
increasing the number of beakers.
results can be found in Table 6. At 40 °C, only 4 and 9% yields
could be achieved after 10 and 20 min, respectively. If the
temperature of the milling beakers was increased, the yields
were improved, and at 80 °C (below the melting points of the
single substrates), quantitative yields could be achieved after 20
min. Even at 70 °C, a yield of 82% was observed. In all cases,
the yields are higher than for reactions performed in a water
bath with intense mixing by glass balls at comparable
temperatures (Table 5). This result indicates that the reaction
is not solely accelerated by temperature increase due to friction,
and that ball milling has a real effect. This can be attributed to
intense mixing of the reactants, the constant generation of
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Article
Table 7. Comparison of Investigated Methods
n1a and n2a
time
yield
[%]
energy intensity [kWh
a
method
PBM P7
[mmol]
[min]
conditions
mol−1
]
2 × 20
100
10
12
νrot = 1000 min−1, dMB = 5 mm, VMV = 45 mL, ΦMB = 0.26, ΦGS = 0.3
νrot = 650 min−1, dMB = 10 mm, VMV = 250 mL, ΦMB = 0.26, ΦGS = 0.3
νrot = 400 min−1, dMB = 10 mm, VMV = 250 mL, ΦMB = 0.29, ΦGS = 0.3
νosc = 30 s−1, dMB = 10 mm, VMV = 35 mL, ΦMB = 0.3, ΦGS = 0.3
νosc = 50 s−1, dMB = 10 mm, VMV = 15 mL, ΦMB = 0.26, ΦGS = 0.3
νrot = 1000 min−1, dMB = 2 mm, VMV = 500 mL, ΦMB = 0.6, ΦGS = 0.3
>97
>97
>97
>97
80
1.89
1.03
PBM P6
PBM P5
4 × 100
2 × 14
6
30
nd
MBM MM400
MBM P23
SMM
35
2.33
3.96
60
200
40
>97
11
nd
mortar and pestle
MM
10
60
50
120
10
200 N siteforce, 100 N downforce
33
16.06
0.14
MAG
100
75 °C, 800 W, 5 mL H2O, V = 2000 mL, νrot = 25 min−1, ΦMB = 0.035,
90
ΦGS = 0.04
TAG
40
60
75 °C, νrot = 100 min−1, V = 250 mL, ΦMB = 0.098, ΦGS = 0.12
75
16.77
a
νrot/νosc = rotation/oscillation frequency, dMB = milling ball diameter, VMV = milling beaker volume, ΦMB = milling ball filling degree, and ΦGS
=
grinding stock filling degree.
was analyzed by a gas chromatography flame ionization
detector (GC-FID) using a 7890A-GC (Agilent Technologies)
with the following measurement conditions: HP5 column (30
m length, 0.32 mm diameter, 0.25 mm film thickness); H2 (12
psi); temperature program of 80 °C (hold for 1 min), 15 K
min−1 up to 200 °C, 30 K min−1 up to 280 °C (hold for 1 min);
injector temperature of 280 °C; detector temperature of 300
°C. NMR spectra were recorded with a Bruker Avance 250 or
400 MHz system at room temperature in DMSO-d6.
For measuring the line power consumption, an Energy
Check 3000 (Voltcraft) was used. The energy intensity was
calculated according to eq 62
Eline power
E =
yield × batch size
(6)
Figure 13. Realization of scaling up reactions in PBMs. Values in
italics are theoretical.
where Eline power is measured in kWh and the batch size is in
mols.
The simulations of the stress conditions were carried out
with EDEM 2.5 (DEM Solutions) based on the discrete
element method. The milling balls and the rotating geometry
are modelled as discrete elements, and in each time step, the
resulting velocities and accelerations as well as contact forces
are computed. The powder is recognized due to an adjustment
of friction and damping coefficients.13
Energy is transferred to the substrate by stress during
collision events between either two colliding milling balls or a
ball and the beaker. The maximum amount of energy that is
transferred is determined by the kinetic energy and thus by the
relative velocity in the normal direction and the mass of the
colliding elements.11b,13
EXPERIMENTAL SECTION
■
All chemicals were purchased from Sigma-Aldrich or Alfa Aesar
and used as received. The reactions were accomplished in a
Fritsch Pulverisette P6 classic line, a Fritsch Pulverisette P7
premium line, and a Fritsch Pulverisette P5 planetary ball mill
(Fritsch GmbH, Idar-Oberstein, Germany). If not otherwise
stated, milling beakers made of stainless or tempered steel were
used with a volume of 250 mL for reactions in PBM P6 and
PBM P5 and of 45 mL for PBM P7. Reactions in MBMs were
accomplished in a MM400 mixer ball mill (Retsch, GmbH)
with 35 mL steel beakers and in Pulverisette 23 (Fritsch
GmbH) with 15 mL steel beakers. The milling balls of various
diameters (dMB) and amounts (nMB) were made of magnesia-
stabilized zirconia. Both, dMB and nMB determine the milling ball
filling degree (ΦMB).
The reactions in MM were performed in a mortar mill
Pulverisette 2 (Fritsch GmbH). Experiments with mortar and
pestle were carried out using devices made of porcelain. A PE
075 agitator bead mill (Netzsch GmbH) was used for the
reactions in the stirred media mill. Reactions with classical
heating were performed with a rotary evaporator Laborota 4001
(Heidolph Instruments GmbH and Co. KG). Experiments
under microwave irradiation were performed with a Rotaprep
microwave system (MLS GmbH).
SEball−ball−collision = 0.25mMB rel,normal
SEball−beaker−collision = 0.50mMB rel,normal
v2
v2
(7)
(8)
By the stress energy distributions, mean SE values were
formed for an export interval of 0.3 s at steady state.
n
∑
j=1 SEj
SE =
(9)
number of collisions
The absolute values of stress frequency (SF) as collisions per
second were directly exported from the simulation. By the
mean stress energy SE and the stress frequency, the upper limit
of transferred power is defined as
For determining the conversion, we extracted samples of the
crude reaction product (100 mg) with ethyl acetate (5 mL) and
filtered them over a thin layer of silica gel. The organic extract
(10)
Power = SE × SF
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Experimental Procedure for Reactions in PBMs and
an MBM. The milling beakers were equipped with the
respective number of milling balls. After, equimolar amounts
of 1a and 2a were added in the given order. Milling was
accomplished at the respective frequency, νrot or νosc, and listed
milling time.
Experimental Procedure for Reactions in an SMM. The
grinding chamber (500 mL) was equipped with 2 mm steel
balls (1860 g). After, equimolar amounts of 1a and 2a were
added in the given order. Milling was accomplished at the listed
stirrer speed and milling time.
Experimental Procedure for Reactions in MM.
Equimolar amounts of 1a and 2a were added in the mortar
bowl made of zirconium oxide in the given order. The grinding
pressure in the pestle axis (downforce) was adjusted to 100 N,
and the grinding pressure against the wall of the mortar
(siteforce) was adjusted to 200 N. The frequency of the mortar
bowl was fixed to 50 s−1. Milling was accomplished at the listed
milling times.
Experimental Procedure for Reactions with Mortar
and Pestle by Hand Grinding. Equimolar amounts of 1a and
2a were added in the mortar bowl in the given order. Grinding
was accomplished at the listed milling time.
5-(3-Hydroxybenzylidene)-1,3-dimethylbarbituric Acid
(3i).32 8.23 (s, 1 H), 7.56 (s, 1 H), 7.39 (d, J = 7.3, 1 H),
7.26 (t, J = 7.6, 1 H), 6.94 (d, J = 7.5, 1 H), 3.21 (s, 3 H), 3.17
(s, 3 H).
5-(4-Nitrobenzylidene)-1,3-dimethylbarbituric Acid (3j).33
8.4 (s, 1 H), 8.25 (d, J = 8.6, 2 H), 7.97 (d, J = 8.6, 2 H), 3.23
(s, 3 H), 3.14 (s, 3 H).
5-(3-Nitrobenzylidene)-1,3-dimethylbarbituric Acid (3k).34
8.82 (s, 1 H), 8.42 (s, 1 H), 8.32 (d, J = 7.5, 1 H), 8.2 (d, J =
7.7, 1 H), 7,73 (t, J = 8, 1 H), 3.24 (s, 3H), 3.16 (s, 3H).
5-(4-Chlorobenzylidene)-1,3-dimethylbarbituric Acid
(3l).35 8.31 (s, 1 H), 8.04 (d, J = 8.4, 2 H), 7.53 (d, J = 8.45,
2 H), 3.22 (s, 3 H), 3.16 (s, 3 H).
ASSOCIATED CONTENT
* Supporting Information
■
S
Pictures of DEM simulations of the milling ball bulk relative to
the diameter of the milling beaker, TAG, MAG, inhomoge-
neous product composition after MAG, and of the custom-
made double-walled steel beaker. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: Achim.Stolle@uni-jena.de. Fax: +49 3641 948402.
Tel: +49 3641 948413.
■
Thermal-Assisted Grinding (TAG). A 250 mL round-
bottom glass flask was charged with 2 mm glass balls (75 g).
After, equimolar amounts of 1a and 2a (40 mmol) were added
in the given order. The water bath of a rotary evaporator was
preheated to 75 °C, and the filled glass flask was fastened to the
rotary evaporator. The rotation frequency was set to 100 min−1,
and the reaction was accomplished at the listed time.
Microwave-Assisted Grinding (MAG). A 2000 mL glass
flask was charged with 2 mm glass balls (220 g). After,
equimolar amounts of 1a and 2a (100 mmol) as well as 5 mL of
water were added in the given order. The reaction was
accomplished under reduced pressure (750 mbar) and with a
rotation frequency of 25 min−1. The reaction mixture was
heated to 75 °C with a maximum power input of 800 W.
Spectral Data of Products Listed in Table 3 (1H NMR,
DMSO-d6, δ (ppm)). 5-(4-Hydroxy-3-methoxybenzylidene)-
barbituric Acid (3a).26 11.24 (s, 1 H), 11.11 (s, 1 H), 10.54 (s,
1 H), 8.46 (s, 1 H), 8.21 (s, 1 H), 7.78 (d, J = 8.1, 1 H), 6.89
(d, J = 8.3, 1 H), 3.81 (s, 3 H).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was funded by the Deutsche Bundesstiftung Umwelt
(DBU, AZ 29622-31) and the Slovak Grant Agency VEGA
(Project 2/0027/14). We thank Timmy Reimann from Ernst-
Abbe-Fachhochschule Jena for the possibility of perform
reactions with PBM P5.
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