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O
R
2
R
2
0.76 equiv. CaCO
3
or CaF
2
MBM
30 s
-1
,
0.5 h
+
CN
CN
R
1
R
1
R
1
= NO
2
,
CN, Br, Cl, CH
3
,
OH, H,
R
2
= CN, CO
2
CH
3
Scheme 2.18 Knoevenagel condensation of aldehydes with malononitrile or methyl
cyanoacetate.
0.5 h milling at 30 Hz. Interestingly, applying the catalyst as fine powder did
not promote the reaction, while adding the catalyst in 1-3 mm pieces led to
good yields. The authors assumed that this effect is based on in situ created
ionic species, acting as strong bases. Ondruschka et al. remarked that the
missing activity of the powder is in fact based on a diluting effect, making
the grinding process less effective.
37
Another catalyst for Knoevenagel condensation with subsequent reduction
of the double bond in a mixer ball mill was reported by Zhang et al.
38
Hantzsch-1,2-dihydropyridine catalyzed the reductive benzylization of mal-
ononitrile with substituted aldehydes. Thereby, 1,2-dihydropyridine acted
on the one hand as catalyst for the Knoevenagel condensation and, on the
other hand, as reductant for the double bond of the coupling product.
Beside catalyzed Knoevenagel reactions several authors have developed
reaction protocols avoiding the use of a catalyst. In milling solid aldehydes
with barbituric acid, Meldrum's acid, malononitrile or methyl cyanoacetate,
quantitative yields were reported after 1 h milling in a mixer ball mill by
Kaupp and co-workers.
39
By using stoichiometric amounts of reactants the
product isolation is straightforward, no further clean-up was necessary and
no further waste was produced. In addition to reactions on a low mmol-
scale, the authors also reported a 200 g-scale reaction using a 2 l horizontal
stirred media mill. The reaction proceeded at 1200 min
1
within 1 h. Based
on the nature of the substrates, the reactions took place as solid-state re-
actions or as reactions in melt, e.g. reactions of Meldrum's acid at 50 1C
proceeded in melt while reactions with barbituric acid occurred in
solid state.
Ondruschka et al. further investigated the influence of reaction par-
ameters in vibration and planetary ball mills for the reaction of aldehydes
with malononitrile.
37
High yields were reported after milling the substrates
at 800 min
1
for 1 h in a planetary ball mill or at 30 Hz in a mixer ball mill.
With regard to energy eciency they compared power consumption for re-
action in ball mills and microwaves. They could show that performing the
reaction in a planetary ball mill is very energy effective and that the power
consumption per mol is 650 times lower in comparison to reaction in
microwaves.
Although there are some example for performing Knoevenagel conden-
sations in ball mills, the influence of process parameters, like rotation fre-
quency, milling ball diameter or milling ball filling degree on the outcome of
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