factor, albeit the overall heterogeneity (considering substrate
and product) allows perhaps a better prediction of a positive
microwave effect. Our experiments could not demonstrate a
microwave effect for homogeneous reactions, but heterogeneity
alone is not sufficient to induce a microwave effect.36 So far a
beneficial microwave effect was only observed in solid-liquid
systems with very low solubilities of the solid substrates,
involving relatively fast reactions in the liquid layer around the
isocytosine particles. It is exactly in these liquid layers where
selective heating can occur.
In the case of the addition of 6-methylisocytosine to
hexamethylene diisocyanate, 6-methylisocytosine slightly dis-
solves which results in an absorption enhancement of micro-
waves. Consequently, the temperature increases locally, leading
to an even higher solubility and reaction rate. The occurrence
of such a microwave effect at the interphase region was also
demonstrated previously through modeling of a chemical
conversion with microwave heating.37-39
In our cases neither the solid nor the liquids used were good
microwave absorbers, which was demonstrated by simple
heating experiments.40 The effects cannot be measured locally
by any sensor, but they are witnessed indirectly by higher
reaction rates and higher pre-exponential factors. Figure 5 (left)
illustrates an example, representing a conversion of 6-methyl-
isocytosine for the conventionally heated experiment at 100 °C,
that is almost similar to the microwave-heated reaction at 85
°C. When the reaction predominantly takes place in the liquid
layer, then this layer conclusively has an average temperature
of about 102 °C, but the bulk temperature is in fact measured
to be 17 °C lower.
In conclusion, significant rate and productivity enhancements
in the UPy-process starting from 6-methylcytosine have been
found. These results provided a better understanding of an
important microwave effect, offering the right scenario for a
microwave-assisted process scale-up.
was filtered and washed twice with cold MTBE (0.5 mL). The
remaining solid was dried under reduced pressure at 40 °C and
1
analyzed by H NMR (conversion based on ratio isocytosine
and product).
Nucleophilic Additions under Microwave Heating. N-(6-
Isocyanatohexyl)-N′-(6-methyl-4-oxo-1,4-dihydropyrimidin-2-
yl)urea. A 20-mL reaction tube was charged with 6-methyl-
isocytosine21 (0.75 g, 6.0 mmol) and hexane-1.6-diisocyanate
(7.5 g, 44.6 mmol). The tube was flushed with argon and closed.
Temperature was measured via a fibre-optic insert. The reaction
mixture was heated at 85 °C with stirring for 2 h in the
microwave oven (average power: 25 W/max: 200 W). There-
after, the mixture was diluted with MTBE (15 mL), and after
cooling the suspension was filtered and washed twice with
MTBE (1.5 mL). The remaining solid was dried under reduced
pressure at 40 °C and analyzed. Yield after workup: 1.39 g
1
(79%); H NMR (400 MHz) in CDCl3/d-TFA (1/1 vol %) δ
6.3 (s, 1H, CHdC-CH3), 3.3 (t, 2H, NH-CH2), 3.2 (t, 2H,
CH2-NCO), 2.5 (s, 3H, CH3-CdCH), 1.8 (m, 2H,
NH-CH2-CH2), 1.6 (m, 2H, CH2-CH2-NCO), 1.5 (m, 4H,
(CH)2-(CH2)2-NCO).
N-(6-Isocyanatohexyl)-N′-(6-ethyl-4-oxo-1,4-dihydropyrimi-
din-2-yl)urea. A 20-mL reaction tube was charged with 6-eth-
ylisocytosine29 (0.84 g, 6.0 mmol) and hexane-1.6-diisocyanate
(7.5 g, 44.6 mmol). The tube was flushed with argon and closed.
Fibre-optic temperature control was measured via an insert. The
reaction mixture was heated at 85 °C with stirring for 2 h in
the microwave oven (average power: 25 W/max: 200 W).
Thereafter, the mixture was diluted with MTBE (15 mL), and
after cooling the suspension was filtered and washed twice with
MTBE (1.5 mL). The remaining solid was dried under reduced
pressure at 40 °C and analyzed. Yield: 1.29 g, 70%; 1H NMR
(400 MHz) in CDCl3/d-TFA (1/1 vol %) δ 6.4 (s, 1H,
CHdC-C3H7), 3.4 (m, 2H, NH-CH2, 3.2 (m, 2H,
CH2-NCO), 2.8 (q, 2H, CH2-CdCH), 1.8 (m, 2H,
NH-CH2-CH2), 1.7 (m, 2H, CH2-CH2-NCO), 1.5 (m, 4H,
(CH2)2-(CH2)2-NCO), 1.4 (t, 3H, CH3-CH2-CdCH).
N-(6-Isocyanatohexyl)-N′-(6-isopropyl-4-oxo-1,4-dihydropy-
rimidin-2-yl)urea. A 20-mL reaction tube was charged with
6-isopropylisocytosine32 (0.92 g, 6.0 mmol) and hexane-1.6-
diisocyanate (7.5 g, 44.6 mmol). The tube was flushed with
argon and closed. Temperature was measured via an insert. The
reaction mixture was heated at 85 °C with stirring for 2 h in
the microwave oven (average power: 24 W/max: 70 W).
Thereafter, the mixture was diluted with MTBE (15 mL), and
after cooling the suspension was filtered and washed twice with
MTBE (1.5 mL). The remaining solid was dried under reduced
pressure at 40 °C and analyzed. Yield: 1.21 g, 63%; 1H NMR
(400 MHz) in CDCl3/d-TFA (1/1 vol %) δ 6.4 (s, 1H,
CHdC-CH3), 3.3 (t, 2H, NH-CH2), 3.2 (t, 2H, CH2-NCO),
3.0 (m, 1H, C2H6-CH-CdCH), 1.8 (m, 2H, NH-CH2-CH2),
1.6 (m, 2H, CH2-CH2-NCO), 1.4 (m, 4H, (CH2)2-(CH2)2-
NCO), 1.3 (d, 6H, (CH3)2-CH-CdCH).
Experimental Section
All microwave-heated experiments were performed in a
MicroSynth of Milestone srl, Italy with internal fibre-optic (type
ATC-FO; fluoroptic probe) temperature measurement via a
Teflon-coated ceramic well. In general, all reactions were
temperature controlled with a set power maximum to obtain
the thermal set-point. A maximal magnetic stirring speed in
the microwave oven was applied. Control experiments using a
pitched-blade overhead stirrer did not alter the presented results.
During reaction, aliquots were taken and quenched in cold
methyl tert-butyl ether (MTBE) (2 mL, 0 °C). The suspension
(36) Dressen, M. H. C. L.; Van de Kruijs, B. H. P.; Meuldijk, J.; Vekemans,
J. A. J. M.; Hulshof, L. A. Green Chem. 2009, 13, 888.
(37) Conner, W. C.; Tompsett, G. A. J. Phys. Chem. B 2008, 112, 2110.
(38) Chemat, F.; Esveld, D. C.; Poux, M.; Di-Martino, J. L. J. MicrowaVe
Power Electromagn. Energy 1998, 33, 88.
(39) Chemat, F.; Esveld, E. Chem. Eng. Technol. 2001, 24, 735.
(40) It can generally be stated that solids are difficult to heat by microwave
irradiation. For ice and water the loss tangents differ 3 orders of
magnitude at 0 °C (ice: 0.00027, water 0.207). Both components (6-
methylisocyosine and HDI) were separately heated in the microwave
oven. 6-Methylisocyosine was dispersed in THF. The heating rate of
this mixture was compared with that of pure THF. HDI was heated
as such. In no case was significant heating observed with the use of
a fibre-optic probe, showing that each individual component is a poor
microwave absorber.
N-(6-Isocyanatohexyl)-N′-(6-phenyl-4-oxo-1,4-dihydropyri-
midin-2-yl)urea. A 20-mL reaction tube was charged with
6-phenylisocytosine32 (1.12 g, 6.0 mmol) and hexane-1.6-
diisocyanate (7.5 g, 44.6 mmol). The tube was flushed with
argon and closed. Temperature was measured via an insert. The
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Vol. 15, No. 1, 2011 / Organic Process Research & Development