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Using 1% of H2WO4 and 4.4 equiv of H2O2 (10% excess),
60 min at 1408C were required to obtain a complete consump-
tion of cyclohexene and an optimum yield of adipic acid (92%
GC–MS selectivity; Table S2 and Figure S3 in the Supporting In-
formation). The acid crystallized upon cooling of the reaction
mixture as a white powder and was isolated in analytically
pure form by filtration and washing with cold 1n HCl (ꢀ3 mL)
in 64% product yield. Due to the rather high solubility of
adipic acid in water (0.53 molLÀ1 at 258C, pH 2.34), significant
amounts of acid were lost into the aqueous phase and concen-
tration of the crude reaction mixture, filtration, and washing
with cold 1n HCl provided somewhat better yields (73%).
It should be emphasized that the selectivity and yields of
adipic acid obtained with this high-T/p protocol (1408C) were
comparable to those obtained in control experiments under
traditional Noyori reaction conditions in the presence of a PTC
(59% isolated yield after 8 h reaction time at 908C; see
Table S2 and Figure S4 in the Supporting Information).
back pressure regulator (BPR, set to 15 bar). The residence
tube was coiled onto a stainless steel cylinder and heated in
a GC oven to the desired temperature. For adipic-acid genera-
tion, the neat cyclohexene (feed A) and a solution of tungstic
acid in 25% aqueous H2O2 (feed B; 0.02 molLÀ1 H2WO4) were
pumped as two separate streams into the T-mixer at flow rates
that established the desired stoichiometry of H2O2 (Figure 2).
Figure 2. Oxidation of cyclohexene under continuous flow conditions. See
the Experimental Section for further details.
Decreasing the amount of catalyst below 1% reduced the
reaction rate, whereas no significant effect on the selectivity
was observed. Decreasing/increasing the amounts of H2O2
below/above 4.4 equiv of H2O2 decreased the yield of adipic
acid. The addition of H3PO4 as acidic promoter and stabilizing
The resulting two-phase liquid–liquid reaction system entered
the PFA residence tube in well-defined liquid–liquid seg-
ments.[21] However, after several minutes residence time, the
mixture became completely homogeneous as the cyclohexene
was oxidized to more polar, better soluble products. The mix-
ture passed the residence tube and left the reactor through
the BPR, which was held at 808C to prevent premature precipi-
tation of adipic acid and clogging of the system. After the pro-
cessed mixture left the BPR, the adipic acid immediately pre-
cipitated and the pure acid was isolated by filtration and wash-
ing with cold 1n HCl as described above. At a reaction tem-
perature of 1408C, the selectivities obtained in these flow reac-
tions were comparable to those obtained in the microwave
batch experiments (see Figure S6 in the Supporting Informa-
tion), but complete oxidation of cyclohexene to adipic acid
was attained already after 20 min residence time and the pure
acid could be isolated in 63% yield after filtration (ꢀ10 mmol
scale, 74% after a concentration step, see Table S7 in the Sup-
porting Information for further details). In fact, cyclohexene
was completely consumed after residence times as short as
5 min, but reaction intermediates (i.e., 4 and 5) were detect-
able under these conditions. The higher turnover rate of cyclo-
hexene achieved in the flow system as compared to the batch
system can be rationalized by a superior mass-transfer perfor-
mance in the small diameter channel and hence increased oxi-
dation rate. The reaction was then ran for 1 h, processing 9.5 g
(116 mmol) of cyclohexene (1408C, 20 min residence time) to
provide 12.2 g (84 mmol; 72%) of pure, crystalline adipic acid
after a simple filtration step (see Experimental Section). Increas-
ing the reaction temperature to 1508C or increasing the con-
centration of H2O2 from 25% to 38% decreased the purity of
the reaction and the yields of adipic acid (Table S7 in the Sup-
porting Information).
[9]
agent for H2O2 had no effect on the purity of the reaction or
on the reaction rate (for more optimization reactions under mi-
crowave batch conditions see Tables S3–S6 in the Supporting
Information).
Even though the reaction described above proceeded well
on a small scale (8 mmol), it should be emphasized that H2O2
is a very reactive chemical and an extremely powerful oxidizer
that forms highly dangerous peroxygen compounds with or-
ganic substrates (such as ketones). The decomposition of H2O2
to H2O and O2 is very exothermic and can accelerate rapidly.
The released O2 increases internal pressure and gives rise to
oxygen-rich, flammable atmospheres with low ignition ener-
gies.[4]
Compared to conventional batch reactors, flow systems with
small-diameter channels or capillaries offer enhanced heat and
mass transport and allow safe operation of reactions in an ex-
tended range of operation conditions, for example, the explo-
sive region.[10,17,18] Furthermore, rapid mixing and excellent
heat transfer can be maintained up to high production sca-
les.[17b] On the other hand, however, the exceptionally high sur-
face-to-volume ratio in microstructured flow systems may
entail pronounced reactor-wall effects and unexpected/un-
wanted side and degradation reactions.[19] Several metal con-
taminants (e.g. Fe, Cu, Cr, or Mn ions) initiate the decomposi-
tion of H2O2, and heterogeneous decomposition can occur on
all material surfaces.[20] Therefore, only a limited selection of
materials are sufficiently compatible with H2O2 and suitable for
high temperature or long-term contact.
For our continuous-flow reactions, a simple flow system free
of metal parts in the heated reaction zone was assembled (see
Figure S5 in the Supporting Information). The system consisted
of two glass syringe pumps, a T-mixer, a residence tube made
of perfluoroalkoxy (PFA; 0.8 mm inner diameter, 50 m length,
ꢀ25 mL internal volume), and an adjustable stainless steel
Finally, the continuous-flow protocol was extended to cyclo-
hexanol and cyclohexanone as substrates without reoptimiza-
tion of the reaction conditions (the stoichiometry of H2O2 was
adjusted to 3.3 equiv for cyclohexanone).[12] Acid-catalyzed re-
actions of H2O2 with ketones are generally quite complex and
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