with reactants and product (see ESIw), but this is clearly open
to further investigation. Whilst high conversions have been
achieved under continuous flow conditions, there is consider-
able scope for further exploitation of this process technology.
In conclusion, we have demonstrated the high yielding,
batch mode synthesis of diaryl ethers by an SNAr fluoride-
mediated process in scCO2. The process is driven by the
strength of the Si–F bond, which emerges as a CO2-miscible
side-product. The use of a polymer-supported fluoride reagent
in batch mode led to the development of a fixed-bed con-
tinuous flow process with high conversions.
Fig. 1 Schematic of the continuous flow apparatus.
We thank AstraZeneca (UK), the Overseas Research Stu-
dents Awards Scheme (Universities UK), the Cambridge Over-
seas Trust, the Engineering and Physical Sciences Research
Council (UK), the Australian Research Council, VESKI and
CSIRO (Australia) for financial support. This project was
carried out with partial support from the Materials World
Network (NSF/ARC).
Table 4 Conversion of para-nitro fluorobenzene (2) into diaryl ether
3 under continuous flow conditions as a function of elapsed timea
Elapsed
time/h
Conversion
(GC, %)b
Entry
1
2
3
4
5
a
1
2
3
4
5
69
61
61
96
96
Notes and references
Reagents and conditions: 2 (1 equiv.), 1 (1.1 equiv.), dose rate
0.01 cm3 minꢁ1, scCO2 flow rate 0.32 cm3 minꢁ1, 110 1C, 26 MPa,
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the synthesis of diaryl ethers and previous work using continuous
flow procedures, see the ESIw.
b
15 cm (L) ꢂ 0.62 cm (id) column containing 24b. Conversion based
on a standardized GC comparison of 2 and 3.
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(matched to the pressure of the continuous flow apparatus).
A JASCOt CO2 delivery pump was used to pass scCO2 at a
constant pressure of 26 MPa through the column. The eluate
was vented into a collection vessel containing ethyl acetate.
Aliquots were collected and analyzed by GC to provide a
conversion yield of the diaryl ether product, 3. The tempera-
ture of the column was maintained at 110 1C to accomplish a
high conversion to the product. However, under this higher
temperature, phosphonium fluoride 24a appeared to decom-
pose slowly, causing a decreasing conversion, and therefore we
adopted a potentially more thermally stable imidazolium
fluoride, 24b (Scheme 1).25 Pleasingly, high conversions were
realized under continuous flow conditions using imidazolium
fluoride resin 24b (Table 4). Optimization revealed the need to
maintain the system pressure above 20 MPa, with a minimum
scCO2 flow rate of 0.32 cm3 minꢁ1. Further optimization of
the flow system is under way to improve upon these promising
results. When a material balance was carried out under small-
scale continuous flow laboratory conditions, absolute yields of
3 were 2–10%. It is thought that the low isolated yields of
product 3 were the result of adsorption of the product and
reactants onto the resin, owing to the lower solubilizing power
of scCO2 under these conditions. When the column was
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¨
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flushed with toluene for several hours (flow rate 2 cm3 minꢁ1
)
after the reaction had been running for 5 h, the ratio of
product to reactant was identical to that observed in entry 5,
Table 4 after 5 h (see ESIw). The qualitative solubilities of aryl
fluoride 2 and product 3 were very similar. We have excluded
the possibility that the column had not been fully saturated
25 Polymer-supported imidazolium salts are recyclable many times.
See: D. W. Kim and D. Y. Chi, Angew. Chem., Int. Ed., 2004,
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ꢀc
This journal is The Royal Society of Chemistry 2008
4782 | Chem. Commun., 2008, 4780–4782