catalyst. Note, however, that the metrics do not show the high
toxicity of some of the activating agents (i.e. thionyl chloride, a
highly corrosive lachrymator) nor do the metrics take into
account the often complex synthesis of the homogeneous
catalysts, another benefit of this approach. End of life
prospects for the K60 catalyst are attractive, as minimal
preparation is required when disposal is eventually needed.
In conclusion, we have developed an ‘off the shelf’ catalyst
for amide formation which is highly active towards a range of
sterically hindered, weakly nucleophilic and highly acidic
reagents, without production of toxic by-products. The
catalyst is based upon a readily available, particularly low
cost and abundant material, which is easily and safely handled.
The heterogeneous nature of the catalyst enables it to be
filtered for reuse with ease, or to be used as a fixed bed in
continuous operation. Once activated, the catalyst remains
active for long periods of time, even on exposure to the
atmosphere. We believe our silica based synthesis is a vast
improvement on current catalysts in terms of scope, economy
and environmental impact.
Fig. 2 Change in the isolated yield of 2,N-diphenylacetamide.
Table 4 A comparison of efficiency between catalysts/promoters in
the synthesis of 4,N-diphenylbutyramide
Mass
intensity
Atom economyb
(%)
Yieldc
(%)
Promoter
E-factora
4
SOCl2
13.5
19.5
378.2
1.1
71.8
55.6
512.7
9.9
87
52
93
93
97
95
46
74
We would like to thank Craig Knight for his input and
Pfizer Global Research and Development for their support.
DCC5
IBAd
K60
0.9e
Notes and references
a
Waste produced in the synthesis of amide (E-Factor—kg of waste
produced per kg of product). Each metric was calculated using
quantities stated in published literature. The E-factors shown do not
account for the waste produced in the synthesis of the homogeneous
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b
catalysts. Atom economy for activating agents was calculated using
c
the activated acid. Isolated yield of 4,N-diphenylbutyramide.
d
ortho-N,N-Di-isopropylbenzylaminoboronic acid catalyst.12 e E-factor
calculated after the catalyst was reused four times.
was used as the model. Even after being exposed for a week the
catalyst remains active due to the hydrophobic surface created
by 700 1C activation. The initial drop in yield (from 81% to
71%) is likely to be due to a small quantity of physisorbed
water. Heating to 120 1C for 2 hours restored full activity.
Long term exposure for 16 weeks led to an isolated yield of
67%, without pre-treatment.
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In addition, we have also carried out preliminary experi-
ments to demonstrate the possibility of using the K60 silica in
continuous flow reactions. A column was packed with 10 g of
activated K60 and heated to 100 1C whilst 12 mmol of
4-phenylbutyric acid and aniline in 60 ml of xylene was flowed
through the column 10 times (at a flow rate of 1 ml minꢀ1).
After 10 hours a yield of 61% was obtained showing the
potential for much safer and cleaner continuous flow type
reactions.
11 P. G. Urben, Brethericks Handbook of Reactive Chemical Hazards,
Butterworth-Heinemann, Oxford, UK, 1999, p. 746.
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Many factors must be considered when designing cleaner
synthetic routes. Table 4 shows a comparison of the K60
system with classic and recently published amide syntheses,
using established green chemistry metrics.16 This shows that
K60 activated at 700 1C is substantially cleaner and more
efficient than alternative methodologies, especially in terms of
the ratio of waste to product (E-factor); there is no need for
complex separation of the product/by-products from the
13 Fluka K60 silica, particle size 0.035–0.070 mm, mesh 220-440.
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16 R. A. Sheldon, Chem. Commun., 2008, 3352–3365.
ꢁc
This journal is The Royal Society of Chemistry 2009
2564 | Chem. Commun., 2009, 2562–2564