Flow synthesis using gaseous ammonia in a Teflon AF-2400 tube-in-tube reactor: Paal-Knorr pyrrole formation and gas concentration measurement by inline flow titration

Article abstract of DOI:10.1039/c2ob25407g

Using a simple and accessible Teflon AF-2400 based tube-in-tube reactor, a series of pyrroles were synthesised in flow using the Paal-Knorr reaction of 1,4-diketones with gaseous ammonia. An inline flow titration technique allowed measurement of the ammonia concentration and its relationship to residence time and temperature.

Full text of DOI:10.1039/c2ob25407g

View Article Online / Journal Homepage / Table of Contents for this issue
Organic &
Biomolecular
Chemistry
This article is part of the
OBC 10th anniversary
themed issue
All articles in this issue will be gathered together
online at
www.rsc.org/OBC10

Dynamic Article Links
Organic &
View Article Online
Biomolecular
Chemistry
Cite this: Org. Biomol. Chem., 2012, 10, 5774
www.rsc.org/obc
COMMUNICATION
Flow synthesis using gaseous ammonia in a Teflon AF-2400 tube-in-tube
reactor: Paal–Knorr pyrrole formation and gas concentration measurement
by inline flow titration†‡
Philippa B. Cranwell, Matthew O’Brien, Duncan L. Browne, Peter Koos, Anastasios Polyzos,
Miguel Peña-López and Steven V. Ley*
Received 24th February 2012, Accepted 21st March 2012
DOI: 10.1039/c2ob25407g
Accordingly, a large amount of research has been undertaken
in the development of efficient synthetic pathways to this impor-
tant heterocycle.10 One of the most important and useful of these
is the Paal–Knorr synthesis which consists of the condensation
of a primary amine with a 1,4 diketone (Scheme 1).11 The syn-
thesis of pyrroles unsubstituted at nitrogen (which display versa-
tile nitrogen nucleophilicity) requires the use of ammonia (or a
source of ammonia) as the amine component. As ammonia is a gas,
however, its use in chemical processes demands special consider-
ation. Although solutions of ammonia are commercially available
in a limited range of solvents, these are often not very convenient
or practical to use. Their concentration varies and diminishes
rapidly upon opening the container (or during the course of reaction
if an open vessel is used) due to the volatility of the ammonia.
Additionally, many reactions require heating and the resulting
increased pressures necessitate containment. This is a serious
safety concern, especially for larger scale reactions. Reactive
gases are often used within industrial-scale process settings.12
Dedicated, bespoke engineering solutions can be found for
specific processes that provide efficient control of phase-transfer
phenomena whilst keeping parameters such as temperature and
pressure within safe operational limits. In research laboratories,
however, where a wide range of techniques are employed in a
flexible and changing manner according to chemical need, the
use of reactive gases is far less commonplace, owing mainly to
safety concerns. For batch mode reactions, the risk of mechanical
failure and unexpected venting of toxic and/or flammable gases
places severe limitations on the scale at which the reaction can
be safely carried out. Flow chemistry, where reagents and reac-
tants are pumped continuously through a relatively small reaction
zone, has emerged in recent years as an enabling technology that
often offers significant advantages compared to batch mode pro-
cesses in laboratory settings.13 These include the possibility of
inline scavenging14 and phase-switching15 purification techniques.
Using a simple and accessible Teflon AF-2400 based tube-in-
tube reactor, a series of pyrroles were synthesised in flow
using the Paal–Knorr reaction of 1,4-diketones with gaseous
ammonia. An inline flow titration technique allowed
measurement of the ammonia concentration and its relation-
ship to residence time and temperature.
The pyrrole moiety is found in a large number of naturally occur-
ring molecules that are of biological importance such as haem,1
vitamin B122 and chlorophyll3 as well as in melanin pigments.4
In addition, many important pharmaceutical compounds, such as
atorvastatin5 (Lipitor, anti-cholesterol), sunitinib6 (anti-tumour),
keterolac7 (analgesic) and tolmetin8 (arthritis) include pyrrole
units (Fig. 1). The electronic properties of pyrrole are important
in the context of conducting polymers, where polypyrroles have
found many useful applications.9
Fig. 1 Pharmaceutical products that contain the pyrrole moiety.
Whiffen Laboratory, Department of Chemistry, University of Cambridge,
Lensfield Road, Cambridge, CB2 1EW, UK. E-mail: svl1000@cam.ac.uk
†This article is part of the Organic & Biomolecular Chemistry 10th
Anniversary issue.
‡Electronic supplementary information (ESI) available: Details of reac-
tion construction, characterisation data for all compounds. See DOI:
10.1039/c2ob25407g
Scheme 1 Paal–Knorr pyrrole synthesis.
5774 | Org. Biomol. Chem., 2012, 10, 5774–5779
This journal is © The Royal Society of Chemistry 2012

View Article Online
Additionally, in terms of safety, only a small amount of material
is being processed at any one time in a relatively small reaction
zone. This minimises the risk of processes which involve high
temperatures or pressures, or which involve toxic or explosive
intermediates (which can be continuously quenched). Addition-
ally, processes which depend on interfacial phenomena (such as
mixing and heat transfer) are often more efficient and consistent.
This is due both to the relatively high surface-area–volume ratios
obtained with the small dimensions of the reactors used, as well
as the fact that, as reactions are scaled over time rather than size,
these phenomena are scale invariant. Conventionally, gas–liquid
flow systems have focussed on the use of biphasic flow, and
many novel engineering solutions have been found to facilitate
the mechanical mixing of the gas and liquid phases.16 In order to
avoid the potential non-linear behaviour associated with biphasic
gas–liquid flow,17 we have developed gas–liquid flow reactors
based on the use of semi-permeable membranes. Specifically,
Teflon AF-240018 – which is highly permeable to a wide range
of gases, and exhibits a broad chemical resistance – has proven
to be a very useful material for this purpose. Single lengths of
the tubing have been used in these reactors with no observable
changes (both physically and in conversion/yield) after several
hundred runs. PDMS (silicone) is also permeable to a range of
gases but, whilst it has the advantages of being cheaper and
more widely available, it is less mechanically robust and suffers
from severe swelling in a range of solvents.19 Our tube-in-tube
configuration allows very compact reactors to be constructed that
minimise the amount of pressurised gas required. These consist
of two concentric tubes, an inner gas-permeable tube and an
outer pressure-containing tube. The gas can either be in the outer
tube (with the liquid in the inner tube) or in the inner tube (with
the liquid in the outer tube).20 We have used these reactors for
chemical reactions with ozone,21 hydrogen,22 carbon dioxide,23
carbon monoxide,24 oxygen,25 ethylene26 and syngas27
(1 : 1 mixture of carbon monoxide and hydrogen). Here we
report our initial findings on the use of this type of reactor for
the Paal–Knorr reaction of ammonia with 1,4-diketones.
Fig. 2 Tube-in-tube gas–liquid flow reactor (held in a clamp). Outer
PTFE tubing: OD 3.18 mm, ID 1.59 mm. Inner Teflon AF-2400 tubing:
OD 1.0 mm, ID 0.8 mm. For purpose of illustration, the gas and liquid
flow-paths contain acetone solutions of blue and red dyes respectively.
The reactor used in this study is shown in Fig. 2. It involves
the use of two Swagelok T-pieces that connect and seal the
lengths of concentric inner and outer tubing (1 m) to the gas and
liquid inputs. All the parts used in these reactors are commer-
cially available and no special skills or tools are required for
their construction. One unit can be built by an unskilled operat-
ive in 30 min. The total volume of pressurised gas in the reactor
itself at any one time is only 0.5 cm3. The flow setup used is
shown in Fig. 3. The solvent (methanol) is pumped from a reser-
voir by a pump (Knauer Smartline K-120) through the tube-in-
tube reactor/injector which was connected to an ammonia cylin-
der via a regulator set to 3.5 bar. The tube-in-tube configuration
used in these experiments had the liquid on the outside and the
gas on the inside. This was to facilitate rapid heat transfer and
allow heating/cooling of the tube-in-tube device by placing it in
a bath at the appropriate temperature. After taking on ammonia,
the flow stream then passes through an additional reaction coil
before passing through the back-pressure regulator at the termi-
nus of the flow system. The compression afforded by this crucial
component ensured that the gas remained in a homogeneous
solution whilst upstream of the regulator (unless specified
otherwise, homogeneous solutions of ammonia were observed at
Fig. 3 Schematic of the flow apparatus used in the Paal–Knorr pyrrole
synthesis.
all times during the course of this study). The substrate was
added to the solvent stream by means of an injection loop.
Initial studies were carried out with 1-phenyl-1,4-penta-
nedione 1a, injected ( via a 5 mL loop) as a 0.1 molar solution
in methanol (Table 1).
Given the trend towards greater solubility of gases in liquids
at low temperature, and literature reports on AF-2400,28 we
hypothesised that the rate of permeation of ammonia into the sol-
ution was likely to be higher at lower temperatures and so the
tube-in-tube device was placed in a cold bath at 0 °C. With a
flow rate of 0.4 mL min−1 and a residence-loop temperature of
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 5774–5779 | 5775

View Article Online
Table 1 Initial optimisation studies, using 1-phenyl-1,4-pentanedione
1a
Temp
Temp
Flow rate
Conversionc
(%)
Entry A.a(°C)
B.b(°C)
(mL min−1
)
1
2
3
4
5
6
0
0
0
0
0
80
100
100
110
120
120
0.4
0.4
0.3
0.3
0.3
0.3
48
62
87
100
51d
50
25
a Temperature of bath, tube-in-tube reactor submerged. b Temperature of
bath, additional reaction coil submerged. c Determined by 1H NMR of
product collected. d Outgassing upstream of back-pressure regulator.
Scheme 2 Synthesis of substrates.
80 °C, a conversion (by NMR spectroscopy) of 48% was
obtained (entry 1). To avoid the possibility of reaction continuing
after product collection, the product was isolated immediately
after collection by removal of ammonia and solvent on a rotary
evaporator under reduced pressure. The reaction appeared to be
clean; only starting material and product were observed. Increas-
ing the temperature of the residence-loop bath to 100 °C led to a
higher conversion of 62% (entry 2). When the flow rate was
reduced to 0.3 mL min−1, increasing the residence time, a con-
version of 87% was achieved (entry 3). Complete conversion
was achieved by increasing the residence-loop temperature to
110 °C (entry 4). At 120 °C, outgassing of ammonia within the
residence-loop was observed (entry 5), indicating that the back-
pressure regulator used was not providing sufficient compression
to maintain homogeneity (this could be avoided by using a
higher pressure back-pressure regulator). Raising the temperature
of the tube-in-tube reactor/injector to room temperature resulted
in a homogeneous solution upstream of the back-pressure regula-
tor once more, indicating that less ammonia was passing into sol-
ution at this higher temperature. This was borne out by the lower
conversion of 50% (entry 6).
Pleasingly, at all concentrations, including neat substrate
(density = 1.142 g mL−1, conc. = 5.6 M), quantitative conver-
sion was observed. The entire residence time in the system for
this neat sample (from the injection loop to the outlet) was
120 min, translating into a scalability of 2.8 mmol per hour
(0.57 g per hour). Having established that the reactor setup was
effective at providing a means of gas–liquid contact in these
pyrrole formations, we sought to examine quantitatively the
operation of the tube-in-tube device. Whilst the results in Table 1
indicate that lower flow rates (and therefore higher residence
times) led to higher conversions, we did not know whether this
was due to a higher concentration of ammonia being obtained
from the tube-in-tube device, or to the extra time for reaction in
the residence-loop (or a combination of these factors). We sought
to investigate the relationship between flow-rate, temperature and
ammonia concentration in methanol in the absence of a reaction.
Using the basicity of ammonia as a means to measure its concen-
tration, we opted to use an in-line colourimetric flow titration31
which would provide a straightforward visual indication. The
setup for this is shown in Fig. 4. At a particular methanol flow
rate a stream of aqueous HCl of known concentration (0.12 M)
was mixed in. The streams were mixed efficiently using an
in-line mixer that was constructed by placing three small
PTFE coated magnetic stirrer bars inside a 3 mm omnifit column
and placing this on a magnetic stirrer/hotplate.
The flow rate of this acidic stream, which had a small amount
of bromocresol green added to it as an indicator, was adjusted
until outflow from the mixer just reached the titration endpoint
(from blue to orange). From this, the number of moles of
ammonia exiting the tube-in-tube reactor per unit time was
known. Dividing this by the flow rate of methanol through the
tube-in-tube reactor gave the concentration of ammonia. Shown
in Fig. 5 are three plots (corresponding to bath temperatures of 0,
25 and 50 °C) of ammonia concentration against residence time
in the tube-in-tube reactor (the liquid volume of the device
divided by the methanol flow rate).
Using the conditions from Table 1, entry 4, the reaction was
carried out with a series of 1,4-diketones to afford substituted
pyrroles. The reactions were all performed on a 0.5 mmol scale.
The diketones 1c–h were prepared using a Stetter coupling29 of
an aldehyde 4 and a vinyl ketone 5 and the substrates 1i–j were
synthesised using the coupling of enamine 6 with phenacyl bro-
mides 7 (Scheme 2).30 The results are shown in Table 2. As can
be seen, complete conversions and very high yields were
observed in most cases. In the majority of cases, where complete
and clean conversion was observed, product isolation was
achieved simply by removing the solvent under reduced
pressure. Chromatographic purification was only used in a min-
ority of cases where conversion was less than complete or bypro-
1
ducts were observed by H NMR spectroscopy. Both aromatic
and aliphatic ketones were well tolerated. The only substrates
which did not give clean conversion were the two p-chloro-
phenylene compounds 1h and 1i, particularly the 4-(p-chloro-
phenylene)-2,5-diketo-undecane compound 1h, whose crude
NMR indicated that multiple products were obtained (entries 8,
9). In order to investigate the scalability and throughput of the
device, substrate 1a (injected via a smaller 1 mL sample loop)
was processed at a range of increasing concentrations (Table 2),
using the same conditions for all other variables.
For each temperature, the concentration of ammonia varies
approximately linearly with the residence time, indicating that
the concentration is much less than the saturation value. Satur-
ation would result in the invariance of concentration with resi-
dence time (a flat line). The slopes of the lines represent the rate
5776 | Org. Biomol. Chem., 2012, 10, 5774–5779
This journal is © The Royal Society of Chemistry 2012

View Article Online
Table 2 Results of Paal–Knorr pyrrole formation in flowa
Entry
1
Product
Conversion (%)
100
Yield (%)
100
2a
2b
2c
2d
2
3
4
100
100
100
100
87
88
5
6
2e
2f
100
89
97
63b
(99 brsm)
100
95
100
100
92
100 (0.65 M)c
100 (1.09 M)c
100 (neat)c
7
8
2g
2h
100d
33
9
2i
2j
100d
100
75
96
10
a Unless specified otherwise, all reactions were performed on a 0.5 mmol scale with a substrate. concentration of 0.1 molar and product isolation was
by removal of solvent under reduced pressure. b Separated from s.m. or impurities by column chromatography on silica gel. c 1 mL of substrate
injected at the indicated concentration. d Significant by-products also observed in 1H NMR of crude material.
Fig. 4 Inline flow titration setup.
of permeation of ammonia through the Teflon AF-2400 and
uptake into the methanol. Clearly the rate of permeation/uptake
increases with decreasing temperature. This validates the use of
separate temperature baths for the gas-injection and reaction
stages of the process and explains the higher conversion when
the tube-in-tube device was at lower temperature and the
Fig. 5 Plots of ammonia concentration in MeOH against residence
time (in tube-in-tube) at various temperatures.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 5774–5779 | 5777

View Article Online
temperatures led to higher rates of gas uptake. It appears from
experiments with DME that the rate of gas permeation is signifi-
cantly affected by the nature of the solvent.
Notes and references
1 (a) P. M. Jordan, Curr. Opin. Struct. Biol., 1994, 4, 902–911;
(b) M. T. Wilson and B. J. Reeder, Exp. Physiol., 2008, 93, 128–132.
2 (a) A. Eschenmoser, Angew. Chem., Int. Ed. Engl., 1988, 27, 5–39;
(b) R. H. Abeles and D. Dolphin, Acc. Chem. Res., 1976, 9, 114–120.
3 H. K. Lichtenthaler, Methods Enzymol., 1987, 148, 350–382.
4 P. A. Riley, Int. J. Biochem. Cell Biol., 1997, 29, 1235–1239.
5 A. V. Susekov and N. V. Khokhlova, Cardiovasc. Ther. Prevent., 2011,
10, 103–112.
6 (a) S. Faivre, G. Demetri, W. Sargent and E. Raymond, Nat. Rev. Drug
Discovery, 2007, 6, 734–745; (b) L. Q. M. Chow and S. G. Eckhardt,
J. Clin. Oncol., 2007, 25, 884–896.
7 R. K. Rajpal, B. B. Cooperman and G. Ketorolac Study, J. Refract. Surg.,
1999, 15, 661–667.
8 J. E. Levinson, E. Brewer, V. Hanson, J. Baum, C. Fink, J. Schaller and
P. S. Lietman, J. Pediatr., 1977, 91, 799–804.
Fig. 6 Plots of ammonia concentration in DME against residence time
(in tube-in-tube) at various temperatures (same scale as Fig. 5).
9 (a) A. F. Diaz, J. I. Castillo, J. A. Logan and W. Y. Lee, J. Electroanal.
Chem., 1981, 129, 115–132; (b) K. K. Kanazawa, A. F. Diaz,
R. H. Geiss, W. D. Gill, J. F. Kwak, J. A. Logan, J. F. Rabolt and
G. B. Street, Chem. Commun., 1979, 854–855.
residence-loop was at a higher temperature. What is not clear is
the exact reason for this increased permeation/uptake at lower
temperature. This could conceivably involve morphological
changes within the membrane itself (whose glass transition
temperature is 240 °C), a higher concentration of ammonia in the
gas phase, or an inherent rate increase for gas transfer across the
gas–liquid interface (or other effect or combination of effects).
To investigate what effect the nature of the solvent has on this
phenomena, we carried out the same measurements using
dimethoxyethane (DME) as solvent. The results are shown in
Fig. 6. As with MeOH, the concentration of ammonia varies
approximately linearly with residence time, and is faster at lower
temperature. However, it appears (from the more shallow gradi-
ents) that the rate of permeation/uptake into DME is lower than
in MeOH. Further investigation into these permeation/uptake
phenomena is clearly needed in order to fully delineate the
factors involved. Having established that inline titration is a
useful means of rapidly acquiring permeation/solubility data, we
are now using the technique to explore this further and will
report our findings in due course.
10 (a) V. Estevez, M. Villacampa and J. Carlos Menendez, Chem. Soc. Rev.,
2010, 39, 4402–4421; (b) C. Schmuck and D. Rupprecht, Synthesis,
2007, 3095–3110; (c) N. Ono, Heterocycles, 2008, 75, 243–284.
11 (a) C. Paal, Ber. Dtsch. Chem. Ges., 1884, 17, 2756–2767; (b) L. Knorr,
Ber. Dtsch. Chem. Ges., 1884, 17, 1635–1642; (c) V. Amarnath,
D. C. Anthony, K. Amarnath, W. M. Valentine, L. A. Wetterau and
D. G. Graham, J. Org. Chem., 1991, 56, 6924–6931; (d) R. U. Braun,
K. Zeitler and T. J. J. Müller, Org. Lett., 2001, 3, 3297–3300.
12 (a) D. Rooke, Chem. Eng.-London, 1987, 56–56; (b) J. Drahos and
J. Cermak, Chem. Eng. Process., 1989, 26, 147–164.
13 Recent reviews and examples:
(a) J. Wegner, S. Ceylan and
A. Kirschning, Adv. Synth. Catal., 2012, 354, 17–57; (b) C. Wiles and
P. Watts, Chem. Commun., 2011, 47, 6512–6535; (c) R. L. Hartman,
J. P. McMullen and K. E. Jensen, Angew. Chem., Int. Ed., 2011, 50,
7502–7519; (d) D. Webb and T. F. Jamison, Chem. Sci., 2010, 1, 675–
680; (e) T. Razzaq and C. O. Kappe, Chem.–Asian. J., 2010, 5, 1274–
1289; (f) J. I. Yoshida, Chem. Rec., 2010, 10, 332–341; (g) V. Hessel,
Chem. Eng. Technol., 2009, 32, 1655–1681; (h) D. L. Browne,
I. R. Baxendale and S. V. Ley, Tetrahedron, 2011, 67, 10296–10303;
(i) X. Y. Mak, P. Laurino and P. H. Seeberger, Beilstein J. Org. Chem.,
2009, 5, # 19; ( j) M. Brasholz, B. A. Johnson, J. M. Macdonald,
A. Polyzos, J. Tsanaktsidis, S. Saubern, A. B. Holmes and J. H. Ryan,
Tetrahedron, 2010, 66, 6445–6449; (k) D. L. Browne, M. Baumann, B.
H. Harji, I. R. Baxendale and S. V. Ley, Org. Lett., 2011, 13, 3312–3315;
(l) B. D. A. Hook, W. Dohle, P. R. Hirst, M. Pickworth, M. B. Berry and
K. I. Booker-Milburn, J. Org. Chem., 2005, 70, 7558–7564;
(m) A. R. Bogdan, S. L. Poe, D. C. Kubis, S. J. Broadwater and
D. T. McQuade, Angew. Chem., Int. Ed., 2009, 48, 8547–8550;
(n) D. L. Browne, B. J. Deadman, R. Ashe, I. R. Baxendale and
S. V. Ley, Org. Process Res. Dev., 2011, 15, 693–697; (o) P. Koos,
D. L. Browne and S. V. Ley, Green Process Synth., 2012, 1, 11–18.
14 S. V. Ley, I. R. Baxendale, R. N. Bream, P. S. Jackson, A. G. Leach,
D. A. Longbottom, M. Nesi, J. S. Scott, R. I. Storer and S. J. Taylor,
J. Chem. Soc., Perkin Trans. 1, 2000, 3815–4195.
15 M. O’Brien, R. Denton and S. V. Ley, Synthesis, 2011, 1157–1192.
16 (a) J. Kobayashi, Y. Mori, K. Okamoto, R. Akiyama, M. Ueno,
T. Kitamori and S. Kobayashi, Science, 2004, 304, 1305–1308;
(b) T. Fukuyama, T. Rahman, N. Kamata and I. Ryu, Beilstein J. Org.
Chem., 2009, 5, # 34; (c) M. Irfan, T. N. Glasnov and C. O. Kappe, Org.
Lett., 2011, 13, 984–987; (d) R. D. Chambers, M. A. Fox, G. Sandford,
J. Trmcic and A. Goeta, J. Fluorine Chem., 2007, 128, 29–33;
(e) S. Hubner, U. Bentrup, U. Budde, K. Lovis, T. Dietrich, A. Freitag,
L. Kupper and K. Jahnisch, Org. Process Res. Dev., 2009, 13, 952–960;
(f) Y. Wada, M. A. Schmidt and K. F. Jensen, Ind. Eng. Chem. Res.,
2006, 45, 8036–8042; (g) E. R. Murphy, J. R. Martinelli, N. Zaborenko,
S. L. Buchwald and K. F. Jensen, Angew. Chem., Int. Ed., 2007, 46,
1734–1737; (h) M. Hamano, K. D. Nagy and K. F. Jensen, Chem.
Commun., 2012, 48, 2086–2088; (i) P. W. Miller, L. E. Jennings,
Conclusion
We have developed an efficient, inexpensive and operationally
simple flow system for the Paal–Knorr synthesis of substituted
pyrroles from 1,4-diketones using a Teflon AF-2400 based tube-
in-tube reactor as a means to effect gas–liquid contact. A tube-
in-tube configuration that has the gas in the central tube and the
liquid on the outside facilitates efficient thermal contact and
allows the liquid to be heated or cooled as appropriate. An
optimal flow setup for the reaction had gas-injection in the tube-
in-tube device taking place at a lower temperature and the sub-
sequent reaction in a residence-loop proceeding at a higher
temperature. A simple colourimetric in-line titration technique
was used to investigate the relationship between ammonia con-
centration downstream of the tube-in-tube device and the
temperature of the device and the residence time of the solvent
in the device. The concentrations, which varied approximately
linearly with residence time, did not approach saturation. Lower
5778 | Org. Biomol. Chem., 2012, 10, 5774–5779
This journal is © The Royal Society of Chemistry 2012

View Article Online
A. J. deMello, A. D. Gee, N. J. Long and R. Vilar, Adv. Synth. Catal.,
2009, 351, 3260–3268; ( j) R. Abdallah, V. Meille, J. Shaw, D. Wenn and
C. de Bellefon, Chem. Commun., 2004, 372–373; (k) X. Han,
R. A. Bourne, M. Poliakoff and M. W. George, Chem. Sci., 2011, 2,
1059–1067; (l) C. Csajagi, B. Borcsek, K. Niesz, I. Kovacs,
Z. Szekelyhidi, Z. Bajko, L. Urge and F. Darvas, Org. Lett., 2008, 10,
1589–1592; (m) S. Saaby, K. R. Knudsen, M. Ladlow and S. V. Ley,
Chem. Commun., 2005, 2909–2911.
21 M. O’Brien, I. R. Baxendale and S. V. Ley, Org. Lett., 2010, 12, 1596–
1598.
22 M. O’Brien, N. Taylor, A. Polyzos, I. R. Baxendale and S. V. Ley, Chem.
Sci., 2011, 2, 1250–1257.
23 A. Polyzos, M. O’Brien, T. P. Petersen, I. R. Baxendale and S. V. Ley,
Angew. Chem., Int. Ed., 2011, 50, 1190–1193.
24 P. Koos, U. Gross, A. Polyzos, M. O’Brien, I. Baxendale and S. V. Ley,
Org. Biomol. Chem., 2011, 9, 6903–6908.
17 (a) X. Wang, Y. Yong, P. Fan, G. Yu, C. Yang and Z.-S. Mao, Chem. Eng.
Sci., 2012, 69, 578–586; (b) S. C. K. De Schepper, G. J. Heynderickx
and G. B. Marin, Chem. Eng. J., 2008, 138, 349–357.
18 (a) P. R. Resnick and W. H. Buck, in Fluoropolymers II, ed.
G. Hougham, P. E. Cassidy, K. Johns and T. Davidson, Kluwer Aca-
demic, New York, 1999; (b) Biogeneral Inc., 9925 Mesa Rim Road, San
Diego, California, USA. www.biogeneral.com (c) Y. P. Yampolskii,
Russ. J. Gen. Chem., 2009, 79, 657–665.
19 (a) R. A. Maurya, C. P. Park and D. P. Kim, Beilstein J. Org. Chem.,
2011, 7, 1158–1163; (b) R. A. Maurya, C. P. Park, J. H. Lee and D.
P. Kim, Angew. Chem., Int. Ed., 2011, 50, 5952–5955; (c) C. P. Park and
D. P. Kim, J. Am. Chem. Soc., 2010, 132, 10102–10106; (d) J. N. Lee,
C. Park and G. M. Whitesides, Anal. Chem., 2003, 75, 6544–6554.
20 Recently, the use of a commercial reactor, which is based on our tube-in-
tube design, was reported. No isolated yields were reported and technical
details (including the identity of the membrane material) were not dis-
closed: M. A. Mercadante and N. E. Leadbeater, Org. Biomol. Chem.,
2011, 9, 6575–6578.
25 T. P. Petersen, A. Polyzos, M. O’Brien, T. Ulven, I. R. Baxendale and
S. V. Ley, ChemSusChem, 2012, 5, 274–277.
26 S. L. Bourne, P. Koos, M. O’Brien, B. Martin, B. Schenkel,
I. R. Baxendale and S. V. Ley, Synlett, 2011, 2643–2647.
27 S. Kasinathan, S. L. Bourne, P. Tolstoy, P. Koos, M. O’Brien,
R. W. Bates, I. R. Baxendale and S. V. Ley, Synlett, 2011, 2648–2651.
28 (a) M. Rudel, J. Kruse, K. Ratzke, F. Faupel, Y. P. Yampolskii,
V. P. Shantarovich and G. Dlubek, Macromolecules, 2008, 41, 788–795;
(b) Y. P. Yampol’skii, A. M. Polyakov and A. Y. Alent’ev, Polym. Sci.
Series A, 2005, 47, 885–890.
29 H. Stetter, Angew. Chem., Int. Ed. Engl., 1976, 15, 639–647.
30 (a) G. Stork, J. Szmuszkovicz, R. Terrell, A. Brizzolara and
H. Landesman, J. Am. Chem. Soc., 1963, 85, 207–222;
(b) V. B. Anderson, M. N. Agnew, R. C. Allen, J. C. Wilker,
H. B. Lassman and W. J. Novick, J. Med. Chem., 1976, 19, 318–325.
31 For early examples of analytical continuous flow titration see:
(a) M. M. Nicholson, Anal. Chem., 1961, 33, 1328–1330;
(b) W. J. Blaedel and R. H. Laessig, Anal. Chem., 1964, 36, 1617–1623.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 5774–5779 | 5779