The Continuous-Flow Synthesis of Carboxylic Acids using CO2 in a Tube-In-Tube Gas Permeable Membrane Reactor

Article abstract of DOI:10.1002/anie.201006618

Keep it simple: A gas-liquid flow reactor has been developed based on a gas permeable tube-in-tube configuration which effectively delivers gas to a liquid substrate stream in a safe, continuous fashion. A series of carboxylic acids were prepared from the reaction of CO₂ with a range of Grignard reagents (see picture).

Full text of DOI:10.1002/anie.201006618

Communications
DOI: 10.1002/anie.201006618
Gas–Liquid Flow Chemistry
The Continuous-Flow Synthesis of Carboxylic Acids using CO2 in a
Tube-In-Tube Gas Permeable Membrane Reactor**
Anastasios Polyzos, Matthew OꢀBrien, Trine P. Petersen, Ian R. Baxendale, and Steven V. Ley*
The use of flow chemistry methods,[1] and immobilized
reagents and scavengers[2] is leading to recognizable advances
in the praxis of molecular assembly. The operation of these
processes can bring wide-ranging benefits, not the least of
which releases human resources so necessary for the intellec-
tual design and planning of the synthesis pathways. The
increasingly competitive climate of chemical research in
industrial and academic programs has necessitated a shift
from the previous inefficient downstream chemical process-
ing methods towards more sustainable approaches that better
reflect the challenges of the discovery process. To address
these issues, we have advocated the use of tools and
techniques that facilitate more of a “machine-assisted”
approach, of which flow chemistry has been particularly
useful for conducting efficient, multistep sequences leading
directly to a drug molecule[3] or even natural products.[4]
When these methods are coupled with the use of immobilized
reagents, scavengers, catch and release, and phase switching
methods, our group has shown that flow chemistry can lead to
demonstrable improvements particularly as they relate to
reaction work-ups by avoiding conventional methods of
chromatography, crystallization, distillation and aqueous
extractions or pH adjustments.[5] Furthermore, flow chemistry
methods can accommodate improved safety through incor-
poration of appropriate monitoring and remote control
methods.[6]
Flow chemical methods may overcome some of the
obstacles to their adoption in useful synthetic transforma-
tions. The introduction of gases into flow streams can be
achieved through plug-flow techniques,[7] microreactors,[8] or
mechanical mixing[9] of gas-liquid phases, however, the
resulting ambient pressures or low throughput can restrict
these approaches. We have previously reported upon the use
of gas permeable membrane tubing (Teflon AF-2400) as a
particularly effective method of delivering gas to a liquid
flow stream in a controlled manner.[10] Teflon AF-2400 is a
chemically inert copolymer of tetrafluoroethylene (TFE)
and
2,2-bis(trifluoromethyl)-4,5-difluoro-1,3-dioxole
(Figure 1).[11] The resulting polymer is an extensively micro-
porous, amorphous material with high gas permeability.[12]
The use of reactive gases in organic synthesis provides
advantages in terms of cost efficiency and work-up. Reactive
gases can often be used in excess and are readily removed
from the reaction mixture, affording cleaner synthesis pro-
cesses. However, there is a general reluctance to use reactive
gases in research laboratories largely owing to problems
related to the containment of pressurized gases, associated
safety factors, and the high capital costs and infrastructure
requirements of large scale gas-liquid reactors.
Figure 1. The tube-in-tube flow reactor: A) structure of Teflon AF-2400.
B) Schematic of the tube-in-tube reactor configuration (Teflon AF-2400
and PTFE=poly(tetrafluoroethylen)). C) Reactor assembly.
Here we extend our original concept of using gas
permeable tubing[13] to deliver gas to a substrate stream in a
continuous fashion using a new, cost-effective prototype
reactor based upon a tube-in-tube configuration. In this
arrangement the Teflon AF-2400 tubing is positioned within a
larger diameter PTFE tube containing the reactive gaseous
input stream (Figure 1). The reactor operates at pressures of
up to 10 bar (although higher pressures are achievable) and
accommodates the high flow rates generated from commer-
cially available pumping units. To demonstrate the potential
advantages and generality of this technology for gas–liquid
flow synthesis, we investigated the carboxylation of Grignard
reagents[14] to produce a collection of carboxylic acids. This
important carbon–carbon bond-forming transformation is
particularly useful in consideration of the ubiquity of
[*] Dr. A. Polyzos, Dr. M. O’Brien, T. P. Petersen, Dr. I. R. Baxendale,
Prof. S. V. Ley
Innovative Technology Centre, Department of Chemistry
University of Cambridge
Lensfield Road, Cambridge, CB1 2EW (UK)
E-mail: svl1000@cam.ac.uk
[**] We thank the following organizations for support and financial
contributions to this project: Sanofi-Aventis, CSIRO Material
Science and Engineering (A.P.), EPSRC (M.O.B.), the Danish
Agency for Science, Technology and Innovation and H. Lundbeck
A/S (T.P.P), the BP 1702 Chemistry Professorship (S.V.L.), and the
Royal Society (I.R.B.).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201006618.
1190
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 1190 –1193

carboxylic acids (and their derivatives) in medicinally rele-
vant compounds and in fine chemicals.[15] Moreover, there is
an increasing need to develop synthetic processes which
utilize CO2 as a renewable feedstock.[16]
the reaction stream. Consequently, increasing the pressure of
CO2 for higher flow rates improved conversion with a plateau
being observed at pressures above 3 bar. Beyond a pressure of
3 bar the Grignard reagent becomes limiting and almost
quantitative conversions are observed up to 6 bar of CO2,
The gas–liquid flow reactor is shown in Figure 1. A key
feature of the design is the tube-in-tube configuration, in
which the Teflon AF-2400 tubing is placed within the 1/8’’
(outer diameter) PTFE tube. This configuration allows the
flow of a substrate stream within the membrane tubing whilst
the gas fills the PTFE outer tubing and diffusion transfers the
reactive gas into the substrate stream. The Teflon AF-2400
(1.0 m, 0.28 mL) and the outer PTFE tubing are separated by
stainless steel T-pieces, thus allowing the substrate and gas
streams to be independently introduced to the reactor with
precise control of the flow rate and pressure for each input.
For the purposes of safety, the gas pressure regulator for this
prototype was set to depressurize the reactor if the 10 bar
limit was exceeded. It should also be noted that the total
volume available for the gas to occupy in the PTFE tubing is
1.5 mL and this represents an added safety feature in that only
a small volume of pressurized gas occupies the reactor at any
given time.
even at
a relatively high reagent-stream flow rate
(800 mLminÀ1). Since the reactions proceeded rapidly at
room temperature, it was not necessary to perform a temper-
ature screen.
From these optimization experiments, we concluded that
a flow rate of 400 mLminÀ1 with a CO2 pressure of 4 bar
provided a general set of conditions to achieve high con-
versions with a short residence time (42 s). The scope of these
conditions was examined using the flow configuration shown
in Figure 3. Although the Vapourtec R2 + remained identi-
Initially, we examined the synthesis of 3,5-dimethoxyben-
zoic acid (1b) from 1a to allow rapid optimization of
conditions in terms of the flow rate and pressure of CO2. A
schematic of the flow configuration for this series of reactions
is shown in Figure 2. A Vapourtec R2 + unit[17] was used to
Figure 3. Flow reactor configuration for the carboxylation of Grignard
reagents 1a–10a.
Figure 2. Flow reactor configuration for the carboxylation of Grignard
reagent 1a.
cally configured to the optimization experiments, polymer-
supported reagents were introduced to permit in-line work-up
and purification. The exiting stream from the reactor was first
directed through a glass cartridge[18] packed with polymer-
supported sulfonic acid (QP-SA) to effect removal of the
magnesium salts and concomitant protonation of the carbox-
ylate to form the corresponding acid. Product clean-up was
achieved by then directing the stream through a second
cartridge containing polymer-supported ammonium hydrox-
ide (A-900) to trap the acid in a “catch-and-release” protocol.
Following a washing step with THF to remove any unwanted
impurities, a third stream was introduced through an external
pump to release the carboxylic acid from the A-900 resin. A
solution of formic acid/THF (1:9) was sufficient to promote
the complete “release” of the acid from resin. The inclusion of
back-pressure regulators before the second T-piece (located
in between the cartridges) was necessary to ensure unidirec-
pump the Grignard reagent to the gas-liquid reactor through a
2 mL PEEK sample loop, however, any other commercial
pumping device can be used. A second stream of THF (under
argon) was used to dilute the Grignard reagent stream and
preclude blocking of the reactor by precipitation of magne-
sium salts formed during the carboxylation step. The two flow
streams were united at a T-piece and the combined streams
directed into the reactor, which was pressurized with CO2. A
liquid back-pressure regulator was installed after the exiting
T-piece to pressurize the solvent and prevent out-gassing of
the dissolved CO2 in the flow stream.
Conversion of 1a into the carboxylic acid 1b at 1 bar of
CO2 was quantitative at low flow rates (see the Supporting
Information). However, a near linear decrease in conversion
was observed with an increasing flow rate. This decrease can
be attributed to the reduced effective concentration of CO2 in
Angew. Chem. Int. Ed. 2011, 50, 1190 –1193
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
1191

Communications
tional flow through the A-900 resin cartridge when the acid
analysis, product purity exceeded 97% in all cases. This
highlights the advantage of using a reactive input gas stream
and the efficiency of the “catch-and-release” strategy, using
polymer-supported reagents.
stream was introduced and also to allow the complete
pressurization of the system to prevent out-gassing of the
dissolved CO2. Similarly, the placement of a back-pressure
regulator after the final cartridge was necessary to prevent
CO2 out-gassing within the cartridges.
To examine the scope and limitations of these conditions,
the carboxylation of a series of Grignard reagents was
investigated. Table 1 shows the yields of carboxylic acids
To examine the scalability of the prototype reactor and
the process in general, we scaled the synthesis of acid 7b to
20 mmol. The larger volumes of Grignard reagent 7a required
the Vapourtec R2 + unit to be fitted with a 20 mL sample
loop, along with large Supelco VersaFlash plastic cartridges to
accommodate the increased masses of QP-SA and A-900
polymer-supported reagents. The total flow rate was adjusted
to 1.0 mLminÀ1 to achieve total residence times similar to the
smaller scale reactions and the CO2 pressure increased to
7 bar. Compound 7b was readily scaled to 3 g and the yield of
the pure isolated product closely matched the yield of the
smaller-scale reaction, highlighting the straightforward scal-
ability of the flow process.
Table 1: Carboxylic acids[a] prepared under continuous-flow conditions
with CO2.
Substrate
Product
1
1a
1b: 93%
The prototype reactor reported here expands the syn-
thesis chemistꢀs ability to perform gas-liquid reactions in a
safe, scalable, and controlled fashion. The hazards, risks, and
precautionary measures associated with the use of traditional
high-pressure batch equipment are circumvented, as the
volume of gas occupying the reactor at any given instance
does not exceed 1–2 mL. The gas–liquid flow reactor proved
to be effective at delivering CO2 into a flow stream enabling
the generation of a series of carboxylic acids, which were
isolated in high yields and purity through the incorporation of
polymer-supported reagents in a “catch-and-release” regime.
Moreover, we have briefly demonstrated the straightforward
scale-up of gas-liquid reactions without significant modifica-
tion to reactor configuration, where carboxylic acid 7b was
prepared on a multigram scale. We envisage that these
methods can be readily extended to other synthetically
important but potentially hazardous gases such as CO, H2,
ammonia, ethylene, SO2, and NO. The simple tube-in-tube
configuration, along with the use of cost-effective and
commercially available hardware, allows all synthesis labo-
ratories to access this technology without the need for the
specialized fabrication techniques usually required for alter-
native technologies.
2
3
2a
3a
2b: 87%
3b: 86%
4
4a
4b: 100%
5
6
7
8
5a
6a
7a
8a
5b: 98%
6b: 86%
7b: 100%,
98%[b]
8b: 95%
9b: 75%
Received: October 22, 2010
Published online: December 22, 2010
9
9a
Keywords: carbon dioxide · flow chemistry · gas-liquid reactions ·
.
microreactor · polymer-supported reagents
10
10a
10b: 100%
[1] X. Y. Mak, P. Laurino, P. H. Seeberger, Beilstein J. Org. Chem.
2009, 5, DOI: 10.3762/bjoc.5.19; I. R. Baxendale, J. J. Hayward,
S. Lanners, S. V. Ley, C. D. Smith in Microreactors in Organic
Synthesis and Catalysis (Ed.: T. Wirth), Wiley-VCH, Weinheim,
2008, chap. 4.2, pp. 84 – 122; T. Fukuyama, M. T. Rahman, M.
Sato, I. Ryu, Synlett 2008, 151 – 163; J. Sedelmeier, S. V. Ley, I. R.
Baxendale, M. Baumann, Org. Lett. 2010, 12, 3618 – 3621; B.
Ahmed-Omer, J. C. Brandt, T. Wirth, Org. Biomol. Chem. 2007,
5, 733 – 740.
[2] M. Baumann, I. R. Baxendale, S. V. Ley, Synlett 2010, 749 – 752;
C. F. Carter, I. R. Baxendale, J. B. J. Pavey, S. V. Ley, Org.
Biomol. Chem. 2010, 8, 1588 – 1595; A. Palmieri, S. V. Ley, A.
Polyzos, M. Ladlow, I. R. Baxendale, Beilstein J. Org. Chem.
[a] 1 mmol scale, yields of isolated, analytically pure products are
reported. [b] Yield of isolated product at 20 mmol scale.
that were obtained from the flow arrangement shown in
Figure 3. Aryl, alkyl and alkynyl Grignard reagents were well
tolerated along with electron-donating and electron-with-
drawing substituents, and the conversion into the carboxylic
acids proceeded smoothly with good to excellent yields.
Furthermore the mesityl derivative (7a) gave an excellent
yield despite the hindered reactive center. By using 1H NMR
1192
www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 1190 –1193

2009, 5, DOI: 10.3762; I. R. Baxendale, S. V. Ley, Bioorg. Med.
Chem. Lett. 2000, 10, 1983 – 1986; F. Venturoni, N. Nikbin, S. V.
Ley, I. R. Baxendale, Org. Biomol. Chem. 2010, 8, 1798 – 1806.
[3] Z. Qian, I. R. Baxendale, S. V. Ley, Synlett 2010, 505 – 508; Z.
Qian, I. R. Baxendale, S. V. Ley, Chem. Eur. J. 2010, 16, 12342 –
12348; M. D. Hopkin, I. R. Baxendale, S. V. Ley, Chem.
Commun. 2010, 46, 2450 – 2452.
[4] I. R. Baxendale, C. M. Griffiths-Jones, S. V. Ley, G. K. Tranmer,
Synlett 2006, 427 – 430; M. Brasholz, B. A. Johnson, J. M.
Macdonald, A. Polyzos, J. Tsanaktsidis, S. Saubern, A. B.
Holmes, J. H. Ryan, Tetrahedron 2010, 66, 6445 – 6449.
Angew. Chem. 2009, 121, 4838 – 4840; Angew. Chem. Int. Ed.
2009, 48, 4744 – 4746; O. Trapp, S. K. Weber, S. Bauch, W.
Hofstadt, Angew. Chem. 2007, 119, 7447 – 7451; Angew. Chem.
Int. Ed. 2007, 46, 7307 – 7310.
[9] M. N. Kashid, L. Kiwi-Minsker, Ind. Eng. Chem. Res. 2009, 48,
6465 – 6485; N. Steinfeldt, R. Abdallah, U. Dingerdissen, K.
Jꢂhnisch, Org. Process Res. Dev. 2007, 11, 1025 – 1031; R. V.
Jones, L. Godorhazy, N. Varga, D. Szalay, L. Urge, F. Darvas, J.
Comb. Chem. 2006, 8, 110 – 116.
[10] M. OꢀBrien, I. R. Baxendale, S. V. Ley, Org. Lett. 2010, 12 1596 –
1598.
[5] C. F. Carter, I. R. Baxendale, M. OꢀBrien, J. B. J. Pavey, S. V.
Ley, Org. Biomol. Chem. 2009, 7, 4594 – 4597; I. R. Baxendale,
S. V. Ley, A. C. Mansfield, C. D. Smith, Angew. Chem. 2009, 121,
4077 – 4081; Angew. Chem. Int. Ed. 2009, 48, 4017 – 4021; I. R.
Baxendale, S. C. Schou, J. Sedelmeier, S. V. Ley, Chem. Eur. J.
2010, 16, 89 – 94.
[11] P. R. Resnick, W. H. Buck in Fluoropolymers II (Eds.: G. G.
Hougham, P. E. Cassidy, K. Johns, T. Davidson), Kluwer, New
York, 1999, pp. 25 – 34; P. R. Resnick, US Patent 3978030, 1976.
[12] I. Pinnau, L. G. Toy, J. Membr. Sci. 1996, 109, 125 – 133.
[13] Supplied by Biogeneral Inc., 9925 Mesa Rim Rd, San Diego,
CA. www.biogeneral.com.
[6] C. F. Carter, H. Lange, S. V. Ley, I. R. Baxendale, B. Wittkamp, J.
Goode, N. Gaunt, Org. Process Res. Dev. 2010, 14, 393 – 404; J. P.
McMullen, M. T. Stone, S. L. Buchwald, K. F. Jensen, Angew.
Chem. 2010, 122, 7230 – 7234; Angew. Chem. Int. Ed. 2010, 49,
7076 – 7080; J. P. McMullen, K. F. Jensen, Org. Proc. Res. Dev.
2010, 14, 1169 – 1176.
[7] M. T. Rahman, T. Fukuyama, N. Kamata, M. Sato, I Ryu, Chem.
Commun. 2006, 2236 – 2238; A. Gꢁnther, S. A. Khan, M.
Thalmann, F. Trachsel, K. F. Jensen, Lab Chip 2004, 4, 278 – 286.
[8] J. Kobayashi, Y. Mori, K. Okamoto, R. Akiyama, M. Ueno, T.
Kitamori, S. Kobayashi, Science 2004, 304, 1305 – 1308; T.
Fukuyama, T. Rahman, N. Kamata, I. Ryu, Beilstein J. Org.
Chem. 2009, 5, No. 34; N. de Mas, A. Gꢁnther, M. A. Schmidt,
K. F. Jensen, Ind. Eng. Chem. Res. 2009, 48, 1428 – 1434; N.
Wang, T. Matsumoto, M. Ueno, H. Miyamyra, S. Kobayashi,
[14] V. Grignard, C. R. Hebd. Seances Acad. Sci. 1900, 130, 1322 –
1324.
[15] L. J. Goossen, N. Rodrꢃguez, K. Goossen, Angew. Chem. 2008,
120, 3144 – 3164; Angew. Chem. Int. Ed. 2008, 47, 3100 – 3120; T.
Sakakura, J. C. Choi, H. Yasuda, Chem. Rev. 2007, 107, 2365 –
2387; A. Metzger, S. Bernhardt, G. Manolikakes, P. Knochel,
Angew. Chem. 2010, 122, 4769 – 4773; Angew. Chem. Int. Ed.
2010, 49, 4665 – 4668.
[16] T. Sakakura, K. Kohno, Chem. Commun. 2009, 1312 – 1330; M.
Mori, Eur. J. Org. Chem. 2007, 4981 – 4993.
[17] The Vapourtec R2 + /R4 flow apparatus is commercially avail-
able from Vapourtec Ltd. http://www.vapourtec.co.uk/.
[18] Omnifit glass columns are commercially available from Kinesis.
http://www.kinesis.co.uk/.
Angew. Chem. Int. Ed. 2011, 50, 1190 –1193
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
1193