Elemental fluorine. Part 20. Direct fluorination of deactivated aromatic systems using microreactor techniques

Article abstract of DOI:10.1016/j.jfluchem.2006.09.010

Continuous flow microreactor technology has been used for the direct fluorination of a range of deactivated di- and tri-substituted aromatic systems.

Full text of DOI:10.1016/j.jfluchem.2006.09.010

Journal of Fluorine Chemistry 128 (2007) 29–33
www.elsevier.com/locate/fluor
Elemental fluorine
Part 20. Direct fluorination of deactivated aromatic
systems using microreactor techniques§
a
Richard D. Chambers a, , Mark A. Fox , Graham Sandford
,
*
a,**
Jelena Trmcic a, Andres Goeta b
a Department of Chemistry, University of Durham, South Road, Durham DH1 3LE, United Kingdom
b Chemical Crystallography Group, Department of Chemistry, University of Durham, South Road, Durham DH1 3LE, United Kingdom
Received 14 August 2006; received in revised form 6 September 2006; accepted 7 September 2006
Available online 19 September 2006
Abstract
Continuous flow microreactor technology has been used for the direct fluorination of a range of deactivated di- and tri-substituted aromatic
systems.
# 2006 Elsevier B.V. All rights reserved.
Keywords: Gas liquid continuous flow microreactor; Direct fluorination; Fluoroarene
1. Introduction
in which the aromatic ring bears both an electron withdrawing
and electron releasing group.
Fluoroarene derivatives have been used for many applica-
tions in the life-science and materials industries [2] and are
usually synthesised on the commercial scale by either Balz–
Schiemann-type fluorodediazotisation or halogen exchange
(‘Halex’) methodologies [3]. Since both of these strategies
require multi-step synthetic sequences, a more direct method
for the synthesis of fluoroaromatic systems is the transforma-
tion of carbon–hydrogen to carbon–fluorine bonds by reaction
of an aromatic substrate with an electrophilic fluorinating
agent, such as elemental fluorine.
Recently, we have reported the successful use of various
continuous flow microreactor systems for direct fluorination
processes [6–10] and, in the context of fluorination of
aromatic derivatives, studies concerning the fluorination of
toluene [11] using falling film and microbubble microreactor
technology [12] giving largely a mixture of mono-fluoroto-
luene isomers have been described [11,13]. There are, of
course, many benefits to using continuous flow methodology
(no downtime, controllability, etc.) and the further advantages
of using microchannels as reaction vessels (better mixing,
heat transfer, control, safety, etc.) have been discussed at
length [14–16].
Grakauskas [4] showed that mono-substituted benzene
derivatives gave isomeric mixtures of fluorinated products
upon reaction with fluorine, consistent with an electrophilic
process. Recently, the use of acids as reaction media for direct
fluorination, allowed the Durham group [5,6] to fluorinate
selectively a variety of 1,4-disubstituted aromatic derivatives,
In recent years, we have developed a very effective
multichannel continuous flow modular reactor for direct
fluorination reactions (Fig. 1) and this is described in detail
in our earlier paper [10]. Fluorination of 1,3-dicarbonyl systems
occurs very effectively and multi-gram quantities of selectively
fluorinated derivatives have been produced.
§
[1] For Part 19, see R.D. Chambers, M. Parsons, G. Sandford, E. Thomas, J.
In this paper, we extend the use of our microreactor
techniques [7,9,10,17,18] to the synthesis of various fluor-
oaromatic systems derived from the fluorination of 1,4- and
1,3-disubstituted aromatic substrates. Whilst the fluorination
of 1,4-disubstituted systems using batch-wise procedures has
Trmcic, J.S. Moilliett, Tetrahedron 62 (2006) 7162–7167.
* Corresponding author. Tel.: +44 191 334 2020; fax: +44 191 384 4737.
** Corresponding author. Tel.: +44 191 334 2039; fax: +44 191 384 4737.
E-mail addresses: R.D.Chambers@durham.ac.uk (R.D. Chambers),
Graham.Sandford@durham.ac.uk (G. Sandford).
0022-1139/$ – see front matter # 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2006.09.010

30
R.D. Chambers et al. / Journal of Fluorine Chemistry 128 (2007) 29–33
Aromatic rings bearing two strong electron withdrawing
groups are, of course, relatively unreactive towards electro-
philic attack. However, reactions between such substrates and
fluorine using a microreactor is possible giving low conversions
to fluorinated products in very selective, clean reactions
(Table 2). Fluorinated products were separated by column
chromatography and identified by comparison with literature
data or full characterisation.
The conversion of 4 to products can be increased by
recycling the entire crude reaction mixture through the
microreactor device several times. For instance the chloro-
derivative 4d gave 53% conversion to product 5d after passing
through the microreactor once but this increased to 75%
conversion after two passages of the same reaction mixture
without any decrease in selectivity.
Fig. 1. Schematic representation of modular microreactor device.
In addition, 2c and 3c were characterised by X-ray
crystallography. Crystals of the fluorinated nitrophenols 2c
and 3c were grown from chloroform and their structures were
determined by X-ray crystallography (Fig. 2). In 2c, the
orientation of the hydroxy group with an Hꢀ ꢀ ꢀF distance of
been reported earlier [6], effective direct fluorination of highly
deactivated 1,3-disubstituted systems bearing two electron
withdrawing groups, has not been described previously.
˚
2.32(3) A suggests a favourable intramolecular Hꢀ ꢀ ꢀF inter-
2. Results and discussion
action. Geometry optimisations at the ab initio (MP2/6-31G*)
level of theory using the Gaussian94 package [19] located two
minima of 2c one with the hydroxy group orientated towards
the F2 atom (as in the crystal of 2c) and the other orientated
towards the H6 atom. The minimum containing an intramo-
lecular Hꢀ ꢀ ꢀF interaction is computed to be more stable than
the minimum without the Hꢀ ꢀ ꢀF interaction by ca.
4.4 kcal molꢁ1. The crystal packing in 2c is probably driven
by a strong intermolecular H1ꢀ ꢀ ꢀO2 interaction between the
Representative direct fluorination reactions of 1,4-disub-
stituted aromatic systems bearing an electron withdrawing and
releasing group, using microreactor technology, are collated in
Table 1. In each case, high selectivity and yields of
monofluorinated products are obtained using either acetonitrile
or formic acid reaction media. High relative permittivity
solvents or protonic acids have been used very effectively for
the fluorination of aromatic systems previously [5,6] because,
in these media, the fluorine molecule is rendered more
susceptible towards nucleophilic attack by interaction with
the solvent while competing free radical processes are
minimised. Indeed, the products obtained here are consistent
with an electrophilic substitution process. Typically, reactions
would be carried out over a 16 h period enabling 5–10 g of
crude product to be collected. All fluoroaromatic products were
identified by comparison with literature data [6] or comparison
with an authentic sample.
˚
hydroxy and nitro groups with a Hꢀ ꢀ ꢀO distance of 2.05(3) A.
In the unit cell of 3c, there are two unique molecules of
similar geometries forming chains along the [2 1 1] direction
˚
through hydroxyl–nitro interactions [H1Aꢀ ꢀ ꢀO2B, 1.96(4) A;
˚
H1Bꢀ ꢀ ꢀO3A, 2.08(4) A]. These chains are interconnected
˚
through weaker C–Hꢀ ꢀ ꢀO contacts (H5Bꢀ ꢀ ꢀO2B, 2.54(3) A;
˚
H3Aꢀ ꢀ ꢀO3A, 2.60(3) A) forming layers held together by
aromatic p–p interactions (Fig. 3).
In summary, these representative examples show that
direct fluorination of aromatic derivatives is effective using
Table 1
Fluorination of 1,4-disubstituted aromatic derivatives
Substrate
X
Y
Solvent
Conversion (%)
Yield 2 (%)
Yield 3 (%)
1a
1a
1b
1c
1d
1e
OCH3
OCH3
OCH3
OH
NO2
NO2
CN
CH3CN
87
43
82
67
78
91
2a, 77
2a, 78
2b, 74
2c, 71
2d, 75
2e, 82
3a, 11
3a, 4
3b, 12
3c, 18
3d, 7
3e, 9
CH3CN/HCOOH (3:2, v/v)
CH3CN
NO2
CN
HCOOH
CH3
CH3CN
OCH3
CHO
CH3CN

R.D. Chambers et al. / Journal of Fluorine Chemistry 128 (2007) 29–33
31
Table 2
Fluorination of 1,3-disubstituted aromatic derivatives
Substrate 4
X
Y
Z
Solvent
Conversion (%)
Yield 5 (%)
4a
4b
4c
4c
4d
4e
4f
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
CN
NO2
NO2
NO2
NO2
NO2
CN
CH3
OCH3
F
CH3CN
38
86
16
34
53
18
19
27
28
5a, 98
5b, 79
5c, 96
5c, 94
5d, 97
5e, 95
5f, 96
5f, 94
5g, 85
CH3CN/HCOOH (3:2, v/v)
CH3CN
F
HCOOH
Cl
H
HCOOH
CH3CN
NO2
NO2
CN
H
HCOOH
4f
4g
H
CH3CN
H
CH3CN
Fig. 2. Molecular structures of 2c and 3c. Only one of two unique molecules in the crystal of 3c is shown. Thermal ellipsoids are drawn at 30% probability level.
Selected bond lengths for 2c: C2–F2 1.3542(14), C1–O1 1.3436(16), O1–H1 0.79(3), N1–O2 1.2441(15), N1–O3 1.2201(15), C4–N1 1.4544(16).
Fig. 3. Views of the two unique molecules in the crystal of 3c with some inter- and intra-molecular hydrogen interactions.

32
R.D. Chambers et al. / Journal of Fluorine Chemistry 128 (2007) 29–33
Table 3
Fluorination of aromatic substrates using microreactor techniques
Substrate
Solvent
Substrate flowa
F2 flowa
F2 substrate
Conversion (%)
Product(s)
(%)
1a
1a
1b
1c
1d
1e
4a
4b
4c
4c
4d
4e
4f
CH3CN
0.43
0.43
0.43
0.43
0.43
0.35
0.87
0.44
0.43
0.30
0.43
0.42
0.45
0.14
0.14
1.72
1.72
1.72
1.72
1.72
1.78
2.60
1.78
1.72
1.78
1.72
1.76
1.78
1.78
1.78
4
4
87
43
82
67
78
91
38
86
16
34
53
18
19
27
28
2a, 77
2a, 78
2b, 74
2c, 71
2d, 75
2e, 82
5a, 98
5b, 79
5c, 96
5c, 94
5d, 97
5e, 95
5f, 96
5f, 94
5g, 85
3a, 11
3a, 4
3b, 12
3c, 18
3d, 7
3e, 9
CH3CN/HCOOH (3:2, v/v)
CH3CN
4
HCOOH
4
CH3CN
4
CH3CN
5
CH3CN
3
CH3CN/HCOOH (3:2, v/v)
CH3CN
4
4
HCOOH
6
HCOOH
4
CH3CN
4.2
4
HCOOH
4f
4g
CH3CN
12
12
CH3CN
a
mmol per channel per hour.
microreactor technology and offers an alternative for the large
scale synthesis of appropriate fluoroarene systems as opposed
to established batch-wise procedures.
After passing through the microreactor and outlet port,
excess fluorine gas and volatile waste products were passed
through a scrubber filled with soda lime. Liquid products were
collected in an FEP tube and the crude product mixture was
examined by 19F NMR spectroscopy. The product mixture was
added to water and extraction of the products from the aqueous
layer into dichloromethane was continued until 19F NMR
spectroscopy showed no carbon-fluorine resonances in the
aqueous layer. Washing the dichloromethane layer with
saturated NaHCO3 solution, drying (MgSO4) and evaporation
3. Experimental
3.1. General
All starting materials were obtained commercially
(Aldrich). NMR spectra were recorded in deuteriochloroform
on a Varian VXR 400S NMR spectrometer operating at
400 MHz (1H NMR), 376 MHz (19F NMR) and 100 MHz (13C
NMR). Mass spectra were recorded on a Fisons VG-Trio 1000
Spectrometer coupled with a Hewlett Packard 5890 series II gas
chromatograph using a 25m HP1 (methyl-silicone) column.
Elemental analyses were obtained on an Exeter Analytical CE-
440 elemental analyser. Accurate mass measurements were
performed at the EPSRC National Mass Spectrometry Service
Centre. Column chromatography was carried out on silica gel
(Merck no. 109385, particle size 0.040–0.063 mm) and TLC
analysis was performed on silica gel TLC plates (Merck).
Fractional distillation was performed on a Fisher Spahltrohr
MS 225 apparatus.
1
of the solvent gave an oil which was analysed by 19F and H
NMR spectroscopy and GC–MS. The composition of a
weighed crude reaction mixture was determined by GC–MS
analysis and the conversion of starting material was calculated
from GC peak areas. The amount of fluorinated derivative in the
crude product was determined by adding a known amount of
fluorobenzene to a weighed amount of the crude product
mixture. Comparison of the relative intensities of the
appropriate 19F NMR resonances gave the yield of fluorinated
derivative, based upon the amount of starting material
consumed, i.e., the conversion obtained above.
Purification of products was carried out by column
chromatography on silica gel with ethylacetate/hexane as
eluent. For all fluorination experiments, the major mono-
fluorinated products were characterised by NMR, MS and
elemental analysis and/or by comparison with literature data
[6,10,20,21] and/or an authentic sample (Aldrich, Fluorochem).
Spectral data for novel fluorinated products are listed
below.
3.2. Direct fluorination of aromatic compounds: general
procedure
After purging the apparatus with nitrogen, fluorine, as a 10%
mixture in nitrogen (v/v), was passed through the microreactor,
described in more detail elsewhere [10] via an inlet port at a
prescribed flow rate, typically around 10 ml minꢁ1 per channel,
that was controlled by a mass flow controller (Brooks1
Instruments). The microreactor was cooled by an external
cryostat to 0–10 8C as required. Substrate mixture was injected
by a mechanised syringe pump into the microreactor channel at
a prescribed flow rate through the substrate inlet port. Typically,
reactions would be carried out over a 16 h period enabling 5–
10 g of crude product to be collected. Substrate and fluorine gas
flow used for the reactions are given in Table 3.
1,2-Fluoro-3,5-dinitrobenzene (5c). (Found: [M]+, 203.9984.
3
C6H2N2O4F2 requires: [M]+, 203.9982); dF ꢁ126.0 (dd, JFF
20.8, 4JHF 7.73, F-2), ꢁ129.0 (dd, 3JFF 20.4, 3JHF 20.4, F-1); dH
8.1 (1H, m, H-6), 8.3 (1H, m, H-4); dc 115.2 (d, 3JCF 3.1, C-4),
2
117.1 (dd, JCF 22.3, 3JCF 2.3, C-6), 137.2 (m, C-3), 141.5 (m,
1
C-5), 149.5 (dd, JCF 278.1, JCF 15.7, C-2), 151.3 (dd, JCF
2
1
2
259.1, JCF 13.2, C-1); m/z (EI+) 204 ([M]+, 58%), 112 (100).
2-Chloro-1-fluoro-3,5-dinitrobenzene (5d). (Found: [M]+,
219.9683. C6H2ClFN2O4 requires [M]+, 219.9687); dF ꢁ103.3
(d, 3JHF 7.8); dH 8.1 (1H, dd, 3JHF 7.5, 4JHH 2.4, H-6), 8.5 (1H,

R.D. Chambers et al. / Journal of Fluorine Chemistry 128 (2007) 29–33
33
Table 4
Acknowledgement
Crystal data for 2c and 3c
Compound
2c
3c
We thank the EPSRC Crystal Faraday Partnership for
funding.
Formula
C6H4FNO3
157.10
Orthorhombic
7.1637(3)
11.1219(4)
7.6021(3)
90
C6H3F2NO3
175.09
M (g/mol)
Crystal system
˚
a (A)
˚
b (A)
˚
c (A)
Triclinic
References
6.8014(9)
9.7327(12)
10.0234(13)
93.181(2)
102.156(2)
97.314(2)
641.03(14)
120(2)
[1] For Part 19, see R.D. Chambers, M. Parsons, G. Sandford, E. Thomas, J.
Trmcic, J.S. Moilliet, Tetrahedron, 62 (2006) 7162–7167.
[2] R.E. Banks, B.E. Smart, J.C. Tatlow, Organofluorine chemistry, in:
P. rinciples and Commercial Applications, Plenum Press, New York, 1994
[3] J.S. Moilliet, in: R.E. Banks, B.E. Smart, J.C. Tatlow (Eds.), Organo-
fluorine Chemistry. Principles and Commercial Applications, Plenum
Press, New York, 1994, pp. 195–219.
a (8)
b (8)
g (8)
90
90
3
˚
V (A )
605.69(4)
120(2)
T (K)
¯
P1
Space group
Pna2(1)
4
[4] V. Grakauskas, J. Org. Chem. 35 (1970) 723–728.
Z
4
[5] R.D. Chambers, C.J. Skinner, J. Hutchinson, J. Thomson, J. Chem. Soc.,
Perkin Trans. I (1996) 605–609.
m (mmꢁ1
Reflns measured
)
0.159
0.182
7825
7055
[6] R.D. Chambers, J. Hutchinson, M.E. Sparrowhawk, G. Sandford, J.S.
Moilliet, J. Thomson, J. Fluorine Chem. 102 (2000) 169–173.
[7] R.D. Chambers, D. Holling, R.C.H. Spink, G. Sandford, Lab on a Chip 1
(2001) 132–137.
Reflns unique [Rint
Goodness-of-fit (on F2)
]
982 [0.0231]
1.272
3106 [0.0423]
1.071
R(F), I > 2s(I)
wRðF2Þ, all data
0.0344
0.0922
0.0627
0.1400
[8] R.D. Chambers, D. Holling, G. Sandford. UK Pat. Appl. 03/01993, 2002.
[9] R.D. Chambers, G. Sandford, Chim. Oggi. 22 (2004) 6–8.
[10] R.D. Chambers, M.A. Fox, D. Holling, T. Nakano, T. Okazoe, G.
Sandford, Lab on a Chip 5 (2005) 191–198.
dd, 4JHH 2.4, 5JHF 1.4, H-4); dc 115.5 (d, 2JCF 26.9, C-6), 116.5
(d, JCF 2.9, C-4), 123.2 (d, JCF 21.8, C-2), 146.0 (s, C-5),
149.0 (s, C-3), 160.0 (d, 1JCF 258.2, C-1); m/z (EI+) 220 ([M]+,
8%), 128 (100), 92 (98).
[11] K. Jahnisch, M. Baerns, V. Hessel, W. Ehrfeld, V. Haverkamp, H. Lowe, C.
Wille, A. Guber, J. Fluorine Chem. 105 (2000) 117–128.
[12] V. Hessel, P. Lob, H. Lowe, Chim. Oggi. 22 (2004) 10–12 (and references
therein).
4
2
[13] P. Lob, H. Lowe, V. Hessel, J. Fluorine Chem. 125 (2004) 1677–1694.
[14] O. Worz, K.P. Jackel, T. Richter, A. Wolf, Chem. Eng. Sci. 56 (2001)
1029–1033.
3.3. X-ray crystallography1
[15] S.J. Haswell, R.J. Middleton, B. O’Sullivan, V. Skelton, P. Watts, P.
Styring, Chem. Commun. (2001) 391–398.
Single crystal structure determinations were carried out
from data collected using graphite monochromated Mo Ka
radiation (l = 0.71073) on Bruker three-circle diffractometers
equipped with an APEX (for 2c) and a SMART-1K (for 3c)
CCD detector. Both data collections were carried out at 120 K
using Oxford Cryosystems Cryostream N2 flow cooling devices
[22]. Series of narrow v-scans (0.38) were performed at several
f-settings in such a way as to cover in each case a sphere of data
[16] W. Ehrfeld, V. Hessel, H. Lowe, Microreactors, New Technology for
Modern Chemistry, Wiley–VCH, New York, 2000.
[17] R.D. Chambers, M.A. Fox, D. Holling, T. Nakano, T. Okazoe, G.
Sandford, Chem. Eng. Technol. 28 (2005) 344–352.
[18] R.D. Chambers, M.A. Fox, G. Sandford, Lab on a Chip 5 (2005) 1132–
1139.
[19] M.J. Frisch, G.W. Trucks, H.B. Schlegel, P.M.W. Gill, B.G. Johnson, M.A.
Robb, J.R. Cheeseman, T. Keith, G.A. Petersson, J.A. Montgomery, K.
Raghavachari, M.A. Al-Laham, V.G. Zakrzewski, J.V. Ortiz, J.B. Fores-
man, J. Cioslowski, B.B. Stefanov, A. Nanayakkara, M. Challacombe,
C.Y. Peng, P.Y. Ayala, W. Chen, M.W. Wong, J.L. Andres, E.S. Replogle,
R. Gomperts, R.L. Martin, D.J. Fox, J.S. Binkley, D.J. Defrees, J. Baker,
J.P. Stewart, M. Head-Gordon, C. Gonzalez, J.A. Pople, Gaussian 94,
Revision E.2, Gaussian, Inc., Pittsburgh, PA, 1995.
˚
to a maximum resolution of 0.71 A. Data collection was
controlled using the SMART software [23], while raw frame
data were integrated using the SAINT program [24]. No
absorption correction was applied to any of the datasets. The
structures were solved using Direct Methods and refined by
full-matrix least squares on F2 using SHELXTL [25]. All non-
hydrogen atoms were refined with anisotropic atomic
displacement parameters (adps). Hydrogen atoms were located
from difference Fourier maps and their fractional coordinates
refined. Isotropic displacement parameters for hydrogen atoms
were restrained to that of their parent C atom, with
[20] F. Effenberger, W. Streicher, Chem. Ber. 124 (1991) 157–161.
[21] T. Kawakami, H. Suzuki, J. Chem. Soc., Perkin Trans. I (2000) 1259–
1264.
[22] J. Cosier, A.M. Glazer, J. Appl. Cryst. 19 (1986) 105–107.
[23] Bruker, SMART V5.63. Data Collection Software, Bruker Analytical X-
ray Instruments Inc., Wisconsin, USA, 2003.
[24] Bruker, SAINT V6.45A. Data Reduction Software, Bruker Analytical X-
ray Instruments Inc., Wisconsin, USA, 2003.
Uiso(H) = 1.2Ueq(C). Crystal data and experimental details
are given in Table 4.
[25] Bruker, SHELXTL, V6.12 Bruker Analytical X-ray Instruments Inc.,
Wisconsin, USA, 2001.
1
Crystallographic data (excluding structure factors) for the structures in this
paper have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication nos. CCDC 612547 and 612548. Copies of the data
can be obtained, free of charge, on application via http://www.ccdc.cam.ac.uk/
cont/retrieving.html or to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
(fax: +44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).