Towards aryl C-N bond formation in dynamic thin films

Article abstract of DOI:10.1039/c4ob00926f

C-N bond forming reactions are important in organic chemistry. A thin film microfluidic vortex fluidic device (VFD) operating under confined mode affords N-aryl compounds from 2-chloropyrazine and the corresponding amine, without the need for a transition

Full text of DOI:10.1039/c4ob00926f

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
COMMUNICATION
Towards aryl C–N bond formation in dynamic
thin films†
Michael N. Gandy,a Colin L. Raston*b and Keith A. Stubbs*a
Cite this: Org. Biomol. Chem., 2014,
12, 4594
Received 6th May 2014,
Accepted 22nd May 2014
DOI: 10.1039/c4ob00926f
www.rsc.org/obc
C–N bond forming reactions are important in organic chemistry. the exfoliation of graphene from graphite15 and the synthesis
A thin film microfluidic vortex fluidic device (VFD) operating under of superparamagnetic nanoparticles,16 controlling the for-
confined mode affords N-aryl compounds from 2-chloropyrazine mation of calcium carbonate polymorphs,17 room temperature
and the corresponding amine, without the need for a transition synthesis of mesoporous silica,18 and the disassembly of self
metal catalyst.
organised systems.19 These applications of the VFD relate to
the device delivering a constant form of ‘soft’ mechanoenergy
within dynamic thin films,6 rather than more intense forms of
mechanoenergy, for example sonication and ball milling.
Within a VFD a tube is rotated at high speed to generate a
centrifugal force, and if it is tilted above the horizontal orien-
tation (>0° tilt angle) then the ensuing thin film experiences
shearing forces for which the intensity thereof depends on the
various operational parameters. This includes the diameter of
the tube which is typically a 10 mm6,10–19 or 20 mm18 diameter
NMR tube. The shear forces act on the liquid contained in the
tube when operating in either the confined mode, which is for
a finite volume of liquid, or the continuous flow mode of oper-
ation.6 For the former the liquid flow is upwards at the
internal surface of the rotating tube, and downwards close to
the liquid surface (Stewartson/Ekman layers).15 For the con-
tinuous flow mode, jet feeds direct reacting liquids to the base
of the tube. Here there is intense uniform micro-mixing with
additional shear associated with the viscous drag as the
liquids whirls along the tube. Thus, the VFD facilitates both
scaling up under continuous flow mode, and small scale syn-
thesis typically encountered at the research level, in the con-
fined mode, with the latter featuring in the present study, for a
10 mm diameter tube. In addition, the confined mode lends
itself to robotic control for scaling up for a large number of
sequential reactions of small aliquots of a reacting liquid.
We report on the use of the VFD in forming C–N bonds for
a variety of different amines reacting with 2-chloropyrazine as
an archetypal aryl halide (Scheme 1). This work is part of a
program towards developing more efficient and alternative syn-
thetic protocols for targeted organic reactions using the VFD,
where the intense shear ensures that the reactions are beyond
diffusion control.
The development of useful methodologies in organic chem-
istry is fundamental to finding new and more efficient ways to
prepare targeted molecules for biological and materials appli-
cations. An area of intense research is in developing new
bond-forming reactions, notably in forming C–N bonds which
are common in nature, including in natural products, and in
synthetic compounds. Indeed, many drugs and drug candi-
dates contain C–N bonds1 and therefore the development
of efficient, cheap, scalable and environmentally friendly
methods to form such synthons is of growing importance.
Flow chemistry involving microfluidic platforms is gaining
attention as a paradigm for the controlled synthesis of organic
molecules.2–9 Most of these platforms use conventional micro-
fluidics where the liquid is confined within channels, under
laminar flow conditions, and where scaling up of the reactions
requires arrays of such channels.4 Other microfluidic plat-
forms instead function by passing liquids over rotating sur-
faces, where the dynamic thin films generated are typically
under turbulent flow conditions.6,9 Here scaling up is achieved
by simply running the same microfluidic platform for longer
times under the same conditions.
We recently developed a thin film microfluidic vortex
fluidic device (VFD), which is an efficient platform for prepar-
ing organic molecules, in controlling chemical reactivity and
selectivity.6,10,11 The VFD is also effective in a number of other
scientific endeavours, including the top-down and bottom-up
syntheses of nanomaterials,12–14 highlighted for example in
aSchool of Chemistry and Biochemistry, The University of Western Australia, Crawley,
WA 6009, Australia. E-mail: keith.stubbs@uwa.edu.au
bSchool of Chemical and Physical Sciences, Flinders University, Bedford Park,
SA 5042, Australia. E-mail: colin.raston@flinders.edu.au
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ob00926f
Typically, the formation of aryl C–N bonds is achieved
using nucleophilic aromatic substitution-based chemistry,20
4594 | Org. Biomol. Chem., 2014, 12, 4594–4597
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Communication
Scheme 1 (A) General palladium-catalysed reaction of 2-chloro-
pyrazine and organic amines. (B) Model reaction for investigating the
utility of the VFD in avoiding the use of a transition metal catalyst.
Fig. 1 Variation in isolated yield for the reaction between 2-chloropyra-
zine and morpholine when varying the choice of base, for the VFD oper-
ating at 7000 rpm, and a tilt angle of 0°, at 100 °C for 12 hours. All
reactions were conducted in triplicate with the average shown. Errors
were within 3%.
Ullmann-type couplings21 and more recently Buchwald–
Hartwig-based conditions,22 with the latter being by far the
most efficient. Given the high cost of palladium and recent
push toward greener syntheses, and with the products being
devoid of trace amounts of any metal catalyst,23 recent efforts
have highlighted some C–N bond forming reactions that avoid
the use of transition metal-based catalysis. Our attention was
drawn to the known C–N bond forming reaction involving
2-chloropyrazine and an amine, which typically involves
palladium-mediated catalysis (Scheme 1), but where the use of
palladium has been avoided, although this uses potassium
fluoride24 which is potentially an issue in avoiding the use of
toxic reagents and glass etching material. A significant devel-
opment would be to ascertain whether this chemistry could be
undertaken in the VFD, which circumvents the inefficient
mixing and heat transfer associated with traditional batch pro-
cessing.6 Furthermore, batch processing often has limitations
with respect to the yield, scalability, reproducibility from one
batch to another, and the nature of the protocol involved, for
example the order of addition of the reagents.
conditions, but the time required for maximum yield was still
12 hours (Fig. 1).
A unique feature of the VFD is that variation in the
rotational speed and angle of inclination is possible and
importantly, changing these parameters have been shown pre-
viously to affect the outcome of organic reactions. This relates
to the presence of different angular and speed dependent
shear regimes.6,10,11
Indeed, in this work the systematic variation of rotational
speed and tilt angle greatly affected the yield (Fig. 2). Changing
the tilt angle for a specific rotational speed affected the yield
in line with previous observations for other organic reac-
tions6,10,11 with lower speeds also generally giving better out-
comes. Overall, optimal conditions for this reaction favour
lower rotational speeds, which translates to thicker films of
liquid in the tube, noting that the average liquid film thick-
ness for 1 mL of solvent in the 10 mm NMR tube inclined at
45° and rotating speed at 7000 rpm is ca. 230 μm whereas at
3500 rpm it is ca. 450–230 μm.6,15 In previous studies, a tilt
angle of 45° where the cross vector of gravity and centrifugal
In the first instance, we chose to study the coupling of
2-chloropyrazine and morpholine in the confined mode of
operation of the VFD as a model reaction, given that this reaction
could be directly compared to the aforementioned batch
method.24 For this mode of operation of the VFD the shear at
high speed arises from the cross vector of centrifugal force and
gravity.15
At the outset, our general procedure involved using the VFD
at standard operating conditions (7000 rpm, 45° tilt angle6) to
couple 2-chloropyrazine and morpholine in the presence of
aqueous K2CO3 solution at 100 °C for 12 h. Gratifyingly, the
yield of the reaction was 62%, which is consistent with that
found in the literature when conducted at the same tempera-
ture, but importantly the time to achieve this yield was
reduced dramatically, by 35%. With this result in hand we
attempted to further investigate whether the processing time
could be reduced, as well as ascertaining if there were any
effects from using different bases. A selection of bases was
chosen that had differing characteristics and we used two reac-
tion times (6 and 12 hours). We found that the best base
Fig. 2 Variation in isolated yield for the reaction between 2-chloropyra-
zine and morpholine when varying the rotational speed and tilt angle of
the VFD. The optimisation procedure used aqueous K3PO4 solution at
100 °C for 12 hours. All reactions were conducted in triplicate with the
was K3PO4 with the yield of 64% using the standard operating average shown. Errors were within 3%.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 4594–4597 | 4595

View Article Online
Communication
Organic & Biomolecular Chemistry
yields to that observed at 45° (Fig. 2). At higher speeds (7000
rpm), a 60° tilt resulted in the highest yield, which is dramati-
cally different relative to a 30° tilt. This demonstrates that the
choice of tilt angle and speed is important in optimising
specific reactions on the VFD. Other reactions thus far studied
include Diels–Alder reaction,6,11 condensation of phenols with
aldehydes in forming calixarenes,10 and sequential aldol con-
densation and Michael addition reactions.6
Table 1 Synthesis of various alkylaminopyrazines using the VFD oper-
ating at 3500 rpm and 45° tilt angle at 100 °C for 12 h in confined mode.
Literature yields for the batch reaction conducted at 100 °C, for 17 h
using aqueous KF as base are shown in brackets24
With suitable reaction conditions established, we sought to
explore this system further to prepare a series of alkylamino-
pyrazines. In all cases the yields were comparable to literature
preparations of respective compounds, but achieved in a con-
siderably shorter time, and avoiding the use of KF (Table 1).
We note that the use of continuous flow mode of operation
of the VFD was limited as the lowest practical flow rate (0.1 mL
min−1) deliverable by the jet feeds does not afford sufficient
residence time to complete the reaction.
Entry
1
Product
Isolated yield (lit. yield)24 (%)
76 (70)
2
3
91 (76)
78
In conclusion, we have established a novel method for the
synthesis of alkylaminopyrazines using a VFD operating in the
confined mode. The yields of the compounds can be con-
trolled by varying the rotational speed and tilt angle of the
tube in the VFD, with a reduction in reaction time. Moreover,
this is without the addition of a transition metal catalyst, and
the scene is now set to explore the utility of the VFD in avoid-
ing the use of a catalyst for a plethora of chemical reactions.
Also of note is that the operating parameters of the VFD are
more specific for a particular reaction, in judgement relative to
earlier studies, and it appears different shear rates effect
different reactions in different ways and this will feature in
further research. The fluid dynamics in the VFD are inherently
complex for tilt angles >0° and <90° under confined mode, as
well as continuous flow mode, and increasing applications in
chemical synthesis are important in understanding the pro-
perties of the dynamic thin films generated in these devices.
Support of this work by the Australian Research Council,
the Government of South Australia, and the Centre for
Microscopy, Characterisation and Analysis at the University of
Western Australia is greatly acknowledged.
4
5
6
7
82 (52)
9
74
81 (81)
8
55
9
12
10
11
12
29
20 (28)
32
Notes and references
1 J. Bariwalab and E. Van der Eycken, Chem. Soc. Rev., 2013,
42, 9283–9303.
2 A. J. deMello, Nature, 2006, 442, 394.
3 N. M. Smith, B. Corry, K. S. Iyer, M. Norret and
C. L. Raston, Lab Chip, 2009, 9, 2021.
4 C. Lee, C. Chang, Y. Wang and L. Fu, Int. J. Mol. Sci., 2011,
12, 3263.
5 M. Faustini, J. Kim, G. Jeong, J. Kim, H. Moon, W. Ahn and
D. Kim, J. Am. Chem. Soc., 2013, 135, 14619.
6 L. Yasmin, X. Chen, K. A. Stubbs and C. L. Raston,
Sci. Rep., 2013, 3, 2282.
13
14
38 (47)
55 (58)
force is at a maximum, results in higher conversions relative to
other tilt angles ≤75°.6,15 In the present case, for lower speeds
ca. 3500 rpm and a tilt angle of 60° and 30° resulted in similar
7 S. G. Newman and K. F. Jensen, Green Chem., 2013, 15,
1456.
8 L. Y. Yeo and J. R. Friend, Biomicrofluidics, 2009, 3, 012002.
4596 | Org. Biomol. Chem., 2014, 12, 4594–4597
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Communication
9 X. Chen, S. M. Smith, K. S. Iyer and C. L. Raston, Chem. 16 E. Eroglu, N. J. D’Alonzo, S. M. Smith and C. L. Raston,
Soc. Rev., 2014, 43, 1387. Nanoscale, 2013, 5, 2627.
10 L. Yasmin, T. Coyle, K. A. Stubbs and C. L. Raston, Chem. 17 R. A. Boulos, F. Zhang, E. S. Tjandra, A. D. Martin,
Commun., 2013, 49, 10932. D. Spagnoli and C. L. Raston, Sci. Rep., 2014, 4, 3616.
11 L. Yasmin, K. A. Stubbs and C. L. Raston, Tetrahedron Lett., 18 C. L. Tong, R. A. Boulos, C. Yu, K. S. Iyer and C. L. Raston,
2014, 55, 2246. RSC Adv., 2013, 3, 18767.
12 F. M. Yasin, R. A. Boulos, B. Y. Hong, A. Cornejo, K. S. Iyer, 19 A. D. Martin, R. A. Boulos, L. J. Hubble, K. J. Hartlieb and
L. Gao, H. T. Chua and C. L. Raston, Chem. Commun., 2012,
48, 10102.
C. L. Raston, Chem. Commun., 2011, 47, 7353.
20 J. F. Bunnett and R. E. Zahler, Chem. Rev., 1951, 49, 273.
13 X. Chen, R. A. Boulos, P. Eggers and C. L. Raston, Chem. 21 G. Evano, N. Blanchard and M. Toumi, Chem. Rev., 2008,
Commun., 2012, 48, 11407. 108, 3054.
14 M. H. Wahid, E. Eroglu, X. Chen, S. M. Smith and 22 A. R. Muci and S. L. Buchwald, Top. Curr. Chem., 2002, 219, 131.
C. L. Raston, Green Chem., 2013, 15, 650. 23 A. M. Thayer, Chem. Eng. News, 2013, 91, 10.
15 X. Chen, J. F. Dobson and C. L. Raston, Chem. Commun., 24 K. Walsh, H. F. Sneddon and C. J. Moody, ChemSusChem,
2012, 48, 3703.
2013, 6, 1455.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 4594–4597 | 4597