Thin film microfluidic synthesis of fluorescent highly substituted pyridines

Article abstract of DOI:10.1039/c4gc00881b

A facile, one pot method for the synthesis of a series of polysubstituted and 2,4,6-trisubstituted pyridines using a thin film vortex fluidic device has been developed, with the compounds obtained in good yield following simple purification procedures. Changes in fluorescence intensity and excitation/emission parameters are demonstrated through variation of functional groups, without significantly impacting on the synthetic yield. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4gc00881b

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Thin film microfluidic synthesis of fluorescent
highly substituted pyridines†
Cite this: Green Chem., 2014, 16,
3450
Lyzu Yasmin,a Paul K. Eggers,a,c Brian W. Skelton,b Keith A. Stubbsa and
Received 14th May 2014,
Accepted 9th June 2014
Colin L. Raston*c
DOI: 10.1039/c4gc00881b
www.rsc.org/greenchem
A facile, one pot method for the synthesis of a series of polysubsti- use of pyridinium salts, which are derived from the reaction of
tuted and 2,4,6-trisubstituted pyridines using a thin film vortex an halogenated-methyl ketone with pyridine. Such one-pot
fluidic device has been developed, with the compounds obtained reactions involve acetophenone, an aryl aldehyde, and
in good yield following simple purification procedures. Changes in ammonium acetate (NH4OAc). They include reactions under
fluorescence intensity and excitation/emission parameters are solventless conditions,12 the use of microwave irradiation,13–15
demonstrated through variation of functional groups, without NaOH in PEG,16,17 catalytic amounts of acetic acid,18 Preyssler-
significantly impacting on the synthetic yield.
type heteropolyacid H14[NaP5W30O110],19 bismuth triflate20
and a Brønsted acidic ionic liquid.21 Although a variety of
approaches toward gaining access to substituted pyridines
have been established, versatile and efficient methods for the
construction of the pyridine core which are compatible with
various functional groups remain highly desirable. Given the
aforementioned chemical and pharmacological significance of
the substituted pyridines, the synthesis of such types of mole-
cules is becoming an attractive area of research, in diverting
efforts to develop simple less waste generating routes for
their syntheses by further applying the principles of green
chemistry.22
An alternative strategy in minimizing the generation of by-
products/waste, is the use of process intensification strategies,
beyond the use of solventless and microwave processing, as in
dynamic thin films, which can allow for the gaining control of
formation of the kinetic favoured product over the thermo-
dynamic favoured product.23 In the present study the process
intensification device of choice is a vortex fluidic device (VFD),
where intense shear is present for the device operating in both
the so called continuous flow and confined modes of oper-
ation, which have recently been studied in detail.24 The thin
film VFD is emerging as a versatile device for a diverse range
of applications, including exfoliation of laminar material,25,26
controlled growth of nano-particles,27,28 disassembly of self-
organised systems,29 preparing mesoporous silica30 entrapping
microalgal cells,31,32 and in controlling reactivity and selecti-
vity in organic synthesis, notably in accelerating Diels–Alder
reactions,33 stereochemical control of the synthesis of calixar-
enes,34 and the synthesis of amino functionalized 2,4,6-triaryl-
pyridines, where formation of the thermodynamically favoured
Schiff base adduct of the chalcone is avoided.24 For the latter,
the same outcome is possible when using a related spinning
Development of new fluorescent organic compounds with high
functionality has been the subject of intense study for more
than a decade because of rapidly increasing applications of
organic fluorescent materials for electroluminescence (EL),
dye-lasers, sensors, probes, and phototherapeutic agents.1–3
Triarylpyridines are structurally related to the symmetrical
triaryl-thiopyrylium, triarylselenopyrylium, and triaryl-telluro-
pyrylium photosensitizers, which have been recommended for
photodynamic cell specific cancer therapy.4
Also noteworthy is that the substituted pyridyl heterocyclic
core is an extensive sub-unit seen in numerous natural pro-
ducts5,6 and is a versatile moiety in coordination chemistry,
as well as in supramolecular chemistry due to its ability to
engage in π-stacking.7–9 This provides a compelling reason to
explore alternative, more efficient and more benign methods
for the synthesis of such heterocyclic compounds. Tradition-
ally these compounds have been prepared through the reaction
of N-phenacylpyridinium salts with α,β-unsaturated ketones,
which is better known as the Kröhnke synthesis.10,11 More
recently one-pot reactions have been developed for the syn-
thesis of some triarylpyridines, in a drive to improve the
associated green chemistry metrics, especially in avoiding the
aSchool of Chemistry and Biochemistry, University of Western Australia, 35 Stirling
Highway, Crawley, WA 6009, Australia
bCentre for Microscopy, Characterisation and Analysis, University of Western
Australia, 35 Stirling Highway, Crawley, WA 6009, Australia
cSchool of Chemical and Physical Sciences, Flinders University, Bedford Park,
SA 5042, Australia. E-mail: colin.raston@flinders.edu.au
†Electronic supplementary information (ESI) available. CCDC 972818. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c4gc00881b
3450 | Green Chem., 2014, 16, 3450–3453
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disc microfluidic platform, albeit due to the limited residence
time of the liquid on the surface of the rapidly rotating disc as
a strictly continuous flow process, several passes are required
for a similar outcome relative to using the VFD.35
Table 1 Synthesis of various polysubstituted pyridines 3a–e in PEG300
using the VFD operating at 7000 rpm and 45° tilt angle at 100 °C for
30 minutes in the confined mode
Fluorescence
Herein, we further develop the utility of the VFD in gaining
access to a series of poly-substituted and N,N-dimethyl con-
taining 2,4,6-trisubstituted pyridines, and investigate the
fluorescent properties of these new molecules. The choice of
the VFD in the present study relates to its ability to scale down
under constant shear using the confined mode, in further
mapping out the novel capabilities of the microfluidic plat-
form in general, as well the potential to develop a robust
benign method for gaining access to a diverse range of
fluorescence molecules.
Previously we reported two synthetic strategies for preparing
2,4,6-triaryl pyridines. The first involved two steps, initially
forming the 1,5-diketone via a sequential aldol and Michael
addition reactions using the VFD in the continuous flow
mode. The second method was a one step method using the
VFD, as a three component condensation in the presence of
NH4OAc, also in the continuous flow mode.24 We have now
expanded these strategies through a study involving the
three component condensation involving 1-indanone 1 as the
ketone with various aldehydes 2a–e. This gains access to poly-
substituted pyridines 3a–e under the confined mode of oper-
ation of the VFD, where the intense shear arises from the cross
vector of centrifugal force and gravity, for a tube rotating at 45°
tilted relative to the horizontal position.
Yield CH3CN
R3 (%) λexc/λem (nm) λexc/λem (nm)
DMSO
Entry R1
R2
H
3a
3b
3c
3d
3e
OH
H
OH
OCH3
(CH3)2N
H
67
65
62
68
60
345/365
240/380
340/365
340/365
340/475
340/370
350/385
340/365
340/365
340/480
–C4H4–
OCH3
OH
H
H
H
H
Table 2 Synthesis of various 2,4,6-triarylpyridines 6a–e in PEG300
using the VFD operating at 7000 rpm and 45° tilt angle at 100 °C for
30 minutes in the confined mode
Fluorescence
CH3CN
λexc/λem (nm)
DMSO
λexc/λem (nm)
Entry
R1
R2
Yield (%)
6a
6b
6c
6d
6e
NO2
H
OCH3
CH3
NH2
H
NO2
H
H
H
66
59
53
62
51
330/460
—
330/435
340/450
330/445
—
—
340/440
340/460
330/465
findings further highlight the versatility of the VFD in control-
ling chemical reactions which operate beyond conventional
diffusion control. In principle, the confined mode lends itself
to robotic control for scaling up for a large number of sequen-
tial reactions of small aliquots of a reacting liquid.
The literature suggests that N,N-dimethylamino-containing
triarylpyridines are potentially efficient fluorophores,2 and
accordingly we also targeted the synthesis of 2,4,6-triarylpyri-
dines using the three component condensation for 4-(di-
methylamino)benzaldehyde 4 with different acetophenones
5a–e. Using the method established for the preparation of 3a–e
we found that this confined mode method using the VFD was
also suitable for the preparation of 6a–e, which were obtained
in good yield (Table 2).
In a typical procedure for the synthesis of 3(a–e), 1-indanone 1
(1 mmol), the aldehyde 2a–e (0.5 mmol) and NH4OAc
(2 mmol) in PEG300 (1 mL) were treated in the confined mode
of VFD at 100 °C for 30 minutes. As a control the reaction was
also carried out in a round bottom flask with a stirrer bar
under the same reaction conditions and no product formation
was observed, as determined using thin layer chromatography.
The yields of the reactions undertaken using the VFD were
good (Table 1) with little to no by-products observed. Also the
scope of the reaction regarding the different aldehydes was
found to be excellent, with a variety of different compounds
prepared. Of note is that using this three component system in
the continuous flow mode of the VFD resulted in low yields, in
consequence of the limited residence time of the liquid in the The crystal structure of 6d was also established using single
tube for less reactive aldehydes/ketones in the presence of crystal diffraction data, as a representative of the atom-to-atom
NH4OAc. Thus while continuous flow mode of the VFD has connectivity, but more importantly to establish the orientation
been used previously for the preparation of other 2,4,6-triaryl- of the planar aromatic rings relative to the central pyridine
pyridines,24 it is not applicable for the present series of com- ring (Fig. 1). Indeed the aromatic rings are essentially co-
pounds here and those discussed below, and the synthetic planar, as would be expected for the maximum overlap of elec-
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> 6b in acetonitrile. In DMSO the fluorescent intensity of 6c
was enhanced over acetonitrile whilst 6d and 6e were mildly
quenched. This data establishes that the fluorescent intensity
is dependent on the parent acetophenone group not bearing
strong electron withdrawing groups. Also, the 3D fluorescent
plots (see ESI†) indicate that the majority of the compounds
synthesised show two excitation peaks resulting in one emis-
sion peak. As first indicated by a paper focused on similar
compounds15 this probably arises from a π–π* and a n–π*
electronic transition.
Conclusions
Fig. 1 Crystal structure of 6d projected onto the plane of the central
ring.‡
We have developed a convenient, relatively low cost, one pot
preparation of polysubstituted and 2,4,6-triaryl pyridines from
readily available starting materials using the confined mode of
operation of the VFD. This is more versatile than using the
continuous flow mode of the device, where the additional
shear associated with the viscous drag as the liquid whirls
along the tube is insufficient in further accelerating the reac-
tions to overcome the consequential short residence time in
the VFD. The photo-physical properties displayed by these
compounds demonstrate that they may be promising candi-
dates for the development of putative fluorescent probes.
The green chemistry metrics of the syntheses relative to
earlier studies include: (i) efficient energy usage, as a constant
safe and ‘soft’ form of energy,24 in contrast to mechanoenergy
used in driving solventless reactions and high energy micro-
wave processing,15 (ii) establishing a one pot reaction of the
tri-substituted pyridines in PEG which is a benign reaction
medium,16 in avoiding the use of toxic volatile solvents, (iii)
avoiding the use of concentrated basic solutions as an
inherently safer process, (iv) circumventing the formation of
tron density from one ring to another, which relates to the
electronic properties of the molecules, including fluorescence.
The dihedral angles between the peripheral phenyl rings and
the central pyridine ring are 7.3(1), 6.4(1), 14.8(1)° for rings 12,
14 and 16.
With the availability of these compounds, we set out to gain
a preliminary insight into their fluorescent properties. As
shown in Table 1 and Fig. 2, the fluorescence spectra of the
compounds in series 3 displayed an increase in emission wave-
length in the order 3a < 3b < 3e. The fluorescence intensity
in series 3 followed the order 3b < 3d < 3c < 3a < 3e in aceto-
nitrile, but compounds 3b, 3c and 3a were quenched signifi-
cantly in DMSO. This data strongly suggests that strong
electron donating groups in the parent aldehyde are a key
factor to increasing the fluorescence intensity in this class of
compounds. For the 2,4,6-triarylpyridine derivatives 6a–e the
fluorescence intensity decreases in the order 6d > 6c > 6e > 6a
Fig. 2 (a) Fluorescence spectra for 3a–e in acetonitrile. (b) Fluorescence spectra for 3a–e in DMSO. (c) Fluorescence spectra for 6a–e in aceto-
nitrile. (d) Fluorescence spectra for 6a–e in DMSO.
3452 | Green Chem., 2014, 16, 3450–3453
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intermediate chalcone en route to the 1,5-diketone for conver- 12 G. W. V. Cave and C. L. Raston, J. Chem. Soc., Perkin Trans.
sion to the corresponding pyridine, and competing formation 1, 2001, 3258–3264.
of cyclohexyl ring systems,16 in minimising the generation of 13 S. Tu, T. Li, F. Shi, Q. Wang, J. Zhang, J. Xu, X. Zhu,
waste, and (v) the thin film ensures that there is rapid heat dis- X. Zhang, S. Zhu and D. Shi, Synthesis, 2005, 3045–3050.
sipation for highly exothermic and otherwise waste generating 14 S. Tu, R. Jia, B. Jiang, J. Zhang, Y. Zhang, C. Yao and S. Ji,
reactions which have been noted in the formation of such Tetrahedron, 2007, 63, 381–388.
pyridines.17 Moreover, the present findings further highlight 15 G. Yin, Q. Liu, J. Ma and N. She, Green Chem., 2012, 14,
the application of the VFD, with the ability to scale up under 1796–1798.
continuous flow, or scale down in confined mode, yet with 16 N. M. Smith, C. L. Raston, C. B. Smith and A. N. Sobolev,
dynamic thin films present for controlling reactions beyond
conventional batch processing.
Green Chem., 2007, 9, 1185–1190.
17 C. B. Smith, C. L. Raston and A. N. Sobolev, Green Chem.,
2005, 7, 650–654.
18 M. Adib, H. Tahermansouri, S. A. Koloogani, B. Mohammadi
and H. R. Bijanzadeh, Tetrahedron Lett., 2006, 47, 5957–5960.
19 M. M. Heravi, K. Bakhtiari, Z. Daroogheha and
F. F. Bamoharram, Catal. Commun., 2007, 8, 1991–1994.
20 P. V. Shinde, V. B. Labade, J. B. Gujar, B. B. Shingate and
M. S. Shingare, Tetrahedron Lett., 2012, 53, 1523–1527.
21 A. Davoodnia, M. Bakavoli, R. Moloudi, N. Tavakoli-Hoseini
and M. Khashi, Monatsh. Chem., 2010, 141, 867–870.
22 Z.-H. Ren, Z.-Y. Zhang, B.-Q. Yang, Y.-Y. Wang and
Z.-H. Guan, Org. Lett., 2011, 13, 5394–5397.
Acknowledgements
We gratefully acknowledge the Australian Research Council,
the Government of South Australia, and the Centre for
Microscopy, Characterisation and Analysis at the University of
Western Australia for support of this work.
Notes and references
23 A. Stankiewicz and J. Moulin, Chem. Eng. Prog., 2000, 22–34.
24 L. Yasmin, X. Chen, K. A. Stubbs and C. L. Raston, Sci.
Rep., 2013, 3, 2282.
‡Crystallographic data (excluding structure factors) for the structure in this
paper have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC 972818.
25 X. Chen, J. F. Dobson and C. L. Raston, Chem. Commun.,
2012, 48, 3703–3705.
26 M. H. Wahid, E. Eroglu, X. Chen, S. M. Smith and
C. L. Raston, Green Chem., 2013, 15, 650–655.
27 F. M. Yasin, R. A. Boulos, B. Y. Hong, A. Cornejo, K. S. Iyer,
L. Gao, H. T. Chua and C. L. Raston, Chem. Commun., 2012,
48, 10102–10104.
28 X. Chen, F. M. Yasin, P. K. Eggers, R. A. Boulos, X. Duan,
R. N. Lamb, K. S. Iyer and C. L. Raston, RSC Adv., 2013, 3,
3213–3217.
29 A. D. Martin, R. A. Boulos, L. J. Hubble, K. J. Hartlieb and
C. L. Raston, Chem. Commun., 2011, 47, 7353–7355.
30 C. L. Tong, R. A. Boulos, C. Yu, K. S. Iyer and C. L. Raston,
RSC Adv., 2013, 3, 18767–18770.
31 E. Eroglu, N. J. D’Alonzo, S. M. Smith and C. L. Raston,
Nanoscale, 2013, 5, 2627–2631.
32 M. H. Wahid, E. Eroglu, X. Chen, S. M. Smith and
C. L. Raston, RSC Adv., 2013, 3, 8180–8183.
33 L. Yasmin, K. A. Stubbs and C. L. Raston, Tetrahedron Lett.,
2014, 55, 2246–2248.
1 S. Coe, W.-K. Woo, M. Bawendi and V. Bulovic, Nature,
2002, 420, 800–803.
2 J.-D. Cheon, T. Mutai and K. Araki, Tetrahedron Lett., 2006,
47, 5079–5082.
3 T. Y. Ohulchanskyy, M. K. Gannon, M. Ye, A. Skripchenko,
S. J. Wagner, P. N. Prasad and M. R. Detty, J. Phys. Chem. B,
2007, 111, 9686–9692.
4 K. A. Leonard, J. P. Hall, M. I. Nelen, S. R. Davies,
S. O. Gollnick, S. Camacho, A. R. Oseroff, S. L. Gibson,
R. Hilf and M. R. Detty, J. Med. Chem., 2000, 43, 4488–4498.
5 D. Barton and D. Ollis, Comprehensive Organic Chemistry,
Pergamon Press, New York, 1979, p. 4.
6 A. R. Katritzky and C. M. Marson, Angew. Chem., Int. Ed.
Engl., 1984, 23, 420–429.
7 G. D. Henry, Tetrahedron, 2004, 60, 6043–6061.
8 M. D. Hill, Chem. – Eur. J., 2010, 16, 12052–12062.
9 E. C. Constable, R. Martinez-Manez, A. M. W. C. Thompson
and J. V. Walker, J. Chem. Soc., Dalton Trans., 1994, 1585–
1594.
34 L. Yasmin, T. Coyle, K. A. Stubbs and C. L. Raston, Chem.
Commun., 2013, 49, 10932–10934.
35 N. M. Smith, B. Corry, I. K. Swaminathan, M. Norret and
C. L. Raston, Lab Chip, 2009, 9, 2021–2025.
10 F. Kröhnke, Synthesis, 1976, 1–24.
11 F. Kröhnke, W. Zecher, J. Curtze, D. Drechsler, K. Pfleghar,
K. E. Schnalke and W. Weis, Angew. Chem., Int. Ed. Engl.,
1962, 1, 626–632.
This journal is © The Royal Society of Chemistry 2014
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