Aldehyde-specific quinazoline ring-closure for highly sensitive fluorescent and redox formaldehyde detection

Article abstract of DOI:10.1246/cl.150193

Structurally tunable small signaling molecules have been specifically designed to probe-free formaldehyde concentrations as low as 0.1 ppm, establishing the utility of probing the exposure limit for safe human consumption according to the guidelines suggested by W.H.O. The substrate, 2-aminobenzoylhydrazide, fluorescent core skeleton was designed for the construction of diverse quinazoline compounds with combinatorial substituent-pending potentials via rapid condensation reactions with aldehyde groups. After identifying the fluorescent species by ¹H NMR and X-ray crystallography, we demonstrate that the fluorescent emission is substituent dependent and that, by simple structural variation, the fluorescence can be tunable through controlling internal charge transfer (ICT) within a dye platform. Finally, by introducing more electron-rich ferrocene into the substrate to further undermine the ICT process, we demonstrate highly sensitive formaldehyde sensing through dual signal output, including fluorescence and redox potential.

Full text of DOI:10.1246/cl.150193

CL-150193
Received: March 9, 2015 | Accepted: March 31, 2015 | Web Released: April 9, 2015
Aldehyde-specific Quinazoline Ring-Closure for Highly Sensitive Fluorescent
and Redox Formaldehyde Detection
Wei Huang, Fuxing Shen, and Dayu Wu*
Jiangsu Key Laboratory of Advanced Catalytic Material, School of Petrochemical Engineering,
Changzhou University, Changzhou, Jiangsu 213164, P. R. China
(E-mail: wudy@cczu.edu.cn)
Structurally tunable small signaling molecules have been
ments.15-19 Concerns over toxic exposure to formaldehyde
provide motivation to explore new methods for monitoring
aqueous HCHO in environmental samples. Additionally, despite
the development of individual single-signaling sensors, multi-
channel signaling receptors have been rarely reported on formal-
dehyde binding.20-25 As a result, developing new and practical
multisignaling sensors for formaldehyde is still a challenge.
Herein, 2-aminobenzoylhydrazide (quantum yield, Φ =
0.3%) as a synthetic platform was introduced as a fluorescent
signaling group that undergoes a “signal reduction” when
reacted with aromatic aldehyde.26 The condensation products
(1, Φ = 0.07%) exhibit weak emission relative to the starting
material. The mechanism for emission reduction is considered
to be ICT. To further validate the fluorescence source, an
electrophilic group, i.e. -NO2, was introduced into the molecular
skeleton, the synthetic species, 2 (Φ µ 0), whose emission
continues to decrease in intensity. Parallel studies reveal that
the introduction of a strong electrophilic group may give rise to
an efficient intramolecular charge-transfer process.
specifically designed to probe-free formaldehyde concentrations
as low as 0.1 ppm, establishing the utility of probing the
exposure limit for safe human consumption according to the
guidelines suggested by W.H.O. The substrate, 2-aminoben-
zoylhydrazide, fluorescent core skeleton was designed for the
construction of diverse quinazoline compounds with combi-
natorial substituent-pending potentials via rapid condensation
reactions with aldehyde groups. After identifying the fluorescent
1
species by H NMR and X-ray crystallography, we demonstrate
that the fluorescent emission is substituent dependent and that,
by simple structural variation, the fluorescence can be tunable
through controlling internal charge transfer (ICT) within a dye
platform. Finally, by introducing more electron-rich ferrocene
into the substrate to further undermine the ICT process, we
demonstrate highly sensitive formaldehyde sensing through dual
signal output, including fluorescence and redox potential.
Small signaling molecules including the chromophore,
fluorophore, and redox active toward specific functional groups,
such as aldehyde, are crucial to molecular sensing and detec-
tion.1-3 The controllable photophysical properties make these
molecules ideal for both in situ and real-time studies. Quinazo-
lines represent the most interesting group of heterocycles that
contain a pyrimidine nucleus in their structure.4-6 The interest
in synthesis of their analogs was widely invoked by interesting
biological and pharmaceutical activity including containment
of inflammatory disorders such as osteoarthritis, inflammatory
bowel syndrome, and neurodegenerative impairments.7,8 How-
ever, the emissive properties concerning the quinazoline plat-
forms were seldom reported.9 Specifically, modulation of the
electron-donating substituents on a quinazoline group affects
both internal charge transfer (ICT) and emission color, as making
this substituent more electron-rich results in ICT-blocked
emission enhancement upon guest binding. We reasoned that
anchoring a more electron-donating group on the quinazoline
group would provide a tunable emissive and sensing platform.
Meanwhile, formaldehyde (HCHO), as a volatile organic
compound (VOC) in the environment, has attracted emerging
attention during the past few years in that HCHO exposure is
of grave concern and brings about serious damage to life even
at low concentrations.10-12 Various analytical methods have
been developed for the detection of formaldehyde in the past
decades.13,14 However, most of these techniques require expen-
sive and bulky instrumentation with high power demand and
well-trained operators. The up-to-now developed formaldehyde
sensors, including film-technology-based sensors and nanostruc-
tured materials can only work in gaseous phase and require a
high temperature (200-400 °C) to achieve optimum measure-
The condensation between aromatic aldehydes and 2-
aminobenzoylhydrazide has been reported to form 1,2-dihydro-
quinazoline in both polar as well as nonpolar solvents like
methanol, acetonitrile, benzene, THF, and chloroform.27,28 The
initial hydrazone further undergoes an intramolecular nucleo-
philic addition across the azomethine group, involving a cyclic
six-membered transition state leading to the formation of the
quinazoline ring.29 The cyclization involved in this type of
reaction was proposed previously based on NMR studies.30 We
herein discovered that the pyrimidine nucleus can be systemati-
cally modulated via stepwise condensation starting from 2-
aminobenzoylhydrazide when we attempted to systematically
prepare the corresponding nitro-appending 1,2-dihydroquinazo-
line chromophore 2a-2f (Scheme 1). Analysis by 1H NMR
spectroscopy demonstrated that the final products can be
stepwise prepared to bear different substituent groups (for
details, see Supporting Information). The discovery of this novel
core skeleton was based on our original attempt at diversity-
oriented synthetic development of a novel core skeleton.
H
R
N
H
N
R-CHO
N
N
N
O
NH2
O
NO2
NO2
2
2 a-f
R
=
OCH3
NO2
F
OH
N(CH3
)
2
a
c
b
e
f
d
Scheme 1. The reaction between 2 and aromatic aldehyde to
produce the corresponding quinazoline derivatives 2a-2f.
896 | Chem. Lett. 2015, 44, 896–898 | doi:10.1246/cl.150193
© 2015 The Chemical Society of Japan

k'
(a)
h
i
H
g
N
f
l
e
c
H
HCHO
N
b
N
j
N
N
NH2
O
O
d
NO2
NO2
k
a
Figure 2. Emission spectra of 1 (1 ¯M) in acetonitrile at 0, 5, 10, 20,
40, and 80 min after the addition of 1 ppm formaldehyde.
To further examine the luminescent properties of 1 and 2
and their reaction with HCHO, the emission spectra were
recorded before and after titration with a formaldehyde aqueous
solution in acetonitrile. However, the analysis of complex 2
revealed negligible emission property and formaldehyde titration
(1 ppm) could not arouse the obvious signal enhancement that
is reminiscent of a system in which the ICT mechanism is
operative. We then discovered that species 1 reacts with HCHO
to yield the corresponding quinazolines (Figure 2). Compound 1
itself showed a weak emission maximum at 430 nm, while the
titration of HCHO (1 ppm) into the solution of 1 aroused an
increasing signal in intensity. Figure 2 indicates the typical
time-dependent emission spectra of 1 after reaction with HCHO.
Unfortunately, the titration of a lower concentration of HCHO,
below 1 ppm, aroused negligible emission changes due to an
unsatisfactory detection limit. However, these reagents quantita-
tively react with HCHO at room temperature and have a continu-
ously increasing emissive signal due to the formation of rigid
(b)
Figure 1. (a) 1H NMR spectra of the reaction between 2 (16 mM)
and formaldehyde solution (HCHO, 2 equiv) in DMSO-d6 over time. 2
is highlighted in yellow, 2-HCHO is highlighted in red, and chemical
shifts are indicated in dotted lines. The asterisks represent trace
amount of unidentified protons. (b) X-ray crystal structure of 2-
HCHO. For clarity, larger images are located in the Supporting
Information. C: grey, N: blue, O: red.
1
cyclization species, as revealed by H NMR titration studies.
The crucial issue for formaldehyde detection is the lower
detection limit. The World Health Organization (WHO) has set
a standard of 0.08 ppm averaged over 30 min. According to
these detection standards, a fast and highly sensitive sensor is
desirable. Electron-rich ferrocene was anchored on the sensing
platforms to suppress ICT and probe 3 (Φ = 0.12) was obtained
on purpose (Figure 3a). As expected, molecule 3 is sensitive
enough to detect an environmentally relevant concentration
of the HCHO molecule. Addition of 0.1 ppm of HCHO to an
acetonitrile solution of 3 affords faster signal enhancement (2.5-
fold in intensity over 120 min) than that of 1 with 1 ppm HCHO
(1.3-fold, 120 min) (Figure 3b). Titration with a high concen-
tration of methanol, acetone, and benzene (10 ppm) will not
undermine the obvious intensity changes (Figure S12, Support-
ing Information). Other aldehyde compounds, i.e., acetaldehyde,
were also tested to find aldehyde-group selective signal
enhancement. LC-MS of the titration solution showed the main
peak at 347.90 (cald. 347.19) and 359.90 (cald. 359.20) before
and after HCHO titration, respectively, (Figure S14, Supporting
Information) indicating the formation of HCHO-induced ring-
closed products, 3-HCHO, as shown in Figure 3a.
As an application of the aldehyde-specific quinazoline ring-
closure reaction, we extended the study to develop a monitoring
reagent for the determination of aqueous HCHO in the near range
from 0.1 to 1.0 ppm, because the recommended occupational
exposure limit based on irritation is 1 ppm.31 The Occupational
and Safety Health Administration (OSHA) also established
a short-term exposure limit of 2 ppm. Analysis by 1H NMR
titration spectroscopy of the congener 2 demonstrated that it can
react with HCHO (180 min; room temperature) to yield a new
species with the emergence of resonance (ppm) at 5.08 and 8.76.
(Figure 1a). Meanwhile, the disappearance of resonance at 11.88
and 6.41 suggested that the condensation reaction occurs at
both amine and imine sites. The presence of HCHO also causes
significant downfield shifts of the Hg-Hh signals on the amine-
appended benzene ring, indicative of the formation of a more
conjugated structure. The ambiguity of the 1H NMR spectra was
further resolved by obtaining crystal structures of the HCHO
condensation product, 2-HCHO (Figure 1b).32,33 Analysis of the
structures unambiguously revealed that the reaction between 2
and HCHO yields a rigid, cyclic pyrimidine heterocycle. The C-
N bond distance involving C9-N4 and C15-N3 is intermediate
between that of a normal single bond and double one in the
pyrimidine moieties of 2-HCHO, indicative of the conjugation
characteristic of the formed quinazoline.
Electrochemical sensing, in particular, is attractive from a
practical standpoint because the signals can be easily read out
on-site. Previous studies on complexation of ferrocene with
binding ligands have shown that a positive shift of the FeII/FeIII
redox couple is observed.34-36 Because the electron-rich cyclo-
pentadienyl group is coplanar with the pyrimidine block, the
electronic density within the ferrocene group is influenced by the
HCHO-induced formation of more electronic conjugation along
Chem. Lett. 2015, 44, 896–898 | doi:10.1246/cl.150193
© 2015 The Chemical Society of Japan | 897

2
3
B. K. Wagner, H. A. Carrinski, Y.-H. Ahn, Y. K. Kim, T. J. Gilbert, D. A.
Fomina, S. L. Schreiber, Y.-T. Chang, P. A. Clemons, J. Am. Chem. Soc.
2008, 130, 4208.
V. C.-L. Wong, H. L. Cash, J. Morse, S. Lu, A. Zhitkovich, Cell Cycle
2012, 11, 2526.
a
b
c
1µA
3-HCHO
3
4
5
6
7
C. Shih, E. L. Fritzen, J. S. Swenton, J. Org. Chem. 1980, 45, 4462.
H. Nakamura, H. Yamamoto, Chem. Commun. 2002, 1648.
G. Stájer, A. E. Szabó, P. Sohár, Heterocycles 1999, 51, 1849.
B. Jiang, S.-J. Tu, P. Kaur, W. Wever, G. Li, J. Am. Chem. Soc. 2009, 131,
11660.
3
3-HCHO
.00 0.15 0.30 0+.45 0.60
Potential
-0.4
/
V
(vs. Fc /Fc)
-0.2
0.0
0.2
0.4
0.6
0.8
Potential / V (vs. Fc+/Fc)
8
9
Z. Chen, J. Chen, M. Liu, J. Ding, W. Gao, X. Huang, H. Wu, J. Org.
Chem. 2013, 78, 11342.
a) S. Achelle, J. Rodríguez-López, F. Robin-le Guen, J. Org. Chem. 2014,
79, 7564. b) D. Liu, Z. Zhang, H. Zhang, Y. Wang, Chem. Commun. 2013,
49, 10001.
Figure 3. (a) Reaction scheme of substance 3 with HCHO. (b)
Emission spectra of 3 (10 ¯M) with 15 min interval after the addition
of 0.1 ppm HCHO over time. (c) CV in CH3CN (10 ¯M) of free 3
(black) and upon titration of 1 ppm formaldehyde after 30 minutes
(red). Inset is the corresponding DPV changes before and after
addition of formaldehyde.
10 Y. Suzuki, N. Nakano, K. Suzuki, Environ. Sci. Technol. 2003, 37, 5695.
11 M. R. Ashmore, C. Dimitroulopoulou, Atmos. Environ. 2009, 43, 128.
12 N. Fiedler, R. Laumbach, K. Kelly-McNeil, P. Lioy, Z.-H. Fan, J. Zhang,
J. Ottenweller, P. Ohman-Strickland, H. Kipen, Environ. Health Perspect.
2005, 113, 1542.
13 I. Castro-Hurtado, G. G. Mandayo, E. Castaño, Thin Solid Films 2013,
548, 665.
14 E.-X. Chen, H. Yang, J. Zhang, Inorg. Chem. 2014, 53, 5411.
15 X. Lai, D. Wang, N. Han, J. Du, J. Li, C. Xing, Y. Chen, X. Li, Chem.
Mater. 2010, 22, 3033.
16 L. Zhang, J. Zhao, J. Zheng, L. Li, Z. Zhu, Appl. Surf. Sci. 2011, 258, 711.
17 L. Wang, J. Deng, T. Fei, T. Zhang, Sens. Actuators, B 2012, 164, 90.
18 P.-R. Chung, C.-T. Tzeng, M.-T. Ke, C.-Y. Lee, Sensors (Basel Switzer-
land) 2013, 13, 4468.
19 L. Xu, R. Xing, J. Song, W. Xu, H. Song, J. Mater. Chem. C 2013, 1,
2174.
20 K. Kawamura, K. Kerman, M. Fujihara, N. Nagatani, T. Hashiba, E.
Tamiya, Sens. Actuators, B 2005, 105, 495.
21 N. Wang, X. Wang, Y. Jia, X. Li, J. Yu, B. Ding, Carbohydr. Polym. 2014,
108, 192.
22 R. Barik, S. K. Tripathy, M. Mohapatra, J. Mater. Sci. 2014, 49, 5345.
23 Q. Ma, H. Cui, X. Su, Biosens. Bioelectron. 2009, 25, 839.
24 H. Xie, C. Sheng, X. Chen, X. Wang, Z. Li, J. Zhou, Sens. Actuators, B
2012, 168, 34.
25 Q. Meng, T. Han, G. Wang, N. Zheng, C. Cao, S. Xie, Sens. Actuators, B
2014, 196, 238.
26 The absolute emission quantum efficiency was measured using the
Edinburgh integrating sphere accessory following the De Mello method.
See: J. C. de Mello, H. F. Wittmann, R. H. Friend, Adv. Mater. 1997, 9,
230.
27 R. S. Hoonur, B. R. Patil, D. S. Badiger, R. S. Vadavi, K. B. Gudasi, P. R.
Dandawate, M. M. Ghaisas, S. B. Padhye, M. Nethaji, Eur. J. Med. Chem.
2010, 45, 2277.
28 D. Tinguiano, A. Sy, I. E. Thiam, M. Gaye, P. Retailleau, Acta
Crystallogr., Sect. E: Struct. Rep. Online 2012, 68, 2374.
29 K. B. Gudasi, R. S. Vadavi, R. V. Shenoy, M. S. Patil, S. A. Patil, M.
Nethaji, Transition Met. Chem. (Weinh.) 2005, 30, 661.
30 F. Fülöp, M. Simeonov, K. Pihlaja, Tetrahedron 1992, 48, 531.
31 D. Paustenbach, Y. Alarie, T. Kulle, N. Schachter, R. Smith, J. Swenberg,
H. Witschi, S. B. Horowitz, J. Toxicol. Environ. Health 1997, 50, 217.
32 The light yellow crystals suitable for X-ray diffraction were obtained by
slow diffusion of Et2O vapor into the titration solution.
33 Crystallographic data for the structures in the form of CIF files have been
deposited with the Cambridge Crystallographic Data Centre as supple-
mentary publication No. CCDC 1038004. Copy of the data can be
obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html or
from the Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, UK (fax: (+44) 1223 336033; E-mail: deposit@
ccdc.cam.ac.uk).
the -N-N- bridge. The amplified fluorogenical responses
corresponding to the HCHO-induced conjugatation formation
should be accompanied with a significant shift of the redox
potential of the ferrocenyl group. As shown in Figure 3c, the
cyclic voltammetric (CV) and differential pulse voltammetric
(DPV) analyses of the substance 3 in an acetonitrile solution
exhibit a quasi-reversible one-electron redox process around
190 mV vs. Fc+/Fc. The addition of 1 ppm HCHO could induce
a significant anodical shift of the ferrocene/ferrocenium redox
couple of 60 and 32 mV in CV and DPV plots, respectively,
over time. The linear relation between peak currents and the
square root of the scan rates demonstrate that the diffusion-
controlled process is dominant. (Figure S15)
In conclusion, we have shown that the quinazoline plat-
forms can be structurally tunable toward highly sensitive
detection of formaldehyde. This acyclic to cyclic “signal
amplification” mechanism is unique, and we suggest that it is
the origin of the excellent aldehyde selectivity observed at room
temperature. We also demonstrate that the emission efficiency is
easily modulated by making changes to the electron-donating
ability in the conjugated backbone. Finally, signal transduction
is optimized by systematically controlling intramolecular charge
transfer, which affords enhanced fluorescence signals even in the
presence of a low concentration of formaldehyde and enables
an enhanced sensitivity during formaldehyde sensing to be
achieved. This sensing scheme, while generic to aldehyde by the
nature of its specific design and the key photophysical probing
properties, might have application in both real-time sensing and
array-based sensor strategies.
We thank the financial support by the Priority Academic
Program Development of Jiangsu Higher Education Institutions
(PAPD). This experiment work is financially funded by NSFC
program (Nos. 21371010 and 21471023) and sponsored by
Jiangsu Provincial QingLan Project.
Supporting Information is available electronically on J-STAGE.
References and Notes
1
D. J. Lloyd, D. J. St Jean, Jr., R. J. M. Kurzeja, R. C. Wahl, K. Michelsen,
R. Cupples, M. Chen, J. Wu, G. Sivits, J. Helmering, R. Komorowski,
K. S. Ashton, L. D. Pennington, C. Fotsch, M. Vazir, K. Chen, S. Chmait,
J. Zhang, L. Liu, M. H. Norman, K. L. Andrews, M. D. Bartberger, G.
Van, E. J. Galbreath, S. L. Vonderfecht, M. Wang, S. R. Jordan, M. M.
Véniant, C. Hale, Nature 2013, 504, 437.
34 D. Wu, W. Huang, Z. Lin, C. Duan, C. He, S. Wu, D. Wang, Inorg. Chem.
2008, 47, 7190.
35 P. R. Singh, A. Q. Contractor, Int. J. Environ. Anal. Chem. 2005, 85, 831.
36 A. J. Tchinda, E. Ngameni, A. Walcarius, Sens. Actuators, B 2007, 121,
113.
898 | Chem. Lett. 2015, 44, 896–898 | doi:10.1246/cl.150193
© 2015 The Chemical Society of Japan