New convenient synthesis of fluorescent 1,8-naphthyridines and the metal-sensing properties of the dyes

Article abstract of DOI:10.1055/s-0033-1339113

A new and efficient approach to a series of highly fluorescent non-aggregating donor-acceptor 1,8-naphthyridines is described. Examination of the photophysical properties of the 1,8-naphthyridines revealed that the presence of donor-acceptor functionality

Full text of DOI:10.1055/s-0033-1339113

1542▌
LETTER
lNetteerw Convenient Synthesis of Fluorescent 1,8-Naphthyridines and the Metal-
Sensing Properties of the Dyes
Green Fluorescent 1,8-Naphthyridines Dyes
Atul Goel,* Pankaj Nag, Shahida Umar
Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India
Fax +91(522)2771941; E-mail: atul_goel@cdri.res.in
Received: 10.03.2014; Accepted after revision: 11.04.2014
Abstract: A new and efficient approach to a series of highly fluo-
to optimize
rescent non-aggregating donor–acceptor 1,8-naphthyridines is de-
scribed. Examination of the photophysical properties of the 1,8-
naphthyridines revealed that the presence of donor–acceptor func-
tionality leads to bright green fluorescence with solvatochromism in
solvents of differing polarities. The application of these molecules
in metal sensing was also explored.
charge transfer
D
tuning of D–A
fluorophore
A
N
N
Ar
planar
nonfluorescent
N
N
Key words: 1,8-naphthyridines, lactones, non-aggregating, solva-
tochromism, metal sensing
nonplanar
highly fluorescent
Figure 1 Strategy for designing non-aggregating donor–acceptor
1,8-naphthyridines
1,8-Naphthyridines and their benzannulated derivatives
represent an important class of heterocyclic compounds
that possess a variety of pharmacological activities.1
These compounds have shown great potential in nucleic
acid biology, for example, as markers for DNA motifs or
DNA intercalators.2 Naphthyridines have also recently
found use as nanomaterials,3 chemodosimeters,4 and light
harvesters.5
We have recently demonstrated that controlled tuning and
swapping of donor and acceptor moieties can be used to
produce a marked modulation of the optical properties of
fluorenes,8 fluoranthenes,9 pyrenylarenes,10 benzo[f]quin-
olines, and benzo[f]acridines,11 potentially useful in elec-
troluminescent organic devices. More recently, we have
identified a fluoranthene dye, FLUN-550, as a fluorescent
probe for the quantification of intracellular lipid drop-
lets.12 Here, we report the synthesis of a novel series of
non-aggregating, donor–acceptor fluorescent naphthyri-
dines, their interesting photophysical properties, and their
applications in metal sensing.
Planar 1,8-naphthyridines are nonfluorescent in nature as
a result of weak (π*, n) radiative transitions from the low-
est state and of rapid intersystem crossing.6 The tendency
of planar 1,8-naphthyridines to aggregate through nonco-
valent interactions, such as parallel and antiparallel π–π
stacking, leads to a bathochromic shift in the photolumi-
nescence and reduces its quantum efficiency, thereby lim-
iting the applications of these compounds as organic
electronic materials.7 In an attempt to design new fluores-
cent naphthyridine derivatives, we proposed a strategy of
equipping the molecule with electron-donating and elec-
tron-withdrawing moieties to modulate the HOMO/LUMO
energy levels and to strengthen radiative transitions.
One of the most common approaches for the synthesis of
1,8-naphthyridines and their benzannulated derivatives is
the Friedlander strategy.13 Recently, Suárez-Ortiz et al.14
reported the synthesis of benzo[b][1,8]naphthyridin-5-
ones from silyl α-keto alkynes by using a nickel(II) cya-
nide/carbon monoxide/potassium cyanide catalytic sys-
tem in an aqueous medium. In an attempt to prepare
donor–acceptor naphthyridines, we devised a new proto-
col that exploits the reactive centers of pyran-2-ones, as
shown in Scheme 1. The key intermediates, the 2H-pyran-
2-ones 3a–e, were readily prepared from ketene S,S-ace-
tals and substituted acetophenones by means of Tominaga’s
protocol (Scheme 1).15 To prepare compounds with a do-
nor functionality, the methylsulfanyl group of substrates
3a–e was replaced by a piperidine moiety to give 6-aryl-
2-oxo-4-piperidin-1-yl-2H-pyran-3-carbonitriles 4a–e in
excellent yields (Scheme 1).16
We therefore designed several new arylated and fused
naphthyridines containing donor (D) and acceptor (A)
moieties, as shown in Figure 1. To suppress aggregation,
this molecular design induces nonplanarity through the
presence of a methyl group or methylene linker on the
naphthyridine ring; this inhibits intermolecular π–π inter-
actions, while permitting tuning of the electronic charac-
teristics (HOMO/LUMO levels) by means of donor and
acceptor groups to enhance selective metal-binding sig-
nals by an intramolecular charge-transfer (ICT) mecha-
nism.
Lactones 4a–e have three electrophilic centers at C-2, C-4,
and C-6, the last of which is highly reactive towards nu-
cleophiles because of the extended conjugation and the
presence of an electron-withdrawing substituent at the 3-
position of the pyranone ring. Finally, Michael addition of
SYNLETT 2014, 25, 1542–1546
Advanced online publication: 23.05.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339113; Art ID: st-2014-d0211-l
© Georg Thieme Verlag Stuttgart · New York

LETTER
Green Fluorescent 1,8-Naphthyridines Dyes
1543
(Φf) for the synthesized molecules are summarized in Ta-
ble 2. The fluorescence quantum yields of 6a–e ranged
from 9% to 21%, relative to harmine (see Supporting In-
formation, Figure S1).
SMe
SMe
N
4
Me
+
CN
O
CN
O
3
ii
i
MeS
MeO
5
CN
O
2
Ar
O
6
Ar
O
Table 2 Photophysical Properties of 1,8-Naphthyridines 6a–e
1
Ar
O
a
b
1a–e
2
3a–e
4a–e
Compound λmax,abs
λmax,em
(nm)
ε × 104 c
(M–1 cm–1) (cm–1)
Stokes shiftd Φfe
(nm)
(%)
Scheme 1 Synthesis of 6-aryl-2-oxo-4-piperidin-1-yl-2H-pyran-3-
carbonitriles 4a–e. Reagents and conditions: (i) KOH, DMSO, r.t.;
(ii) piperidine, MeOH, reflux.
6a
6b
6c
6d
6e
347
353
351
361
351
457
458
464
455
454
0.86
0.91
1.15
1.18
1.12
7000
6500
7000
5800
6500
21
16
9
the conjugate base of 1-(2-methyl-1,8-naphthyridin-3-
yl)ethanone17 (5) at the C-6 position of the 2H-pyran-2-
ones 4a–e, followed by decarboxylation and intramolecu-
lar cyclization, gave the functionalized 1,8-naphthyri-
14
16
dines 6a–e in good yields (Scheme 2 and Table 1).18
A
a Absorption maximum in CH2Cl2.
b Fluorescence maxima.
plausible reaction mechanism for the formation of substi-
tuted naphthyridines 6a–e is shown in Scheme 2.
c Molar extinction coefficient.
d Stokes shift (cm–1) = (1/λabs – 1/λem).
e Fluorescence quantum yield relative to harmine in 0.1 M aq H2SO4
Table 1 Synthesis of Substituted 1,8-Naphthyridines 6a–e
as a standard (Φ = 45%).
Product
Ar
Yielda (%)
Intramolecular rotation in flexible structures promotes
nonradiative decay processes that cause energy loss and
fluorescence quenching. Partial or complete inhibition of
free rotation induces rigidity in the fluorophore, promot-
ing radiative decay.19 To inhibit possible nonradiative
transitions in 6a–e, we attempted to induce rigidity in the
naphthyridine system by incorporating a methylene linker
between the naphthyridine moiety and the benzene ring.
We therefore synthesized a series of 5,6-dihydronaph-
tho[2,1-b]-1,8-naphthyridines 8a–e in good yields by
treating a mixture of the appropriate pyrancarbonitrile 4a–e
with 8,9-dihydrobenzo[b]-1,8-naphthyridin-6(7H)-one
(7)20 and potassium hydroxide in N,N-dimethylformamide
under an inert atmosphere (Table 3).
6a
6b
6c
6d
6e
Ph
65
67
64
70
61
4-ClC6H4
4-BrC6H4
4-MeOC6H4
4-Tol
a Isolated yield after purification by column chromatography.
The photophysical properties of 6a–e were examined by
UV/vis and fluorescence spectroscopy in dichlorometh-
ane. The electronic absorbance maxima (λmax,abs), emis-
sion maxima (λmax,em), and the fluorescence quantum yield
O
O
N
O
N
CN
O
CN
+
KOH–DMF
r.t., N2
N
Ar
O
O
N
N
N
Ar
4a–e
5
O
N
N
O
CN
OH
N
CN
CN
H+
O
Ar
– CO2
Ar
N
– H2O
H
N
Ar
N
N
N
N
6a–e
Scheme 2 Plausible reaction mechanism for the synthesis of functionalized 1,8-naphthyridines 6a–e
© Georg Thieme Verlag Stuttgart · New York
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A. Goel et al.
LETTER
concentration quenching. At all concentrations, the emis-
sion band of 8a corresponded exclusively to that of the
monomer at 488 nm. No bathochromic shift or additional
peaks for aggregate formation were observed, confirming
the absence of the intermolecular π–π interactions or
stacking.
Table 3 Synthesis of 5,6-Dihydronaphtho[2,1-b]-1,8-naphthyri-
dines 8a–e
O
N
N
CN
CN
N
N
7
Ar
KOH–DMF, r.t., N2
Ar
O
O
N
N
4a–e
8a–e
Product
Ar
Yielda (%)
8a
8b
8c
8d
8e
Ph
62
54
56
52
60
4-ClC6H4
4-BrC6H4
4-MeOC6H4
4-Tol
Figure 2 Fluorescence spectra of 8a at concentrations of 10–5 to 10–2
M in dichloromethane
a Isolated yields after purification by column chromatography.
As expected, rigidification of the flexible parts of fluoro-
phore reduced the nonradiative pathway and nearly dou-
bled the fluorescence quantum yields for products 8a–e
(Table 4). Compounds 8a–e showed photoluminescence
in the blue-green region (λPL = 482–488 nm) in dichloro-
methane (10–6 M), with Stokes shifts ranging from 5600
to 6700 cm–1 (see Supporting Information, Figure S1).
To investigate the stabilization of the ground and excited
states of the synthesized 5,6-dihydronaphtho[2,1-b]-1,8-
naphthyridines, we examined the absorption and photolu-
minescence spectra of 8a in a series of solvents of differ-
ing polarity indices, and we did not observe any
significant changes in the absorption spectra. Interesting-
ly, on changing the solvent, bathochromic shifts in the
photoluminescence were observed from 461 nm in nonpo-
lar cyclohexane to 488 nm in moderately polar dichloro-
methane to 517 nm in highly polar N,N-dimethyl-
formamide (Figure 3).
Table 4 Photophysical Properties of 5,6-Dihydronaphtho[2,1-b]-
1,8-naphthyridines 8a–e
a
b
Compound λmax,abs
λmax,em
(nm)
ε × 104 c
(M–1 cm–1) (cm–1)
Stokes shiftd Φfe
(nm)
(%)
8a
8b
8c
8d
8e
369
378
380
370
376
488
482
482
486
487
1.28
0.88
0.82
1.01
1.09
6700
5700
5600
6500
6100
49
40
43
42
48
a Absorption maxima in CH2Cl2.
b Fluorescence maxima.
c Molar extinction coefficient.
d Stokes shift (cm–1) = (1/λabs – 1/λem).
e Fluorescence quantum yield relative to harmine in 0.1 M aq H2SO4
as a standard (Φ = 45%).
To examine the non-aggregating behavior of the highly
fluorescent product 8a, we examined the effects of con-
centration on its photoluminescence in dichloromethane
(Figure 2). It is evident from the photoluminescence spec-
trum of 8a that the fluorescence intensity gradually in-
creased at concentrations of up to 2.5 × 10–4 M but then
decreased at concentrations above 10–2 M as a result of
Figure 3 (A) Solvatochromism, and (B) Lippert–Mataga plot of
naphthyridine 8a in solvents of increasing polarity
Synlett 2014, 25, 1542–1546
© Georg Thieme Verlag Stuttgart · New York

LETTER
Green Fluorescent 1,8-Naphthyridines Dyes
1545
The solvent sensitivity of the emission band of naphthyri- Large downfield shifts of the protons of the naphthyridine
dine 8a was further examined by means of a Lippert– moiety (Ha, Hb, Hc) were observed upon addition of
Mataga plot. Figure 3 shows the changes in the emission zinc(2+). The downfield shift can be rationalized in terms
wavelength and the Stokes shift with respect to solvent of the electron affinity of the bound cation.
polarity. A linear correlation (r2 = 0.995) between the
Stokes shift and the orientation polarizability (Δf) with a
large solvatochromism slope (6902.48) confirmed the
charge-transfer nature of the emissive state of 8a (see
Supporting Information, Table S1). The positive solvato-
chromism revealed that the excited state is strongly stabi-
lized by solvent molecules and has a high intramolecular
charge-transfer character and a large dipole moment com-
pared with the ground state.
To examine the metal-binding nature of the designed flu-
orescent donor–acceptor naphthyridines, they were
screened with a series of alkali (Li+, Na+, K+, and Cs+), al-
kaline (Mg2+, Ca2+, and Ba2+), and transition-metal ions
(Mn2+, Ni2+, Co2+, Cu2+, and Zn2+) in acetonitrile solution.
Figure 5 Portion of the 1H NMR spectrum of naphthyridine 8a (a)
in the presence and (b) the absence of Zn2+ ions
Compound 8a was selected for detailed binding studies
because of its good quantum yield. Photoluminescence
studies in the presence of the various metal ions revealed
that naphthyridine 8a showed complete fluorescence
quenching in the presence of zinc(2+) ions, but no fluores-
cence enhancement was observed with any of the ions
studied. Gradual addition of zinc(2+) ions (from 0 to 10
equivalents) to a solution of 8a successively decreased the
fluorescence, as shown in Figure 4. The fluorescence in-
tensity was dramatically reduced in the presence of 1.3
equivalents of zinc(2+) ions, complete loss of fluores-
cence occurring at 2.5 × 10–4 M (I/Io = 0.03, where I and
Io are the fluorescence intensities in the presence and ab-
sence of zinc ions, respectively).
The stoichiometry of the 8a–zinc(2+) complex was estab-
lished by the method of continuous variation (Job plot)22
(see Supporting Information, Figure S2); this showed that
8a forms a 2:1 complex with zinc(2+). Electrospray-ion-
ization mass spectrometric analysis showed a peak at m/z
–
= 995.0 corresponding to [(8a2·Zn2+) + ClO4 ] (see Sup-
porting Information, Figure S3).
The relative selectivity of the ligand 8a towards zinc(2+)
was verified by screening with a series of other metal ions
(Li+, Na+, K+, Cs+, Mg2+, Ca2+, Ba2+, Mn2+, Ni2+, Co2+, and
Cu2+) under the same conditions (see Supporting Informa-
tion, Figure S4). We found that of the metal ions tested,
only zinc(2+) ions exhibited a marked fluorescence
quenching (33-fold).
The equilibrium binding constant for the 8a–zinc(2+)
complex was evaluated for 2:1 ligand–metal complex-
ation by using a nonlinear expression23 for the fluores-
cence titration curve; this revealed strong complexation
with a binding constant (β) of 3.9 × 1010 M–2. From the
fluorimetric titration curve,24 we estimated the detection
limit of 8a for zinc(2+) to be 8.9 × 10–6 M (see Supporting
Information, Figure S5). Furthermore, Io–I increased lin-
early with increasing concentration of zinc(2+) (0 M to
3.3 × 10–5 M) when 8a was used at a concentration of
2.5 × 10–5 M (see Supporting Information, Figure S6).
Figure 4 Absorption and emission spectra of naphthyridine 8a
(2.5 × 10–5 M) in acetonitrile (λex 370 nm) upon titration with Zn2+ (0
to 2.5 × 10–4 M)
In conclusion, we have synthesized a new class of non-ag-
gregating donor–acceptor-based fluorescent benzannulat-
ed 1,8-naphthyridines and have demonstrated an efficient
method for their synthesis through C–C bond formation
without the use of a transition-metal catalyst. These mol-
ecules showed interesting photophysical properties with
high fluorescence quantum yields. We also discovered a
metal-sensing application of naphthyridine 8a, which
shows 33-fold fluorescence quenching in the presence of
zinc(2+). Further studies on these molecules for their ap-
plication as bioprobes are underway.
The addition of zinc(2+) ions might alter the energy of one
of the triplet states so that the efficiency of S1/Tn intersys-
tem crossing becomes more efficient upon coordination,
leading to fluorescence quenching. Note that there are re-
ports in the literature on many of fluorescent sensors for
zinc, with applications in ratiometric detection and bio-
imaging.21
We also studied the binding mode of naphthyridine 8a
with zinc(2+) by means of 1H NMR spectroscopy in ace-
tonitrile-d3–deutereochloroform (4:1 v/v) (Figure 5).
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1542–1546

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A. Goel et al.
LETTER
(17) Reddy, K. V.; Mogilaiah, K.; Sreenivasulu, B. J. Indian
Acknowledgment
Chem. Soc. 1986, 63, 443.
We gratefully acknowledge financial support from CSIR, New Del-
hi, India, under Network Projects (BSC0102 and BSC0114). The
spectroscopic data provided by SAIF, CDRI is gratefully acknow-
ledged. The CSIR-CDRI communication number for this article is
8657.
(18) Naphthyridines 6a–e and 8a–e; General Procedure
A mixture of the appropriate carbonitrile 4a–e (1 mmol) with
1-(2-methyl-1,8-naphthyridin-3-yl)ethanone (5; 1.2 mmol)
or 8,9-dihydrobenzo[b]-1,8-naphthyridin-6(7H)-one (7; 1.2
mmol) and KOH (1.5 mmol) in anhyd DMF (5 mL) was
stirred at r.t. under N2 for 25–30 min. When the reaction was
complete (TLC), the mixture was poured onto crushed ice
with vigorous stirring then neutralized with 10% aq HCl.
The resulting precipitate was collected by filtration and
purified by column chromatography (silica gel, CHCl3–
MeOH).
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000083.SunpfgIpi
o
o
nr
i
3-(2-Methyl-1,8-naphthyridin-3-yl)-5-piperidin-1-yl-
biphenyl-4-carbonitrile (6a)
References and Notes
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Yellow solid; yield: 262 mg (65%); mp 130–132 °C
(CHCl3–MeOH); Rf = 0.54 (CHCl3–MeOH, 24:1); IR
(KBr): 2932 (s), 2852 (s), 2213 (s), 1656 (m), 1591 (m),
1553 (m) cm–1; 1H NMR (300 MHz, CDCl3, TMS):
δ = 1.52–1.96 (m, 6 H), 2.74 (s, 3 H), 3.19–3.42 (m, 4 H),
7.03–7.71 (m, 8 H), 7.98–8.30 (m, 2 H), 9.03–9.23 (m, 1 H);
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105.0, 116.9, 117.1, 120.8, 121.3, 121.9, 127.2, 128.8,
129.0, 133.9, 136.8, 137.4, 139.4, 144.8, 146.3, 153.8,
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(KBr): 2939 (s), 2850 (w) 2214 (s), 1584 (s), 1443 (m) cm–
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Synlett 2014, 25, 1542–1546
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