Microwave-assisted synthesis and photophysical studies of novel fluorescent N-acylhydrazone and semicarbazone-7-OH-coumarin dyes

Article abstract of DOI:10.1039/c6nj01532h

A microwave-assisted synthesis of novel N-acylhydrazone and semicacarbazone-7-hidroxy-coumarins derivatives, starting from 3-acetyl-7-hydroxy-2H-chromen-2-one, is described. This optimized protocol led to higher yields and considerable reduction in reaction time from ～24 to ～1 hour. Aqueous solutions of these compounds showed bright blue to cyan emission and maximum quantum yields of 0.244. The stereoelectronic effects of the attached groups led to modulation of the spectral characteristics by favoring syn or anti amide conformers. The synthesized compounds showed pH dependent luminescence and a strong batochromic shift up to 65 nm in a low polarity medium (methanol) due to a better stabilization of the syn-conformer promoting this redshifted emission. These characteristics can be exploited for designing new luminescent probes for pH as well as polar microenvironments.

Full text of DOI:10.1039/c6nj01532h

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Microwave-Assisted Synthesis and Photophysical Studies of Novel
Fluorescent N-acylhydrazone and Semicarbazone-7-OH-Coumarin
Dyes
Received 00th January 20xx,
Accepted 00th January 20xx
Thiago Moreira Pereira,a Felipe Vitório,a Ronaldo Costa Amaral,b Kassio Papi Silva Zanoni,b Neyde
Yukie Murakami Ihab and Arthur Eugen Kümmerle*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
A microwave-assisted synthesis of novel N-acylhydrazone and semicacarbazone-7-hidroxy-coumarins derivatives, starting
from 3-acetyl-7-hydroxy-2H-chromen-2-one, is described. This optimized protocol led to higher yields and considerable
reduction in reaction times of ~23 hours. Aqueous solutions of these compounds showed bright blue to cyan emission and
maximum quantum yields of 0.244. The stereoelectronic effects of the attached groups led to modulation of the spectral
characteristics by favoring syn or anti amide conformers. The synthesized compounds showed pH dependent
luminescence and a strong batochromic shift up to 65 nm in a less polar medium (methanol) due to a better stabilization
of syn-conformer promoting this redshifted emission. These characteristics can be exploited for designing new
luminescent probes for pH as well as polar microenvironments.
coumarins were designed by molecular hybridization20 of a
fluorescent 7-OH-coumarin nucleus (blue, Figure 1) with N-
acylhydrazone and/or semicarbazone moieties (green and red,
Introduction
Coumarins are widely described organic heterocycles, with
numerous methodologies in synthesis,1-5 that find applications
in science and technology,6-7 such as optical brighteners,6
biological and polymeric matrix probes,6-8 fluorescent sensors,7
both in water and in micellar systems,7-9 mainly due to their
interesting emissive characteristics that are often responsive
to the environment.
Figure 1), which are known as privileged structures21 capable
of interacting with a variety of biological systems. Different
groups were selected as substituents in “R” aiming to change
the carbonyl electron density, which in turn is directly attached
to the hydrazone moiety that can exert a π-conjugation
extension with the fluorescent coumarin nucleus. Therefore,
the influence of the "R" group on the photophysical
characteristics of the synthesized compounds was evaluated.
The emergence of new fluorescent labeling led to new
strategies for visualization of biochemical systems and
complex mixtures, with an increasing interest in making
variations in the molecular structure for specific medical
applications such as diagnostics, therapeutics and
biomaterials.10-12 In biological systems, water is the main
solvent and pH can be addressed to some pathologies13-15 or
organelle characteristics. Synthetic polar and pH-dependent
fluorescent probes with simple structures15,16 can be employed
in cellular experiments, both in vitro and in vivo,17 encouraging
the development of highly selective molecules for specific cells
with certain pathologies.17-19
Figure 1. Designed fluorescent N-acylhydrazone- and semicarbazone-7-OH-
coumarins.
In this work, new N-acylhydrazone- and semicarbazone-7-OH-
Results and discussion
Synthesis of coumarins
Coumarin dyes (3a-h) were synthesized by a three-step
protocol. As shown in Scheme 1, the first step was the
synthesis of 3-acetyl-7-hydroxy-2H-chromen-2-one
means of Knoevenagel condensation between 4-
hydroxysalicylaldehyde and ethyl acetoacetate ),
(1) by
a
(
4
)
(5
refluxing in ethanol for 24h using piperidine (0.15eq) as
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catalyst, Scheme 1. The ketone (
1)
was obtained after apparatus to avoid evaporation. Although yields of the desired
products were good (70-88%), the total consumption of the
precipitation (64% yield).
ketone (1), monitored by thin layer chromatography, was
observed only after 24 h.
Aiming to decrease reaction times for 3a-h, microwave
reaction conditions were evaluated, Table 1. In fact, the
microwave assisted synthesis has already been proven suitable
in obtaining different N-acylhydrazones from common
aromatic ketones but never from coumarin ketones.24-25
At first, the microwave synthesis was carried out using similar
conditions to the reflux method – i.e. one drop of acetic acid in
ethanol at 80 oC – leading to a decrease in the reaction time of
compound 3a to 45 min. This compound was obtained with
Scheme 1. Synthesis of 3-acetyl-7-hydroxy-2H-chromen-2-one (1).
The second step was the synthesis of hydrazides (2b-h),
Scheme 2, as previously described.22 Aromatic aldehydes (6b-
g
) were converted to their correspondent esters (7b-g) by
means of a Yamada oxidation23 and subsequently reacted with
93% yield with no traces of starting reactant (
acylhydrazone 3b-h reactions still presented
amount of the ketone precursor ( ). Reactions at higher
1
), yet the N-
hydrazine hydrate leading to substituted benzohydrazides (2b-
(
)
a
certain
g) (78 to 91% yield). 2-methylimidazo[1,2-a]pyridinyl hydrazide
1
(
2h) was synthesized (84% yield) by hydrazinolysis of the 2-
temperatures were also attempted in sealed tubes, however
no differences were observed by increasing the temperature
to 100 °C, and the further increase to 150 °C led to
degradations (monitored by thin layer chromatography).
Therefore, a new condition was evaluated using three drops of
acetic acid instead of using only one, with the reaction under
80 °C for 1 hour. This set of conditions was the most effective
in decreasing the reaction times for N-acylhydrazone
compounds (3b-h) with higher yields when compared to the
synthesis under conventional heating, Table 1.
methylimidazo[1,2-a]pyridinyl derivative (10) precursor, which
in turn was obtained by the regioselective cyclocondensation
of 2-aminopyridine (8) with ethyl 2-chloro-acetoacetate (9) in
absolute ethanol at reflux.22
Table 1. Optimization of 7-OH-coumarin (3a-h) synthesis.
Prod.
Conventional Heating
Microwave
Temp oC
Time
Temp oC
%Yield
Time
%Yield
3a
3b
3b
3b
3b
3c
3d
3e
3f
20 h
24 h
-
80
80
-
88a
69a
-
45 min
1 h
1 h
1 h
-
80
80 / 100
150
80
93a
Nda,b
Nda,c
89d
-
95d
98d
93d
97d
74d
85d
82d
Scheme 2. Synthesis of hydrazides 2b-h
.
-
-
-
Finally, in the third step, coumarin dyes (3a-h) were obtained
by the condensation reaction between 3-acetyl-7-hydroxy-2H-
24 h
24 h
24 h
24 h
24 h
24 h
-
80
80
80
80
80
80
-
71d
78a
87a
82a
70a
83a
-
-
1 h
1 h
1 h
1 h
1 h
1.5 h
1 h
80
chromen-2-one (1) (1eq) and semicarbazide hydrochloride (2a)
80
or hydrazides (2b-h) (1.05eq) in ethanol, using acetic acid as
catalyst, Scheme 3. The optimization studies of this step are
described in the next paragraphs.
80
80
3g
3g
3h
80
80
24 h
80
72a
80
a
b
one drop of AcOH; not determined due to the presence of starting
reactants; c not determined due to degradations; d three drops of AcOH.
Structural Elucidation
1
The desired coumarin derivatives (3a-h) were confirmed by H
and 13C NMR analyses and obtained as a single isomer with E
configuration, as confirmed by NOESY experiment (SI for 3c).
All data in the spectra were in good accordance with the
structures, as demonstrated for 3c and 3h (Figure 2). Signal
duplications in 3h were ascribed to the high conversion barrier
energy between anti and syn-periplanar conformers of the CO-
Scheme 3. Synthesis of semicarbazone-
coumarins (3b-h).
(3a) and N-acylhydrazone-7-OH-
In a first attempt, the synthesis of the desired compounds 3a-h
was carried out around 80 oC by using a sealed borosilicate
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NH bond (proportion of 4:1, respectively), arising from the electronic effects to 3c and 3d, respectively, hence their
stereo-electronic effects of imidazopyridine group.26
photophysical properties were not investigated.
1
We could postulate that the H and 13C NMR signal duplication
for 3h belongs to the presence of E/Z isomers (SI). However,
HPLC analysis showed the presence of only one peak, as
expected for compounds with conformer populations and not
for E/Z isomers. Furthermore, a dynamic 1H NMR assay carried
out in DMSO-d6 at 60 oC demonstrated a partial coalescence of
some signals, specially the CO-NH one. This is typical for
solutions with interconversion between syn and anti
conformers, and is facilitated at the higher temperature (SI).
As proposed in Figure 3, the interconversion between syn and
anti-conformers can be achieved through a transition state
(TS) where the nitrogen loses its conjugation with carbonyl,
resulting in a pyramidal N atom with two resonance forms (
A
Figure 3. Structural features of NAH-coumarins 3c and 3h in the stabilization of
the transition state of the amide bond rotamers.
and ). For 3a-g, π electrons of R moiety can coplanarize to the
B
C+-O- p orbital that stabilize the resonance form B1, with a
decrease in the TS energy.26 This lower energy barrier leads to
a thermal equilibrium between both syn- and anti-conformers
in solution, with the observation of only single NMR signals. On
the other hand, for 3h, the ortho-methyl-induced loss of
coplanarization and the strong electron withdrawing effect of
UV-vis spectra of 3a-d and 3h in water at 298 K (Figure 4)
exhibit a characteristic band at 350 - 357 nm (ε ~ 2.5 × 104 L
mol–1 cm–1) from a πcoum to π*
transition localized at the 7-
coum
OH-coumarin nucleus (i.e. locally excited state, 1LEcoum). The
insertion of an aromatic or heteroaromatic group to the “R” of
the carbonyl moiety leads to higher molar extinction
coefficients and redshifted bands (λmax = 357 nm) when
the imidazopyridine radical destabilize the resonance form B2
,
increasing the rotational barrier energy.26
This fact decreases the interconversion rate and inhibits the
dynamic equilibrium, favouring the observation of duplicate
NMR signals.
compared to 3a (λmax = 350 nm).
Compound 3h exhibits two bands at 357 and 425 nm due to
the presence of anti and syn conformers with a higher
concentration of the anti-conformer in solution as ascertained
by 1H NMR (Figure 2). The minor lower energy band can be
ascribed to the syn-conformer based on previous
conformational studies of aromatic amides and similar N-
acylhydrazones.27-29
Photophysical properties
Considering their different stereo-electronic effects, five
representative compounds 3a-d and 3h were selected to
determine the general photophysical characteristics of these
7-OH coumarins in water; compounds 3e-f and 3g show similar
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3.0
2.5
2.0
1.5
1.0
0.5
0.0
Worth of note, the water pH (4.9) was carefully controlled with
addition of an acetate buffer solution since the imine group
and the lactone moieties in the coumarin compounds can be
protonated at lower pHs,33-36 which can lead to a considerable
decrease in their kr constants, hence to lower emission
quantum yields (φF < 0.065, SI). On the other hand, at pHs
higher than 5.0, the phenol group can deprotonate (pKa = 6.7,
as experimentally obtained for 3b, SI), resulting in spectral
changes in the absorption and emission (SI).33-36
3a
3b
3c
3d
3h
The coumarin emissions are short-lived (few nanoseconds) as
typically observed for similar fluorescent compounds.37 The
emission quantum yield and lifetime are related to the rate
constants for radiative (kr) and nonradiative (knr) excited-state
decays as shown in Equations 1a and 1b.
250
300
350
400
450
500
λ
Figure 4. Absorption spectra in water (pH 4.9) at 298 K.
/ nm
ꢁr
ꢀ =
ꢃ =
(1ꢂ)
ꢁr + ꢁnr
1
The excitation from 250 to 410 nm of 3a-d and 3h in water at
pH 4.9 (298 K) leads to an intense emission (λmax = 456 nm),
with a narrow, vibronically-resolved spectrum profile that
resembles the mirror shape of the excitation (Figure 5), typical
of ππ* 1LE fluorescence. The Stoke’s shift between the
excitation and emission maxima is relatively large (ꢀλ = 99
nm), as has also been observed for other similar compounds.30
Moreover, "R" groups have negligible influence on emission
and absorption energies in this solvent.
(1ꢄ)
ꢁr + ꢁnr
For excited states with similar character, kr varies as the square
of the transition dipole moment and to the cube of the
average emission energy.38-40 By considering the same
emission energy for compounds 3b-d and 3h (λmax = 456 nm),
their higher radiative rate constants indicate a more effective
transient displacement of charges between the ground and the
excited states. In other words, these results indicate that their
emissive 1LEcoum excited state possess a small extent of
charge transfer character. These facts lead to a πcoum electron
Their emission quantum yields (φF) range from 0.130 for
semicarbazone 3a to 0.244 for N-acylhydrazones 3b-d and 3h
(Table 2). The presence of the methyl group in the imine
moiety creates a conformational restriction in bond twisting,
decreasing its isomerisation that usually causes a quench in
density restricted at the coumarin nucleus while its π
more delocalized through the entire molecule, extending to
*
is
coum
the semicarbazone and N-acylhydrazone moieties.
luminescence.31 Their relatively high
φF, especially for N-
Spectral variations are observed in the absorption spectra of
substituted compounds by changing the medium polarity from
acylhydrazones, allied to a reduced inner-filter effect due to
their large Stoke's shift, make these compounds promising
candidates for laser dyes.32
water, ε= 80.1, to methanol, ε= 32.7.
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Table 2. Photophysical parameters in water at 298 K.
kr / 107 s-1
knr / 107 s-1
a
φF
τ
/ nsa
Compound
3a
3b
0.130 (± 0.001)
0.244 (± 0.001)
2.1 (± 0.3)
2.3 (± 0.4)
6.2
10
41
32
3c
3d
3h
0.235 (± 0.001)
0.234 (± 0.001)
0.205 (± 0.001)
0.83 [36]
2.5 (± 0.3)
2.4 (± 0.4)
2.3 (± 0.4)
9.4
9.8
8.9
---
31
32
35
---
ethyl-7-OH-coumarin-3-
carboxylate
4.8 (this work)
or 5.4 [36]
a Values are given as: average (± standard deviation).
3.0
3a
3b
3c
3d
3h
2.5
2.0
1.5
1.0
0.5
0.0
250
300
350
400
450
500
λ
/ nm
Figure 6. Absorption spectra in methanol at 298 K.
Figure 7. Emission spectra in methanol at 298 K (
λ
exc = 410 nm).
In methanol (Figure 6), a increase in lower-lying shoulder The x and y CI coordinates for the emission of compounds 3a-
related to the syn-conformer is observed around 420 nm, 3d and 3h in water and in methanol, Figure 8, were calculated
while the LE band at 357 nm exhibits lower extinction by Equations 2a and 2b from their X, Y and Z tristimulus
coefficients than in water. These facts are ascribed to an integrals, Equations 3a-3c.
ꢆ
increase of the more-stabilized syn-conformer in less-polar
solvents, as supported by other reports in the literature.26,43
The excitation of N-acylhydrazone compounds in methanol at
298 K leads to the syn-conformer emission at the cyan-green
region, and in broader vibronically-resolved spectra, as
exemplified in Figure 7 for compounds 3b-3d and 3h. The syn-
emission energy clearly responds to the electron withdrawing
strength of the semicarbazone nucleus, with a distinctly larger
redshift for compound 3h due to the presence of the stronger
electronwithdrawing 2-methylimidazo[1,2-a]pyridinyl group.
Their emission spectra also exhibit a small shoulder around
455 nm ascribed to the emission of the anti-conformer,
present in the solution in a much smaller concentration. For
comparison, the emission of 3a, non-substituted, in methanol
(Figura 7) is ascribed solely to the coumarin emission, with a
slightly smaller energy (λmax = 465 nm) and a similar spectral
profile to its emission in water.
ꢅ =
(2ꢂ)
ꢆ + ꢇ + ꢈ
ꢇ
ꢉ =
(2ꢄ)
ꢆ + ꢇ + ꢈ
ꢍꢎꢏ
ꢆ = ꢊ ꢋ(ꢌ)ꢅ
̅
(ꢌ)dꢌ
(3ꢂ)
(3ꢄ)
(3ꢓ)
ꢐꢎꢏ
ꢍꢎꢏ
ꢇ = ꢊ ꢋ(ꢌ)ꢉꢑ(ꢌ)dꢌ
ꢐꢎꢏ
ꢍꢎꢏ
ꢈ = ꢊ ꢋ(ꢌ)ꢒ̅(ꢌ)dꢌ
ꢐꢎꢏ
The CIE coordinates are very useful for an absolute and
quantitative comparison of emission colors. As evidenced by
Figure 8, changes in the CIE coordinates are more significant
In terms of perceived color, the human vision responds to
trichromatic stimuli on the virtual cortex,39,40 quantified by the
Commission Internationale de L’Eclairage (CIE) in three
than a routine comparison of the λmax of different compounds,
because they also implicitly respond to spectral changes in
band-shape. The syn-emission tuning is even more highlighted,
clearly responding to the electron withdrawing strength of the
matching functions or spectral sensitivity curves, x(
and z(
), available as free-access tables.46
λ), ̅y(λ)
̅
λ
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spectrometer (AC-400 or AC-500), using DMSO-d6 or CDCl3 and
TMS as internal standard. IR spectra were obtained using a
Perkin-Elmer Spectrometer model 1600. Mass spectrometry
was obtained by negative ionization using an Esquire 6000-ESI
Ion Trap MSn Bruker Daltonics and data were analyzed using a
Compass 1.3.SR2 software. The melting points recorded are
uncorrected. Elemental analyzes were carried out using a
Thermo Scientific Flash EA 1112 Series CHN-Analyzer. UV-
visible spectra were recorded using an Agilent 8453 diode
array
spectrophotometeror
or
a
Jasco
J-815
spectropolarimeter using 1.000 cm optical path quartz
cuvettes. Steady-state emission spectra were recorded using a
PC1 photon-counting spectrofluorimeter (ISS) with
photomultiplier based, photon-counting detector with
detector sensitivity correction or using Jasco J-815
a
a
spectropolarimeter, using 1.000 cm optical path quartz
cuvettes with four polished faces. Emission decays were
recorded using a ISS Chronos time-resolved fluorometer using
a diode laser (λex = 378 nm, frequency = 10 kHz) as an
excitation light source. Biotage Initiator 2 Reactor was used for
microwave reactions using an internal IR temperature probe.
Figure
photoluminescence of compounds 3a-3d and 3h in water (
8
.
Color space chromaticity diagram with CIE coordinates for the
) or in methanol (●).
▼
Synthesis of 3-acetyl-7-hydroxy-2
A mixture of 4-hydroxysalicylaldehyde (
mmol), ethyl acetoacetate ( ) (1.85 mL, 14.48 mmol) and
H
-chromen-2-one (1)
semicarbazone nucleus. These results are inspiring for a deep
comprehension of emission-tuning strategies and the
molecular engineering of new molecules with desired
properties.
4) (2.00 g, 14.48
8
piperidine (215 µL, 2.17 mmol) in ethanol (40 mL) was refluxed
at 90°C for 24h. Most of the solvent was evaporated and the
beige solid was filtered off after refrigeration, consisting of
pure product (
Mp 238°C. IR (KBr): 3488 (O-H), 2985, 2927, 1716 (C=O), 1602,
1452 (C=C) cm-1. 1H NMR (500 MHz, DMSO-d6):
2.54 (s, 3H),
1) as indicated by TLC analysis (1,887g, 64%).
Conclusion
δ
Herein we addressed the synthesis of novel 7-OH coumarin
derivate dyads using two synthetic approaches, for which the
microwave irradiation led to higher yields and a considerable
reduction in the reaction times from 24 hours to about 1 hour.
Five compounds were selected for their photophysical
characterization demonstrating an LE emission with relatively
high quantum yields in water compared to other
iminocoumarins31, making them potential candidates to be
applied as biological probes.
6.73 (s, 1H), 6.83-6.84 (d, J= 8.51Hz, 1H), 7.76-7.77 (d, J=
8.51Hz, 1H), 8.57 (s, 1H). 13C NMR (500 MHz, DMSO-d6): 30.6,
102.2, 111.1, 114.8, 119.4, 133.2, 148.4, 157.8, 159.6, 165.0,
195.1 ; MS (ESI-) m/z 204.0.
Synthesis of hydrazides (2b-h)
Hydrazine hydrate 100% (1.94 mL, 40 mmol) was added to the
corresponding ester (7b-g or 10) (4 mmol) – obtained as
previously described22 – dissolved in 10 mL of ethanol. The
resulting solution was heated at 70 °C for for 2 to 4 hours for
the total consumption of the ester. The solvent was almost
completely evaporated in a rotary evaporator and the residue
Finally, the modulation of the electron withdrawing effect at
the “R” position can lead to a variable stabilization of syn
conformer in methanol (lower polarity than water), resulting in
considerable bathocromic shifts in their emission. These
results are inspiring for more detailed photophysical
characterizations in different media with different polarities,
which are our ongoing efforts to be addressed in forthcoming
works.
was poured into an ice/water mixture. Some hydrazides (2d
,
2e and 2h) precipitated and they were just filtered off and
washed with cold water, while others were extracted from
aqueous media using AcOEt.
Benzohydrazide (2b)
Experimental section
82% yield. Mp: 121°C. IR (KBr): 3299 (NH2), 3186 (NH), 1616
(C=O), 1349 (C-O) cm-1.1H NMR (200 MHz, DMSO-d6):
δ 4.51 (s,
NH-NH2), 7.54-7.39 (m, 3H, H3, H4), 7.83 (d, H2, J= 7.6Hz), 9.78
(s, CO-NH). 13C NMR (50 MHz, DMSO-d6):
δ 126.9, 128.3, 131.0,
Materials and instruments
All chemicals were purchased from commercial suppliers and
used without further purification. 4-hydroxysalicylaldehyde
and semicarbazide were obtained from Sigma-Aldrich. Other
chemicals were purchased from Vetec. 1H and 13C NMR spectra
were recorded using a 400 MHz or 500 MHz Brucker Avance
133.3, 165.9 (C=O).
6
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4-methoxybenzohydrazide (2c)
3-acetyl-7-hydroxy-2H-chromen-2-one (
1) (200mg, 0.97 mmol)
and the corresponding hydrazide 2a-h (1.02 mmol) were
added into a sealable microwave tube and dissolved in 4 mL of
ethanol, then 3 drops of acetic acid were added. The reactions
were irradiated for 45 minutes (for 2a) or 1 hour (for 2b-h) at
80°C and the solution was poured into ice and the precipitate
was filtered off and dried at room temperature. The solid was
washed with small portions of cold ethyl acetate.
88% yield. Mp: 136°C. IR (KBr): 3316 (NH2), 3183 (NH), 1623
(C=O), 1307-1256 (C-O) cm-1.1H NMR (200MHz, DMSO-d6):
δ
3.79 (s, 3H, O-CH3), 4.43 (s, NH-NH2), 6.67 (d, 2H, H3, J= 8.8Hz),
7.82 (d, 2H, H2, J= 8.8Hz), 9.62 (s, CO-NH). 13C NMR (50MHz,
DMSO-d6): δ 113.5, 125.5, 128.7, 161.4, 165.6 (C=O).
4-Chlorobenzohydrazide (2d)
84% yield. Mp: 131°C. IR (KBr)
:
3309 (NH2), 3208 (NH), 1618
4.52 (s,
(E)-2-(1-(7-hydroxy-2-oxo-2H-chromen-
3yl)ethylidene)hydrazinecarboxamide (3a)
(C=O), 1348 (C-O) cm-1. 1H NMR (200 MHz, DMSO-d6):
δ
NH-NH2), 7.52 (d, 2H, H3, J= 8,0Hz), 7.84 (d, 2H, H2, J=8,0Hz),
9.85 (s, CO-NH). 13C NMR (50 MHz, DMSO-d6):
88% (CH) or 93% (MAOS) yields. Mp: 225°C. IR (KBr): 3513 (O-
δ 128.9, 129.1,
H), 3403 (N-H), 2922, 2852, 1691 (C=O), 1623 (C=N), 1566
(C=C) cm-1. H NMR (500 MHz, DMSO-d6):
132.6, 136.4, 165.4 (C=O).
1
δ 2.12 (s, 3H), 6.53
(s, 2H), 6.73 (s, 1H), 6.81- 6.83 (d, J= 8.5Hz, 1H), 7.58-7.60 (d,
J= 8.5Hz, 1H), 8.24 (s, 1H), 9.46 (s, 1H), 10.70 (s, 1H). 13C NMR
benzo[d][1,3]dioxole-5-carbohydrazide (2e)
91% yield. MP: 170oC. IR (KBr)
:
3316 (NH2), 3184 (NH), 1605
(500 MHz, DMSO-d6): δ 15.9, 102.2, 112.0, 114.0, 122.2, 130.8,
1
(C=O), 1265-1248 (C-O) cm-1. H NMR (200 MHz, DMSO-d6):
δ
142.1, 143.1, 155.8, 157.7, 160.2, 162.0. MS (ESI-): m/z 260.1.
elemental analysis calcd (%) for C12H11N3O4: C 55.17, H 4.24, N
16.09; found: C 54.84, H 4.47, N 15.92.
4.43 (s, NH-NH2), 6.08 (s, O-CH2-O), 6.96 (d, H5, J= 8,1Hz), 7.41
(d, H6, J= 8,1Hz), 7.45 (s, H2), 9.62 (s, CO-NH). 13C NMR (50
MHz, DMSO-d6):
δ 101.7 (O-CH2O), 107.0, 107.9, 121.9, 127.2,
147.3, 149.6, 165.3 (C=O).
(E)-N'-(1-(7-hydroxy-2-oxo-2H-chromen-3-
yl)ethylidene)benzohydrazide (3b)
4-hydroxybenzohydrazide (2f)
69% (CH) or 89% (MAOS) yields. Mp: 225°C. IR (KBr): 3435 (O-
H), 3058 (N-H), 2923, 2852, 1690 (C=O), 1602 (C=N), 1527
80% yield. MP: 250oC. IR (KBr)
:
3428 (-OH); 3319, 3199 (N-H);
1
1622 (C=O); 1280 (C-O) cm-1. H NMR (200 MHz, DMSO-d6):
δ
(C=C), 1456 (C=C) cm-1. 1H NMR (500 MHz, DMSO-d6):
δ 2.30 (s,
4.42 (s, NH-NH2), 7.32 (d, 2H, H3, J= 8,0Hz), 7.95 (d, 2H, H2, J=
8,0Hz), 9.50 (s, CO-NH), 9.96 (s, OH). 13C NMR (400 MHz,
3H), 6.77 (s, 1H), 6.83-6.85 (d, J= 8.4Hz, 1H), 7.51-7.54 (m, J=
6.7Hz, 2H), 7.58-7.60 (d, J= 5.7Hz, 1H), 7.71-7.70 (d, J=6.1Hz,
1H), 7.88-7.89 (d, J= 6.3Hz, 2H), 8.17 (s, 1H), 10.79 (s, 2H). 13C
DMSO-d6):
δ 110.0, 125.5, 129.4, 160.5, 165.5 (C=O).
NMR (500 MHz, DMSO-d6): δ 16.9, 102.3, 111.7, 114.2, 122.5,
128.4, 128.8, 131.2, 132.1, 134.4, 142.8, 156.1, 160.1, 162.4.
4-fluorobenzohydrazide (2g)
78% yield. Mp: 123°C. IR (KBr): 3302, 3218 (N-H), 3019, 1661 MS (ESI-): m/z 321.1. elemental analysis calcd (%) for
(C=O), 1618, 1564 (N=C), 1507 cm-1. 1H NMR (500 MHz, DMSO- C18H14N2O4: C 67.07, H 4.38, N 8.69; found: C 67.18, H 4.50, N
d6): δ 4.51 (s, NH2), 7.28-7.32 (t, 2H), 7.89-7.92 (m, 2H), 9.82 (s, 8.55.
1H). 13C NMR (400 MHz, DMSO-d6):
δ
115.6, 130.1, 130.2, (E)-N'-(1-(7-hydroxy-2-oxo-2H-chromen-3-yl)ethylidene)-4-
163.0, 165.4.
methoxybenzohydrazide (3c)
2-methylimidazo[1,2-a]pyridine-3-carbohydrazide (2h)
78% (CH) or 95% (MAOS) yields. Mp: 235°C. IR (KBr): 3431 (O-
84% yield. Mp: 180°C. IR (KBr): 3290, 3218 (N-H); 1626 (C=O); H), 2922, 2852, 1704 (C=O), 1609 (C=N), 1527 (C=C), 1423
1
1
744 (N=C) cm-1. H NMR (200 MHz, DMSO-d6):
δ δ 2.32 (s, 3H), 3.34
2.53 (s, 3H, - (C=C) cm-1. H NMR (500 MHz, DMSO-d6):
CH3), 4.56 (s, NH-NH2), 7.00 (t, H6, J= 8,0Hz), 7.36 (t, H5, J= (s, 2H), 6.77 (s, 1H), 6.83-6.85 (d, J= 8.2Hz, 1H), 7.04-7.06 (d, J=
8,0Hz), 7.55 (d, H4, J= 8,0Hz), 8.94 (d, H7, J= 6,0Hz), 9.18 (s, CO- 8.2Hz, 2H), 7.69-7.70 (d, J=8.20, 1H), 7.88-7.90 (d, J=8.20, 2H),
NH). 13C NMR (50 MHz, DMSO-d6):
δ
16.0, 113.33, 115.4, 8.13 (s, 1H), 10.61 (s, 1H), 10.74 (s,1H). 13C NMR (500 MHz,
116.7, 126.9, 127.4, 145.5, 145.6, 161.9.
Synthesis of N-acylhydrazone- (3b-h) and semicarbazone-7-OH-
coumarins (3a)
DMSO-d6): δ 16.7, 55.9, 102.3, 111.7, 114.0, 114.1, 122.6,
126.3, 131.1, 142.6, 156.0, 160.1, 162.4. MS (ESI-): m/z 351.1.
elemental analysis calcd (%) for C19H16N2O5: C 64.77, H 4.58, N
7.95; found: C 64.71, H 4.60, N 7.92.
Synthesis by conventional heating (CH).
3-acetyl-7-hydroxy-2H-chromen-2-one
(1) (100 mg, 0.48
(E)-4-chloro-N'-(1-(7-hydroxy-2-oxo-2H-chromen-3-
yl)ethylidene)benzohydrazide (3d)
mmol) and the corresponding hydrazide 2a-h (0.50 mmol)
were added into a borosilicate sealable tube and dissolved in 2
mL of ethanol, then 1 or 3 drops of acetic acid were added.
87% (CH) or 98% (MAOS) yields. Mp: 255°C. IR (KBr): 3431 (O-
o
H), 2921, 2852, 1704 (C=O), 1616 (C=N), 1528 (C=C), 1432
(C=C) cm-1. H NMR (500 MHz, DMSO-d6):
The reaction was heated at 80 C for 24 h, then poured into
1
δ 2.32 (s, 3H), 6.77
ice. The precipitate was filtered off and dried at room
temperature. The solid was washed with small portions of cold
ethyl acetate.
(s, 1H), 6.83-6.85 (d, J= 8.5Hz, 1H), 7.59-7.61 (d, J= 5.7Hz, 2H),
7.71 (s, 1H), 7.91 (s, 2H), 8.17 (s, 1H), 10.78 (s, 1H), 10.85 (s,
1H). 13C NMR (500 MHz, DMSO-d6): 17.0, 102.3, 111.7, 114.2,
Microwave-assisted synthesis (MAOS)
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122.4, 128.9, 130.4, 131.2, 142.9, 160.1, 162.5. MS (ESI-): m/z 160.1, 160.1, 162.4. MS (ESI-): m/z 375.1. elemental analysis
355.1. elemental analysis calcd (%) for C18H13ClN2O4: C 60.60, H calcd (%) for C20H16N4O4: C 63.82, H 4.28, N 14.89; found: C
3.67, N 7.85; found: C 60.49, H 3.55, N 7.91.
63.66, H 4.45, N 14.78.
(E)-N'-(1-(7-hydroxy-2-oxo-2H-chromen-3-
Emission quantum yields
yl)ethylidene)benzo[d][1,3]dioxole-5-carbohydrazide (3e)
The emission quantum yields in water at 298 K were calculated
82% (CH) or 93% (MAOS) yields. Mp: 249°C. IR (KBr): 3440 (O- by Equation 1 using ethyl-7-OH-coumarin-3-carboxylate as a
1
H), 2921, 1704 (C=O), 1616 (C=N), 1529, 1259 cm-1. H NMR reference compound ( = 0.83,45 λex = 350 nm). Usually, the
φ
(500 MHz, DMSO-d6): 2.31 (s, 3H), 6.13 (s, 2H), 6.77 (s, 1H), imine and the hydroxyl groups of similar molecules can ionize
6.83-6.85 (d, J= 8.5Hz, 1H), 7.03-7.05 (d, J= 7.9Hz, 1H), 7.45 (s, at pHs lower than 4 and higher than 6, respectively; thus the
1H), 7.49-7.51 (d, J= 8.2Hz, 1H), 7.68-7.70 (d, J= 8.5Hz, 1H), pH was controlled to ~4.9 with addition of an acetate buffer
8.13 (s, 1H), 10.58 (s, 1H), 10.74 (s, 1H). 13C NMR (500 MHz, solution to ensure their molecular identity.
ꢘꢚꢛꢜ
DMSO-d6): 16.8, 102.2, 102.3, 108.4, 111.7, 114.2, 122.5,
ꢙ
ꢋꢚ
ꢀꢋꢚ = ꢀꢚꢛꢜ
ꢙꢚꢛꢜ ꢘꢋꢚ
Emission quantum yield for the sample;
128.1, 131.1, 142.7, 156.1, 160.1, 162.4. MS (M+H) and
(M+Na+): m/z 367.0 and 389.0. elemental analysis calcd (%) for ꢀꢔꢕ
(3)
=
C19H14N2O6: C 62.30, H 3.85, N 7.65; found: C 61.98, H 3.99, N ꢀꢕꢖꢗ
=
Emission quantum yield for the reference in the same
solvent;
ꢘꢔꢕ Absorbance of the sample at the excitation wavelength;
ꢘꢕꢖꢗ Absorbance of the reference at the excitation
wavelength;
Integral of the sample phosphorescence spectrum;
Integral of the reference phosphorescence spectrum.
7.60.
=
=
(E)-4-hydroxy-N'-(1-(7-hydroxy-2-oxo-2H-chromen-3-
yl)ethylidene)benzohydrazide (3f)
ꢙ
=
ꢔꢕ
70% (CH) or 97% (MAOS) yields. Mp 266°C. IR (KBr): 3434 (O-
H), 3167 (O-H), 3064 (N-H), 2922, 2853, 1680 (C=O), 1598
(C=N), 1524 (C=C), 1462 (C=C) cm-1. 1H NMR (500 MHz, DMSO-
ꢙꢕꢖꢗ
=
d6):
δ 2.30 (s, 3H), 6.77 (s, 1H), 6.83-6.85 (d, 2H), 6.87 (s, 1H), General Procedure for pKa determination.
7.69-7.71 (d, J= 8.5Hz, 1H), 7.78-7.79 (d, J=8.5Hz, 2H), 8.13 (s,
1H), 10.12 (s, 1H), 10.52 (s, 1H), 10.77 (s, 1H). 13C NMR (500
Sample analysis was prepared by dissolving the compound 3b
in 100% milli-Q water and filtering through a millipore filter.
MHz, DMSO-d6):
δ 16.7, 102.3, 111.7, 114.1, 115.3, 122.6,
The final concentration was adjusted for
a maximum
124.7, 113.1, 142.6, 156.0, 160.2, 162.4. MS (ESI-): m/z 337.1.
elemental analysis calcd (%) for C18H14N2O5: C 63.90, H 4.17, N
8.28; found: C 63.77, H 4.16, N 8.23.
absorbance of around 0.4. At the same time, a saturated
solution of NaOH was prepared and 1 µL aliquots of this
solution were added to the previously prepared solution of
compound 3b. UV-vis scan was performed in a range of 200
nm to 800 nm after each addition. An increase was observed in
the band centred at 390nm and reduction at 335nm
(E)-4-fluoro-N'-(1-(7-hydroxy-2-oxo-2H-chromen-3-
yl)ethylidene)benzohydrazide (3g)
83% (CH) or 85% (MAOS - 1.5 h) yields. Mp: 290°C. IR (KBr): depending on pH. These wavelengths were used as references
3437 (O-H), 3048, 2926, 2849, 1693 (C=O), 1601 (C=N), 1532 for pKa calculation. From these spectral variations, a graph of
1
(C=C), 1456 (C=C), 1345 (C-F) cm-1. H NMR (500 MHz, DMSO- pH versus log ((A-Af) / (A0-A)) was plotted to determine the
d6):
(m, 2H), 7.70-7.71 (d, J= 6.6Hz, 1H), 7.97 (m, 2H), 8.16 (s, 1H),
10.81 (s, 1H). 13C NMR (500 MHz, DMSO-d6):
16.9, 102.3,
δ 2.32 (s, 3H), 6.77 (s, 1H), 6.83-6.85 (d, J= 8.5Hz, 1H), 7.36 pKa of compound 3b as 6.7 (SI).
δ
Acknowledgements
111.7, 114.2, 115.7, 122.4, 130.8, 131.2, 142.8, 148.4, 156.1,
160.1, 162.4. MS (ESI-): m/z 339.1. elemental analysis calcd
(%) for C18H13N2O4: C 63.53, H 3.85, N 8.23; found: C 63.61, H
3.94, N 8.20.
This work is supported by Fundação de Amparo à Pesquisa do
Estado do Rio de Janeiro (FAPERJ), Fundação de Amparo à
Pesquisa do Estado de São Paulo (FAPESP), Conselho Nacional
de Desenvolvimento Científico e Tecnológico (CNPq) and
Coordenação de Aperfeiçoamento de Pessoal de Nível
Superior (CAPES).
(E)-N'-(1-(7-hydroxy-2-oxo-2H-chromen-3-yl)ethylidene)-2-
methylimidazo[1,2-a]pyridine-3-carbohydrazide (3h)
72% (CH) or 82% (MAOS) yields. Mp: 240°C. IR (KBr): 3435 (O-
H), 2922, 2853, 1698 (C=O), 1616 (C=N), 1585 (C=C), 1452
(C=C), 1232cm-1. 1H NMR (500MHz DMSO-d6):
δ 2.32 (s,3H),
Notes and references
2.62 (s,2H), 6.77 (s, 1H), 6.83-6.85 (d, J= 8.5Hz, 1H), 7.09-7.12
(t, J= 6.9Hz, 1H), 7.44-7.46-7.47 (t, J= 7.9Hz, 1H), 7.56-7.58 (d,
J= 8.8Hz, 1H), 7.64-7.65 (d, J= 8.8Hz, 1H), 7.68-7.69 (d, J=
8.5Hz, 1H), 8.13 (s, 1H), 10.53 (s, 1H), 10.78 (s, 1H). 13C NMR
1
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(500 MHz, DMSO-d6):
δ 16.2, 16.3, 16.5, 16.8, 102.3, 102.5,
111.7, 113.8, 114.2, 116.6, 116.7, 116.8, 122.4, 127.5, 127.6,
130.6, 131.2, 142.6, 143.4, 145.8, 145.9, 147.4, 156.0, 156.1,
2
3
8
|
J. Name., 2012, 00, 1-3
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DOI: 10.1039/C6NJ01532H
Emissive 7-OH-Coumarins were synthesized by a microwave-assisted protocol and
spectral changes were induced after conformational changes in low polarity media.