Synthesis and photophysical insights of new fused N-heterocyclic derivatives with isoquinoline skeleton

Article abstract of DOI:10.1016/j.molliq.2020.113196

Six new fused isoquinoline based compounds (compounds 5a–c with pyrrolo[2,1-a] isoquinoline structure and compounds 6a–c with imidazo[2,1-a]isoquinoline skeleton) have been synthesized using the [3 + 2] cycloaddition of the several in situ generated cycloimmonium ylides to ethyl propiolate or ethyl cyanoformate. All the synthesized compounds have been investigated in solution by UV–VIS absorption, steady and time-resolved fluorescence methods. The effect of the substituents on the spectral characteristics has been demonstrated. These derivatives displayed an intense emission between 360 and 420 nm. The emission quantum yields (Φ = 0.54–0.64) of pyrroloisoquinoline derivatives in dimethylsulfoxide (DMSO) were significantly higher than those of imidazoquinolines (0.03–0.16). The fluorescence decay of isoquinoline derivatives follows a biexponential law. A noticeable response of these isoquinoline derivatives to sodium hydroxide was observed.

Full text of DOI:10.1016/j.molliq.2020.113196

Journal of Molecular Liquids 310 (2020) 113196
Contents lists available at ScienceDirect
Journal of Molecular Liquids
journal homepage: www.elsevier.com/locate/molliq
Synthesis and photophysical insights of new fused N-heterocyclic
derivatives with isoquinoline skeleton
a
a
b,
a
Carmen Gherasim a, Anton Airinei a, , Radu Tigoianu , Anda M. Craciun , Ramona Danac , Alina Nicolescu ,
⁎
⁎
Dragos Lucian Isac a, Ionel I. Mangalagiu b
a
Petru Poni Institute of Macromolecular Chemistry, Grigore Ghica Voda Alley 41A, Iasi 700487, Romania
Alexandru Ioan Cuza University of Iasi, Chemistry Department, 11 Carol I Bd., Iasi 700506, Romania
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Six new fused isoquinoline based compounds (compounds 5a–c with pyrrolo[2,1-a] isoquinoline structure and
compounds 6a–c with imidazo[2,1-a]isoquinoline skeleton) have been synthesized using the [3 + 2] cycloaddi-
tion of the several in situ generated cycloimmonium ylides to ethyl propiolate or ethyl cyanoformate. All the syn-
thesized compounds have been investigated in solution by UV–VIS absorption, steady and time-resolved
fluorescence methods. The effect of the substituents on the spectral characteristics has been demonstrated.
These derivatives displayed an intense emission between 360 and 420 nm. The emission quantum yields
(Φ = 0.54–0.64) of pyrroloisoquinoline derivatives in dimethylsulfoxide (DMSO) were significantly higher
than those of imidazoquinolines (0.03–0.16). The fluorescence decay of isoquinoline derivatives follows a
biexponential law. A noticeable response of these isoquinoline derivatives to sodium hydroxide was observed.
© 2020 Elsevier B.V. All rights reserved.
Received 12 March 2020
Received in revised form 14 April 2020
Accepted 19 April 2020
Available online 22 April 2020
Keywords:
Pyrrolo[2,1-a]isoquinoline
Imidazo[2,1-a]isoquinoline
Fluorescence
Quantum yields
Lifetimes
1. Introduction
optoelectronic devices, we decided to synthesize several new pyrrolo
[2,1-a]isoquinolines and imidazo[2,1-a]isoquinolines in order to realize
The application of polyheterocycles based on privileged structures as
isoquinoline covers a vast therapeutic area [1–3]. For this reason, fused
scaffolds containing isoquinoline have received much attention as drug
candidates, a variety of improved synthetic methods being reported re-
cently [4–8]. Among this class of compounds, pyrrolo[2,1-a]isoquinoline
framework remarks as part of various synthesized compounds showing
different biological activities, but also as part of many natural com-
pounds as lamellarins, crispines, oleraceins and trollines [1]. Imidazo
[2,1-a]isoquinoline is another skeleton of interest due to its biological
properties including anti-inflammatory, anticancer, anti-HIV-1 or anti-
microbial properties [9,10]. In addition to their biological properties,
such molecules possess extended π-conjugated systems that make
them excellent candidates for photophysical applications. Despite
their huge potential in this field, there are only several reported studies
regarding the fluorescence of molecules containing pyrrolo[2,1-a]
isoquinoline or imidazo[2,1-a]isoquinoline core [11–15].
a complete study regarding their photophysical properties and potential
applications in the field.
2. Experimental
2.1. Materials and instrumentation
All reagents and solvents were commercially available and were
used without further purification. For spectral measurements the sol-
vents were of spectroscopic grade. 1H NMR and 13C NMR spectra were
recorded on Bruker Avance III 500 MHz and Bruker Avance NEO
400 MHz spectrometers at room temperature. Coupling constants (J)
are given in Hz. Chemical shifts were reported as relative values δ
(ppm) to the residual signal of the deuterated solvent. The following ab-
breviations used to explain the multiplicity of the chemical shifts: s -
singlet, d - doublet, t - triplet, q - quartet, m - multiplet, dd - doublet
of doublet, as - apparent singlet. FTIR spectra were registered on a FT-
IR Bruker Vertex 70 spectrophotometer (KBr discs). Thin layer chroma-
tography (TLC) was performed using silica gel plates Merck 60 F254. TLC
plates were visualized using a UV lamp (λmax = 254 or 365 nm). Melt-
ing points were determined on a Krüss Optronic melting point meter
KSPI and are uncorrected. Electronic absorption spectra were measured
In that context and considering the growing interest for highly fluo-
rescent materials with extended π-conjugation and their applications as
sensors and biosensors, electroluminescent materials, lasers and other
⁎
Corresponding authors.
E-mail addresses: airineia@icmpp.ro (A. Airinei), rdanac@uaic.ro (R. Danac).
https://doi.org/10.1016/j.molliq.2020.113196
0167-7322/© 2020 Elsevier B.V. All rights reserved.

2
C. Gherasim et al. / Journal of Molecular Liquids 310 (2020) 113196
with a SPECORD 200Plus Analytik Jena spectrophotometer using quartz
cells with the light path length of 10 mm. The fluorescence spectra were
obtained using a Perkin Elmer LS55 luminescence spectrometer in a
10 mm four-window quartz cuvette. The quantum yield of
photoluminescence was determined on a FLS980 spectrometer using
an integrating sphere. Dilute solutions (A b 1 at the excitation wave-
length corresponding to the maximum of the first absorption band)
were utilized for emission measurements. Luminescence decay curves
were recorded on an Edinburgh FLS980 time-resolved single photon-
counting fluorescence spectrometer using a 375 nm laser as excitation
source. The time-resolved fluorescence decay curves were evaluated
by fitting the spectral data to a sum of discrete exponentials: I(t) =
Σaiexp(−t / τi), where I(t) represents the fluorescence intensity at
time t, τi and ai are the emission decay time of component i and the
pre-exponential factor, respectively, such that Σai = 1. The fit quality
has been estimated in terms of chi-squared (χ2) and the visual analysis
of the residuals.
Diethyl pyrrolo[2,1-a]isoquinoline-1,3-dicarboxylate (5c). White solid,
η = 64%, m.p. = 126–129 °C. IR (KBr, cm−1): 3128, 2980, 1709, 1697,
1376, 1232, 1077, 787. 1H NMR (CDCl3, 500 MHz): δ = 1.42–1.47 (6H,
overlapped signals, 2 × CH2CH3), 4.39–4.45 (4H, overlapped signals,
2 × CH2CH3), 7.19 (d, J = 7.5 Hz, 1H, H5), 7.60–7.66 (2H, overlapped sig-
nals, H7, H8), 7.72 (d, J = 8.0 Hz, 1H, H6), 8.05 (s, 1H, H2), 9.40 (d, J =
7.0 Hz, 1H, H4), 9.82 (d, J = 8.0 Hz, 1H, H9). 13C NMR (CDCl3,
125 MHz): δ = 14.7 2 × CH2CH3, 60.7 2 × CH2CH3, 109.8 C1, 115.1 C5,
116.1 C3, 124.5 C4, 125.1 C11, 125.3 C2, 127.2 C6, 127.8 C9, 127.9 C8,
129.0 C7, 129.8 C10, 136.1 C12, 161.2 C14, 165.0 C13. Anal. calc. for
C18H17NO4: C 69.44; H 5.50; N 4.50. Found: C 69.48; H 5.42; N 4.54.
Ethyl 3-cyanoimidazo[2,1-a]isoquinoline-2-carboxylate (6a). White
solid, η = 40%, m.p. = 207–209 °C. IR (KBr, cm−1): 2929, 2224, 1708,
1536, 1374, 1257, 1156, 793. 1H NMR (CDCl3, 500 MHz): δ = 1.51 (t,
J = 7.0 Hz, 3H, CH2CH3), 4.57 (q, J = 7.0 Hz, 2H, CH2CH3), 7.44 (d,
J = 7.50 Hz, 1H, H5), 7.77 (2H, overlapped signals, H7, H8), 7.85 (dd,
J = 6.5; 3.0 Hz, 1H, H6), 8.15 (d, J = 7.0 Hz, 1H, H4), 8.85 (dd, J = 8.5;
3.5 Hz, 1H, H9). 13C NMR (CDCl3, 125 MHz): δ = 14.4 CH2CH3, 62.5
2.2. Synthetic procedures
CH2CH3, 103.0 C3, 110.3 C14, 117.6 C5, 121.3 C4, 122.3 C2, 123.4 C11
,
125.0 C9, 127.6 C6, 129.8 C8, 130.7 C10, 130.9 C7, 145.2 C12, 160.9 C13
.
2.2.1. General procedure for synthesis of the quaternary isoquinolinium
salts (3a–c)
Anal. calc. for C15H11N3O2: C 67.92; H 4.18; N 15.84. Found: C 67.96; H
4.10; N 15.91.
All three monoquaternary isoquinolinium salts were prepared ac-
cording to previously reported procedures [16,17]. Shortly, the starting
substrate isoquinoline (1) (1 mmol, 1 eq.) was dissolved in acetone and
then the corresponding halide (1 mmol, 1 eq.) was added. The reaction
mixture was refluxed for 24 h under magnetic stirring. Subsequently,
the reaction mixture was cooled at room temperature and the resulting
precipitate was filtered and washed with acetone. The obtained
monoquaternary salts (3a–c) have been used without purification in
the next step.
2-Ethyl 3-methyl imidazo[2,1-a]isoquinoline-2,3-dicarboxylate (6b).
White solid, η = 40%, m.p. = 142–146 °C. IR (KBr, cm−1): 3125, 2992,
1739, 1716, 1392, 1214, 806. 1H NMR (CDCl3, 500 MHz): δ = 1.45 (t,
J = 7.0 Hz, 3H, CH2CH3), 3.98 (s, 3H, OCH3), 4.51 (q, J = 7.0 Hz, 2H,
CH2CH3), 7.30 (d, J = 7.5 Hz, 1H, H5), 7.66–7.70 (2H, overlapped signals,
H7, H8), 7.77 (dd, J = 6.0; 3.0 Hz, 1H, H6), 8.75 (dd, J = 6.0; 3.5 Hz, 1H,
H9), 8.93 (d, J = 7.5 Hz, 1H, H4). 13C NMR (CDCl3, 125 MHz): δ = 14.4
CH2CH3, 52.3 OCH3, 62.1 CH2CH3, 115.9 C5, 116.4 C3, 123.1 C11, 123.5
C4, 124.7 C9, 127.0 C6, 128.8 C8, 130.1 C7, 130.5 C2, 141.5 C10, 144.8 C12
,
160.5 COO, 164.0 COO. Anal. calc. for C16H14N2O4: C 64.42; H 4.73; N
9.39. Found: C 64.46; H 4.69; N 9.45.
2.2.2. General procedure for synthesis of the compounds 5a–c and 6a–c
The monoquaternary salts (3a-c) (1 mmol, 1 eq.) and dipolarophile
(ethyl propiolate or ethyl cyanoformate) (1.1 mmol, 1.1 eq.) were
suspended in chloroform (10 mL). Then triethylamine (3 mmol, 3 eq.)
was added dropwise under magnetic stirring and nitrogen atmosphere.
The obtained reaction mixture was refluxed with vigorous stirring for
24 h under nitrogen. After cooling at room temperature, to the resulting
solution, 5 mL of methanol was added, and the mixture was kept with-
out stirring until a precipitate was obtained. The solid was filtered and
washed with a small amount of methanol to give the desired
compound.
Diethyl imidazo[2,1-a]isoquinoline-2,3-dicarboxylate (6c). Cream
solid, η = 35%, m.p. = 133–135 °C. IR (KBr, cm−1): 3138, 2988, 1732,
1706, 1403, 1216, 807. 1H NMR (CDCl3, 500 MHz): δ = 1.43 (t, J =
7.0 Hz, 3H, CH2CH3), 1.46 (t, J = 7.0 Hz, 3H, CH2CH3), 4.46 (q, J =
7.0 Hz, 2H, CH2CH3), 4.51 (q, J = 7.0 Hz, 2H, CH2CH3), 7.33 (d, J =
7.5 Hz, 1H, H5), 7.70–7.73 (2H, overlapped signals, H7, H8), 7.80 (dd,
J = 6.0; 3.5 Hz, 1H, H6), 8.82 (dd, J = 6.0; 3.5 Hz, 1H, H9), 9.67 (d, J =
7.5 Hz, 1H, H4). 13C NMR (CDCl3, 125 MHz): δ = 14.3 CH2CH3, 14.4
CH2CH3, 62.0 CH2CH3, 62.3 CH2CH3, 116.0 C5, 116.5 C3, 123.0 C11
,
123.6 C4, 124.9 C9, 127.1 C6, 128.9 C8, 130.3 C7, 130.6 C2, 141.2 C10
,
Ethyl 3-cyanopyrrolo[2,1-a]isoquinoline-1-carboxylate (5a). Orange
solid, η = 63%, m.p. = 137–139 °C. IR (KBr, cm−1): 3120, 2973, 2224,
2848, 1716, 1684, 1501, 1365, 1199. 1H NMR (CDCl3, 500 MHz): δ =
1.43 (t, J = 7.0 Hz, 3H, CH2CH3), 4.39 (q, J = 7.0 Hz, 2H, CH2CH3), 7.13
(d, J = 7.00 Hz, 1H, H5), 7.57–7.66 (3H, overlapped signals, H7, H8,
H6), 7.77 (s, 1H, H2), 7.98 (d, J = 7.0 Hz, 1H, H4), 8.85 (d, J = 8.5 Hz,
1H, H9). 13C NMR (CDCl3, 125 MHz): δ = 14.5 CH2CH3, 60.9 CH2CH3,
98.3 C3, 110.5 C1, 112.5 C14, 116.0 C5, 122.2 C4, 124.9 C11, 126.1 C2,
144.6 C12, 160.1 COO, 164.0 COO. Anal. calc. for C17H16N2O4: C 65.38;
H 5.16; N 8.79. Found: C 65.36; H 5.09; N 8.87.
3. Results and discussion
The chosen method for the assembly of fused target
polyheterocycles relied on 1,3-dipolar cycloaddition [8,16] of different
isoquinolinium ylides to ethyl propiolate or ethyl cyanoformate. First,
isoquinoline 1 (Scheme 1) was used together with halides 2a–c for
the synthesis of the monoquaternary salts 3a–c [17,18]. As shown in
Scheme 1, ethyl propiolate was reacted first with the corresponding
isoquinolinium ylides 4a–c (in situ generated in basic medium from
salts 3a–c) to give the intermediate dihydropyrrolo[2,1-a]isoquinolines
5′a–c, which in turn underwent oxidative dehydrogenation under at-
mospheric conditions, yielding the final compounds 5a–c in good yields
(63–80%). Compound 5c was obtained also by Chen using a different re-
cently reported approach [19]. Using ethyl cyanoformate as
dipolarophile in similar conditions, we obtained imidazo[2,1-a]
isoquinolines 6a–c presumably via dihydroderivatives 6′a–c. All com-
pounds have been fully characterized using spectral methods (IR,
NMR) and quantitative elemental analyses (C, H, N). The NMR spectra
prove the formation of the new fully aromatized pyrrolo[2,1-a]
127.2 C6, 127.8 C9, 128.5 C8, 129.6 C10, 129.4 C7, 134.9 C12, 163.7 C13
.
Anal. calc. for C16H12N2O2: C 72.72; H 4.58; N 10.60. Found: C 72.76; H
4.50; N 10.64.
1-Ethyl 3-methyl pyrrolo[2,1-a]isoquinoline-1,3-dicarboxylate (5b).
White solid, η = 80%, m.p. = 138–140 °C. IR (KBr, cm−1): 3132, 2975,
2951, 1693, 1457, 1376, 1228, 1187, 1082, 762. 1H NMR (CDCl3,
500 MHz): δ = 1.45 (t, J = 7.0 Hz, 3H, CH2CH3), 3.94 (s, 3H, OCH3),
4.42 (q, J = 7.0 Hz, 2H, CH2CH3), 7.18 (d, J = 7.5 Hz, 1H, H5),
7.59–7.65 (2H, overlapped signals, H7, H8), 7.71 (d, J = 8.0 Hz, 1H,
H6), 8.04 (s, 1H, H2), 9.37 (d, J = 7.5 Hz, 1H, H4), 9.82 (d, J = 8.5 Hz,
1H, H9). 13C NMR (CDCl3, 125 MHz): δ = 14.6 CH2CH3, 51.7 OCH3,
60.7 CH2CH3, 109.9 C1, 115.1 C5, 115.7 C3, 124.4 C4, 125.1 C11, 125.5 C2,
126.8 C6, 127.8 C9, 127.9 C8, 129.0 C7, 129.8 C10, 136.1 C12, 161.6 C14
,
164.9 C13. Anal. calc. for C17H15NO4: C, 68.68; H, 5.09; N, 4.71%. Found:
C, 68.65; H, 5.01; N, 4.73%.

C. Gherasim et al. / Journal of Molecular Liquids 310 (2020) 113196
3
Scheme 1. Synthetic pathway for pyrrolo[2,1-a]isoquinolines 5a–c and imidazo[2,1-a]isoquinolines 6a–c.
isoquinoline cycle in case of compounds 5a–c and imidazo[2,1-a]
isoquinoline cycle in case of compounds 6a–c.
The electronic absorption spectra of pyrroloisoquinolines 5a–c dis-
play three main absorption bands located in the following ranges in di-
chloromethane (DCM): 300–400 nm, 260–300 nm and around 240 nm,
respectively (Fig. 1). The absorption band at longer wavelengths pre-
sents a vibronic structure with an absorption maximum at 340 nm for
5b, 5c and at 356 nm for 5a. This absorption band can be assigned to a
π-π* transition of the pyrroloisoquinoline ring [12]. The substituents
on the nitrogen ring can exert a significant effect on the position of ab-
sorption and emission bands of these isoquinoline derivatives. The ab-
sorption spectra of compounds 5b and 5c are practically similar
(Fig. 1), while the introduction of CN group in the position 3 on the pyr-
role ring induces a prominent hypsochromic shift of the longer wave-
length absorption band of 5a (Fig. 1). It can be seen in Fig. 2 that the
absorption spectra of imidazoisoquinolines 6a–c differ from the ones
of the pyrrolo derivatives 5a–c. Thus, the imidazoisoquinolines 6a–c ex-
hibit two main absorption bands: a lower intensity long wavelength
band with vibrational structure (300–350 nm), centered at about
323 nm as well as two absorption bands at 339 and 309 nm, on both
sides of the central absorption maximum and a high intensity broad ab-
sorption band with an absorption maximum around 250 nm in dichlo-
romethane (Fig. 2).
The red-shift absorption profile observed when compared to
imidazoisoquinolines can be attributed to the extended π-π* conjuga-
tion in this system due to the substituents from the positions 1 and 3
on the pyrrole ring. The blue shift of the absorption band from longer
wavelengths in pyrroloisoquinolines occurs also in DMSO (Table 1).
The spectral pattern of pyrroloisoquinolines 5b and 5c is much less in-
fluenced by the presence of substituents in the positions 1 and 3 on
the pyrrole ring (COOMe, COOEt). As shown in Table 1, the electronic
absorption spectra of pyrrolo- and imidazo- isoquinolines showed
Fig. 1. UV–Vis absorption spectra of pyrroloisoquinolines 5a–c in dichloromethane.
Table 1
Photophysical properties of isoquinoline derivatives.
Sample
Solvent
λmax
λem
Φ
(nm)
(nm)
(%)
5a
5b
5c
6a
6b
6c
DCM
DMSO
DCM
DMSO
DCM
DMSO
DCM
DMSO
DCM
DMSO
DCM
352, 335, 320, 275, 244
353, 336, 321, 276
358, 341, 325, 274, 246
358, 341, 325, 275
358, 341, 324, 274, 247
358, 341, 325sh, 275
338, 323, 309, 252
339, 324, 309
338, 323, 309, 251
339, 324, 309
338, 323, 309, 252
339, 323, 309
356, 374, 392, 415sh
359, 376, 395, 415sh
363, 381, 401, 425sh
361, 382, 401, 425sh
363, 381, 401, 425sh
364, 382, 400, 425sh
340, 356, 375, 395sh
345, 361, 378
344, 360, 374, 400sh
346, 360, 374
344.5, 359, 375, 400sh
346, 359, 372
28.37
63.47
20.10
53.95
31.28
55.76
41.04
3.36
18.37
7.96
29.41
15.95
DMSO
Fig. 2. Electronic absorption spectra of imidazoisoquinolines 6a–c in dichloromethane.

4
C. Gherasim et al. / Journal of Molecular Liquids 310 (2020) 113196
ring are shifted to shorter wavelengths both in DCM and DMSO (Fig. 3,
Table 1). Also, the position of the emission maxima was not affected by
the increase of solvent polarity (Table 1). The fluorescence bands of
imidazoisoquinolines 6a-c were found in the spectral range
350–420 nm (Fig. 4). The position of emission bands for derivatives
6a–c is not practically influenced by the substituents on the pyrrole
ring excepting compound 6a which displays a blue shift in dichloro-
methane (Fig. 4, Table 1). Compared to pyrroloisoquinoline derivatives
5a–c, the emission bands of imidazoisoquinolines 6a–c are blue shifted
in DCM and DMSO. The values of absorption and emission maxima as
well as the values of fluorescence quantum yields and fluorescence life-
times of the isoquinolines derivatives are collected in Table 1.
The emission quantum yield values of isoquinoline derivatives are
strongly dependent on the substituent and the solvent nature. The fluo-
rescence quantum yield had the highest values in DMSO for
pyrroloisoquinolines 5a–c (Φ = 63.47% for 5a) (Table 1). However,
the fluorescence quantum yield of derivatives 5a–c is significantly re-
duced in dichloromethane (e.g. in case of compound 5b, the quantum
yield decreased from 53.95% in DMSO to 20.10% in DCM). The quantum
efficiencies (Φ) of imidazoisoquinolines 6a–c ranged from 18.37% to
41.04% in DCM and from 3.36% to 15.95% in DMSO, respectively
(Table 1). Thus, the pyrroloisoquinolines show much higher emission
quantum yields in DMSO than imidazoisoquinolines, while in DCM
close values of quantum efficiencies were found for 5b–c and 6b-c de-
rivatives. The exception is product 6a which provided a high quantum
yield in DCM of 41.04% by comparison with 5a (Φ = 28.37%). These re-
sults revealed that the presence of CN acceptor groups determines an
important enhancement of quantum yield in DMSO for
pyrroloisoquinolines 6a (63.47%) and in DCM for imidazoisoquinolines
6a (41.04%). The substituent –COOMe in the position 3 on the pyrrole
and imidazo rings affected the emission as the compounds 5b and 6b
displayed the lowest values of quantum yield in DCM (20.10% and
18.37%, respectively). It is worth noting that COOEt substituent on the
imidazole ring induced an increase of quantum yield for 6c in DMSO
(Table 1). The quantum yield values of derivatives 6a–c are higher in
DCM because the non-radiative processes in these compounds are di-
minished in solvents having low polarity [20].
Fig. 3. Fluorescence spectra of isoquinoline derivatives 5a–c in DMSO (λex = 275 nm).
The luminescence lifetimes has been determined by time-correlated
single photon counting (TCSPC) technique. Emission decays for all in-
vestigated compounds were found to be the best characterized by a
double-exponential function in DMSO over the entire emission range.
The radiative rate constant, kr, and the non-radiative rate constant
knr, for isoquinolines derivatives can be estimated from the determined
emission quantum yield (Φ) and the double-exponential emission
decay lifetimes (τ) using the following relations:
Fig. 4. Emission spectra of isoquinoline derivatives 6a–c in dichloromethane (λex
339 nm).
=
Φ
kr ¼
τ
almost no changes in solvent with different polarities, suggesting that
the ground state of these derivatives is not significantly modified by sol-
vent polarity.
The emission spectra of derivatives 5a–c in DMSO at room tempera-
ture when excited at their absorption maxima are depicted in Fig. 3. The
emission bands for 5b and 5c are located at 363, 381 and 401 nm, re-
spectively, with a shoulder band around 425 nm. Similar to absorption
spectra, the emission maxima of 5a containing CN group on the pyrrole
and
1−Φ
knr
¼
τ
Table 2
Decay parameters of isoquinoline derivatives in DMSO.
Sample
τ1
τ2
a1%
a2%
χ
k1r ∗ 10−9
k1nr ∗ 10−9
k2r ∗ 10−9
k2nr ∗ 10−9
(ns)
(ns)
(ns)
(ns)
(ns)
(ns)
5a
5b
5c
6a
6b
6c
0.069
0.866
0.112
0.031
0.060
0.036
3.115
3.095
3.219
2.785
2.700
5.400
94.42
27.17
4.59
89.46
98.30
99.63
5.58
0.99
0.99
0.99
0.99
1.00
0.99
9.19
0.64
4.82
1.10
1.33
4.43
5.29
0.51
4.11
31.68
15.34
23.35
0.20
0.18
0.17
0.01
0.03
0.03
0.12
0.14
0.14
0.35
0.34
0.16
72.83
95.41
10.54
1.70
0.37

C. Gherasim et al. / Journal of Molecular Liquids 310 (2020) 113196
5
Fig. 7. Effect of NaOH addition on the emission spectra of 5c (λex = 275 nm).
Fig. 5. Time-resolved decay profile of 5a–c in DMSO.
The values of the fluorescence lifetimes (τj) and rate constants (kr,
nr), as well as their intensity amplitudes (ai) are summarized in Table 2.
Representative time-resolved profiles of pyrroloisoquinolines 5a–c
pyrroloisoquinolines, the greatest value being attained for compound
5a. Following the changes in the quantum yield values and lifetimes,
the same tendency was also observed for non-radiative rate constants
(knr) of the both classes of isoquinolines. The values of kr determined
for these isoquinolines derivatives are higher when compared to those
estimated for other quinoline compounds [21,22].
To study the changes of the absorption and fluorescence spectra in
the presence of NaOH 0.1 N, titration experiments with various amounts
of NaOH were performed. The addition of NaOH 0.1 N determines the
progressive decrease of the emission intensity of 5c, without the modi-
fication of emission profile in the first stages of NaOH addition (Fig. 7).
The change in the emission spectra of 5c during the addition of NaOH
occurs at 30 μl of NaOH, when the emission band becomes broad and
structureless with a maximum located at 390 nm. Adding higher
amounts of NaOH does not change the emission profile (Fig. S1). Also,
in case of compound 5b, the intensity of the long wavelength absorption
band decreases up to 40 μl by adding NaOH and then the vibrational
subbands become broader with a small decrease in intensity and a
shift to longer wavelengths (Fig. 8).
k
and imidazoisoquinolines 6a–c in DMSO are depicted in Figs. 5 and 6.
The decay patterns were fitted to the double exponential model, indi-
cating probably the formation of two geometrical conformers for all de-
rivatives. We would like to mention that the lifetime τ1 is always shorter
than τ2 at a particular emission wavelength (Table 2). The fluorescence
lifetime τ1 of pyrroloisoquinolines 5a–c were longer than those of
imidazoisoquinolines 6a–c (Table 2) in DMSO. For derivatives 5a–c
the short-lived component of lifetime varies in the range of 0.069 to
0.866 ns, the shortest values of τ1 being observed for 5a (Table 2). How-
ever, the contributions corresponding to the τ2 long-lived component
increase for 5b and 5c, being 72.83 and 95.41%, respectively, whereas
for 5a the contribution from τ1 becomes predominant (94.42%). In the
case of imidazoisoquinolines the lifetime values of τ2 are higher than
τ1 and the major contribution results from the short-lived components
of τ1 with amplitudes of 98.3, 99.6 and 89.5%, respectively. An extension
of the long-lived component of lifetime was observed for 6a. The values
of the rate constant of radiative deactivation (kr) estimated from the
lifetimes of the short-lived component of the fluorescence decay in-
The recovery of the emission band centered at 382 nm for 5c was no-
ticed by adding HCl 0.1 N to the solution containing NaOH (Fig. S2) and
the initial emission spectrum was restored. We would like to mention
creased from 0.64
∗ ∗
109 to 9.19 109 s−1 in the series of
Fig. 6. Profiles of emission decay of 6a–c in DMSO.
Fig. 8. Evolution of the absorption spectra of 5b upon addition of NaOH.

6
C. Gherasim et al. / Journal of Molecular Liquids 310 (2020) 113196
for 5a after adding only 20 μl of NaOH and the broad emission band was
located at 390 nm. At higher addition levels of NaOH (N40 μl), the emis-
sion band of 5a at about 410 nm increases gradually in intensity and the
initial profile of the emission band was restored (Fig. 9).
The sensitivity of pyrroloisoquinoline derivatives in the presence of
NaOH has been checked by NMR titration experiments in DMSO‑d6. Re-
sults are presented in Fig. 10 for derivative 5a. The NMR data indicated
that a hydrolysis reaction took place on both ester and cyano groups,
with formation of a sodium dicarboxylate derivative. The 1H NMR spec-
tra recorded during the NaOH titration experiment contained several
sets of signals, with variable intensities, suggesting the presence of
more derivatives. As can be seen in Fig. 10 four spectra recorded after
the addition of different volumes of NaOH are presented for derivative
5a, illustrating the formation and the disappearance of two intermedi-
ary derivatives. For a better visualization, only the region 7–8 ppm is
given, the signals of interest being the two doublets from 7.22 and
7.31 ppm, respectively, assigned to the proton in position 5 in the two
intermediary derivatives. Valuable information about the structure of
these intermediary derivatives was obtained from a long-range
proton‑carbon correlation experiment (H,C-HMBC) illustrated in
Fig. 11. For one derivative, correlations were obtained between the pro-
ton in position 2 (a singlet at 8.00 ppm) and ester carboxylic carbon
from 164.6 ppm, indicating a derivative with unaffected ester group
and hydrolyzed cyano group (the follow-up signal is the doublet from
7.31 ppm, Fig. 10). Other correlation supporting this conclusion was
made between the ester carboxylic carbon from 164.6 ppm and methy-
lene protons (quartet centered at 4.32 ppm) Figs. 11, S6). For the other
intermediary derivatives, there was no correlation with ester carboxylic
Fig. 9. Evolution of the emission spectra of 5a upon addition of different NaOH levels
(λex = 278 nm).
that the absorption or emission spectra after 24 h have the same profile
confirming the stability of derivative 5c in basic medium.
The other pyrroloisoquinoline derivatives (5a, 5b) exhibited similar
modifications in the emission and absorption spectra by adding NaOH
in the first stages (Figs. S3–S5). However, these changes occurred faster
Fig. 10. Evolution of 1H NMR spectra for 5a after addition of different volumes of NaOH, illustrating the hydrolysis of ester and cyano groups, with the formation of two intermediary
derivatives.

C. Gherasim et al. / Journal of Molecular Liquids 310 (2020) 113196
7
Fig. 11. H,C-HMBC spectrum for 5a after the addition of 90 μl NaOH 0.1 N. The correlations of interest proving the existence of the two intermediary compounds are marked in the 2D plot.
Fig. 12. Change in the 1H NMR spectrum of 6a upon addition of different volumes of NaOH, illustrating the hydrolysis of ester and cyano groups, with the formation of the sodium
dicarboxylate derivative.

8
C. Gherasim et al. / Journal of Molecular Liquids 310 (2020) 113196
carbon. Instead, a correlation between the proton in position 2 (a singlet
at 7.61 ppm) and a quaternary carbon from 95.3 ppm, assigned to car-
bon in position 3, when it is chemically bonded with cyano group was
observed. This fact suggested an intermediary derivative with an unaf-
fected cyano group and hydrolyzed ester group (the follow-up signal
is the doublet from 7.22 ppm, Fig. 10).
amounts of HCl did not change the emission spectral pattern. In acidic
medium the absorption spectra of these derivatives are practically sim-
ilar. As reported in literature, for other pyrrazoloisoquinoline deriva-
tives the presence of an acid modifies significantly the absorption and
emission spectra due to the protonation effect of the acid [14,23].
The fluorescence signal of 6c was investigated in organic solvents
containing various amount of water. The study was made in DMSO as
polar aprotic solvent. The influence of water content on the emission
spectra of 6c was depicted in Fig. 14. As can be seen from Fig. 14 the
emission intensity of 6c gradually decreased with increasing water con-
tent. Upon incremental addition of water into the solution, the emission
band shifts to longer wavelengths and a new broad and structureless
emission band centered at 410 nm appeared (Fig. 14). At the same
time, the intensity of longer wavelength absorption band decreased in
intensity as the water content increased without other change in the ab-
sorption spectra.
The titration experiment was stopped when only one set of signals
was observed in the 1H NMR spectrum, suggesting the presence of a sin-
gle final derivative. Long-range correlation signals between the proton
in position 2 and the two quaternary carbons from 165.3 and
172.1 ppm, indicated the presence of two carboxylic groups in the struc-
ture of the final compound (the follow-up signal is the doublet from
7.02 ppm, Fig. 10). Because the number and the shape of the signals at
the end of the titration experiment were similar with that of the initial
compound, we concluded that the rest of the structure remained intact,
the hydrolysis of the ester and cyano groups being the only chemical
modifications. The formation of the ethanol during NaOH titration was
followed in the 1H NMR spectra through the characteristic signals
from 1.03 ppm (triplet, assigned to methyl protons) and 3.45 ppm
(quartet, assigned to methylene protons). A similar titration experiment
was performed for compound 5b. In this case, the hydrolysis of the ester
and cyano groups occurs, with the formation of corresponding sodium
carboxylate derivative and ethanol (Fig. S7). During NaOH titration,
the vibronic structure of the absorption band at longer wavelengths is
diminished, the absorption bands become broader and their intensities
do not change (Fig. S5), probably due to the presence of more species
close structurally in system according to NMR data.
Adding different amounts of NaOH 0.1 N to a DMSO solution of
imidazoisoquinoline 6c, its emission intensity decreases progressively
and after additions of 70 μl NaOH a new broad emission band appeared
at about 400 nm. This emission band increases in intensity adding new
NaOH aliquots (Fig. 12). As anticipated, the addition of hydrochloric acid
to the basic solution of 6c determines the increase of emission intensity
to the starting value (Fig. S9). The spectral emission behaviour of deriv-
atives 6a and 6b was similar to that observed for related compounds 5c
and 5b, respectively (Figs. S10, S11). Also, the titration experiment
made for compound 6a takes place with the hydrolysis of the ester
and cyano groups and the appearance of the corresponding sodium car-
boxylate derivative and ethanol (Fig. 13).
4. Conclusions
A series of luminescent fused N-heterocyclic derivatives with
isoquinoline skeleton was successfully synthesized and characterized.
The pyrroloisoquinoline derivatives exhibited strong fluorescence
with maxima ranged between 350 and 420 nm and high quantum
yields in DMSO solution, values much higher that imidazoisoquinoline
compounds. All compounds exhibited excited-state lifetimes in the
nanosecond timescale. Emission bands of pyrroloisoquinoline deriva-
tives 5a-c occur at wavelengths over 350 nm and they are clear
hypsochromic shifts of the absorption and emission bands provided
by imidazoisoquinolines 6a-c. 1H NMR titration experiments with
NaOH revealed that the hydrolysis occurred to cyano and ester groups
with the formation of a sodium dicarboxylate derivative.
Authorship statement
All persons who meet authorship criteria are listed as authors, and
all authors certify that they have participated sufficiently in the work
to take public responsibility for the content, including participation in
the concept, design, analysis, writing, or revision of the manuscript. Fur-
thermore, each author certifies that this material or similar material has
not been and will not be submitted to or published in any other publica-
tion before its appearance in the Journal of Molecular Liquids.
The effect of hydrochloric acid on the emission and absorption bands
of isoquinoline derivatives was investigated in DMSO solutions. The ad-
dition of HCl 0.1 N leads to a small decrease of the intensity in the fluo-
rescence spectra range between 10 and 15% for imidazo- and
pyrroloisoquinoline derivatives (Fig. S12). The addition of higher
Fig. 14. Influence of the water content on the emission spectra of 6c in DMSO solution
(λex = 287 nm).
Fig. 13. Effect of NaOH adding on the emission spectra of 6c (λex = 287 nm).

C. Gherasim et al. / Journal of Molecular Liquids 310 (2020) 113196
9
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