Synthesis and fluorescence properties of 4-aminobenzo[f]isoindole derivatives

Article abstract of DOI:10.3184/174751911X13007329600661

We report a new route to benzo[f]isoindole derivatives that possess strong fluorescence. The structure of the newly synthesised compounds was confirmed by NMR, IR and mass spectra, along with X-ray crystallographic studies. Absorption and fluorescence spectra of the new compounds were recorded. It was established that tautomerism of 4-aminobenzo[f]isoindoles defines the properties of these compounds. Also, the influence of substituents at the N-2 position on the luminescence properties was studied; the fluorescence intensity is dependent on the water content in organic solvents, and can be used to indicate their moisture content.

Full text of DOI:10.3184/174751911X13007329600661

JOURNAL OF CHEMICAL RESEARCH 2011
RESEARCH PAPER 209
APRIL, 209–213
Synthesis and fluorescence properties of 4-aminobenzo[f]isoindole
derivatives
Igor V. Levkova*, Zoia V. Voitenkoa, Olga A. Zaporozhetsa, Rostislav P. Linnika,
Svetlana V. Shishkinab and Oleg V. Shishkinb
aKiev NationalTaras Shevchenko University, 64 Str Volodymyrs’ka, 01033 Kiev, Ukraine
bSTC "Institute for Single Crystals" NASU, 60 Lenina ave, 61001 Kharkiv, Ukraine
We report a new route to benzo[f]isoindole derivatives that possess strong fluorescence. The structure of the newly
synthesised compounds was confirmed by NMR, IR and mass spectra, along with X-ray crystallographic studies.
Absorption and fluorescence spectra of the new compounds were recorded. It was established that tautomerism of
4-aminobenzo[f]isoindoles defines the properties of these compounds. Also, the influence of substituents at the N-2
position on the luminescence properties was studied; the fluorescence intensity is dependent on the water content
in organic solvents, and can be used to indicate their moisture content.
Keywords: isoindoles, maleimides, cycloadditions, rearrangements, fluorescence spectra
One of the major aspects of isoindole chemistry1,2 is the aspect
of isoindole–isoindoline tautomerism.3 It is well-known that
the isoindole tautomer easily undergoes the Diels–Alder reac-
tion. This fact allows not only the identification of unstable
isoindoles4–6 but also, which is highly important, enables the
design of unusual spatial structures that cannot be formed by
other synthetic routes. Depending on the type of reaction con-
trol (kinetic or thermodynamic) it is possible to isolate either
the endo- or the exo-adducts, and a variety of methods can be
used to determine their structure.7,8
The aptitude of non-fused isoindoles, which exist primarily
in the isoindoline form, to undergo cycloaddition reactions has
not been investigated and therefore is of interest. Recently, we
have shown that 1-aminoisoindole, with its primary form being
the isoindoline tautomer, is also capable of undergoing [2+4]-
cycloaddition which can be accounted for by the Curtin–
Hammett principle. Diels–Alder adducts derived from fused
azino- and azoloisoindoles with maleimides undergo further
rearrangements and form compounds with addends in both a
1:1 and 1:2 ratio, that possess intriguing properties.9–12
Reaction of 2,4-dimethylpyrimido[2,1-a]isoindole with a
variety of maleimides gives derivatives of 4-aminobenzo[f]
isoindole which exhibit notably strong fluorescence.12 In the
current research, we developed a new synthetic route to the
latter compounds, giving better yields and easier to implement
than the existing one.12 The structures of the substances syn-
thesised were confirmed by spectral methods and X-ray crystal
analysis. Absorption and fluorescence spectra were recorded
and it was noted that these spectral data are highly dependent
upon substituents and on the water content in organic solvents.
Solvatochromic dyes have been used as indicators for the
determination of micro water content in aprotic organic sol-
vents. There are fluorescence lifetime-based sensors, and
wavelength-based fluorescent and intensity-based indica-
tors.13–15 However, measurement of lifetime is not applicable
to convenient on-line determinations. Indicators based on
decreasing of fluorescence suffer greatly from external distur-
bance of the indicator dye and signal drift of the measuring
equipment, especially in determinations of low-level water
concentrations. The compounds described in the manuscript
can be used as increasing intensity-based indicators for
determining the water content in aprotic organic solvents.
Compared with the decreasing intensity-based indicators, the
new dyes could be less susceptible to these adverse effects.
Results and discussion
We have recently shown that a bis-Michael adduct 5 is formed
when 1-aminoisoindole reacts with maleimide derivatives.16
We noticed that a small amount of a substance having strong
blue fluorescence was also obtained. Analysis of the data12 and
the newly acquired data proved the fluorescent product to be a
derivative of benzo[f]isoindole. Formation of this compound
provided evidence that the reaction involves formation of the
Diels–Alder cycloaddition product which can transform into
either the bis-Michael adduct 5 (when the C–C bond is cleaved)
or the adduct 4 (when a molecule of ammonia is eliminated).
However, the new route to fluorescent benzo[f]isoindole
derivatives is strongly dependent upon the nature of the
Scheme 1 Interaction of 1-aminoisoindole hydrobromide with N-methylmaleimide in the ratio 1:2.
* Correspondent. E-mail: levkov.igor@gmail.com

210 JOURNAL OF CHEMICAL RESEARCH 2011
Product
4a
R
Yield (%)
Me
40
85
77
4b
4-CH3C6H4
C6H5
4c
Scheme 2 Mechanism of rearrangement of the compounds 5a–c with the formation of the fluorescent compounds 4a–c.
substituent R and gives low yields. The major product of the
transformation is the bis-Michael adduct 5.
We have now succeeded in finding the optimal conditions
for the rearrangement of the product 5 into 4 with higher yields
(Scheme 2). Thus, refluxing 5 and 10-fold excess of acetylac-
etone in acetic acid saturated with hydrogen chloride leads to
the formation of 4.
The mechanism for the transformation outlined in Scheme 2
is based upon studies of the interaction of 2,4-dimethylpyrim-
ido[2,1-a]isoindole with maleimide.12 Condensation of the
1-aminoisoindole fragment and acetylacetone is accompanied
by elimination of maleimide, giving the pyrimidine ring. The
liberated maleimide then acts as a dienophile in a Diels–Alder
reaction and the adduct so formed undergoes rearrangement
including elimination of the pyrimidine ring fragment, as
shown.
The X-ray diffraction study demonstrated that compound 4c
exists in the crystal phase as a solvate with DMF and water.
The asymmetric part of the unit cell contains four crystallo-
graphically independent molecules of 4c (A, B, C and D), one
molecule of DMF and one water molecule. The solvate mole-
cules are disordered over two positions in the ratio 59:41 % for
the dimethylformamide and 58:42 % for the water molecule.
The tricyclic fragment of 4c is planar within 0.02 Å in all
Fig. 1 The X-ray crystal structure of compound 4c. Only one
molecules within the asymmetric part of the unit cell. The
amino group has a pyramidal configuration with different
degrees of pyramidality (the sum of bond angles centred on the
N2 atom is 349° in the molecule A, 343° in B, 347.5° in C and
359° in D). The formation of the N2–H…O2 intramolecular
hydrogen bond between amino group and the C12–O2 car-
bonyl group (H…O 2.28 Å N–H…O 133° A, 2.23 Å and 130°
B, 2.27 Å and 135° C, 2.29 Å and 128° D) contribute to some
elongation of the C12–O2 bond (1.228(2) Å A, 1.227(3) Å B,
molecule located in asymmetric part of unit cell is depicted for
clarity.
1.224(3) Å D as compared to average value17 1.210 Å). The
phenyl substituent at the N1 atom is twisted relative to the
planar tricyclic fragment (the C12–N1–C13–C18 torsion
angle is −77.8(4)° A, −126.6(3)° B, 126.3(3)° C, 129.8(3)° D).
The pyrrolidine ring adopts an envelope conformation with

JOURNAL OF CHEMICAL RESEARCH 2011 211
Scheme 3 Tautomerism of 4-aminobenzo[f]isoindole
derivatives 4.
Fig. 2 Absorption spectra of 2.6·x 10−5 M acetonitrile solution
of 4b, 4c (1, 2) and DMSO solution of 4a–c (3–5). l = 10 mm.
different degrees of puckering. The deviation of the C19 atom
from the mean plane of the remaining atoms of the ring is
−0.22 Å A, 0.32 Å B, −0.25 Å C, 0.14 Å D. The substituent
at the C3 atom is twisted relative to the plane of the tricyclic
fragment (the C2–C3–C19–C20 torsion angle is −55.6(3)° A,
−50.5(3)° B, −49.7(4)° C, 58.1(3)° D). Such an orientation of
the substituent is caused by the balance of repulsion between
the oxygen atoms of carbonyl groups and hydrogen atoms at
the C5 and C19 atoms (shortened H…H intramolecular con-
tacts are within 1.90–1.93 Ǻ, the sum of van der Waals radii18
is 2.32 Ǻ). The phenyl group at the N3 atom is turned relative
to the mean plane of the pyrrolidine ring (the C21–N3–C23–
C24 torsion angle is −50.7(3)° A, −54.7(3)° B, −42.0(3)° C,
92.6(3)° D).
Fig. 3 Partial 1H NMR spectrum of compound 4b.
The absorption spectra of 4a–c for acetonitrile and for
DMSO solutions are presented in Fig. 2. All of the compounds
showed five absorption bands at 232, 260, 284, 344 and
406 nm. The compounds in acetonitrile showed maxima in the
spectra at shorter wavelengths (232 nm) in comparison
with those in the DMSO solutions (260 nm). The absorption
characteristics of 4a–c are summarised in the Table 1.
The primary fragment responsible for fluorescence in com-
pounds 4a–c is the aminophthalimide core.19 Low reactivity of
the amino group (which practically does not react with metal
ions, such as Cu(II), Zn(II), that form amino complexes) can
be explained by conjugation of the amino group with the
aromatic ring and with the electron-withdrawing amide group
and also by tautomerism (Scheme 3).
Fig. 4 Fluorescence spectra of 1·10−6 M DMSO solution of 4a–c
(1–3, 6–8) and acetonitrile solution of 4b, 4c (4, 5 and 9, 10) and
λex = 400 (9,10), 415 (6–8) nm, λem = 460 (4, 5), 470 (1–3) nm. l =
10 mm.
The 1H NMR spectral data show the presence of the minor
tautomeric form, best indicated by the signal of the methine
proton from the succinimide moiety, which is shifted down-
field in the minor tautomer (Fig. 3). The large chemical shift
difference (~1 ppm) can be explained by the presence of an
ortho-quinonoid system that strongly influences the chemical
shift of the methine proton. Other proton signals from the
minor tautomer unfortunately cannot be seen because of over-
lapping by the signals of the major tautomer. The presence
of the minor tautomer can also be confirmed by the abnormal
bathochromic luminescence maximum shift in DMSO
(Fig. 4), and in water–organic mixtures by increased lumines-
cence upon addition of a proton-donor solvent (Fig .5). 20
Table 1 Absorption data of 4a–c solutions in organic solvents. (4a is not soluble in acetonitrile)
Compound (solvent)
ε232, 104
ε284, 104
ε344, 104
ε406, 104
L mol−1 cm−1
L mol−1 cm−1
L mol−1 cm−1
L mol−1 cm−1
4b (acetonitrile)
4c (acetonitrile)
4a (DMSO)
8.04
4.10
0.37
1.12
0.78
3.70
1.70
1.18
1.69
1.85
1.46
0.81
0.80
0.79
0.93
1.58
0.92
0.92
0.79
1.05
4b (DMSO)
4c (DMSO)

212 JOURNAL OF CHEMICAL RESEARCH 2011
17.6 Hz, 1H), 5.07 (dd, J = 7.2, 9.2 Hz, 1H), 7.30 (s, NH2), 7.64 (t,
J = 7.8 Hz, 1H), 7.75 (t, J = 7.8 Hz, 1H), 8.34 (d, J = 7.8 Hz, 1H),
8.46 (d, J = 7.8 Hz, 1H). 13C NMR (DMSO-d6) δ: 23.98, 25.05, 37.35,
38.62, 101.98, 122.48, 125.19, 125.50, 126.05, 126.23, 128.06,
130.49, 136.41, 144.98, 168.59, 169.05, 176.96, 178.80. MS: m/z =
338.0 [MH+].
4-Amino-9-(2,5-dioxo-1-(4-methylphenyl)-pyrrolidin-3-yl)-1-(4-
methylphenyl)benzo[f]isoindole-1,3-dione (4b): Yield: 85%; 0.41 g;
m.p. = 279 ºC; [Found: C, 73.58; H, 4.78; N, 8.65. C30H23N3O4 requires
C, 73.61; H, 4.74; N, 8.58] IR (KBr): νmax 3440, 3352, 3032, 2916,
1696, 1632, 1508, 1372, 1164, 760 cm−1. 1H NMR (400 MHz, DMSO-
d6) δ: 2.39 (s, 3H), 2.42 (s, 3H), 2.88 (dd, J = 7.2, 17.6 Hz, 1H), 3.30
(dd, J = 9.2, 17.6 Hz, 1H), 5.33 (dd, J = 7.2, 9.2 Hz, 1H), 7.19 (d, J =
8.0 Hz, 2H), 7.25–7.33 (m, 6H), 7.49 (s, NH2), 7.71 (t, J = 7.8 Hz,
1H), 7.81 (t, J = 7.8 Hz, 1H), 8.43 (d, J = 7.8 Hz, 1H), 8.53 (d, J =
7.8 Hz, 1H). 13C NMR (DMSO-d6) δ: 21.29, 37.24, 38.83, 101.55,
122.67, 125.23, 125.34, 126.13, 126.31, 127.42, 127.53, 128.29,
129.85, 129.90, 130.80, 130.98, 136.64, 137.84, 138.18, 145.75,
167.54, 168.79, 176.04, 177.81. MS: m/z = 490.0 [MH+].
4-Amino-9-(2,5-dioxo-1-phenylpyrrolidin-3-yl)-1-phenylbenzo[f]
isoindole-1,3-dione (4c): Yield: 77%; 0.37 g; m.p. = 273 ºC; [Found:
C, 72.83; H, 4.11; N, 9.17. C28H19N3O4 requires C, 72.88; H, 4.15; N,
9.11] IR (KBr): νmax 3428, 3334, 3066, 1698, 1638, 1494, 1370, 1164,
1
764 cm−1. H NMR (400 MHz, DMSO-d6) δ: 3.06 (dd, J = 7.2, 17.6
Fig. 5 Fluorescence spectra of 1.04·10−6 M acetonitrile aqueous
solution of 4c in the presence of added H2O in the following
concentrations, %: 0 (1); 10 (2); 20 (3). λex = 255 nm, l = 10 mm.
Hz, 1H), 3.36 (dd, J = 9.2, 17.6 Hz, 1H), 5.46 (dd, J = 7.2, 9.2 Hz,
1H), 7.32 (d, J = 7.6 Hz, 2H), 7.40–7.54 (m, 8H), 7.58 (s, NH2), 7.78
(t, J = 7.8 Hz, 1H), 7.87 (t, J = 7.8 Hz, 1H), 8.48 (d, J = 7.8 Hz, 1H),
8.58 (d, J = 7.8 Hz, 1H). 13C NMR (DMSO-d6) δ: 37.39, 39.01, 101.65,
122.81, 125.37, 125.51, 126.29, 126.47, 127.78, 127.89, 128.49,
128.53, 128.88, 129.53, 129.68, 131.01, 132.69, 133.72, 136.80,
146.00, 167.64, 168.84, 176.13, 177.89. MS: m/z = 462.0 [MH+].
The crystals of 4c were grown from the solvent system: acetone:
N,N-dimethylformamide:water in the ratio 10:1:1). The crystals of 4c
(4 C28H19N3O4 · C3H7NO · H2O) are triclinic. At 100 K a = 12.4913(5),
The increase of luminescent properties in the series
4c>4b>4a (Fig. 4) can be explained by progressive weakening
of the interaction of the imide nitrogen lone pair with the
N-substituent.
The fluorescence of 4c was strongly dependent on the water
content in aqueous organic solvents (Fig. 5).
In 100% acetonitrile, 4c exhibited a fluorescence emission
maximum at 461 nm. As the water content increased up to
around 10%, the emission of 4c was increased with a red shift
to 467.5 nm. The chemosensing behavior of 4c was found to be
efficient and is thus of potential as a sensitive indicator of the
water content in acetonitrile.
b = 16.9446(7), c = 23.068(1) Å, α = 72.296(4)°, β = 84.766(4)°, γ =
87.003(3)°, V = 4630.5(4) , M = 1936.96, Z = 2, space group P1,
3
¯
Ǻ
r
dcalc = 1.389 g cm−3, μ(MoKα) = 0.096 mm−1, F(000) = 2020. Intensi-
ties of 31367 reflections (16152 independent, Rint = 0.060) were mea-
sured on the Xcalibur-3 diffractometer (graphite monochromated
MoKα radiation, CCD detector, ω-scaning, 2Θmax = 50°). The structure
was solved by direct methods using the SHELXTL package.21 Posi-
tions of the hydrogen atoms were located from electron density differ-
ence maps and refined by “riding” model with Uiso = nUeq of the
carrier atom (n = 1.5 for methyl groups and for water molecule and
n = 1.2 for other hydrogen atoms). Full-matrix least-squares refine-
ment against F2 in anisotropic approximation for non-hydrogen atoms
using 15943 reflections was converged to wR2 = 0.074 (R1 = 0.044 for
6722 reflections with F>4σ(F), S = 0.685). The final atomic coordi-
nates, and crystallographic data for molecule 4c have been deposited
to with the Cambridge Crystallographic Data Centre, 12 Union Road,
CB2 1EZ, UK (fax: +44-1223-336033; E-mail: deposit@ccdc.cam.
ac.uk) and are available on request quoting the deposition numbers
CCDC 793608).
Experimental
1
The Н NMR spectra (400.396 MHz) were recorded with a Varian
Mercury 400 with TMS as internal standard. The IR-spectra were
recorded on Specord M82. The chromatomass-spectra were recorded
on Agilent 1100 Series with selective detector Agilent LC/MSD SL.
Elemental analyses were determined using a Carlo Erba Strumeniza-
tion analyser. Fluorescence measurements were performed using a
Perkin Elmer Spectrometer LS 55 equipped with a xenon flash lamp
and a computer. All working measurements took place in a standard
10 mm path-length quartz cell, thermostated at 25 0.5 °C, with 5 nm
bandwidths for the emission and excitation monochromators. All sol-
vents (acetonitrile, DMSO) used for spectroscopic measurements
were purchased from Aldrich Chemical Co. as ‘anhydrous’ grade
having water content less than 0.1%. l = 10 mm. Absorption spectra
were recorded on UV-Vis Spectrometers Lambda-20 (Perkin Elmer)
and UV-2800 (UNICO) at l = 10 mm.
Conclusions
We have developed a new synthetic route to fluorescent deriva-
tives of 4-aminobenzo[f]isoindoles, that is much simpler and
gives better yields than the one described earlier in the litera-
ture.18 We proved the structure of the products using NMR, IR,
mass-spectroscopy and X-ray crystallography. It was shown
that 4-amino-benzo[f]isoindoles exhibit tautomerism, and the
presence of the minor tautomer defines the properties of the
compounds, such as the low reactivity of the amino group, the
luminescent properties and the dependence of the fluorescence
spectra on the nature of the solvent. Finally, as the luminescent
properties of the compounds are sensitive to the water content
in organic solvents, they may be used for quantitative analysis
of the moisture content in solvents.
Synthesis of compounds 4a–c
The appropriate 3-amino-1,1-bis-(1-substituted-2,5-dioxopyrrolidin-
3-yl)-1Н-isoindole 5a–c (0.50 g)16 was refluxed for 15 h with acetyl-
acetone (1.5 mL) in acetic acid (5 mL) saturated with hydrogen
chloride. On cooling of the reaction mixture the precipitate was
collected by filtration and washed with methanol. The product
was obtained with 99–100% purity as indicated by liquid chromatog-
raphy.
4-Amino-9-(1-methyl-2,5-dioxopyrrolidin-3-yl)-1-methylbenzo[f]
isoindole-1,3-dione (4a): Yield: 40%; 0.19 g; m.p. = 265 ºC; [Found:
C, 64.01; H, 4.51; N, 12.43. C18H15N3O4 requires C, 64.09; H, 4.48;
N, 12.46] IR (KBr): νmax 3432, 3340, 2944, 1728, 1684, 1520, 1432,
1372, 1280, 1112, 676 cm−1. 1H NMR (400 MHz, DMSO-d6) δ: 2.59
(dd, J = 7.2, 17.6 Hz, 1H), 2.98 (s, 3H), 3.02 (s, 3H), 3.06 (dd, J = 9.2,
Received 27 December 2010; accepted 8 March 2011
Paper 1000496 doi: 10.3184/174751911X13007329600661
Published online: 3 May 2011

JOURNAL OF CHEMICAL RESEARCH 2011 213
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