Two new fluorescent heterocyclic perimidines: first syntheses, crystal structure, and spectral characterization

Article abstract of DOI:10.1016/j.tetlet.2010.02.077

An efficient one-pot synthesis of two new heterocyclic perimidines 4-(2,3-dihydro-1H-perimidin-2-yl)-2-methoxyphenol and 2-(quinoxalin-2-yl)-2,3-dihydro-1H-perimidine in good yields is presented. This methodology provides a simple, straightforward synthetic route to these interesting classes of heterocycles. Crystal structure, solvatochromism, and antibacterial activity of these organic compounds are discussed.

Full text of DOI:10.1016/j.tetlet.2010.02.077

Tetrahedron Letters 51 (2010) 2174–2177
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Two new fluorescent heterocyclic perimidines: first syntheses, crystal structure,
and spectral characterization
G. Varsha a, V. Arun a, P. P. Robinson a, Manju Sebastian a, Digna Varghese a, P. Leeju a, V. P. Jayachandran b,
K. K. M. Yusuff a,
*
a Department of Applied Chemistry, Cochin University of Science and Technology, Cochin 682 022, Kerala, India
b Department of Biosciences, Sree Narayana Guru Institute of Science and Technology, North Paravur 683 520, Kerala, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient one-pot synthesis of two new heterocyclic perimidines 4-(2,3-dihydro-1H-perimidin-2-yl)-2-
methoxyphenol and 2-(quinoxalin-2-yl)-2,3-dihydro-1H-perimidine in good yields is presented. This
methodology provides a simple, straightforward synthetic route to these interesting classes of heterocy-
cles. Crystal structure, solvatochromism, and antibacterial activity of these organic compounds are
discussed.
Received 19 December 2009
Revised 12 February 2010
Accepted 15 February 2010
Available online 18 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Nitrogen heterocycles
Perimidines
1,8-Diaminonaphthalene
Solvatochromism
Crystal structures
Antibacterial activity
The 1H-perimidine system has been known since 1874, when it
1,8-Diaminonaphthalene possesses excellent fluorescence proper-
ties.14 Photoluminescence is an intrinsic molecular property of
great interest for the preparation of advanced materials required
for applications such as organic light-emitting devices or liquid
crystal displays.15 It has previously been shown16 that usually per-
imidine formation needs special reagent or vigorous reaction con-
ditions, but here we have succeeded in preparing the perimidines,
4-(2,3-dihydro-1H-perimidin-2-yl)-2-methoxyphenol (compound
1) and 2-(quinoxalin-2-yl)-2,3-dihydro-1H-perimidine (compound
2) by very simple and efficient procedure in good yield without any
other byproducts.
Compound 1 (Scheme 1) was synthesized by refluxing 0.16 g
(1 mmol) of purified 1,8-diaminonaphthalene17,18 and 0.15 g
(1 mmol) of 4-hydroxy-3-methoxy benzaldehyde in methanol. It
was refluxed for 3 h under nitrogen atmosphere. The product
was collected by removing the solvent with rotavapor. The crude
product was purified by chromatography on silica gel with hex-
ane/ethyl acetate (80/20 mixture) to get colorless crystals in 80%
yield. The crystal suitable for X-ray crystallography was obtained
by keeping the solution of the compound in methanol for 4–5 days.
Compound 2 (Scheme 1) was synthesized by following the same
procedure given above except that the reaction was carried out
at room temperature to obtain orange crystals in 85% yield.
The reaction involves two steps. The first step is the condensa-
tion to form Schiff’s base and the second step is the intramolecular
nucleophilic attack of the amino group at the imino carbon to bring
was obtained by de Aguiar.1 These peri-naphtho-fused pyrimidines
have the characteristics both of
p-deficient and p-excessive sys-
tems.2 They have long been used as dye intermediates and coloring
materials for polymers3, polyester fibers4, and more recently as a
source of a novel carbene ligand.5 Perimidines are of wide inter-
est6,7 because they exhibit a diverse range of biological activities,
for example, their potential to act as anti-fungal, anti-microbial,
anti-ulcer, and anti-tumor agents.4,8
Synthetic method4 for the preparation of perimidines is the
condensation reaction of 1,8-diaminonaphthalene with various
carbonyl groups. Acyl chlorides9 and anhydrides, carboxylic
acids10,11 afford the mono-amide derivatives, and these undergo
acid-catalyzed cyclization to 2-substituted perimidines. Although
a wide range of 2-alkyl-, aryl-, and heterocycle-substituted perimi-
dines have been prepared by these approaches, there have been no
examples synthesized with quinoxaline-2-carboxaldehyde or with
4-hydroxy-3-methoxybenzaldehyde so far. Quinoxaline12a–c deriv-
atives are an important class of nitrogen-containing heterocycles
in medicinal chemistry.13a–d For example, quinoxaline is a part of
various antibiotics such as echinomycin, levomycin, and actinoleu-
tin that are known to inhibit the growth of Gram-positive bacte-
ria13c, and are active against various transplantable tumors.13d
* Corresponding author. Tel./fax: +91 484 2575804.
E-mail addresses: yusuff15@gmail.com, yusuff@cusat.ac.in (K.K.M. Yusuff).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.077

G. Varsha et al. / Tetrahedron Letters 51 (2010) 2174–2177
2175
Scheme 1. Synthesis of compound 1 and 2.
about the C–N coupling. The imino (or azomethine, C@N) carbon is
partially positively charged, and therefore is susceptible to inter-
molecular or intramolecular nucleophilic attack19, as illustrated
in Scheme 1 in Supplementary data. In particular the intramolecu-
lar reactions give five- or six-membered heterocycles.
Spectroscopic characterizations of the perimidines were carried
out by 1H, 13C NMR, IR as well as by elemental analysis. IR spec-
trum of compound 1 exhibits broad absorption bands at 3167
(NH) and 3367 (OH) cmÀ1. Compound 2 exhibits bands at 3284
(NH) and 1599 (C@N, quinoxaldehyde ring) cmÀ1. The 1H and 13C
NMR spectra of compound 1 show signals at dH 4.50 (2H, NH),
5.37 (1H, OH), 5.79 (1H, C8), and dc 132.0 (C4), 68.3 (C8) and the
spectra of the compound 2 exhibit signals at dH 5.01 (2H, NH),
5.83 (1H, C9), 9.25 (1H, C7) and dc 154.1 (C8), 67.2 (C9). Also the
purity of these compounds in methanol (10À5 mol LÀ1) is checked
by HPLC. The HPLC chromatogram (For figures: see Supplementary
data) gave only one peak with retention times 3.10 min and
3.35 min for compounds 1 and 2, respectively. Corresponding
UV–vis spectra of the HPLC peaks of the compounds 1 and 2 are gi-
ven in Supplementary data.
Figure 1. ORTEP drawing of compound 1 at 50% probability level.
Further structural information for 1 and 2 was rendered by the
single crystal X-ray diffraction analyses (Table 1; Figs. 1 and 2).
Compound 1 crystallized in an orthorhombic system. The asym-
metric unit of compound 1 contains two crystallographically inde-
pendent molecules. The naphthalene moiety of perimidine ring
and benzene ring of 3-methoxy-4-hydroxybenzaldehyde is nearly
perpendicular with an angle of 86.53°. The loss of planarity of
the perimidine ring is worth mentioning. The C8 atom lies
Figure 2. ORTEP drawing of compound 2 at 50% probability level.
Table 1
0.578 Å above the plane of perimidine ring and hence there is a
large deviation. Compound 1 is stabilized by intermolecular O–
HÁ Á ÁO hydrogen bonding.
Crystal data of the compounds 1 and 2
Crystal data
Parameters
Compound 1
Compound 2
Compound 2 crystallizes in a monoclinic system. The naphtha-
lene moiety of the perimidine ring and quinoxaline ring of com-
pound 2 is nearly parallel. The loss of planarity of the compound
is affected by the position of C9 which is 0.559 Å above the plane
of quinoxaline ring. There is no classical hydrogen bonding ob-
Empirical formula
Formula weight
Temperature (K)
Crystal system
Space group
a (Å)
C18H16N2O2
292.33
298(2)
Orthorhombic
Pna21
8.7813 (15)
7.4057 (12)
45.282 (8)
90
C19H14N4
298.34
298(2)
Monoclinic
P21/c
13.729 (4)
5.3352 (15)
20.104 (5)
90
97.530
90
1459.9 (7)
4
served in compound 2. The CHÁ Á Áp interaction of C9–H9 with sym-
b (Å)
c (Å)
metry-related naphthalene ring at a distance of 2.46 Å contributes
to the stability of crystal packing. In both the crystals, the carbon
atoms C8 and C9 lie 0.578–0.559 Å above the perimidine ring
plane. This feature of both crystals closely parallels that of the tri-
methylsilyl analogue20 in which the Si atom lies 0.88 Å above the
plane of the naphthalene ring.21 There are no reports of organic
compounds in which loss of planarity of perimidine ring moiety
is mentioned.
a
(°)
b (°)
90
90
c
(°)
V (Å3)
2944.8 (9)
8
1.319
0.09
1232
Z
Dcalcd (Mg/m3)
1.357
0.08
624
0.977
V (mmÀ1
F (0 0 0)
Tmin
)
The UV–vis absorption spectra of the compounds 1 and 2 in
0.971
Tmax
0.990
2713
0.061
0.157
0.991
1662
0.129
0.257
methanol exhibit well-defined p?p
* transition absorption bands
with the wavelength maximum at 337 and 345 nm, respectively
(Fig. 3a). In the electronic spectrum of compound 2 absorption at
Number of reflections with I > 2
r(I)
R[F2 > 2
wR(F2)
r
(F2)]
*
322 nm is due to the n?p transition of the –C@N group in

2176
G. Varsha et al. / Tetrahedron Letters 51 (2010) 2174–2177
Figure 3. UV–vis absorption spectra and fluorescence spectra of the compounds 1 and 2 in methanol.
quinoxaline ring.22 The UV–vis spectra corresponding to the peaks
in the HPLC chromatogram of compounds 1 and 2 in methanol
(10À5 mol LÀ1) and UV–vis spectra of the compounds in methanol
(10À5 mol LÀ1) are almost identical to each other. The effect of var-
ious solvents on the absorption spectra of these compounds is
studied (Table 2). For compound 1, the absorption spectra are
bathochromically shifted in going from cyclohexane to acetonitrile,
but are hypsochromically shifted in methanol (polar solvents).14
This positive solvatochromism in non-hydrogen bonding solvents
may be due to the effect of dipole moment changes in the excited
state; whereas the negative solvatochromism in polar solvents
may be due to the combined effect of dipole moment changes
and hydrogen bonding.12a In the case of compound 2, the obtained
results showed no solvatochromic effect suggesting that UV–vis
spectrum of the compound is independent23 of the solvent
polarity.
Table 3
Evaluation of antibiotic sensitivity of Staphylococcus aureus
Name
Diameter of zone of inhibition (mm)
Ciprofloxacin (10
l
g)
12
8
13
15
14
0
17
25
21
Ampicillin (10
Tetracycline (30
Erythromycin (15
Gentamicin (30 g)
Pencillin G (10 g)
Amikacin (30 g)
l
g)
g)
g)
l
l
l
l
l
Compound 1 (30
Compound 2 (30
l
l
g)
g)
suggesting that this may be due to the apparent stabilization of the
ground state through dipole–dipole interaction or a possible
hydrogen bonding in polar solvents. On the other hand, a constant
bathochromic shift25 (positive fluorescent solvatochromism) is no-
ticed in the fluorescence spectra of compound 2. This might be due
to the absence of hydroxyl group in compound 2 and consequent
hydrogen bonding interactions. The Stokes shift observed in the
case of compound 2 is smaller than that observed for compound
1. The fluorescence quantum yields were determined using a solu-
tion of quinine sulfate in 1 N H2SO4 (aq) with a concentration of
1 Â 10À5 mol LÀ1 as the reference standard (UF = 0.546)26 (see Sup-
plementary data). Here solvents have only minor effects on the
excitation spectra but a strong impact on the emission. In com-
pound 1, the fluorescence efficiencies in non-polar solvents (chlo-
roform and ethyl acetate) are very high (UF = 0.32 and 0.81) but are
moderate in polar hydrogen bonding and non-hydrogen bonding
donor solvents (UF = 0.21–0.07). Whereas in compound 2, the
fluorescence efficiencies in non-polar solvents are moderate
The fluorescence band maxima of these compounds at longer
wavelengths (Table 2) are compared with that of literature reports
of 1,8-diaminonaphthalene.14 Fluorescence spectra of compounds
1 and 2 in methanol are shown in Figure 3b. In compound 1,
hypsochromic shift (negative fluorescent solvatochromism)24 is
noticed on changing the nature of solvent from non-polar to polar
Table 2
UV–vis absorption data, fluorescence spectral data, Stokes shift, and quantum yield of
compound 1 and 2 in various solvents
Solvent
AbsorptioÀn5(nm) Emission Stokes shift Quantum
(
emax
(nm)
(nm)
yield (UF)
Â
(L molÀ110cmÀ1))
Compound 1
Cyclohexane
Dioxane
Tetrahydrofuran
Ethyl acetate
Acetonitrile
Methanol
332 (0.31)
345 (0.13)
346 (0.26)
346 (0.06)
348 (0.08)
337 (0.12)
335 (0.24)
376
387
388
386
386
384
385
389
389
44
42
42
40
38
47
50
54
60
0.07
0.13
0.14
0.81
0.11
0.21
0.07
0.08
0.32
(UF = 0.31) but are high in polar non-hydrogen bonding donor
solvents (acetonitrile and dioxane) (UF = 0.22 and 0.82).
These perimidines were screened for their antibacterial activi-
ties and a comparative study was made with antibiotics of known
potencies. Antibacterial activities of compounds were checked
against clinical isolates of Escherichia coli, Klebsiella pneumoniae,
and Pseudomonas aeruginosa by well diffusion method (see Supple-
mentary data). Both the compounds are more active toward Staph-
ylococcus aureus than antibiotic discs of known potency (Table 3).
In conclusion, we have achieved a practical and simple proce-
dure for the synthesis of new highly fluorescent antibacterial het-
eroaromatic compounds in good yield.
Ethanol
Dichloromethane 335 (0.31)
Chloroform
329 (0.06)
Compound 2
Cyclohexane
Dioxane
Tetrahydrofuran
Ethyl acetate
Acetonitrile
Methanol
a
a
a
a
—
—
—
—
346 (0.04)
345 (0.28)
382
375
36
30
0.82
0.07
a
a
a
a
—
—
—
—
345 (0.08)
345 (0.21)
345 (0.21)
383
389
388
385
373
38
44
43
40
58
0.24
0.04
0.01
0.05
0.31
Acknowledgments
Ethanol
Dichloromethane 345 (0.11)
Chloroform 315 (0.17)
The authors thank Department of Science and Technology, In-
dia, for using the Sophisticated Analytical Instrumentation Facility
(SAIF) at STIC, Cochin University of Science and Technology,
a
Due to the weak fluorescence, the evaluation of photophysical properties of
compound 2 in cyclohexane and ethyl acetate was not possible.

G. Varsha et al. / Tetrahedron Letters 51 (2010) 2174–2177
2177
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Supplementary data
Supplementary data (details regarding various experimental
methods and spectroscopic data, single crystal XRD data and anti-
bacterial studies. Crystallographic data for the structures of com-
pounds
1 and 2 have been deposited in the Cambridge
Crystallographic Data Centre as CCDC 726819 and CCDC 726820)
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2010.02.077.
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