1456-1459 synthesis of diphenylamine-based novel fluorescent styryl colorants by knoevenagel condensation using a conventional method, biocatalyst, and deep eutectic solvent

Article abstract of DOI:10.1021/ol902976u

(Figure Presented) Novel Y-shaped acceptor-π-donor-π-acceptor-type compounds, synthesized from 4,4'-hexyliminobisbenzaldehyde as electron donors and different active methylene compounds as electron acceptors, were produced by conventional Knoevenagel condensation alone, with a deep eutectic solvent, or with a lipase blocatalyst to compare the yield and recyclability among the three methods. Yield, reaction time, reaction temperature, and recyclability were compared among the three methods. The photophysical properties and thermal stability of the products were also investigated.

Full text of DOI:10.1021/ol902976u

ORGANIC
LETTERS
2010
Vol. 12, No. 7
1456-1459
Synthesis of Diphenylamine-Based
Novel Fluorescent Styryl Colorants by
Knoevenagel Condensation Using a
Conventional Method, Biocatalyst, and
Deep Eutectic Solvent
Yogesh A. Sonawane,† Sunanda B. Phadtare,† Bhushan N. Borse,‡
Amit R. Jagtap,† and Ganapati S. Shankarling*,†
Department of Dyestuff Technology and Department of Fibres and Textile Processing
Technology, Institute of Chemical Technology, N. P. Marg, Matunga,
Mumbai 400019, India
gs.shankarling@ictmumbai.edu.in; gsshankarling@gmail.com
Received January 3, 2010
ABSTRACT
Novel Y-shaped acceptor-π-donor-π-acceptor-type compounds, synthesized from 4,4′-hexyliminobisbenzaldehyde as electron donors and different
active methylene compounds as electron acceptors, were produced by conventional Knoevenagel condensation alone, with a deep eutectic solvent,
or with a lipase biocatalyst to compare the yield and recyclability among the three methods. Yield, reaction time, reaction temperature, and recyclability
were compared among the three methods. The photophysical properties and thermal stability of the products were also investigated.
Organic fluorescent heterocyclic chromophores have a wide
range of applications in biochemistry, for example, in
traditional textile coloration, molecular probes,1 organic light-
emitting diodes,2 photovoltaic cells,3 and mass coloration
of polymers.4 Electron acceptor isophorone derivatives,
substituted phenyl acetonitrile compounds, and aliphatic
active methylene compounds are used for the synthesis of
chromophores. Traditional catalysts such as alkali metal
hydroxides (e.g., NaOH and KOH), pyridine, and piperidine
are used in condensation reactions. Basic zeolites, such as
Cs-exchanged NaX (CsNaX) and GeX, Cs, Cs-lanthanum
impregnated mesoporous MCM-415-7 and alkali-exchanged
zeolites,8 however, are also used.
The emerging area of green chemistry seeks to minimize
environmental hazards as performance criteria in the design of
new chemical entities. Biocatalysts in organic synthesis have
attracted the attention of organic chemists because of their
synthetic utility.9-12 The high potential of lipases as biocata-
† Department of Dyestuff Technology.
‡ Department of Fibres and Textile Processing Technology.
(1) Topics in Fluorescence Spectroscopy; Lakowicz, J. R., Ed.; Plenum:
New York, 1994; Vol. 4, p 501.
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10.1021/ol902976u  2010 American Chemical Society
Published on Web 03/03/2010

lysts for organic synthesis are well recognized.13 Lipases can
be used in a wide variety of organic solvents without the
need for coenzymes for their activity.14 Lipases combine
broad substrate recognition with high efficiency and selectiv-
ity. Therefore, lipases offer an excellent alternative to
classical organic techniques in the selective transformation
of complex molecules. Lipases are the most frequently used
enzymes in organic synthesis because of their stability, ready
availability, and their acceptance of a broad range of
substrates.15 The use of lipases is now well established in
transesterification,16 ester hydrolysis,17 numerous applications
in kinetic resolutions18 or enantioselectivity syntheses based
on meso compounds,19 and amidation of racemic esters or
amine,20,21 but their application in Knoevenagel condensation
has not been well explored. We focused our attention on
the condensation of 4,4′-hexylimino-bisbenzaldehyde using
lipase from Aspergillus oryzae with different active meth-
ylene compounds.
Ionic liquids have recently attracted increasing interest in
the context of green synthesis. Ionic liquids were initially
introduced as alternative green reaction media because of
their unique chemical and physical properties of nonvolatility,
nonflammability, thermal stability, and controlled miscibil-
ity.22 Deep eutectic solvents (DESs), effectively eutectics
formed between the two components, result in a very large
depression of freezing point which can be in the region of
200 °C. The interaction between the ammonium salt and the
hydrogen-bond donor is an example. Deep eutectic solvents
have physical and solvent properties similar to those of ionic
liquids formed with discrete ions. Abbott et al.23 published
a series of studies on the low melting point of deep eutectic
liquid systems based on choline chloride ([Ch][Cl]). Choline
is a naturally occurring biocompatible compound that is not
hazardous if it is released back into nature as choline or its
deep eutectic mixture.24 Urea is a compound present in all
animals. Because choline chloride and urea are both inex-
pensive, processes that use this deep eutectic solvent are also
economically viable. Many ionic liquids leave hazardous
materials in the environment. Their toxicity is similar to or
higher than that of organic solvents.25,26 An alternative
approach to overcome these drawbacks is the development
of a deep eutectic solvent from components that are nontoxic
to the environment, possess biodegradable properties, or are
obtained from biodegradable resources, and are readily
available and inexpensive. The ability of a deep eutectic
mixture to serve as a solvent has not been extensively
explored in the field of synthetic organic chemistry. We now
report a Knoevenagel reaction using a deep eutectic solvent.
A series of novel diphenylamine-based chromophores a-k
was synthesized in which the acceptors were attached to the
central diphenylamine group by a traditional Knoevenagel
condensation using piperidine as the base in ethanol solvent at
reflux temperature. Three different types of active methylene
compounds, i.e., aliphatic, substituted phenyl acetonitrile, and
isophorone-based active methylene compounds, were introduced
at the peripheral phenyl groups. The results of the experiments
are summarized in Table 1. Use of the conventional method
required a higher temperature and longer reaction time; how-
ever, in some cases (c and h-k) reaction time using the
conventional method was shorter as compared to the lipase-
catalyzed reaction. The lowest yield observed in b and c in the
lipase-catalyzed reaction may be attributed to the weaker nature
of the active methylene compound due to the presence of amide
linkage. In entry i, the yield is markedly less due to the weaker
nature of active methylene compound.
A biocatalyst was used to explore its synthetic utility in
Knoevenagel condensation. The reaction mechanism of the
condensation using a biocatalyst involved a sequential dehydra-
tion process. The active site of lipase functions as a nucleophile,
which condenses the acidic proton of the active methylene
group, and then dehydration gives a carbon-carbon double
bond. To optimize the reaction parameters, the reaction of 4,4′-
hexyliminobisbenzaldehyde with ethyl cyano acetate in the
presence of lipase was selected as a model reaction. Optimum
results were obtained when reactions were conducted in the
presence of 50 mg (10% by weight of aldehyde) of lipase for
4.72 mmol of aldehyde at 50-55 °C. No major change in the
product yield was observed when 20% (by weight of aldehyde)
lipase catalyst was used. No product formed when the reaction
mixture was stirred at 60 °C for 15 h in the absence of lipase.
Under the optimum conditions, aldehyde was condensed with
different active methylene groups in the presence of lipase,
giving moderate to good yield of the product. To make the
biocatalytic processes more economical on a large scale, the
recyclability of lipase must be considered. During this study,
lipase was recycled for up to four cycles. There was no
significant decrease in product yield after completion of the first
cycle, but the yield declined up to 50% after the completion of
the fourth cycle (Table 3).
(10) Wong, C. H. Science 1989, 244, 145
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(11) Jones, J. B. Tetrahedron 1986, 42, 3351.
(12) Chen, C.-S.; Sih, C. J. Angew. Chem., Int. Ed. Engl. 1989, 28, 695.
(13) Whitesides, G. M.; Wong, C.-H. Angew. Chem., Int. Ed. Engl. 1985,
24, 61.
(14) For reviews, see: (a) Biotransformations in Organic Chemistry, 5th
ed.; Faber, K., Ed.; Springer: Berlin, 2004; pp 94-123, 344. (b) Enzyme
Catalysis in Organic Synthesis, 2nd ed.; Gais, H. J., Theil, F., Drauz, K.,
Waldmann, H., Eds. Wiley-VCH: Weinheim, 2002; p 335.
(15) Klibanov, A. M. Chemtech. 1986, 16, 354.
(16) Chen, C. S.; Sih, C. J. Angew. Chem., Int. Ed. Engl. 1989, 28,
695.
(17) For a recent review, see: Fang, J.-M.; Wong, C.-H. Synlett 1994, 393.
(18) Whitesides, G. M.; Wang, C.-H. Angew. Chem., Int. Ed. Engl. 1985,
24, 617. Enzymes as Catalysts in Organic Synthesis; Schneider, M. P., Ed.;
Reidel: Dordrecht, FRG, 1986.
(19) (a) Brown, K. J.; Berry, M. S.; Murdoch, J. R. J. Org. Chem. 1985,
50, 4345. (b) Smrcina, M.; Lorenc, M.; Hanus, V.; Sedmera, P.; Kocovsky,
P. J. Org. Chem. 1992, 57, 1917. (c) Oi, S.; Matsuzaka, Y.; Yamashita, J.;
Miyano, S. Bull. Chem. Soc. Jpn. 1989, 62, 956.
(20) (a) Davies, H. G.; Green, R. H.; Kelly, D. R. Roberts, S. M.
Biotransformations in PreparatiVe Organic Chemistry; Academic Press: New
York, 1989. (b) Ahern, J. J.; Klibanov, A. M. Science 1985, 228, 1280
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(21) De Castro, M. S.; Gago, J. V. S. Tetrahedron 1998, 54, 2877
(22) Wilson, C. V. Org. Synth. 1955, 3, 575.
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(25) (a) Welton, T. Chem. ReV. 1999, 99, 2071. (b) Burrell, A.; Del Sesto,
(23) Abbott, A.; Capper, G.; Davies, Munro, D.; Rasheed, H. R.;
Tambyrajah, V. Chem. Commun. 2001, 2010.
R.; Baker, S.; McCleskey, T. M.; Baker, G. A. Green Chem. 2007, 9, 449.
(26) (a) Jain, N.; Kumar, A.; Chauhan, S. Tetrahedron 2005, 61, 1015.
(b) Ranu, B.; Jana, J. Eur. J. Org. Chem. 2006, 3767. (c) Li, Y.; Xu, X.;
Zhou, M. Chin. Chem. Lett. 2003, 448. (d) Ce, S.; Zhen-Chu, C.; Qin-Guo,
Z. Synthesis 2003, 4, 555. (e) Cai, Y.; Peng, Y.; Song, G. Catal. Lett. 2006,
(24) (a) Ranke, J.; Stolte, S.; Stormann, R.; Arning, J.; Jastorff, B. Chem.
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Jastorff, B.; Ranke, J. Green Chem. 2006, 8, 621.
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Org. Lett., Vol. 12, No. 7, 2010
1457

Table 1. Results of Knoevenagel Reaction in Three Different Conditions
a Yield by conventional Knoevenagel condensation. b Yield by lipase- catalyzed reaction. c Yield by deep eutectic solvent.
The problems of a longer reaction time, use of toxic bases,
higher temperature, selectivity, difficulty in product separa-
tion, and recyclability of lipases were approached using green
technology, i.e., a deep eutectic solvent. A deep eutectic
solvent was easily prepared by a previously reported
method23 with 100% atom economy. Choline chloride (1
mol) was reacted with urea (2 mols) at 80 °C. The resulting
molten salt was used directly in reactions without purifica-
1458
Org. Lett., Vol. 12, No. 7, 2010

tion. This method produced no byproducts; therefore, there
was no loss during isolation of the solvent. Recycling of the
deep eutectic solvent was also effectively achieved by
the representative reaction of compound (a) and could be
performed five times without a significant decrease in the
product yield. There was no need for further purification of
the deep eutectic solvent before its reuse for the same
transformation. The reactions using the recycled deep eutectic
solvent also showed good results.
increase. Compound b, however, showed a larger Stokes shift
at 166 nm despite its shorter conjugation; perhaps because only
one electron acceptor was condensed to an electron donor. The
fluorescence spectra of dyes a-k in chloroform were recorded.
Emission spectra were obtained using the excitation wavelength
which is nothing but absorption maxima of respective com-
pounds. The emission spectra of isophorone-based long con-
jugated compounds a-d and f were observed at 624, 586, 590,
658, and 588 nm, respectively (Table 2, see the Supporting
Information). Absorption and emission maxima of a-d and f
were significantly higher than those of chromophores e and g-k.
Compounds a-k were subjected to the thermogravimetric
analysis to investigate their thermal stability. Stepwise
isothermal ramping up to 600 at 10 °C/minute was performed
in a nitrogen atmosphere. The change in the weight of the
colorants was measured as a function of temperature.
Thermal stability is defined as the temperature up to which
∼95% of the composition of the compound remains stable.
For compound a, 94.75% of the weight composition was
stable up to 314 °C and underwent rapid thermal decomposi-
tion thereafter. Colorants e and g were stable up to 362 and
325 °C, respectively. The compound containing a methoxy
group (j) had the lowest thermal stability at 274 °C, possibly
due to the labile nature of the methoxy group. These data
indicate that all of these chromophores had good thermal
stability and are therefore applicable for polymers requiring
higher extrusion temperature ranges.
The effect of reaction time on conversion was investigated.
Increasing the temperature up to 60 °C and prolonging the
reaction time did not significantly improve the reaction.
Key intermediate 4,4′-hexyliminobisbenzaldehyde was syn-
thesized by N-hexylation of diphenylamine, followed by
Vilsmeier-Haack formylation. Isophorone derivatives were
synthesized from isophorone using different active methylene
compounds. All colorants were soluble in common organic
solvents, such as chloroform, dichloromethane, 1,2-dichloro-
ethane, acetonitrile, tetrahydrofuran, and N,N-dimethylforma-
mide due to the introduction of long hexyl chains in the
compounds. The structures of these compounds were elucidated
1
by FTIR, H NMR, and 13C NMR spectroscopy, mass spec-
trometry, and elemental analysis. The coupling constant (J ≈
16 Hz) of olefinic protons in purified chromophores indicates
that the reaction afforded trans isomers.
Knoevenagel condensation of 4,4′-hexyliminobisbenzal-
dehyde with a variety of active methylene compounds viz.
2-(3,5,5-trimethylcyclohex-2-enylidene)malononitrile, (2E)-
2-cyano-2-(3,5,5-trimethylcyclohex-2-enylidene)aceta-
mide, (2E)-2-(benzo[d]thiazol-2-yl)-2-(3,5,5-trimethylcyclo
hex-2-enylidene)acetonitrile, (2E)-2-cyano-2-(3,5,5-trimeth-
ylcyclohex-2-enylidene)acetate, 2-(4-methoxy phenyl)aceto-
nitrile, 2-phenylacetonitrile, 2-(4-nitrophenyl) acetonitrile,
2-(thiophene-2-yl)acetonitrile, ethyl 2-cyanoacetate, and ma-
lononitrile was performed.
These dyes may become valuable colorants for high
technologic applications. An efficient protocol has been
developed for Knoevenagel condensation of aromatic alde-
hydes with an active methylene group as an ecofriendly
reaction medium. The lipase catalyst exhibited activity and
was reusable for up to four consecutive cycles. The reaction
is applicable to a wide variety of active methylene com-
pounds with aromatic aldehydes.
Here we describe the synthesis and photophysical studies of
novel synthesized diphenylamine-based styryl molecules that
are potential candidates for application in organic electronics.
The linear long alkyl chain was introduced to a 4,4′-hexylimi-
nobisbenzaldehyde 4 moiety to improve the solubility of the
resulting fluorescent compounds in common organic solvents.
Absorption and photoluminescence spectra of the dyes in
dichloromethane (1 × 10-4 M) solution were consistent with
our expectation. The absorption maxima were in the range of
385-525 nm. The absorption maxima, Stokes shifts, of the
isophorone based dyes a-d and f varied in the range of 88-166
nm, which is a significantly greater variation than for other
simple styryl dyes (Table 2, see the Supporting Information).
As expected, the bathochromic shift of colorants a-d and f in
the absorption band showed higher absorption maxima and a
larger Stokes shift because of the isophorone-bridged conjuga-
tion system. These extended chromophores displayed dramati-
cally enhanced absorption, fluorescence properties, and a greater
Stokes shift. The more conjugated molecule d displayed larger
absorption maxima, a greater Stokes shift, and a larger molar
absorption coefficient due to its relatively more extended
conjugation. For given donor-acceptor compounds, the Stokes
shift increase was associated with the conjugation length
The Knoevenagel condensation using a readily available and
biodegradable ammonium deep eutectic solvent (choline chloride/
urea) also provides an efficient and convenient method without
the use of other catalysts or organic solvents. This method offers
marked improvements in terms of simplicity, decreased reaction
time, simple reaction conditions, general applicability, high
isolated product yields, and the use of environmentally benign
procedures and solvents. This method also eliminates the use
of hazardous organic solvents and toxic catalysts, and thus
provides a better and practical alternative to existing procedures.
It is easy to separate the catalyst and substrate after completion
of the reaction. Deep eutectic solvents provide a good alternative
for industrial synthesis as the reaction is readily scalable (Table
3, see the Supporting Information). We have synthesized a series
of symmetrical and unsymmetrical chromophores with good
thermal stability and photophysical properties by grafting donor
at the core and strong acceptors at the edge of the periphery.
Supporting Information Available: Details of experi-
mental procedure, structure characterization, and figures. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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