Synthesis of novel quinaldine-based squaraine dyes: Effect of substituents and role of electronic factors

Article abstract of DOI:10.1021/ol048411y

(Chemical Equation Presented) Condensation of squaric acid with quinaldinium salts containing electron-donating substituents gave only the semisquaraines. However, with salts possessing electronegative and electron-withdrawing groups, the squaraine dyes were isolated in quantitative yields. The semisquaraines formed undergo condensation with highly nucleophilic salts yielding the unsymmetrical squaraine dyes. These results demonstrate the role of electronic factors and provide valuable information for the design of efficient squaraine-based sensitizers that can have potential applications in photodynamic therapy.

Full text of DOI:10.1021/ol048411y

ORGANIC
LETTERS
2
004
Vol. 6, No. 22
965-3968
Synthesis of Novel Quinaldine-Based
Squaraine Dyes: Effect of Substituents
and Role of Electronic Factors
3
Kuthanapillil Jyothish, Kalliat T. Arun, and Danaboyina Ramaiah*
Photosciences and Photonics DiVision, Regional Research Laboratory (CSIR),
TriVandrum 695 019, India
d_ramaiah@rediffmail.com; rama@csrrltrd.ren.nic.in
Received August 11, 2004
ABSTRACT
Condensation of squaric acid with quinaldinium salts containing electron-donating substituents gave only the semisquaraines. However, with
salts possessing electronegative and electron-withdrawing groups, the squaraine dyes were isolated in quantitative yields. The semisquaraines
formed undergo condensation with highly nucleophilic salts yielding the unsymmetrical squaraine dyes. These results demonstrate the role
of electronic factors and provide valuable information for the design of efficient squaraine-based sensitizers that can have potential applications
in photodynamic therapy.
5
Squaraines form a class of dyes possessing sharp and intense
absorption bands in the red to near-infrared region. The
and IR absorbers in organic optical disks. The semisquaraine
derivatives and the squaraine dyes also find application as
sensors for metal ions and biologically important molecules.6
Due to the very low intersystem crossing efficiency of these
1
photophysical and photochemical properties of these have
been studied extensively,1 because their absorption and
photochemical characteristics make them highly suitable for
a number of industrial applications. These include, photo-
,2
1,2
dyes, their potential as sensitizers in photodynamic therapy
7
(PDT) has not yet been explored.
3
4
receptors in copiers, photoconductors in organic solar cells,
Our objective has been to explore the use of suitable
squaraine dyes as sensitizers for PDT. In this context, we
(1) (a) Law, K. Y. J. Phys. Chem. 1987, 91, 5184. (b) Law, K. Y. Chem.
ReV. 1993, 93, 449. (c) Liang, K.; Law, K. Y.; Whitten, D. G. J. Phys.
Chem. B 1997, 101, 540. (d) Das, S.; Thomas, K. G.; George, M. V. Mol.
Supramol. Photochem. 1997, 1, 467.
(5) (a) Fabian, J.; Nakazumi, H.; Matsuoka, M. Chem. ReV. 1992, 92,
1197. (b) Emmelius, M.; Pawlowski, G.; Vollmann, H. W. Angew. Chem.,
Int. Ed. Engl. 1989, 28, 1445.
(2) (a) Liang, K.; Farahat, M. S.; Perlstein, J.; Law, K. Y.; Whitten, D.
G. J. Am. Chem. Soc. 1997, 119, 830. (b) Kamat, P. V.; Das, S.; Thomas,
K. G.; George, M. V. J. Phys. Chem. 1992, 96, 195. (c) Das, S.; Thomas,
K. G.; Kamat, P. V.; George, M. V. J. Phys. Chem 1994, 98, 9291. (d)
Chen, H.; Farahat, M. S.; Law, K. Y.; Whitten, D. G. J. Am. Chem. Soc.
(6) (a) Xie, J.; Comeau, A. B.; Seto, C. T. Org. Lett. 2004, 6, 83. (b)
Ros-Lis, J. V.; Garcia, B.; Jimenez, D.; Martinez-Manez, R.; Sancenon,
F.; Soto, J.; Gonzalvo, F.; Valldecabres, M. C. J. Am. Chem. Soc. 2004,
126, 4064. (c) Kukrer, B.; Akkaya, E. U. Tetrahedron Lett. 1999, 40, 9125.
(d) Ros-Lis, J. V.; Martinez-Manez, R.; Soto, J. Chem. Commun. 2002,
2248.
(7) (a) Dougherty, T. J. Photochem. Photobiol. 1987, 45, 879. (b) Kessel,
D. Photodynamic Therapy of Neoplastic Disease; CRC Press: Boca Raton,
FL, 1990; Vol. 2. (c) Moser, J. G. Photodynamic Tumor Therapy: 2nd
and 3rd Generation Photosensitizers; Harwood Academic Publishers:
Amsterdam, 1998. (d) Bonnett, R. Chemical Aspects of Photodynamic
Therapy; Gordon and Breach Science Publishers: The Netherlands, 2000.
1
996, 118, 2584.
3) (a) Law, K. Y.; Bailey, F. C. J. Imaging Sci. 1987, 31, 172. (b) Tam,
A. C.; Balanson, R. D. IBM J. Res. DeVelop. 1982, 26, 186.
4) (a) Loufty, R. O.; Hsiao, C. K.; Kazmaier, P. M. Photogr. Sci. Eng.
983, 27, 5. (b) Merritt, V. Y. IBM J. Res. DeVelop. 1978, 22, 353. (c)
Piechowski, A. P.; Bird, G. R.; Morel, D. L.; Stogryn, E. L. J. Phys. Chem.
(
(
1
1
1
984, 88, 934. (d) Liang, K. N.; Law, K. Y.; Whitten, D. G. J. Phys. Chem.
995, 99, 16704.
1
0.1021/ol048411y CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/30/2004

Scheme 1
Figure 1. Change in absorption spectra obtained for the reaction
between the quinaldinium salt 1a and squaric acid in a mixture
have recently synthesized a few halogen-substituted squaraine
(1:1) of benzene and n-butanol at various time intervals. Time: (a)
8
dyes and investigated their photophysical and in vitro
0, (b) 1, (c) 2, (d) 4, (e) 6, (f) 9, (g) 12, and (h) 15.5 h.
9
photobiological properties. The encouraging results obtained
from these studies prompted us to design new sensitizers
with improved photophysical and photobiological properties.
We felt that quinaldine-based squaraine dyes could be
potential sensitizers because these dyes are expected to have
improved photophysical properties such as long-wavelength
absorption (>700 nm) in the near-infrared region and high
extinction coefficients (>10 M cm ). Moreover, the
benzene ring of the quinaldine moiety can be suitably
substituted so as to enhance their triplet quantum yields as
well as their cellular pharmacokinetics.
Herein we report the synthesis of a few quinaldine-based
squaraine dyes and the interesting effects of various substit-
uents on the dye-forming reaction. It has been observed that
semisquaraines are formed as the sole product in the reaction
of quinaldinium salts containing electron-donating substit-
uents with squaric acid. Interestingly, they could be converted
into the squaraine dyes by reacting with the quinaldinium
salts having electronegative and/or electron-withdrawing
groups. These results demonstrate the role of electronic
factors and the usefulness of this strategy for the synthesis
of unsymmetrical squaraine dyes with improved photophysi-
cal and photobiological properties.
With a view to synthesizing 6-hydroxyl-substituted quinal-
dine-based squaraine dye, we have carried out the reaction
between the quinaldinium salt 1a and squaric acid with 2:1
equivalents, respectively, in a mixture (1:1) of benzene and
n-butanol (Scheme 1). Since the expected squaraine dye
1, no absorption band in the near infrared region was
observed during the initial stages of the reaction. However,
an absorption band around 485 nm was observed within 4 h
of the reaction and this band increased in intensity with
reaction time. After prolonged heating, a faint absorption
around 715 nm was observed, which showed negligible
enhancement in intensity with increasing reaction time,
indicating thereby that the dye is formed in insignificant
amounts. Similar observations were made when the conden-
sation reactions were carried out with the quinaldinium salts
1b and 1c and squaric acid (Scheme 1) (Figures S1 and S2,
Supporting Information).
5
-1
-1 10
For a better understanding of the dye-forming reaction,
we have monitored the progress of the reaction between
squaric acid and the unsubstituted quinaldinium salt 1d,
1
0
reported earlier (Figure 2). As can be seen from Figure 2,
after about an hour, the absorption spectrum showed two
absorption bands at 485 nm as well as at 714 nm. The
intensity of both these bands increased with an increase in
reaction time. After about 7 h, the absorption at 485 nm
decreased with time, while the absorption band at 714 nm
intensified and reached a plateau by about 19 h (inset of
Figure 2). The initial formation of the absorption band at
485 nm, followed by its decrease in intensity with concomi-
tant increase in absorption around 714 nm (isosbestic point
around 540 nm), indicates that the species having absorption
at 485 nm is an intermediate in the dye-forming reaction.
On the basis of spectral and analytical evidence and
literature information, we assign the species formed with
absorption at 485 nm to the semisquaraine intermediate 2d,
in the reaction between squaric acid and the corresponding
quinaldinium salt. The species with absorption at 714 nm is
assigned to the squaraine dye 3d (experimental details, Sup-
(squaraine dyes in general are highly colored) is a brightly
colored compound with absorption in the near-infrared
region, we monitored the progress of the reaction by
absorption spectroscopy (Figure 1). As is evident from Figure
(8) (a) Ramaiah, D.; Joy, A.; Chandrasekhar, N.; Eldho, N. V.; Das, S.;
George, M. V. Photochem. Photobiol. 1997, 65, 783. (b) Arun, K. T.; Epe,
B.; Ramaiah, D. J. Phys. Chem. B 2002, 106, 11622.
(
9) (a) Ramaiah, D.; Eckert, I.; Arun, K. T.; Weidenfeller, L.; Epe, B.
Photochem. Photobiol. 2002, 76, 672. (b) Ramaiah, D.; Eckert, I.; Arun,
K. T.; Weidenfeller, L.; Epe, B. Photochem. Photobiol. 2004, 79, 99.
(10) Bernstein, J.; Tristani-Kendra, M.; Eckhardt, C. J. J. Phys. Chem.
1986, 90, 1069.
3966
Org. Lett., Vol. 6, No. 22, 2004

Scheme 2
1
2
of the aryl species. In the present study, the nucleophile is
13
an enamine formed from the quinaldinium salt, which reacts
with the squaric acid resulting in the formation of the
semisquaraine. Subsequently, the semisquaraine undergoes
further reaction with another moiety of the enamine to give
the squaraine dye (Scheme 1).
Figure 2. Change in absorption spectra obtained for the reaction
between the quinaldinium salt 1d and squaric acid in a mixture
(1:1) of benzene and n-butanol at various time intervals. Time: (a)
1, (b) 2, (c) 3, (d) 5, (e) 7, and (f) 9 h. Inset shows the change in
absorption spectra obtained for the same reaction after long reaction
time intervals. Time: (f) 9, (g) 11, and (h) 16 h.
The presence of electron-donating groups on the benzene
ring of the quinaldinium salts 1a-c reduces the acidity of
the hydrogen atoms of the 2-methyl group and thereby
decreases the formation of the enamine nucleophile. Never-
theless, the enamine formed reacts with squaric acid, resulting
in the corresponding semisquaraines 2a-c. Further, the
electrophilic terminus of these semisquaraines is rendered
less reactive by the electron-donating substituents, and hence
further reaction with the less acidic salts becomes extremely
difficult. As a result, the reaction stops with the formation
of the semisquaraine only in the case of the salts 1a-c.
However, in the presence of electronegative (1e,f) and
electron-withdrawing substituents (1g,h), the hydrogen atoms
of the 2-methyl group are relatively more acidic and thereby
favor the formation of the enamine nucleophile very ef-
ficiently. These salts yield higher concentrations of the
nucleophile and hence results in the corresponding semi-
squaraine intermediates 2e-h followed by formation of the
corresponding squaraine dyes 3e-h in quantitative yields.
To confirm the above suggestion, we have examined the
reaction of the semisquaraine 2a, which possesses a weak
electrophilic terminus with quinaldinium salts of varying
acidity (1a and 1e). Interestingly, we observed the formation
of the unsymmetrical dye 4 only with the highly reactive
salt 1e, which can generate the enamine nucleophile ef-
ficiently. As expected, negligible reaction was observed with
the less acidic salt 1a as indicated in Scheme 2. The progress
of the reaction between 2a and the salts 1e and 1a was
followed spectroscopically (Figure 3).
porting Information).10 The reaction between the quinal-
dinium salts with electron-donating groups (1a-c) and
squaric acid did not result in the formation of the correspond-
ing squaraine dyes (Scheme 1). Instead, only butyl adducts
of the semisquaraines 2a-c were isolated in 90-95% yields.
To investigate the effect of substituents on the formation
of the semisquaraine intermediates and subsequently the
squaraine dyes, we have synthesized the substituted quinal-
dinium salts 1e,f, which can induce electron-withdrawing and
inductive effects on the quinaldine moiety. The quinaldine
derivatives and their corresponding quaternary salts 1e,f were
prepared by reported procedures with modifications wherever
necessary (experimental details, Supporting Information).
The reaction of the quinaldinium salt 1e with squaric acid
under analogous conditions gave the corresponding squaraine
dye 3e in 85% yield through the intermediacy of the
semisquaraine 2e. The absorption spectra recorded at various
reaction time intervals, showed the formation of the semi-
squaraine intermediate 2e (λmax 492 nm) and the squaraine
dye 3e (λmax 725 nm) with an isosbestic point at 545 nm
(Figure S3, Supporting Information). Similar observations
were made with the quinaldinium salts substituted with
bromine (1f) and electron-withdrawing nitro (1g) and cyano
(
1h) groups. These salts on reaction with squaric acid gave
their corresponding squaraine dyes 3f-h in 84-96% yields
Scheme 1), which were characterized on the basis of spectral
(
data and analytical results (experimental details, Supporting
Information).
(
11) (a) Treibs, A.; Jacob, K. Angew. Chem., Int. Ed. Engl. 1965, 4,
694. (b) Schmidt, A. H. Synthesis 1980, 961.
12) (a) Law, K. Y.; Bailey, F. C. Can. J. Chem. 1986, 64, 2267. (b)
The variation in the reactivity of the substituted quinal-
dinium salts 1a-h with squaric acid can be explained on
the basis of the electronic effects of the various substituents.
Squaraine dye-forming reaction involves the reaction between
(
Law, K. Y.; Bailey, F. C. J. Org. Chem. 1992, 57, 3278. (c) Block, M. A.
B.; Khan, A.; Hecht, S. J. Org. Chem. 2004, 69, 184.
(13) (a) Havinga, E. E.; ten Hoeve, W.; Wynberg, H. Synth. Met. 1993,
5
5-57, 299. (b) Havinga, E. E.; ten Hoeve, W.; Wynberg, H. Polymer
Bull. 1992, 29, 119. (c) Havinga, E. E.; Pomp, A.; ten Hoeve, W.; Wynberg,
H. Synth. Met. 1995, 69, 581.
1
1
an electron-rich aromatic derivative and squaric acid. The
success of the reaction depends mainly on the nucleophilicity
Org. Lett., Vol. 6, No. 22, 2004
3967

In conclusion, we have demonstrated that substitution on
the benzene ring of the quinaldine moiety can affect the
reaction between the quinaldinium salts and squaric acid,
resulting in the formation of the corresponding squaraine
dyes. The quinaldinium salts with electron-donating substit-
uents hinder the formation of the dye and result only in the
formation of the semisquaraine, while electronegative and
electron-withdrawing substituents facilitate the formation of
the corresponding squaraine dyes with the intermediacy of
the corresponding semisquaraines. These electronic effects,
observed during the course of our studies, could provide
valuable information on the choice of substituents for the
design of novel and efficient sensitizers based on squaraine
dyes. Efforts are underway in our laboratory to evaluate the
potential applications of these dyes as sensitizers in photo-
dynamic therapy.
Figure 3. Change in absorption spectra obtained for the reaction
between the semisquaraine 2a and the quinaldinium salt 1e at
various time intervals. Time: (a) 1, (b) 2, (c) 4, (d) 6, and (e) 8 h.
Inset shows the change in absorption spectra obtained for the
reaction between 2a and the salt 1a at various time intervals.
Time: (a) 0, (b) 1, (c) 4, and (d) 6 h.
Acknowledgment. We thank the Council of Scientific
and Industrial Research (COR-0003), Department of Science
and Technology, Government of India, for the financial
support of this work. This is contribution No. RRLT-PPD-
187 from the Regional Research Laboratory (CSIR), Trivan-
drum, India.
As the reaction progressed, in the case of 1e, a new band
at 723 nm appeared, which increased in intensity with time
and with a concomitant decrease in intensity of the band at
Supporting Information Available: Synthetic details
along with spectroscopic data of the quinaldine derivatives,
the quinaldinium salts, the semisquaraines, and the squaraine
dyes, H and C NMR spectra of the representative semi-
squaraines and squaraine dyes, and the absorption spectra
showing the progress of the condensation reaction between
squaric acid and the quinaldinium salts 1b, 1c, and 1e. This
material is available free of charge via the Internet at
http://pubs.acs.org.
4
(
2
85 nm, indicating the formation of the squaraine dye 4
Figure 3). However, when the reaction of the semisquaraine
a with the less reactive quinaldinium salt 1a was attempted
1
13
under similar conditions, none of the squaraine dye 3a was
formed (inset of Figure 3). In this case, we observed a
nonnegligible decrease in absorbance at 485 nm; however,
this was found to be <7% even after 6 h of refluxing (100-
105 °C) under the reaction conditions.
OL048411Y
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Org. Lett., Vol. 6, No. 22, 2004