Conjugating a cyanine dye to a polymer surface. In search of a monomeric dye in apolar media

Article abstract of DOI:10.1021/jo7027294

(Chemical Equation Presented) Solution and solid-phase syntheses of a cyanine dye conjugated to polystyrene beads (desired for potentially interesting electronic properties) are described.

Full text of DOI:10.1021/jo7027294

Conjugating a Cyanine Dye to a Polymer
Surface. In Search of a Monomeric Dye in
Apolar Media
Fabrizio Pertusati and Fredric M. Menger*
Department of Chemistry, Emory UniVersity, Atlanta, Georgia
30033
FIGURE 1. (a) Delocalization in a cyanine dye imparting +1/2 on
each nitrogen. (b) A colorless carbon analogue of the dye.
menger@emory.edu
ReceiVed December 21, 2007
FIGURE 2. (a) A tight ion pair of the cyanine dye. (b) A dimer in
which both ion-paring and delocalization stabilization are possible.
The challenge, of course, is to devise a transiently nonreso-
nating cyanine system. One might presume that if the cyanine
were forced into a tight ion pair with its counteranion (Figure
2a), then the positive charge would be localized only at the
nitrogen proximate to the counteranion. Cyanine-type delocal-
ization within the ion pair would be impeded because the
cationic charge cannot readily shift to the other nitrogen. If this
did happen, the cationic and anionic charges would be widely
separated, imparting high energy to the contributor. Even if the
counteranion located itself equidistant from the two nitrogens,
charge separation would be substantial. In summary, the dye
as a tight ion pair would likely have lost some or all of its color.
When cyanine dyes are dissolved in nonpolar solvents,
conditions that favor tight ion pairing, their colors persist (in
apparent conflict with our prediction). Yet in actual fact, this
does not negate our speculations about possible color loss
because cyanine dyes in nonpolar solvents form dimers (or
higher J- and H-aggregates) in which both ion pairing and
delocalization effects are both readily accommodated (Figure
2b).1
Solution and solid-phase syntheses of a cyanine dye conju-
gated to polystyrene beads (desired for potentially interesting
electronic properties) are described.
Fascination with synthetic dyes can be traced back to 1856
when a precocious William Henry Perkin, only 18 years of age,
converted a coal tar derivative, aniline, into a purple dye he
called “mauve”. The discovery prompted Perkin to leave his
Royal College of Chemistry and build a factory that manufac-
tured his dye. Hundreds of synthetic dyes followed soon after
Perkin’s discovery: magenta (Verguin, 1858); methyl violet
(Lauth, 1861); Hofmann’s violet (Hofmann, 1862); alizarin
(Graebe and Lightfoot, 1868), and malachite green (Dobner and
Fisher, 1877) to name a few. A century-and-a-half after Perkin,
we initiated our own particular approach to dye construction
(although there are no immediate plans to abandon the comfort
of a university!). In order to understand the motivation for our
studies, certain important features of dye chemistry must be
detailed, and this will be done via cyanine dyes of the type
drawn in Figure 1a.
According to simple resonance theory, color arises from an
electron delocalization in which the two identical nitrogens each
bear exactly one-half of a positive charge. The longer the
distance between the conjugated nitrogens, the longer the
wavelength of light absorption. Now suppose nitrogen is
replaced by carbon as in the analog in Figure 1b. This compound
does not absorb in the visible range because there is far less
electron delocalization compared with the cyanine dye. The
comparison suggests that if one could somehow prevent
delocalization effects in the cyanine dye (i.e., impose conditions
that confine the compound to only one of the two delocalization
contributors), then the color would vanish. Exposing the dye to
“normal” conditions would cause the color to reappear. Thus,
the elements of a “color/no-color” switch would be in hand.
In order to preclude this complication, cyanine dyes must be
constructed that remain monomeric even in nonionizing media.
(1) (a) West, W.; Pearce, S. J. Phys. Chem. 1965, 69, 1894. (b)
Khairutdinov, R. F.; Serpone, N. J. Phys. Chem. B 1997, 101, 2602. (c)
Fidder, H.; Wursma, D. A. Phys. ReV. Lett. 1991, 66, 1501. (d) Perlatein,
J.; Penner, T. L.; Witten, D. G. Langmuir 2000, 16, 9042. (e) Da¨hne, S.;
Nolte, K. D. Chem. Commun. 1972, 1076.
(2) (a) Demchuck, M. I.; Ishcenko, A. A.; Mikhailov, V. P.; Avdeeva,
V. I. Chem. Phys. Lett. 1988, 144, 99. (b) Kwon, O. P.; Im, J-K.; Kim,
J-H.; Lee, S-H. Macromolecules 2000, 32, 9310. (c) Lindsay, G. A.; Ashley,
P. R.; Davis, M. C.; Guenthner, A. J.; Sanghadasa, M.; Wright, M. E. Mater.
Sci. Eng., B 2006, 132, 8-11. (d) Barlow, S.; Marde, S. R. Nonlinear Optical
Properties of Organic Materials. In Functional Organic Materials; Mu¨ller,
T. J. J., Bunz, U. H. F., Eds.; Wiley & Sons: New York, 2007; Chapter
11, pp 393-437. (e) Onclin, S.; Ravoo, J. B.; Reinhoudt, D. N. Angew.
Chem., Int. Ed. 2005, 44, 6282. (f) Pereverzev, Y. V.; Oleg, V. P.; Dalton,
L. R. ChemPhysChem 2004, 5, 1821. (g) Wu¨rthner, F.; Wortmann, R.;
Meerholz, K. ChemPhysChem 2002, 3, 17. (h) Van der Boom, M. E. Angew.
Chem., Int. Ed. .2002, 41, 3363. (i) Grishina, A. D.; Pereshivko, L. Y.;
Tameev, A. R.; Krivenko, T. V.; Savelyev, V. V.; Vannikov, A. V.;
Rychwalski, R. W. Synth. Met. 2004, 144, 113.
* To whom correspondence should be addressed. Tel: 404-727-6599. Fax:
404-727-6586.
10.1021/jo7027294 CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/29/2008
J. Org. Chem. 2008, 73, 2939-2942
2939

SCHEME 1 a
SCHEME 2 a
a Reagents and conditions: (a) Br(CH2)5COOH (2 equiv), 120 °C, 24 h,
40%; (b) EtI, CH3CN, reflux, 54%; (c) HC(OEt)3, (1.05 equiv), aniline
(1.2 equiv), 120 °C, 30 min, 78%; (d) PhNdCNHPh (1.1 equiv), Ac2O, 30
min reflux, 76%.
We reasoned that this is best accomplished by attaching isolated
dye molecules to a solid apolar surface such as provided by
polystyrene beads. Consequently, dye/polystyrene bead systems
became a synthetic objective described herein.
a Reagents and conditions: (a) method A: 5 (1 equiv), pyridine, reflux,
3 h, 58%; (b) method B: 2 (1 equiv), NEt3 (2 equiv) ethanol, reflux, 30
min, 90%.
Although dye/polymer and other dye/solid systems have been
widely examined, most of them involve noncovalent associa-
tion.2 For example, cyanine dyes, adsorbed from ethanol onto
the surface of single-crystal rutile, exist predominantly as
monomer.3 However, since ethanol, which probably coadsorbed,
is not a good ion-pairing medium, the results may not be relevant
to our interests. In many solid-phase syntheses of various
cyanines, polymer beads were merely a synthetic aid to be
removed as quickly as possible.4
by precipitation via addition of diethyl ether. Further purification,
although not strictly necessary, was carried out by crystallization
from methanol/ether mixture. Compound 5 was then transformed
into the corresponding N-acetanilide 6 by treatment with
diphenylformamidine in refluxing acetic anhydride for 30 min
according to the procedure developed by Almeida6 and Glazer.7
Pure 6 was obtained in 76% yield after crystallization from
methanol/ether mixture.
A cyanine dye bearing a carboxyalkyl chain on one of its
nitrogens was initially selected for our studies because it is
relatively easy to couple carboxylic acids to hydroxylmethyl
and chloromethyl substituents on polystyrene supports.5 The
required N-carboxyalkyl salt was prepared from 2,3,3-trimeth-
ylindolenine 1 and 6-bromohexanoic acid (Scheme 1), following
the method of Almeida,6 by heating at 120 °C for 24 h in the
absence of solvent.
Quaternary salt 2 was obtained in excellent purity, in 40%
yield, by triturating the resulting solid mass with boiling acetone.
N-Carboxyalkyl indoleninium bromide 2 was then converted
into the vinyl aniline 3 in a good yield by heating a mixture of
2, triethyl orthoformate, and aniline at 120 °C for 30 min
(Scheme 1).
The synthesis of the key trimethine dye 8 was accomplished
via two different methods (Scheme 2). Method A involved the
reaction between compound 3 and benzoxazolium iodide 5 in
refluxing pyridine for 3 h. The crude dye was then precipitated
from the reaction mixture, previously cooled to room temper-
ature, with diethyl ether, and the resulting amorphous mass was
washed copiously with ether and crystallized from acetonitrile/
diethyl ether mixture. The workup difficulties and modest yields
forced us to attempt method B. Thus, the cyanine 8 was also
prepared through the base-catalyzed condensation of acetanilide
6 with bromide 2 that gave us, with only 30 min of reflux, a
cleaner product in higher yields (90%) after precipitation with
diethyl ether and further crystallization from acetonitrile/ether.
Dye 8, red powder, was finally coupled with Merrifield
polystyrene (loading 1.1 mmol/g) using a procedure developed
by Frenette and co-workers (Scheme 3).5b This was obtained
by shaking a suspension of Merrifield resin in DMF with
carboxylate 8 together with cesium carbonate (3 equiv relative
to the acid) and catalytic amount of potassium iodide (0.5 equiv)
for 48 h at 80 °C. The reaction was judged complete when a
colorimetric test for chloromethyl groups on the polymer using
4-(4-nitrobenzyl)pyridine proved negative.8 Presence of a band
at 1733 cm-1 in the IR spectra of polymer confirmed the
presence of the carbonyl group. The solid dye/polystyrene
conjugate 9 was dark-orange in color.
Benzoxazolium iodide 5 was synthesized by heating under
reflux in an inert atmosphere a solution of 4 with an excess of
ethyl iodide in acetonitrile.6 The resulting salt was readily
separated in excellent purity from the crude reaction mixture
(3) Lu, Y.; Spiller, M. T.; Parkinson, B. A. Langmuir 2007, 23, 11637.
(4) (a) Mason, S. J.; Balasubramanian, S. Org. Lett. 2002, 4, 4261. (b)
Mason, S. J.; Hake, J. L.; Nairne, J.; Cummins, W. J.; Balasubramanian, S.
J. Org. Chem. 2005, 70, 2939. (c) Isacsson, J.; Westman, G. Tetrahedron
Lett. 2001, 42, 3207. (d) Merrington, J.; James, M.; Bradley, M. Chem.
Commun. 2002, 33, 140.
(5) (a) Yao, T.; Yue, D.; Larock, R. C. J. Comb. Chem. 2005, 7, 809.
(b) Frenette, R.; Friesen, R. W. Tetrahedron Lett. 1994, 35, 9177. (c) Stadler,
A.; Kappe, C. O. Eur. J. Org. Chem. 2001, 919. (d) Kurth, M. J.; Ahlberg,
L. A.; Randall, R.; Chen, C.; Melander, C.; Miller, R. B. J. Org. Chem.
1994, 59, 5862.
(7) Hung, S-C.; Ju, J.; Mathies, R. A.; Glazer, A. N. Anal. Biochem.
1996, 243, 15.
(8) Gaggini, F.; Porcheddu, A.; Reginato, G.; Rodriquez M.; Taddei, M.
J. Comb. Chem. 2004, 6, 805 and references therein.
(6) (a) Boto, R. E. F.; Santos, P. F.; Reis, L. V.; Almeida, P. Dyes Pigm.
2007, 75, 298. (b) Boto, R. E. F.; El-Shishtawy, R. M.; Santos, P. F.; Reis,
L. V.; Almeida, P. Dyes Pigm. 2007, 73, 195.
2940 J. Org. Chem., Vol. 73, No. 7, 2008

SCHEME 3 a
SCHEME 5 a
a Reagents and conditions: (a) 6 (5 equiv), NEt3 (2 equiv), pyridine,
80 °C, 24 h.
a Reagents and conditions: (a) Cs2CO3 (3 equiv), KI (0.5 equiv), DMF,
80 °C, 2 days.
SCHEME 4 a
reactive species have been successfully isolated on highly cross-
linked polymer supports10 we are optimistic, but without direct
proof, that monomeric dye has been achieved with Merrifield
polymers at 0.5 mmol/g Cl. At this low loading, the normally
red dye becomes pale yellow-orange. It is unclear whether this
color change is due to ion pairing, low surface concentration,
or both. At any rate, with the synthesis problem now solved,
we are in a position to examine the spectroscopic properties of
conjugated dye exposed to apolar media where ion pairing, and
thus reduced delocalization (if our postulate is correct), is
possible. Technical problems remain. Careful drying of the dye/
polymer, reducing further the loading, extending the conjugation,
or shortening of the linker may be necessary for further success.
High-level calculations on free and ion-paired dye are also
anticipated.
a Reagents and conditions: (a) 2 (1.5 equiv), Cs2CO3 (3 equiv), KI (0.5
equiv), DMF, 80 °C, 2 days.
It also seemed desirable to construct the dye on the polymer
itself. Solid-phase synthesis of cyanine dyes has not been
extensively explored in the literature, and to the best of our
knowledge only a few examples are known.4 In all of these
cases, the dye was cleaved from the polymeric support since
dye/polymer conjugates per se were not the objective. In our
pursuit of a polymer-bound dye, we initially used the chlorinated
Wang resin. Thus, compound 2 was successfully anchored to
benzyloxybenzyl chloride, polymer bound (100-200 mesh, 1%
cross-linked with DVB, 1.1 mmol/g) by using cesium carbonate
and potassium iodide protocol as depicted in Scheme 4.
The reaction was judged complete when the colorimetric test
specific for benzyl chlorides was negative.6 Polymer 7 was then
subjected to IR analysis (revealing the presence of a carbonyl
signals at 1718 cm-1) and elemental analysis which gave a
nitrogen percentage of 1.22 corresponding to a loading of 0.87
mmol/g. The final step of the synthesis was accomplished by
shaking a suspension of polymer 7, acetanilide 6 (5 equiv), and
triethylamine (2 equiv) in pyridine for 24 h as outlined in
Scheme 5. Formation of an orange polymeric bead occurred
immediately after the addition of compound 6. Control experi-
ments showed that neither polymer 7 nor compound 6 turns
colored under the reaction conditions. Following cleavage of
the dye from the polymer9 with 80% TFA in DCM, a reddish
Experimental Section
Preparation of 2-[3-[1-[(5-Carboxypentyl)-1,3-dihydro-3,3-
dimethyl-2H-indol-2-ylidene]-1-propenyl]-1-ethylbenzoxazol-3-
ium Inner Salt 8. Method A. A mixture of the salt 3 (0.80 g, 1.75
mmol) and benzoxazolium bromide 5 (0.51 g, 1.75 mmol) was
refluxed in 15 mL of dry pyridine for 3 h under a nitrogen
atmosphere. After the mixture was cooled to room temperature,
diethyl ether was added and the resulting mixture refrigerated to
allow complete precipitation. The solvent was decanted, and the
resulting gummy mass was triturated with cold diethyl ether until
a deep red powder was formed. Crystallization from acetonitrile/
diethyl ether mixture gave the final product 8 as deep red powder
(0.45 g, 58%). Method B. A mixture of the salt 2 (0.80 g, 2.26
mmol), enamide 6 (0.98 g, 2.26 mmol), and dry triethylamine (4.5
mmol, 0.45 g, 0.63 mL) in absolute ethanol (20 mL) was refluxed
for 30 min under nitrogen. The mixture was allowed to cool to
room temperature and diethyl ether was slowly added until complete
precipitation occurred. The red residue was filtered, washed with
cold ether and further crystallized from acetonitrile/diethyl ether
mixture to give the dye 8 as a deep red powder (0.9 g, 90%). IR
(neat): 2974, 2936, 2736, 2674, 2599, 2489, 1563, 1468, 1432,
1396, 1383, 1169, 1067, 1033, 848, 803 cm-1. 1H NMR (600 MHz,
DMSO-d6): δ 8.39 (1H, t, J ) 13.2 Hz), 7.93 (1H, d, J ) 7.6 Hz),
7.88 (1H, d, J ) 7.6 Hz), 7.53-7.63 (3H, m), 7.43 (1H, t, J ) 7.8
Hz), 7.38 (1H, d, J ) 8.4 Hz), 7.25 (1H, t, J ) 7.6 Hz), 6.50 (1H,
d, J ) 13.6 Hz), 6.34 (1H, d, J ) 13.2 Hz), 4.41 (2H, t, J ) 7.2
Hz), 4.06 (2H, t, J ) 7.2 Hz), 2.27 (2H, t, J ) 7.6 Hz), 1.75 (2H,
m), 1.70 (6H, s), 1.62 (2H, m), 1.45 (5H, t, J ) 7.2 Hz). 13C NMR
(150 MHz DMSO-d6): δ 174.2, 171.4, 161.5, 147.7, 146.7, 140.1,
1
solid was obtained. Mass spectrometry and H NMR analysis
were consistent with 8, as prepared in Scheme 2.
In summary, we utilized a quick and reliable method to bind
a cyanine dye to a hydrophobic polystyrene matrix. Since very
(9) Cleavage of the dye from Merrifield resin gave poor yields even under
forcing conditions.
(10) Jayalekshmy, P.; Mazur, S. J. Am. Chem. Soc. 1976, 98, 6710.
J. Org. Chem, Vol. 73, No. 7, 2008 2941

140.1, 130.5, 128.3, 126.2, 125.8, 123.9, 122.2, 111.9, 111.4, 110.4,
98.4, 90.8, 48.2, 42.9, 33.4, 28.0, 26.3, 25.6, 24.1, 13.0; MS (ESI)
m/z: 445.24 (M + H, 100), 430.22 (15). HRMS [C28H33N2O3+]:
expected 445.2413, observed 445.2428. UV (methanol) λmax: nm
(ꢀ): 521 (145250). Mp: 120-122 °C.
General Procedures To Anchor Dye 8 onto Polymeric
Support. Merrifield resin (0.5 g, 1.1 mmol/g) was suspended in
dry DMF (10 mL) for 30 min. To the suspension were then added
dye 8 (0.37 g, 0.82 mmol, 1.5 equiv), Cs2CO3 (0.54 g, 1.65 mmol,
3 equiv), and potassium iodide (0.044 g, 0.27 mmol, 0.5 equiv)
and the resulting mixture heated at 80 °C for 48 h. The resin was
filtered, washed with DMF (4 × 5 mL), DMF/water 1:1 (4×),
methanol (4×), and DCM (4×), and finally dried under vacuum
overnight for 24 h at room temperature affording a bright red bead.
IR: 1733 (CdO), 1372 cm-1. The same procedure was applied
when Wang resin was employed.
1718 (CdO), 1152 (CO) cm-1. Anal. Calcd: N, 1.50; Cl, 0.
Found: N, 1.22; Cl, 0.46 (loading 0.87 mmol/g). The residual
chloride represent unreacted -CH2Cl groups in wang polymer.
Synthesis of Polymer 9. Polymer 7 (1.50 g, loading 0.87 mmol/
g) was suspended in pyridine (10 mL) and allowed to swell for 30
min. After that time, to the suspension was added a solution of
2-methyl-3-ethylbenzoxazol-3-ium iodide 5 (1.88 g, 6.52 mmol, 5
equiv) in pyridine (2 mL) and 0.36 mL of triethylamine (0.26 g,
2.61 mmol, 2 equiv). After a few minutes, the resin bed turned
from orange to red and the mixture was shaken at 80 °C for further
24 h. After the mixture was allowed to cool at room temperature,
the polymer was filtered and sequentially washed with MeOH/THF/
MeOH/CHCl3/MeOH/DCM and finally dried in vacuo for 24 h at
room temperature affording a bright red bead. IR: 1733 (CdO),
1372 cm-1
.
Synthesis of Polymer 7. Wang resin (1.34 g, 1.1 mmol/g) was
suspended in dry DMF (20 mL) for 30 min. To the suspension
was then added acid 2 (0.78 g, 2.21 mmol, 1.5 equiv), Cs2CO3
(1.44 g, 4.42 mmol, 3 equiv), and KI (0.12 g, 0.74 mmol, 0.5 equiv),
and the resulting mixture was stirred at 80 °C for 48 h. After the
mixture was allowed to cool at room temperature, the polymer was
filtered and sequentially washed with MeOH/THF/MeOH/CHCl3/
MeOH/ DCM and finally dried in vacuo for 24 h at room
temperature. Polymer 7 was obtained as bright orange beads. IR:
Acknowledgment. This work was supported by the Petro-
leum Research Foundation and National Institutes of Health.
Supporting Information Available: General experimental
1
procedure, cleavage procedure, and copies of H and 13C NMR
spectra for dye 8. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO7027294
2942 J. Org. Chem., Vol. 73, No. 7, 2008