Near-infrared bis(indolium heptamethine cyanine) dyes with a spacer derived from oligo(ethylene glycol)

Article abstract of DOI:10.1002/jhet.171

(Chemical Equation Presented) Synthesis of a series of near-infrared dimeric dyes is presented. The intramolecular dimers contain two chromophores linked with a conformationally flexible ether or oligoether bridge. Optical properties of the dyes are discu

Full text of DOI:10.1002/jhet.171

September 2009
Near-Infrared Bis(indolium heptamethine cyanine) Dyes with a
Spacer Derived from Oligo(ethylene glycol)
925
Ewa Wolinska [1], Maged Henary, Ekaterina Paliakov,
and Lucjan Strekowski*
Department of Chemistry, Georgia State University, Atlanta, Georgia 30302-4098
*E-mail: lucjan@gsu.edu
Received January 14, 2009
DOI 10.1002/jhet.171
Published online 2 September 2009 in Wiley InterScience (www.interscience.wiley.com).
Synthesis of a series of near-infrared dimeric dyes is presented. The intramolecular dimers contain
two chromophores linked with a conformationally flexible ether or oligoether bridge. Optical properties
of the dyes are discussed.
J. Heterocyclic Chem., 46, 925 (2009).
INTRODUCTION
been used as agents for latent fingerprint detection
[5,12]. These dimeric dyes exhibit strongly enhanced
fluorescence upon interaction with the hydrophobic fats
of fingerprints that results in a clear fluorescence image
of the fingerprint.
Currently, there is substantial interest in dimeric dyes
in which two chromophoric subunits are linked by a
conformationally flexible chain. Under low concentra-
tion conditions in aqueous solution, these bichromo-
phoric molecules tend to exist in an intramolecular
clam-shell conformation with the two chromophores in
close proximity to each other. The intermolecular aggre-
gation of such intramolecular foldamers becomes impor-
tant with the increase in concentration. Normally, these
are H-type stacking interactions characterized by hypso-
chromic absorption and low fluorescence quantum yield
as compared to the characteristics of non-interacting dye
molecules. In general, the stacking interactions are less
important in solvents of low polarity. Several dimeric
dyes have been designed as non-covalent labels for the
detection of nucleic acids [2,3] and proteins [4–7]. More
specifically, upon binding with a biopolymer, the intra-
molecular complex of a dimeric cyanine undergoes dis-
sociation and the clam-shell of the inner complex opens
up. Binding of the open form of the dimeric dye usually
results in a batochromic shift in absorption and a greatly
increased quantum yield of fluorescence. Several bichro-
mophoric squaraines have been developed as cation-
specific chemosensors [8–11]. These dimeric dyes bind
metal cations and the resulting complexes show different
spectral properties in comparison to non-complexed
dyes. Finally, several bichromophoric cyanine dyes have
Synthesis of dimeric dyes 14–16 and 21–26 with an
ether or oligoether linker in the molecule is described
in this report. The molecules were designed as
improved non-covalent labels for nucleic acids and
proteins. The presence of oxygen atom(s) in the bridge
linking the two dye moieties results in an increased
solubility of the bifunctional molecules in water and
aqueous buffers in comparison to the more hydropho-
bic analogs containing a polymethylene linker. The di-
meric dyes 21–26 are additionally substituted with
hydrophilic sulfonatobutyl groups. These dyes are
bifunctional heptamethine cyanines that absorb and
fluoresce in the near-infrared region (>700 nm). Few
biomolecules absorb and fluoresce within the near-
infrared region, and as a result Raman and Rayleigh
light scattering are greatly reduced in this region. Con-
sequently, improved signal-to-noise ratios are typically
observed in the near-infrared region. In addition, typi-
cal impurities need not be considered because such
species are not detected at wavelengths longer than
700 nm. All bis-dyes contain indolium moieties as
end-heterocyclic subunits because such derivatives are
relatively stable in solution [13].
C
V
2009 HeteroCorporation

926
E. Wolinska, M. Henary, E. Paliakov, and L. Strekowski
Vol 46
Scheme 1
RESULTS AND DISCUSSION
The key intermediate products are bis-indolium salts
5–7 (Scheme 1).
These compounds were obtained by quaternization of
indolenine 1 with a,x-diiodo-substituted ethers 2, 3 or
a,x-bis-tosylate derivative 4. In the latter case, the re-
sultant bis-tosylate salt 7 was transformed into a more
reactive diodide salt 8 by treatment with sodium iodide
in acetone. The application of the intermediate dimeric
salts 5, 6, and 8 in the synthesis of dimeric near-infrared
cyanines 14–16 and 21–26 is shown in Scheme 2.
The successful strategy for the synthesis of N-butyl
derivatives 14–16 involved quaternization of 2,3,3-tri-
methylindole-nine and 2,3,3-trimethylbenzo[e]indolenine
with n-butyl iodide followed by condensation of the
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2009 Near-Infrared Bis(indolium heptamethine cyanine) Dyes with a Spacer Derived
from Oligo(ethylene glycol)
927
Scheme 3
dyes 12, 13, 19, and 20 can be used for the condensa-
tion reaction. The final dimeric dyes, however, must be
purified by chromatography. The final yields of these
highly polar products are quite low, even for the opti-
mized procedures described in the experimental
section. Nevertheless, the described preparations are
inexpensive and highly reproducible, and the final dyes
are analytically pure, as judged by the results of
the elemental, thin-layer-chromatographic, and spectral
analyses.
The near-infrared spectra of dyes 14–16 and 21–26
are listed in Table 1. As can be seen, for the spectra of
14–16 taken in methanol, the maximum absorption
wavelengths decrease in the order 14 > 15 > 16, and
these decreases parallel the increases in the length of
the linker joining two terminal dye subunits in these di-
meric compounds. A similar pattern is observed in the
spectra of the individual series of NIR dyes 21–23, and
24–26. The differences between the shortest and the lon-
gest absorption wavelengths are remarkably similar
(about 20 ꢀ 1 nm) for each individual series of dyes.
These large differences cannot be due to an electronic
effect of the linker on the absorption because the corre-
sponding monomeric dyes that are N-substituted with
ethyl, butyl, or 2-hydroxyethyl groups all show similar
absorption within 1 nm in methanol [7,16]. It can be
suggested that the spectral differences reflect different
foldamers in which two dye subunits are in close prox-
imity to each other. More specifically, it appears that
the length of the linker dictates the stereochemistry of
the foldamer.
resultant indolium salts 9 and 10 with a dialdehyde 11.
The condensation reaction was conducted in a mixture
of n-butanol and benzene with azeotropic removal of
water.
Under these conditions, the formation of mono-con-
densation products 12 or 13 is strongly favored [14].
Crude products 12 and 13, without purification, were
then allowed to react with dimeric salts 5, 6, and 8 to
furnish the corresponding final dyes 14–16. In a similar
way, quaternization of 2,3,3-indolenine or its benzo
counterpart with 1,4-butanesultone yielded the respective
4-sulfonatobutyl inner salts 17 and 18 that were subse-
quently used for mono-condensation with dialdehyde 11.
The resultant products 19 and 20 were subjected to con-
densation with dimeric indolium salts 5, 6, and 8 to fur-
nish the desired corresponding dimeric cyanines 21–26.
A bis-anilinium derivative of the bis-aldehyde 11
[15] (27, structure in Scheme 3) is normally used in
the synthesis of cyanine dyes by the reaction with
methyl-substituted cationic heterocycles. The anilinium
derivative 27 is more stable than the parent compound
11 and is easily purified by crystallization. The initial
synthesis plan called for condensation of excess 27
with a dimeric salt 5, 6, or 8 followed by condensation
of the expected product 28 with the indolium salt 9 or
analogs. This approach failed because compound 28 (n
¼ 1–3) was not formed. A detailed separation analysis
showed the presence of the corresponding cyanine dye
29–31 in which the terminal indolium subunits are
bridged by an ether moiety. By contrast, the half-dyes
12, 13 and 19, 20 were the major products of the reac-
tions conducted with bis-aldehyde 11. The procedure is
simple in that crude bis-aldehyde 11 and crude half-
It was of interest to compare spectral properties of the
ether-linked NIR dyes with those of their oligomethylene-
linked analogs, a limited number of which have been pub-
lished by us previously [5–7]. A striking difference is the
lack of correlation between the maximum absorption
wavelength and the length of the polymethylene chain.
Thus, the analogs of 21–23 containing 4, 6, 8, and 10
methylene (CH2) units show absorption in methanol at 783
nm, 787 nm, 780 nm, and 787 nm, respectively. Yagi
et al. [9] and Liang et al. [17] have synthesized a series of
bichromophoric squarains containing intramolecular poly-
methylene chains of various length and reported their
spectra. It escaped their attention, however, that, as in our
analysis, there is no correlation between the length of
a polymethylene linker and absorption wavelengths of
the bichromophoric squaraines. The spectral differences
between bichromophoric molecules containing polymethy-
lene and ether chains can be explained in terms of their
different conformational flexibility with the latter linkers
showing more conformational freedom. This conclusion is
strongly supported by conformational analysis of polyeth-
ylene (CH2CH2)n, polyoxyethylene (OCH2CH2)n, and
related low molecular-weight molecules [18].
Journal of Heterocyclic Chemistry
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E. Wolinska, M. Henary, E. Paliakov, and L. Strekowski
Vol 46
Table 1
Vis-NIR spectra of dyes 14–16, and 21–26 taken in methanol.
Linker, No (C þ O)
Dye
kmax
Dye
kmax
Dye
kmax
5
8
14
15
16
817
799
797
21
22
23
794
776
775
24
25
26
818
802
797
11
We conducted conformational studies of dimeric dyes
14–16. The conformations were computer-simulated in
an aqueous environment and in vacuo, resembling con-
ditions in solvents of high and low polarity, respec-
tively. The technical aspects of the calculations are
given in the experimental section. A general result is
that there are a number of computed low-energy struc-
tures in an aqueous environment that contain the two
cyanine subunits in close proximity to each other,
strongly suggesting attractive hydrophobic interactions
between these two subunits (not shown). By contrast,
low-energy conformations of 14–16 in the absence of
water contain an unfolded ether bridge and the two cya-
nine subunits away from each other. When the closed-
shell conformations, as obtained from computing the
structures in an aqueous environment, were taken as the
starting structures for computation in the absence of
water, all conformations opened-up, losing the presumed
intramolecular interactions. The computed energy differ-
ences between the more stable solvated structures and
the conformations in the absence of water are in the
range of 70–100 kcal/mol. Compound 16 was selected
for a detailed analysis. The molecular modeling work
generated a number of water-induced conformations of
16 in which the two cyanine subunits are in close prox-
imity to each other. Some of these structures are consist-
ent with partial stacking of the planar portions of the
dyes, suggesting a p–p interaction. Other computer-
generated low-energy conformations of 16 in aqueous
environment are consistent with hydrophobic interac-
tions, but not stacking, between the cyanine chromo-
phores. We have also conducted similar calculations for
the analog of 16 in which the ether linkage is replaced
by an eleven-methylene bridge. Despite the similar
lengths of the two linkages, the number of low-energy
conformations is larger for 16 than for its polymethylene
analog. These computational results are consistent with
the greater conformational flexibility of 16 in compari-
son to its analog containing an all-carbon bridge, as dis-
cussed earlier.
of HSA are highly structure dependent. On the other
hand, only the cationic molecules 14–16 bind with DNA
as evidenced by the observed spectral changes. Mole-
cules 21–26 that contain a zero net charge do not inter-
act with anionic DNA. Complete biophysical studies
will be reported in due course.
EXPERIMENTAL
General. Where applicable, products were purified on a
chromatotron with silica gel-coated rotors. Melting points are
greater than 300ꢁC in all cases. All 1H NMR spectra were
taken at 400 MHz. Near-infrared (NIR) spectra were taken in
methanol or dichloromethane for solutions with absorptivities
<1.0. The intermolecular aggregation of cyanine dyes is
negligible under such conditions.
Dimeric indolium salts 5, 6, 8. Bis(2-iodoethyl) ether (2)
was prepared by refluxing bis(2-chloroethyl) ether with sodium
iodide in 2-butanone for 24 h as reported previously [19]. A
mixture of 2,3,3-trimethylindolenine (1, 0.48 g, 3 mmol), a
diiodo derivative 2 or 3 (1.5 mmol), and pyridine (one drop)
was heated to 110ꢁC for 4 days to give the respective bis-salt
5 or 6. In a similar way, product 7 was obtained by treatment
of 1 with a bis-tosylate derivative 4. Crude bis-tosylate salt 7
in acetone (10 mL) was treated with a saturated solution of so-
dium iodide (0.30 g, 2 mmol) in methanol, and the mixture
was heated under reflux for 2 h. Cooling of the mixture to 0ꢁC
for several hours caused precipitation of sodium p-tosylate,
leaving bis-indolium diiodide 8 in solution. The diiodides 5, 6,
and 8 were purified by silica gel chromatography eluting with
methanol/ethyl acetate (1:3).
N,N0-(3-Oxopentane-1,5-diyl)-bis(2,3,3-trimethyl-3H-indo-
lium) diiodide 5. This compound was obtained in a 63%
yield; 1H NMR (DMSO-d6): d ¼ 1.26 (s, 12H), 3.18 (s, 6H),
4.35 (t, J ¼ 5Hz, 4H), 5.02 (t, J ¼ 5Hz, 4H), 7.41 (m, 8H).
Anal. Calcd for C26H34I2N2O2: C, 48.46; H, 5.32; N, 4.35.
Found: C, 48.28; H, 4.98; N, 4.29.
N,N0-(3,6-Dioxaoctane-1,8-diyl)-bis(2,3,3-trimethyl-3H-in-
dolium) diiodide 6. This compound was obtained in a 58%
yield; 1H NMR (DMSO-d6): d ¼ 1.49 (s, 12H), 2.76 (s, 6H),
3.66 (t, J ¼ 5Hz, 4H), 3.79 (t, J ¼ 5Hz, 4H), 4.67 (t, J ¼
5Hz, 4H), 7.61 (m, 4H), 7.85 (d, J ¼ 8Hz, 2H), 7.92 (d, J ¼
8Hz, 2H). HR-MS (ESI). Calcd for (C28H38N2O2)2þ: m/z ¼
217.1464. Found: m/z
¼
217.1456. Anal Calcd for
C28H38I2N2O2: C, 48.84; H, 5.56; N, 4.07. Found: C, 48.95;
H, 5.62; N, 4.03.
We have conducted preliminary binding studies of
14–16 and 21–26 with human serum albumin (HSA)
and calf thymus DNA. All compounds bind with the
protein, albeit the absorption and fluorescence differen-
ces between the compounds in the absence and presence
N,N0-(3,6,9-Trioxaundecane-1,11-diyl)-bis(2,3,3-trimethyl-
3H-indolium) diiodide 8. This compound was obtained in a
1
73% yield; H NMR (DMSO-d6): d ¼ 1.50 (s, 12H), 2.35 (s,
6H), 3.25 (t, J ¼ 5Hz, 4H), 3.34 (t, J ¼ 5Hz, 4H), 3.83 (t, J
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2009 Near-Infrared Bis(indolium heptamethine cyanine) Dyes with a Spacer Derived
from Oligo(ethylene glycol)
929
¼ 5Hz, 4H), 4.71 (t, J ¼ 5Hz, 4H), 7.59 (m, 4H), 7.84 (d, J ¼
8Hz, 2H), 7.98 (d, J ¼ 8Hz, 2H); 13C NMR (DMSO-d6): d ¼
14.8, 21.9, 47.9, 54.2, 66.6, 69.4, 69.6, 115.6, 123.5, 128.8,
129.3, 140.8, 141.6, 189.1. HR-MS (ESI). Calcd for
(C30H42N2O3)2þ: m/z ¼ 239.1592. Found: m/z ¼ 239.1592.
Near-infrared dyes 14–16 and 21–26. A mixture of bis-
aldehyde 11 [14] (173 mg, 1 mmol), a quaternary salt [5,19] 9,
10, 17, or 18 (1 mmol), n-butanol (50 mL), and benzene (15
mL) was stirred at 23ꢁC for 2 h. The resultant crude product
12, 13, 19, or 20, without isolation, was treated in the same
flask with a dimeric salt 5, 6, or 8 (0.5 mmol) and the mixture
was heated under reflux for an additional 12 h. The product
was isolated by concentration of the mixture on a rotary evap-
orator followed by chromatography eluting with dichlorome-
thane/methanol (10:1 for 14–16 and 9:1 for 21–26).
3000-Oxapentane-1000,5000-diyl[bis[2-[70-(300-butyl-100,100-dim-
ethylbenzo[e]indolin-200-ylidene)-40-chloro-30,50-trimethyle-
ne-10,30,50-heptatrien-10-yl]-3,3-dimethyl-3H-indol-1-ium]]
diiodide 14. This compound was obtained in a 17% yield;1H
NMR (CDCl3): d ¼ 1.02 (t, J ¼ 6Hz, 6H), 1.54 (m, 4H), 1.68
(s, 12H), 1.90 (m, 4H), 1.94 (m, 4H), 2.02 (s, 12H), 2.74 (m,
8H), 4.05 (m, 4H), 4.36 (m, 8H), 6.20 (d, J ¼ 11Hz, 2H), 6.32
(d, J ¼ 11Hz, 2H), 7.09 (d, J ¼ 6Hz, 2H), 7.18 (t, J ¼ 6Hz,
2H), 7.26 (t, J ¼ 6Hz, 2H), 7.34 (d, J ¼ 6Hz, 2H), 7.44 (d, J
¼ 6Hz, 2H), 7.48 (t, J ¼ 6Hz, 2H), 7.63 (t, J ¼ 6Hz, 2H),
7.96 (m, 4H), 8.13 (d, J ¼ 6Hz, 2H), 8.28 (d, J ¼ 11Hz, 2H),
8.48 (d, J ¼ 11Hz, 2H); NIR: kmax ¼ 817 nm. Anal. Calcd for
C80H90Cl2I2N4Oꢂ2H2O: C, 64.73; H, 6.38; N, 3.77. Found: C,
64.85; H, 6.22; N, 3.85.
8H), 7.44 (m, 2H), 7.55 (m, 4H), 7.65 (d, J ¼ 7Hz, 2H), 8.13
(d, J ¼ 14Hz, 2H), 8.28 (d, J ¼ 13Hz, 2H); NIR: kmax ¼ 794
nm. Anal. Calcd for C72H84Cl2N4O7S2ꢂ5H2O: C, 64.41; H,
7.06; N, 4.17. Found: C, 64.29; H, 6.82; N, 4.02.
3
0000,60000-Dioxaoctane-1,8-diyl[bis[2-[70-[100-(4000-sulfonatob-
uty-l)-300,300-dimethylindolin-200-ylidene]-40-chloro-30,50-tri-
methylene-10,30,50-heptatrien-10-yl]-3,3-dimethyl-3H-indol-
1-ium]] diiodide 22. This compound was obtained in a 14%
1
yield; H NMR (DMSO-d6): d ¼ 1.62 (s, 12H), 1.68 (s, 12H),
1.78 (m, 16H), 2.71 (m, 8H), 3.38 (m, 4H), 3.45 (s, 4H), 4.20
( m, 4H), 4.30 (m, 4H), 6.35 (d, J ¼ 13Hz, 2H), 6.44 (d, J ¼
14Hz, 2H), 7.27 (m, 6H), 7.44 (m, 6H), 7.62 (m, 4H), 8.24 (d,
J ¼ 13Hz, 2H), 8.27 (d, J ¼ 14Hz, 2H); NIR: kmax ¼ 776 nm.
Anal. Calcd for C74H88Cl2N4O8S2ꢂ5H2O: C, 64.08; H, 7.12; N,
4.04. Found: C, 63.97; H, 6.94; N, 3.81.
30000,60000,90000-Trioxaundecane-10000,110000-diyl[bis[2-[70-[100-(4000-
sulfonatobutyl)-300,300-dimethylindolin-200-ylidene]-40-chloro-30,50-
trimethylene-10,30,50-heptatrien-10-yl]-3,3-dimethyl-3H-indol-
1-ium]] diiodide 23. This compound was obtained in a 12%
1
yield; H NMR (DMSO-d6): d ¼ 1.62 (s, 12H), 1.65 (s, 12H),
1.73 (m, 16H), 2.59 (m, 8H), 3.27 (m, 4H), 3.37 (m, 4H), 3.71
(m, 4H), 4.24 (m, 4H), 4.36 (m, 4H), 6.35 (d, J ¼ 14Hz, 2H),
6.39 (d, J ¼ 15Hz, 2H), 7.41 (m, 16H), 8.20 (d, J ¼ 14Hz,
2H), 8.25 (d, J ¼ 15Hz, 2H); NIR: kmax ¼ 775 nm. Anal.
Calcd for C76H92Cl2N4O9S2ꢂ5H2O: C, 63.80; H, 7.18; N, 3.91.
Found: C, 64.01; H, 6.92; N, 3.81.
30000-Oxapentane-10000,50000-diyl[bis[2-[70-[300-(4000-sulfonatob-
utyl)-100,100-dimethylbenzo[e]indolin-200-ylidene]-40-chloro-30,50-
trimethylene-10,30,50-heptatrien-10-yl]-3,3-dimethyl-3H-indol-1-
ium]] diiodide 24. This compound was obtained in a 26%
3000,6000-Dioxaoctane-1000,8000-diyl[bis[2-[70-(300-butyl-100,100-
dimethylbenzo[e]indolin-200-ylidene)-40-chloro-30,50-trimethy-
lene-10,30,50-heptatrien-10-yl]-3,3-dimethyl-3H-indol-1-ium]]
1
yield; H NMR (DMSO-d6): d ¼ 1.56 (m, 4H), 1.59 (s, 12H),
1.79 (m, 4H), 1.93 (s, 12H), 1.95 (m, 4H), 2.52 (m, 8H), 2.74
(m, 4H), 3.84 (m, 4H), 4.28 (m, 4H), 4.42 (m, 4H), 6.16 (d, J
¼ 14Hz, 2H), 6.55 (d, J ¼ 15Hz, 2H), 7.16 (m, 2H), 7.25 (m,
2H), 7.55 (m, 4H), 7.67 (m, 2H), 7.88 (m, 2H), 8.10 (m, 6H),
8.31 (m, 2H), 8.41 (d, J ¼ 15Hz, 2H); NIR: kmax ¼ 818 nm.
Anal. Calcd for C80H88Cl2N4O7S2ꢂ5H2O: C, 66.60; H, 6.84; N,
3.88. Found: C, 66.58; H, 6.70; N, 3.66.
1
diiodide 15. This compound was obtained in a 26% yield; H
NMR (CDCl3): d ¼ 1.02 (t, J ¼ 7Hz, 6H), 1.54 (m, 4H), 1.73
(s, 12H), 1.90 (m, 4H), 1.97 (m, 4H), 2.01 (s, 12H), 2.76 (m,
8H), 3.56 (s, 4H), 3.92 (m, 4H), 4.32 (m, 4H), 4.41 (m, 4H),
6.29 (d, J ¼ 14Hz, 2H), 6.34 (d, J ¼ 14Hz, 2H), 7.24 (m,
4H), 7.40 (m, 6H), 7.49 (t, J ¼ 6Hz, 2H), 7.62 (t, J ¼ 6Hz,
2H), 7.94 (m, 4H), 8.13 (d, J ¼ 8Hz, 2H), 8.32 (d, J ¼ 14Hz,
2H), 8.45 (d, J ¼ 14Hz, 2H); NIR: kmax ¼ 799 nm. Anal.
Calcd for C82H94Cl2I2N4O2ꢂ2H2O: C, 64.43; H, 6.46; N, 3.66.
Found: C, 64.44; H, 6.48; N, 3.64.
30000,60000-Dioxaoctane-10000,80000-diyl[bis[2-[70-[300-(4000-sulfon-
atobutyl)-100,100-dimethylbenzo[e]indolin-200-ylidene]-40-chloro-
30,50-trimethylene-10,30,50-heptatrien-10-yl]-3,3-dimethyl-3H-in-dol-
1-ium]] diiodide 25. This compound was obtained in a 25%
1
3000,6000,9000-Trioxaundecane-1000,11000-diyl[bis[2-[70-(300-buty-
l-100,100-dimethylbenzo[e]indolin-200-ylidene)-40-chloro-30,50-
trimethylene-10,30,50-heptatrien-10-yl]-3,3-dimethyl-3H-indo-
l-1-ium]] diiodide 16. This compound was obtained in a 12%
yield; H NMR (DMSO-d6): d ¼ 1.64 (s, 12H), 1.81 (m, 4H),
1.93 (s, 12H), 1.98 (m, 4H), 2.51 (m, 8H), 2.66 (m, 4H), 2.74
(m, 4H), 3.47 (s, 4H), 3.72 (m, 4H), 4.24 (m, 4H), 4.41 (m,
4H), 6.24 (d, J ¼ 14Hz, 2H), 6.53 (d, J ¼ 14Hz, 2H), 7.18
(m, 2H), 7.25 (m, 2H), 7.33 (m, 2H), 7.54 (m, 4H), 7.65 (m,
2H), 7.85 (m, 2H), 8.08 (m, 4H), 8.18 (d, J ¼ 14Hz, 2H), 8.27
(m, 2H), 8.40 (d, J ¼ 14Hz, 2H); NIR: kmax ¼ 802 nm. Anal.
Calcd for C82H92Cl2N4O8S2ꢂ2H2O: C, 68.74; H, 6.75; N, 3.91.
Found: C, 68.43; H, 6.79; N, 3.82.
1
yield; H NMR (CDCl3): d ¼ 1.02 (t, J ¼ 6Hz, 6H), 1.53 (m,
4H), 1.72 (s, 12H), 1.94 (m, 8H), 2.02 (s, 12H), 2.77 (m, 4H),
3.56 (m, 12H), 3.96 (m, 4H), 4.38 (m, 8H), 6.28 (d, J ¼ 14Hz,
2H), 6.33 (d, J ¼ 14Hz, 2H), 7.22 (m, 4H), 7.35 (m, 4H), 7.48
(m, 4H), 7.63 (m, 2H), 7.95 (m, 4H), 8.13 (m, 2H), 8.31 (d, J
¼ 14Hz, 2H), 8.47 (d, J ¼ 14Hz, 2H); NIR: kmax ¼ 797 nm.
Anal. Calcd for C84H98Cl2I2N4O3ꢂ4H2O: C, 62.73; H, 6.64; N,
3.48. Found: C, 62.88; H, 6.42; N, 3.38.
3
0000,60000,90000-Trioxaundecane-10000,110000-diyl[bis[2-[70-[300-
(4000-sulfonatobutyl)-100,100-dimethylbenzo[e]indolin-200-yli-
dene]-40-chloro-30,50-trimethylene-10,30,50-heptatrien-10-yl]-3,3-di-
methyl-3H-indol-1-ium]] diiodide 26. This compound was
obtained in a 12% yield; 1H NMR (DMSO-d6): d ¼ 1.66 (s,
12H), 1.83 (m, 12H), 1.95 (s, 12H), 2.69 (m, 4H), 2.77 (m,
4H), 3.40 (m, 8H), 3.76 (m, 4H), 4.35 (m, 4H), 4.42 (m, 4H),
6.33 (d, J ¼ 14Hz, 2H), 6.53 (d, J ¼ 15Hz, 2H), 7.22 (m,
2H), 7.36 (m, 4H), 7.56 (m, 4H), 7.69 (m, 2H), 7.89 (m, 2H),
8.12 (m, 4H), 8.18 (d, J ¼ 14Hz, 2H), 8.32 (m, 2H), 8.33 (d,
3
0000-Oxapentane-10000,50000-diyl[bis[2-[70-[100-(4000-sulfonatob-
utyl)-300,300-dimethylindolin-200-ylidene]-40-chloro-30,50-trime-
thylene-10,30,50-heptatrien-10-yl]-3,3-dimethyl-3H-indol-1-ium]]
diiodide 21. This compound was obtained in a 16% yield; H
1
NMR (DMSO-d6): d ¼ 1.58 (s, 12H), 1.66 (s, 12H), 1.76 (m,
16H), 2.50 (m, 4H), 2.69 (m, 4H), 3.84 (m, 4H), 4.28 (m, 8H),
6.19 (d, J ¼ 13Hz, 2H), 6.46 (d, J ¼ 14Hz, 2H), 7.25 (m,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

930
E. Wolinska, M. Henary, E. Paliakov, and L. Strekowski
Vol 46
J ¼ 15Hz, 2H); NIR: kmax ¼ 797 nm in methanol. Anal.
Calcd for C84H96Cl2N4O9S2ꢂ4H2O: C, 66.91; H, 6.92; N, 3.70.
Found: C, 66.61; H, 6.65; N, 3.63.
Macrocyclic dyes 29–31. A mixture of Vilsmeier-Haack re-
agent 27 [15] (360 mg, 1 mmol), sodium acetate (82 mg, 1
mmol), and a dimeric salt, 5, 6, or 8 (732 mg, 1 mmol) in
ethanol (30 mL) was stirred at 35ꢁC for 1 h. The crude dye
29–31 was purified by chromatography eluting with dichloro-
methane/methanol (10:1) and then crystallized from ethanol/
hexanes.
from vacuum to aqueous solution. In vacuum, the structures
are opened, and in water, the individual cyanine moieties of
the dimeric molecules are close to each other in all cases
studied.
REFERENCES AND NOTES
[1] On leave of absence from University of Podlasie, Siedlce
08–110, Poland.
[2] Armitage, B. A. In Topics Heterocycl Chem; Gupta, R. R.,
Strekowski, L., Eds.; Springer: Berlin, Germany, 2008; Vol. 14, Chap-
ter 14, p 11.
N,N00-(3000-Oxapentane-1000,5000-diyl)-[2-[70-(300,300-dimethyli-
ndolin-200-ylidene)-40-chloro-30,50-trimethylene-10,30,50-hep-
tatrien-10-yl]-3,3-dimethyl-3H-indol-1-ium] iodide 29. This
[3] Gadjev, N. I.; Deligeorgiev, T. G.; Timcheva, I.; Maxi-
mova, V. Dyes Pigm 2003, 57, 161.
1
compound was obtained in a 10% yield; H NMR (DMSO-d6):
[4] Kim, J.; Watson, A.; Henary, M.; Patonay, G. In Topics
Heterocycl Chem; Gupta, R. R., Strekowski, L., Eds.; Springer: Berlin,
Germany, 2008; Vol. 14, Chapter 14, p 31.
d ¼ 1.57 (s, 12H), 1.62 (m, 2H), 2.66 (m, 4H), 3.91 (m, 4H),
4.46 (m, 4H), 6.31 (d, J ¼ 14Hz, 2H), 7.24 (m, 2H), 7.36 (m,
4H), 7.57 (m, 2H), 8.18 (d, J ¼ 14Hz, 2H). HR-MS (ESI).
Calcd for (C34H38ClN2O)þ: m/z ¼ 525.2667. Found: m/z ¼
525.2687.
[5] Patonay, G.; Strekowski, L.; Kim, J. S.; Henary, M. NIR
News 2007, 18, 7.
[6] Patonay, G.; Kim, J. S.; Kodagahally, R.; Strekowski, L.
Appl Spectrosc 2005, 59, 682.
N,N00-(3000,6000-Dioxaoctane-1000,8000-diyl)-[2-[70-(300,300-dimet-
hylindolin-200-ylidene)-40-chloro-30,50-trimethylene-10,30,50-he-
ptatrien-10-yl]-3,3-dimethyl-3H-indol-1-ium] iodide 30. This
[7] Kim, J. S.; Kodagahally, R.; Strekowski, L.; Patonay, G.
Talanta 2005, 67, 947.
1
compound was obtained in a 20% yield; H NMR (DMSO-d6):
[8] Yagi, S.; Nakamura, A.; Watanabe, D.; Nakazumi, H. Dyes
Pigm 2009, 80, 98.
d ¼ 1.57 (s, 12H), 1.84 (m, 2H), 2.63 (m, 4H), 3.52 (s, 4H),
3.72 (m, 4H), 4.29 (m, 4H), 6.32 (d, J ¼ 14Hz, 2H), 7.24 (m,
2H), 7.38 (m, 4H), 7.58 (m, 2H), 8.14 (d, J ¼ 14Hz, 2H);
Anal. Calcd. for C36H42ClIN2O2ꢂH2O: C, 60.46; H, 6.20; N,
3.91. Found: C, 60.61; H, 6.11; N, 3.85.
[9] Yagi, S.; Hyodo, Y.; Hirose, M.; Nakazumi, H.; Sakurai,
Y.; Ajayaghosh, A. Metallo Org Lett 2007, 9, 1999.
[10] Arunkumar, E.; Chithra, P.; Ajayaghosh, A. J Am Chem
Soc 2004, 126, 6590.
N,N00-(3000,6000,9000-Trioxaundecane-1000,11000-diyl)- [2-[70-(300,
300-dimethylindolin-200-ylidene)-40-chloro-30,50-trimethylene-10,
[11] Arunkumar, E.; Ajayaghosh, A.; Daub, J. J Am Chem Soc
2005, 127, 3156.
30,50-heptatrien-10-yl]-3,3-dimethyl-3H-indol-1-ium]
iodide
[12] Patonay, G.; Eckenrode, B.; Krutak, J. J.; Salon, J.; Stre-
kowski, L. In Forensic Analysis on the Cutting Edge; Blackledge, R.
D., Ed.; Wiley: Hoboken, New Jersey, 2007; p 115.
[13] Henary, M.; Mojzych, M. In Topics Heterocycl Chem;
Gupta, R. R., Strekowski, L., Eds.; Springer: Berlin, Germany, 2008; p
221.
31. This compound was obtained in a 32% yield; 1H NMR
(CDCl3): d ¼ 1.54 (s, 12H), 2.00 (m, 2H), 2.72 (m, 4H),
3.72 (m, 4H), 3.81 (m, 4H), 3.99 (m, 4H), 4.53 (m, 4H),
5.96 (d, J ¼ 15Hz, 2H), 7.24–7.46 (m, 8H), 8.52 (d, J ¼
15Hz, 2H); NIR: kmax
¼
777 nm. Anal Calcd. for
[14] Narayanan, N.; Strekowski, L.; Lipowska, M.; Patonay, G.
J Org Chem 1997, 62, 9387.
C38H46ClIN2O3ꢂ2H2O: C, 58.72; H, 6.48; N, 3.60. Found: C,
58.92; H, 6.19; N, 3.48.
[15] Makin, S. M.; Boiko, L. I.; Shavrygina, O. A. Zh Org
Khim 1977, 13, 1189.
Molecular modeling. Energy minimizations were per-
formed using SYBYL (running on SGI O2 station) using
MMFF94 force field and the minimum energy change of
[16] Strekowski, L.; Lipowska, M.; Patonay, G. J Org Chem
1992, 57, 4578.
˚
0.01 kcal/mol per A as a convergence criterion. Charges
[17] Liang, K.; Farahat, M. S.; Perlstein, J.; Law, K.-Y.; Whit-
ten, D. G. J Am Chem Soc 1997, 119, 830.
were calculated using the MMFF94 method as implemented
in SYBYL. The molecules in aqueous environment were
minimized using the Molecular Silverware option in
SYBYL, which resulted in change of energy (Emin) and in
the conformation of dyes. The values of Emin decreased of
about 70–100 kcal/mol when the environment was changed
[18] Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of
Organic Compounds; Wiley: New York, 1994; p 610.
[19] Jousselme, B.; Blanchard, P.; Levillan, E.; Delaunay, J.;
Allain, M.; Richomme, P.; Rondeau, D.; Gallego-Planas, N.; Roncali,
J. J Am Chem Soc 2003, 125, 1363.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet