Microwave-Assisted Synthesis of Near-Infrared Fluorescent Indole-Based Squaraines

Article abstract of DOI:10.1021/acs.orglett.5b01453

(Graph Presented) A microwave-assisted method for the preparation of a wide color range of 2,3,3-trimethylindolenine-based squaraines and their intermediates is described. This practical approach allows the rapid preparation of both symmetrical and nonsymmetrical squaraine dyes, reducing reaction time from days to minutes with more than 2-fold improvement in product yields when compared to conventional methods.

Full text of DOI:10.1021/acs.orglett.5b01453

Letter
pubs.acs.org/OrgLett
Microwave-Assisted Synthesis of Near-Infrared Fluorescent Indole-
Based Squaraines
†
†
†,§
†
†
Nadia Barbero, Claudio Magistris, Jinhyung Park, Davide Saccone, Pierluigi Quagliotto,
†
‡
,†
†
Roberto Buscaino, Claudio Medana, Claudia Barolo,* and Guido Viscardi
†
‡
Department of Chemistry and NIS Interdepartmental Centre and Dipartimento di Biotecnologie Molecolari e Scienze per la Salute,
University of Torino, Via Giuria 7, I-10125 Torino, Italy
*
S Supporting Information
ABSTRACT: A microwave-assisted method for the preparation of a wide color range of 2,3,3-trimethylindolenine-based
squaraines and their intermediates is described. This practical approach allows the rapid preparation of both symmetrical and
nonsymmetrical squaraine dyes, reducing reaction time from days to minutes with more than 2-fold improvement in product
yields when compared to conventional methods.
ince the first reports on the use of microwave (MW) heating
counterpart is not completely regioselective and a certain
amount of the 1,2-condensation product can be formed. The
8
S
to accelerate organic chemical transformations by the groups
1
2
of Gedye and Giguere and Majetich in 1986, microwave-
assisted organic synthesis (MAOS) has proven to be a powerful
synthesis of unsymmetrical squaraine dyes is a little more
challenging and requires the isolation of the semisquaraine
intermediate and its condensation with a different activated
molecule in a subsequent step, typically affording mixtures of the
desired compound along with unreacted hemisquaraine and
undesired symmetrical analogues. To avoid time-consuming
purifications, we recently proposed crystallization methods for
the purification of symmetrical squaraines which does not apply
to unsymmetrical structures, where the presence of side products
3
technique for promoting a variety of chemical reactions.
Microwave heating has been shown to dramatically reduce
reaction times, increase product yields, and enhance product
purities by reducing unwanted side reactions compared to
4
conventional heating methods.
Squaraines are polymethine dyes obtained as dicondensation
products between electron-rich substrates and squaric acid
possessing sharp and intense absorption mainly localized in the
red-NIR region associated with a strong fluorescence. These
peculiar properties, along with wide molecular structure
diversity, promoted their use as molecular components of a
9
is too large.
To date, no reactions dealing with MW synthesis of squaraines
are reported in the literature even if MW was already used for the
1
0
11
synthesis and functionalization of related cyanine dyes and
12
5
,6
their intermediates. However, there is still a great demand for
the development of a facile synthetic method for the preparation
of squaraine dyes above all for their increasing use in solar cell
great number of technological applications.
Conventional synthetic methods for the preparation of
symmetrical squaraine dyes are based on the condensation
between activated arenes, π-excessive heterocycles, or suitable
1
3
14
devices and PDT applications.
7
Herein, we report a common synthetic pathway for the
preparation of a wide color range of symmetrical and
unsymmetrical 2,3,3-trimethylindolenine-based squaraine dyes
anhydrobases and squaric acid. The commonly accepted
reaction mechanism involves the condensation of the first
electron-rich derivative with squaric acid leading to the formation
of a semisquaraine intermediate. Condensation with a second
equivalent of the electron-rich molecule affords the final
compound. It should be noted that the reaction of the
semisquaraine with the second equivalent of electron-rich
(
see Figure 1 and Figure S1; details of the substituents are
Received: May 21, 2015
Published: June 22, 2015
©
2015 American Chemical Society
3306
DOI: 10.1021/acs.orglett.5b01453
Org. Lett. 2015, 17, 3306−3309

Organic Letters
Letter
Table 1. General Quaternization Synthesis of Indolenines and
Benzoindolenines (for the Complete Entry List, See Table S2)
a
entry (compd)
Y
R
M
time (min)
yield (%)
1
7d
1
4
5
7
9
1
1
2
2
(3a)
(3a)
H
H
C H
A
B
A
B
B
A
B
B
B
1440
9
59
91
79
94
86
75
66
77
51
2
5
C H
2
5
Figure 1. General structures of synthesized compounds.
1
9
(3b)
COOH
COOH
COOH
COOH
COOH
COOH
COOH
C H
2
1440
20
5
(3b)
C H
2
5
(3c)
C H
4
20
reported in the Supporting Information and specified in the
following tables), using MW methodologies, which offers a
practical approach to the rapid preparation of a variety of
squaraines. Reaction time under MW was reduced from days to
minutes, with more than 2-fold improvement in product yields
when compared to conventional methods. Crystallization
methods were developed on the crude symmetrical and
unsymmetrical products, while some unsymmetrical dyes were
isolated with good purity only after column chromatography (for
a detailed account, see the Supporting Information).
9
1
7f
0 (3d)
1 (3d)
4 (5a)
6 (5b)
C H
8
660
25
17
17
5
C H
8
2
2
0
0
C H
2
40
C H
8
40
17
a
M: method A, Dean−Stark apparatus; B, MW heating.
19
synthesis of 3b, the yield increased from 79 to 94%, while
reaction times decreased from 24 h to 20 min. The presence of an
electron-withdrawing group on the heterocycle generally results
2,3,3-Trimethylindolenine and 5-carboxy-2,3,3-trimethyl-3H-
1
7b,22,23
indolenine are commercially available. For the other derivatives,
we exploited the Fischer indole synthesis that, for 5-bromo
derivatives (see Scheme S1), was carried out using microwaves
in a decrease of yields.
This general trend is also evident
with microwave heating. Moreover, while anhydrous conditions
seem to be important in the conventional synthesis, they were
uninfluential when the reaction was performed with microwaves,
thus simplifying reaction conditions. The elongation on the
halide chain, useful for broadening the range of structures in
order to extend their potential applications, also results in longer
15
instead of conventional heating procedures.
The general synthetic procedure for symmetrical and
unsymmetrical squaraines starts with the quaternization of the
indolenine ring. Thanks to the nitrogen quaternization, an
increase of the acidity of the methyl group will occur enabling the
19
reaction times and a decrease of yields; however, again, in the
quaternization with octyl iodide (3d) with MW, reaction times
16
bridge formation. Its conjugated base attacks the carbonyl of
the squaric acid or the diethyl squarate. The reaction has
traditionally been carried out with an excess of alkylating agent
19
shorten from 72 h to 25 min. With other indolenines, the
reaction similarly profited from MW conditions. For example,
the synthesis of 5a afforded the product in 77% yield, while in the
classical way the reaction simply does not proceed. This method
works well with a wide variety of alkylating agents, also in the
presence of sensitive functional groups like carboxyl, hydroxyl,
and hexyl.
17
with and without solvent over several hours or days.
With the purpose of investigating the reaction under
microwave conditions, we first performed a screening analysis
using Design of Experiment (DoE) on the reaction of 5-carboxy-
2,3,3-trimethylindolenine with 1-iodooctane. The influence of
temperature, time, and ratio between indolenine and solvent was
investigated on the yield of the reaction, keeping the indolenine/
iodooctane ratio constant (see Table S1). Heating at 155 °C for
Symmetrical squaraine dyes are usually obtained by classical
24
heating over several hours (18 h ) by reacting squaric acid with a
2-fold excess of the heterocyclic quaternary ammonium salts in
polar solvents such as acetic acid or high boiling point alcohols
such as butanol, often in a mixture with aromatic hydrocarbons
such as toluene or benzene in order to azeotropically remove the
water formed in the condensation reaction (Dean−Stark
2
5 min gave 62% yield as best result. Starting from these results, a
18
more detailed D-Optimal Design was set up for the reaction
with 1-iododecane, introducing the ratio between indolenine and
iodide as a further parameter. The results were processed
statistically, in order to delete factors whose influence was
unimportant (as time proved to be). The obtained model (see
Figure S2) suggests optimized conditions (solvent/reagent ratio
of 5, 155 °C, 40 min and large excess of iodide) that were checked
experimentally, obtaining an average yield (65%) even larger
than the software prediction. The optimized conditions were
then applied to the other quaternization reactions using the same
approach to the different iodides (see Table 1).
16
apparatus). In the case of MW heating, squaric acid with a 2-
fold excess of the quaternized indolenine and benzoindolenine is
overheated, in a closed vessel, in a 1-butanol/toluene mixture
(1:1, v/v), drastically reducing reaction time and increasing
2
0,21
yields (Table 2).
By choosing the right amount of solvent to
be used, we were able to obtain the direct crystallization of the
desired squaraine dye in the reaction vessel during the cooling
time. This crystallized product shows a high purity (see Figure
S3), avoiding the need for expensive and time-consuming
column chromatography purification.
This simple and general method works well for differently
functionalized (benzo)indolenines and opens up the way to
further modification in order to tune molecular properties as
Compared to the classical method of synthesis, microwave-
assisted quaternization afforded the target products in
comparable or higher yields, dramatically shortening reaction
1
0,21
times.
For example, in the synthesis of 3a, reaction times
17d
decreased from 24 h (entry 1) to 9 min (entry 4). In the
3
307
DOI: 10.1021/acs.orglett.5b01453
Org. Lett. 2015, 17, 3306−3309

Organic Letters
Letter
Table 2. General Synthesis of Symmetrical Squaraines (VG1
and VG10 Series)
If the synthesis of symmetrical squaraines is quite easy even
with conventional heating, the preparation of unsymmetrical
structures required a multiple step procedure. In fact, it requires
the isolation of the hemisquaraine intermediate, and its
condensation with a second activated molecule in a subsequent
step. Hemisquaraines are usually prepared directly in two-step
protocols based on squaric acid derivatives (esters or squarylium
chlorides). The hydrolysis of the resulting hemichloride or
a
16
hemisquarate affords the hemisquaraine.
We also tried to perform the synthesis through MW heating, in
a sealed tube, of a series of differently quaternarized hemi-
squarates starting from diethylsquarate in ethanol and triethyl-
amine as catalyst obtaining several kinds of hemisquarates in
good yield (see Table S3).
We noticed that working at 90 °C or higher, the short-chain
hemisquarate (6a) was not detected because we directly obtained
the corresponding symmetrical squaraine (VG1-C2). This
interesting observation inspired us to directly perform the
subsequent condensation reaction on the hemisquarate, in order
to obtain unsymmetrical squaraine dyes skipping the hydrolysis
step (Table 4).
b
entry (compd)
R
Y
M
time (min) yield (%)
c
24
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
(SQ-NH)
(SQ-NH)
H
H
H
H
H
Br
H
H
A
B
B
A
B
A
B
B
A
B
A
A
B
A
B
A
B
B
B
A
B
A
B
120
20
77
61
66
45
48
58
99
82
2
2
1
5
6
9
(Br-NH)
30
(R1)
C H
2
480
15
5
(R1)
C H
2
5
(VG1-C2)
(VG1-C2)
(Br-C2)
C H
2
COOH
COOH
Br
1080
20
5
C H
2
5
C H
2
30
Table 4. General Synthesis of Unsymmetrical Squaraines
5
(Br-C4)
C H
4
Br
9
0 (Br-C4)
C H
4
Br
30
900
1080
25
69
69
46
73
54
63
55
28
72
68
32
90
35
63
9
9
1
1 (VG1-C8)
2 (VG1-C8)
3 (VG1-C8)
4 (VG1-C10)
5 (VG1-C10)
6 (VG1-C12)
7 (VG1-C12)
8 (Br-C12)
9 (VG1-H6)
0 (VG10-C2)
1 (VG10-C2)
2 (VG10-C8)
3 (VG10-C8)
C H
8
COOH
COOH
COOH
COOH
COOH
COOH
COOH
Br
17
17
17
9
9
C H
8
C H
8
5
1
C H
1
360
20
0
21
21
25
25
25
C H
1
0
C H
1
1080
15
2
C H
1
2
C H
1
30
2
C H
6
COOH
COOH
COOH
COOH
COOH
20
9
5
5
2
2
0
0
C H
2
960
40
C H
2
C H
8
960
40
17
17
C H
8
a
b
Indolenine/squaric acid (1:1), toluene/butanol (1:1). M: method A,
c
time
(min)
yield
(%)
Dean−Stark apparatus, 120 °C; method B, MW, 160 °C. A: under
acid catalysis.
a
entry (compd)
R1
R2
Y
M
1
7f
1
(SQ01)
(SQ01)
C H
C H
H
H
A
B
A
B
B
A
1080
25
81
69
8
17
2
5
5
9
9
9
9
2
3
C H
C H
2
8
17
(VG1-C2-H6) C H5
C H
6
COOH
COOH
COOH
COOH
2
2
7
desired. In fact, this procedure can be successfully applied for
4 (VG1-C2-H6)
C
2
H
5
C
6
H
25
25
36
61
28
5
6
(VG1-C8-H6) C H
C H
6
the synthesis of core-substituted squaraines (Table 3).
8
17
(VG1-C10-
H6)
C H
C H
6
10
21
Table 3. General Synthesis of Symmetrical Squaraines with
Core Functionalization
7
(VG1-C10-
H6)
C H
C H
COOH
H
B
35
52
1
0
21
6
9
2
3
0
1
8
9
1
(VG13)
(VG5)
B
A
B
35
180
60
53
10
15
0 (VG5)
a
M: method A, Dean−Stark apparatus; method B, MW heating.
As an example, we synthesized SQ01 with a slightly modified
a
9,17f
entry (compd)
R
Y
M
time (min)
yield (%)
procedure from what has been reported in the literature.
If we
29
compare the two procedures, the one reported in literature needs
a further step which consists of hydrolysis of the hemisquarate in
hemisquaraine to be reactive with the quaternized salt. By using
MW heating, this step can be skipped to obtain the unsym-
metrical squaraine dye directly from the hemisquarate (see
Scheme S2).
1
2
3
4
(VG2-C4)
(VG2-C4)
(VG2-Br)
(VG2-Br)
C H
4
COOH
COOH
Br
A
B
A
B
780
30
15
20
51
31
9
9
5
5
C H
4
30
C H
2
300
30
C H
2
Br
a
M: method A, Dean−Stark apparatus; B, MW heating.
3
308
DOI: 10.1021/acs.orglett.5b01453
Org. Lett. 2015, 17, 3306−3309

Organic Letters
Letter
In conclusion, we have developed a practical MW-assisted
method for the rapid and efficient synthesis of both symmetrical
and unsymmetrical differently substituted squaraines in high
yield and purity. The ease of preparation and the possibility of
providing a good amount of pure dyes in a short time could lead
to the achievement of a large variety of novel structures that can
be easily tested in technological applications such as PDT and
DSC, where large amounts of these dyes are required.
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Corresponding Author
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Present Address
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ACKNOWLEDGMENTS
̈
■
We gratefully acknowledge financial support by the DSSCX
project (PRIN 2010-2011, 20104XET32) from MIUR, the
University of Torino (Ricerca Locale ex-60%, Bando 2013), and
Dyepower Consortium. We thank G. Ferraro, N. Havet, and G.
Magnano (University of Torino, Department of Chemistry) for
their help in the laboratory. N.B. thanks MIUR for partial
financial support of her research grant.
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DOI: 10.1021/acs.orglett.5b01453
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