Novel unsymmetrical leuco-TAM, (2E, 2′E)-2,2′-{(E)-4- phenylpent-2-ene-1,5-diylidene}bis(1,3,3-trimethylindoline) derivatives: Synthesis and structure elucidation

Article abstract of DOI:10.1016/j.dyepig.2011.01.002

Novel unsymmetrical leuco-TAM, (2E, 2′E)-2,2′-{(E)-4- phenylpent-2-ene-1,5-diylidene}bis(1,3,3-trimethylindoline) derivatives were synthesized from a reaction of commercially available 2-methylene-1,3,3- trimethylindoline (FB) and substituted cinnamaldehyde derivatives. The chemical structures of the resulting molecules were determined using 1D and 2D NMR spectroscopy experiments, including COSY, HMBC and NOESY. The compounds had the EEE configuration and were potent precursors for Cy5 TAM⁺ dyes. This is different from the Malachite green FB-analogs, which generally have a ZE configuration and are precursors to Cy3 TAM⁺ dyes. The formation of unsymmetrical LTAM molecules as the sole product suggests that the Michael-type addition of a FB molecule occurs on the δ-carbon of the α, β, γ, δ-unsaturated imminium salts, which were formed as an intermediate at the first step.

Full text of DOI:10.1016/j.dyepig.2011.01.002

Dyes and Pigments 90 (2011) 233e238
Contents lists available at ScienceDirect
Dyes and Pigments
journal homepage: www.elsevier.com/locate/dyepig
Novel unsymmetrical leuco-TAM, (2E, 20E)-2,20-{(E)-4-phenylpent-2-ene-1,
5-diylidene}bis(1,3,3-trimethylindoline) derivatives: Synthesis
and structure elucidation
*
Sam-Rok Keum , Min-Hyung Lee, So-Young Ma, Do-Kyung Kim, Se-Jung Roh
Department of Advanced Materials Chemistry, Korea University, Jochiwon, ChoongNam, Se-Jong Campus 339-700, South Korea
a r t i c l e i n f o
a b s t r a c t
Novel unsymmetrical leuco-TAM, (2E, 20E)-2,20-{(E)-4-phenylpent-2-ene-1,5-diylidene}bis(1,3,3-trime-
thylindoline) derivatives were synthesized from a reaction of commercially available 2-methylene-1,3,3-
trimethylindoline (FB) and substituted cinnamaldehyde derivatives. The chemical structures of the
resulting molecules were determined using 1D and 2D NMR spectroscopy experiments, including COSY,
HMBC and NOESY. The compounds had the EEE configuration and were potent precursors for Cy5 TAMþ
dyes. This is different from the Malachite green FB-analogs, which generally have a ZE configuration and are
precursors to Cy3 TAMþ dyes. The formation of unsymmetrical LTAM molecules as the sole product
Article history:
Received 4 October 2010
Received in revised form
3 January 2011
Accepted 5 January 2011
Available online 13 January 2011
Keywords:
suggests that the Michael-type addition of a FB molecule occurs on the
d-carbon of the a, b, g, d-unsatu-
Unsymmetrical leuco-TAM dye
The Malachite green FB-analog
The Cy5 TAMþ dye
rated imminium salts, which were formed as an intermediate at the first step.
Ó 2011 Elsevier Ltd. All rights reserved.
The
a, b, g, d-unsaturated imminium salts
COSY
HMBC
NOESY
1. Introduction
trimethylindoline) derivatives prepared from a reaction of excess
Fischer base and substituted salicylaldehydes [14e16].
Triarylmethane (TAM) compounds are used in a range of
chemical, pharmaceutical and life science industries including
thermal imaging and carbonless copying materials, etc. [1,2] They
are sometimes called “leuco-TAM (LTAM)” and have been applied as
either building-blocks or blocking groups in the synthesis of
a range of functional organic compounds [3e6].
Although significant progress has been made toward the
synthesis of symmetric LTAM dyes, the synthesis of unsymmetrical
LTAM dyes are still a challenge [17e19]. As part of an ongoing study
on the structural modification of leuco-TAM molecules, we report
the synthesis and structural elucidation of unsymmetrical leuco-
TAM, (2E,20E)-2,20-{(E)-4-phenylpent-2-ene-1,5-diylidene}bis(1,3,3-
trimethylindoline) derivatives, Un-LTAM 1e4, whose chemical
structures are shown in Scheme 1.
LTAM molecules can be oxidized to form TAMþ dyes, which have
medicinal activities e.g. photochemotheraphy agents in eye protec-
tion devices [7,8]. Among the TAMþ dye molecules available, Mala-
chite green (MG, 4-[(4-dimethylaminophenyl)-phenyl-methyl]-N,
N-dimethyl-aniline), which is generally called “aniline green”, is
used primarily as a dye in the textile industry [9,10]. MG is also useful
for treating fungal and bacterial infections in fish and fish eggs,
even though it is toxic. Consequently, there is strong demand for
substitutes for MG compounds. Many research groups [11e13], have
examined the structural modification of leuco-TAM molecules.
We previously reported the synthesis of symmetrical leuco-TAM
molecules, (2Z, 20E)-2,20-(2-phenyl propane-1,3-diylidene) bis(1,3,3-
2. Experimental section
2.1. Materials
Fischer base (2-methylene-1,3,3-trimethylindoline) and salicy-
laldehyde derivatives were purchased from Aldrich Chemical Co.
and used as received. p-Nitrocinnamaldehyde was obtained from
the nitration of cinnamaldehyde with sulfuric acid and fuming
nitric acid.
The following procedure was used to prepare the Un-LTAM
dyes (2Z,20E)-2,20-((E)-4-phenylpent-2-ene-1,5-diylidene)bis(1,3,3-
trimethylindoline) derivatives, 1e4. Fischer’s base (3.26Eꢀ3 kg,
* Corresponding author. Tel.: þ41 860 1332; fax: þ41 867 5369.
E-mail address: keum@korea.ac.kr (S.-R. Keum).
0143-7208/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.dyepig.2011.01.002

234
S.-R. Keum et al. / Dyes and Pigments 90 (2011) 233e238
Scheme 1. Chemical structures of the unsymmetrical LTAM molecules.
18.8 mmol) was added drop-wise to an ethanolic solution of cinna-
maldehyde (1.0Eꢀ3 kg, 7.5 mmol). The reaction mixture was stirred
in an ice bath for 5e6 h. The precipitate was filtered from the reac-
tion mixture and washed thoroughly with cold ethanol. Purification
was achieved by precipitation from acetone/hexane.
(2E,20E)-2,20-{(E)-4-(4-nitrophenyl)pent-2-ene-1,5-diylidene}
bis(5-chloro-1,3,3-trimethylindoline) Un-LTAM 4, orange, Yield
55%, M.p. 177 ꢁC, 1H NMR(500 MHz, CDCl3)
d 1.47(s, 3H), 1.52(s, 3H),
1.59(s, 3H), 3.02(s, 3H), 4.40(d, J ¼ 10.5 Hz, 1H), 4.78(q, J ¼ 6.3,
10.8 Hz,1H), 5.26(d, J ¼ 11.1 Hz,1H), 5.56(q, J ¼ 6.3,14.7 Hz, 1H), 6.40
(d, J ¼ 8.1 Hz,1H), 6.42(d, J ¼ 8.1 Hz,1H), 6.62(q, J ¼ 11.1, 14.7 Hz, 1H),
6.99(d, J ¼ 2.4 Hz, 1H), 7.00(d, J ¼ 2.1 Hz, 1H), 7.06(d, J ¼ 8.1 Hz, 1H),
7.07(d, J ¼ 8.1 Hz, 1H), 7.53(d, J ¼ 8.7 Hz, 1H), 8.18(d, J ¼ 8.7 Hz, 1H);
(2E,20E)-2,20-{(E)-4-phenylpent-2-ene-1,5-diylidene}bis(1,3,
3-trimethylindoline) Un-LTAM 1, brown, Yield 42%, M.p. 191 ꢁC, 1H
NMR(500 MHz, CDCl3)
d 1.49(s, 3H), 1.57(s, 3H), 1.61(s, 3H), 3.03(s,
3H), 4.48(d, J ¼ 10.8 Hz, 1H), 4.73(q, J ¼ 5.4, 10.5 Hz, 1H), 5.28(d,
J ¼ 11.4 Hz, 1H), 5.63(q, J ¼ 6.0, 15.0 Hz, 1H), 6.47(d, J ¼ 7.5 Hz, 1H),
6.51(d, J ¼ 7.8 Hz, 1H), 6.62(q, J ¼ 11.4, 15.0 Hz, 1H), 6.71(t, J ¼ 7.2 Hz,
1H), 6.74(t, J ¼ 7.2 Hz, 1H), 7.05(d, J ¼ 7.5 Hz, 1H), 7.10(t, J ¼ 7.5 Hz,
1H), 7.20(t, J ¼ 6.9 Hz, 1H), 7.35(d, J ¼ 16.2 Hz, 1H), 7.35(t, J ¼ 15.0,
13C NMR(125 MHz, CDCl3)
d 28.2, 28.4, 28.5, 28.6, 29.1, 29.4, 44.6,
45.1, 95.6, 96.2, 105.6, 106.1, 122.1, 123.1, 123.7, 123.8, 126.6, 127.5,
128.3, 128.5, 139.6, 140.1, 144.3, 144.7, 146.4, 153.4, 153.9, 154.8; ES-
Mass for C33H33Cl2N3O2, Mw: 574.5; 575 m/z; C, 68.99; H, 5.79; Cl,
12.34; N, 7.31 obtained C, 68.83; H, 5. 68; N, 7.28.
15.9 Hz, 1H); 13C NMR(125 MHz, CDCl3)
d 28.3, 28.4, 28.7, 28.8, 28.9,
29.2, 44.3, 44.9, 45.1, 95.5, 97.5, 104.6, 105.2, 117.9, 118.6, 121.5, 121.5,
125.8, 126.0, 127.7, 127.8, 128.0, 128.5, 130.1, 138.3, 138.7, 144.9, 145.9,
146.4, 152.7, 154.8; ES-Mass for C33H42N2, Mw: 466.7; 467 m/z; C,
84.93; H, 9.07; N, 6.00 obtained C, 84.87; H, 9.09; N, 5.89.
2.2. Measurements
The melting points were determined using a Nikon Labophot-2
polarizing microscope equipped with a Mettler FP82HT hot stage
and were uncorrected. All NMR data was acquired on a Varian
UNITY-INOVA 500 MHz spectrometer equipped with a 5 mm PFG H
{C, N} triple-resonance probe and a 5 mm CeN broadband probe.
Samples of the Un-LTAM 1e5 were dissolved in CDCl3. The NMR
experiments included 1H and 13C 1D NMR, DEPT, 2D COSY, 2D NOESY,
HETCOR, 2D HSQC, and 2D HMBC. The HSQC spectra and gradient
HMBC were acquired in phase-sensitive mode and magnitude
mode, respectively. The pulse conditions were as follows: for the 1H
NMR spectra, spectrometer frequency (SF) ¼ 500.13 MHz, acquisi-
tion time (AQ) ¼ 2.936 s, relaxation delay (RD) ¼ 2.0 s, 90ꢁ pulse
(2E,20E)-2,20-{(E)-4-phenylpent-2-ene-1,5-diylidene}bis
(5-chloro-1,3,3-trimethylindoline) Un-LTAM 2, brown, Yield 46%,
M.p. 186 ꢁC, 1H NMR(500 MHz, CDCl3)
d 1.46(s, 3H), 1.54(s, 3H), 1.61
(s, 3H), 3.00(s, 3H), 4.48(d, J ¼ 10.8 Hz, 1H), 4.69(q, J ¼ 6.6, 10.5 Hz,
1H), 5.26(d, J ¼ 11.7 Hz, 1H), 5.62(q, J ¼ 6.6, 14.4 Hz, 1H), 6.36(d,
J ¼ 8.4 Hz, 1H), 6.39(d, J ¼ 6.3 Hz, 1H), 6.55(q, J ¼ 11.7, 14.4 Hz, 1H),
6.97(d, J ¼ 2.1 Hz, 1H), 6.98(d, J ¼ 2.1 Hz, 1H), 7.21(t, J ¼ 6.9 Hz, 1H),
7.34(d, J ¼ 6.9 Hz, 1H), 7.35(t, J ¼ 6.9 Hz, 1H); 13C NMR(125 MHz,
CDCl3)
d 28.2, 28.3, 28.5, 28.7, 29.1, 29.3, 44.4, 45.0, 45.0, 96.1, 98.0,
105.3, 105.9, 121.2, 122.0, 123.0, 123.5, 126.6, 127.0, 127.3, 127.4,
127.5, 128.2, 128.3, 140.0, 140.3, 144.5, 144.9, 145.9, 151.1, 153.9; ES-
Mass for C33H34Cl2N2, Mw: 529.5; 531 m/z; C, 74.85; H, 6.47; Cl,
13.39; N, 5.29 obtained C, 74.79; H, 6.38; N, 5.18.
width ¼ 6.0 s, spectral width (SW) ¼ 5580.4 Hz, and Fourier trans-
m
form (FT) size ¼ 16 384; for the 13C NMR spectra, SF ¼ 125.75 MHz,
AQ ¼ 1.042 s, RD ¼ 2.0 s, 90ꢁ pulse width ¼ 6.0
s, SW ¼ 31446.5 Hz,
m
(2E,20E)-2,20-{(E)-4-(4-nitrophenyl)pent-2-ene-1,5-diylidene}
bis(1,3,3-trimethylindoline) Un-LTAM 3, orange, Yield 53%, M.p.
line broadening (LB) ¼ 3.0 Hz, and FT size ¼ 32768; for the 1He1H
COSY and NOESY spectra, AQ ¼ 0.092 s, RD ¼ 1.5 s, SW ¼ 5580.4 Hz,
182 ꢁC,1H NMR(500 MHz, CDCl3)
d
1.50(s, 3H),1.54(s, 3H),1.61(s, 3H),
90ꢁ pulse width ¼ 6.0
s, number of points (NP) ¼ 1024, number of
m
3.05(s, 3H), 4.39(d, J ¼ 11.1 Hz, 1H), 4.83(q, J ¼ 6.3, 10.5 Hz, 1H), 5.28
(d, J ¼ 11.7 Hz,1H), 5.56(q, J ¼ 6.3,14.7 Hz,1H), 6.51(d, J ¼ 7.2 Hz,1H),
6.54(d, J ¼ 7.5 Hz, 1H), 6.67(q, J ¼ 11.7, 14.4 Hz, 1H), 6.75(t, J ¼ 7.2 Hz,
1H), 6.77(t, J ¼ 7.2 Hz, 1H), 7.07(d, J ¼ 7.2 Hz, 1H), 7.13(t, J ¼ 7.8 Hz,
1H), 7.55(d, J ¼ 8.4 Hz,1H), 8.19(d, J ¼ 8.7 Hz,1H); 13C NMR(125 MHz,
increments (NI) ¼ 256, and the mixing time of NOESY ¼ 0.8 s; and for
the HMQC and HMBC spectra, AQ ¼ 0.092 s, RD ¼ 1.8 s, SW ¼ 5580.4
(1H) and 31253.9 (13C) Hz, NP ¼ 1024, and FT size ¼ 1024 ꢂ1024.
3. Results and discussion
CDCl3) d 28.3, 28.5, 28.6, 28.7, 29.0, 29.2, 44.4, 45.1, 94.9, 95.6, 104.9,
105.4, 118.3, 118.8, 121.5, 121.6, 123.9, 126.9, 127.8, 128.6, 128.8, 138.0,
138.5,145.7,146.1,146.3,153.8,154.4,155.6; ES-Mass for C33H35N3O2,
Mw: 505.7; 506 m/z; C, 78.38; H, 6.98; N, 8.31 obtained C, 78.29; H,
6.91; N, 8.24.
3.1. Synthesis of unsymmetrical leuco-TAM dyes
Generally, leuco-TAM (LTAM) dyes can be obtained from
a reaction of a molar excess of Fischer base and substituted aryl
Scheme 2. General scheme for the formation of a Cy3 TAMþ, via a LTAM molecule.

S.-R. Keum et al. / Dyes and Pigments 90 (2011) 233e238
235
Scheme 3. Synthetic scheme of the symmetric and unsymmetrical LTAM molecules.
Scheme 4. Mechanistic processes of the Michael-type addition of a FB molecule to the
b and d carbon of the a, b, g, d-unsaturated imminium salts B to form symmetrical and
unsymmetrical LTAM dyes, respectively.
aldehydes according to the known procedure [14,15]. The prepared
symmetric LTAM dyes are the precursor of the Cy3 TAMþ dyes [20],
where three carbon units are connected to two symmetric FB
groups, as shown in Scheme 2.
For the structural modification of leuco-TAM molecules, an
attempt was made to prepare a styryl ring pendant LTAM (viz.
R ¼ styryl in Scheme 2) instead of the phenyl ring, which was
expected to have elongated conjugation from the Nþ center of the
FB ring to the phenyl ring.
Surprisingly, unsymmetrical LTAM 1e4 were obtained from
a reaction of excess Fischer’s base with the substituted cinna-
maldehydes (CA), as shown in Scheme 3. The symmetrical LTAM
consisted of two symmetric FB rings on the central carbon, where
a styryl ring was located, whereas unsymmetrical LTAM had two
different FB derivatives on the central carbon, a 1,3,3-trimethyl-2-
3.2. Structural elucidation of unsymmetrical LTAM molecules
by 1H NMR spectroscopy
According to earlier reports [14], Malachite green FB-analogs,
(2Z, 20E)-2,20-(2-phenyl propane-1,3-diylidene) bis(1,3,3- trime-
thylindoline) derivatives (Fig. 1), show the very characteristic 1H
NMR resonance patterns of the three adjacent protons, two N-
methyl and diastereotopic gem-dimethyl groups. Therefore, these
N-methyl and three consecutive protons (Ha, Hb and Hc), or
sometimes gem-dimethyl peaks can be used to discriminate
between the diastereomers. Namely the methylene protons Ha and
Hb resonate at w4.3 and w4.4 ppm, respectively, as two doublets
and the central proton Hc is observed as a doublet of doublets
at w5.4 ppm. Two N-methyl groups are well separated in the range
of 1.3e1.4 and 1.5e1.7 ppm, for the E- and Z- indoline groups,
respectively. The four diastereotopic methyl groups are also sepa-
rated distinctively in the range of 1.32e1.44 and 1.50e1.70 ppm for
the E- and Z- indoline groups, respectively.
methyleneindoline and
group.
a
2-allylidene-1,3,3-trimethylindoline
Interestingly, no symmetrical LTAM dyes were formed. In terms
of the mechanism, symmetrical LTAM molecules could be formed
from the Michael-type addition of the second Fischer base mole-
The spectrum of the EE diastereomer shows a doublet and
triplet at w4.5 and w5.1 ppm for the Ha/Hb and Hc, respectively.
The N-methyl groups are collapsed into a single resonance at
3.0 ppm, and two, instead of four, diastereotopic methyl groups are
shown at 1.4 and 1.6 ppm, for the EE diastereomer.
cule onto the
On the other hand, unsymmetrical LTAM molecules are expected
from carbon-attack of -unsaturated imminium salts (B).
b carbon of a, b, g, d-unsaturated imminium salts (B).
d
a, b, g, d
Another possible route for the formation of symmetric LTAM might
be direct nucleophilic attack of a FB molecule toward the carbinol
carbon of the carbinol intermediate (A) formed in the presence of
a Lewis acid. Scheme 4 shows the mechanistic processes for the
formation of symmetric and unsymmetrical LTAM dyes.
Experimentally, unsymmetrical LTAM molecules were formed
as the sole product. This suggests that the Michael-type addition of
a FB molecule occurs on the
d -carbon and not on the b-carbon of
Fig. 1. The ZE, EE and ZZ diastereomers of the Malachite green FB-analogs.
the -unsaturated imminium salts.
a, b, g, d

236
S.-R. Keum et al. / Dyes and Pigments 90 (2011) 233e238
The symmetrical vinyl-analog LTAM (in Scheme 2) are expected
to have a similar pattern for the three consecutive protons in A in
Fig. 2, in addition to the vinyl protons of the styryl group. However,
the 1H NMR spectra of the synthesized unsymmetrical LTAM 1e4
dyes displays very distinct signals for the five closely-correlated
protons of Ha, Hb, Hc, Hd and He, as indicated by B in Fig. 2. They are
well-separated over a wide range, w4.4e6.8 ppm.
COSY was used to identify the protons belonging to the aromatic
rings, particularly the five consecutive protons on the connecting
carbon chain between the two indoline groups. Hb was correlated
with the two Ha and Hc protons simultaneously. Similarly, Hd was
also correlated with Hc and He. This correlation pattern could not
be expected from the structure of symmetrical LTAM. Fig. 3 pres-
ents a typical COSY spectrum of Un-LTAM 2 in the range,
4.0e8.5 ppm.
HMBC experiments identify which protons belong to which ring
component. The remaining chemical shift assignments within the
FB rings, A and B, of the molecules were mostly made from the
HMBC and NOESY data. Since the A and B rings are not identical,
HMBC was needed to differentiate between the two different FB
groups of the molecules. As a representative example, the HMBC
experiment for Un-LTAM 4 showed the C20 correlated with Hd, H80,
H90, and H100 of ring A and C2 correlated with Hb, H8, H9, and H10
in ring B. Similarly, C3 in ring A correlated with Ha, H-4, H-8 and H-
9, and C30 in ring B correlated with He, H40, H80, and H90. HMBC
correlated C3a of ring A with H7, H8 and H9 of ring A, and C3a0 of
ring B with H70, H80, and H90 in ring B.
Fig. 2. The five correlated protons (B) of unsymmetric Un-LTAM 1e4 examined,
compared to the three correlated protons (A) of the symmetric FB-analog.
The gem-dimethyl peaks of ring B resonated in the range of
1.52e1.57 and 1.59e1.61 ppm. This suggests that ring B has an E
configuration and those gem-dimethyl protons are located in prox-
imity to the aromatic ring and are thus deshielded (
compared to the reported value [14] of the Z-configuration of the
FB-analog.
D
ppm ¼ w0.15)
Fig. 4 shows the possible structures with five consecutive
protons and one FB unit with an E configuration.
Among the three possible structures of LTAM molecules in Fig. 4,
symmetrical structure A could be ruled out from the 1H NMR and
COSY experiment, as mentioned above.
The final question remains as to whether the configuration of
the double bonds at the position 2e700 is E or Z. NOESY was used to
solve this problem. Fig. 5 shows the 2D NOESY of Un-LTAM 4 with
the spatial correlations of Ha-H10, Hb-H8/H9, H80/H90-H200/600, and
H100eHe. In addition, an unexpected correlation HbeHe was found.
This NOE phenomenon indicates an EEE geometry counting from
the A to B rings.
All data obtained from the COSY, NOE and NOESY showed that
the structure of the reaction product is coincident with unsym-
metrical (EEE)-LTAM, which is C in Fig. 5.
For Un-LTAM 4, the gem-dimethyl groups H8 & H9 are not dia-
stereotopic and equivalent with a difference of Dd ¼ >0.01 ppm
because ring A is located adjacent to the chiral center C1000.
Although ring B is located at the proximity of the chiral center, C1000,
the gem-dimethyl groups, H80 & H90, are diastereotopic and two
Fig. 3. A 1He1H COSY spectrum of Un-LTAM 4 in the range of 4.0e8.5 ppm.
Fig. 4. 1He1H NOE (blue-colored dot) and 1He1H COSY (red-colored dot) correlation expected for symmetrical vinyl-analog (ZEE)-LTAM (A), unsymmetrical (ZEE)-LTAM (B) and
unsymmetrical (EEE)-LTAM (C). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

S.-R. Keum et al. / Dyes and Pigments 90 (2011) 233e238
237
Fig. 5. NOESY of Un-LTAM 4, showing the spatial correlations of Ha-H10, Hb-H8/H9, H80/H90-H200/600, and H100eHe.
different NMR signals are observed, i.e. 1.52 and 1.59 ppm. Two
well-separated gem-dimethyl peaks in the range, 1.52e1.59 ppm,
were also fully assigned from the strong NOE correlation between
the protons, H80/H90 and H200/H600.
may behave as an extended conjugation of TAMþ molecules, as
indicated in Fig. 6.
Structurally, the symmetric and unsymmetric TAMþ dyes in this
work belong to a Cy3 and Cy5 dye, respectively, according to Ernst,
et al. [21] for closed chain cyanines. It was reported that Cy3 is
excited maximally at 550 nm and emits maximally at 570 nm in the
In summary, the prepared Un-LTAM 1e4 molecules belonging to
Cy5 dyes have an EEE configuration, which is different from the
Malachite green FB-analogs, which are Cy3 dyes with a ZE config-
uration as the major diastereomer.
Table 1 lists the selected 1H resonances and coupling constants
for Un-LTAM 1e4 in CDCl3.
Table 1
Selected 1H resonances (
CDCl3.
d, in ppm) and coupling constants (Hz) of Un-LTAM 1e4 in
3.3. Potent unsymmetrical TAMþ dyes
Ringa
Proton Un-LTAM 1 Un-LTAM 2 Un-LTAM 3 Un-LTAM 4
E1
8-Me
9-Me
N-Me
1.49
1.49
3.03
1.46
1.46
3.00
1.50
1.50
3.05
1.47
1.47
3.02
Typical TAM dyes showed a range of structural forms, such as (a)
leuco-, (b) carbinol-, and (c) chromatic- forms. Indeed, the struc-
tures of the TAM compounds are very important because they are
related to their chemical and biological properties, such as how
they are absorbed in the body and how reactive they are [20]. For
example, malachite green (MG) is commonly in the chromatic form,
and is generally called a green dye. However, it is converted to other
forms when it is absorbed into the body. The first carbinol-form
spreads across the cell membranes faster and then metabolizes into
a leuco-form of MG.
In UVeVis spectroscopy, MG shows absorption maxima at 620
and 430 nm for the x- and y-band, respectively, whereas the
absorption maxima of the vinyl-log of MG are red-shifted for both
the x- and y-bands, i.e. 651 and 488 nm, respectively. This suggests
that the vinyl effects of a vinyl unit may, to a large extent, behave as
an extended conjugation for both the x- and y-bands. The vinyl unit
E2
80-Me
90-Me
N0-Me
1.61
1.57
3.03
1.61
1.54
3.00
1.61
1.54
3.05
1.59
1.52
3.02
2-pent enyl Ha
5.28
6.62
5.63
4.73
4.48
5.26
6.55
5.62
4.69
4.48
5.28
6.67
5.56
4.83
4.39
5.26
6.62
5.56
4.78
4.40
Hb
Hc
Hd
He
b
JHaeHb
JHbeHc
JHceHd
JHdeHe
11.4
15.0
6.00
10.7
11.7
14.4
6.60
10.7
11.7
14.4
6.30
10.8
11.1
14.7
6.30
10.7
b
b
b
a
The E1 and E2 denote the left and right ring (in Scheme 1) of the Un-LTAM
molecules, respectively.
b
Coupling constants in Hz.

238
S.-R. Keum et al. / Dyes and Pigments 90 (2011) 233e238
Fig. 6. Chemical skeleton for the NwNþ and C(phenyl)wNþ responsible for the x- and y-band, respectively, in the absorption spectrum.
[7] Indig GL, Anderson GS, Nichols MG, Bartlett JA, Mellon WS, Sieber F. Effect of
orangeered part of the spectrum, whereas Cy5 is excited maximally
at 649 nm and emits maximally at 670 nm, which is in the red part
of the spectrum. Therefore, the x-band of the Un-TAMþ are
expected to be higher than 650 nm and 550 nm, for the y-band and
x-band, respectively. A more detailed UVeVis spectroscopic study
of the Un-TAMþ dyes will be needed.
molecular structure on the performance of triarylmethane dyes as therapeutic
agents for photochemical purging of autologous bone marrow grafts from
residual tumor cells. Journal of Pharmaceutical Sciences 2000;89:88e99.
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security inks in the presence of other colorants, on currency and fabrics, by
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1172e8.
4. Conclusion
[10] Kumar D, Singh AC, Usha PN, Tandon R, Triphathi K. Primary amyloidosis
presenting with predominant lymphnodal masses. Journal of Association of
Physicians of India 2005;53:312e3.
[11] Nair V, Abhilash KG, Vidya N. Practical synthesis of triaryl- and triheteroar-
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(III) chloride. Organic Letters 2005;7:5857e9.
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domain: highly selective alkylation of arenes and heteroarenes with aromatic
aldehydes. Journal of Organic Chemistry 2007;72:3100e3.
Unsymmetrical LTAM 1e4 molecules were obtained as the sole
product from a reaction of excess Fischer’s base with substituted
cinnamaldehydes. The chemical structures of these compounds
were determined by 1D and 2D NMR experiments, including COSY,
HMBC and NOESY. The prepared compounds had the EEE configu-
ration and were potent precursors of a Cy5 TAMþ dyes. This is
different from the Malachite green FB-analogs, which generally
have a ZE configuration. The formation of unsymmetrical LTAM
molecules as the sole product suggests that the Michael-type
[13] Liu CR, Li MB, Yang CF, Tian SK. Catalytic selective bis-arylation of imines with
anisole, phenol, thioanisole and analogues. Chemical Communications; 2008:
1249e51.
[14] Keum SR, Roh SJ, Lee MH, Saurial F, Buncel E. 1Hand 13C NMR assignments for
new heterocyclic TAM leuco dyes, (2 Z,2_ E)-2,2_-(2-phenyl propane-1,3-
diylidene)bis(1,3,3-trimethylindoline) derivatives. Part II. Magnetic Reso-
nance in Chemistry 2008;46:872e7.
addition of a FB molecule occurs on the d-carbon of the a, b, g, d-
unsaturated imminium salts, which were formed as an interme-
diate in the first step.
[15] Keum SR, Roh SJ, Kim YN, Im DH, Ma SY. X-ray crystal structure of hetaryl
leuco-TAM dyes, (2Z,20 E)-2,20-(2-phenylpropane-1,3-diylidene) bis(1,3,3-tri-
methyl indoline) derivatives. Bulletin of the Korean Chemical Society
2009;30:2608e12.
Acknowledgments
[16] Keum SR, Roh SJ, Ma SY, Kim DK, Cho AE. Diastereomeric isomerization of
hetaryl leuco-TAM dyes, (2Z, 20E)-2,20-(2-phenyl propane-1,3-diylidene)bis
(1,3,3-trimethylindoline) derivatives in various organic solvents. Tetrahedron
2010;66:8101e7.
[17] Lin S, Lu X. Cationic Pd(II)/bipyridine-catalyzed addition of arylboronic acids
to arylaldehydes. One-pot synthesis of unsymmetrical triarylmethanes. Jour-
nal of Organic Chemistry 2007;72:9757e60.
[18] Li Z, Duan Z, Kang J, Wang H, Yu L, Wu Y. A simple access to triarylmethane
derivatives from aromatic aldehydes and electron-rich arenes catalyzed by
FeCl3. Tetrahedron 2008;64:1924e30.
[19] Sun FL, Zheng XJ, Gu Q, He QL, You SL. Enantioselective synthesis of unsym-
metrical triarylmethanes by chiral Bronsted acids. European Journal of
Organic Chemistry; 2010:47e50.
This study was supported by a Korea University Grant (2009).
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