Meta-Substituted triphenylamines as new dyes displaying exceptionally large Stokes shifts

Article abstract of DOI:10.1016/j.tetlet.2010.06.082

A straightforward synthesis of fluorescent tris-meta-substituted triphenylamines (m-TPAs) is presented. These new fluorophores display a unique feature that is a remarkably high Stokes shift up to 250 nm, as compared to their para counterparts. Although the meta substitution is made at the expense of the quantum yield, the latter is maintained at an appreciable level (5%) making the m-TPAs a new class of fluorophores adaptable to a large range of applications from biology to materials science.

Full text of DOI:10.1016/j.tetlet.2010.06.082

Tetrahedron Letters 51 (2010) 4429–4432
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
meta-Substituted triphenylamines as new dyes displaying exceptionally
large Stokes shifts
*
Guillaume Bordeau, Rémy Lartia , Marie-Paule Teulade-Fichou
Institut Curie, CNRS UMR-176, bat 110, Centre Universitaire, 91405 Orsay Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A straightforward synthesis of fluorescent tris-meta-substituted triphenylamines (m-TPAs) is presented.
These new fluorophores display a unique feature that is a remarkably high Stokes shift up to 250 nm, as
compared to their para counterparts. Although the meta substitution is made at the expense of the quan-
tum yield, the latter is maintained at an appreciable level (5%) making the m-TPAs a new class of fluoro-
phores adaptable to a large range of applications from biology to materials science.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 7 May 2010
Revised 14 June 2010
Accepted 16 June 2010
Available online 20 June 2010
Keywords:
Triphenylamines
Fluorescence
Stokes shift
Rapid development of fluorescence imaging and microscopy
technologies in recent years has stimulated the emergence of
sophisticated new fluorescent dyes displaying specific advantages
including high quantum yield (UF), high photostability, long life-
time, excimer formation, biocompatibility, chemical conjugability,
etc.
phore leads to the emission of the fourth, resulting in an apparent
Stokes shift of 240 nm. However, an intense research effort has
been focused on increasing DSt of common families of dyes.1,8
Consequently, there is an urgent need for simpler molecular
fluorophores displaying high DSt while maintaining appreciable
quantum yield. In regard to the wide range of possible applications
for such dyes, their synthesis should be straightforward and versa-
tile. For example, fluorescence properties of a common fluorogenic
scaffold could be easily tuned by the incorporation of peripheral
groups that modulate the electronic features of the ground and ex-
cited states.
In our ongoing research on fluorescent triphenylamine (TPA)
derivatives,9,10 we were pleased to find that the TPA fluorescence
properties could be dramatically modified by switching from the
extensively studied 4,40,400-substitution pattern toward the previ-
ously unknown 3,30,300-substituted derivatives (Scheme 1).
It is generally accepted that electron-donor and electron-accep-
tor groups linked to a benzene ring in a meta fashion are not con-
jugated. This is true in ground state. However, the work of
Zimmermann et al.11,12 and Yates and Sinha13 demonstrated that
electron delocalization occurred in the excited state.
As an example, fluorescence properties of the well-known
Green Fluorescence protein (GFP) have been elegantly tuned by
turning its natural para substitution pattern into the unusual
meta.14 The so-called ‘meta effect’ has been further investigated
by Lewis15,16 and others17,18 on various stilbene derivatives substi-
tuted on position 3 by a donor or acceptor group. They demon-
strated that the meta19 isomer of a TPA/stilbene hybrid, namely
(N,N-diphenylamino)stilbene, exhibits higher DSt than the para20
(107 nm vs 33 nm in hexane). This prompted us to further investi-
gate the fluorescence properties of the little studied 3,30,300-tris-
However, most of the dyes used in microscopy notably for bio-
logical purposes (fluorescein, rhodamine, boron-dipyrromethene
dyes, and cyanines) display a small Stokes shift (DSt), that is, a
small difference between the maximum of the lowest-energy
absorption band and the maximum of the emission band. Indeed,
in the case of the dyes listed above, DSt often lies in the 10–
50 nm range. This results in the overlap of both excitation and
emission bands leading to many disadvantages such as self-
quenching and reabsorption effects, as well as measurement error
due to excitation light and scattered light.1,2 This can be partially
corrected by the use of filters, which in turn may significantly de-
crease the collected emission especially in the case of a very small
Stokes shifts and thus reduce the detection sensitivity to a great
extent. In addition, the overlapping bands are incompatible with
applications for materials such as solid-state fluorescence3 or or-
ganic scintillators development4,5 which require fluorophores hav-
ing well-separated absorption and emission bands. To circumvent
this issue, strategies based on sophisticated systems containing up
to four dyes have been devised.6,7 Owing to three consecutive
transfers of excitation energy (FRET), excitation of the first fluoro-
* Corresponding author. Tel.: +33 1 69 86 30 86; fax: +33 1 07 53 81.
E-mail address: marie-paule.teulade-fichou@curie.fr (M.-P. Teulade-Fichou).
Present address: Département de Chimie Moléculaire, UMR 5250, ICMG FR 2607,
CNRS, Université Joseph Fourier, BP 53, 38041 Grenoble Cedex 9, France.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.082

4430
G. Bordeau et al. / Tetrahedron Letters 51 (2010) 4429–4432
CHO
OEt
OEt
(i)
OHC
N
Br
1m
CHO
O
P
OEt
OEt
(ii)
O
(ii)
N
P
N
X
OEt
2', X = O
3', X = S
4'
OEt
N
X
N
N
N
X
N
N
N
X
4m
2m, X = O
3m, X = S
N
Scheme 1. Reagents and conditions: (i) Pd2(dba)3, P(C12H9)(t-Bu)2, LiNH2, t-BuONa, dioxane, 85 °C, 30 h, 64%; (ii) phosphonate, NaH, THF, rt, 48 h, 58–64%.
substituted-TPA (m-TPA). The synthesis of the m-TPAs relies on the
key intermediate 3,30,300-tris-formyl-TPA (1m) which is easily ob-
tained in one step by a Buchwald reaction between the ammonia
equivalent LiNH2 and an aryl bromide followed by in situ deprotec-
tion (Scheme 1).21,22 It should be noted that the para counterpart
1p (Scheme 2), could also be synthesized in only one step which
compares favorably with the previously described two-step syn-
thesis.23,24 Starting from 1m, the use of the Wittig reaction allows
incorporation of various groups and hence the tuning of fluores-
cence properties.25 In this way, compounds 2m–4m were obtained
with a pure E,E,E stereochemistry and their photophysical proper-
ties compared to that of the para analogs 2p–4p previously synthe-
sized (Scheme2).10
Considering the m and p series, several observations can be
drawn (Fig. 1). Firstly the emission spectra of both the series are
identical in shape and reach their maxima at a similar wavelength.
Quantum yields (UF) of the m series are around ten times lower as
compared to those of their p counterparts (Table 1) but nonethe-
less stay in the range of the quantum yields of the widely used
stains Cy326 or thiazole orange27 (values near 0.05).
to strongly depend on the electron delocalization between the
branches (involving the lone pair of the central nitrogen) and on
the rate of the trans–cis photoisomerization in the excited state
that causes non-radiative decay.20
It might well be that these two features are modified for the
present vinyl TPA series while shifting from para to meta substitu-
tion. On the contrary, the absorption spectra maxima of the m ser-
ies are strongly blue-shifted by about 100 nm as compared to those
of their p counterparts and as expected from the lower degree of
electron delocalization within the meta connected branches in
the ground state. Finally, both m and p compounds exhibit
unstructured absorption spectra and very high molar extinction
coefficients that are significantly larger for compounds 2m and
4m (up to 100,000 Mꢀ1 cmꢀ1) as compared to their 2p and 4p
isomers.
Interestingly, while absorption and emission spectra of the p ser-
ies overlap to some extent, those of the m series are totally resolved
Table 1
Spectroscopic properties of m-TPA (2m–4m) and p-TPA (2p–4p)a
This fluorescence decrease due to para- versus meta-substituent
modification has been already observed in certain cases.18,20 In
particular, in the case of structurally related N-diphenyl trans-
aminostilbenes, the fluorescence quantum yields have been shown
Absorbanceb
Emissionc
DSt (nm)d
k (nm)
e
(Mꢀ1 cmꢀ1
)
k (nm)
UF
2m
2p
3m
3p
311
424
331
432
325
406
332
327
108,270
88,980
96,610
97,260
91,570
59,450
499
518
527
534
509
511
568
572
0.05
0.50
0.04
0.52
0.06
0.51
188
94
196
102
184
105
236
245
4m
4p
1p
R = -CHO
R
3me
3mf
(X = O)
N
2p
3p
4p
R =
X
a
b
c
d
e
f
Recorded in chloroform at rt.
At 10 M.
At 1 M.
(X = S)
l
l
N
R =
Stokes shift.
In EtOH.
R
R
N
In MeCN. Quantum yields were measured using quinine bisulfate in 1 N H2SO4
as a reference.
Scheme 2.

G. Bordeau et al. / Tetrahedron Letters 51 (2010) 4429–4432
4431
A
B
C
1
0.8
0.6
0.4
0.2
0
1
0.8
0.6
0.4
0.2
0
400
450
500
550
600
650
700
250
350
450
550
650
750
wavelength (nm)
Wavelength (nm)
Figure 2. Normalized emission spectra of 2m (1 lM) recorded in various solvents
(from left to right: toluene, chloroform, ethyl acetate, dichloromethane, ethanol,
acetonitrile, DMSO) at rt.
1
0.8
0.6
0.4
0.2
0
tionally large DSt. This is illustrated herein by the three compounds
(2m, 3m, and 4m) which feature the m-TPA scaffold thus display-
ing base-to-base resolved absorption and emission spectra. Conse-
quently, the new family of m-TPA represents a robust starting
point for the development and fluorescence engineering of dyes
circumventing reabsorption problems.
Acknowledgment
250
350
450
550
650
750
The authors wish to thank Dr. Jason Martin for careful reading
of the manuscript.
Wavelength (nm)
References and notes
1
0.8
0.6
0.4
0.2
0
1. Peng, X.; Song, F.; Lu, E.; Wang, Y.; Zhou, W.; Fan, J.; Gao, Y. J. Am. Chem. Soc.
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F.; Tauc, P.; Teulade-Fichou, M.-P. ChemBioChem 2007, 8, 424–433.
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Charra, F.; Teulade-Fichou, M. P. J. Org. Chem. 2008, 73, 1732–1744; (b) Leriche,
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12. Zimmerman, H. E. J. Am. Chem. Soc. 1995, 117, 8988–8991.
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250
350
450
550
650
750
Wavelength (nm)
Figure 1. Normalized absorption spectra (dashed lines, recorded at 10 M dye
concentration) and fluorescence spectra (plain lines, recorded at 1 lM dye
concentration) of m-TPA (in red) and their para counterparts (in blue) recorded in
dichloromethane at room temperature. Compounds 2m, 2p (A); 3m, 3p (B); and
4m, 4p (C).
l
due to their impressive DSt. This phenomenon should reduce the
reabsorption effect to almost zero, thereby enabling the use of these
dyes in the aforementioned applications. DSt was further evaluated
by solvatochromism studies performed on 3m (Fig. 2, Table 1).
While absorption maxima are virtually independent from the
solvent used, emission maxima are red-shifted with increasing
polarity of the solvent, thus providing evidence for a strong inter-
nal charge transfer in the lowest singlet excited state.19,20 In partic-
ular, a DSt value of 245 nm was obtained with 3m in acetonitrile;
15. Lewis, F. D.; Yang, J. S. J. Am. Chem. Soc. 1997, 119, 3834–3835.
16. Lewis, F. D.; Kalgutkar, R. S.; Yang, J. S. J. Am. Chem. Soc. 1999, 121, 12045–
12053.
17. Crompton, E. M.; Lewis, F. D. Photochem. Photobiol. Sci. 2004, 3, 660–668.
18. Ohshima, A.; Ikegami, M.; Shinohara, Y.; Momotake, A.; Arai, T. Bull. Chem. Soc.
Jpn. 2007, 80, 561–566.
19. Yang, J. S.; Liau, K. L.; Tu, C. W.; Hwang, C. Y. J. Phys. Chem. A 2005, 109, 6450–
6456.
20. Yang, J. S.; Chiou, S. Y.; Liau, K. L. J. Am. Chem. Soc. 2002, 124, 2518–2527.
21. Huang, X.; Buchwald, S. L. Org. Lett. 2001, 3, 3417–3419.
22. Synthesis of 1m: In dry and degassed dioxane (4 mL) were suspended Pd2(dba)3
(121 mg, 132 lmol, 3%) and P(o-C6H4–C6H5)(t-Bu)2 (100 mg, 335 lmol, 7.5%).
this impressively high DSt largely exceeds that of most other dyes
After 15 min of stirring were added 3-bromobenzaldehyde diethylacetal
(2.85 mL, 13.98 mmol, 3.2 equiv), lithium amide (100 mg, 4.35 mmol,
1 equiv), and t-BuONa (1.25 g, 13.06 mmol, 3 equiv). The resulting
suspension was heated at 85 °C for 30 h. Then Pd2(dba)3 (121 mg) and P(o-
C6H4–C6H5)(t-Bu)2 (100 mg) were added and the mixture was heated for 16
additional hours. The mixture was cooled down to room temperature, diluted
1,4,5,28–30
designed to exhibit high DSt
.
In conclusion, the novel 3,30,300-trisformyl compound 1m is
found to be a versatile and easy-to-synthesize precursor enabling
the preparation of fluorescent vinyl derivatives displaying excep-

4432
G. Bordeau et al. / Tetrahedron Letters 51 (2010) 4429–4432
by CH2Cl2, and washed with HCl 1 M and water. Organic layer was dried over
J = 8.6 Hz, 3H), 7.99 (d, J = 8.6 Hz, 3H). 13C NMR (300 MHz, CDCl3) d: 166.8,
153.9, 148.1, 137.2, 137.0, 134.4, 130.1, 126.3, 125.4, 125.3, 123.2, 123.0, 122.7,
122.3, 121.5. HRMS (DCI+) calcd for C45H31N4S3, 723.1711; found 723.1721.
Compounds 2m and 4m were obtained using the same procedure and the
MgSO4 and concentrated. The resulting yellow oil was purified by column
chromatography (n-hexane/CH2Cl2, 1:1–1:0, v/v). Trituration in Et2O afforded
363 mg (1.10 mmol) of the title compound in 25% yield. mp 149–150 °C. 1H
NMR (300 MHz, CDCl3): d 7.39 (m, 3H), 7.51 (t, J = 7.8 Hz, 3H), 7.61 (m, 3H),
7.63 (m, 3H), 9.96 (s, 3H). 13C NMR (75 MHz, CDCl3): d 191.5, 147.7, 138.1,
130.6, 130.0, 125.7, 124.2. HRMS (DCI+) calcd for C21H16NO3, 330.1130; found
330.1127.
corresponding phosphonate: 4m pale yellow powder. Mp 132–134 °C (dec). 1
H
NMR (300 MHz, CDCl3) d: 6.93 (d, J = 16.3 Hz, 3H), 7.10 (d, J = 7.6 Hz, 3H), 7.18–
7.32 (m, 18H), 8.55 (m, 6H). 13C NMR (75 MHz, CDCl3) d: 120.77, 121.56,
122.85, 124.57, 126.36, 129.88, 132.69, 137.54, 144.32, 147.96, 150.04. MS
(ESI+) m/z 555.2 [M+H]+ (100%), 577.3 [M+Na]+ (10%). 2m, pale yellow powder.
Mp 136–138 °C (dec). 1H NMR (300 MHz, CDCl3) d: 7.00 (d, J = 16.3 Hz, 3H),
7.18 (d, J = 6.5 Hz, 3H), 7.26–7.35 (m, 15H), 7.48–7.50 (m, 3H), 7.68–7.73 (m,
6H). 13C NMR (75 MHz, CDCl3): 110.27, 114.42, 119.85, 122.29, 123.26, 124.47,
125.23, 125.45, 130.10, 136.65, 138.91, 142.08, 147.87, 150.34, 162.56. MS
(ESI+): m/z 675.3 [M+H]+ (100%), 697.2 [M+Na]+ (70%).
23. Mallegol, T.; Gmouh, S.; Meziane, M. A.; Blanchard-Desce, M.; Mongin, O.
Synthesis 2005, 1771–1774.
24. Lai, G.; Bu, X.; Santos, J.; Mintz, E. Synlett 1997, 1275–1276.
25. A typical procedure for Wittig reaction: In dry THF (15 mL) were added diethyl-
[(benzothiazol-2-yl)methyl)]phosphonate (288 mg, 1.00 mmol, 3.3 equiv) and
NaH (27 mg, 1.12 mmol, 3.7 equiv, 60% in mineral oil). After 15 min of stirring,
a solution of 1m (100 mg, 304
l
mol, 1 equiv) in THF (5 mL) was added and the
26. Mujumdar, R. B.; Ernst, L. A.; Mujumdar, S. R.; Lewis, C. J.; Waggoner, A. S.
Bioconjugate Chem. 1993, 4, 105–111.
resulting mixture was stirred at room temperature for 48 h in the dark. Water
and dichloromethane were added, and after decantation the aqueous layer was
extracted 3 times with dichloromethane and the organic layer was washed
with brine, dried over MgSO4, filtered, and concentrated to dryness. The crude
residue was purified by dissolution in a minimal amount of dichloromethane,
precipitated with pentane, and filtered to afford 3m as a yellow powder
27. Nygren, J.; Svanvik, N.; Kubista, M. Biopolymers 1998, 46, 39–51.
28. Butlera, R. N.; Fahya, A. M.; Foxa, A.; Stephensa, J. C.; McArdlea, P.;
Cunninghama, D.; Ryderb, A. G. Tetrahedron Lett. 2006, 47, 1721–1724.
29. Nakazono, M.; Nanbu, S.; Uesaki, A.; Kuwano, R.; Kashiwabara, M.; Zaitsu, K.
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(195
l
mol, 140 mg) in 64% yield. Mp 118 °C (dec). 1H NMR (300 MHz, acetone
30. Gryko, D. T.; Piescowska, J.; Vetokhina, V.; Wojcik, D. Bull. Chem. Soc. Jpn. 2009,
82, 1514–1519.
d6) d: 7.19 (m, 3H), 7.37–7.56 (m, 18H), 7.63 (d, J = 16.2 Hz, 3H), 7.94 (d,