1,2,4-Triphenylpyrroles: Synthesis, Structure and Luminescence Properties

Article abstract of DOI:10.1055/s-0039-1690828

Pyrroles are widely found in natural products and play an important role in biological processes. Certain pyrrole derivatives are fluorescent and may be used as molecular probes or biomarkers in the diagnosis of diseases, such as Alzheimer's or Parkinson'

Full text of DOI:10.1055/s-0039-1690828

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© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–C
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J. R. Ferreira et al.
Letter
Synlett
1,2,4-Triphenylpyrroles: Synthesis, Structure and Luminescence
Properties
Joana R. M. Ferreiraa
Raquel Nunes da Silvaa,b
João Rochac
O
5 examples
up to 34% yield over 3 steps
R1, R2, R3 = H, OMe, NMe2
0
0
0
0-0
0
0
1-
8
7
2
4-8
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4
R1
R2
Et2NH, DBU
NO2
Artur M. S. Silvaa
Samuel Guieu*a,c
0
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3-2
8
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R3
NO2
Me
R3
i) KOH
ii) H2SO4
O
a QOPNA, LAQV-REQUIMTE, Department of Chemistry, Univer-
sity of Aveiro, 3810-193 Aveiro, Portugal
N
NH2
sguieu@ua.pt
R1
R2
R1
R2
b Institute of Biomedicine (iBiMED), Department of Medical Sci-
ences, University of Aveiro, 3810-193 Aveiro, Portugal
c CICECO, Aveiro Institute of Materials, Department of Chemis-
try, University of Aveiro, 3810-193 Aveiro, Portugal
Received: 07.01.2020
Accepted after revision: 31.01.2020
Published online: 13.02.2019
luminescent when aggregated in concentrated solutions or
when cast into solid films.15 We later demonstrated this
phenomenon in various families of compounds in which in-
termolecular hydrogen bonds16 or weak supramolecular in-
teractions17–19 rigidify the crystalline structure. This is dif-
ferent from the observation of solid-state phosphores-
cence20 or the formation of J-aggregates,21,22 both of which
induce a red-shift of the emission wavelength. In particular,
AIEE of pyrrole-based fluorophores and their analogues has
been assessed, and their crystal structures have been stud-
ied to rationalize the phenomenon.23–25
DOI: 10.1055/s-0039-1690828; Art ID: st-2020-d0010-l
Abstract Pyrroles are widely found in natural products and play an im-
portant role in biological processes. Certain pyrrole derivatives are fluo-
rescent and may be used as molecular probes or biomarkers in the diag-
nosis of diseases, such as Alzheimer’s or Parkinson’s. Herein is reported
the synthesis of five new pyrrole derivatives bearing phenyl rings on po-
sitions 1, 2, and 4, with electron-donating groups at the periphery. The
introduction of more or stronger electron-donating groups red-shifts
and increases the efficiency of the fluorescence emission.
Here, we wish to report the synthesis, characterization,
and photophysical properties of a series of new 1,2,4-tri-
phenylpyrroles. Their syntheses were achieved in moderate
yields, and the compounds showed fair quantum yields in
dilute solutions. Determination of the crystal structure of
one of these pyrroles enabled us to rationalize the quench-
ing observed in concentrated solutions and in the solid
state.
The synthetic route encompassed an aldol condensa-
tion, a Michael addition, Nef reaction, and a Paal–Knorr re-
action (Scheme 1). In the first step, acetophenones were
condensed with benzaldehydes to form the corresponding
chalcones 1a–c. The substituents in the 2- and 4-positions
of the final products were introduced at this stage. The
Michael addition of nitromethane catalyzed by diethylamine
(also used as solvent) and 1,8-diazabicyclo[5.4.0]undec-7-
ene (DBU) afforded intermediates 2a–c in nearly quantita-
tive yields.10 A Nef reaction transformed the nitro substitu-
ent into an aldehyde, yielding the key intermediates 3a–c.
The second step of this reaction was carried out in metha-
nol containing concentrated sulfuric acid, and consequently
the major component of the product was obtained as the
dimethyl acetal. Because this did not cause a problem in the
next step, 3a–c were used, without purification, as mix-
Key words triphenylpyrroles, Nef reaction, Paal–Knorr reaction, fluo-
rescence, crystal structure
Heterocyclic compounds, which are often pharmacolog-
ically active molecules obtained from either natural or syn-
thetic sources, are receiving considerable attention due to
their potential applications in biology and in industry.1
Among them, pyrrole is a versatile scaffold, the derivatives
of which are found in various pharmacophores. Pyrroles are
also widely used as intermediates in syntheses of pharma-
ceuticals, agrochemicals, dyes, photographic chemicals, and
perfumes. Pyrroles are backbone components of complex
macrocycles, such as porphyrin rings (e.g., heme and vita-
min B12) or bile pigments (bilirubin, biliverdin).2 Pyrrole de-
rivatives exhibit a wide range of biological properties,3
namely antibacterial,4–7 antifungal, antiviral,8 antiinflam-
matory, anticancer, and antioxidant activities.9 This has
prompted much recent research on the synthesis of pyr-
roles,1 especially from chalcones.10,11
Luminogenic materials are of considerable interest,12,13
especially those displaying aggregation-induced emission
enhancement (AIEE).14 The first report on such a material
dates from 2001, and it describes a series of silole deriva-
tives that do not luminesce in dilute solutions but are highly
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–C
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
J. R. Ferreira et al.
Letter
Synlett
NO2
O
O
H
O
O
CH3NO2
Et2NH, DBU
MeOH
NaOH
+
R1
2a, R1 = R2 = H, 93%
2b, R1 = R2 = OMe, 93%
2c, R1 = H; R2 = NMe2
quantitative
R2
R1
R2
rt
rt
R1
R2
1a, R1 = R2 = H, quantitative
1b, R1 = R2 = OMe, quantitative
1c, R1 = H; R2 = NMe2, 54%
i) KOH
rt
ii) H2SO4
MeOH
R3
R3
O
O
O
O
H
O
+
N
NH2
R1
R2
R2
R1
R1
R2
3a, R1 = R2 = H, quantitative
3b, R1 = R2 = OMe, 91%
3c, R1 = H; R2 = NMe2, 34%
4a, R1 = R2 = R3 = H, 37%
4b, R1 = R2 = H, R3 = OMe, 28%
4c, R1 = R2 = R3 = OMe, 11%
4d, R1 = R2 = OMe; R3 = H, 7%
4e, R1 = H; R2 = NMe2; R3 = OMe, 44%
Scheme 1 Synthetic routes to compounds 4a–e
tures of the aldehyde and the acetal. In the last step, 3a–c
reacted with aniline or anisidine in a Paal–Knorr reaction,
leading to 4a–e in fair yields.26,27
The new pyrrole derivatives were characterized by NMR
spectroscopy and mass spectrometry (see Supporting Infor-
mation). In the case of 4b, single crystals suitable for X-ray
diffraction were successfully grown from a saturated di-
chloromethane solution (Figure 1).28 All bond lengths and
angles were in the normal ranges.29 The crystal structure
showed that due to steric repulsions, the three phenyl rings
are not coplanar with the pyrrole ring, reducing conjuga-
tion of the backbone.
Figure 2 Absorption and emission spectra of dyes 4a–e at 10–5 mol L–1
in dichloromethane (excitation at 300 nm for 4a–d and at 400 nm for 4e)
molar absorptivity is difficult to assess, but it seems to de-
crease when more-electron-donating groups are present.
All the pyrroles studied emit in solution with quantum
yields of less than 1% (Table 1 and Figure 2). However, 4e,
which contains a stronger electron-donating dimethylami-
no groups showed an increased emission efficiency. None
of the dyes is luminescent in the solid state, and no AIEE is
observed. This is at odds with the results reported for phe-
Figure 1 Molecular structure (a) and unit cell content (b) of 4b. Thermal
ellipsoids are shown at the 50% probability level. Hydrogen atoms are
shown with an arbitrary radius (0.30 Å). C, gray; O, red; N, blue; H, white.
The absorption and emission spectra of 1,2,4-triphen-
ylpyrroles 4a–e were recorded in dichloromethane solution
(Figure 2), and the photophysical properties of the com-
pounds are presented in Table 1.
The absorption and emission wavelengths are in the
ranges 265–410 nm and 375–515 nm, respectively, depend-
ing on the substituents. Electron-donating substituents
red-shift the absorption and emission maxima, with a
small shift for methoxy groups and a larger one for a dime-
thylamino group. The influence of the substituents on the
Table 1 Selected Optical Data Measured in Dichloromethane
Dye
4a
abs (nm)
265
 (M–1 cm–1
54 000
)
em (nm)
375
ϕf (%)
0.15
0.11
< 0.1
< 0.1
0.26
4b
4c
265
46 000
375
275
45 000
390
4d
4e
285
18 000
390
410
15 000
515
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–C

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J. R. Ferreira et al.
Letter
Synlett
nyl-substituted pyrroles,25 among which 1,2,4-triphen-
ylpyrrole, 1,3,4-triphenylpyrrole, and pentaphenylpyrrole
all display AIEE. Presumably, the introduction of substitu-
ents onto the phenyl ring disrupts the organization of the
dyes in the solid state, promoting emission quenching.
In conclusion, starting from simple building blocks, five
new pyrrole derivatives were successfully prepared through
Nef and Paal–Knorr reactions. The pyrroles were selectively
substituted in the 1-, 2-, and 4-positions with phenyl rings
bearing electron-donating substituents. The influence of
these groups on the optoelectronic properties of the dyes
was studied, and all compounds presented emission prop-
erties in dilute solutions. This strategy is valuable for the
synthesis of novel molecules with a pyrrole backbone, and
for fine-tuning their photophysical properties by function-
alization with electron-donating or electron-withdrawing
groups for an improved push–pull effect.
(9) Lee, H.; Lee, J.; Lee, S.; Shin, Y.; Jung, W.; Kim, J.-H.; Park, K.;
Kim, K.; Cho, H. S.; Ro, S.; Lee, S.; Jeong, S. W.; Choi, T.; Chung,
H.-H.; Koh, J. S. Bioorg. Med. Chem. Lett. 2001, 11, 3069.
(10) Hall, M. J.; McDonnell, S. O.; Killoran, J.; O’Shea, D. F. J. Org.
Chem. 2005, 70, 5571.
(11) Kikuchi, K.; Hibi, S.; Yoshimura, H.; Tokuhara, N.; Tai, K.; Hida,
T.; Yamauchi, T.; Nagai, M. J. Med. Chem. 2000, 43, 409.
(12) Cardona, F.; Rocha, J.; Silva, A. M. S.; Guieu, S. Dyes Pigm. 2014,
111, 16.
(13) Guieu, S.; Cardona, F.; Rocha, J.; Silva, A. M. S. New J. Chem. 2014,
38, 5411.
(14) Hong, Y.; Lam, J. W. Y.; Tang, B. Z. Chem. Soc. Rev. 2011, 40, 5361.
(15) Luo, J.; Xie, Z.; Lam, J. W. Y.; Cheng, L.; Chen, H.; Qiu, C.; Kwok, H. S.;
Zhan, X.; Liu, Y.; Zhu, D.; Tang, B. Z. Chem. Commun. 2001, 1740.
(16) Guieu, S.; Rocha, J.; Silva, A. M. S. Tetrahedron 2013, 69, 9329.
(17) Vaz, P. A. A. M.; Rocha, J.; Silva, A. M. S.; Guieu, S. New J. Chem.
2016, 40, 8198.
(18) Guieu, S. Quimica (Lisboa, Port.) 2018, 42, 97.
(19) Guieu, S.; Cardona, F.; Rocha, J.; Silva, A. M. S. Chem. Eur. J. 2018,
24, 17262.
(20) Guieu, S.; Rocha, J.; Silva, A. M. S. Tetrahedron Lett. 2013, 54, 2870.
(21) Guieu, S.; Pinto, J.; Silva, V. L. M.; Rocha, J.; Silva, A. M. S. Eur. J.
Org. Chem. 2015, 3423.
Funding Information
(22) Würthner, F.; Kaiser, T. E.; Saha-Möller, C. R. Angew. Chem. Int.
Ed. 2011, 50, 3376.
(23) Kim, E.; Lee, Y.; Lee, S.; Park, S. B. Acc. Chem. Res. 2015, 48, 538.
(24) Feng, X.; Tong, B.; Shen, J.; Shi, J.; Han, T.; Chen, L.; Zhi, J.; Lu, P.;
Ma, Y.; Dong, Y. J. Phys. Chem. B 2010, 114, 16731.
Thanks are due to the University of Aveiro, FCT/MEC for financial sup-
port to the QOPNA research Unit (FCT UID/QUI/00062/2019), CICECO–
Aveiro Institute of Materials (FCT Ref. UID/CTM/50011/2019), fi-
nanced by national funds through FCT/MEC, and also to the Portu-
guese NMR Network. This work was also supported by the Integrated
Programme of SR&TD ‘pAGE – Protein Aggregation Across the Lifes-
pan’ (reference CENTRO-01-0145-FEDER-000003), co-funded by the
Centro 2020 program, Portugal 2020, and the European Union,
(25) Lei, Y.; Liu, Q.; Dong, L.; Cai, Z.; Shi, J.; Zhi, J.; Tong, B.; Dong, Y.
Chem. Eur. J. 2018, 24, 14269.
(26) 1,2,4-Triphenylpyrroles 4a–e; General Procedure The appro-
priate nitro ketone 2a–c (1 equiv) was dissolved in a mixture of
MeOH (8 mL) and THF (12 mL) then KOH (1 equiv) was added.
The mixture was stirred for 2 h. The solution, cooled in ice, was
added dropwise to an ice-cold solution of concd H2SO4 (4 mL ) in
MeOH (10 mL), and the mixture was stirred for ~1 h at rt. Half of
the solvent was removed under reduced pressure and the
mixture was poured in ice–water. The product was extracted
with CH2Cl2 and the organic layer was dried (Na2SO4) and con-
centrated to dryness to give compound 3a–c, which was used in
the following step without purification. The appropriate amine
(1 equiv) was added to a solution of the acetal 3a–c (1 equiv) in
MeOH (5 mL), and the resulting solution was stirred for 24 h at
rt. During this time a precipitate formed. H2O was then added,
and the product was extracted with CH2Cl2. The organic phase
was dried (Na2SO4) and concentrated under reduced pressure.
The crude product was purified by flash column chromatogra-
phy (silica gel).
through the European Regional Development Fund.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690828.
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References and Notes
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A.; Mullen, G.; Bryant, J.; Embrey, K.; Gao, N.; Breeze, A.; Timms,
D.; Andrews, B.; Uria-Nickelsen, M.; Demeritt, J.; Loch, J. T. III.;
Hull, K.; Blodgett, A.; Illingworth, R. N.; Prince, B.; Boriack-
Sjodin, P. A.; Hauck, S.; MacPherson, L. J.; Ni, H.; Sherer, B. Anti-
microb. Agents Chemother. 2012, 56, 1240.
(6) Pagadala, L. R.; Mukkara, L. D.; Singireddi, S.; Singh, A.;
Thummaluru, V. R.; Jagarlamudi, P. S.; Guttala, R. S.; Perumal,
Y.; Dharmarajan, S.; Upadhyayula, S. M.; Ummanni, R.;
Basireddy, V. S. R.; Ravirala, N. Eur. J. Med. Chem. 2014, 84, 118.
(7) Rane, R. A.; Naphade, S. S.; Bangalore, P. K.; Palkar, M. B.; Shaikh,
M. S.; Karpoormath, R. Bioorg. Med. Chem. Lett. 2014, 24, 3079.
(8) He, X.-Y.; Lu, L.; Qiu, J.; Zou, P.; Yu, F.; Jiang, X.-K.; Li, L.; Jiang, S.;
Liu, S.; Xie, L. Bioorg. Med. Chem. 2013, 21, 7539.
(27) 1,2,4-Tris(4-methoxyphenyl)-1H-pyrrole (4c)Yellow–brown
1
oil; yield: 23 mg (0.06 mmol, 11%). H NMR (300 MHz, CDCl3):
 = 7.50 (d, J = 8.8 Hz, 2 H), 7.15–7.08 (m, 4 H), 7.07 (d, J = 2.0 Hz,
1 H), 6.91 (d, J = 8.8 Hz, 2 H), 6.85 (d, J = 9.0 Hz, 2 H), 6.77 (d, J =
8.9 Hz, 2 H), 6.58 (d, J = 2.0 Hz, 1 H), 3.82 (s, 3 H), 3.81 (s, 3 H),
3.77 (s, 3 H). 13C NMR (75 MHz, CDCl3):  = 158.4, 158.3, 158.0,
134.7, 133.8, 129.7, 128.3, 127.1, 126.3, 125.6, 124.9, 119.8,
114.3, 114.3, 113.7, 107.3, 55.6, 55.4, 55.3. ESI(+)–HRMS: m/z [M +
H]+ calcd for C25H24NO3: 386.1751; found: 386.1743 (–1.99 ppm).
(28) CCDC 1879235 contains the supplementary crystallographic
data for compound 4b. The data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/getstructures.
(29) Allen, F. H.; Kennard, O.; Watson, D. G.; Brammer, L.; Orpen, A.
G.; Taylor, R. J. Chem. Soc., Perkin Trans. 2 1987, S1.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–C