SNAr nucleophilic substitution of 1,9-dihalodipyrrins by S- and N- nucleophiles. Synthesis of new dipyrrins bearing pendant substituents

Article abstract of DOI:10.1016/j.dyepig.2016.02.018

5-Aryl-1,9-dichlorodipyrrins react with a series of S- and N- nucleophiles (both alkyl- and aryl- ones). Reagents with mercapto group yield product of double nucleophilic substitution of 5-pheny-1,9-dichlorodipyrrin, i.e. the respective 1,9-bis(alkyl-of arylthio)dipyrrin. On the contrary, 5-(4-nitrophenyl)-1,9-dichlorodipyrrin causes disulfides formation from the S-aliphatic substrates, whereas nucleophilic substitution remains the main path of the reaction for S-aryl ones. The reaction of N-Alkyl nucleophiles proceeds as mono-substitution. UV-Vis spectra feature a batochromic shift for bis-S-substituted products and a hypsochromic shift for mono-N-substituted ones, with respect to the starting dichlrorides.

Full text of DOI:10.1016/j.dyepig.2016.02.018

Accepted Manuscript
S Ar Nucleophilic substitution of 1,9-dihalodipyrrins by S and N nucleophiles.
N
Synthesis of new dipyrrins bearing pendant substituents
Evgenia Leushina, Ksenia Tikhomirova, Anastasiya Permyakova, Pavel Ilin, Maria
Terenina, Alexander Anisimov, Andrey Khoroshutin
PII:
S0143-7208(16)30036-5
10.1016/j.dyepig.2016.02.018
DYPI 5108
DOI:
Reference:
To appear in: Dyes and Pigments
Received Date: 24 December 2015
Revised Date: 20 February 2016
Accepted Date: 22 February 2016
Please cite this article as: Leushina E, Tikhomirova K, Permyakova A, Ilin P, Terenina M, Anisimov
A, Khoroshutin A, S Ar Nucleophilic substitution of 1,9-dihalodipyrrins by S and N nucleophiles.
N
Synthesis of new dipyrrins bearing pendant substituents, Dyes and Pigments (2016), doi: 10.1016/
j.dyepig.2016.02.018.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
SNAr Nucleophilic substitution of 1,9-dihalodipyrrins by S
and N nucleophiles. Synthesis of new dipyrrins bearing
pendant substituents.1
Evgenia Leushina, Ksenia Tikhomirova, Anastasiya Permyakova, Pavel Ilin, Maria
Terenina, Alexander Anisimov, Andrey Khoroshutin*
a
Chemistry Department, M.V. Lomonosov Moscow State University, 1 Leninskie Gory
Bld. 3, Moscow 119991 Russia
e-mail: khorosh@petrol.chem.msu.ru
Abstract
5-Aryl-1,9-dichlorodipyrrins react with a series of S and N nucleophiles (both alkyl and
aryl containing ones). Reagents with mercapto group yield product of double nucleophilic
substitution of 5-pheny-1,9-dichlorodipyrrin, i.e. the respective 1,9-bis(alkyl- of
arylthio)dipyrrin. On the contrary, 5-(4-nitrophenyl)-1,9-dichlorodipyrrin causes disulfides
formation from the S-aliphatic substrates, whereas nucleophilic substitution remains the main
path of the reaction for S-aryl ones. Reaction of N-Alkyl nucleophiles proceeds as mono-
substitution. UV-Vis spectra feature batochromic shift for bis-S-substituted products and a
hypsochromic shift for mono-N-substituted ones, with respect to the starting dichlrorides.
1
Part of this work was reported at 6th EuCheMS Conference on Nitrogen Ligands in Coordination
Chemistry, Metal-Organic Chemistry, Bioinorganic Chemistry, Materials and Catalysis, Beaune, France, September
13-17.
1

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Keywords
1,9-dihalo-H-dipyrrins, nucleophilic substitution, S-nucleophiles, N-nucleophiles, UV-
Vis spectra, NMR
Introduction
Dipyrrins (DPs) and their metal complexes [1, 2] are attracting much of researchers
attention, in spite of being somewhat in the shade of their boron derivatives (BODIPY) [3-6].
DP-metal complexes have been studied for applications in dye-sensitized solar cells [7-9],
catalysis[10] and as new fluorescent dyes.[11] They have been studied as prospective substance
of anti-tumor activities[12-14] Besides, DP-metal complexes can govern the geometry and
composition of supramolecular aggregates[15, 16] depending on both the mode of metal
coordination and the geometry and steric demand of a DP ligand. [17-19] These factors also
control the formation of metal-organic frameworks. [20, 21] Extensive studies focused on the
substutients’ influence on the energies of the ground and excited states manifested in their redox
properties and optical spectra. .[22] Additional substituents at the periphery of DP bearing extra
complexing groups had also been shown to drastically change complexes properties. [23, 24]
Known synthetic pathways to substituted DPs include condensation of substituted
pyrroles. [25-32] Also, series of methods such as electrophilic substitution, oxidative couplings,
a direct H-substitution and halogenation-Pd-catalyzed cross coupling sequences have been
shown to work for BODIPY derivatization[33, 34] as well as conversion of a methyl group
adjacent to the electronegative heterocycle to a double bond and nucleophilic substitution at the
BODIPY core. [5] Some examples of these methods applied to non-borylated dipyrrins can be
also found in the literature. [35] Research groups of Thompson, Ravikanth and Hao have
developed synthetic methods leading to H-dipyrrins based on F-BODIPY deborylation by boron
trihalides[36] or other Lewis acids[37], as well as by potassium tert-butoxide [38, 39]. However
2

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the scope of these methods is rather limited, e.g. no dipyrrins possessing groups with substantial
Lewis basicity are reported to stand these BF2-removal conditions.
On the other hand no accounts on an aromatic nucleophilic substitution in free dipyrrins
are found in the literature, although there are papers on the reactions of C-, S-, N- and O-
nucleophiles with more electrophilic 1,9-dichloroBODIPY.[40] We were interested in the access
to 1,9-disubstituted dipyrrins that possess additional pendant complexing substituents. 1,9-
Modification of the dipyrrin framework was employed for the sterical encumbering to be used in
catalysis[27, 41], the extension of a π-conjugation (regulated both by metal complexation[42]
and hydrogen bonding[38]), used in photophysical applications.
This communication reveals first results of the study. It is aimed at filling this gap, being
focused on the either bulky substrates or those possessing additional coordinating substituents.
As there is an NH acidic proton in the dipyrrin, reaction of 5-aryl-1,9-dichlorodipyrrins 1 with C-
nucleophiles is more difficult to study, so at first we limited the scope to N-, O- and S-
nucleophiles
Materials and Methods
All solvents were distilled before use. Reagents were purchased from Aldrich and Acros
companies, solvents were bought from Reakhim. CH3CN and triethylamine have been distilled
from
CaH2.
1,9-dichloro-5-(4-nitrophenyl)-dipyrromethene,
1,9-dichloro-5-phenyl-
dipyrromethene [43], methyl 2-mercaptobenzoate [44], methyl mercaptoacetate [45], and methyl
3-mercaptopropanoate [46] were prepared according to the literature procedures.
NMR spectra, unless otherwise stated, were recorded on Bruker Avance 400
spectrometer, at 400.13 MHz for 1H (standard – HMDS, 0.05 ppm) and 100.13 for 13C (standard
– 13C signal of the solvent, 77.0 ppm for CDCl3). For APT experiments, signals of secondary and
quaternary atoms are marked with an asterisk.
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LDI-TOF spectra have been collected on Bruker Daltonics Autoflex II spectrometer,
samples were irradiated by N2 laser (λ = 337 nm), accelerating voltage 19 kV. High resolution
mass spectra (HRMS) were measured on a Bruker micrOTOF II instrument using electrospray
ionization (ESI) [47]. The measurements were done in a positive ion mode (interface capillary
voltage – 4500 V); mass range from m/z 50 to m/z 3000 Da; external or internal calibration was
done with Electrospray Calibrant Solution (Fluka). A syringe injection was used for solutions in
methanol (flow rate 3 µL/min). Nitrogen was applied as a dry gas; interface temperature was set
at 180 °C.
TLC has been performed on DC-Alufolien Kieselgel 60 F254 plates (Merck). Kieselgel
60 0.063-0.200 мм (Merck) was used for column chromatography.
UV-Vis spectra were measured on Agilent-8453, in all cases a drop of Et3N had been
added to the sample before measurement. Extinction coefficients were reported for 5 10-5 M
concentrations, unless otherwise stated.
General procedure for nucleophilic substitution.
Dichlorodipyrrin (1 eq.) and dry acetonitrile were placed to three necked round bottom
flask equipped with magnetic stirring bar, stoppered by rubber septa and flushed with argon via
needles. Then a solution of the nucleophile (ca. 4 eq.) in CH3CN and triethylamine (ca. 6 eq.)
have been added by the syringe, reaction flask was immersed into an oil bath heated to 65oC
(unless otherwise specified). After a specified time period, the solvent was removed on rotary
evaporator, the residue was dried on the vacuum line at 5*10-2 Torr at 80-90oC to remove the
base and one of the substrates and processed as cited below.
1,9-bis(methoxycarbonylmethylthia)-5-phenyl dipyrrin (7). 1a (8.9 mg, 30.1 µmol) in 4 ml of
CH3CN and 3a (13.1 mg, 124 µmol) in 6 ml of CH3CN and Et3N (17 µl, 12.4 mg, 122 µmol),
rxn time 48 h, purified by TCL Al2O3 neutral, hexane/CHCl3 2:1 + 1% CH3OH. 7: (6.4 mg,
1
14.93 µmol, 49%). H NMR (CDCl3): δ = 3.79 (6H, s), 3.88 (4H , s), 6.38 (2H, d, J = 4.1 Hz),
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13
6.44 (2H, d, J = 4.1 Hz), 7.36-7.44 (5H, m) ppm. C NMR (CDCl3) δ= 35.56, 52.76, 120.42,
127.60, 128.58, 128.79, 130.77, 134.41, 136.77, 141.76, 147.65, 170.02 ppm. LDI-TOF: m/z =
429 [M+H]+, 467[M+K]+. HRMS (ES): C21H21N2O4S2 Found 429.0921 Calculated 429.0337.
λmax = 453 nm (ε=2.4×104 M-1cm-1).
1,9-bis(2-methoxycarbonylethylthia)-5-phenyl dipyrrin (8). 1a (25.1 mg, 86.8 µmol) in 10 ml
of CH3CN and 3b (41.7 mg, 347 µmol) in 4 ml of CH3CN and Et3N (48 µl, 35.2 mg, 348 µmol),
rxn time 120 h, purified by TCL Al2O3 neutral, hexane/CHCl3 2:1 . 8: (33.0 mg, 72.3 µmol,
83%). 1H NMR (CDCl3): δ = 2.73 (4H, t, J = 7.2 Hz), 2.91 (4H, t, J = 7.2 Hz), 3.69 (6H, s), 6.38
(2H, d, J = 4.1 Hz), 6.44 (2H, d, J = 4.1 Hz), 7.36-7.44 (5H, m) ppm. 13C NMR (CDCl3) δ=
28.87*, 34.42*, 51.88, 120.77, 127.72, 128.44, 128.64, 130.75, 133.61*, 136.63*, 141.91*,
148.24*, 172.06* ppm. LDI-TOF: m/z = 458 [M]+. HRMS (ES): C23H25N2O4S2 Found 457.1242
Calculated 457.1250. λmax = 456 nm (ε=1.9×104 M-1cm-1).
Nucleophilic substitution of 1a with 3b – conversion and products distribution. All the
experiments have been carried out according to the general procedure. After the evaporation and
high vacuum drying reaction mixtures have been analyzed by NMR.
Methyl 3-({(2Z)-2-[(5-chloro-1H-pyrrol-2-yl)(phenyl)methylene]-2H-pyrrol-5-yl}
thio)propanoate (7') 1a (30 mg, 104 µmol) in 8 ml of CH3CN and 3b (50.6 mg, 374 µmol) in
2 ml of CH3CN and Et3N (54 µl, 39.3 mg, 728 µmol), rxn time 17 h. Reaction mixture has been
evaporated to dryness, then oily orange residue has been subjected to heating(95oC, 40 min) at
high vacuum (1·10-2- Torr) for the nucleophile excess to be dried off. The product was isolated
by column chromatography (SiO2 neutral, petroleum ether/ethyl acetate 4:1). 7': (13.5 mg,
34.8 µmol, 33%). ): 1H NMR (CDCl3) δ = 2.83 (2H, t, J = 7.2 Hz), 3.31 (2H, t, J = 7.2 Hz), 3.72
(3H, s), 6.33 (1H, d, J = 4.2 Hz), 6.48 (1H, d, J = 4.2 Hz), 6.25 (1H, d, J = 4.2 Hz), 6.54(1H, d,
J = 4.2 Hz), 7.40 (5H, m). ppm. 13C NMR (CDCl3) δ= 28.63, 29.28, 33.92, 51.5 8, 117.53,
5

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118.64, 127.36, 128.68, 130.37, 135.62, 171.51 ppm. LDI-TOF: m/z = 373 [M]+. HRMS (ES):
C20H20ClN2O2S Found 373.0778 Calculated 373.0772. λmax = 454 nm (ε=0.9×104 M-1cm-1).
1,9-bis(4-methylphenylthia)-5-phenyl dipyrrin (9). 1a (14 mg, 48.4 µmol) in 8 ml of CH3CN
and 4 (24.1 mg, 194 µmol) in 2 ml of CH3CN and Et3N (27 µl, 19.7 mg, 194 µmol), rxn time
20 h (at 64oC). Purified by column chromatography SiO2, CCl4. 9: (21 mg, 45.2 µmol, 93%). 1H
NMR (CDCl3): δ = 2.30 (6H, s) 6.27 (2H, d, J = 4.1 Hz), 6.44 (2H, d, J = 4.1 Hz), 7.13 (4H, d,
13
J = 8.1 Hz), 7.33 (4H, d, J = 8.1 Hz), 7.37 – 7.41(5H, m), 12.2 (broad s, 1H) ppm. C NMR
(CDCl3) δ= 21.23, 120.35, 127.64, 128.45, 128.57, 129.26*, 130.16, 130.75, 131.65, 134.46*,
136.66*, 136.66*, 138.14*, 141.91* ppm. LDI-TOF: m/z = 465 [M+H]+. HRMS (ES): [M+H]+
C29H24N2S2 Found 465.1464 Calculated 465.1454. λmax = 462 nm (ε = 2.1×104 M-1cm-1).
1,9-bis(2-methoxycarbonylphenylthia)-5-phenyl dipyrrin (10). 1a (14.6 mg, 50.5 µmol) in
8 ml of CH3CN and 5 (43.8 mg, 260 µmol) and Et3N (27 µl, 19.7 mg, 194 µmol), rxn time 72 h
(at 76oC). Purified by column chromatography SiO2, hexane-EtOAc 4:1. Dried residue was
1
chromatographed on Al2O3, hexane-EtOAc. 10: (23 mg, 41.6 µmol, 82%). H NMR (CDCl3): δ
= 3.91 (6H, s), 6.44 (2H, d, J = 4.4 Hz), 6.52 (2H, d, J = 4.4 Hz), 7.10-7.14 (2H, m), 7.21-7.27
(4H, m), 7.38-7.47 (5H, m), 7.85 (2H, dd, J = 7.8 Hz, 1.1 Hz) ppm. 13C NMR (CDCl3) δ= 29.68,
52.25*, 122.60*, 126.50*, 127.73*, 128.65*, 128.79*, 129.55, 130.82*, 130.87*, 132.34*,
134.56, 136.54, 137.13, 147.03, 166.80 ppm. LDI-TOF: m/z = 465 [M+H]+. HRMS (ES):
C29H24N2S2 Found 465.1464 Calculated 465.1454. λmax = 456 nm (ε = 2.1×103 M-1cm-1).
1,9-bis(4-methylphenylthia)-5-(4-nitrophenyl) dipyrrin (15). 1b (33.3 mg, 100 µmol) in 16 ml
of CH3CN and 4 (50.7 mg, 408 µmol) and Et3N (54 µl, 39 mg, 388 µmol), rxn time 48 h (at
65oC). Washed by hot hexanes four times, removing this by decantation 15: (19.6 mg,
38.4 µmol, 39%). 1H NMR (CDCl3): δ = 2.34 (3H, s), 6.27 (2H, d, J = 4.3 Hz), 6.33 (2H, d, J =
4.3 Hz), 7.16 (4H, d, J = 7.9 Hz), 7.35 (4H, d, J = 7.9 Hz), 7.58 (2H, d, J = 8.8 Hz), 8.27 (2H, d,
13
J = 8.8 Hz) ppm. C NMR (CDCl3) δ= 21.26, 120.75, 122.99, 127.76, 128.62, 130.28, 131.61,
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131.93, 138.55, 141.16, 143.47, 147.95, 150.59 ppm. LDI-TOF: m/z = 510.6 [M+H]+. HRMS
(ES): C29H23N3O2S2 Found 510.1298 Calculated 510.1304 λmax = 467 nm (ε = 7.6×103 M-1cm-1).
1,9-bis(2-methoxycarbonylphenylthia)-5-(4-nitrophenyl)dipyrrin
(16).
1b
(33.8 mg,
101 µmol) in 16 ml of CH3CN and 5 (68 mg, 550 µmol) and Et3N (54 µl, 40 mg, 380 µmol), rxn
time 4 h (at 70oC). ). Washed by hot hexanes four times, removing this by decantation. 16:
1
(47.4 mg, 79.2 µmol, 79%). H NMR (CDCl3): δ = 3.91 (6H, s), 6.41 (2H, d, J = 4.2 Hz), 6.46
(2H, d, J = 4.2 Hz), 7.12-7.16 (2H, m), 7.24 (the peak is overlaid by the CDCl3 residual one,
confirmed by COSY expt.), 7.63 (2H, d, J = 8.6 Hz), 7.87 (2H, d, J = 7.6 Hz), 8.30 (2H, d,
J = 8.6 Hz), 11.92 (1H, br.s.) ppm. 13C NMR (CDCl3): δ = 52.26, 123.05, 123.38, 126.70,
127.70, 129.59*, 130.88, 130.95, 131.68, 132.37,136.75*, 142.14*, 143.28*, 148.07*, 166.72*
ppm. LDI-TOF: m/z = 598.1 [M+H]+. HRMS (ES): C31H23N3O6S2 Found 598.1051 Calculated
598.1101. λmax = 461 nm (ε=1.7×104 M-1cm-1).
1,9-bis(2-methoxycarbonylmethylthia)-5-(4-nitrophenyl)dipyrrin
(17). 1b
(49.6 mg,
150 µmol) in 28 ml of CH3CN and 3a (63.6 mg, 600 µmol) and Et3N (155 µl, 113 mg,
1.12 µmol), rxn time 21 h (at 70oC). 17: (58,2 mg, 123 µmol, 82%). 1H NMR (CDCl3): δ = 3.75
(6H, s), 3.87 (4H, br.s.), 6.32 (2H, d, J = 4.2 Hz), 6.38 (2H, d, J = 4.2 Hz), 7.58 (2H, d, J =
13
8.6 Hz), 8.26 (2H, d, J = 8.6 Hz). C NMR (CDCl3): δ = 35.35, 52.75, 120.89, 122.88, 128.06,
131.13, 131.60, 140.90, 143.48, 147.84, 148.99, 169.84 ppm. LDI-TOF: m/z = 474 [M+H]+.
HRMS (ES): C21H19N3O6S2 Found 474.0783 Calculated 474.0794. λmax = 458 nm
(ε = 1.9×104 M-1cm-1).
1,9-bis(2-methoxycarbonylethylthia)-5-(4-nitrophenyl)dipyrrin (18). 1b (51.2 mg, 154 µmol)
in 27 ml of CH3CN and 3b (72 mg, 600 µmol) and Et3N (159 µl, 218 mg, 2.16 µmol), rxn time
21 h (at 70oC). 18: (64,8 mg, 129,4 µmol, 84%). 1H NMR (CDCl3): δ = 2.83 (4H, t, J = 7.1 Hz),
3.32 (4H, t, J = 7.1 Hz), 3.70 (s, 6H), 6.37 (4H, t, J = 4.4 Hz), 7.60 (2H, d, J = 8.6 Hz), 8.28 (2H,
d, J = 8.6 Hz), 12.42 (1H, br.s.) ppm. 13C NMR (CDCl3): δ = 28.79, 34.23, 51.89, 121.25,
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123.01, 127.75, 130.30, 131.59, 141.09, 143.36, 147.93, 149.61, 171.88 ppm. LDI-TOF: m/z =
502 [M+H]+. HRMS (ES): C23H23N3O6S2 Found 502.1096 Calculated 502.1107. λmax = 463 nm
(ε=2.1×104 M-1cm-1).
9-chloro-1-((2-hydroxyethyl)amino)-5-phenyldipyrrin (19) 1a (15 mg, 52 µmol) in 8 ml of
CH3CN and 6a (16 mg, 262 µmol) and Et3N (27 µl, 20 mg, 190 µmol), rxn time 163 h (at 70oC).
After the solvent removal on the vacuum line the reaction mixture was dissolved in 10 ml of
CH2Cl2, washed with 0.1M HCl. Water phase was neutralized by an equal volume of saturated
aq. NaHCO3 and extracted with CH2Cl2. Combined organic phases were dried over Na2SO4 and
the solvent was removed on rotary evaporator. The residue was loaded onto silica gel column
(hexane/EtOAc 1:3). Second fraction was collected giving dark orange crystals after drying.
19 (7 mg, 22 mol, 45%).
1H NMR (CDCl3): = 3.69-3.72 (2H, m), 3.94-3.97 (2H, m), 6.00-6.02 (2H, m), 6.15 (1H, d, J =
13
4.7 Hz), 6.71 (1H, d, J = 4.7 Hz), 7.36-7.43 (5H, m) ppm. C NMR (CDCl3): = 45.7*, 62.3*,
108.19, 116.77, 117.72, 120.11*, 127.64, 127.74*, 128.03, 130.94, 132.29*, 137.04*, 137.92,
166.80* ppm. LDI-TOF: m/z = 314.1 [M+H]+. HRMS (ES): C17H16ClN3O Found 314.1055
Calculated 314.1055. λmax = 416 ( ε=9.7×104 M-1cm-1); 521(ε=2.2×104 M-1cm-1) (c = 7.6×10-6
M).
9-chloro-1-((N-2-hydroxyethyl-N-methyl)amino)-5-phenyldipyrrin (20) 1a (15 mg, 52 µmol)
in 8 ml of CH3CN and 6b (16 mg, 213 µmol) and Et3N (27 µl, 20 mg, 190 µmol), rxn time 57 h
(at 70oC). ). After the solvent removal on the vacuum line reaction mixture was dissolved in
10 ml of CH2Cl2, washed with brine and with water. Organic phase was dried over Na2SO4 and
the solvent was removed on rotary evaporator. The dark orange solid of 20 were collected with
1
the quantitative (17 mg, 52 µmol) yield. H NMR (CDCl3): = 3.27 (1H, s), 3.74-3.77 (2H, m),
3.94-3.97 (2H, m), 6.01 (2H, AB system, J = 3.9 Hz), 6.38 (2H, d, J = 4.76 Hz), 6.77 (2H, d, J =
4.76 Hz), 7.36-7.43 (5H, m) ppm. 13C NMR (CDCl3): δ = 37.8, 54.0, 61.4, 108.1, 116.1, 116.3,
119.8, 127.1, 127.6, 127.9, 131.0, 132.7, 137.1, 138.2, 146.5, 168.4 ppm. LDI-TOF: m/z =327
8

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[M], 328 [M+H]+. HRMS (ES): C17H16ClN3O Found 328.1207 Calculated 328.1211 λmax
=
432 nm (ε =1.9×104 M-1cm-1), 530 (ε =0.49×104 M-1cm-1).
9-chloro-1-((2-hydroxyethyl)amino)-5-(4-nitrophenyl)-dipyrrin (21) 1b (19.4 mg, 61 µmol)
in 10 ml of CH3CN and 6a (19 mg, 310 µmol) and Et3N (32 µl, 23 mg, 230 µmol), rxn time 24 h
(at 73oC). The solvent has been removed on the rotary evaporator, then the residue has been
1
dried on high vacuum line (10-2 Torr) at 77oC for 40 min. 17: (21.5 mg, 59.6 µmol, 96%). H
NMR (CDCl3): δ = 3.68 (2H, m), 3.93 (m, 2H), 6.04 (1H, d, J = 4.0 Hz), 6.13 (1H, d,
J = 4.0 Hz), 6.38 (1H, d, J = 5.1 Hz), 6.64 (1H, d, J = 5.1 Hz), 7.56 (2H, d, J = 8.8 Hz), 8.29
(2H, d, J = 8.8 Hz) ppm. 13C (CDCl3) 45.9, 61.8, 108.9, 116.5, 117.2, 118.5, 121.7, 123.1, 125.1,
130.6, 131.1, 131.8, 131.9, 137.4, 143.9, 147.8, 166.6 ppm. LDI-TOF: m/z = 358 [M]+, 359
[M+H]+. C17H15ClN4O3 [M+H]+ Found 359.0895 Calculated 359.0905 λmax = 424 nm (ε =
1.3×104 M-1cm-1), 523(0.26×104 M-1cm-1).
9-chloro-1-((N-2-hydroxyethyl-N-methyl)amino)-5-(4-nitrophenyl)-dipyrrin (22) 1b (23 mg,
73 µmol) in 11 ml of CH3CN and 6b (24.3 mg, 323 µmol) in 2ml of CH3CN and Et3N (38 µl,
28 mg, 270 µmol), rxn time 24 h (at 73oC). After the solvent removal on the vacuum line (40
1
min at 80oC). The dark orange solid of 22 were collected with 95% (26 mg, 70 µmol) yield. H
NMR (CDCl3): = 3.31 (1H, s), 3.70-3.81 (2H, m), 3.96-3.98 (2H, m), 5.91 (1H, d, J = 3.9 Hz),
6.03 (1H, d, J = 3.9 Hz), 6.45 (1H, d, J = 4.8 Hz), 6.67 (1H, d, J = 4.8 Hz), 7.57(2H, d, J =
8.8 Hz), 8.25(2H, d, J = 8.8 Hz) ppm. 13C NMR (CDCl3): δ = 38.06, 54.35*, 60.81*, 108.9,
116.6, 123.0, 132.0*, 131.8*, 131.9, 134.8*, 137.8, 144.2*, 147.7*, 167.0* ppm. LDI-TOF: m/z
=372 [M], 323 [M+H]+. HRMS (ES): C18H17ClN4O3 Found 372.1001 Calculated 372.0989 λmax
= 441 nm (ε =1.4×104 M-1cm-1); 530 nm (ε =3.4×103 M-1cm-1) .
9

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Results
Two dipyrrins differing in electrophilicity have been chosen to probe their substitution
reactions, i.e. 5-phenyl-1,9-dichlorodipyrromethene (Ph-DP) 1a, 5-(4-nitrophenyl)-1,9-
dichlorodipyrromethene (NO2Ph-DP) 1b.
Figure 1. Starting compounds used in this study.
R
HS
CH3O
HS
COOCH3
(CH2)n
R'HN
OH
HS
O
NH
N
Cl
Cl
R = H, 1a
NO2, 1b
3a n = 1
3b n = 2
4
5
6a, R=H
b, R=CH3
All reactions have been carried out as for the BODIPY[40] , i.e. in refluxing acetonitrile with
triethylamine as the base. The reactions occurred at much slower rates than their F-BODIPY
counterparts (e.g. 48 h for 7 vs 8h for its BF2 counterpart[40]). Despite the oxygen-free
conditions, formation of the disulfides 11-14 were detected along with disubstituted products in
all cases, indicating that the DP also acts as an oxidant. The results are presented in the
Scheme 1.
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Scheme 1.
Both shorter reaction times and lower excess of 3a give rise to either lower conversion or
to the formation of the mixture of mono- and di-substitution products 7' and 7 (Scheme 2).
However no conditions can be found for selective formation of 7'.
Scheme 2
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Nitrogen nucleophiles – react with 1a and 1b to yield mono-substitution product only. All
attempts to effect disubstitution (severe conditions, long reaction time, solvent variation) failed
(Scheme 3).
Scheme 3
R
R
(C2H5)3N
4 eq.
NHR'
+
CH3CN
reflux
>24 h
argon
OH
NH
NH
N
N
Cl
Cl
NR'
Cl
1
6
HO
Nucleophile, R'
6a, H
6b, CH3
6a, H
DP adduct
19, 45%
20, 99%
21, 99%
22, 95%
R
H
H
NO2
NO2
Entry
1
2
3
4
6b, CH3
No products were observed when reacting 1 with EtOH in similar conditions.
Use of DMF as the solvent caused no substantially different results: all reactions have
been accelerated ca. 1.5 times, no disubstitution in the case of N-nucleophiles has been observed,
no substitution products by O-nucleophiles have been detected.
NMR of the disubstituted products feature much less difference between signals of
pyrrolic protons (0.05 – 0.1 ppm) than in, e.g. 1a (0.27 ppm [29]). Spectra of mono-substituted
ones 19-22 exhibit two pairs of the pyrrolic protons: for pyrrole and pyrrolene units (see the
Supporting Info). One may expect two possible tautomeric forms which distinctly differ in
energy for such compounds (Fig.2). To get more insight to which form (A or B, Fig. 2)
predominates we did the NOESY experiment 22. Its results (see the Supporting Info)
unambiguously indicate that N-methyl-N-(2-hydroxyethyl) group is attached to the doublet with
the splitting of 4.8 Hz, not to the doublet with 3.8 Hz. Mono N-substituted BODIPY [48-51] and
12

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O-substituted dipyrrins [52] do possess doublets with coupling constants that differ in their
values for ca. 1 Hz. However, no authors appear to discuss this difference in terms of pyrrole-
pyrrolene tautomerism. Analyzing the literature one can make the conclusion that, it's the
pyrrolene ring in dipyrrins that has the constant 4.8 Hz (for instance, as in C [53]), and pyrrole
ring features 3 Hz coupling constant (for instance, as in D [54])
Figure 2. Possible tautomeric equilibrium (A, B) of 20 and NOE correlation (see
Supplementraty Info); literature examples 3J values in pyrrole and pyrrolene rings (C, D).
H
H
H
H
H
H
H
H
NOE
N
HN
NH
N
H
H
H
H
Cl
Cl
N
N
A
B
HO
HO
Thus we assume that 4.8 Hz doublet belongs to the ring existing predominantly in the
pyrrolene form, whereas the residual chlorine substutuent is attached to a "pyrrole-character"
ring. This hypothesis supports the observed complete inability of the chlorine atom to be
substituted after the first reaction occurred.
Tautomerism in the dipyrrin series due to the migration of the inner proton is widely
accepted phenomenon, [55] although there are few papers that discuss possible position of this
equilibrium. For instance, Lightner and Datta [56] discuss the equilibrium in 1-methoxy-3,8-
diethyl-2,7-dimethyldipyrrin (Fig 3). They point out that the equilibrium is shifted to the left, as
judged by the bond lengths in the X-ray structure. Falk et.al. [57] also point out that the
tautomeric form in which the pyrrolene ring is attached to the π-donor substituent predominates.
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Figure 3. Tautomers of 9-methoxy-3,8-dimethyl-2,7-diethyldipyrrin [56]
UV-Vis spectra
UV-Vis spectra (for examples, see Figure 3) show the following trend. First, substitution
of the S atoms for Cl (Table 1, entries 11, 12, 17, 18) yields a bathochromic shift of an
absorption maximum that amounts ca. 30 nm if an additional π-substituent, i.e. p-tolyl group, is
attached (entry 11). On the contrary the introduction of a N-substituent yields a substantial
hypsochromic shift (entries 21-24).
Figure 4. Samples of the UV-Vis spectra (CH3CN) of the starting compound 1a (dashed
line), bis-S-substituted 10 (grey line) and mono- N-substituted 20(solid line).
3.00
2.50
2.00
1.50
1.00
0.50
0.00
300
350
400
450
500
550
600
-0.50
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Table 1. UV-Vis spectral data of DPs in CH3CN at r.t.
Cmpd
Cmpd
λmax (ε)
λmax (ε)
(at 5×10-5M)
461(1.7 104)
458(1.9 104)
463(2.1 104)
416(9.4 104)
521(2.2 104)*)
432(1.9 104);
530(0.49 104)
424(1.3 104)
523(0.26 104)
441(1.4 104)
530(0.34 104)
440(1.4 104)
448(2.4 104)
453(2.4 104)
1a
1b
7
16
17
18
8
456(1.9 104) 19
462(2.1 104) 20
456(2.1 104) 21
9
10
15
467(7.6 103)
22
*) Measured at 7.6×10-6M
This effect of a mono N-substitution has already been observed in the series of BODIPY
dyes [40, 58-63] and reasons for it were comprehensively analyzed. Boens et.al. [50] carried out
solvent-dependent UV-Vis and fluorescence studies of the dye 23, as well as quantum chemical
calculations of the ground and the excited state of the molecule. The authors suggested that the
dipole moment of the exited state being lower than that of the ground state is responsible for the
blue shift of the UV-Vis maximum of 23 with respect to 24. On the other hand, mono S-
substitution does not cause such an effect [40, 64, 65].
15

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Figure 5. Mono-N-substituted BODIPY 23 [50] and its precursor 24.
N
N
N
N
B
B
Cl
HN
Cl
Cl
F F
F F
23
24
Besides, a low intensity bathochromically shifted band is observed in the UV-Vis spectra
of mono-N-substituted products. However, we currently were are unable to make any plausible
assignment of this band, although it is reproduced in all studied spectra. The analysis of more
data will make it possible to attribute the band.
Conclusions
This study demonstrate that dihalo-H-dipyrrins can undergo the nucleophilic substitution
reaction with S- and N-nucleophiles and are inert to O-nucleophiles. This relatively simple and
mild method for substituted dipyrrins is complementary to the recently emerged "BODIPY
nucleophilic substitution – deborylation" sequence. Also, the specific mono-N-substitution may
be regarded as a reliable and clean procedure both for mono-N-substituted dipyrrins and for
mono-N-substituted BODIPYs , eliminating the need to adjust the reaction conditions and/or the
chromatography isolation of dyes [61, 66]. This work is in progress and will be reported in due
course.
Acknowledgements
The authors are grateful to Prof. A. Masunov (University of South Florida), Sergey
Pisarev (Institute of Physiologically Active compounds, RAS, Chernogolovka, Russia) and Prof.
Andrey Ivanov (The Irkutsk Scientific Center, Siberian Branch of RAS, Irkutsk, Russia) for
16

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helpful and stimulating discussions. Financial support of Russian Foundation for Basic Research
(Grant No. 14-03-93105) is gratefully acknowledged.
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Supplementary Info
SNAr Nucleophilic substitution of 1,9-dihalodipyrrins by S and N nucleophiles.
Synthesis of new dipyrrins bearing pendant substituents.
Evgenia Leushina, Ksenia Tikhomirova, Anastasiya Permyakova, Pavel Ilyin, Alexander
Anisimov, Andrey Churakov, Andrey Khoroshutin *
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1.NMR spectra of S-substitution products
1H and 13C NMR spectra of products:
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2.NMR spectra of N-substitution products
28