Large scale synthesis of 4′-(4-bromophenyl)-2,2′:6′,2″-terpyridine and nature of the mysterious green by-product

Article abstract of DOI:10.1515/znb-2003-0514

4′-(4-Bromophenyl)-2,2′:6′,2″-terpyridine (5) was prepared on a large scale (up to 100 g batches) from 2-[3-(4-bromophenyl)-1-oxoprop-2-enyl]pyridine (3a) and N-[2-oxo-2-(2-pyridyl)-ethyl]pyridinium iodide (4). In the presence of substoichiometric amounts

Full text of DOI:10.1515/znb-2003-0514

Large Scale Synthesis of 4’-(4-Bromophenyl)-2,2’:6’,2”-terpyridine and
Nature of the Mysterious Green By-product
Ulrich Siemelinga, Jens Vor der Bru¨ggena, Udo Vorfelda, Anja Stammlerb,
and Hans-Georg Stammlerb
a Department of Physics, University of Kassel, Heinrich-Plett-Str. 40, D-34132 Kassel, Germany
b Faculty of Chemistry, University of Bielefeld, Universita¨tsstr. 25, D-33615 Bielefeld, Germany
Reprint requests to Prof. Dr. U. Siemeling. E-mail: siemeling@uni-kassel.de
Z. Naturforsch. 58b, 443 – 446 (2003); received December 9, 2002
4’-(4-Bromophenyl)-2,2’:6’,2”-terpyridine (5) was prepared on a large scale (up to 100 g
batches) from 2-[3-(4-bromophenyl)-1-oxoprop-2-enyl]pyridine (3a) and N-[2-oxo-2-(2-pyridyl)-
ethyl]pyridinium iodide (4). In the presence of substoichiometric amounts of 4, 1-[3-(4-
bromophenyl)indolizin-1-yl-1-imino]-3-[4-bromophenyl]-1H-indolizinium iodide (6aI) was formed
as an intensely coloured by-product. The synthesis of several related novel indolizinium deriva-
tives is described, including 1-[3-(4-methylphenyl)indolizin-1-yl-1-imino]-3-[4-methylphenyl]-1H-
indolizinium hexafluorophosphate (6cPF6), whose crystal structure has been determined.
Key words: Rigid-Rod Molecules, Indolizinium Compounds, X-Ray Data
4’-(4-Bromophenyl)-2,2’:6’,2”-terpyridine (5) is a
key compound in many studies concerned with metal
complexes of rigid-rod type architectures. The com-
pound was first synthesised by Spahni and Calza-
ferri [1] in 20% yield, employing a one-pot method.
We have devised a two-step synthesis, which follows
the Kro¨hnke procedure [2] and gives an overall yield of
55%. Our approach is similar to that recently published
˚
by Akermark and co-workers [3], whose protocol gives
a 64% yield, but involves tedious chromatographic pu-
rification of the crude product on a very small scale
(≤ 1 g). We have used our method to prepare large
batches of the compound (up to 100 g), which is ob-
tained in analytically pure form by simple recrystalli-
sation of the crude product (Scheme 1).
If the reaction is performed with substoichiometric
amounts of N-[2-oxo-2-(2-pyridyl)ethyl]pyridinium
iodide (4), for example by inadvertently using impure
material, an intensely coloured by-product is formed,
which can be removed fairly easily owing to its poor
solubility in most organic solvents. The solubility of
this substance is highest in DMSO, from which it
can be recrystallised forming large dark green leaves,
which show an impressive metallic lustre. The forma-
tion of unidentified by-products of very similar appear-
ance in the synthesis of terpyridines is a common phe-
nomenon and has already been reported by Spahni and
Calzaferri [1].
Scheme 1.
We have identified the coloured by-product as the
ionic indolizine derivative 6aI, which results from
the reaction of 2-[3-(4-bromophenyl)-1-oxoprop-2-
c
0932–0776 / 03 / 0500–0443 $ 06.00 ꢀ 2003 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
Brought to you by | University of Florida
Authenticated
Download Date | 11/23/17 2:25 PM

444
U. Siemeling et al. · Large Scale Synthesis of 4’-(4-Bromophenyl)-2,2’:6’,2”-terpyridine
Scheme 2.
Fig. 1. Molecular structure of the cation of 6c[PF6] in
enyl]pyridine (3a) with ammonium acetate in the pres-
ence of pyridinium iodide, as has been proved by
an independent synthesis. Only two examples of re-
lated species have been reported to date [4]. They
were formed by the reaction of 2-[3-(4-X-phenyl)-1-
oxoprop-2-enyl]pyridine (X = Cl, OMe) with ammo-
nium acetate in acetic acid and have been isolated
as iodides and perchlorates, when pyridinium iodide
and perchlorate, respectively, was present in the reac-
tion mixture, and as acetates in the absence of pyri-
dinium salts. Only very limited data are available for
these compounds, which, in a simplified view, may be
looked upon as indolizines bearing a substituent NR+
in the 1-position. Quantum-chemical studies have re-
vealed that such substituted indolizines are most stable
when the electron-withdrawing substituent is attached
to just this position [5].
We have prepared the new indolizine derivatives
6a+ – 6c+ by rational synthesis (isolated as acetates
having the stoichiometry 6OAc•HOAc) (Scheme 2).
We have investigated 6c+ in some detail, since
its solubility is the most favourable. Solutions of
this species are intensely blue (λmax = 635 nm,
ε = 153000 M−1 cm−1), whereas crystalline salts are
dark green or golden green, showing metallic sheen.
6cOAc•HOAc is very soluble in DMSO and fairly sol-
uble in dichloromethane and hot ethanol. 6c+ is most
conveniently isolated as the chloride salt, which is pre-
cipitated by bubbling HCl into a solution of the crude
acetate in ethanol or dichloromethane. Since crystals
of the acetate and chloride proved notoriously unsuit-
able for a single-crystal X-ray structure analysis, we
synthesised the hexafluorophosphate by stirring a sat-
urated dichloromethane solution of the chloride with
◦
the crystal. Selected bond lengths (pm) and angles ( )
not mentioned in the text: N(1)-C(1) 1.365(5), N(1)-
C(5) 1.389(5), N(1)-C(8) 1.427(5), N(2)-C(6) 1.335(5),
N(2)-C(21) 1.337(5), N(3)-C(16) 1.373(5), N(3)-C(20)
1.386(5), N(3)-C(23) 1.428(5), C(1)-C(2) 1.355(6), C(2)-
C(3) 1.400(6), C(3)-C(4) 1.366(6), C(4)-C(5) 1.389(6),
C(6)-C(7) 1.433(6), C(8)-C(9) 1.464(6), C(16)-C(17)
1.356(6), C(17)-C(18) 1.400(6), C(18)-C(19) 1.375(6),
C(19)-C(20) 1.387(6), C(21)-C(22) 1.426(6), C(22)-C(23)
1.371(6), C(23)-C(24) 1.458(6); C(1)-N(1)-C(5) 121.7(4),
C(1)-N(1)-C(8) 129.4(4), C(5)-N(1)-C(8) 108.9(3), C(16)-
N(3)-C(20) 120.4(3), C(16)-N(3)-C(23) 130.1(4), C(20)-
N(3)-C(23) 109.4(3).
solution and subjected to an X-ray diffraction study. A
view of the cation is shown in Fig. 1, representing the
first example of a structurally characterised compound
of this kind.
The bond lengths in the six-membered heterocycles
range from 135.6(6) to 140.0(6) pm and are very simi-
lar considering the margin of experimental error. Those
in the five-membered rings range from 135.8(6) pm for
C(7)–C(8) to 143.5(6) pm for C(5)–C(6) and C(20)–
C(21), respectively, and thus show quite significant dif-
ferences. In comparison to other structurally charac-
terised indolizines, the bonds C(5)–C(6) and C(20)–
C(21) are exceptionally long, usual values being in the
range of 137 pm [6]. The elongated bonds correspond
to a bond order which is lower than usual as is reflected
by the resonance structures shown in Scheme 2. The
distances between N(2) and the two C atoms attached
to it are identical within experimental error (average
value 133.6 pm) and correspond to a C–N bond order
of 1.5. The angle at N(2) is 125.1(4)◦, which is in ac-
cord with an sp2 hybridisation of this atom.
In summary, we have developed a convenient large-
an aqueous solution of KPF6. Single crystals of 6cPF6 batch synthesis of 5, which is of central importance for
were grown by cooling of the dried dichloromethane studies involving rigid-rod coordination compounds.
Brought to you by | University of Florida
Authenticated
Download Date | 11/23/17 2:25 PM

U. Siemeling et al. · Large Scale Synthesis of 4’-(4-Bromophenyl)-2,2’:6’,2”-terpyridine
445
We have further elucidated the nature of the mysteri- 149.0, 149.1, 156.0. – MS (EI): m/z (%) = 389 (97) [5+
(
81Br)], 387 (100) [5+ 79Br)]. – C21H14BrN3 (388.3): calcd.
(
ous green by- product of the synthesis and have uncov-
ered the reason for its occurrence and the way it can be
avoided.
C 64.96, H 3.63, N 10.82; found C 64.47, H 3.82, N 10.79.
Synthesis of 1-[3-(4-bromophenyl)indolizin-1-yl-1-imino]-3-
(4-bromophenyl)-1H-indolizinium acetate (6aOAc•HOAc)
Experimental Section
A suspension of 3a (14.0 g, 46.6 mmol) and ammonium
acetate (23.0 g, 298 mmol) in acetic acid (100 ml) was
slowly heated to 100 ◦C. After 10 min at this temperature the
dark blue solution was allowed to cool to room temperature.
The product was isolated by filtration, washed with diethyl
ether (3 × 20 ml) and dried in vacuo. Yield 13.5 g (82%).
Compounds 3a [3], 3c [7] and 4 [8] were prepared by
slight modification of published procedures. All other com-
pounds were commercially available. Solvents were purified
by standard procedures. – NMR: Bruker Avance DRX 500
and Varian Unity INOVA 500 (500.13 MHz for 1H). – MS:
VG Autospec (EI; LSIMS, 3-nitrobenzyl alcohol matrix).
– UV/vis: Perkin Elmer Lambda 9. – Elemental analyses:
Beller (Go¨ttingen), H. Kolbe (Mu¨lheim an der Ruhr) and mi-
croanalytical laboratory of the University of Bielefeld.
–
1H NMR (DMSO-d6): δ = 1.75 (s, 6 H), 7.54 (m, 2 H),
7.79 (“d”, apparent J = 8.5 Hz, 4 H), 7.86 (“d”, apparent
J = 8.5 Hz, 4 H), 8.00 (s, 2 H), 8.05 (m, 2 H), 8.55 (“d”, ap-
parent J = 8.4 Hz, 2 H), 8.79 (“d”, apparent J = 6.6 Hz, 2 H),
1
13.69 (br. s, 1 H). – 13C{ H} NMR (DMSO-d6): δ = 21.6,
Synthesis of 2-[3-(4-methoxycarbonylphenyl)-1-oxoprop-2-
enyl]pyridine (3b)
113.5, 122.0, 123.6, 126.7, 130.0, 133.1, 134.2, 135.3, 137.5,
138.3, 142.8, 146.1, 176.6. – MS (LSIMS): m/z = 556 [6a+].
– C32H25N3Br2O4 (675.4): calcd. C 56.91, H 3.73, N 6.22;
found: C 57.13, H 3.92, N 6.01.
2-Acetylpyridine (2) (7.40 g, 61.0 mmol) was added to a
solution of methyl 4-formylbenzoate (10.0 g, 61.0 mmol) in
methanol (100 ml) cooled to 0 ◦C. A 2 N solution of sodium
hydroxide (100 ml) was added with vigorous stirring. Af-
ter 14 h at room temperature the yellow precipitate was iso-
lated by filtration, washed with methanol (10 ml) and wa-
ter (5 × 50 ml) and dried in vacuo. Yield 12.4 g (76%). –
1H NMR (CDCl3): δ = 3.89 (s, 3 H), 7.45 – 7.49 (m, 1 H),
7.74 (“d”, apparent J = 8.2 Hz, 2 H), 7.82 – 7.91 (m, 2 H),
8.03 (“d”, apparent J = 8.2 Hz, 2 H), 8.15 (d, J = 7.8 Hz,
Synthesis of 1-[3-(4-bromophenyl)indolizin-1-yl-1-imino]-3-
(4-bromophenyl)-1H-indolizinium iodide (6aI)
A solution of 6aOAc•HOAc (1.00 g, 1.48 mmol) and
pyridinium iodide (310 mg, 1.50 mmol) in ethanol (10 ml)
was heated to reflux for 2 h. The mixture was allowed to cool
to room temperature. The product was isolated by filtration
and dried in vacuo. Yield 935 mg (83%). Alternatively, the
product may be obtained in similar yield from the reaction
of 3a with ammonium acetate in the presence of pyridinium
iodide. An analytical sample was obtained by recrystallisa-
tion from DMSO and had the composition 6aI•DMSO. –
1H NMR (DMSO-d6): δ = 7.54 (m, 2 H), 7.79 (“d”, ap-
parent J = 8.5 Hz, 4 H), 7.86 (“d”, apparent J = 8.5 Hz,
4 H), 8.00 (s, 2 H), 8.05 (m, 2 H), 8.55 (“d”, apparent
J = 8.4 Hz, 2 H), 8.79 (“d”, apparent J = 6.6 Hz, 2 H). –
1 H), 8.34 (d, J = 16.0 Hz), 8.71 (d, J = 4.0 Hz, 1 H).
1
–
13C{ H} NMR (CDCl3): δ = 52.2, 122.9, 123.0, 127.1,
128.5, 130.0, 131.4, 137.0, 139.3, 143.0, 148.9, 153.9, 166.5,
189.2. – MS (EI): m/z = 267 [3b+]. – C16H13NO (267.3):
calcd. C 71.90, H 4.90, N 5.24; found C 71.70, H 5.01,
N 5.13.
Synthesis of 4’-(4-bromophenyl)-2,2’:6’,2”-terpyridine (5)
1
13C{ H} NMR (DMSO-d6): δ = 113.5, 122.0, 123.6, 126.7,
In a typical run, 2-[3-(4-bromophenyl)-1-oxoprop-2-
enyl]pyridine (3a) (46.7 g, 162.0 mmol), N-[2-oxo-2-(2-
pyridyl)ethyl)]pyridinium iodide (4) (53.0 g, 162.5 mmol)
and ammonium acetate (340 g, 4.41 mol) were suspended
130.0, 133.1, 134.2, 135.3, 137.5, 138.3, 142.8, 146.1. –
MS (LSIMS): m/z = 556 [6a+]. – C30H24N3Br2IOS (761.3):
calcd. C 47.32, H 3.18, N 5.74, Br 20.99, I 16.67, O 2.10,
S 4.21; found: C 46.91, H 3.31, N 5.74, Br 21.13, I 16.90,
O 2.32, S 4.28.
◦
in acetic acid (600 ml) and heated with stirring to 90 C
for 2 h. The mixture was allowed to cool to room temper-
ature with stirring, affording the product as colourless nee-
dles, which were filtered off, washed with water and dried in
vacuo. Yield 34.8 g (55%). The reaction may be scaled up
by at least a factor of two without a decrease of the yield.
Synthesis of 1-[3-(4-methoxycarbonylphenyl)indolizin-1-yl-
1-imino]-3-(4-methoxycarbonylphenyl)-1H-indolizinium io-
dide (6bOAc•HOAc)
–
1H NMR (CDCl3): δ = 7.32 – 7.37 (m, 2 H), 7.61 (“d”,
apparent J = 8.6 Hz, 2 H), 7.75 (“d”, apparent J = 8.6 Hz,
By
a procedure analogous to that described for
2 H), 7.83 – 7.89 (m, 2 H), 8.63 (d, J = 8.6 Hz, 2 H), 8.66 (s, 6aOAc•HOAc, 17.3 g (56%) of 6bOAc•HOAc was obtained
1
2 H), 8.71 (d, J = 4.2 Hz, 2 H). – 13C{ H} NMR (CDCl3): from the reaction of 3b (13.0 g, 48.6 mmol) and ammonium
δ = 118.5, 121.3, 123.4, 123.9, 128.9, 132.1, 136.9, 137.4, acetate (23.0 g, 300 mmol) in acetic acid (100 ml). Owing
Brought to you by | University of Florida
Authenticated
Download Date | 11/23/17 2:25 PM

446
U. Siemeling et al. · Large Scale Synthesis of 4’-(4-Bromophenyl)-2,2’:6’,2”-terpyridine
to the poor solubility of the product, no interpretable NMR (LSIMS): m/z = 426 [6c+]. – C30H28N3ClO2 (498.0): calcd.
spectra could be obtained. – MS (LSIMS): m/z = 514 [6b+]. C 72.35, H 5.67, N 8.44; found: C 71.95, H 5.92, N 8.82.
– C36H31N3O8 (633.7): calcd. C 68.23, H 4.93, N 6.63;
found C 68.33, H 5.25, N 6.86.
Synthesis of 1-[3-(4-methylphenyl)indolizin-1-yl-1-imino]-
3-(4- methylphenyl)-1H-indolizinium hexafluorophosphate
(6cPF6)
Synthesisof1-[3-(4-methylphenyl)indolizin-1-yl-1-imino]-3-
(4-methoxycarbonylphenyl)-1H-indoliziniumacetate(6cOAc
• HOAc)
A saturated aqueous solution of potassium hexafluo-
rophosphate (10 ml) was added to a saturated solution of
6cCl•2H2O in dichloromethane (10 ml). The mixture was
stirred vigorously for 1 h. The organic layer was separated
By
a procedure analogous to that described for
6aOAc•HOAc, 13.7 g (83%) of 6cOAc•HOAc was obtained
from the reaction of 3c (13.5 g, 60.5 mmol) and ammonium
acetate (20.0 g, 359 mmol) in acetic acid (90 ml). – 1H NMR
(CDCl3): δ = 1.99 (s, 6 H), 2.42 (s, 6 H), 7.22 (s, 2 H),
7.35 (“d”, apparent J = 7.7 Hz, 4 H), 7.45 (m, 2 H), 7.48 (“d”,
apparent J = 7.9 Hz, 4 H), 7.91 (m, 2 H), 8.37 (d, J = 8.3 Hz,
◦
and dried with sodium sulfate. Crystallisation at 4 C af-
forded a small amount of the product as dark green nee-
dles. The compound was characterised by single-crystal X-
ray diffraction.
Crystal structure determination of compound 6cPF6
CH2Cl2
•
2 H), 8.50 (d, J = 6.5 Hz, 2 H). – 13C{ H} NMR (DMSO-
1
d6): δ = 21.6, 22.9, 109.2, 119.6, 120.2, 124.0, 128.2, 128.4,
130.2, 134.6, 140.9, 141.1, 143.1, 176.4. – MS (LSIMS):
m/z = 426 [6c+]. – C34H31N3O4 (545.6): calcd. C 74.84,
H 5.73, N 7.70; found: C 75.00, H 6.03, N 7.71.
Siemens P21 four-circle diffractometer, graphite-mono-
˚
chromated Mo-Kα radiation (λ = 0.71073 A). Structure so-
lution by direct methods; full-matrix least-squares refine-
ment on F2 (Siemens SHELXTL PLUS, SHELXL 97).
C31H26Cl2F6N3P (656.42), monoclinic, space group P21/n,
Synthesis of 1-[3-(4-methylphenyl)indolizin-1-yl-1-imino]-3-
(4-methylphenyl)-1H-indolizinium chloride (6cCl•2H2O)
˚
a = 8.365(2), b = 19.955(4), c = 17.520(5) A, β = 97.31(2),
V = 2900.7(12) A , Z = 4, dcalcd = 1.503 g/cm3, µ =
3
˚
0.346 mm−1, F(000) = 1344. A metallic-green needle (0.7×
0.2 × 0.2 mm3) was used for data collection at 173 K. θ
Range 2.0 – 25.0◦, 0 ≤ h ≤ 9, 0 ≤ k ≤ 23, −20 ≤ l ≤ 20;
5463 reflections collected, 5090 independent (Rint = 0.0423);
no absorption correction was applied; 389 parameters; no re-
straints. The non-hydrogen atoms were refined anisotropi-
cally. Hydrogen atoms were included at calculated positions
using a riding model. Final R1 = 0.0622, wR2 = 0.1560.
A suspension of 3c (13.5 g, 60.5 mmol) and ammo-
nium acetate (20.0 g, 259 mmol) in acetic acid (90 ml) was
◦
slowly heated to 100 C. After 10 min at this temperature
the dark blue solution was allowed to cool to room tem-
perature. Dichloromethane (100 ml) was added and subse-
quently water (200 ml). The organic layer was separated and
dried with sodium sulfate. HCl was bubbled through the so-
lution. The product was isolated by filtration, washed with
ethanol (10 ml) and water (2 × 10 ml) and dried in vacuo.
Yield 8.42 g (76%). – 1H NMR (DMSO-d6): δ = 2.43 (s,
6 H), 3.61 (s, 4 H), 7.44 (“d”, apparent J = 7.7 Hz, 4 H),
7.49 (m, 2 H), 7.69 (“d”, apparent J = 7.7, 4 H), 7.89 (s, 2 H),
8.00 (m, 2 H), 8.47 (d, J = 8.3 Hz, 2 H), 8.73 (d, J = 6.4 Hz,
3
˚
Residual electron density: 0.287/−0.376 e/A . Crystallo-
graphic data for the structure have been deposited with the
Cambridge Crystallographic Data Centre, CCDC-192341.
Copies of the data can be obtained free of charge on appli-
cation to The Director, CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK [Fax: int.code+(1223)336-033; e-mail for in-
quiry: fileserv@ccdc.cam.ac.uk].
1
2 H). – 13C{ H} NMR (DMSO-d6): δ = 21.0, 109.7, 118.9,
120.3, 124.8, 128.9, 129.7, 134.4, 134.8, 140.0, 142.9. – MS
[1] W. Spahni, G. Calzaferri, Helv. Chim. Acta 67, 450
(1984).
[6] T. L. Gilchrist, Heterocyclenchemie, p. 16, VCH,
Weinheim (1995).
[2] F. Kro¨hnke, Synthesis 1 (1976).
[3] P. Korall, A. Bo¨rje, P.-O. Norrby, B. Akermark, Acta
[7] C. Mikel, P. G. Potvin, Inorg. Chim. Acta 325, 1
(2001).
˚
Chem. Scand. 51, 760 (1997).
[8] G. U. Priimov, P. Moore, P. K. Maritim, P. K. Butalanyi,
N. W. Alcock, J. Chem. Soc., Dalton Trans. 445 (2000).
[4] F. W. Kro¨ck, F. Kro¨hnke, Chem. Ber. 104, 1645 (1971).
[5] D. A. Maiboroda, E. V. Babaev, K. Jug, J. Org. Chem.
62, 7100 (1997).
Brought to you by | University of Florida
Authenticated
Download Date | 11/23/17 2:25 PM