Synthesis and structure determination of pyrazine-containing macrocyclic polyazomethines

Article abstract of DOI:10.1016/j.cclet.2010.05.017

Two pyrazine-containing macrocyclic polyazomethines 2 and 3 were synthesized by direct [2 + 2] and [3 + 3] condensation reactions between 2,2′-[pyrazine-2,3-diylbis(oxy)]dibenzaldehyde (1) and hydrazine. Both 2 and 3 were characterized by NMR, HRMS, and t

Full text of DOI:10.1016/j.cclet.2010.05.017

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 1263–1266
www.elsevier.com/locate/cclet
Synthesis and structure determination of pyrazine-containing
macrocyclic polyazomethines
Liang Chun Wu a, Long Qing Liu a, Hai Shan Jin a, Ming Liang Ma a,
Xiao Li Zhao b, Ke Wen a,
*
a Division of Supramolecular Chemistry and Medicinal Chemistry, Key Laboratory of Brain Functional Genomics, MOE,
and Shanghai Key Laboratory of Brain Functional Genomics, East China Normal University, Shanghai 200062, China
b Shanghai Key Laboratory of Green Chemistry and Chemical Processes, and Department of Chemistry,
East China Normal University, Shanghai 200062, China
Received 4 March 2010
Abstract
Two pyrazine-containing macrocyclic polyazomethines 2 and 3 were synthesized by direct [2 + 2] and [3 + 3] condensation
reactions between 2,20-[pyrazine-2,3-diylbis(oxy)]dibenzaldehyde (1) and hydrazine. Both 2 and 3 were characterized by NMR,
HRMS, and their structures were determined via X-ray crystal diffraction studies.
# 2010 Ke Wen. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Azomethine; Macrocycles; Schiff base; Pyrazine
Macrocyclic compounds such as crown ethers [1], cyclodextrins [2], calixarenes [3], cucurbiturils [4], and
macrocyclic bipyridinium ions [5] are intensive research topics in the areas of supramolecular chemistry.
Incorporation of functional groups in macrocyclic scaffolds could generate supramolecular systems with specific guest
binding and self-assembling abilities, for instance, introduction of heterocyclic rings into aza- and oxa-calixaromatics
resulted in heterocalixaromatics capable of interacting with neutral molecular guests [6], selective binding of metal
ions [7], and coordination-driven molecular self-assembly [8]. Azomethines are very useful scaffolds for construction
of cyclic compounds via ring closure between primary amines and aldehydes [9]. Azomethines are also known to have
biological activities, such as antitumour [10] and antibacterial [11]. They have also been found in wide application in
the areas of dyes and pigments owing to their luminescent properties [12]. However, the number of research reports on
the incorporation of azomethines into macrocycles is quite limited [13].
In this communication, two new macrocycles, 2 and 3, containing both pyrazinyl rings and polyazomethines, were
synthesized successfully via a two-step reaction sequence. First, aromatic nucleophilic substitution of 2,3-
dichloropyrazine by 2-hydroxybenzaldehyde, using K2CO3 as a base, under refluxing condition in DMF, resulted in
the formation of 2,20-[pyrazine-2,3-diylbis(oxy)]dibenzaldehyde (1) in 83% yield; 1 was then reacted with hydrazine
in methanol to give macrocyclic polymethines 2 and 3 in the yields of 8.4% and 11.1% (see Section 1), respectively
* Corresponding author.
E-mail address: kwen@brain.ecnu.edu.cn (K. Wen).
1001-8417/$ – see front matter # 2010 Ke Wen. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.05.017

[(Scheme_1)TD$FIG]
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L.C. Wu et al. / Chinese Chemical Letters 21 (2010) 1263–1266
Scheme 1. Reagents and condition: (a) K2CO3, DMF, reflux, 12 h; (b) hydrazine hydrate, methanol, 24 h.
(Scheme 1), along with some inseparable by-products. Prolonged reaction time and high reaction temperature have not
improved the yields of compounds 2 and 3. Additionally, catalytic amount of Zn(OAc)2 could accelerate the reaction,
but did not change the yields of products 2 and 3 and product distribution. Refluxing the reaction mixture in methanol
under Zn(OAc)2 overnight resulted in the improvement of the yield of compound 2 to 14%, but significantly decreased
the yield of compound 3 (only traces could be detected in TLC). Attempts to reduce the azomethines in compounds 2
and 3 with both NaBH4 and H2 (under Pd/C) failed to give the corresponding hydrazines.
Both macrocyclic products 2 and 3 give very simple 1H and 13C NMR spectra, indicating symmetrical structure in
solution; or compounds 2 and 3 are very fluxional in solution, and the rates of interconversion of various
conformational structures are very rapid relative to the NMR time scale.
The macrocyclic structures of 2 and 3 were unambiguously established by single crystal X-ray diffraction analysis.
As shown in Fig. 1, compound 2 adopts an 1,3,5-alternate conformation with a non-planer C2 symmetric structure in
the solid state. Judging from the C–O bond lengths, conjugation between the bridging oxygen atoms and the pyrazine
rings exists (C–O distances: 0.1360 and 0.1374 nm), while the bridging oxygen atoms do not conjugate to the phenyl
[(Fig._1)TD$FIG]
Fig. 1. Crystal structure of 2: (left) side view, (right) top view. Color code: O (red), N (blue), C (gray), H (white). (For interpretation of the references
to color in this figure caption, the reader is referred to the web version of the article.)

[(Fig._2)TD$FIG]
L.C. Wu et al. / Chinese Chemical Letters 21 (2010) 1263–1266
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Fig. 2. Crystal structure of 3, all hydrogen atoms are emitted for clarity; (left) side view, (right) top view. Color code: O (red), N (blue), C (gray). (For
interpretation of the references to color in this figure caption, the reader is referred to the web version of the article.)
rings (C–O: 0.1404 and 0.1406 nm). Two CH N groups (C N distances: 0.1265 and 0.1271 nm) connected to each
N–N function adopt trans-configuration with the N–N bond length of 0.1408 nm, and the hydrogen atoms of the
CH N groups are oriented out of the cycle hole. The diameter of the macrocycle hole is 0.5438 nm (distance between
the two N–N bonds), and no guest molecules (solvents) were found being included in the macrocyclic cavity. Shown in
Fig. 2, compound 3 reveals a 36-member macrocycle ring. Due to its highly flexible nature, no macrocyclic hole could
be defined for 3 in the solid state. The molecule 3 folded in a way that its hole space was occupied by part of the
molecule itself. Similar to compound 2, the bridging oxygen atoms in compound 3 conjugate to the pyrazine rings, but
not the phenyl components. The pairs of CH N groups connected to each N–N function are arranged in trans-
configuration with the C N bond distances varied from 0.1259 nm to 0.1274 nm, and the three N–N bond distances of
0.1404 nm, 0.1411 nm and 0.1414 nm, respectively.
Both compounds 2 and 3 showed maximal adsorption at 302 nm and emission at 471 nm. No changes were
observed in their adsorption and emission spectra when C60 was added to their benzene solution, indicating no
molecular interaction between the polyazomethine macrocycles (2 and 3) and C60 in benzene. Attempts to create metal
(Ag+, Cu2+, Zn2+) complexes with compounds 2 and 3 failed to give any positive results.
In summary, two macrocyclic polymethines 2 and 3 were synthesized in a two-step reaction sequence. X-ray
crystallographic analysis revealed that the 24-member ring (2) has a defined macrocyclic hole, while no defined
macrocyclic hole could be observed for the 36-member ring (3) due to its high flexible nature in the solid state. No
molecular interactions were found between the two macrocyclic compounds and C60 in benzene. Additionally, the
polymethine and pyrazinyl functions in the two macrocyclic compounds were found not to form metal complexes with
Ag+, Cu2+, Zn2+ ions. Works on the synthesis, molecular interaction and metal coordination of macrocyclic
polymethines are currently ongoing in our laboratory; the results will be reported in due course.
1. Experimental
Synthesis of compound 1: 2,3-Dichloropyrazine (2.98 g, 20 mmol), 2-hydroxybenzaldehyde (5.86 g, 48 mmol),
and K2CO3 (11.06 g, 80 mmol) were mixed in 100 mL DMF, the reaction mixture was heated to reflux for 12 h. After
cooling down, the reaction mixture was poured into 300 mL water and neutralized with 1 mol/L HCl, extracted with
ethyl acetate for three times (3 ꢀ 100 mL). The combined organic layer was washed with water and brine, dried over
Na2SO4. The solvent was evaporated and the crude product was purified by FC (PE/AcOEt 6:1) to give pure 1 (5.31 g,
83%) as white solid. 1H NMR (500 MHz, CDCl3): d 10.27 (s, 2H), 8.00 (d, 2H, J = 10 Hz), 7.73 (t, 2H,
J1 = J2 = 10 Hz), 7.71 (2H, s), 7.46 (t, 2H, J1 = J2 = 10 Hz), 7.40 (d, 2H, J = 10 Hz); 13C NMR (500 MHz, CDCl3): d
188.83, 154.27, 150.10, 135.59, 134.91, 130.65, 128.44, 126.24, 123.23; HRMS: [M+Na]+, C18H12N2O4Na+ m/z
calcd. 343.0689, found 343.0771.
Synthesis of compounds 2 and 3: Compound 1 (960 mg, 3 mmol) and hydrazine hydrate (80%, 156.25 mg,
3.6 mmol) were dissolved in 30 mL methanol, and the reaction mixture was stirred and kept in room temperature for
24 h. The solvent was then evaporated and redissolved in 40 mL ethyl acetate, washed with water and brine, dried over
Na2SO4. The ethyl acetate was evaporated and the crude products were purified by FC (PE/AcOEt, 4:1–1:1) in neutral
Al2O3 to give pure 2 (94 mg, 8.4%) and 3 (123 mg, 11.1%). 1H NMR (500 MHz, CDCl3) for 2: d 8.55 (4H, s), 7.82 (d,
4H, J = 7.75 Hz), 7.78 (4H, s), 7.46 (t, 4H, J1 = 6.5 Hz, J2 = 7.45 Hz), 7.28 (d, 4H, J = 7.25 Hz), 7.16 (d, 4H,
J = 8.15 Hz,); 13C NMR (500 MHz, CDCl3): d 157.18, 152.63, 150.32, 135.31, 131.90, 130.73, 126.10, 125.38,

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121.64; HRMS: [M+Na]+, C36H24N8O4Na+ m/z calcd. 655.1813, found 655.1984. 1H NMR (500 MHz, CDCl3) for 3:
d 8.63 (s, 6H), 7.83 (d, 6H, J = 7.25 Hz), 7.42 (s, 6H), 7.30 (t, 6H, J1 = 7.3 Hz, J2 = 7.1 Hz), 7.10 (m, 12H); 13C NMR
(500 MHz, CDCl3): d 157.45, 152.06, 150.46, 133.75, 131.88, 129.33, 126.89, 125.79, 123.04; HRMS: [M+Na]+,
C54H36N12O6Na+ m/z calcd. 971.2773, found 971.2792.
Acknowledgments
The authors thank Shanghai Commission for Science and Technology (Nos. 06Pj14034, 06DZ19002, and
10ZR1409700), Ministry of Education (No. 106078) for financial support.
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