Synthesis and fluorescence properties 2-N-piperidinopyrazines

Article abstract of DOI:10.14233/ajchem.2013.15201

2-N-Piperidinopyrazine, 2-N-(3-methyl)piperidinopyrazine and 2-N-(4-methyl)piperidinopyrazine were synthesized by reacting 2-chloropyrazine with piperidine, 3-methylpiperidine, 4-methylpiperidine respectively. The structures of these compounds were confir

Full text of DOI:10.14233/ajchem.2013.15201

Asian Journal of Chemistry; Vol. 25, No. 14 (2013), 8121-8124
http://dx.doi.org/10.14233/ajchem.2013.15201
Synthesis and Fluorescence Properties 2-N-Piperidinopyrazines
1
1
1
1,2,*
AZILA MOHD IDRIS , AZHAR ARIFIN , HASNA NADIAH JOHARI and ZANARIAH ABDULLAH
1Department of Chemistry, Faculty of Science, Universiti of Malaya, Kuala Lumpur, Malaysia
2Section for Co-curricular Courses, External Faculty Electives & TITAS (SKET), Universiti of Malaya, Kuala Lumpur, Malaysia
*Corresponding author: Fax: +60 3 79674193/5488; Tel: +60 3 79674240/5410; E-mail: zana@um.edu.my
(Received: 25 January 2013;
Accepted: 5 August 2013)
AJC-13886
2-N-Piperidinopyrazine, 2-N-(3-methyl)piperidinopyrazine and 2-N-(4-methyl)piperidinopyrazine were synthesized by reacting
2-chloropyrazine with piperidine, 3-methylpiperidine, 4-methylpiperidine respectively. The structures of these compounds were confirmed
by spectroscopic methods. Fluorescence studies were carried out in tetrahydrofuran, acetonitrile, ethyl acetate and ethanol. 2-N-
Piperidinopyrazine showed the highest fluorescence intensity in tetrahydrofuran followed by 2-N-4-methylpiperidinopyrazine. The
fluorescence intensity decreases as the polarity of the solvent increases.
Key Words: 2-N-Piperidinopyrazine, 2-N-(3-Methyl)piperidinopyrazine, 2-N-(4-Methyl)piperidinopyrazine, Fluorescence.
MHz and FT-NMR ECA 400 MHz spectrometers, IR spectra
were recorded on a Perkin-Elmer 1600 series FT-IR or a
Perkin-Elmer RX1 FT-IR spectrophotometer. Melting point
was carried out in glass capillaries recorded on a melting point
apparatus Fargo MP-ID and are uncorrected. Mass spectro-
scopic analyses were performed at a Hewlett-Packard HP 6890
Series of GC System with mass selective indicator and GCMS
QP5050A Shimadzu. Fluorescence spectra were recorded
using Fluorescence Spectrometer, Model F2000, Hitachi and
Luminescence Spectrometer, Model LS 50B, Perkin Elmer.
The measurements were recorded at room temperature at the
same setting in quartz cells.
INTRODUCTION
Pyrazine represents an important class of heterocyclic
compounds1-4. The structural unit is found in many natural
products. They are important flavour ingredient in food5,6,
which also occur as flavour constituents of peas, coffee,
capsicum peppers and wines7. Although present in very small
amounts, they are extremely odorous and can be detected at
concentration as low as 0.00001 ppm. Pyrazine is an aromatic
heterocycles, therefore it undergoes electrophilic aromatic
substitution. However, nucleophilic substitution of pyrazine
has been reported8,9. The nucleophilic reagents can attack at
the 2, 3, 5 and 6 positions of the pyrazine ring. Studies have
shown that the nucleophiles attacked the ring becomes easier
in the presence of at least one powerful electron releasing group
such as NH2, OH, SH in another position on the ring.
The fluorescence characteristic of heterocyclic compounds
in general and pyrazine in particular is less studied. However,
our group has reported on the fluorescence characteristics of
pyridines, pyrimidines and purines9-12. In this paper, the
fluorescence characteristics of 2-piperidinopyrazines will
be reported.
2-N-Piperidinopyrazine: 2-Chloropyrazine (0.40 mL)
was added to a solution of piperidine (5.00 mL) in ethanol
and the mixture was refluxed for 2 h. The mixture was then
cooled and the solvent was evaporated off. The residue was
dissolved in water and then extracted with diethyl ether (3 ×
10 mL). The ether extracts were washed with water (3 × 10
mL) and dried over anhydrous sodium sulphate. Evaporation
of the solvent gave the product, a yellowish liquid which was
purified by washing with several portions of diethyl ether.
(0.5606 g, 76 %); IR (KBr, νmax, cm-1): 1672 (C=N), 1517
1
(C=C), 2935 (C-H); H NMR (ppm, 400 MHz, CDCl3) δH:
EXPERIMENTAL
8.05 (1H, d, J = 1.4 Hz, H-3), 7.96 (1H, dd, J = 2.6 Hz, 1.4
Hz, H-5), 7.69 (1H, d, J = 2.6 Hz, H-6), 3.49 (4H, s, H-2',
H-6'), 1.55 (6H, s, H-3', H-4', H-5'); 13C NMR (ppm, 100 MHz,
CDCl3) δC: 155.0 (C-2), 141.6 (C-3), 131.7 (C-5), 130.9 (C-
6), 45.4 (C-2', C-6'), 25.0 (C-5',C-3'), 24.4 (C-4'); GCMS:
Found M+ = 163.00; C9H13N3 requires M+ = 163.22.
Organic solvents were distilled prior to use. Thin Layer
Chromatography (TLC) was performed using MERCK 25
TLC plates 20 20 cm silica gel 60 F254 precoatedaluminium
plate. Nuclear magnetic resonance (NMR) spectra were taken
in deuterated chloroform on the JEOL FT-NMR Lambda 400

8122 Idris et al.
Asian J. Chem.
2-N-(3-Methyl)piperidinopyrazine: 2-Chloropyrazine
the sensitivity is 2) and Luminescence Spectrometer, Model
LS 50B, Perkin Elmer using 2.5 mm slits. Quinine sulphate
(10 ppm in 0.1 N sulphuric acid) was used as the standard. All
spectra were recorded at room temperature and are corrected
for phototuberesponse and by substraction of the solvent back-
ground. The fluorescence spectra of all the compounds were
measured in tetrahydrofuran acetonitrile, ethyl acetate and
ethanol of concentrations of 10-6 M in capped and uncapped
conditions.
(0.20 mL) was added to 3-methylpiperidine (1.33 mL) and
refluxed in oil bath at 120-140 ºC. The reaction was stopped
when starting material could no longer be detected on TLC.
The mixture was then cooled and dissolved in 10 mL of
water. The aqueous layer was extracted with ether (3 × 10
mL). The ethereal layer was washed twice with water (10 mL)
and dried over anhydrous sodium sulphate. Filtration and
evaporation of the solvent gave the crude mixture which was
purified using preparative thin layer chromatography. Ethyl
acetate-hexane mixture (1:2) was used as the solvent system.
(0.1337 g, 34 %); IR (KBr, νmax, cm-1): 1673 (C=N), 1517
RESULTS AND DISCUSSION
2-N-Piperidinopyrazine (1), 2-N-(3-methyl)piperidino-
pyrazine (2) and 2-N-(4-methyl)piperidinopyrazine (3) were
obtained when 2-chloropyrazine were treated with piperidine,
3-methylpiperidine and 4-methylpiperidine respectively as
shown in Fig. 1.
1
(C=C), 2927 (C-H); H NMR (ppm, 400 MHz, CDCl3) δH:
8.04 (1H, d, J = 1.4 Hz, H-3), 7.94 (1H, dd, J = 2.6Hz, 1.4 Hz,
H-5), 7.66 (1H, d, J = 2.6 Hz, H-6), 4.10 (2H, d, J = 12 Hz,
H-6'), 2.73 (1H, td, J = 12.6 Hz, 2.9 Hz, H-2'), 2.41 (1H, t, J =
10.9 Hz, H-2'), 1.42 (4H, m, H-5', H-4'), 1.03 (1H, m, H-3'),
0.86 (3H, d, J = 6.5 Hz, CH3); 13C NMR (ppm, 100 MHz,
CDCl3) δC: 155.0 (C-2), 141.7 (C-3), 131.8 (C-5), 131.1
(C-6), 52.2 (C-6'), 45.0 (C-2'), 33.1 (C-5'), 30.6 (C-4'), 24.8
(C-3'), 19.3 (CH3); GCMS: Found M+ = 177.00; C10H15N3
requires M+ = 177.25.
2-N-(4-Methyl)piperidinopyrazine: 2-Chloropyrazine
(0.20 mL) was added to 4-methylpiperidine (2.20 mL). The
reaction mixture was refluxed in an oil bath for 2 h. The
mixture was then cooled and the solvent was evaporated off.
The reaction mixture was dissolved in water and then extracted
with diethyl ether (3 × 10 mL). The ether extracts were washed
with water and dried over anhydrous sodium sulphate. Evapo-
ration of solvent gave 2-N-(4-methyl) piperidinopyrazine, a
yellowish liquid. (0.3049 g, 77 %); IR (KBr, νmax, cm-1): 1673
(C=N), 1518 (C=C), 2924 (C-H); 1H NMR (ppm, 400 MHz,
CDCl3) δH: 8.08 (1H, d, J = 1.4 Hz, H-3), 7.98 (1H, dd, J = 2.6
Hz, 1.4 Hz, H-5), 7.69 (1H, d, J = 2.6 Hz, H-6), 4.22 (2H, d,
J = 12 Hz, H-2'), 2.79 (2H, td, J = 12.6 Hz, 2.4 Hz, H-6'), 2.60
(2H, d, J = 12 Hz, H-3'), 1.54 (1H, m, H-4'), 0.99 (2H, m,
H-5'), 0.85 (3H, d, J = 4 Hz, CH3); 13C NMR (ppm, 100 MHz,
CDCl3) δC: 155.1 (C-2), 141.7 (C-3), 131.9 (C-5), 131.2
(C-6), 45.0 (C-2', C-6'), 33.6 (C-3', C-5'), 31.0 (C-4'), 21.9
(CH3); GCMS: Found M+ = 177.00; C10H15N3 requires M+ =
177.25.
Fig. 1. Formation of 2-N-piperidinopyrazine (1), 2-N-(3-methyl)
piperidinopyrazine (2) and 2-N-(4-methyl)piperidinopyrazine (3)
from 2-chloropyrazine
The structure of 2-N-piperidinopyrazine (1), 2-N-(3-
methyl)piperidinopyrazine (2) and 2-N-(4-methyl)
piperidinopyrazine were confirmed by spectroscopic methods.
In general, the presence of the adjacent electron withdrawing
nitrogen atom in pyrazine makes the 2-position of pyrazine
ring activated towards the nucleophilic attack. Thus, nucleo-
philic substitution reaction occurs at this position. The detail
Fluorescence studies: Fluorescence spectra were recorded
using fluorescence spectrometer, Model F2000, Hitachi (with
TABLE-1
FLUORESCENCE EMISSION PEAKS PIPERIDINOPYRAZINE DERIVATIVES IN
TETRAHYDROFURAN, ACETONITRILE, ETHYL ACETATE AND ETHANOL
2-Y-Pyrazine
Solvent
Tetrahydrofuran
Acetonitrile
Ethyl acetate
Ethanol
Excitation wavelength (nm)
Fluorescence wavelength (nm)
Intensity
62.27
51.64
26.3
345
348
344
349
347
347
345
348
345
347
343
348
403
411
404
422
402
414
401
424
402
411
404
425
-N-Piperidino (1)
4.183
27.42
11.31
15.32
3.37
Tetrahydrofuran
Acetonitrile
Ethyl acetate
Ethanol
-N-3-Methylpiperidino (2)
-N-4-Methylpiperidino (3)
Tetrahydrofuran
Acetonitrile
Ethyl acetate
Ethanol
29.62
17.80
21.88
2.56

Vol. 25, No. 14 (2013)
Synthesis and Fluorescence Properties 2-N-Piperidinopyrazines 8123
assignments of protons and carbons of compounds 1, 2 and 3
are given in experimental section.
around the system, thus low fluorescence intensity was
observed. It is also believed that both compounds formed
complex with the solvent as shown in Fig. 3, whereby the
intramolecular charge transfer transitions via hydrogen
bonding are formed.
Fluorescence studies: Table-1 shows the fluorescence
emission peaks of piperidinopyrazine derivatives in tetrahy-
drofuran, acetonitrile, ethyl acetate and ethanol respectively.
It can be seen from Table-1 that all compounds showed the
highest fluorescence intensity in tetrahydrofuran followed by
acetonitrile, ethyl acetate and ethanol.
The fluorescence spectrum of 2-N-piperidinopyrazine in
various solvents is as shown in Fig. 2.
Fig. 3. Formation of hydrogen bonding with the solvent
This phenomenon is also explained by Weisstuch and
Testa16 which they had reported that in some aromatic hetero-
cyclic compounds with hydrogen bonding formation quenched
the fluorescence intensity. The formation of hydrogen bond
which is capable of conjugating with the π-electron system of
the heterocyclic ring, results in the mobility of the π-electron
been disturbed and caused the fluorescence intensity to be
reduced. This phenomenon also favours the low lying n → π*
transitions which refers to the excitation of a non-bonding
electron to an antibonding orbital It was pointed out that n → π*
transitions are usually not observed in fluorescence spectra
and when present are weak16.As the results, a decrease in fluore-
scence intensity was observed. Similar observation was recorded
with 2-N-(3-methyl)piperidinopyrazine and 2-N-(4-methyl)-
piperidinopyrazine.
Wavelength (nm)
Fig. 2. Fluorescence spectra of 2-N-piperidinopyrazine in various solvents
Table 1 and Fig. 2 show that there is a shift in fluore-
scence maxima in polar solvents for all compounds. This
observation is due to the fact that in most polar molecules, the
excited state is more polar than the ground state. Hence, an
increase in the polarity of the solvent produces a greater
stabilization of the excited state than of the ground state. Conse-
quently, a shift in fluorescence spectra to longer wavelength
is observed as the polarity and dielectric constant of the
solvents increases13. 2-N-Piperidinopyrazine showed a higher
shifting of fluorescence peak in THF and acetonitrile which
both are polar aprotic solvents and have higher dielectric
constant. This observation is in the agreement with the work
Both 2-N-(3-methyl)piperidinopyrazine and 2-N-(4-
methyl)piperidinopyrazine showed lower fluorescence
intensity in all solvents compared to 2-N-piperidinopyrazine.
The reduced fluorescence intensity observed is probably due
to the reduction in the rigidity of the piperidino ring. The pres-
ence of methyl group on the piperidino ring increases the
vibrational amplitudes of thering, thus energy absorbed was
dissipated as heat. This phenomena was in agreement with
the work done by Yang et al.17 and Joshi nee Pant et al.18.
Table-2 shows the fluorescence intensity of 2-N-piperi-
dinopyrazine, 2-N-(3-methyl)piperidinopyrazine and 2-N-(4-
methyl)piperidinopyrazine in tetrahydrofuran and acetonitrile
at different concentrations.
done by Drobnik and Augenstein14,15
.
2-N-Piperidinopyrazine showed the lowest fluorescence
intensities in ethanol. The observations are believed to be due
to the quenching effect from the "hydrogen bonded solvents"
associated with the lone pair of electrons on the pyrazine ring
and the amino group. As the result, it is not available to move
TABLE-2
FLUORESCENCE INTENSITY OF, 2-N-(3-METHYL)PIPERIDINOPYRAZINE AND 2-N-(4-METHYL)PIPERIDINOPYRAZINE
IN TETRAHYDROFURAN, AND ACETONITRILE AT DIFFERENT CONCENTRATIONS
2-N-Piperidinopyrazine
Concentration (M)
× 10-5
Fluorescence wavelength (nm)
Intensity
× 10-5
Solvent
× 10-4
6.127
6.127
× 10-6
6.127
6.127
10-4
401
419
10-5
402
415
10-6
403
411
× 10-4
560.0
460.6
× 10-6
62.27
51.64
THF
6.127
382.7
CH3CN
6.127
262.4
2-N-(3-Methyl)piperidinopyrazine
THF
5.578
5.578
5.578
5.578
5.578
5.578
401
414
404
414
402
414
505.4
364.8
235.3
84.34
27.42
11.31
CH3CN
2-N-(4-Methyl)piperidinopyrazine
THF
5.578
5.578
5.578
5.578
5.578
5.578
403
415
400
415
402
411
518.5
399.6
208.0
130.3
29.62
17.80
CH3CN

8124 Idris et al.
Asian J. Chem.
3. K.J. McCullough, In ed.: M. Sainsbury, In Rodd’s Chemistry of Car-
bon Compounds, Elsevier: Amsterdam, edn. 2, Vol. 4, pp. 99-171
(2000).
It can be seen that the fluorescence intensity increases
with increasing concentration at relatively low concentrations.
This observation was in agreement with the work reported
earlier, where by at higher concentrations, the fluorescence
intensity reaches its limiting value which normally results in
concentration quenching and sometime accompanied by a shift
in fluorescence wavelength19.
4. N. Sato, In eds.: A.R. Katritzky, C.W. Rees and A.J. Boulton, In Com-
prehensive Heterocyclic Chemistry II, Elsevier: Oxford, Vol. 6, p. 233
(1996).
5. J.A. Maga, Food Rev. Int., 8, 479 (1992).
6. (a) T. Shibamoto, J. Food Sci., 51, 1098 (1986); (b) G. Buchbauer,
C.T. Klein, B. Wailzer and P. Wolschann, J. Agric. Food Chem., 48,
4273 (2000).
Conclusion
7. Y.-J. Cherng, Tetrahedron, 58, 887 (2002).
2-N-Piperidinopyrazine, 2-N-(3-methyl)piperidino-
pyrazine and 2-N-(4-methyl)piperidinopyrazine were success-
fully prepared and fluorescence characteristics of these
compounds were studied in various solvents. 2-N-Piperidino-
pyrazine showed the highest fluorescence intensity amongst
the piperidino derivatives and the highest fluorescence intensity
was recorded in tetrahydrofuran. The fluorescence intensity
of all the derivatives decreases with decreasing concentrations.
8. C.W. Lindsley, Z. Zhao, W.H. Leister, R.G. Robinson, S.F. Barnett, D.
Defeo-Jones, R.E. Jones, G.D. Hartman, J.R. Huff, H.E. Huber and
M.E. Duggan, Bioorg. Med. Chem. Lett., 13, 761 (2005).
9. N. Mohd Salleh, Z.Abdullah, M.AA. Bakar,A. MohdIdris and Z.Aiyub,
Int. J. Chem. Sci., 6, 933 (2008).
10. Z. Abdullah, M.A.A. Bakar, Z. Aiyub and R. Yahya, J. Sci. Technol.
Tropics, 3, 39 (2007).
11. Z. Abdullah and M.A.A. Bakar, Int. J. Chem. Sci., 4, 241 (2006).
12. Z. Abdullah, M.A.A. Bakar and A. MohdIdris, Afr. J. Chem. Sci., 1, 1
(2008).
13. G.G. Guibault, Molecular Fluorescence Spectroscopy in Comprehen-
sive Analytical Chemistry, Elsevier Scientific Publication Company,
Vol. 8, Ch. 2 (1977).
ACKNOWLEDGEMENTS
The authors thank Universiti of Malaya for the
financial support for this project through RG047/2010AFR,
RG233/2012AFR, PV081/2012A.
14. J. Drobnik and L. Augenstein, Photochem. Photobiol., 5, 83 (1996).
15. J. Drobnik and L. Augenstein, Photochem. Photobiol., 5, 13 (1996).
16. J. Weisstuch and A.C. Testa, J. Phys. Chem., 7, 2999 (1970).
17. S. Yang, J. Liu, P. Zhou and G. He, J. Phys. Chem. B, 115, 10692
(2011).
REFERENCES
18. G.J. Pant, P. Singh, B.S. Rawat, M.S. Rawat and G.C. Joshi, Spectrochim.
Acta A, 78, 1075 (2011).
1. V.M. Dembitsky, T.A. Gloriozova and V.V. Poroikov, Mini-Rev. Med.
Chem., 5, 319 (2005).
19. M. Nakazono, K. Saita, Y. Oshikawa, K. Tani, S. Nanbu and K. Zaitsu,
Spectrochim. Acta A, 78, 905 (2011).
2. A. Gryszkiewicz-Wojtkielewicz, I. Jastrzebska, J.W. Morzycki and D.B.
Romanowska, Curr. Org. Chem., 7, 1257 (2003).