An improved synthesis, characterization, and X-ray studies of 5-tert-butyl-3-nitrophthalonitrile

Article abstract of DOI:10.1016/j.tetlet.2013.05.045

An improved six-step synthesis of 5-tert-butyl-3-nitrophthalonitrile (1) is described. The title compound and all the intermediates are fully characterized spectroscopically (FT-IR, ¹H NMR, ¹³C NMR, MS). In addition, single-crystal X

Full text of DOI:10.1016/j.tetlet.2013.05.045

Tetrahedron Letters 54 (2013) 3816–3818
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Tetrahedron Letters
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An improved synthesis, characterization, and X-ray studies of
5-tert-butyl-3-nitrophthalonitrile
⇑
Łukasz Łapok , Alicja Siudak, Maria Nowakowska
Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Kraków, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
An improved six-step synthesis of 5-tert-butyl-3-nitrophthalonitrile (1) is described. The title compound
and all the intermediates are fully characterized spectroscopically (FT–IR, 1H NMR, 13C NMR, MS). In
addition, single-crystal X-ray diffraction further confirmed the structure of the title compound.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 7 January 2013
Revised 12 April 2013
Accepted 10 May 2013
Available online 20 May 2013
Keywords:
Phthalonitrile
Electrophilic substitution
Phthalocyanines
Phthalocyanines are an important industrial commodity with a
wide range of applications. They can be prepared from aromatic
ortho-disubstituted derivatives including o-cyanobenzamides,
phthalic acids, phthalic anhydrides, phthalimides, phthalamides,
1,3-diiminoisoindolines, and phthalonitriles.1 The most useful of
all the phthalocyanine precursors are phthalonitriles.2 Heating of
phthalonitriles in high boiling solvents in the presence of metal salts
results in templated cyclotetramerization and formation of a phtha-
locyanine dye. Unsubstituted and some simple substituted phthalo-
nitriles are available from commercial sources, but the vast majority
need to be synthesized, often via multi-step, challenging routes.
Recently, as part of an ongoing project, we became interested in
phthalocyanines with electron-donating/electron-accepting prop-
erties suitable for energy conversion applications. For this purpose
we needed a precursor that would result in a phthalocyanine hav-
ing bulky groups at the periphery of the molecule, thereby increas-
ing its solubility while suppressing aggregation. We were also
looking for a precursor possessing a functional group with electron
donating/electron-accepting properties. After an extensive litera-
ture review we turned our attention to 5-tert-butyl-3-nitrophthalo-
nitrile which possessed both properties, viz. the presence of both a
bulky tert-butyl group and a nitro functionality (electron-with-
drawing), which upon reduction to an amino group would provide
the target phthalocyanine with electron-donating properties.
5-tert-Butyl-3-nitrophthalonitrile (1) was first reported in 1975
by Mikhalenko and Lukyanets,3 who proposed a synthetic pathway
starting from ortho-xylene, which after seven consecutive steps
(alkylation, introduction of the nitro functionality, oxidation to
phthalic acid, dehydration to the anhydride, conversion into the
phthalimide, ammonolysis into the phthalamide, followed by
dehydration to the phthalonitrile), resulted in formation of
5-tert-butyl-3-nitrophthalonitrile. Unfortunately, no spectral char-
acterization of the final product or intermediates, that would cor-
roborate the identity of the compounds, was provided. Moreover,
it lacked experimental details, including reaction conditions,
separation methods, and reaction yields. Thus, we decided to re-
investigate the synthesis of 5-tert-butyl-3-nitrophthalonitrile (1)
as well as to provide full spectroscopic characterization of all the
intermediates and X-ray characterization of the final product.
The subject of this paper is an improved synthesis and charac-
terization of 5-tert-butyl-3-nitrophthalonitrile (1).
The synthesis of 5-tert-butyl-3-nitrophthalonitrile (1) is pre-
sented in Scheme 1. In the first step, the tert-butyl group was intro-
duced to ortho-xylene (2) by a modification of a well-established
Friedel–Crafts alkylation in a higher 85% yield than that previously
reported.4,5
Regioselective nitration of 4-tert-butyl-o-xylene (3) was first de-
scribed by Brundrett and White in 1974.6 They claimed that 5-tert-
butyl-3-nitro-o-xylene (4a) was obtained in a 60% yield. However,
we failed to reproduce this protocol. Contrary to the report by
Brundrett and White, we found that nitration of 3 resulted in a rather
complex mixture of at least three derivatives, one of which was in-
deed 5-tert-butyl-3-nitro-o-xylene (4a) (48% yield). After arduous
separation and detailed spectroscopic analysis, two other products
were identified as 4-tert-butyl-3,6-dinitro-o-xylene (4b) (7% yield)
and 5-tert-butyl-3,4-dinitro-o-xylene (4c) (10% yield) (Fig. 1).
Oxidation of the methyl groups in 5-tert-butyl-3-nitro-o-xylene
(4a) with KMnO4 in water/pyridine solution gave phthalic acid 5 in
74% yield. The IR spectrum of 5 was dominated by a sharp
⇑
Corresponding author. Tel.: +48 12 6632083; fax: +48 12 6340515.
E-mail addresses: lapok@chemia.uj.edu.pl, lukasz.a.lapok@gmail.com (Ł. Łapok).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.045

Łukasz Łapok et al. / Tetrahedron Letters 54 (2013) 3816–3818
3817
Scheme 1. Reagents and conditions: (a) FeCl3, t-BuCl, 0 °C to rt, 24 h, 85%; (b) fuming HNO3/conc. H2SO4, rt, 24 h, 48%; (c) KMnO4, py/H2O, 4 h, reflux, 74%; (d) AcCl, 2 h, reflux,
54%; (e) urea, 180 °C, 45 min, 88%; (f) formamide, 190 °C, 1 h, 78%; (g) NH3, MeOH, rt, ca. 24 h, 73%; (h) POCl3, py, 0 °C to rt, 1.5 h, 59%; (i) NH3, MeOH, rt, quant.
stretch, while two strong absorption bands at 1782 cmÀ1 and
1725 cmÀ1 were evidence of a C@O stretching vibration. The
MALDI–TOF spectrum of phthalimide 7 was dominated by a peak
at m/z 271.050 which was interpreted as the sodium adduct
[M+Na+]+.
Treatment of phthalimide 7 with a saturated methanolic solu-
tion of ammonia, followed by chromatographic separation gave
the corresponding phthalamide 8 in a satisfactory 73% yield. In
the IR spectrum of 8 three bands at 3373 cmÀ1 (N–H), 3180 cmÀ1
(N–H), and 1660 cmÀ1 (C@O) were characteristic of primary amides.
Conversion of phthalamide 8 into the corresponding phthalo-
nitrile 1 was carried out with phosphorus oxychloride as the dehy-
drating agent in dry pyridine.9 Finally, after chromatographic
Figure 1. Structures of 4-tert-butyl-3,6-dinitro-o-xylene (4b) and 5-tert-butyl-3,4-
dinitro-o-xylene (4c) isolated after nitration of 4-tert-butyl-o-xylene (3).
separation, pure phthalonitrile 1 was obtained in 59% yield. The
1H NMR spectral data, confirmed the assigned structure of 1, both
by the splitting pattern of the signals in the aromatic region (d = 8.1
absorption band at 1701 cmÀ1 (C@O) and
a
broad band at
and 8.52 ppm, both seen as doublets with coupling constants of
1.87 Hz) and by integration of the signals observed for the alkyl
and aromatic protons (9:2 ratio). The splitting of the aromatic pro-
ton signals was particularly valuable for identifying the substitu-
tion pattern of the aromatic ring. The coupling constants of
1.87 Hz clearly indicated that both protons were located at ortho
and para positions with respect to the nitro group, and therefore
the 1,2,3,5-substitution pattern was corroborated unambiguously.
Due to the presence of the strong electron-withdrawing –NO2
group attached to the aromatic ring, both aromatic protons experi-
ence deshielding, causing their signals to move downfield. In the IR
spectrum a prominent band at 2236 cmÀ1 was characteristic of
aromatic nitriles. In addition, a molecular ion peak at m/z 229 [M
À] was observed in the ESI mass spectrum.
3417 cmÀ1 (–OH). Negative ion mode ESI-MS revealed a molecular
ion peak at m/z 266 [MÀH+]À.
The classic protocol used to obtain phthalonitriles requires that
phthalic acids be converted into phthalic anhydrides. This was
achieved by refluxing 5-tert-butyl-3-nitrophthalic acid (5) in acetyl
chloride. Upon chromatographic separation, anhydride 5 was iso-
lated in 54% yield. Two strong bands at 1799 cmÀ1 and 1735 cm
À1
observed in the IR spectrum, along with the disappearance of
the previously observed absorption band at 1701 cmÀ1 corrobo-
rated unambiguously the formation of cyclic anhydride 6. It was
however found that anhydride 6 had limited stability, and with
time decomposed to phthalic acid 5. Thus, it is important to con-
sume the obtained phthalic anhydride 6 immediately after its for-
mation. However, we found that the phthalic acid 5 could be
directly converted into the phthalimide 7, which allowed us to skip
one reaction step, thereby simplifying the procedure and improv-
ing the total reaction yield. We applied the procedure first
disclosed in a Japanese patent7 and then successfully adopted by
Hanack and Vagin.8 Treatment of phthalic acid 5 at elevated tem-
perature with formamide (190 °C) afforded phthalimide 7 in a good
78% yield. Simple extraction with dichloromethane was sufficient
to obtain a product with good purity. A strong absorption in the
IR spectrum at 3203 cmÀ1 indicated the presence of an N–H
Slow evaporation of a saturated hexane solution of 1 resulted in
crystals with good morphology, and the molecular structure of 1
was further determined by single crystal X-ray diffraction (Fig. 2).
This revealed that the nitro group was indeed introduced regiose-
lectively at position 3. Detailed crystallographic data such as bond
10
lengths and angles are presented in the Supplementary Data.
It is worth noting that phthalonitrile 1 could be easily trans-
formed into its more reactive form, namely 1,3-diiminoisoindoline
9. Diiminoisoindolines are the precursors of choice for the synthe-
sis of metal-free, silicon and germanium phthalocyanines as well

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Ł. Łapok et al. / Tetrahedron Letters 54 (2013) 3816–3818
Figure 2. ORTEP plot of phthalonitrile 1 and the monoclinic unit cell representation with P21/c space group.
as in those cases where phthalocyanine complexes of less reactive
metals are to be obtained.2,11 The reaction was straightforward and
simply involved reacting ammonia gas with a methanolic solution
of 1 at room temperature (sodium methoxide as a catalyst was not
needed). 1,3-Diiminoisoindoline 9 (as confirmed by ESI-MS, m/z
247 [M+H]+) was obtained quantitatively.
In summary, we have investigated and improved the protocol
for the synthesis of 5-tert-butyl-3-nitrophthalonitrile (1) starting
from inexpensive and easily available ortho-xylene (2). Contrary
to previous reports, it was found that nitration of 4-tert-butyl-o-
xylene (3), gave a complex mixture of mono-nitro and di-nitro
derivatives. This mixture, when separated into its individual com-
ponents, constitutes a useful source of di-nitro derivatives of 4-
Supplementary data
Supplementary data (computational details and a list of atomic
coordinates and their estimated standard deviations for 5-tert-bu-
tyl-3-nitrophthalonitrile (1). 1H NMR, IR, and MS spectra of se-
lected intermediates.) associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
05.045.
References and notes
1. Phthalocyanines: Properties and Applications; Leznoff, C. C., Lever, A. B. P., Eds.;
VCH: Weinheim, 1989–1996; Vols. 1–4,.
2. Sharman, W. M.; van Lier, J. E. Synthesis of Phthalocyanine Precursors. In The
Porphyrin Handbook In ; Academic Press, 2003; Vol. 15,.
3. Mikhalenko, S. A.; Lukyanets, E. A. Zh. Org. Khim. 1975, 11, 2216.
4. Nightingale, D.; Janes, J. R. J. Am. Chem. Soc. 1944, 66, 154.
5. Contractor, R. B.; Peters, A. T. J. Chem. Soc. 1949, 1314.
6. Brundrett, R. B.; White, E. H. J. Am. Chem. Soc. 1974, 96(24), 7497–7502.
7. Kaneko, T.; Sakamoto, M. Jpn. Kokai Tokkyo Koho, 06065200, 08/03/1994, 4 pp.
Heisei. Chemical Abstract Number: P 85717d.
tert-butylphthalonitrile, which represents
a potentially useful
building block for the synthesis of nitro-substituted phthalocya-
nines. By applying a direct transformation of phthalic acid 5 into
phthalimide 7 we were able to skip one reaction step (i.e., the for-
mation of phthalic anhydride) thus simplifying the entire protocol
and improving the total yield of the target compound. The phthalo-
nitrile under discussion was recently used in our laboratory to pre-
pare a set of nitro- and amino-substituted phthalocyanines for
solar energy conversion applications.3
8. Vagin, S.; Hanack, M. Eur. J. Org. Chem. 2004, 600–606.
9. 5-tert-butyl-3-nitrophthalonitrile (1): 5-tert-butyl-3-nitrophthalamide (8)
(2.63 g, 10 mmol) was dissolved in pyridine (dry, freshly distilled, 15 mL) and
cooled to 0 °C, followed by slow addition of POCl3 (4.6 g, 2.75 mL, 30 mmol).
The mixture was kept at 0 °C for 0.5 h and then at room temperature for 1 h.
After completion of the reaction, the mixture was poured onto ice and
extracted with CH2Cl2. The organic layer was washed with H2O three times.
After evaporation of the solvent, the residue was chromatographed on silica gel
(column length 20 cm). A mixture of toluene/hexane 2:1 was passed through
the silica gel to remove impurities and then it was changed to toluene to elute
the pure product (1.33 g, 59%). 1H NMR (300 MHz, CDCl3) d: 1.43 (s, 9H), 8.1 (d,
Acknowledgements
This project operating within the Foundation for Polish Science
Team Program was financed by the EU European Regional Devel-
opment Fund, PolyMed TEAM/2008-2/6. The research was carried
out with equipment purchased, thanks to financial support of the
European Regional Development Fund in the framework of the
Polish Innovative Economy Operational Program (POIG.02.01.00-
12-023/08). We would like to thank Professor Jerzy Silberring’s
team for obtaining the ESI mass spectra, Dr. Marta Gawin for
performing MALDI–TOF measurements, and Dr. Sergiu Gorun for
collecting X-ray data and analyzing the structure of the title
compound.
4
4
1H, Jmeta 1.87 Hz), 8.52 (d, 1H, Jmeta 1.87 Hz). 13C NMR (300 MHz, CDCl3) d:
30.6, 36.3, 108.5, 111.8, 114.3, 119.4, 126.3, 135.2, 149.3, 159.9. GC–MS: m/z
229 M+, 214 [MÀCH3]+. ESI-MS (negative ion mode): m/z = 229 [MÀ], 199
[MÀNO+]À. FT–IR (KBr): v = 3080 (Ar–H), 2968 (t-Bu) m, 2912, 2874, 2236 (CN)
s, 1609, 1556 (NO2) s, 1544 (NO2) s, 1479, 1464, 1402, 1368, 1350 (NO2) s,
1282, 1246, 1217, 1176, 927, 805, 772, 762, 644, 548 cmÀ1
.
10. Crystallographic data for the structure in this Letter have been deposited with
the Cambridge Crystallographic Data Centre as supplementary publication
number CCDC 933174. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +44 0 1223
336033 or e-mail: deposit@ccdc.cam.ac.uk].
11. McKeown, N. The Synthesis of Symmetrical Phthalocyanines. In The Porphyrin
Handbook In ; Academic Press, 2003; Vol. 15,.