Structural elucidation of an oxidation product of sedimentary porphyrins by one-pot synthesis of 3-methylphthalimide

Article abstract of DOI:10.1246/bcsj.74.1975

One-pot synthesis of 3-methylphthalimide was achieved from 1,2,3-trimethylbenzene. The starting compound was oxidized in two steps to produce methylphthalic acids. The o-isomer was converted into its anhydride, which was subjected to thermal reaction with urea to form 3-methylphthalimide. The product was identical with the reported oxidation product of sedimentary porphyrins.

Full text of DOI:10.1246/bcsj.74.1975

c. Jpn.
Bull. Chem. Soc. Jpn., 74, 1975–1976 (2001) 1975
e Chemical
ciety of Ja-
n
Short Articles
e Chemical
ciety of Ja-
n
Structural Elucidation of an Oxida-
tion Product of Sedimentary Porphy-
rins by One-Pot Synthesis of 3-Meth-
ylphthalimide
01
S. Nomoto et al.
75
76
Shinya Nomoto,* Masaki Kozono, Hajime Mita,
and Akira Shimoyama
SJA8
09-2673
1018
Department of Chemistry, University of Tsukuba,
Tsukuba 305-8571
01
01
(Received May 25, 2001)
Scheme 1. (a) Br2, CCl4, reflux; (b) 7 M HNO3, reflux, 5 h;
(c) Ac2O, reflux, 1 h; (d) urea, 140 °C, 2 h.
One-pot synthesis of 3-methylphthalimide was achieved
from 1,2,3-trimethylbenzene. The starting compound was
oxidized in two steps to produce methylphthalic acids. The
o-isomer was converted into its anhydride, which was sub-
jected to thermal reaction with urea to form 3-methylphthal-
imide. The product was identical with the reported oxidation
product of sedimentary porphyrins.
step was bromination of hemimellitene (2), which was per-
formed to facilitate selective oxidation of a bromomethyl in
preference to a methyl group on the benzene ring. Although
formation of the desired dibromide, 2,3-bis(bromomethyl)tolu-
ene (3), is sterically disadvantageous, the bromination gave an
appreciable amount of 3. Thus, to a solution of hemimellitene
(2) (10 g) in carbon tetrachloride (50 mL) 2 equivalents of bro-
mine (78 g) were added dropwise under reflux. The resulting
mixture was revealed to contain dibromides 3 and 411 in the ra-
tio of 1 to 7, as analyzed with GC-MS.
.1
.2
Sedimentary porphyrins, first found by Treibs in 1934,1 are
usually complicated mixtures with various substituents on pyr-
role or pyrroline rings as a result of diagenetic modification of
precursor chlorophylls.2 The substitution patterns can be con-
veniently determined after decomposition to maleimides by
the chromic acid oxidation method.3 In previously reported
oxidation products of petroleum and sediments, the most abun-
dant maleimide was usually 2-ethyl-3-methylmaleimide,
which can be attributed to the predominance of 3-ethyl-4-me-
thylpyrrole or pyrroline rings in many chlorophylls.4,5 Barwise
and Whitehead found phthalimide and an unidentified isomer
of its methyl homologs in the oxidation products of porphyrins
obtained from a crude oil in 1980,6 giving the first piece of
chemical evidence for the presence of sedimentary benzopor-
phyrins.7 Furthermore, the discovery of methylphthalimide
provided an important source of information about the precur-
sors in diagenetic generation of benzoporphyrins. Although
authentic 3- and 4-methylphthalimides are required for their
identification and determination in such geological samples,
no appropriate intermediate for synthesis of the former,8 such
as 3-methylphthalic acid or its derivatives, is now commercial-
ly available, and no convenient synthetic method for the com-
pound has hitherto been reported.9,10 In this study, we estab-
lished a one-pot synthetic route to 3-methylphthalimide (1)
from commercially available hemimellitene (1,2,3-trimethyl-
benzene) and determined the structure of the methylphthal-
imide discovered by Barwise and Whitehead.
The reaction mixture was evaporated to dryness under re-
duced pressure and the cycle of dissolution of the residue in
benzene (50 mL) and evaporation to dryness was repeated five
times to remove hydrogen bromide formed in the bromination.
To the residual oil, 300 mL of 7 M nitric acid were added and
the mixture was heated under reflux for 5 h. It was preferable
to stir vigorously the reaction mixture for effective oxidation,
since the dibromide otherwise stayed at the bottom of the reac-
tion vessel. Nitric acid was evaporated under reduced pres-
sure, and the dissolution and evaporation cycle was performed
10 times, at first using water (100 mL each) and then 5 times
using benzene (50 mL each) to remove water as an azeotropic
mixture.
To the oily residue, which was considered to contain meth-
ylphthalic acids 5 and 6, acetic anhydride (50 mL) was added
and the mixture was heated under reflux for an hour to give a
light yellow solution. The reaction mixture was concentrated
under reduced pressure and subjected to the dissolution and
evaporation cycle 5 times using benzene (50 mL each). The
residue was confirmed to contain 3-methylphthalic anhydride
(7) in a separate run, in which the desired anhydride was puri-
fied by silica-gel column chromatography using benzene-ethyl
acetate as eluents followed by crystallization from benzene-
hexane to give needles.12
In the final step of the one-pot synthesis, the above-stated
residue, containing 7, was allowed to react with urea (10 g) at
140 °C for 2 h, according to the method of Muir.13 The reac-
tion mixture, which solidified at room temperature, was
washed thoroughly with chloroform (200 mL). The precipitate
was filtered off and the filtrate was applied to a silica-gel col-
One-pot synthesis of 3-methylphthalimide: In the syn-
thetic path illustrated in Scheme 1, we selected all the reagents
and solvents which can be evaporated, except for the one used
in the final step, in order to attain a one-pot synthesis. The key

1976 Bull. Chem. Soc. Jpn., 74, No. 10 (2001)
© 2001 The Chemical Society of Japan
methylphthalimide discovered by Barwise and Whitehead was
identified as the 3-methyl isomer by comparing its mass spec-
trum reported with that of the authentic compound synthesized
in this study (Fig. 2). We recently discovered both 3- and 4-
methylphthalimides in oxidative extracts from the Neogene
sediments, together with alkyl maleimides, among which 3-
ethyl-4-methylmaleimide predominated. Furthermore, the iso-
mer ratio of methylphthalimide is expected to be utilized as a
maturity assessment parameter of sedimentary organic matter,
similarly to methylnaphthalene or methylphenanthrene indi-
ces.17–19 These organic geochemical investigations are now
under way and will be reported elsewhere.
References
1
2
3
A. Treibs, Justus Liebigs Ann. Chem., 510, 42 (1934).
W. W. Howe, Anal. Chem., 33, 255 (1961).
G. W. Hodgson, M. Strosher, and D. J. Casagrande, Adv.
Fig. 1. 1H NMR spectra of methylphthalimides.
Org. Geochem., 1971, 151.
4
E. T. Furlong and R. Carpenter, Geochim. Cosmochim. Ac-
ta, 52, 87 (1988).
5
J. Martin, E. Quirke, G. J. Shaw, P. D. Soper, and J. R.
Maxwell, Tetrahedron, 36, 3261 (1980).
6
A. J. G. Barwise and E. V. Whitehead, Adv. Org. Geochem.,
1980, 181.
7
S. Kauer, M. I. Chicarelli, and J. R. Maxwell, J. Am. Chem.
Soc., 108, 1347 (1986).
8
W. O. Siegel, F. C. Ferris, and P. A. Mucci, J. Org. Chem.,
42, 3442 (1977).
9
V. Jürgens, Ber., 40, 4409 (1907).
10 S. Gabriel and A. Thieme, Ber., 52, 1079 (1919).
11 MS data for both 3 and 4: m/z 276, 278 and 280 (M+), 197
and 199 (M+ − Br), 118 (M+ − 2Br).
1
12 Selected physical data for 7: mp 104–5 °C; H NMR (500
MHz, CDCl3) δ 2.75 (3H, s, CH3), 7.69 (1H, d, J = 7.6 Hz, aro-
matic H), 7.79 (1H, dd, J = 7.5 and 7.6 Hz, aromatic H), 7.86
(1H, d, J = 7.5 Hz, aromatic H). Found: C, 65.89; H, 3.43%.
Calcd for C9H6O3: C, 66.67, H, 3.73%.
Fig. 2. Mass spectra of methylphthalimides.
13 H. M. Muir and A. Neuberger, Biochem. J., 45, 163 (1949).
14 Selected physical data for this compound: mp 235–6 °C; Rf
on TLC (benzene–ethyl acetate, 9:1) 0.85; H NMR (500 MHz,
umn (3 cm I.D. × 50 cm). The desired 3-methylphthalimide
was eluted by chloroform–methanol (19:1) together with a by-
product. This by-product could not be separated from 1 on sil-
ica-gel TLC using chloroform–methanol (19:1) as a develop-
ing solvent, and was assigned to be either 4- or 6-bromo deriv-
ative of 3-methylphthalimide,14 as judged from MS and NMR
spectra. The mixture of these phthalimides was finally separat-
ed by a silica-gel column (2 cm I.D. × 60 cm) eluting with
benzene-ethyl acetate (19:1) to afford pure 3-methylphthalim-
ide. The total yield from hemimellitene was 525 mg (3.9%). It
was recrystallized from ethanol for further purification to give
needles,15 and the structure of this product was confirmed by
elemental analysis and MS and NMR spectra, as shown in
Figs. 1 and 2 together with those of 4-methylphthalimide.16
Structural elucidation of an oxidation product of sedi-
mentary porphyrins: According to the synthetic scheme
described here, 3-methylphthalimide can be easily obtained in
a practical yield without using any special reagent. This work
enabled definitive identification and quantification of 3-meth-
ylphthalimide in geological samples. Indeed, the above-stated
1
CD3OD) δ 2.74 (3H, s, CH3), 7.55 (1H, d, J = 7.9 Hz, aromatic
H), 7.96 (1H, d, J = 7.9 Hz, aromatic H); MS: m/z 239 and 241
(M+), 221 and 223 (M+ − H2O), 168 and 170 (M+ − CO-NH-
CO), 89 (M+ − CO-NH-CO − Br). Found: C, 45.36; H, 2.52; N,
5.80%. Calcd for C9H6BrNO2: C, 45.03, H, 2.52; N, 5.84%.
15 Selected physical data for 1: mp 193–5 °C; Rf on TLC
(benzene–ethyl acetate,9:1) 0.75. Found: C, 66.62; H, 4.36; N,
8.57%. Calcd for C9H7NO2: C, 67.07, H, 4.38; N, 8.69%.
16 4-Methylphthalimide was synthesized by the reaction of
commercially available 4-methylphthalic anhydride with urea.
Selected physical data for 4-methylphthalimide: mp 197–8 °C.
Found: C, 67.08; H, 4.35; N, 8.90%. Calcd for C9H7O2N: C,
67.07, H, 4.38; N, 8.69%.
17 M. Radke, H. Willsh, and D. Leythaeuser, Geochim. Cos-
mochim. Acta, 46, 1831 (1982).
18 A. C. Raymond and D. G. Murchson, Org. Geochem., 18,
725 (1992).
19 S. Nomoto, M. Hagiwara, Y. Nakano, and A. Shimoyama,
Bull. Chem. Soc. Jpn., 73, 1437 (2000).