Photolysis of NSAIDs. Part 3: Structural elucidation of photoproducts of tolmetin in methanol

Article abstract of DOI:10.1016/j.tetlet.2004.08.177

Photolysis of tolmetin in methanol produces eight photoproducts via a novel α-cleavage of a ketone, decarboxylation, and oxidation. A sample of 10 mM tolmetin in methanol was photo-irradiated with a Hanovia 200 W high-pressure quartz Hg lamp for four days. In total, eight photoproducts were observed from the HPLC chromatogram. Three major photoproducts were separated, and their structures were elucidated by spectroscopic methods. The structures of all photoproducts were further determined by LC-ESI-MS. A reaction scheme of tolmetin was proposed.

Full text of DOI:10.1016/j.tetlet.2004.08.177

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8107–8109
Photolysis of NSAIDs. Part 3: Structural elucidation of
photoproducts of tolmetin in methanol
Ming-Thau Sheu,a Jender Wu,b Chih-Jui Chen,a Su-Hui Chaoa and An-Bang Wua,*
aGraduate Institute of Pharmaceutical Sciences, College of Pharmacy, Taipei Medical University, 250 Wu Hsing Street,
Taipei 110, Taiwan
bDepartment of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan
Received 6 February 2004; revised 15 August 2004; accepted 23 August 2004
Available online 21 September 2004
Abstract—A sample of 10mM tolmetin in methanol was photo-irradiated with a Hanovia 200W high-pressure quartz Hg lamp for
four days. In total, eight photoproducts were observed from the HPLC chromatogram. Three major photoproducts were separated,
and their structures were elucidated by spectroscopic methods. The structures of all photoproducts were further determined by LC–
ESI-MS. A reaction scheme of tolmetin was proposed.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Tolmetin (TLM), 1-methyl-5-(p-toluoyl)-1H-pyrrole-2-
acetic acid sodium salt dihydrate, is a non-steroidal
anti-inflammatory drug (NSAID), which is widely used
as an analgesic and antirheumatic agent.1 However,
drug-induced photosensitivity or phototoxicity is always
related to photoproducts.2 Photolysis showed that
0.1mM TLM in phosphate-buffered saline solution
undergoes photodecarboxylation to p-toluoyl-1,2-di-
methyl-5-pyrrolyl ketone in nitrogen and to p-toluoyl-
A novel a-cleavage of a ketone: Photoproduct 2 had a
molecular weight of 109gmolꢀ1, and its structure is
most likely to be N-methyl-2-formylpyrrole. The suc-
cessful identification of 2 represents an interesting find-
ing, which indicates that a typical radical reaction of
a-cleavage of a ketone8 into two moieties occurred.
TLM is a diaryl ketone with a phenyl ring on one side
and a pyrrolyl group on the other. Consideration of
the resonance energy of benzene versus pyrrole9 in con-
jugation with the carbonyl group, which equals 36 ver-
sus 22kcalmolꢀ1, implies the double bond character of
C80–C10 is stronger than C80–C5 due to the greater elec-
tron distribution of the former bond. The counterpart of
the cleavage is photoproduct 3, p-methylbenzaldehyde,
as verified by NMR spectroscopy. Due to the apparently
weaker bond strength of C80–C5 in the parent drug,
TLM, the bond fission occurs mainly along C80–C5 to
generate acyl (m/z 119) and pyrrolyl radicals (m/z 138).
Next, each of the two radicals picks up a hydrogen atom
from the solvent molecules and the former becomes pho-
toproduct 3. The latter pyrrolyl radical forms firstly an
acetic acid derivative, which decarboxylates and follows
by oxidation with singlet oxygen producing photoprod-
uct 2 (MW = 109gmolꢀ1 equivalent to m/z 138 ꢀ
30 + 1; when the functional group changed from
–CH2(C@O)OH to –CHO, m/z would decrease by 30
units). Meanwhile, TLM is a weak acid, which releases
protons as the catalyst. An equilibrium reaction of
nucleophilic addition of methanol to the carbonyl group
of 2 (m/z increases by 32 units) produces a hemiacetal 1
(MW = 141gmolꢀ1).
1-methyl-2-hydroxymethyl-5-pyrrolyl
ketone
and
5-(p-toluoyl)-1-methyl-2-pyrrole carbaldehyde in air.3
In the present study, an amount of 10mM TLM in
methanol was irradiated with a Hanovia 200W high-
pressure mercury lamp4 for four days. In total, eight
photoproducts were observed from the HPLC5 and
LC–MS6 chromatograms. Three major photoproducts
3, 7, and 8, were separated according to the elution
order by the preparative HPLC. The structures of photo-
products 3, 7, and 8 were identified by spectroscopic
methods to be p-methylbenzaldehyde, 5-(p-toluoyl)-1-
methyl-2-pyrrole carbaldehyde, and p-toluoyl-1,2-
dimethylpyrrolyl ketone, respectively.7 The molecular
weights of the remaining five minor photoproducts were
determined by LC–ESI-MS with a positive mode of
polarity.
Keywords: Tolmetin; Photoproducts; LC–ESI-MS.
*
Corresponding author. Tel.: +886 2 27361661x6121/27366518; fax:
+886 2 27366518; e-mail: anbangwu@tmu.edu.tw
0040-4039/$ - see front matter ꢀ 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.177

8108
M.-T. Sheu et al. / Tetrahedron Letters 45 (2004) 8107–8109
Decarboxylation and oxidation: By decarboxylation of
TLM and N-methyl-2-pyrrolyl acetic acid (m/z decreases
by 44 units) initially forms methylene radical intermedi-
ates. The following reactions split into two ways. First,
the former intermediate intercepts a hydrogen atom
hol 4 (MW = 229gmolꢀ1), two aldehydes 3 (MW =
120gmolꢀ1), and 7 (MW = 227gmolꢀ1), respectively.3
Photoproduct 5 is simply a hydrated form of 7
(MW = 245gmolꢀ1; m/z increases by 18 units indicating
that 1mol of H2O is added to 7), just like its parent drug
(TLM) with a dihydrate structure. Photoproduct 6
forms neither a negative nor positive charged species,
thus its molecular weight could not be determined. In
all, seven of the eight photoproducts with their chemical
from methanol to form compound
8
(MW =
213gmolꢀ1). Second, the two intermediates proceed
via similar reaction pathways by oxidation with the
singlet oxygen to generate the oxidized forms of an alco-
Table 1. Structure elucidation based on LC–MS of TLM and photoproducts
Compound
Retention time (min)
Quasimolecular ion and fragment (m/z)
Difference in m/za
Chemical structureb
1
2.41
[MH]+: 14 2
Fragmentation: 110
ꢀ116 (ꢀ118 ꢀ 30 + 32)
2
3
2.51
[MH]+: 110
Fragmentation: 82, 99
ꢀ148 (ꢀ118 ꢀ 30)
ꢀ139 (ꢀ109 ꢀ 30)
6.04[MH]
+: 119
Fragmentation: N.D.c
4
9.99
[MH]+: 230
Fragmentation: 212, 119
ꢀ28
TLM
10.77
[MH]+: 258
Fragmentation: 119
—
5
12.29
[MH]+: 24 6
ꢀ12 (ꢀ30 + 18)
Fragmentation: 228, 214, 119
—
6
7
15.49
24.20
—
—
[MH]+: 228
Fragmentation: 214, 119
ꢀ30
8
41.21
[MH]+: 214
Fragmentation: 119
ꢀ44
a [MH]+ in m/z units. The difference in MW by subtracting the molecular ion of TLM from compound 1–8.
b IUPAC names: TLM, 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetic acid; 1, a hemiacetal of 2; 2, N-methyl-2-formylpyrrole; 3, p-methyl-
benzaldehyde; 4, p-toluoyl-1-methyl-2-hydroxymethyl-5-pyrrolyl ketone; 5, hydrate of 7; 7, 5-(p-toluoyl)-1-methyl-2-pyrrole carbaldehyde; 8, p-
toluoyl-1,2-dimethyl-5-pyrrolyl ketone. The structures of photoproduct 3, 7, and 8 confirmed by spectroscopic methods.
c N.D., no data.
Figure 1. A proposed photodegradation reaction scheme of TLM: (a) a-cleavage of a ketone; (b) decarboxylation; (c) oxidation with singlet oxygen.

M.-T. Sheu et al. / Tetrahedron Letters 45 (2004) 8107–8109
8109
p-Methylbenzaldehyde (3): 1H NMR (in CD3OD): d in
ppm relative to TMS, 9.89 (s, 1H, C80O@C–H), 7.88–7.90
(m, 2H, C20 and C60), 7.25–7.27 (m, 2H, C30 and C50),
structures were further checked by LC–ESI-MS10 and
listed in Table 1. A proposed reaction scheme of photo-
lysis of TLM in methanol is shown in Figure 1.
13
2.39 (s, 3H, p-CH3). C NMR (in CD3OD): 191.7 (C80),
144.9 (C40), 130.8 (C20 and C60), 130.1 (C30 and C50),
0
129.4(C1 ), 21.6 (C70). EI-MS (70eV): m/z (rel int. %) 136
References and notes
(47), 119 (45), 91 (100). IR: 1681 (strong, C@O), 1612.3
(medium, C@C). UV, kmax in nm (absorbance): 203
(1.543), 236 (1.335).
1. Squires, J. E.; Mintz, P. D.; Clark, S. Transfusion 1985, 25,
410–413.
2. Moore, D. E. Drug Safety 2002, 25, 345–372.
3. Giuffrida, S.; De Guidi, G.; Sortino, S.; Chillemi, R.;
Costanzo, L. L.; Condorelli, G. J. Photochem. Photobiol.
B-Biol. 1995, 29, 125–133.
4. Irradiation conditions: A Hanovia 200W high-pressure
quartz mercury lamp (Union, NJ) was used as a light
source. The light intensity of the monochromatic radiation
was measured at 310nm to be 0.65mW/cm2.
5-(p-Toluoyl)-1-methyl-2-pyrrole carbaldehyde (7): 1H
NMR (in CD3OD): d 9.79 (s, 1H, C7, O@C–H), 7.73–
0
0
7.74(m, 2H, C2 and C60), 7.33–7.34(m, 2H, C3 and
C50), 7.03 (d, 1H, J = 4.2Hz, C2@C3–H), 6.67 (d, 1H,
J = 4.3Hz, C5@C4–H), 2.41 (s, 3H, C70, p-CH3). 13C
NMR (in CD3OD): 189.0 (C80), 183.6 (C7), 145.2 (C40),
138.1(C2), 137.3 (C10), 130.9 (C20 and C60), 130.4(C5),
130.2 (C30 and C50), 122.4(C3), 120.6 (C4), 35.0 (C6), 21.6
(C70). EI-MS (70eV): m/z (rel int. %): 227 (66), 212
(83), 119 (37), 91 (100). IR (KBr) in cmꢀ1: 1682.1 (strong,
H–C@O) and 1635.4(strong, RR 0C@O), 1607.4(weak,
C@C). UV, kmax in nm (absorbance): 202 (0.398), 317
(0.608).
5. HPLC apparatus and separation conditions: An Alcott
760 HPLC pump system (Norcross, GA) equipped with a
Jasco 875-UV detector (Tokyo, Japan) set at 254nm, and
a preparative YMC-Pack Pro C18 of 250 · 20mm id
column (Tokyo, Japan) was used with a mobile phase of
CH3CN–CH3OH–1% HOAc (4:63:33, v/v/v). The flow
rate was 10mL/min, and the injection volume was 200lL.
6. LC–MS instrument and conditions: An HP series 1100LC/
MSD (Palo Alto, CA) instrument consisted of an Inertsil 5
ODS-80A column (150 · 2.1mm id) and a mobile phase of
CH3OH–0.1% HOAc (55:45, v/v). The UV detector was
set at 254nm, the flow rate at 0.3mL/min, and the
injection volume at 10lL. The MS conditions were
optimized as follows: API electron spray interface, posi-
tive mode polarity, a drying gas flow of 10L/min, a
nebulizer gas pressure of 60psi, a drying gas temperature
of 350ꢁC, a fragmentor voltage of 100V, a capillary
voltage of 3500V, and a scan range of m/z 0–600, at 1.15s/
scan.
p-Toluoyl-1,2-dimethylpyrrolyl ketone (8): 1H NMR (in
CD3OD): d 7.59–7.61 (m, 2H, C20 and C60), 7.26–7.28 (m,
2H, C30 and C50), 6.61 (d, 1H, J = 4.0Hz, C4, C@C–H),
5.98 (d, 1H, J = 3.9Hz, C3, C@C–H), 2.41 (s, 3H, C70, p-
CH3), 2.31 (s, 3H, C7, C@C–CH3). 13C NMR (in
CD3OD): 187.4(C8 0), 143.2 (C40), 142.0 (C2), 138.9
(C10), 131.6 (C5), 130.3 (C30 and C50), 129.7 (C20 and
C60), 125.1 (C4), 109.7 (C3), 33.2 (C6), 21.5 (C70), 12.5
(C7). EI-MS (70eV): m/z (rel int. %): 212 (100), 198 (40),
122 (33), 91 (24). IR (KBr) in cmꢀ1: 3103, 2947, 2919, and
2857 (weak, C–H stretching), 1614.0 (strong, C@O),
1569.1 (weak, C@C). UV, kmax in nm (absorbance): 205
(1.267), 254(0.850), 316 (1.751).
8. Turro, N. J. Modern Molecular Photochemistry, 1st ed.;
University Science Book: Mill Valley, CA, 1991; pp 224–
228.
7. Characterization the photoproducts: NMR: The 1H and
13C NMR spectra were taken on a Bruker, ACE-500 FT-
¨
NMR (500MHz) (Ettlingen, Germany). 2D NMR of
heteronuclear multiple quantum coherence (HMQC) for
determining 1J (C, H) correlation, and heteronuclear
multiple bond connectivity (HMBC) for showing 2J (C, H)
9. Carey, F. A. In E-Book t/a Organic Chemistry, CD-ROM;
5th ed.; McGraw-Hill Science: New York, 2003; Chapter
11.
10. Sheu, M. T.; Ho, H. O.; Wang, P. Y.; Liou, Y. P.; Wu, A.
B. J. Chromatogr. Sci. 2003, 41, 200–204.
3
and J (C, H) long-range coupling relations were used.