Electron ionization mass spectrometry of curcumin analogues: An olefin metathesis reaction in the fragmentation of radical cations

DOI: 10.1002/(SICI)1096-9888(199804)33:4<319::AID-JMS636>3.0.CO;2-U

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Journal of Mass Spectrometry p. 319 - 327 (1998)

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Van Baar, Ben L. M.

Rozendal, Jelle

Van Der Goot, Henk

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Article abstract of DOI:10.1002/(SICI)1096-9888(199804)33:4<319::AID-JMS636>3.0.CO;2-U

The natural compound curcumin, used in cosmetics, traditional medicines and as a spice in food, is known as a multi-factorial anti-inflammatory agent. To study the anti-inflammatory activity of curcumin derivatives, 24 analogues were synthesized and their structures were confirmed by ¹H NMR and electron ionization (EI) mass spectrometry. Most signals in the EI mass spectra can be attributed to commonly known fragmentations, but the formation of ring-substituted 1,2-diphenylethene (stilbene)-type radical cations, observed in the spectra of all compounds investigated and resulting in the base peak for some compounds, requires a peculiar rearrangement. Metastable ion spectra and ¹³C labelling studies show that the stilbene-type ions are formed directly from the molecular ions and contain the two original aryl groups and the 1 and 7 carbon atoms of the olefinic system. It is proposed that the formation of stilbene-type ions results from an intramolecular olefin metathesis reaction; this suggestion is supported by semi-empirical (MNDO/PM3) calculations.

Full text of DOI:10.1002/(SICI)1096-9888(199804)33:4<319::AID-JMS636>3.0.CO;2-U

JOURNAL OF MASS SPECTROMETRY, VOL. 33, 319È327 (1998)

Electron Ionization Mass Spectrometry of

Curcumin Analogues: an Olefin Metathesis

Reaction in the Fragmentation of Radical Cations

Ben L. M. van Baar,1* Jelle Rozendal1 and Henk van der Goot2

1 Department of Organic Chemistry, Vrije Universiteit, De Boelelaan 1083, NL-1081 HV Amsterdam, The Netherlands

2 Leiden/Amsterdam Center for Drug Research, Department of Pharmacochemistry, Vrije Universiteit, De Boelelaan 1083,

NL-1081 HV Amsterdam, The Netherlands

The natural compound curcumin, used in cosmetics, traditional medicines and as a spice in food, is known as a

multi-factorial anti-inÑammatory agent. To study the anti-inÑammatory activity of curcumin derivatives, 24 ana-

logues were synthesized and their structures were conÐrmed by 1H NMR and electron ionization (EI) mass spec-

trometry. Most signals in the EI mass spectra can be attributed to commonly known fragmentations, but the

formation of ring-substituted 1,2-diphenylethene (stilbene)-type radical cations, observed in the spectra of all com-

pounds investigated and resulting in the base peak for some compounds, requires a peculiar rearrangement. Meta-

stable ion spectra and 13C labelling studies show that the stilbene-type ions are formed directly from the molecular

ions and contain the two original aryl groups and the 1 and 7 carbon atoms of the oleÐnic system. It is proposed

that the formation of stilbene-type ions results from an intramolecular oleÐn metathesis reaction; this suggestion is

supported by semi-empirical (MNDO/PM3) calculations. ( 1998 John Wiley & Sons, Ltd.

J. Mass Spectrom. 33, 319È327 (1998)

KEYWORDS: Curcumin, Rearrangement, EI

benzaldehyde (vanillin) and pentane-2,4-dione. Com-

INTRODUCTION

pounds with various substituents in the A, B and C ring

positions or the aliphatic D position (Fig. 1) were syn-

thesized from appropriately substituted benzaldehyde

or pentane-3,5-dione, using PabonÏs method.7

Curcumin, 1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,

6-diene-3,5-dione (Fig. 1), may be obtained from various

plant roots (among others from Curcuma longa). This

orangeÈyellow phytochemical is often used as a color-

ant in cosmetics and food; it was Ðrst isolated in 1870

and its structure was elucidated in 1910.1 The anti-

inÑammatory and possible anti-tumor activity2,3 and

the low toxicity of curcumin inspired us to investigate a

wide variety of symmetric curcumin analogues. A syn-

thetic route to curcumin, developed by Pavolini et al.4,5

and by Pabon,6 starts with 4-hydroxy,3-methoxy-

Although some curcumin analogues are even amen-

able to gas chromatography with electron ionization

mass spectrometric (EIMS) detection and the EI mass

spectrum of curcumin is included in common EI mass

spectral libraries,8 the fragmentation behaviour of these

compounds has not been studied. Indeed, most frag-

mentations under EI conditions are straightforward and

would not justify any further investigation, but one par-

ticular reaction appears strange. In the spectra of many

of our synthetic curcumin analogues, this fragmentation

reaction even gives rise to the base peak. Here, we

report on the fragmentation of curcumin and its ana-

logues, focusing attention on a new, peculiar rearrange-

ment of the molecular ions.

* Correspondence to: B. L. M. van Baar, Research Group Analysis

of Toxic and Explosive Substances, TNO Prins Maurits Labor-

atorium, P.O. Box 45, 2280 AA Rijswijk (ZH), The Netherlands

Figure 1. Structure of curcumin with indication of substituent positions.

CCC 1076È5174/98/040319È09 $17.50

( 1998 John Wiley & Sons, Ltd.

Received 27 January 1997

Accepted 18 December 1997

320

B. L. M. VAN BAAR, J. ROZENDAL AND H. VAN DER GROOT

shows the data for the analogues with a substituent on

EXPERIMENTAL

Synthesis

the 4-position of the heptadienedione moiety and Table

2 gives data for aryl-substituted analogues. Some

important cleavage reactions are envisaged in Scheme

1; the characters refer to the product ions in Tables 1

and 2. For example, the cleavage of the CwCO bond,

pathway A, speciÐcally produces ene-acylium ions,

[RwCHxCHwCO]`. Many of the product ions

formed can be explained by similar simple fragmenta-

tion reactions.

All compounds were synthesized from the appropriately

substituted benzaldehyde and pentane-2,4-dione follow-

ing the procedure described by Pabon.6 The reaction

was performed at room temperature using tributyl

borate, with 1-aminobutane as

catalyst. All

compounds were characterized by their 1H NMR and

In contrast, most compounds also show open-and

closed-shell product ions that can only result from

extensive rearrangement reactions. The product ions of

some of these rearrangements are given in Scheme 2,

with characters again corresponding to Tables 1 and 2.

The formation of ring-substituted styrene radical

cations, F, can proceed either via a b-hydrogen shift

(shown in Scheme 2) to the double bond or via a

EI mass spectra and by exact mass measurement.7

1,7-13C -labelled 1,7-diphenylhepta-1,6-diene-3,5-dione,

14-13C , was obtained from a-[13C]benzaldehyde

(99.9% 13C; Campro ScientiÐc, Veenendaal, The

Netherlands) and pentane-2,4-dione, by scaling down the

procedure to the mmole scale; in this case the Ðnal re-

crystallization step of PabonÏs procedure was omitted

and 1H NMR was not applied.

McLa†erty rearrangement involving

hydroxy-

hydrogen from the ketoÈenol-type molecules (not

shown). The formation of ring-substituted benzyl

cations, G, can only occur after the transfer of a hydro-

gen atom to the C-1 atom of the heptadienedione

moiety, but the origin of the hydrogen atom involved is

not speculated upon here. One particular rearrange-

ment reaction, denoted X in Tables 1 and 2 (not shown

in Scheme 2), becomes dominant in the fragmentation

of curcumin analogues with bulky substituents. When

the substituents at the E position (Fig. 1) become as

large as phenyl, this rearrangement produces the base

peak ions (m/z 272, Table 1) and the same holds for

compounds with substituents in the aryl A and C posi-

tions becoming larger than ethyl groups. The promi-

nence of the product ion signals of this particular

rearrangement prompted us to investigate the formation

of the product ions.

Mass spectrometry

Common EI mass spectra and mass-analysed ion

kinetic energy (MIKE) mass spectra were obtained on a

Finnigan MAT 90 mass spectrometer (Finnigan MAT,

Bremen, Germany), operated under EI conditions (70

eV ionization energy, 0.2 mA collector current, 250 ¡C

source temperature) and using the standard direct inlet

probe. Full MIKE spectra were recorded at an overall

mass resolution of D800 and metastable ion peak

shapes for kinetic energy release deteminations were

recorded at a main beam width at half-height, w , of

\2.0 eV at an ion kinetic energy of D4750 eV.

0.5

RESULTS AND DISCUSSION

The MIKE mass spectra of the molecular ions all

have a prominent signal for the formation of the X

product ions, thus conÐrming that the product ions

result directly from the molecular ions. The kinetic

The structures and partial mass spectra of the curcumin

derivatives are given in Tables 1 and 2. These tables

were obtained by Ðrst taking all signals with an inten-

sity of more than 10%, relative to the base peak and

then comparing them with similar masses and/or frag-

mentation products with an intensity of \10%. Table 1

energy release (KER, speciÐed by T ), determined from

0.5

the Gaussian-shaped peaks for this fragmentation and

the intensity of the metastable ion peak relative to the

precursor ion main beam are given in Table 3 for a

Scheme 1

( 1998 John Wiley & Sons, Ltd.

JOURNAL OF MASS SPECTROMETRY, VOL. 33, 319È327 (1998)

Table 1. Partial EI mass spectra of curcumin (1) and some of its 4-substituted derivatives

Compounda, R

n-Pr

i-Pr

n-Bu

PhCH

4-MePH

4-MeOPh

4-FPh

4-ClPh

4-CF Ph

Attributionb

M½~

368 (31)

350 (39)

367 (1)

234 (2)

232 (12)

—

382 (18)

364 (1)

—

396 (18)

—

410 (29)

—

410 (21)

—

424 (19)

—

458 (23)

—

444 (10)

426 (5)

—

458 (12)

440 (5)

—

474 (15)

456 (4)

—

462 (3)

444 (1)

—

478 (6)

460 (3)

—

512 (9)

494 (7)

—

ÍM ÉH OË½~

ÍM ÉR Ë½

367 (1)

—

367 (1)

—

367 (2)

—

248 (1)

246 (2)

—

324 (15)

322 (4)

—

324 (5)

322 (8)

—

340 (6)

338 (6)

—

328 (6)

326 (3)

—

344 (4)

342 (3)

—

378 (4)

376 (4)

—

ÍM É134Ë½~

262 (2)

—

274 (3)

—

274 (2)

—

288 (2)

302 (7)

—

308 (6)

—

ÍM É136Ë½~

298 (2)

219 (3)

244 (4)

—

298 (2)

233 (1)

258 (6)

206 (2)

205 (2)

204 (2)

272 (18)

—

298 (3)

247 (1)

—

298 (4)

261 (1)

286 (6)

234 (3)

233 (1)

232 (1)

272 (20)

—

298 (5)

261 (1)

286 (5)

234 (3)

233 (2)

232 (2)

272 (9)

219 (5)

—

275 (2)

—

309 (1)

—

295 (7)

—

309 (10)

—

325 (5)

—

313 (1)

—

329 (3)

—

363 (2)

—

220 (2)

219 (1)

218 (1)

272 (20)

—

248 (3)

247 (2)

246 (1)

272 (17)

—

282 (4)

281 (19)

280 (2)

272 (23)

—

268 (2)

267 (2)

266 (2)

272 (100)

—

282 (5)

281 (3)

280 (2)

272 (100)

—

298 (8)

297 (2)

296 (2)

272 (100)

—

286 (3)

285 (1)

—

302 (1)

301 (1)

300 (1)

272 (100)

—

336 (1)

335 (3)

334 (1)

272 (100)

—

191 (32)

190 (39)

272 (16)

—

272 (33)

—

217 (14)

—

205 (5)

191 (5)

190 (1)

177 (100)

—

191 (3)

190 (1)

177 (100)

—

191 (5)

190 (1)

177 (100)

—

191 (5)

190 (3)

177 (100)

—

190 (6)

177 (74)

—

177 (100)

175 (12)

174 (4)

—

177 (100)

—

177 (100)

—

177 (42)

—

177 (56)

—

177 (100)

—

177 (49)

—

177 (35)

—

174 (4)

—

174 (4)

—

174 (6)

—

174 (5)

—

174 (4)

—

152 (40)

151 (55)

150 (16)

149 (7)

—

150 (24)

149 (13)

148 (6)

147 (13)

145 (39)

137 (39)

135 (10)

134 (13)

131 (27)

124 (2)

123 (1)

—

150 (9)

149 (7)

—

150 (6)

149 (7)

—

150 (7)

149 (8)

—

150 (7)

149 (9)

—

150 (9)

149 (7)

—

150 (26)

149 (5)

—

150 (29)

149 (5)

—

150 (22)

149 (7)

148 (15)

—

150 (39)

149 (7)

—

150 (39)

149 (6)

—

150 (33)

—

145 (30)

137 (8)

135 (4)

134 (6)

131 (2)

—

145 (29)

137 (6)

135 (2)

134 (6)

131 (3)

—

145 (28)

137 (7)

135 (3)

134 (6)

131 (3)

—

145 (30)

137 (9)

135 (3)

134 (6)

131 (2)

—

145 (25)

137 (10)

135 (3)

134 (5)

131 (3)

124 (1)

123 (1)

—

145 (21)

137 (14)

—

145 (16)

137 (16)

135 (6)

134 (5)

131 (2)

124 (3)

—

145 (19)

137 (16)

135 (6)

134 (5)

131 (4)

124 (2)

—

145 (23)

137 (15)

135 (18)

134 (5)

131 (2)

124 (1)

—

145 (26)

137 (13)

135 (7)

134 (4)

131 (1)

124 (1)

123 (9)

—

145 (16)

137 (18)

135 (7)

134 (4)

131 (2)

124 (2)

—

145 (14)

137 (20)

135 (6)

134 (4)

131 (2)

124 (2)

—

131 (9)

124 (1)

123 (2)

—

119 (7)

117 (10)

115 (3)

—

117 (22)

—

117 (15)

—

117 (14)

115 (2)

—

117 (12)

—

117 (13)

—

117 (11)

115 (2)

—

117 (11)

—

117 (10)

115 (5)

—

117 (10)

115 (2)

—

117 (10)

115 (1)

109 (11)

105 (2)

103 (1)

91 (1)

89 (8)

—

117 (8)

115 (1)

—

117 (7)

115 (1)

—

105 (12)

103 (15)

91 (17)

89 (27)

—

105 (4)

103 (1)

91 (4)

89 (10)

—

105 (3)

103 (1)

91 (3)

89 (12)

—

105 (3)

103 (1)

91 (3)

89 (9)

—

105 (3)

103 (2)

91 (3)

89 (11)

—

105 (3)

103 (1)

91 (2)

89 (8)

—

105 (2)

103 (2)

91 (16)

89 (10)

86 (13)

84 (23)

77 (6)

78 (6)

105 (5)

103 (1)

91 (3)

89 (13)

—

105 (4)

103 (3)

91 (7)

89 (10)

—

105 (3)

103 (1)

91 (3)

89 (9)

—

105 (2)

103 (1)

91 (1)

89 (9)

—

105 (2)

103 (1)

91 (1)

89 (6)

—

78 (17)

77 (22)

78 (5)

77 (5)

78 (6)

77 (5)

78 (4)

77 (3)

78 (5)

77 (4)

77 (3)

78 (4)

78 (6)

77 (8)

78 (5)

77 (6)

78 (5)

77 (7)

78 (3)

77 (4)

78 (4)

77 (4)

78 (3)

77 (2)

a Structure indication relates to Scheme 1, with R ¼OMe, R ¼OH, R and R ¼H.

b Attribution corresponding to Schemes 1 and 2.

Table 2. Partial EI mass spectra of aryl-substituted curcumin derivatives

Compoundsa

OMe

i-Pr

t-Bu

OMe

Attributionb

276 (88)

275 (10)

258 (16)

257 (18)

248 (13)

—

304 (33)

303 (3)

—

336 (44)

335 (1)

—

336 (85)

335 (2)

318 (12)

—

336 (29)

335 (2)

318 (30)

—

396 (30)

—

456 (69)

—

364 (12)

363 (1)

346 (20)

—

420 (18)

419 (2)

402 (40)

—

476 (21)

475 (2)

458 (44)

—

532 (24)

M½~

ÍM ÉHË½

531 (1)

378 (39)

—

438 (83)

—

ÍM ÉH OË½~

—

504 (1)

—

276 (1)

—

308 (1)

—

308 (1)

—

308 (3)

—

368 (1)

—

428 (3)

423 (17)

—

336 (1)

—

392 (3)

—

448 (2)

—

ÍM ÉCOË½~

—

287 (13)

—

373 (19)

324 (44)

271 (1)

270 (1)

260 (4)

258 (16)

257 (2)

—

180 (1)

199 (21)

198 (1)

—

208 (5)

213 (3)

—

240 (5)

229 (3)

228 (4)

—

240 (2)

229 (7)

—

240 (22)

229 (3)

228 (7)

—

300 (13)

259 (1)

258 (3)

248 (10)

—

360 (8)

289 (1)

288 (2)

278 (3)

—

268 (12)

—

380 (100)

299 (1)

298 (1)

288 (3)

286 (25)

285 (1)

—

436 (100)

—

202 (5)

—

218 (17)

—

232 (14)

230 (5)

—

316 (28)

314 (17)

313 (1)

301 (19)

—

185 (5)

—

199 (5)

—

215 (8)

—

215 (10)

—

215 (7)

—

245 (2)

—

275 (2)

—

201 (11)

—

214 (12)

187 (1)

185 (1)

189 (30)

188 (13)

175 (100)

174 (14)

—

187 (10)

185 (11)

159 (34)

158 (21)

145 (100)

144 (10)

—

187 (4)

185 (1)

175 (19)

174 (14)

161 (100)

—

187 (10)

185 (10)

175 (44)

174 (14)

161 (100)

160 (19)

—

187 (6)

185 (2)

175 (25)

174 (40)

161 (100)

—

187 (1)

185 (2)

205 (32)

204 (26)

191 (100)

190 (11)

—

187 (1)

185 (1)

235 (33)

234 (60)

221 (100)

220 (15)

219 (18)

—

187 (6)

185 (5)

217 (19)

216 (13)

203 (100)

—

187 (11)

185 (3)

—

187 (7)

185 (3)

—

145 (23)

144 (19)

131 (100)

—

231 (72)

—

259 (93)

—

129 (10)

—

243 (10)

—

207 (11)

205 (17)

204 (33)

—

128 (14)

—

127 (12)

141 (12)

—

131 (20)

—

128 (11)

—

117 (20)

—

147 (13)

—

147 (13)

—

115 (29)

—

119 (15)

135 (4)

134 (4)

133 (2)

132 (4)

131 (17)

—

135 (7)

134 (9)

133 (20)

132 (4)

131 (8)

—

135 (7)

134 (24)

133 (32)

132 (8)

131 (11)

—

165 (8)

164 (10)

163 (14)

162 (3)

161 (8)

160 (4)

151 (39)

—

195 (7)

194 (11)

193 (11)

192 (5)

191 (21)

190 (16)

181 (53)

179 (18)

177 (14)

176 (13)

—

149 (30)

148 (16)

147 (15)

146 (7)

145 (8)

144 (1)

135 (24)

—

104 (10)

118 (13)

176 (15)

175 (18)

—

204 (10)

—

103 (62)

117 (37)

203 (11)

—

102 (10)

116 (18)

—

101 (2)

115 (77)

—

91 (27)

—

105 (31)

—

191 (42)

189 (59)

—

121 (29)

—

121 (14)

—

121 (52)

—

163 (41)

161 (15)

—

219 (36)

217 (11)

—

203 (11)

—

174 (12)

173 (15)

—

163 (14)

161 (15)

147 (11)

—

161 (12)

147 (11)

—

147 (13)

145 (14)

131 (10)

128 (11)

—

131 (11)

—

118 (23)

115 (18)

105 (21)

103 (14)

—

118 (18)

115 (11)

—

118 (11)

115 (14)

—

118 (6)

115 (4)

—

118 (6)

115 (4)

—

115 (13)

—

115 (21)

—

115 (12)

—

115 (7)

—

77 (37)

91 (27)

—

91 (48)

—

91 (22)

90 (10)

89 (13)

77 (21)

91 (6)

90 (8)

89 (6)

77 (11)

—

91 (8)

90 (2)

89 (5)

77 (7)

91 (6)

90 (2)

89 (3)

77 (5)

91 (24)

—

91 (16)

—

91 (6)

—

91 (4)

—

90 (2)

89 (8)

77 (8)

90 (10)

89 (10)

77 (10)

89 (1)

—

89 (2)

77 (16)

89 (1)

77 (6)

—

77 (2)

a Structure indication relates to Scheme 1, with R ¼H.

b Attribution corresponding to Schemes 1 and 2.

324

B. L. M. VAN BAAR, J. ROZENDAL AND H. VAN DER GROOT

Scheme 2

variety of compounds. The KER lies between 36 and

150 meV, has a common value for rearrangement or

direct bond cleavages and does not give any indication

two substituted aryl rings and an additional 26 u. This

suggests, for all compounds, that the a- and u-aryl

groups of the molecular ion are somehow joined in the

of either a high reverse activation energy (large T ) or

product ion. The minimum reorganization in a

0.5

the involvement of an ionÈmolecule complex (small

rearrangement reaction producing ions with the

observed mass would give (aryl-substituted) 1,2-

diphenylethene (stilbene)-type radical cations and a

closed-shell neutral species. Two ways are conceivable

of generating stilbene-type product ions, depicted in

Scheme 3 for the fully unsubstituted compound, 14.

These pathways, either a formal 1,6-phenyl shift (I) or a

formal intramolecular [2 ] 2] cycloaddition with sub-

sequent ring opening (an oleÐn metathesis reaction, II),

are unconventional and, to our knowledge, unprece-

dented in cationic fragmentation.

). The relative intensity indicates that in the normal

0.5

EI mass spectra the particular fragmentation is

enhanced by large substituents on the E position (Fig.

1) or on the aryl system. The MIKE data show that a

rate-determining isomerization of the molecular ions,

prior to fragmentation, would be possible.9

A simple calculation shows that the mass of the

product ions consistently agrees with the mass of the

It is noted that a considerable part of the molecules

may have one of the keto groups in the tautomeric enol

form at the time of ionization; the enoloneÈdione equi-

librium is a general feature for neutral b-diketones, even

in the gas phase.10h13 The enolone form would,

however, not lead to markedly di†erent product ions

Table 3. Kinetic energy release (T values) and relative peak

0.5

intensities for the proposed formation of aryl-

substituted stilbene-type radical cations

KERa,b

(meV)

Intensity ratioc

(Ã104)

KERa,b

(meV)

Intensity ratioc

(Ã104)

Compound

but to

di†erent neutral species (i.e. 3-

110

130

1.9

3.9

6.6

4.2

1.1

3.0

1.3

hydroxycyclopenta-2,4-dien-1-one instead of cyclopent-

2-ene-1,4-dione in the case of 14). Although it is known

for simple b-diketones that some of the product ion

relative abundances reÑect the amount of dione and

enolone molecules,12 there is no way of obtaining

spectra of either pure form. As far as the reaction

mechanism for the formation of ions X is concerned, the

possible involvement of the enolone will be considered

along with that of the dione.

The most straightforward test for distinguishing

between the two mechanisms depicted in Scheme 3 is

provided by 13C labelling at the 1- and 7-positions of

the heptadienedione moiety. These positions can in

principle be labelled by using the 13C-labelled

(substituted) arylaldehyde, i.e. with the 13C in the car-

bonyl function, in the synthesis of a curcumin analogue.

1.2

0.64

0.31

0.38

1.3

130

0.68

0.92

0.90

1.4

120

5.9

obtained at a main beam width, w , of 1.5–2 eV and a

0.5

main beam energy of 4750–4800 eV.

b 1 meV B 96 J molÉ1.

c Intensity determined from peak height, with

ratio ¼IÍfragmentË/IÍmain beamË.

( 1998 John Wiley & Sons, Ltd.

JOURNAL OF MASS SPECTROMETRY, VOL. 33, 319È327 (1998)

EIMS OF CURCUMIN ANALOGUES

325

Scheme 3

Here 14-13C was synthesized, because the labelled pre-

pounds allows a reasonable approximation, because a

systematic error is nearly eliminated. The complemen-

tary reaction with respect to charge retention was

cursor, a-[13C]benzaldehyde, was commercially avail-

able. The disadvantage of the low relative product ion

abundance in the EI mass spectrum (m/z 180, 1%) is

partly compensated for by the relative simplicity of the

mass spectrum of 14. The EI mass spectrum shows an

exclusive mass shift of 2 u (to m/z 182) for the product

considered, but the enthalpy of formation of

stilbene molecule and the radical cation of cyclopent-

2-ene-1,4-dione (calculated: *H298[stilbene] \ 310,

ions of ionized 14-13C . Figure 2 shows the relevant

part of the MIKE mass spectra of 14 and 14-13C

radical cations. The most prominent signals in this part

of the spectrum represent the loss of a benzyl radical

(m/z 185 and 186 for 14`~ and 14`~-13C , respectively).

From the signals at m/z 180 (14`~) and 182 (14`~-13C ),

it is clear that both 13C atoms are present in the

product ions and that no 13CÈ12C scrambling occurs in

the process of fragmentation. This experiment readily

a†ords evidence for the formal breaking of two double

bonds in the course of a rearrangement reaction; more-

over, it shows that the rearrangement can only be an

intramolecular oleÐn metathesis-type reaction (Scheme

3, pathway II).

The proposed involvement of a bicyclo[3.2.0]hep-

tane type intermediate (Scheme 3, II) has a notable

analogy in organic synthesis. Many reactions have

been described either for the formation of substi-

tuted bicyclo[3.2.0]heptane from the appropriate

diene14h19 or for the dissociation of substituted

bicyclo[3.2.0]heptane into two oleÐns.19h23 Some atten-

tion has been devoted to the formation of the four-

membered ring via a concerted [2 ] 2] addition or via

a (non-concerted) biradical mechanism.15 Only in the

work of Salomon et al.19 has the intramolecular oleÐn

metathesis been completed, albeit in three steps (Scheme

4). These examples show that the proposed fragmenta-

tion mechanism in ionized curcumin analogues is at

least feasible. Moreover, the symmetry restrictions that

might apply to a concerted [2 ] 2] cycloaddition in

neutral molecules are broken by the charge and, there-

fore, the reaction should be thermodynamically more

favourable in ions than in neutral species.

MNDO/PM324 calculations were conducted in order

to investigate this peculiar rearrangement in more

detail. Although it is known that the MNDO formalism

does not give correct predictions of the heat of forma-

tion of open-shell ions in general,25 a comparison of

calculation results within the set of the present test com-

Figure 2. Partial MIKE mass spectra of the molecular ions of (A)

14 and (B) 14-13C .

( 1998 John Wiley & Sons, Ltd.

JOURNAL OF MASS SPECTROMETRY, VOL. 33, 319È327 (1998)

326

B. L. M. VAN BAAR, J. ROZENDAL AND H. VAN DER GROOT

Scheme 4

*H298[cyclopent-2-ene-1,4-dione] \ 812, *H298[prod]

Table 4. MNDO/PM3-calculated enthalpies of formationa and

of reactionb for the formation of (substituted)

stilbene-type ions from ionized curumin analogues

\ 1122 kJ mol~1) lies well above that of ionized stil-

bene and the neutral cyclopentenedione

(*H298[prod] \ 877 kJ mol~1). This implies that

DH298ÍM½~Ë

(kJ molÉ1)

DH298ÍStilb½~Ëc

(kJ molÉ1)

DH298ÍcpdËc

(kJ molÉ1)

DH298

(kJ molÉ1)

cyclopentenedione-type ions need not be present in the

Compound

mass spectrum as a complementary fragmentation to

any mechanism forming neutral cyclopentenedione and

ionized stilbene. Table 4 gives the calculated enthalpies

218

161

147

128

134

108

284

334

300

156

158

315

É309

877

779

536

504

532

227

É68

303

236

176

152

355

1097

999

760

757

735

456

155

532

476

389

406

É220

É238

É257

É279

É231

É302

É109

É82

É83

É44

É49

É52

É10

É55

É38

É61

É64

É42

É64

É67

É77

of reaction, *H298, and the enthalpies of formation,

*H298, of the species involved in the fragmentation

according to the mechanism of Scheme 3 (II).

The calculated *H298 of the molecular radical

cations, 1`~È24`~, is strongly inÑuenced (^50 kJ

mol~1) by the molecular conÐguration chosen; the

values speciÐed in Table 4 were obtained for the con-

Ðgurations of lower energy, i.e. with two E double

bonds in stretched molecules. The calculations show

that the reaction is nearly thermoneutral in all cases.

However, the calculated values for stilbene and its

radical cation (310 and 1097 kJ mol~1, respectively) lie

well above the experimental values (252 and 1005 kJ

mol~1, respectively26). If this is taken to be a general

trend for the substituted stilbenes and if it is assumed

(no experimental data available) that MNDO/PM3

closely predicts the heats of formation of the neutrals

and of the molecular ions, the reaction is exothermic

rather than close to thermoneutral.

É119

É241

É261

É107

É741

É220

É17

É9

É7

In order to obtain some information on a possible

intermediate in the reaction and on variations in the

reaction pathway, e.g. with the enolone-type precursor

cations, MNDO/PM3 calculations were performed for

the fully unsubstituted compound, 14, and fragments

a Stretched configuration of molecular ions, cis-configuration for

stilbenes.

b Assuming formation of the cyclopentenedione neutral.

c Stilb¼stilbene; cpd¼cyclopentenedione.

Scheme 5

( 1998 John Wiley & Sons, Ltd.

JOURNAL OF MASS SPECTROMETRY, VOL. 33, 319È327 (1998)

EIMS OF CURCUMIN ANALOGUES

327

derived therefrom. The calculations were limited to the

case of the [2 ] 2] cycloaddition with the

bicyclo[3.2.0]heptane-type intermediate. The calcu-

lation results are given in Scheme 5 (results obtained for

the fully 12C compound), which also shows the approx-

imate conÐguration (14b) of the reactant 14`~, the pos-

sible intermediates and the products. First the

ÏstretchedÏ conÐguration (cf. Table 4, for the dione) was

brought to the possible conÐguration preceding ring

closure. In the case of the dione, this reacting conÐgu-

ration was not a local minimum and collapsed to give

the distonic Ðve-membered ring intermediate, 14b,

whereas the enolone has a distinct local minimum for

both structures 14aº and 14bº. The relative stability of

the distonic 14b may imply that it can also act as an

intermediate in other fragmentations, e.g. in the loss of

CO or in the net loss of the mass of [aryl ] CH];

however, given the complexity of the system, it would

be difficult to prove that this intermediate is the key in

some rate determining isomerization. The two

bicyclo[3.2.0]heptane-type intermediates, 14c and 14cº,

are both local minima. The overall reaction is thermon-

eutral and the envisaged intermediates have an enthalpy

of formation below that of the reactant ions and that of

the products. Hence it is clear that the intermediates

required for the oleÐn metathesis reaction are accessible

once ionization of 14, be it in the enolone or the dione

form, has taken place. The calculations show that the

overall oleÐn metathesis reaction can proceed once the

neutral molecules, be they of dione or enolone type, are

ionized.

CONCLUSION

Although much of the fragmentation behaviour of sub-

stituted curcumins can be explained by conventional

fragmentation mechanisms, all 24 curcumin-type com-

pounds investigated in this study after ionization

undergo a rearrangement to form substituted stilbenes.

13C labelling shows that the stilbene product ions are

probably formed via a [2 ] 2] cycloaddition and a sub-

sequent retro-[2 ] 2] cycloaddition, formally an oleÐn

metathesis-type reaction. The possible involvement of a

bicyclo[3.2.0]heptane-type intermediate, analogous to

particular organic synthetic pathways, was conÐrmed

by MNDO/PM3 calculations.

Acknowledgement

A. N. NurÐna and A. M. Supardjan (Department of Pharmacy, Uni-

versitas Gadjah Mada, Yogyakarta, Indonesia) are gratefully acknow-

ledged for the synthesis of unlabelled compounds. The authors thank

the CAOS/CAMM Centre of the University of Nijmegen for the use

of calculation facilities. B.L.M.v.B. also thanks Privat Doz. Dr D.

Kuck for stimulating discussions.

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Electron ionization mass spectrometry of curcumin analogues: An olefin metathesis reaction in the fragmentation of radical cations

DOI: 10.1002/(SICI)1096-9888(199804)33:4<319::AID-JMS636>3.0.CO;2-U

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