The role of methoxy group in the Nazarov cyclization of 1,5-bis-(2-methoxyphenyl)-1,4-pentadien-3-one in the gas phase and condensed phase

Article abstract of DOI:10.1007/s13361-013-0785-8

ESI-protonated 1,5-bis-(2-methoxyphenyl)-1,4-pentadien-3-one (1) undergoes a gas-phase Nazarov cyclization and dissociates via expulsions of ketene and anisole. The dissociations of the [M + D]⁺ ions are accompanied by limited HD scrambling that supports the proposed cyclization. Solution cyclization of 1 was effected to yield the cyclic ketone, 2,3-bis-(2- methoxyphenyl)-cyclopent-2-ene-1-one, (2) on a time scale that is significantly shorter than the time for cyclization of dibenzalacetone. The dissociation characteristics of the ESI-generated [M + H]⁺ ion of the synthetic cyclic ketone closely resemble those of 1, suggesting that gas-phase and solution cyclization products are the same. Additional mechanistic studies by density functional theory (DFT) methods of the gas-phase reaction reveals that the initial cyclization is followed by two sequential 1,2-aryl migrations that account for the observed structure of the cyclic product in the gas phase and solution. Furthermore, the DFT calculations show that the methoxy group serves as a catalyst for the proton migrations necessary for both cyclization and fragmentation after aryl migration. An isomer formed by moving the 2-methoxy to the 4-position requires relatively higher collision energy for the elimination of anisole, as is consistent with DFT calculations. Replacement of the 2-methoxy group with an OH shows that the cyclization followed by aryl migration and elimination of phenol occurs from the [M + H]⁺ ion at low energy similar to that for 1. [Figure not available: see fulltext.]

Full text of DOI:10.1007/s13361-013-0785-8

B American Society for Mass Spectrometry, 2014
J. Am. Soc. Mass Spectrom. (2014) 25:398Y409
DOI: 10.1007/s13361-013-0785-8
RESEARCH ARTICLE
The Role of Methoxy Group in the Nazarov Cyclization
of 1,5-bis-(2-Methoxyphenyl)-1,4-Pentadien-3-one
in the Gas Phase and Condensed Phase
June Cyriac,1 Justin Paulose,1 Mathai George,1 Marupaka Ramesh,2
Ragampeta Srinivas,2 Daryl Giblin,3 Michael L. Gross3
1Department of Chemistry, Sacred Heart College, Thevara, Cochin, Kerala, India
2National Center for Mass Spectrometry, IICT, Hyderabad, India
3Department of Chemistry, Washington University in St. Louis, St. Louis, MO 63130, USA
+
m/z 295
Abstract. ESI-protonated 1,5-bis-(2-methoxyphenyl)-1,4-pentadien-3-one (1) un-
dergoes a gas-phase Nazarov cyclization and dissociates via expulsions of ketene and
anisole. The dissociations of the [M + D]+ ions are accompanied by limited HD scrambling
that supports the proposed cyclization. Solution cyclization of 1 was effected to yield the
cyclic ketone, 2,3-bis-(2-methoxyphenyl)-cyclopent-2-ene-1-one, (2) on a time scale that
is significantly shorter than the time for cyclization of dibenzalacetone. The dissociation
characteristics of the ESI-generated [M + H]+ ion of the synthetic cyclic ketone closely
resemble those of 1, suggesting that gas-phase and solution cyclization products are the
same. Additional mechanistic studies by density functional theory (DFT) methods of the
gas-phase reaction reveals that the initial cyclization is followed by two sequential 1,2-aryl
OH
C19H19O3
1
OCH3 CH3O
Nazarov cyclization
- ketene
m/z 253
17H17O2
- anisole
m/z 187
C12H11O2
•
C
+
OH
OCH3
CH3O
2
m/z 295
C
19H19O3
migrations that account for the observed structure of the cyclic product in the gas phase and solution. Furthermore, the
DFT calculations show that the methoxy group serves as a catalyst for the proton migrations necessary for both
cyclization and fragmentation after aryl migration. An isomer formed by moving the 2-methoxy to the 4-position
requires relatively higher collision energy for the elimination of anisole, as is consistent with DFT calculations.
Replacement of the 2-methoxy group with an OH shows that the cyclization followed by aryl migration and elimination
of phenol occurs from the [M + H]+ ion at low energy similar to that for 1.
Key words: Ion chemistry, Density functional theory, Nazarov cyclization, Solution and gas phase, Analogies,
Electrospray ionization, Tandem mass spectrometry
Received: 30 August 2013/Revised: 17 November 2013/Accepted: 18 November 2013/Published online: 11 January 2014
and chiral molecules [6]. Molecular orbital calculations
Introduction
indicate that various substituents at the third carbon relative
to the carbonyl group of the divinyl ketone affect the activation
energy required for cyclization [7]. The reaction mechanism of
cyclization and the effect of acids on the activation energy for
cyclization were also explored by molecular orbital calcula-
tions using DFT methods [8]. Molecular orbital calculations
have established the catalytic role of a water molecule in the
hydrogen rearrangements involved in the metal-mediated
Nazarov cyclization [9]. The catalytic role of other
solvents (e.g., methanol [10] and acetonitrile [11]) are
known in effecting symmetry-forbidden 1,3-hydrogen
migrations in acetone radical cations, as demonstrated
by mass spectrometry (MS) and supported by molecular
orbital calculations.
ne of the methods of choice for the synthesis of
substituted cyclopentenones is the acid-catalyzed,
O
electrocyclic ring closure of divinyl ketones, a reaction known
as the Nazarov cyclization [1, 2] and one for which the effects
of substituents and transition metal catalysts have been
explored [3]. The proposed mechanism involves a conrotatory
ring closure of the protonated divinyl ketone followed by
hydrogen migrations to yield the product [3], Scheme 1, first
part. The reaction is a useful synthesis tool for synthesis of
compounds including natural products [4], heterocycles [5],
Electronic supplementary material The online version of this article
(doi:10.1007/s13361-013-0785-8) contains supplementary material, which
is available to authorized users.
The utility of MS for the study of gas-phase reactions
[12] and their relationship to condensed phase reactions is
now well established, a classic example being the gas-phase
Correspondence to: Michael L. Gross; e-mail: mgross@wustl.edu

J. Cyriac et al.: Nazarov Cyclization in Gas Phase and Solution
399
H
H
H
H
+
O
+
O
O
O
Furthermore, we determined by DFT calculations the role
that phenyl or hydroxyl migration plays after the ring closure
leading to the observed cyclization product. To further
delimit the roles the methoxy group plays in the gas-phase
cyclization, we also investigated the fragmentations of
protonated 1,5-bis-(4-methoxyphenyl)-1,4-pentadien-3-one
(3), dibenzalacetone (4), and 1,5-bis-(2-hydroxyphenyl)-
1,4-pentadien-3-one (5, Scheme 2). The 2,3-bis-(2-
methoxyphenyl)-cyclopent-2-ene-1-one (2) was synthesized
by cyclization of 1 in a mixture (1:1) of formic acid and
phosphoric acid at 80 °C to afford a reference compound for
testing for the cyclization in the gas phase.
- H+
+H+
- H+
+
H
H
Ph
H
Ph
Ph
Ph
Ph
+H+
Ph
Ph
Ph
(ii)
(i)
H
H
+
O
OH
O
- H+
H
Ph
Ph
Ph
Ph
Ph
Ph
(iii)
Scheme 1.
Experimental
Synthesis
Claisen rearrangement of allyl phenyl ether as ionized by
chemical ionization [13]. Electrospray ionization (ESI) also
facilitates production of protonated or deprotonated mole-
cules in the ion source of a mass spectrometer and their
introduction into the gas phase for studies by tandem MS.
Combining the results with those from DFT calculations
provides a useful approach in exploring reaction mecha-
nisms, especially for protonated or deprotonated molecules.
Examples are the investigation of mechanisms of the
rearrangement of protonated 2-nitophenylphenyl ethers [14,
15] and that of the Smiles rearrangement [16, 17].
The acid-catalyzed (formic and phosphoric acid 1:1)
cyclization of protonated dibenzalacetone (i) (1,5-diphenyl-
1,4-pentadien-3-one) occurs at 90 °C in 28 h to give a
cyclopentenone in moderate yield. The structure of the
product, characterized as 2,3-diphenylcyclopent-2-ene-1-one
(iii), appears to have changed the position of the carbonyl
group, and a tentative reaction scheme was proposed
(Scheme 1) [18]. The mechanism of product formation
may be that the initially formed enol (ii) of the
cyclopenteneone isomerizes via a 1,2-shift of the OH group,
in acid medium, to yield the enol form of the product, which
then tautomerizes to the keto form (iii). Recent studies on
Nazarov cyclizations revealed that under certain conditions,
1,2-shifts of groups such as phenyl or alkyl occur after the
cyclizations, a process utilized for the synthesis of spiro-
compounds [19].
Recently, we investigated the gas-phase Nazarov cycli-
zation of protonated 2-methoxychalcone by using tandem
MS and DFT calculations [20]. We concluded that the gas-
phase cyclization is analogous to its solution-phase process;
the latter is promoted by microwave irradiation in
trifluoroacetic acid [21]. Moreover, we demonstrated that
the methoxy group serves as an effective catalyst for proton
transfers involved in completion of the gas-phase cyclization
and subsequent rearrangement and dissociation. Encouraged
by those results, we designed an ESI tandem MS study of
1,5-bis-(2-methoxyphenyl)-1,4-pentadien-3-one (1) to inves-
tigate whether the Nazarov cyclization occurs upon proton-
ation of this molecule. We again employed DFT methods to
understand the catalytic role that the methoxy group plays in
facilitating the reaction and subsequent fragmentations.
The dibenzalacetones 1, 3, 4, and 5 used for the experiments
were prepared from acetone and the appropriate benzalde-
hyde by following literature procedures [22–24]. The
substituted cyclopentenone 2 was obtained by the cycliza-
tion of 1 following a previously reported procedure [18] for
the cyclization of 4, but the temperature used for the
experiment was only 80 °C and the reaction was essentially
complete in 5 h as determined by TLC analysis. The reaction
mixture was diluted with water, and the product was
extracted with ethyl acetate and purified by silica gel column
chromatography, using a mixture of petroleum ether and
1
ethyl acetate. A comparison of the HNMR spectra of 1, 3,
4, and 5 with those previously reported [23] confirmed that
the structures were correct. The 1HNMR spectrum of 2
showed the following signals: δ 7.18–7.20 (2H, m), 6.99–
7.18 (2H, m), 6.70–6.90 (4H, m), 3.55 (3H, s), 3.68, (3H, s),
3.1 (2H, m), 2.70 (2H, m).
Mass Spectrometry
The protonated molecules were introduced into the gas
phase by using ESI of a solution of the compounds in 1:1
mixture of H2O/acetonitrile by direct infusion (flow rate: 5
μL/min). The dissociation pathways of the [M + H]+ ions
were first explored by ESI MS and collisionally activated
dissociation experiments (MS/MS and MS3) were initially
O
O
1
3
OCH3 CH3O
CH3O
OCH3
O
O
4
OCH3
CH3O
O
2
5
OH
HO
Scheme 2.

400
J. Cyriac et al.: Nazarov Cyclization in Gas Phase and Solution
(a)
100
maximum sensitivity. The needle voltage was 3 kV, and
295.1318
cone voltage was 90 V. Dry nitrogen gas at 150 oC was used
to desolvate the ions. The collision energies were set to a
minimum value required to make the abundance of the most
abundant fragment exceed that of the precursor ion (between
16 % and 30 % of the available energy). To aid in
elucidation of the rearrangement processes, [M + D]+ ions
were produced in the gas phase by ESI from solutions of the
compounds in 1:1 D2O/acetonitrile mixture by direct
infusion, and CAD spectra were recorded at low mass
resolving power.
187.0750
80
60
40
20
0
159.0802
150
253.1220
267.1375
121.0645
200
m/z
250
300
(b)
100
295.1326
187.0753
Theoretical Calculations
80
60
40
20
0
To characterize the potential energy surface (PES) associated
with fragmentation, we performed theoretical calculations.
Conformer spaces for precursors and intermediates were explored
by Monte-Carlo/MMFF molecular mechanics/dynamics
methods. From these results, structures of precursors, intermedi-
ates, and scans for associated transition states were explored by
using the PM3 semi-empirical [25, 26] algorithm (Spartan for
Linux; Wavefunction, Inc., Irvine, CA), and if necessary, scans
were also performed by DFT: B3LYP/6-31G(d,p). The possible
minima and transition states so obtained were geometrically
optimized by DFT (Density Functional Theory, part of Gaussian
98/03/09 suites [27–29], by Gaussian Inc., running on various
computer systems) to level B3LYP/6-31G(d,p) and confirmed by
vibrational frequency analysis (geometries in Supplementary
Data, Table 5). Connections of transition states to minima were
examined by inspection, projections along normal reaction
coordinates, and path calculations as necessary. Final single-
point energies were calculated at level M06/6-311+G(2d,p),
which employed the M06 hybrid functional with good general
accuracy [30, 31], on the B3LYP/6-31G(d,p) geometries to
which scaled thermal-energy corrections were applied [32] and
reported in Tables 2, 3, 4. DFT was selected for high-level
159.0808
253.1228
250
121.0650
150
200
m/z
300
Figure 1. Positive-ion ESI CAD mass spectra of (a) bis-(2-
methoxybenzal)acetone (1), (b) 2,3-bis-(2-methoxyphenyl)-
cyclopent-2-ene-1-one (2): Thermo LTQ Orbitrap mass
spectrometer
performed by using the Thermo LCQ Deca Ion-Trap (San
Jose, CA, USA) mass spectrometer operated in the positive-
ion mode at low mass resolving power. To determine the
elemental compositions of the precursor ions and fragment
ions, the ESI MS and ESI-CAD experiments were repeated
at a mass resolving power of 30,000 by using the Thermo
LTQ-Orbitrap mass spectrometer operated in the positive-
ion mode. The source parameters were optimized to get
Table 1. Measured Accurate Masses and Elemental Compositions of the [M + H]+ Ions and Major Fragment Ions of Compounds 1–5
Compound No.
1
[M + H]+
[M + H- ketene]+
[M + H – anisole/C6H6/phenol]+
295.1318
253.1220
187.0750
C19H19O3
C17H17O2
C12H11O2
Calc.295.1329
Calc.253.1223
Calc.187.0754
2
3
4
5
295.1326
C19H19O3
Calc.295.1329
253.1228
C17H17O2
Calc.253.1223
187.0753
C12H11O2
Calc.187.0754
295.1319
C19H19O3
Calc.295.1329
253.1221
187.0748
C12H11O2
Calc.187.0754
C17H17O2
Calc.253.1223
235.1114
193.1009
C15H13
Calc.193.1012
157.0646
C11H9O
Calc.157.0648
C17H15
O
Calc.235.1117
267.1012
225.0907
173.0597
C17H15O3
C15H13O2
C11H9O2
Calc.267.1016
Calc.225.0910
Calc.173.0597

J. Cyriac et al.: Nazarov Cyclization in Gas Phase and Solution
401
H
H
H
O
+
O
+
O
+
CH3
+
+
[C17H17O2]
O
OCH3
CH3
m/z 253
O
H
H
[C12H11O2]
H
H
m/z 187
O
O
OCH3
+
CH3
CH3
a
b
[M + H] , m/z 295
+
[C19H19O3]
Scheme 3.
calculations because it requires less computational overhead than
ab initio methods and performs adequately [33]. In addition for
comparison purposes, single-point energies were calculated at
levels B3LYP/6-311+G(2d,p) and MP2(fc)/6-311+G(2d,p) on
the B3LYP/6-31G(d,p) geometries, with the results being
averaged [34] to which scaled thermal-energy corrections were
applied. The differences and their sum as an RMS deviation are
reported in kJ/mol (Supplementary Data, Tables S1–S4). All
results are reported in kJ/mol as enthalpies of formation relative to
a selected, suitable precursor designated as A1 for all precursors
that have conformations suitable for Nazarov cyclization.
cule upon CAD. Given that Compound 1 is a divinyl ketone, a
gas-phase Nazarov cyclization is likely for the [M+H]+ ions of
1; hence, we proposed that the observed fragmentation results
from an intermediate initially formed by Nazarov cyclization,
(Scheme 3). Further, it was initially envisaged that the
intermediate a, formed by the cyclization, rearranges to b
owing to the abstraction of the proton from carbon-3 by the
methoxy group. Subsequent hydrogen migrations in ion b
mediated by the methoxy group are necessary for the formation
of the fragment ions, a hypothesis explored further by
molecular orbital calculations.
The most appropriate reference compound for establish-
ing the gas-phase cyclization of Compound 1 would be the
neutral ketone corresponding to the cyclic intermediate b. To
prepare this reference compound, the cyclization of 1 was
conducted by heating the precursor in solution in a 1:1
mixture of formic and phosphoric acids at 80 °C. The
reaction, essentially complete in 5 h, yields the product, 2,3-
bis-(2-methoxyphenyl)-cyclopent-2-ene-1-one (2). This
product does not have structure of b in Scheme 3 but an
isomer (Scheme 4). The results show that the Nazarov
reaction does occur at a lower temperature and shorter time
when the methoxy group is present at the 2-position of
dibenzalacetone than for the unsubstituted compound. The
structures of the products from both compounds, however,
have the same relative positions of the phenyl groups with
respect to the carbonyl group [18].
Results and Discussion
Empirical Results
Protonated 1,5-bis-(4-methoxyphenyl)-1,4-pentadien-3-one, as
the [M + H]+ generated by electrospray ionization of our
synthetic sample, yields fragment ions of m/z 253 and 187 by
the eliminations of the elements of ketene and anisole, as
evidenced by its CAD mass spectrum. CAD at high mass
resolving power (Figure 1a) afforded the molecular formula of
the fragment ions and confirmed the proposed eliminations
(Table 1). To determine the course of the rearrangement
processes, the corresponding [M + D]+ ions were investigated
by CAD. The [M + D]+ ions dissociate via eliminations of
ketene and ketene-d, to yield fragment ions of m/z 254 and 253
in the ratio 2:1, and of anisole and anisole-d to generate
fragment ions of m/z 188 and 187 in the ratio 2.5:1, as revealed
by the CAD mass spectrum. The elimination of ketene and
anisole together with the occurrence of HD scrambling in the
course of fragmentation of the [M + D]+ ions of 1 indicate some
rearrangement/scrambling processes of the protonated mole-
The ESI positive-ion CAD spectrum of 2 is closely similar to
that of 1, and the molecular ions of both compounds dissociate by
the same set of fragmentations (Figure 1b). The elemental
compositions of each of the fragment ions are identical from both
precursors as revealed by the measured accurate masses (Table 1).
Moreover, MS3 experiments show that the dissociations of the
H
+
H
+
O
O
+
O
H
HCOOH/H3PO4
80 oC/ 5 hr
O CH3
CH3
O
O CH3
CH3
O
+
O
O
CH3
CH3
Not Formed
1
2
Scheme 4.

402
J. Cyriac et al.: Nazarov Cyclization in Gas Phase and Solution
H
+
O
OCH3
m/z 187
12H11O2
O
Nazarov
Cyclization
+
C
+
O
O
1
H3C
O
O
Common
CH3
CH3
m/z 295
Intermediate
C19H19O3
+
+
H
O
H
O
CH3
- CH2CO
O CH3
CH3
O
H3C
2
m/z 253
17H17O2
C
Scheme 5.
major fragment ions of m/z 253 and 187 originating from
Compounds 1 and 2 are closely similar. Moreover, CAD also
demonstrates that the [M + D]+ ion of 2 dissociates by the
expulsion of ketene without HD scrambling into the ketene to
yield a fragment ion of m/z 254, whereas the elimination of
anisole from the [M + D]+ ion involves HD scrambling so that
peaks corresponding to fragment ions of m/z 188 and 187 (1:1) are
observed. By comparison, the elimination of ketene from the [M +
D]+ ion of 1 indicates HD scrambling involving at least 2H. The
elimination of ketene from protonated 2, likely generated from the
carbonyl and adjacent methylene, must involve no HD scram-
bling between the methylene and the charging protons; the latter
must be transferred elsewhere. The expulsion of anisole appears to
involve HD scrambling of the carbonyl proton/deuteron with the
equivalent of one other proton. The similarities in the dissociation
pattern of 1 and 2 suggest that ESI protonation of 1 induces it to
rearrange to protonated 2 via Nazarov cyclization followed by
shift of either the hydroxyl or aryl groups. Fragmentations of both
compounds likely occur via a common intermediate, resulting in
identical fragmentations (Scheme 5).
(a) At collision energy of 30.0
295.1319
100
187.0748
80
60
40
20
0
277.1219
253.1221
227.1065
121.0647
159.0804
144.0568
150
200
m/z
250
300
(b) At collision energy of 30.0
235.1114
100
80
60
40
20
0
217.1008
157.0646
129.0695
193.1009
The CAD mass spectrum of the ESI-generated [M + H]+
of 3 shows m/z 187 and 253 fragment ions by expulsions of
anisole and ketene, respectively. The molecular formulae of
the fragment ions given in Table 1 also support the proposed
eliminations of anisole and ketene. The collision energy,
however, needed to obtain a mass spectrum with similar
abundances for the ion of m/z 187 (90 % of the precursor
ion) (Figure 2a) is greater than that for Compound 1. Thus,
the Nazarov cyclization and subsequent eliminations of
anisole and ketene also appear to occur for the 4-methoxy
compound, 3, but the CAD requires higher energy than for 1
and 2 and must necessarily involve different pathways. In
addition, the elimination of anisole from the [M + D]+ ion of
3 occurs with HD scrambling to yield fragment ions of m/z
188 and 187 in the ratio 0.8:1, compared with 1:1 for 1 and
2. In contrast, the elimination of ketene occurs with HD
scrambling to yield fragment ions of m/z 254 and 253 in the
ratio 4:1, whereas for 1 and 2 there is no HD scrambling.
Moreover, the ESI generated [M + H]+ of m/z 235 of
150
200
m/z
250
300
(c) At collision energy of 19.0
147.0436
100
80
60
40
20
0
267.1012
249.0908
225.0907
173.0597
150
200
m/z
250
300
Figure 2. The CAD mass spectra of the [M + H]+ ions of
Compounds (a) 3, (b) 4, and (c) 5; from the Thermo LTQ
Orbitrap mass spectrometer

J. Cyriac et al.: Nazarov Cyclization in Gas Phase and Solution
403
H
+
- ketene
- phenol
O
m/z 225, C15H13O2
m/z 173, C11H9O2
5
OH
+
O
OH
HO
C
[ M + H]+; m/z 267, C17H15O3
m/z 147, C9H7O2
Scheme 6.
dibenzalacetone, 4, dissociates to give ions of m/z 193 and
257 corresponding to eliminations of ketene and benzene,
respectively (Figure 2b); the formulae of the neutrals were
determined by accurate mass measurements of the fragment
ions (Table 1). However, the major fragmentation pathway
for 4 is the loss of H2O. The collision energy required for
dissociating protonated 4 (relative collision energy 30) is
significantly higher than that for the [M + H]+ of 1 (relative
collision energy 18), the compound containing a methoxy
group at 2-position. The dissociation of the [M + D]+ of 4
occurs with HD scrambling for the expulsions of benzene,
the ratio of the abundances for ions of m/z 158 to 157 is 1:1.
Replacing the OCH3 groups at the 2,2′-positions in compound
1 with OH groups causes the [M + H]+ ion (m/z 267, compound
5) to dissociate at low collision energy to yield fragment ions of
m/z 225 and 173 by eliminations of ketene and phenol (Figure 2c),
processes that are analogous to the two fragmentations of
compound 1 (Scheme 5). This implies that the CH3 groups have
only a limited role in the fragmentation processes, and by
implication, the lone pair of electrons on the oxygen atoms must
play a key role in the fragmentation (i.e., facilitating the proton
transfers that follow the Nazarov cyclization. In addition, the most
abundant fragment is of m/z 147, whereas the corresponding
fragment of compound 1 (m/z 171) is not formed, indicating that
the acid protons of the phenol rings must play a role in the
148
100
90
80
70
60
50
40
30
20
10
0
270
175
227
174
149
147
140
250
242
240
122
120
173
160
180
200
m/z
220
260
Figure 3. The CAD mass spectrum of [M-d2 + D]+ ion
generated from 5 by ESI

404
J. Cyriac et al.: Nazarov Cyclization in Gas Phase and Solution
generation of m/z 147. Furthermore, the formulae of the neutrals
lost in the fragmentations were substantiated by accurate mass
measurement of the fragment ions.
points for calculating relative enthalpies of formation and
reaction for all species and reactions (Tables 3, 4, for
compound 1 only). In addition to A1, there is an ensemble of
other open forms related by rotations about various bonds
between the two phenyl rings and the carbonyl group and by
means of proton transfer from the carbonyl group. The
formation of a protonated cyclization product (2) from the
initial open protonated precursor (1) requires not only a
Nazarov condensation but also a migration of the OH group
or equivalently the migration of both aryl groups on the ring
formed by cyclization. An alternative would be the migra-
tion of the protonated carbonyl C=OH+ to an adjacent site
prior to Nazarov condensation. We did not discover,
however, an energetically feasible route for the migration
of the OH moiety either before or after the Nazarov
cyclization. We did find, however, that the migration of
the aryl groups for the 2-methoxy compound (1) (Scheme 7)
is facile; analogous routes apply, as determined by DFT
calculations, to the unsubstituted compound (4), the 2-
hydroxy (5), the 4-methoxy (3), and additionally to the 3-
methoxy (7) and 3,4-dimethoxy (6) analogs; the latter two
we did not investigate experimentally (Table 2).
The dissociations of the [M-d2 + D]+ ion of m/z 270 were
determined by recording the CAD mass spectrum, which reveals
that all three fragmentations possible for Compound 5 (Scheme 6)
are accompanied by HD scrambling (Figure 3). Eliminations of
ketene and ketene-d occur with equal probability unlike for [M +
D]+ of Compound 1. The retention of 1, 2, and 3 D occurs during
the expulsion of phenol, indicating more extensive HD scram-
bling, likely due to the labile phenolic protons. The observed HD
patterns accompanying the fragmentation processes for these
compounds are consistent with the proposed Nazarov cyclization
of the original protonated molecules.
Proposed Mechanisms and Theoretical
Calculations
We performed theoretical calculations (see Experimental) to
aid in the elucidation of the cyclization and fragmentation
mechanisms. We addressed cyclization, aryl migration, and
subsequent fragmentation of the substituted dibenzalacetone:
(1) 1,5-bis-(2-methoxyphenyl)-1,4-pentadien-3-one and the
cyclization product (2) 2,3-bis-(2-methoxyphenyl)-
cyclopent-2-ene-1-one. Calculations reveal that the preferred
protonation site occurs on the carbonyl oxygen in all cases.
We chose the initial forms, A1 (Table 2), to be the reference
For Compound 1, the reaction trajectory of A1 → C1 →
C1M → M1, begins with a Nazarov condensation of A1 to
form a metastable intermediate C1 that converts to C1M
,
Table 4. Calculated Relative Enthalpies of Formation/Reaction (Figure 6,
Scheme 9 in kJ/mol)
Table 3. Calculated Relative Enthalpies of Formation/Reaction (Figure 5,
Fragmentation - loss of ketene/arene:
Scheme 8 in kJ/mol)
2-methyoxy(1)
Proton migration: 2-methoxy(1)
Corr. H
(Hartree)
Δ2Hf/Δ2H‡
(kJ/mol)
Δ2Hrxn
(kJ/mol)
Corr. H
Δ2Hf /Δ2H‡
Label
Label
(Hartree)
(kJ/mol)
M3
−960.091108
−960.090036
−960.062019
−960.067870
−960.073040
−960.053562
−960.067245
−807.540968
−152.520672
−960.091171
−960.063801
−960.089460
−960.063719
−960.071879
−613.578823
−346.474167
−960.059049
−960.047967
−960.040415
−960.054346
−960.049736
−960.065835
−960.052227
−960.056033
−960.059922
−960.046945
−960.050375
4.4
7.2
M1
−960.085517
−960.091319
−960.056741
−960.075713
−960.079446
−960.071093
−960.091108
−960.087164
−960.122106
−960.083390
−960.060868
−960.058937
−960.070442
−960.055579
−960.049593
−960.057758
−960.052313
−960.057718
−960.080465
−960.063781
−960.077833
−960.052436
−960.047349
−960.044170
−960.013145
−960.019680
19.1
3.8
M3S
M9S
M9I
M9M
GZ
IDCK
HZ
K
M10
M10X
M11
M11X
IDCQ
PZ
M1R
M1X
M2
M2R
M2X
M3
M3R
MZ
M2RS
M2RY
M6
TS(M1-M1R
TS(M1R-M1X
TS(M1X-M2)
TS(M2-M2R
TS(M2R-M2X
TS(M2X-M3)
TS(M3-M3R
TS(M3R-MZ)
TS(M2R-M2RS
TS(M2RS-M2RY
TS(M2RY-MZ)
TS(M1-M6)
80.8
65.4
51.8
103.0
67.1
94.6
44.8
35.0
57.0
4.4
81.8
14.8
−77.0
24.7
83.8
88.9
58.7
97.7
113.4
92.0
106.3
92.1
32.3
76.1
39.3
105.9
119.3
127.6
209.1
191.9
4.2
76.1
8.7
76.3
54.9
)
)
)
105.7
Q
)
TS(M3-M3S
TS(M3S-M9S
TS(M9S-M9I)
TS(M9I-M9M
TS(M9M-M10
TS(M10-M10X
TS(M10X-M11
TS(M11-M11X
TS(M11X-IDCQ)
TS(M9M-GZ)
)
88.6
117.7
137.5
100.9
113.0
70.8
106.5
96.5
86.3
)
)
)
)
)
)
)
)
)
TS(M6-MZ)U
TS(M6-MZ)L
120.3
111.3
TS(GZ-IDCK)

J. Cyriac et al.: Nazarov Cyclization in Gas Phase and Solution
405
2H rxn = 155
H + K:
H
+
H2C
Aryl Migration
C1M
Ketene Loss
A1
C1
O
H
H
+
O
+
O
H
O CH3
CH3
O
nonplanar
R
+
TS(A1-C1)
2H = 95
O
TS(C1-C1M
2H = 84
)
H
‡
1
‡
H
O R
- CH2CO
H
H
H
2H rxn = 82
K
Hz + K:
2H f = 82
O
R
O
R
O
R
O
R
+
Hz
2H f = 0
2H f = 91
TS(C1M -M1)
2H ‡ = 102
OR
TS(A1-A2)
2H ‡ = 38
H
TS(C1-C2)
2H ‡ = 121
Start Form
OR
- CH2CO
Nazarov
Cyclization
TS(C1-M1)
M1
+
O
A2
C2
H
K
O
+
nonplanar
H
+
H+ Migration
R
+
TS(A2-C2)
O
O
O
MZ
2H = 91
‡
H
nonplanar
Common
Intermediate
H
H
O R
R O
O R
H
H
•
2
O
R
O
R
O
R
O
2H f = - 1
R
Lowest
Energy Form
2H f = 81
2H f = 19
2H f = -77
2H rxn = 106
PZ + Q:
PZ
planar
nonplanar
O
R
A0
+
A0K
R
O
R
R
+
OH
O
O
O
O
O
+
R
+
Arene Loss
H
H
2H f = 67
2H f = - 15
Lowest Energy Open Form
OR
+
O
P1
Q
+
H
R = H, CH3, none, or other ring substitutions: 3-OCH3, 4-OCH3, or 3,4-bis-OCH3
All enthalpies given as relative in kJ/mol, calculated results for R = CH3
O
R
2H rxn = 134
P1 + Q:
Scheme 7. Proposed mechanism for initial cyclization and aryl migration with considerations for proton migration and
fragmentation. enthalpies are given for 2-methoxy(1) form, R = CH3 in kJ/mol
which is a stable Wagner-Meerwein intermediate stabilized
by the 2-methoxy group (Figure 4). From that intermediate,
the 1,2-aryl shift occurs and is followed, without any
intermediate, by a second 1,2-aryl shift of the other aryl
group thus producing M1, protonated 2,3-bis-(2-
methoxyphenyl)-cyclopent-4-ene-1-one. The transformation
of A1 to M1 is accomplished with maximum transition-state
barrier of 102 kJ/mol, a modest energetic investment.
Similarly, the 4-methoxy (3) and the 3,4-dimethoxy (6)
analogs follow the same trajectory. For both the
unsubstituted (4) and 3-methoxy (7) analogs, which provide
little stabilization to the intermediate C1M and, surprisingly,
also the 2-hydroxy (5) form, C1M is unstable. Instead,
conversions by asynchronous 1,2-aryl Wagner-Meerwein
shifts take place directly from C1 yielding M1 (Scheme 7)
and again with modest energetic barriers (Table 2).
to MZ and likely proceed from a common intermediate
along the trajectory from M1 to MZ. Given the 1,2-diaryl
configuration of MZ, the most direct routes to ketene and
arene losses involve the formation of 1,2-diaryl-allyl and
protonated 3-aryl-cyclopentadienone cations. But these
TS(C1M-M1)
P1 + Q H + K
PZ + Q
TS(A1-C1)
TS(C1-C1M
)
C1
C1m
HZ + K
M1
The conversion of M1 to MZ, protonated 2,3-bis-(2-
methoxyphenyl)-cyclopent-2-ene-1-one (2) from com-
pound 1, is effected by a series of proton transfers
(Scheme 7, Scheme 8a, b). MZ is a very stable form on
the potential energy surface at Δ2Hf = −77 kJ/mol
relative to A1. Given that MZ fragments by the same
losses in similar proportions to A1, but requiring higher
collision energy, the products resulting from ketene and
arene (anisole) loss must also be energetically accessible
A1
MZ
Figure 4. Relative enthalpies of formation/reaction – initial
cyclization and aryl migration of o-methoxy Compound (1) as
example (Scheme 7, Table 2)

406
J. Cyriac et al.: Nazarov Cyclization in Gas Phase and Solution
a
H+ Migration - Direct
TS(M6-MZ)
2H ‡ = 192
TS(M1-M6)
2H ‡ = 128
M6
MZ
M1
H
O
+
H
H
H
O
+
+
H
O R
O R
H
H
O
H
O
H
+
R O
O
R
O
R
RO
H
H
O
R
O
R
2H f = - 77
2H f = 19
2H f = 89
b
H+ Migration -
O-assisted Transfer
M1
M2RS
TS(M2RS-M2RY
2H ‡ = 106
+
)
M2RY
H
O
O
+
H
O
+
H
H
H
H
O
R
O
O
R
R
H
O
O
O
TS(M2RY-MZ)
2H ‡ = 119
TS(M2R-M2RS
2H ‡ = 39
)
Shunt
R
R
R
2H f = 19
2Hf = 25
2Hf = 84
TS(M1-M1R
2H ‡ = 59
)
TS(M2-M2R
2H ‡ = 92
)
TS(M3-M3R
2H ‡ = 32
)
M1R
M2
M2R
M3
M3R
MZ
H
O
H
+
+
H
H
H
O
O
O
O
O
+
+
H
H
O
R
H
H
H
H
H
H
+
+
O
R
RO
RO
RO
RO
RO
H
O
R
O
O
O
O
R
R
R
R
2H f = 4
2H f = 15
2H f = - 77
2H f = 4
2H f = 35
2H f = 45
M1X
M2X
H
O
H
TS(M1R-M1X
2H ‡ = 98
)
TS(M1X-M2)
2H ‡ = 113
TS(M2R-M2X
2H ‡ = 106
)
TS(M2X-M3) TS(M3r-MZ)
2H ‡ = 92 2H ‡ = 76
O
O
H
H
R
H
+
O R
RO
RO
H
O
+
HO
O
+
OH-transfer
intermediates
R
2H f = 57
R
2H f = 95
Scheme 8. (a) Proposed mechanisms for proton migrations, 2-methoxy(1) form, R = CH3. (b) Proposed mechanisms for
proton transfers, 2-methoxy(1) form, R = CH3
TS(M2RY-MZ)
TS(M6-MZ)
TS(M1-M6)
TS(M2RS-M2RY
TS(M2X-M3)
TS(M2R-M2X)
)
TS(M1X-M2)
TS(M1R-M1X)
TS(M2-M2R
)
TS(M1-M1R
)
M6
M1X
M2RY
M2RS
M3
M2X
M2
M2R
M3R
M1
M1R
TS(M2X-M2RS
)
TS(M3-M3R
)
MZ
TS(M3R-MZ)
Figure 5. Relative enthalpies of formation/reaction – routes of proton migration in cyclized intermediates from o-methoxy
Compound (1) (Scheme 8, Table 3)

J. Cyriac et al.: Nazarov Cyclization in Gas Phase and Solution
407
M3
H
O
H
+
IDCK
CH2CO
+
RO
O
R
K
2H f = 4
Common Route
Ketene Elimination
HZ
OR
TS(M3-M3S
2H ‡ = 89
M3S
H
)
TS(GZ-IDCK)
2H ‡ = 111
TS(M9I-M9M
2H ‡ = 101
)
TS(M9S-M9I
2H ‡ = 138
)
TS(M3S-M9S
2H ‡ = 118
)
TS(M9M -Gz)
2H ‡ = 120
M9M
H
GZ
M9I
H
M9S
+
CH2CO
RO
R
O
O
+
O
O
O
R O
H
H
H
H
+
+
H
+
H
H
H
H
O
R
R O
RO
OR
O
O
O
2Hf = 103
2H f = 52
2H f = 65
RO
R
R
R
2H f = 81
2H f = 7
2H f = 67 ( IDC)
2H rxn = 82
TS(M9M -M10
2H ‡ = 113
)
Arene Elimination
R
TS(M11-M11X
2H ‡ = 96
)
TS(M10X-M11
2H ‡ = 106
O
)
TS(M10-M10X
2H ‡ = 71
)
TS(M11X-IDCQ)
PZ
M10
M10X
M11
M11X
O
2H ‡ = 86
O
+
+
O
O
O
+
H
H
O
H
H
H
H
O
+
R
O
O
H
O
H
O
R
R
R
+
R
R
H
Q
+
OR
O
O
R
2H f = 76
2H f = 9
2H f = 76
2H f = 4
R
H
IDCQ
2H f = 55 (IDC)
2H rxn = 106
Scheme 9. Proposed mechanisms for fragmentation from a common intermediate, 2-methoxy (1), R = CH3
products (Table S4 in Supplementary Data) require
Δ2Hrxn = 232 and 211 kJ/mol, respectively, not including
transition state barriers, with respect to MZ. In contrast,
formation of 1,3-diaryl-allyl and protonated 3-aryl-
cyclopent-4-ene-1-one cations would require 159 and
183 kJ/mol, respectively. Thus, a feasible route to these
fragments would require the back migration of the
second aryl group as part of the trajectory; these
considerations apply to all analogs we explored by DFT
calculations. (For fuller discussion of energetically
feasible and non-feasible forms, see Table S4 and
Schemes S1, S2, S3 in Supplementary Data.)
The conversion of M1 to MZ can proceed by direct 1,2-
proton migrations over carbon atoms or by aryl-ring assisted
or O-facilitated proton transfers (Scheme 8a, b, Table 3,
Figure 5). The lowest-energy direct route we discovered is
M1 → M6 → MZ (Scheme 8a). The first step is proton
transfer from C2 to C1, the next step is proton transfer from
TS(M9M-M10X)
TS(M11-M11X)
TS(M9S-M9I)
TS(M9M-GZ)
TS(M9I-M9M
)
TS(GZ-IDCK)
TS(M3S-M9S
)
TS(M11X-IDCQ)
TS(M10X-M11)
PZ + Q
GZ
M10X
TS(M3-M3S
)
M9S
M11X
IDCK
M9I
IDCQ
M9M
TS(M10-M10X
HZ + K
)
M3
M11
M3S
M10
Figure 6. Relative enthalpies of formation/reaction – routes to fragmentation by loss of ketene or arene (Anisole) from o-
methoxy Compound (1) (Scheme 9, Table 4)

408
J. Cyriac et al.: Nazarov Cyclization in Gas Phase and Solution
C3 to C4, followed by spontaneous proton transfer from C1
to C5 forming MZ; the greatest transition state requires
192 kJ/mol relative to A1, yielding a non-competitive route.
However, the most energetically favorable route from M1 to
MZ constitutes an example of intramolecular proton-trans-
port catalysis [35–38], where the mediator is the basic
oxygen of the 2-methoxy groups (Scheme 8b). That group is
sufficiently basic to abstract protons from the carbon
backbone of the five-membered ring. The trajectory for this
route is M1 → M1R → M1X → M2 → M2R → M2X → M3
→ M3R → MZ in which all proton transfers are to or from a
2-methoxy oxygen coupled with necessary group rotations
involving three OH-transfer intermediates; the highest
barrier for these processes is 113 kJ/mol (Figure 5). A
Conclusions
We present here another example of the facility of mass
spectrometry to study gas-phase reactions that are models of
solution chemistry. The significant similarity in the CAD
fragmentations of protonated 1,5-bis-(2-methoxyphenyl)-1,4-
pentadien-3-one (1) and that of the product of cyclization in the
condensed phase, 2,3-diphenylcyclopent-2-ene-1-one (2) indi-
cates that Nazarov cyclization occurs in the gas phase as well as
in solution and leads to the same product. Moreover, a methoxy
or hydroxy group at the 2-position exerts a catalytic effect on the
cyclization, rearrangement, and fragmentation series of reac-
tions as seen by the requirement for lower collision energy for
the 2-methoxy versus the 4-methoxy isomer and the
unsubstituted compound. Theoretical calculations using DFT
methods reveal that the basic oxygen of the methoxy group acts
as mediator for the various H-migrations following the
cyclization. Alternate routes are possible for the unsubstituted
and the 4-methoxy analog, but higher energy transition states
are required. The application of such gas-phase processes
promises to increase the opportunities to use mass spectrometers
as preparative devices to synthesize trace amounts of valuable
materials and isolate them by soft landing, for example [39, 40].
subroute involves a shunt of trajectory M2R → M2RS
→
M2RY → MZ; this route has its highest barrier of 119 kJ/mol
(Table 3) compared with previous route of 106 kJ/mol and
would be competitive starting from 1 but not from 2.
Obviously, the O-assisted routes will not be available for the
analogs without a 2-methoxy or 2-hydroxyl moiety, which
explains why greater collision energy is required to promote
losses of ketene and arene from these protonated ionic species.
Intermediate M3 of the proton migration route is the
common intermediate from which routes to losses of
ketene and arene commence (Scheme 9, Table 4,
Figure 6). Of importance is that the distribution of
protons on carbons is different than for C1 and, hence,
the details of aryl migration are different. The trajectory
for the common processes is M3 → M3S → M9S → M9I
→ M9M, where the second arene is transferred from C3
to C4 over a maximum relative barrier of 137 kJ/mol. In
the last common intermediate, M9M, there is a five-
membered ring formed involving C3 and the C2-aryl
methoxy oxygen. Cleavage of the C1–C2 bond followed
another C–C cleavage frees nascent ketene for elimina-
tion; the trajectory of M9M → GZ → IDCK → HZ+K
has a maximum relative barrier of 120 kJ/mol. Starting
with M9M, a series of O-assisted proton transfers and a
final C–C bond cleavage frees the arene (anisole) for
elimination; trajectory of M9M → M10 → M10X → M11
→ M11X → IDCQ → PZ + Q has a maximum relative
barrier of 113 kJ/mol. The difference in maximum
relative enthalpic barrier heights from common M9M is
in accord with the differences in spectral abundance.
Starting with MZ and running back through M3
(Scheme 8b) and then through to product HZ (Scheme 9),
we see that the fate of the charging proton, (indicated by
boldface magenta), does not include the adjacent C that is
the methylene part of the eliminated ketene. Hence, only
ketene, and not d-ketene, is eliminated in accord with
experiment starting with 2, and the charging proton ends
up on C1 in the product. In addition, the original charging
proton from 1 in Scheme 7 and running through Scheme 8b,
Scheme 9 is shown in black boldface and indicates
possibilities for scrambling: A0 interchange with A0k
(Scheme 7) and the back migration of the arene in Scheme 9.
Acknowledgments
The authors J.C., J.P., and M.G. thank the principal, Sacred Heart
College, Thevara, for providing infrastructure. R.S. and V.R.
thank Dr. J. S. Yadav, Director, IICT, Hyderabad, for facilities.
Research at WU was supported by the National Centers for
Research Resources of the NIH, NIGMS grant P41 GM103422-
35, and by the Washington University Computational Chemistry
Facility, supported by NSF grant CHE-0443501.
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