Nazarov Cyclization of 1,5-Bis-(2-methoxyphenyl)-1,4-pentadien-3-one in the Gas and Condensed Phases:
An Experimental and Theoretical Study
George Mathai1, June Cyriac1, Daryl Giblin2 and M.L. Gross2.
(1) Sacred Heart College, Thevara, Kochi, India. (2) Washington University in St. Louis, Missouri USA: Center for Biomedical and Bioorganic Mass Spectrometry - NCRR
and DFT calculations.
• CA of the ESI-produced [M + H]+ ions of 1 yield major fragment ions
resulting from the eliminations of ketene and anisole.
• The [M + D]+ ion of 1 dissociates similarly via eliminations of
ketene/ketene-d and anisole/ anisole-d.
• Upon heating in a mixture of formic and phosphoric acids, 1 cyclizes
to yield ketone 5; the reaction is faster than that of dibenzalacetone
(4).
• CA fragmentations of the [M + H]+ of 1 are analogous to those of the
[M + H]+ ion of 5, implying:
1. Cyclization take place both in gas phase and solution.
2. Two 1,2-phenyl shifts occur following Nazarov cyclization.
3. Several 1,3 H+-shifts occur before the fragmentations.
4. Methoxy group serves as catalyst for H+-shifts.
• The phenyl shifts account for the observed positions of the phenyl
groups in the cyclic ketone 5 and the faster cyclization of 1 in
solution compared to 4.
Introduction
Motivation: One method of choice for synthesis of cyclopentenones
is acid-catalyzed electrocyclic ring closure of divinyl ketones (Nazarov
cyclization) via conrotatory ring closure of the protonated ketone
followed by 1,3-type H+-shifts [1,2], which are solvent-assisted but
forbidden in gas-phase.
Recently, we demonstrated by MS/MS and DFT that proximal methoxy
and hydroxyl groups are catalysts for proton transfers in gas-phase
rearrangement and fragmentation of protonated 2-methoxychalcone [3].
The gas-phase cyclization reaction becomes analogous to its solution
rearrangement
H+-transporting
property of methoxy group in
To explore further the
facilitating rearrangement of protonated divinyl ketones, we use MS/MS
of 1 (and analogs 2-4) and DFT, as 1 is likely candidate for gas and
soln Nazarov cyclizations.
O
+
H
O
• Low resolving-power MS and CA (MS/MS and MS3) were with a
Thermo LCQ Deca Ion-Trap (San Jose, CA). Analogous high
resolving-power experiments were performed with a Thermo
LTQ-Orbitrap mass spectrometer operated in the positive-ion
mode (RP for product ions was 30000, both MS/MS and MS3).
• To track fragmentation, [M + D]+ ions were generated by ESI
from 1:1 D2O/acetonitrile mixture, introduced by direct infusion
and analyzed.
Theoretical Calculations:
Theoretical calculations characterized potential-energy surface
(PES) associated with fragmentation:
• Conformer space for precursors and intermediates were initially
explored by Monte-Carlo/MMFF and then by PM3 semi-empirical
[7] algorithm.
• Scans for structures of associated transition states were
explored using the PM3 semi-empirical [7] algorithm (Spartan for
Linux: Wavefunction, Inc.), and if necessary, augmented by
DFT: B3LYP/6-31+G(d,p)
• Minima and transition states were re-optimized by DFT
(Gaussian 98/03/09 suites) to B3LYP/6-31+G(d,p) and
confirmed by vibrational-frequency analysis. Transition-state
connections were determined by examination, projections along
normal reaction coordinates, or path calculations as necessary.
Single-point
energies
were
calculated
at
M06/6311+G(2d,p)//B3LYP/6-31+G(d,p) and scaled thermal-energy
corrections applied [8].
• Results are in kcal/mol as enthalpies relative to suitable
precursor.
• DFT was selected; it requires less computational overhead than
ab initio methods and yet incorporates correlation and performs
adequately [9,10].
Note: Theory yields information about the potential-energy surface,
but fragmentation patterns depend on kinetics.
References
1. M. A. Tius, Eur. J. Org. Chem. 2005, 11, 2193
2. M. George, V. S. Sebastian, P. Nagi Reddy, R. Srinivas, D.
Giblin, and M. L. GrW. Nakanishi and F. G West, Current
Opinion in Drug Discovery & Development 2009 12(6):732-751.
3. oss, J. Am. Soc. Mass Spectrom., 2009, 20, 805– 818.
4. Howell, J. A. S.; O’Leary, P. J.; Yates, P. C. Tetrahedron,
1995, 51(26), 7231-7246.
Formic acid/ Phosphoric acid
90 °C, 28 hrs
5. J. Huang, D. Leboeuf, and A. J. Frontier, J. Am. Chem. Soc.
2011, 133, 6307–6317.
The cyclization of protonated 1,5-bis(phenyl)-1,4-pentadien-3-one (4)
does occur in a mixture of formic and phosphoric acid at 90 °C for 28 h,
yielding an isomeric cyclopentenone [4]. Structure was attributed to OH
migration, but recent studies indicate that phenyl migrations may occur
instead [5].
We conducted Nazarov cyclization of 1 in solution and isolated cyclic
ketone 5 to compare gas-phase fragmentation (ESI MS/MS) with that
of 1.
O
OCH3
O
H3CO
OH
O
O
O
CH3
O
CH3
3
O
H3CO
5
OCH3
7. (a) J. J. P Stewart, J Comp. Chem. 1989, 10, 209; (b) J. J. P.
Stewart, J Comp. Chem. 1989, 10, 221.
8. J. A. Pople, A. P. Scott, M. W. Wong, L. Radom, Israel J.
Chem. 1993, 33, 345-350.
9. M. J. Shephard, M. N. Paddon-Row, J. Phys. Chem. 1995, 99,
3101-3108.
4
• Ketene elimination from [M + D]+ ion of 1, but not from 5, is accompanied by scrambling.
• Therefore, protonation of 1 forms an intermediate via a Nazarov cyclization that rearranges to
protonated 5. Both compounds fragment via the same intermediates yielding the same
fragment ions (Scheme 1).
• CA of compounds 1 and 5 require less collision energy compared to those of compounds 3
and 4, indicating that proximal methoxy group at 2-position is needed for transport catalysis
of the H+-shifts that occur after cyclization.
• The solution cyclization of 1 is faster than that of 4, the unsubstituted dibenzalacetone;
hence, proximal methoxy group accelerates cyclization is solution. The relative position of
the phenyl groups with respect to the carbonyl are the same (Scheme 2).
• Given that CA of protonated 1 and 5 are nearly identical, rearrangement after Nazarov
cyclization involves either phenyl or hydroxyl migrations in addition to H+ transfers. The
observed product is energetically more favorable than the expected isomer (Scheme 2).
1,5-bis(2-hydroxyphenyl)-1,4-pentadien-3-one (2): CAD results:
• CA of [M + H]+ of 2 results in analogous elimination of ketene (m/z 225) and phenol (m/z 173)
(Fig. 5). The collision energy required is comparable to that for compound 1. Again dscrambling occurs in the fragmentations of the d-labeled analog.
• However, eliminations of water (m/z 249) and 2-hydroxystyrene (m/z 147) become more
competitive, owing to the presence of active protons on the proximal hydroxy groups.
1,5-bis(4-methoxyphenyl)-1,4-pentadien-3-one (3) and 1,5-bis(phenyl)-1,4pentadien-3-one (4): CAD results:
• CA of [M + H]+ of 3 and 4 results in analogous elimination of ketene and arene (m/z 253, 187
[anisole] for 3; m/z 193, 157 [benzene] for 4) (Figs. 6 and 7). The collision energy required is
greater than that for compound 1.
• For both compounds, no proximal methoxy or hydroxy groups assist proton transfers, hence
required assisting proton transfers employ the phenyl rings.
Theoretical Calculations: proposed mechanisms
• Reaction trajectory from protonated precursor (1,A1) to fragmentation products proceeds in
stages from acyclic forms, Nazarov cyclization, aryl migration and proton migration to give
protonated compound 5 (Mz).
• Proton migration converts the product from Nazarov cyclization (M1) to the observed product
(5,Mz).
• The proximal methoxy group functions as base to effect efficient proton transport in moving
the benzylic H’s to the 4,5 positions of the cyclopentenone ring to give protonated 5 (Mz)
[11].
Proton Migration (Scheme 4 - Ketene loss section)
• Ketene loss proceeds from intermediates M3r or M3 by scission of the C1-C2 bond of the
cyclopentenone ring.
• The resultant acylium ion is unstable, however, and re-cyclizes forming different ring
structures of intermediate energies from which ketene is lost instead.
Arene Loss (Scheme 5)
• Loss of ketene from [M + D]+ of 5 (Mz) would proceed without scrambling, whereas loss
from 1 (A1) along with the arene losses from either precursor would afford opportunity of
H/D scrambling, as observed experimentally.
This poster will be available on WU website shortly after ASMS
Conference
Note: highest barrier occurs at final fragmentation steps.
Concluding Comments:
Upon protonation 1,5-bis(2-methoxyphenyl)-1,4-pentadien-3-one underges Nazarov cyclization
both in the solution phase and gas phase. The cyclization is followed by two aryl shifts, verified
by theoretical calculations. The reaction is influenced by the methoxy group, both in presence or
in the absence of solvent; in the gas phase the methoxy groups serve as catalysts for the
putative 1,3-H migrations, verified by calculations.
Scheme 1:
CH3 O
CH3O
H2C
40
20
+
O
+
60
O
CH3
159.0802
145.0645
140
160
180
O
CH3
O
m/z 295 CH3
C19H19O3
253.1220
220
240
m/z
Jcket_1aa_100911132529 #2-49 RT: 0.03-0.76 AV: 48 NL: 6.88E7
of the[80.00-350.00]
ESI produced [M+H]+
T: FTMS. +CAD
p ESI mass
Full ms2spectrum
295.13@cid24.00
200
Fig. 2
260
280
m/z 253 C17H17O2
+ H
O
+
O
295.1326
HCOOH/H3PO4
H
+
O
80
40
CH3 O
H
O CH3
+
80 oC/ 5 hr
OCH3
H3CO
60
O
CH3
159.0808
Not Formed
Scheme 3: General Overview
0
140
160
180
200
220
m/z
240
260
280
H
A1 +O
300
C1
188
100
D
O
296
60
187
40
O
CH3
20
O
R
TS
2H‡ = 9.2
O
CH3
O
R
Cyclization
254
O
160
180
200
220
m/z
240
260
280
R
300
Jket_2 #1-169 RT: 0.00-1.39 AV: 169 NL: 2.17E7
Fig.
4. CAD
mass
spectrum [100.00-400.00]
of the ESI produced [M+D]+ ion of Cyclic ketone 5
T: + p ESI
Full ms2
296.10@cid29.00
O
R
296
TS
2H‡ =
C2
O
187
 Hrxn = 36.0
H
O+
H
H
H+ Migration
O
R
O
O
2Hf = 19.2 R R
2Hrxn = 32.1
P1
Q
Scheme 4: Proton Migration and Ketene Loss
160
180
200
220
m/z
240
260
280
O
300
J2_2_100907042019 #1-22 RT: 0.01-3.40 AV: 22 NL: 7.20E4
147.0436
H
O
+
267.1012
OH
173.0597
225.0907
M1r
0
160
180
200
220
240
260
280
+
m/z
J1_b_100907151343 #1-39 RT: 0.01-3.61 AV: 39 NL: 8.88E5
mass
of the
ESI produced
T: FTMS. +CAD
p ESI Full
ms2 spectrum
295.10@cid30.00
[80.00-350.00]
Fig. 6
H
187.0748
[M+H]+ ion of ketone 3
+
O
80
60
O
CH3
O
CH3
O
R
2Hf = 0.9
180
200
220
m/z
260
235.1114
H
O
M1
217.1008
+
207.1165
193.1009
H
0
160
180
200
220
m/z
240
260
280
59th ASMS Conference – Denver 2011
www.chemistry.wustl.edu/~msf/
M3
+
O
H
O
O R
RO
M1y
H
O
H
OR
RO
2
 Hf = -18.4
TS
TS
2 ‡
2 ‡
O  H = 22.0  H =
18.2
H
O
H +
OR
RO
H+
O
R
+
O
H
OR
O
H
+
RO
TS
2H‡ = 28.1
OR
H
O
H
H TS
O 2H‡ = 29.6
H +
O R
H
O
R
H
2Hf = 27.3
TS
2H‡ = 41.8
No TS
RO
IDC
OR
P1
2Hf = 24.3
H
O+
Q
+
RO
Arene Loss
2Hf = 24.7
M1z
TS
2 ‡
 H = 25.3
2
 Hf = 26.1
M4
RO
+
2Hf = 27.8
O
R
2Hf = 4.6
Mz

7.7
O
R
2Hf = 1.0 2Hf = 3.5
M2x
O
H
H
+
RO
TS M
3r
2 ‡
H =
2Hf = 13.6
TS
H
2H‡ = 27.1
R O+
H
157.0646
20
H
TS
2H‡ =
TS
H
O 2H‡ = 27.1
Scheme 5: Loss of Arene
+
80
60
M2r
RO
R
2Hf = 21.3
J_b_100907151343 #1-21 RT : 0.01-1.75 AV: 21 NL: 2.41E6
Fig.
7.+ CAD
mass
spectrum of[60.00-300.00]
the ESI produced [M+H]+ ion of ketone 4
T: FTMS
p ESI Full
ms2 235.10@cid30.00
100
H
H+
O
280
TS
2Hrxn = 36.0
2H‡ = 19.8 Ketene Loss
H+ Migration
H
267.1376
RO
240
OR
RO
H1
O
O
R
R
2Hf = 10.7 2Hf = 8.4
M1x
0
160
H
O
R
253.1221
227.1065
144.0568
RO
OR
TS
H 2H‡ =
O+
22.0
RO
TS
2H‡ = 23.4
159.0804
M2
H
O
TS CH2CO K
2H‡ = 39.7 +
H2C
+
OR
TS
2H‡ = 22.5
H
H
295.1319
100
O
TS
2H‡ = 14.0
2Hf = 4.6
249.0908
239.1064
G1 CO +
2
 Hf = 23.5
CH3 O+
OR
O
R
HO
20
140
H
H
60
40
H
O
OR
+
RO
2Hf = 19.4
M1
+
80
140
+
RO
Fig.
5. +CAD
of the
ESI produced [M+H]+ ion of ketone 2
T: FTMS
p ESI mass
Ful l ms2 spectrum
267.10@ci d19.00
[70.00-300.00]
40
H
O R
H
O+
RO
254
160
140
140
+
O
2Hf = -18.4
2Hf = 4.6
0
40
Mz
nonplanar
H
40
145
- CH2CO
R O
OR
Arene Loss
20
O R
M1
H
+
OCH3
H3CO
60
+
Aryl Migration
D
+
O
80
H2C
R O
2
H
2Hf = -0.3
Ketene Loss
O R
H
H
O
R
TS
2H‡ = 21.7
nonplanar
H
+
H
O
R
2Hf = 21.7
2Hf = 0.0
H
+
A2 O
160
O
TS
2H‡ = 24.4
OR
H
H
0
140
H
+
nonplanar
+
80
O
TS
2H‡ = 22.6
gm090410J3_c RAW #1-99 RT: 0.00-0.98 AV: 99 NL: 1.17E7
Fig.
. CAD
mass
spectrum [100.00-600.00]
of the ESI produced [M+D]+ ion of compound 1
T: + p 3
ESI
Full ms2
296.10@cid28.00
20
O CH3
CH3 O
O
CH3
253.1228
145.0649
20
100
m/z 295
C19H19O3
- CH2CO
- CH2CO
+ H
O
Scheme 2:
H
O CH3
O CH3
O
CH3
300
ion of Cyclic ketone 5
187.0753
100
+
CH3 O
0
• Trajectory rationalizes product in soln and inferred in gas phase.
Proton Migration (Scheme 4 - H+ migration section)
11. A. J. Chalk, L. Radom, J. Am. Chem. Soc. 1997 119, 75737578.
Acknowledgment
O
Relative enthalpies in kcal/mol
Calculations for R=CH3
CH3O
+ H
O
80
Overall Reaction (Scheme 3)
• Arene loss proceeds from intermediate M1 whereby a benzylic proton in transferred via
adjacent methoxy group to C1 of other phenyl ring to activate that CC bond for cleavage.
G.M. and J.C. thank Principal, S.H. College, Thevara for providing
infrastructure. Research at WU was supported by the NCRR of the
NIH, Grant P41RR00954; research also made use of the
Washington University Computational Chemistry Facility, supported
by NSF grant #CHE-0443501.
H
187.0750
+
100
• Other processes (e.g. loss of water and CO) become competitive in both cases.
10. Y. Zhao, D. G. Truhlar, Acct. Chem. Res., 2008, 41(2), 157167.
HO
2
1
6. W. M. Weber, L. A. Hunsaker, S. F. Abcouwer, L. M. Decka, V.
D. L. Jagt, Bioorganic & Med. Chem. 2005, 13, 3811–3820.
• CA of the [M + D]+ ions from 1 and 5 exhibits D-scrambling in anisole elimination (Fig. 3 and
4), consistent with extensive rearrangement needed by loss of anisole.
Relative Abundance
• Formation of the positive-ion precursors, via protonation, was
achieved by ESI from 1:1 acetonitrile/water by direct infusion.
• CA of [M + H]+ of cyclic ketone 5, m/z 295, yields same fragment ions by eliminations of
ketene and anisole (Fig. 2). CAD of m/z 253 & 187 ions (MS3) from 1 and 5 are similar.
295.1318
100
H
O+
m/z 187
C12H11O2
Fig.
1.+CAD
mass
of the[80.00-350.00]
ESI produced [M+H]+ ion of compound 1
T: FTMS
p ESI Full
ms2spectrum
295.10@cid18.00
Relative Abundance
cyclization product (5) by MS/MS,
MS3
Mass Spectrometry:
Schemes
J3_d_100907042019 #1-31 RT: 0.01-7.28 AV: 31 NL: 1.05E4
• [M + H]+ of 1, m/z 295, upon CA yields fragment ions of m/z 253.1220 and 187.0750 via
eliminations of CH2CO (ketene) and C7H8O (anisole), respectively, (Fig 1).
Relative Abundance
• Theory by DFT to determine the potential energy surface: structures
and mechanisms.
Results: We compared fragmentation of the [M + H]+ of (1) and its
1,5-bis(2-methoxyphenyl)-1,4-pentadien-3-one (1) : CAD of [M + H]+ of 1 and 5
Relative Abundance
• Fragmentation by CAD with further characterization by accuratemass measurements, D labeling, and comparison with model
compounds.
Dibenzalacetones 1-4 were synthesized by literature procedures
from acetone and the appropriate benzaldehyde [6]. 5 was
synthesized by heating compound 1 in a mixture of formic acid and
phosphoric acid at 80 0C for 5 h following that for cyclization of
dibenzalacetone [4]. Structures of compounds were confirmed by
1HNMR, IR, and HRMS.
Relative Abundance
Methods: Experimental and Theoretical.
Mass Spectrometry Results (Positive-ion ESI MS/MS and MS3)
Relative Abundance
pentadien-3-one (1) undergoes Nazarov cyclization in the gas phase,
(b) role of methoxy group in the mechanism of cyclic-product formation
and its fragmentation, and (c) whether cyclization of 1 occurs in solution
and gives cyclic ketone 5 (to be used as reference).
Spectra
Results and Discussion
Synthesis:
Relative Abundance
Methods
Overview
Purpose: To determine: (a) whether 1,5-bis(2-methoxyphenyl)-1,4-
M5
O R
HH
O+
R
2Hrxn = 32.1
P2
H TS
O 2 ‡
 H = 39.3
No TS
IDC
2
 Hf = 34.6
2Hrxn = 41.3
H
O + RO
OR
+
Q