Gas phase retro-Michael reaction resulting from dissociative protonation: Fragmentation of protonated warfarin in mass spectrometry

Article abstract of DOI:10.1002/jms.3055

A mass spectrometric study of protonated warfarin and its derivatives (compounds 1 to 5) has been performed. Losses of a substituted benzylideneacetone and a 4-hydroxycoumarin have been observed as a result of retro-Michael reaction. The added proton is initially localized between the two carbonyl oxygens through hydrogen bonding in the most thermodynamically favorable tautomer. Upon collisional activation, the added proton migrates to the C-3 of 4-hydroxycoumarin, which is called the dissociative protonation site, leading to the formation of the intermediate ion-neutral complex (INC). Within the INC, further proton transfer gives rise to a proton-bound complex. The cleavage of one hydrogen bond of the proton-bound complex produces the protonated 4-hydroxycoumarin, while the separation of the other hydrogen bond gives rise to the protonated benzylideneacetone. Theoretical calculations indicate that the 1, 5-proton transfer pathway is most thermodynamically favorable and support the existence of the INC. Both substituent effect and the kinetic method were utilized for explaining the relative abundances of protonated 4-hydroxycoumarin and protonated benzylideneacetone derivative. For monosubstituted warfarins, the electron-donating substituents favor the generation of protonated substituted benzylideneacetone, whereas the electron-withdrawing groups favor the formation of protonated 4-hydroxycoumarin. Copyright

Full text of DOI:10.1002/jms.3055

Research Article
Received: 11 April 2012
Revised: 27 June 2012
Accepted: 28 June 2012
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI 10.1002/jms.3055
Gas phase retro-Michael reaction resulting
from dissociative protonation: fragmentation
of protonated warfarin in mass spectrometry
a
a
b
b
Jia Zhang, Yunfeng Chai, Kezhi Jiang, Huameng Yang,
a
a
Yuanjiang Pan * and Cuirong Sun
A mass spectrometric study of protonated warfarin and its derivatives (compounds 1 to 5) has been performed. Losses of a
substituted benzylideneacetone and a 4-hydroxycoumarin have been observed as a result of retro-Michael reaction. The added
proton is initially localized between the two carbonyl oxygens through hydrogen bonding in the most thermodynamically
favorable tautomer. Upon collisional activation, the added proton migrates to the C-3 of 4-hydroxycoumarin, which is called the
dissociative protonation site, leading to the formation of the intermediate ion-neutral complex (INC). Within the INC, further
proton transfer gives rise to a proton-bound complex. The cleavage of one hydrogen bond of the proton-bound complex produces
the protonated 4-hydroxycoumarin, while the separation of the other hydrogen bond gives rise to the protonated
benzylideneacetone. Theoretical calculations indicate that the 1, 5-proton transfer pathway is most thermodynamically favorable
and support the existence of the INC. Both substituent effect and the kinetic method were utilized for explaining the
relative abundances of protonated 4-hydroxycoumarin and protonated benzylideneacetone derivative. For monosubstituted
warfarins, the electron-donating substituents favor the generation of protonated substituted benzylideneacetone, whereas
the electron-withdrawing groups favor the formation of protonated 4-hydroxycoumarin. Copyright © 2012 John Wiley
&
Sons, Ltd.
Supporting information may be found in the online version of this article.
Keywords: retro-Michael reaction; dissociative proton transfer; ion-neutral complex; warfarin; mass spectrometry
[
10–12]
which is termed the dissociative proton attachement.
INTRODUCTION
However, in some cases, no fragmentation occurs when proton-
ation takes place at the thermodynamically preferred site, but a
major reaction is found when the added proton is transferred to
a different position, which is described as the dissociative pro-
Electrospray ionization mass spectrometry (ESI-MS), which creates
solvent-free and unimolecular conditions for gas phase reactions,
not only can provide extensive structure information for small
organic molecules and biological macromolecules, but also can
play an important role in understanding the intrinsic character of
the reaction and throwing light on reactivity trends in the con-
[
13–16]
tonation site.
Dissociative protonation sometimes does not directly form
the final products but result in the non-conventional ion-neutral
INCs are frequently formed as reactive
intermediates in the course of unimolecular dissociation reac-
[1]
[13,17]
densed phase. In fact, the mass spectrometer has been termed
complex (INC).
[
2]
a ‘complete chemical laboratory’.
[
18–21]
The Michael reaction is one of the most important carbon–carbon
and carbon–heteroatom bond-forming process in organic
tions in a mass spectrometer.
In an INC, the ionic fragment
and the neutral molecule are held together by electrostatic
interactions. Within INC, various chemical reactions may occur
either between the two partners or inside the ion moiety
alone prior to the final separation. Recently, more examples on
INC-mediated fragmentation reactions in ESI MS have been
[3–5]
synthesis.
Over the past decades, a tremendous amount of
effort has been devoted to the utilization of the Michael reaction
to generate drug-like scaffolds. Warfarin and its derivatives are
successful examples of Michael addition of 4-hydroxycoumarin to
benzylideneacetone. Warfarin, which has been introduced for
clinical use as Marevan, is one of the most widely prescribed anti-
thrombotics to help prevent and treat blood clots associated with
heart-value replacement or an irregular, rapid heartbeat. As an
important chemical pathway of this anti-thrombotic drug, a
[
22–31]
reported.
In this paper, we report the results of retro-
Michael reaction of warfarin and its derivatives initiated by
dissociative proton transfer in MS in conjunction with auxiliary
theoretical calculations.
n
thorough understanding of the MS/MS and MS data of warfarin
compounds is essential for bioactivity mechanisms, degradation
pathways and metabolism research.
* Correspondence to: Yuanjiang Pan, Department of Chemistry, Zhejiang University,
Hangzhou 310027, Zhejiang, China. E-mail: panyuanjiang@zju.edu.cn
Protonation and proton transfer are of fundamental importance
[
6–9]
a Department of Chemistry, Zhejiang University, Hangzhou, 310027, China
in the explanation of chemical reactions in gas phase.
The
positive charge brought in by protonation is usually the driving
force for fragmentation reactions of the protonated molecules,
b Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry
of Education, Hangzhou Normal University, Hangzhou, 310012, China
J. Mass. Spectrom. 2012, 47, 1059–1064
Copyright © 2012 John Wiley & Sons, Ltd.

J. Zhang et al.
EXPERIMENTAL
Table 1. Structures of the compounds studied
MS
All collision-induced dissociation (CID) experiments were carried
out on a Varian 500-MS mass spectrometer equipped with an ESI
source in positive ion mode, an ion trap analyzer and the Varian
MS Workstation (Varian, America). Nitrogen gas was used as the
nebulizing gas and the drying gas. Ionization was performed using
ꢀ
the following settings: spray chamber temperature 50 C, nebulizer
pressure 35 psi, drying gas pressure 15 psi, drying gas temperature
Compounds
Molecular mass
R
ꢀ
3
50 C, needle voltage 5000 V, spray shield voltage 600 V, infusion
ꢁ
1
1
2
3
4
5
386
342
308
322
338
Br
Cl
H
rate 10 mL min . The CID mass spectra were obtained with helium
as the collision gas after isolation of the desired precursor ion, and
the collision energy (resonance mode) was adjusted properly to
give suitable energy for the dissociation of all compounds studied.
Accurate masses were measured on an Apex III (7.0 Tesla) Fourier
transform ion cyclotron resonance (FTICR) MS (Bruker, Billerica, MA,
USA) equipped with an ESI source in the positive ion mode. Sodium
trifluoroacetate was used as an external calibration compound.
Nitrogen was used as nebulizing gas and drying gas. Argon was
used as collision gas. The capillary voltage was set at ꢁ4448 V,
CH
OCH
3
3
respectively, as shown in Fig. 1. The product ion at m/z 291
arising from the loss of water and the ion at m/z 251 deriving
from elimination of acetone are not discussed in this paper. To
confirm the proposed structure of product ions, high-resolution
FTICR MS was used for the exact mass measurements. The errors
between the calculated values and the observed masses are
within 1.4 ppm (Table S1 in Electronic supplementary infor-
mation), indicating the probable elemental compositions of the
product ions are of high confidence.
ꢀ
and drying gas temperature was set at 150 C.
Theoretical calculations
All theoretical calculations were carried out using the Gaussian 03
package of programs. Candidate structures of the reactants,
products, intermediates and transition states were optimized at the
B3LYP level of theory with the 6-31G (d) basis set. No symmetry
constraints were imposed on the optimizations. The reaction
pathways were traced forward and backward by the intrinsic
reaction coordinate method. All optimized structures were subjected
to vibrational frequency analysis to ensure a transition state had
only one imaginary vibrational frequency while a local or global
minimum had no imaginary vibrational frequency. The energies
discussed here are the sum of electronic and thermal energies.
Dissociative proton transfer
+
Fragmentation reactions of the protonated molecules [M+ H] are
usually triggered by the positive charge formed upon protonation.
The warfarin molecules may be protonated at various positions,
including the two carbonyl oxygen atoms, the ester oxygen of
the 4-hydroxycoumarin moiety, the aromatic rings and the polar
substituent. For the identification of the most favorable proton-
ation site, theoretical calculations were carried out using the
density functional theory (DFT) at the B3LYP/6-31G (d) level of
theory. Overall, the computation results indicate that the carbonyl
groups in a chelating conformation are the most thermodynami-
cally favorable protonation sites as shown in Scheme 1. For warfarin
and its derivatives, the fragmentation takes place only when the
proton is attached to C-3 (Table 1). However, protonation at C-3 is
by 17.8 kcal/mol higher than the most thermodynamically favorable
protonation involving the two carbonyl groups (Scheme 1).
MATERIALS
Warfarin and its derivatives bearing substituents in the para position
[32]
were synthesized in a previous work. Samples were dissolved in
methanol for mass spectrometric analysis.
RESULTS AND DISCUSSION
Since the protonation at C-3 of 4-hydroxycoumarin is the neces-
sary step for C-3–C-a bond cleavage, there may be four pathways
Retro-Michael reaction of protonated warfarin
(
Scheme 2) to generate the dissociative structure. In Route 1, MH-1
In the synthesis of warfarin and its derivatives, Michael reaction
was utilized for the carbon–carbon bond forming process of
transforms to the formation of MH-2 first. Then, the proton migrates
4
-hydroxycoumarin and substituted benzylideneacetone. In the
+
CID mass spectra of the [M+ H] ions of all warfarin compounds
studied (Table 1), loss of a benzylideneacetone leading to
protonated 4-hydroxycoumarin and loss of a 4-hydroxycoumarin
generating protonated benzylideneacetone derivative were
observed as retro-Michael reaction, along with other minor
reactions. The representative compound 3, warfarin, was selected
as a model to give an explanation of the possible dissociation
pathways. The full scan ESI mass spectrum of Compound 3 showed
an abundant ion at m/z 309. Upon collisional activation, it yielded
two product ions at m/z 163 and 147, corresponding to the pro-
tonated 4-hydroxycoumarin and protonated benzylideneacetone
+
Figure 1. CID mass spectrum of the [M + H] ion of compound 3.
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Copyright © 2012 John Wiley & Sons, Ltd.
J. Mass. Spectrom. 2012, 47, 1059–1064

Retro-Michael reaction in mass spectrometry
from the carbonyl oxygen of the benzylideneacetone moiety to the
C-3 of 4-hydroxycoumarin, via a 1, 5-proton shift through a six-
membered ring transition state (TS 2–5), to form MH-5. In Route 2,
the formation of MH-3 is derived from the cleavage of one hydrogen
bond, followed by proton transfer from the carbonyl oxygen of the
4-hydroxycoumarin moiety to the C-3 of the 4-hydroxycoumarin
moiety via a 1, 3-proton shift (TS 3–5), to form MH-5, again. The
INC-1 arising from Route1 and Route 2 may directly separate leading
to ion a1 or form the proton-bound complex which would give
rise to ion a2 and ion b. The migration of the internal proton also
probably triggers the fragmentation. In Route 3, the dissociation is
invoked by the internal proton transfer from the C-b to the C-3 of
the 4-hydroxycoumarin moiety via a 1, 3-proton shift (TS 1–6). Direct
cleavage induced by the formal positive charge results in the forma-
tion of the proton-bound complex, in which the hydrogen bonds
bind the 4-hydroxycoumarin moiety and benzylideneacetone
moiety together. In Route 4, the migration of the hydroxyl hydrogen
to the C-3 via a 1, 3-proton shift (TS 4–7) triggers the cleavage of
the C-3–C-a bond, forming the INC-2. The proton-bound complex
may again be generated from INC-2.The following proton transfers
within proton-bound complex are similar with Route1 and Route
2, leading to ion a2 and ion b.
Scheme 1. Protonation sites and dissociative protonation site for warfarin.
Scheme 2. Proposed fragmentation mechanisms for the protonated warfarin.
J. Mass. Spectrom. 2012, 47, 1059–1064
Copyright © 2012 John Wiley & Sons, Ltd.
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J. Zhang et al.
different substituents at para position of the phenyl ring were
measured. Generally, all the compounds underwent similar
fragmentation in the CID experiments, whereas the nature of
the substituents merely affected the relative abundances (RAs)
of the product ions. The RAs of the product ions are listed in
Table 2 for all the compounds studied. A plot of abundance ratios
+
+
of these two ions, ln[(C
9
H
7
O
3
)/(RC10
H10O )] versus the substituent
[
36]
+
constants,
s ,was obtained as shown in Fig. 3. The trend
p
indicates that the electron-donating substituents favor the loss
of 4-hydroxycoumarin, whereas the electron-withdrawing groups
favor the loss of substituted benzylideneacetone. It seems that
the substituents have no effect on the transition state for there
is no conjugative effect. The reason for this trend is probably that
for the compounds with electron-donating groups, the positive
charge can be delocalized into substituent, resulting in more
stable product ions.
The formation of the protonated 4-hydroxycoumarin and
protonated benzylideneacetone derivative can also be explained
[
37,38]
+
by the kinetic method.
For [M+ H] ions producing two
+
+
individual protonated molecules [A+ H] and [B + H] through
intermediate [A⋯H ⋯B], the two neutral species A and B
Figure 2. Potential energy diagram for the formation of the product ions
a1, a2 and b from protonated warfarin using DFT at the B3LYP level of theory
with the 6–31 G (d) basis set. Relative energies are given in kcal/mol.
+
compete for the shared proton to form the corresponding final
fragment ions. The fragmentation is governed by the proton
affinities (PAs) of the molecules A and B. The PA for the following
reaction is defined as the negative of reaction enthalpy at 298.15K.
To quantitatively describe the energy requirements for the migra-
tion of the proton, theoretical calculations were carried out using the
DFT at B3LYP/6-31G (d) level of theory. A schematic potential energy
diagram for the four possible routes of fragmentation of protonated
warfarin is given in Fig. 2. The activation barriers of the 1, 5-proton
shift in Route 1, 1, 3-proton shift in Route 2, 1, 3-proton shift in
Route 3 and 1, 3-proton shift in Route 4 are 22.1, 72.1, 50.9,
A þ Hþ ¼ ½A þ Hꢂþ
(1)
+
Table 2. Major product ions observed in the CID spectra of the [M + H]
6
4.1 kcal/mol in energy, respectively. This indicates that the acti-
ions of the compounds studied
vation energy of 1, 5-proton shift through a six-membered ring is
the lowest of the four routes, that is to say, the Route 1 is most
reasonable in terms of energy.
+
Compounds
[M + H]
Ion a
Ion b
a
1
2
3
4
5
387
343
309
323
339
225 (4.6)
181 (5.9)
147 (8.9)
163 (100)
163 (100)
163 (100)
163 (94.1)
163 (5.8)
Proton transfer via the INC
161 (100)
177 (100)
In Route 1, to generate the product ion b (m/z 163), i.e. the proton-
ated 4-hydroxycoumarin, there must be at least three steps: the
addition of the external proton at C-3, the cleavage of C-3–C-a bond
and the migration of a proton from the benzylideneacetone moiety
to the 4-hydroxycoumarin moiety. The INC-mediated reaction
mechanism can provide a convincing explanation of these crucial
steps. The cleavage of the carbon–carbon bond linking the two
moieties forms the intermediate INC-1 (Scheme 2). Within the
INC-1, the hydrogen at the C-b of benzylideneacetone moiety is
transferred to the 4-hydroxycoumarin, generating the proton-
bound complex, while direct dissociation generates the ion a1.
The cleavage of one hydrogen bond of proton-bound complex
produces the ion b, and the separation of the other hydrogen bond
gives rise to the ion a2 which is 11.8 kcal/mol lower than that of
its isomer ion a1.The isomerization of a1 to a2 via intramolecular
a
m/z (Relative abundance %).
1, 3-proton shift needs to surmount a considerable energy barrier
of 34.6 kcal/mol (not shown in Fig. 2). However, this isomerization
can be promoted by the 4-hydroxycoumarin within INC-1, which is
[16,33–35]
known as a proton-transport catalysis process.
Investigation of the substituent effects
+
+
Figure 3. Plot of ln[(C
constants, s
9
H
7
O
3
)/(RC10
H
10O )] versus the substituent
+
To study the influence of the substituents on the formation of the
p
for the fragmentation of protonated warfarin being mono-
two product ions, the spectra of a series of compounds with
substituted at the para position of the phenyl ring.
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Copyright © 2012 John Wiley & Sons, Ltd.
J. Mass. Spectrom. 2012, 47, 1059–1064

Retro-Michael reaction in mass spectrometry
Table 3. Computed proton affinities (PAs) of substituted benzylide-
neacetone (A) and 4-hydroxycoumarin (B)
retro-Michael reaction only takes place when the external proton
migrates from the most thermodynamically favorable proton-
ation site to the dissociative protonation site C-3 of the coumarin
moiety. And of all these proton transfers, energy barrier of the
proton transfer from the carbonyl oxygen of benzylideneacetone
to the C-3 is the lowest. The kinetic method was successfully applied,
and a linear free-energy relationship was found between the RAs of
the final product ions a and b and the PA of the two aromatic
moieties of the warfarin scaffold.
a
b
Compounds
PA(A)
PA(B)
PA(A)- PA(B)
1
2
3
4
5
215.2
216.9
218.6
221.8
226.2
217.8
217.8
217.8
217.8
217.8
2.3
0.9
ꢁ0.8
ꢁ4.0
ꢁ8.4
a
B3LYP/6-31 G (d)
b
kcal/mol
Acknowledgement
The authors gratefully acknowledge financial support form
the National Science Foundation of China (Nos. 21025207
and 20975092).
Supporting Information
Supporting information may be found in the online version of
this article.
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