Functionality, Effectiveness, and Mechanistic Evaluation of a Multicatalyst-Promoted Reaction Sequence by Electrospray Ionization Mass Spectrometry

Article abstract of DOI:10.1002/chem.201502640

A multicatalytic three-step reaction consisting of epoxidation, hydrolysis, and enantioselective monoacylation of cyclohexene was studied by using mass spectrometry (MS). The reaction sequence was carried out in a one-pot reaction using a multicatalyst. All reaction steps were thoroughly analyzed by electrospray ionization (ESI) MS (and MS/MS), as well as high-resolution MS for structure elucidation. These studies allow us to shed light on the individual mode of action of each catalytic moiety. Thus, we find that under the epoxidation conditions, the catalytically active N-methyl imidazole for the terminal acylation step is partially deactivated through oxidation. This observation helps to explain the lower efficiency of the catalyst in the last step compared to the monoacylation performed separately. All reactive intermediates and products of the reaction sequence, as well as of the side-reactions, were monitored, and we present a working mechanism of the reaction.

Full text of DOI:10.1002/chem.201502640

DOI: 10.1002/chem.201502640
Full Paper
&
Reaction Mechanisms
Functionality, Effectiveness, and Mechanistic Evaluation of
a Multicatalyst-Promoted Reaction Sequence by Electrospray
Ionization Mass Spectrometry
M. Wasim Alachraf,[a] Raffael C. Wende,[b] Sçren M. M. Schuler,[b] Peter R. Schreiner,[b] and
Wolfgang Schrader*[a]
Abstract: A multicatalytic three-step reaction consisting of
epoxidation, hydrolysis, and enantioselective monoacylation
of cyclohexene was studied by using mass spectrometry
(MS). The reaction sequence was carried out in a one-pot re-
action using a multicatalyst. All reaction steps were thor-
oughly analyzed by electrospray ionization (ESI) MS (and
MS/MS), as well as high-resolution MS for structure elucida-
tion. These studies allow us to shed light on the individual
mode of action of each catalytic moiety. Thus, we find that
under the epoxidation conditions, the catalytically active N-
methyl imidazole for the terminal acylation step is partially
deactivated through oxidation. This observation helps to ex-
plain the lower efficiency of the catalyst in the last step com-
pared to the monoacylation performed separately. All reac-
tive intermediates and products of the reaction sequence, as
well as of the side-reactions, were monitored, and we pres-
ent a working mechanism of the reaction.
Introduction
situ and consumed rapidly. Methods allowing the characteriza-
tion of structural changes typically are NMR[4] and, to a minor
extend, IR spectroscopy.[4e,5] A powerful tool for the investiga-
tion of complex organocatalytic reactions is mass spectrometry
(MS) due to its advantages to detect components at low con-
centrations within short lifetimes. Even structural data can be
derived with MS/MS experiments.[6] The fragmentation of indi-
vidual intermediates can be utilized for the characterization of
catalytic reactions.[7]
Various synthetic methods have been developed utilizing small
organic molecules as organocatalysts.[1] One especially intrigu-
ing development has been the use of cascade or tandem reac-
tions,[2] in which several reactions are subsequently carried out
in one pot. These types of reactions promise higher efficiency
while minimizing resource and energy requirements. Typical
cascade or tandem reactions combine the reactants from the
beginning,[2] often giving rise to a broad variety of side-reac-
tions. An alternative concept for cascade reactions is a catalyst
bearing multiple catalytic moieties, separated by a spacer mol-
ecule, a so-called multicatalyst.[2l,3] This methodology is remi-
niscent of an assembly line, in which a complex molecule is
consecutively assembled from simple starting materials in
a manner that at the correct time each catalytic moiety is se-
lectively activated.[3]
Due to the novelty of the multicatalyst approach, no mecha-
nistic studies have been carried out yet. Herein, we report a de-
tailed mechanistic investigation concerning the catalytic epoxi-
dation of olefins followed by hydrolysis and enantioselective
kinetic resolution through acylation.[8] Each individual step can
be defined by reaction intermediates as reaction markers that
can be detected by ESI-MS. The multicatalyst A0B0 used in this
study consists of a chiral peptide backbone[9] including an ada-
mantane spacer[3,10] separating two catalytic moieties. Dicar-
boxylic acid A0 is responsible for the first reaction step, an ep-
oxidation,[11] and N-methyl imidazole moiety B0 catalyzes the
terminal acylation.[3b] The individual catalytic moieties are acti-
vated by adding the corresponding reagent after a particular
time interval, and this is the key difference to cascade reac-
tions. Various catalysts have been developed, in which the cat-
alytically active moieties were placed in different positions of
the peptide backbone; herein, we employed the most effective
catalyst A0B0 (Scheme 1).[3b]
The elucidation of reaction mechanisms of such complex re-
actions is rather challenging, because many intermediates are
short-lived and occur often only in minor quantities. Indeed,
one advantage of such reactions is that isolation of short-lived
intermediates can be neglected, because they are generated in
[a] Dr. M. W. Alachraf, Prof. Dr. W. Schrader
Max-Planck Institut für Kohlenforschung
Kaiser Wilhelm Platz 1, 45470 Mülheim an der Ruhr (Germany)
Fax: (+49)208-306-2982
E-mail: wschrader@mpi-muelheim.mpg.de
[b] R. C. Wende, S. M. M. Schuler, Prof. Dr. P. R. Schreiner
Institute of Organic Chemistry
Justus-Liebig University Giessen
Heinrich-Buff-Ring 17, 35392 Giessen (Germany)
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tached to the peptide is the for-
mation of N-acylurea A1’, which
was reported by Montalbetti and
co-workers.[12] We also observed
this rearrangement, but the mo-
lecular ion is present in such low
intensity that it is under stan-
dard conditions almost not de-
tectable, implying that it is rela-
tively unimportant for the cata-
lytic step (Scheme 2; Figure 2).
Due to the short lifetime of
those and other intermediates, it
was not possible to determine
Scheme 1. Reaction sequence using multicatalyst A0B0.
Results and Discussion
The first step in the mechanistic evaluation of a catalytic reac-
tion with ESI-MS is the determination and characterization of
reaction markers that allow an unequivocal assignment of the
reaction intermediates. The first step of the reaction under
consideration is the epoxidation of cyclohexene (1) to cyclo-
hexene oxide (2). Although the reaction itself is straightfor-
ward, the identification of catalytically active moieties is more
challenging. For the activation of catalytic moiety A0, diisopro-
pylcarbodiimid (DIC) was added forming the O-acylisourea
(A1), which, after cleavage, removes a molecule of water pro-
viding the corresponding anhydride A2. This further reacts
with hydrogen peroxide to give the catalytically active peracid
moiety A3. After formation of peracid A3, the catalyst reacts
with 1 to give 2 (Scheme 2). The ESI MS/MS spectra of 2 and
the appearing catalytic species are shown in Figures 1 and 2,
respectively. One potential side reaction of O-acylisourea A1 at-
Figure 1. ESI MS/MS spectrum of epoxide intermediate 2 obtained with
a triple quadrupole MS.
them from the reaction mixture alone. Therefore, some addi-
tional studies were carried out using an online microflow reac-
tor as shown in Figure 6 in the Experimental Section. In these
experiments, two different syringes were filled with different
Scheme 2. Reaction cycle for the epoxidation reaction.
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Figure 2. ESI MS/MS spectra of a) A0B0; b) A1B0 and A1’B0; c) A2B0; and d) A3B0; and the associated fragmentation. The spectrum of intermediate A1B0
was obtained by using a microflow reactor set-up by high-resolution MS.
reaction solutions. The reaction takes place after the two flows
are combined in a mixing T-piece. The reaction time depends
on the length of the capillary after the mixing T-piece and can
be adjusted to the time frame of interest. This allows studying
very reactive and short-lived intermediates. Due to the contin-
uous formation of the same components, it is possible to
study them in detail by MS and MS/MS methods.
signal was found at m/z 908 (Figure 3a and b); the difference
of 16 Da indicates oxidation of the catalyst. The position of the
oxygenation was studied thoroughly with highly accurate
MS/MS and MSn experiments, in which the molecule was frag-
mented and the structural differences were analyzed (Fig-
ure 3c, d). We determined the oxidation to occur at the imida-
zole group: activation of moiety A also leads to oxidation of
moiety B, resulting in the formation of a hydantoin derivative
B1 (Scheme 2 and Figure 3). The oxidation of the imidazole
moiety leads to reduced effectiveness of the catalyst due to
the resulting lower amount of active catalytic moiety utilizing
the multicatalyst.
Catalyst A0B0 converts 57% (Æ3) into the final product 4 in
the separately performed acylation reaction (2 mol% catalyst
loading, 3 h). However, only 35% of the monoacetylated prod-
uct 4 were obtained when the reaction was performed under
multicatalysis conditions, even at 5 mol% catalyst loading and
after longer reaction time (17 h), indicating a somewhat lower
activity of the multicatalyst.[3b] When studying the formation of
the moiety A3, we found that another reaction occurs that
could have a direct impact on the effectiveness of the methyl
imidazole group B0 that is responsible for the subsequent cat-
alytic acylation. During formation of peracid A3, an additional
For the epoxide opening forming diol hydrazine bisulfate
and water have to be added to the reaction mixture.[7b] The hy-
drolysis of 2 was not investigated mechanistically, because the
peptide catalyst is not involved in this step.
The second catalytic step investigated in this reaction se-
quence is the kinetic resolution of racemic diol. At the begin-
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Figure 3. Characterization of completely oxidized catalyst A3B1: a) and b) MS spectra of the activation of catalytic moiety A [a) after adding DIC; b) after
adding DIC and H2O2]; c) and d) ESI MS/MS spectra and the associated fragmentation(1) of A3B1.(1) Red numbers indicate the fragments of the oxidized imida-
zole functionality. Measuring was achieved by HRMS.
ning, both catalytic sites of multicatalyst A0B0 are inactive.
After completion of the preceding reactions, the activation of
catalytic moiety B0 is accomplished by adding acetic anhy-
dride to the reaction mixture providing acylium ion B2
(Figure 4).
the enantioselectivity due to potential conformational changes
in the peptide backbone. Indeed, the multicatalyst provides
somewhat lower selectivities compared to the originally devel-
oped acylation catalyst.[3b,10a]
After activation of the catalyst, monoacylation of diol takes
place. The corresponding MS/MS spectrum is depicted in
Figure 4.
Conclusion
A triple-cascade sequence consisting of an epoxidation, an ep-
oxide opening, and an enantioselective acylation reaction cata-
lyzed by an oligopeptide multicatalyst was studied thoroughly
by using ESI-MS. The key reaction intermediates were success-
fully characterized. In addition to the activation of the catalytic
moieties A0 to A3 in the first reaction step by reagents DIC
and H2O2, a side-reaction takes place on the catalytic moiety
for the second reaction step B0 into B1 leading to a partially
oxidized methyl imidazole moiety that causes reduction of the
Our results also indicate that during the last step of the reac-
tion, not only moiety B was activated by acetic anhydride, but
also moiety A was directly converted to the intramolecular an-
hydride A2 (Figure 4). In a subsequent step, A2B2 was oxidized
to A3B2 by hydrogen peroxide, which is still present due to
the one-pot conditions. Figure 5 shows the MS, the MS/MS, as
well as the MS3 spectra of the detected catalytic species. The
observed side-reactions may also have a direct influence on
Figure 4. Activation of the catalytic moiety B0 and MS/MS spectrum of the monoacetylated product by triple quadrupole MS/MS.
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Figure 5. MSn spectra of the catalytic species of the last reaction step by HRMS: a) MS spectrum of the activation sequence using acetic anhydride and hydro-
gen peroxide; b) MS/MS spectrum of catalyst A3B2 after activation with acetic anhydride; c) MS3 spectra of catalyst A3B2 detailing the structural characteriza-
tion of both catalytic moieties.
added, and the kinetic resolution was monitored by chiral GC.
After 17 h, the reaction mixture was quenched by adding metha-
nol (10 mL), the solvents were evaporated under reduced pressure,
and the column chromatography on silica gel in hexane/EtOAc
(1:1) gave 56 mg (35%) of 1-acetoxy-2-cyclohexane alcohol (60%
yield).
activity of catalytic moiety B0 for the acetylation in the termi-
nal step.
Our detailed mass spectrometric study of the present multi-
catalyst allows the individual characterization of both catalytic
reactions. This is a prime example how detailed mechanistic
studies using highly accurate MS and MSn data can help in un-
derstanding complex organocatalytic reactions.
Microreactor procedure
One example that could only be investigated by the microreactor
experiment is the intermediate A2B0. For this experiment, syringe I
was filled with catalyst (0.005 mmol, 4.5 mg) in DCM (1 mL), syrin-
ge II with reagent diisopropyl carbodiimide (DIC; 0.12 mmol,
15 mg, 18.7 mL) in DCM (1 mL; Figure 6). The reaction took place in
polyether ether ketone (PEEK) capillary after combining reactants
from syringes I and II in the mixing chamber. Syringe pumps for I
and II were adjusted to flow rates of 5 mLminÀ1 and connected di-
rectly to the ion source. It was not just possible to determine the
intermediate itself, but also the rearrangement product of this in-
termediate as fragments at m/z 917.54, 861.48, and 817.49, respec-
tively, using tandem MS.
Experimental Section
Reaction procedure
Catalyst (0.05 mmol, 21.9 mg, 5 mol%), cyclohexene (1 mmol,
101 mL, 1 equiv), and DIC (1.2 mmol, 185 mL, 1.2 equiv) were dis-
solved in dichloromethane (DCM; 2 mL). To this mixture, hydrogen
peroxide (30%; 130 mL, 1.2 equiv) was added, and the resulting re-
action mixture was stirred at room temperature for 24 h. After this
time, the addition of DIC (1.2 mmol, 185 mL, 1.2 equiv) and 30% hy-
drogen peroxide (130 mL, 1.2 equiv) was repeated, and the reaction
mixture was stirred under the same conditions for additional 24 h.
Then toluene (6 mL) was added, followed by the addition of H2O
(10 mmol, 180 mL, 10 equiv) and hydrazine bisulfate (0.1 mmol,
13 mg, 0.1 equiv), and the mixture was stirred at room temperature
for 18 h. In the next step, toluene (180 mL) and iPr2EtN (5.3 mmol,
901 mL, 5.3 equiv) were added, and the reaction mixture was
cooled to 08C. Finally, Ac2O (5.3 mmol, 501 mL, 5.3 equiv) was
Mass spectrometry
MS and MS/MS experiments were carried out using a Thermo TSQ
Quantum Ultra AM triple quadrupole mass spectrometer (Thermo
Scientific, Dreieich, Germany) equipped with an ESI source, which
was controlled by Xcalibur software. The ESI spray voltages were
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Acknowledgements
The authors acknowledge the generous funding from the
Deutsche Forschungsgemeinschaft (DFG) under the Priority
Program on Organocatalysis (SPP 1179).
Keywords: electrospray ionization
· mass spectrometry ·
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Received: July 6, 2015
Published online on September 25, 2015
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