Reprint of “The benzoin condensation: Charge tagging of the catalyst allows for tracking by mass spectrometry”

Article abstract of DOI:10.1016/j.ijms.2014.07.043

A novel thiazolium with a sulfonate charge tag was synthesized to test the feasibility of tracking the progress of a thiazolylidene-catalyzed benzoin condensation reaction using electrospray ionization-mass spectrometry (ESI–MS). Intermediates in the benz

Full text of DOI:10.1016/j.ijms.2014.07.043

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International Journal of Mass Spectrometry
journal homepage: www.elsevier.com/locate/ijms
Reprint of “The benzoin condensation: Charge tagging of the catalyst
ଝ
allows for tracking by mass spectrometry”
∗
Hao Zeng, Kai Wang, Yuan Tian, Yijie Niu, Landon Greene, Zhichao Hu, Jeehiun K. Lee
Department of Chemistry and Chemical Biology Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel thiazolium with a sulfonate charge tag was synthesized to test the feasibility of tracking the
progress of a thiazolylidene-catalyzed benzoin condensation reaction using electrospray ionization-mass
spectrometry (ESI–MS). Intermediates in the benzoin condensation were “fished” out of a reaction mix-
ture and detected using MS. Tandem MS and calculations were used to support structural assignments.
The results are consistent with the Breslow mechanism. These data show the viability of synthesizing neg-
atively charged compounds that will both catalyze and track reactions involving N-heterocyclic carbene
organocatalysis, which are becoming increasingly prevalent in organic synthesis.
Received 29 May 2014
Received in revised form 5 June 2014
Accepted 10 June 2014
Available online xxx
Dedicated to Professor Veronica M.
Bierbaum.
©
2014 Elsevier B.V. All rights reserved.
Keywords:
Benzoin condensation
Charge tag
N-heterocyclic carbene
Thiazolylidene
Organic reactivity
ESI–MS/MS
1
. Introduction
functional group [12]. A classic example is the benzoin condensa-
tion, first reported by Wöhler and Liebig in 1832 with a proposed
mechanism in 1903 by Lapworth; cyanide is used as a catalyst to
effect the dimerization of two benzaldehyde units [13]. In 1943,
Ukai et al. discovered the ability of thiazolium salts to catalyze the
condensation. Fifteen years later, Breslow proposed the deproto-
nated thiazolium – the thiazolylidene (which can also be thought
of as a thiazolium zwitterion) – as the catalytic species [14–17].
His proposed mechanism (Scheme 1) involves deprotonation of the
thiazolium to yield thiazolylidene/thiazolium zwitterion, which
attacks a benzaldehyde, followed by a proton transfer to form the
so-called Breslow intermediate, which can then display the umpol-
ung reactivity (the aldehyde becomes nucleophilic rather than
electrophilic, adding to a second aldehyde). This reaction, as well as
its related counterpart, the Stetter (addition to an enone), has seen
a renaissance in the last decade, with chiral versions catalyzed by
a variety of N-heterocyclic carbenes (thiazolylidenes, imidazolyli-
denes, and triazolylidenes) [18–25].
Electrospray ionization (ESI) is now a well-established method
for the transfer of ions from solution to the gas phase [1–3]. Cou-
pled with mass spectrometry (MS), ESI opens the door to tracking
the progress of organic reactions that involve nonvolatile interme-
diates [4–6].
To use ESI–MS to track the progress of a reaction, the rele-
vant species must be charged. This is often achieved by tracking
reactions that either already involve charged species, or have inter-
mediates that are in equilibrium with their respective protonated
forms [4–9]. If relevant species are not charged, then a charge
tag can be used [10,11]. For example, Vikse et al. used a negative
charge tag on a palladium phosphine ligand to follow a palladium-
catalyzed Sonogashira reaction by MS [9].
A particularly intriguing class of reactions in organic synthesis
is the umpolung, which involves the reversal of the polarity of a
The Breslow mechanism is commonly accepted, with many
attempts to isolate the Breslow intermediate, which had proven
to be elusive until 2012, when both an analogue and the inter-
mediate itself were observed and characterized spectroscopically
DOI of original article: http://dx.doi.org/10.1016/j.ijms.2014.06.008.
This article is a reprint of a previously published article. For citation purposes,
please use the original publication details “International Journal of Mass Spectrom-
ଝ
[
26–28]. Mechanisms involving a thiazolylidene dimer (first pro-
etry 369 (2014) 92–97”.
∗ Corresponding author. Tel.: +1 8484456562; fax: +1 8484455312.
posed by Lemal) have also been proposed; data both in support of
and against such mechanisms exist [29–41].
E-mail address: jee.lee@rutgers.edu (J.K. Lee).
http://dx.doi.org/10.1016/j.ijms.2014.07.043
1
387-3806/© 2014 Elsevier B.V. All rights reserved.
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H. Zeng et al. / International Journal of Mass Spectrometry xxx (2014) xxx–xxx
Scheme 1. Breslow mechanism for the benzoin condensation.
◦
Because of the ever-growing prevalence and synthetic utility of
reactions catalyzed by ylidenes, we sought to explore the poten-
tial of using ESI–MS to track such reactions, focusing on the classic
benzoin condensation. Because the intermediates are not charged,
the reaction is potentially difficult to track using mass spectrome-
try. An imidazolylidene-catalyzed conjugate umpolung reaction to
form a lactone was successfully studied using ESI–MS by Glorius
and co-workers in 2007, who relied on the protonation of the inter-
mediates in the electrospray process, enabling the use of positive
ion mass spectrometry for detection [4]. To explore the possibility
of charging the catalyst itself in order to track all steps involving the
catalyst in the benzoin condensation, we successfully synthesized a
thiazolium with a sulfonate charge tag. The synthesized compound
was used to catalyze the benzoin condensation, and intermediates
were detected using negative ion ESI–MS. Calculations and MS/MS
were also used to aid in interpretation of results.
triethylamine (5 mmol, 0.35 ml) in CH CN (20 ml) was stirred at 0 C
3
for 2 h, under argon. After rotary evaporation, the crude product
was dissolved in ethanol (25 ml). Potassium thioacetate (3 mmol,
343 mg) was added dropwise and the mixture was allowed to
reflux for 72 h. The product mixture was rotary evaporated to dry-
ness, then the resultant crude solid was dissolved in formic acid
(5 ml). Performic acid was generated by stirring hydrogen perox-
ide (14 mmol, 1.8 ml) and formic acid (30 mmol, 1.4 ml) at room
◦
temperature for 1 h. The performic acid solution was cooled to 0 C
and added to the reaction mixture. The mixture was left stirring
for 48 h. Excess solvent was removed by rotary evaporation and
the final crude product was purified by HPLC. 1H NMR (300 MHz,
DMSO-d ) ı 9.90 (s, H), 4.05 (s, 3 H), 3.14–3.19 (t, J = 7.1 Hz, 2 H),
6
2.70–2.75 (t, J = 7.0 Hz, 2 H), 2.41 (s, 3 H).
2.2. Benzoin condensation reaction conditions
The synthesized thiazolium was dissolved in methanol to make
a 0.1 M solution. Argon was bubbled in for 5 min to expel oxygen.
Ten equivalents of benzaldehyde and 2.5 equivalents of triethyl-
amine were added to the reaction solution. The reaction was stirred
at room temperature and tracked over time. To track the reaction
by mass spectrometry, an aliquot from the reaction mixture was
2
. Material and methods
2.1. Synthesis details
A mixture of 1,5-dimethyl-4-(hydroxyethyl) thiazolium iodide
(
2.5 mmol, 700 mg), methylsulfonyl chloride (3 mmol, 0.25 ml) and
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Scheme 2. Synthesis of charge tagged thiazolium.
diluted to make a 100 uM (in thiazolium) solution, which was then
injected into the ESI source.
has not heretofore been synthesized. A commercially available thi-
azolium with a hydroxyl side chain was allowed to react with
methanesulfonyl chloride to yield the sulfonic ester. Reaction with
potassium thioacetate yields the thioester. The final step is oxi-
dation by performic acid to yield the sulfonate-tagged thiazolium
product.
An electrospray needle voltage of ∼4 kV and flow rate of
2
5 ␮l/min was used to volatilize the reaction mixture. Full scan
spectra are an average of forty scans. For MS/MS, the ions were iso-
lated and activated for 30 ms, at varying (5–30%) collision energies.
Fragmentations at 25% (isolation width of 2) are reported herein.
Ten scans were averaged for the product ions.
3.2. Benzoin condensation reaction and MS
2.3. Calculational method
The charge-tagged thiazolium was allowed to react with benz-
aldehyde in the presence of triethylamine (to ensure that both the
sulfonic acid moiety and C2 are deprotonated, to yield catalyst 1,
Scheme 1). The mass spectrum of the reaction after 5 min of reaction
time is shown in Fig. 1. The m/z signals corresponding to the catalyst
Calculations were conducted at B3LYP/6-31+G(d) using Gaus-
sian09; the geometries were fully optimized and frequencies were
calculated [42–46]. All the values reported are at 298 K. No scaling
factor was applied. For the solvation calculations, the integral equa-
tion formalism variant of the polarizable continuum model, using
radii and non-electrostatic terms for Truhlar and coworkers SMD
solvation model, was utilized [47–49].
(
1, m/z 220), the intermediate resulting from addition of one benz-
aldehyde (2, m/z 326), and thiazolylidene-thiazolium dimer (5, m/z
41) are observed. We also see m/z 121, which is deprotonated ben-
4
zoic acid, resulting from the facile air oxidation of the benzaldehyde
reactant. As the reaction proceeds, oxidation products (benzoate at
m/z 121, as well as oxidized catalyst (m/z 236)) become increas-
ingly prevalent. No appreciable signal for the second intermediate
(3, Scheme 1, m/z 432) nor the deprotonated product (deprotonated
3
. Results and discussion
3
.1. Charge-tagged catalyst
4
, m/z 211) is observed.
The intermediates in the benzoin condensation are uncharged;
In order to lend support to our structural assignments, we also
in order to track the benzoin condensation by ESI–MS, we synthe-
sized a thiazolium with a sulfonate tag (Scheme 2). This molecule
conducted MS/MS experiments. We presume m/z 220 is the cata-
lyst 1, although a doubly charged dimerized structure could also
Fig. 1. Mass spectrum of reaction mixture after 5 min.
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ketone 2c and the epoxide 2d (Fig. 2) [28,30,41,50–54]. MS/MS of
•
m/z 326 yields m/z 311 (loss of CH3 ) and m/z 220 (catalyst 1) as
the two strongest signals, with the m/z 311 signal being more than
twice that of m/z 220. While these fragments do not aid in the dif-
ferentiation of the possible structures for m/z 326, we did conduct
calculations to lend further insight. Our calculations indicate that of
the four possible structures for 2 (m/z 326), the ketone 2c is the most
stable, by 7 kcal/mol over the Breslow intermediate 2b, 14 kcal/mol
over the initial intermediate 2a and 19 kcal/mol over the epoxide
2
d (Fig. 4). The calculated high stability of 2c is consistent with the
isolation of a ketone structure in benzoin condensation studies by
Berkessel and co-workers in 2010 [28,50,53,54].
3.3. Mechanistic comments
Previous mechanistic studies indicate that addition of the first
benzaldehyde, formation of the Breslow intermediate, and addi-
tion of the second benzaldehyde are all “partially rate determining”
[
55]. By mass spectrometry, we see the deprotonated thiazolium
(catalyst 1) at m/z 220 and the ion corresponding to the Breslow
intermediate at m/z 326. Calculations indicate that 2c is the most
stable structure for m/z 326 (Fig. 4); however, we cannot discount
the presence of the catalytically active Breslow intermediate 2b.
It probably is present, though not isolable nor detectable by mass
spectrometry [4,27,28]. The lack of m/z 432 (after addition of the
second benzaldehyde, 3 in Scheme 1) may be because once formed,
the release of the final stable benzoin product (4) provides a driv-
ing force for the reaction such that intermediate 3 is relatively
short-lived. The lack of m/z 211 (deprotonated benzoin, 4) is not
too surprising as ketones have pKa values of 19–20 and triethyl-
amine is not a strong enough base to significantly deprotonate the
benzoin product.
Also interesting to consider is how the sulfonate charge tag
might affect the catalytic activity of 1. We calculated the proton
affinity of the thiazolylidene 1 and its neutral counterpart (1H).
In the gas phase, the negatively charged sulfonate group renders
1 71 kcal/mol more basic than 1H at the reactive carbene center.
However, this difference essentially disappears when solvation is
considered (calculations in a water dielectric). In fact, in water, 1H is
calculated to be more basic than 1, though not by much (3 kcal/mol).
Therefore, in water, our negatively charge-tagged catalyst is proba-
bly not different enough in basicity as compared to more commonly
used neutral counterparts to significantly affect catalytic ability.
Fig. 2. Possible structures for observed m/z signals.
be possible (1’ or a noncovalent analog, Fig. 2). MS/MS of m/z 220
yields only m/z 81, corresponding to HSO3
−
(Fig. 3). If m/z 220
−
were a dimer, loss of HSO3 would leave behind an ion of m/z 359,
which we do not observe. Also, exposing m/z 220 to increasingly
higher collision energies results in the decrease and eventual dis-
appearance of m/z 220; a dimer might be expected to break apart to
produce m/z 220 as a daughter ion. For these reasons we attribute
m/z 220 to the catalyst 1. The ion at m/z 441 is presumably the over-
all singly charged thiazolylidene-thiazolium dimer 5 (Fig. 2, or a
noncovalent equivalent). MS/MS yields m/z 220, which corresponds
to loss of thiazolium.
The signal at m/z 326 corresponds to the first intermediate
formed upon addition of the thiazolylidene catalyst to benzalde-
hyde (2a, Scheme 1, Fig. 2). The subsequent step of the Breslow
mechanism is the formation of the Breslow intermediate 2b, which
also has a m/z ratio of 326. Other possible structures include the
Fig. 3. MS/MS spectrum of m/z 220.
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Fig. 4. Relative stabilities for the possible structures for 2, m/z 326 (ꢀH at 298 K, B3LYP/6-31+G(d).
Scheme 3. Dimer mechanism for benzoin condensation.
is m/z 273. We do not see this ion under our conditions.56 While
the lack of m/z 273 cannot be used as definitive proof against the
dimer mechanism (since it may be short-lived), it certainly implies
that this may not be an operative path under our conditions.
Last, we consider the “dimer mechanism,” which over the years
has been invoked as a possible alternate to the Breslow mechanism
(
3
(
Scheme 3) [29–41]. Several ions have the same m/z ratios (220,
26) as other ions in the Breslow mechanism. We do see m/z 441
5), but it may not be catalytically active. The unique identifying
ion, resulting from the addition of one benzaldehyde to the dimer,
56A reviewer raised the concern that if we do not see m/z 211 (deprotonated
benzoin), how would we expect to see m/z 273, as both are relatively basic ions.
However, benzoin is a neutral product that has to be deprotonated for detection,
whereas m/z 273 is generated via reaction as an already-charged species.
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. Conclusions
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A new negatively charge-tagged catalyst has been synthesized
and used to probe the benzoin condensation for the first time. The
tag allows intermediates to be “fished out” of the reaction mixture.
The results indicate that under these conditions, the Breslow mech-
anism is likely, but not a dimer mechanism. We detect the presence
of an ion consistent with the Breslow intermediate. Calculations
indicate that the detected intermediate may be the tautomerized
structure 2c. No ions corresponding to the dimer mechanism are
observed. These results show the viability of synthesizing nega-
tively charged catalysts to track reactions involving N-heterocyclic
carbene organocatalysis, which are becoming increasingly preva-
lent in organic synthesis.
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