On-line reaction monitoring and mechanistic studies by mass spectrometry: Negishi cross-coupling, hydrogenolysis, and reductive amination

Article abstract of DOI:10.1002/anie.201310493

Reaction monitoring using inductive ESI mass spectrometry allows chemical reactions to be tracked in real time, including air- and moisture-sensitive as well as heterogeneous reactions. Highly concentrated solutions can also be monitored for long periods without emitter clogging. Sheath gas assists in nebulization and a sample splitter reduces the delay time and minimizes contamination of the instrument. Short-lived intermediates (ca. 5 s) were observed in Pd/C-catalyzed hydrogenolysis, and several intermediates were seen in Negishi cross-coupling reactions. Fast and simple: A reaction monitoring system based on inductive ESI mass spectrometry provides a fast and simple way to monitor chemical reactions, including air-/moisture-sensitive reactions, continuously. It also provides information on solution-phase organic reaction mechanisms as shown by the observation of short-lived intermediates in Pd/C-catalyzed hydrogenolysis and several intermediates in Negishi cross-coupling reactions.

Full text of DOI:10.1002/anie.201310493

Angewandte
Chemie
DOI: 10.1002/anie.201310493
Mass Spectrometry
On-Line Reaction Monitoring and Mechanistic Studies by Mass
Spectrometry: Negishi Cross-Coupling, Hydrogenolysis, and Reductive
Amination**
Xin Yan, Ewa Sokol, Xin Li, Guangtao Li, Shiqing Xu, and R. Graham Cooks*
[
3d,e,m]
Abstract: Reaction monitoring using inductive ESI mass
spectrometry allows chemical reactions to be tracked in real
time, including air- and moisture-sensitive as well as heteroge-
neous reactions. Highly concentrated solutions can also be
monitored for long periods without emitter clogging. Sheath
gas assists in nebulization and a sample splitter reduces the
delay time and minimizes contamination of the instrument.
Short-lived intermediates (ca. 5 s) were observed in Pd/C-
catalyzed hydrogenolysis, and several intermediates were seen
in Negishi cross-coupling reactions.
monitoring systems
tions.
is inapplicable to air-sensitive reac-
We describe an inductive ESI-MS-based on-line reaction
monitoring system (Figure 1) which overcomes these limita-
tions. In this method, a positive potential is pulsed repeatedly
to produce transient strong electric fields in the spray
solution, thereby resulting in the emission of charged droplets
in bursts. The reaction solution is transferred to the emitter-
R
eaction monitoring for the purpose of process control is
critical to assure quality and purity in the manufacture of
chemicals and pharmaceuticals. The detailed information
acquired during reaction monitoring can help in elucidating
[
1]
reaction mechanisms. Many monitoring methods—absorp-
tion and fluorescence spectroscopy, NMR spectroscopy, and
electrochemical methods—are already well-established and
[
2]
widely used. Mass spectrometry (MS) is also useful in
reaction monitoring because of its capabilities for structural
characterization, and its high specificity, sensitivity, and
speed. Recent publications on reaction monitoring using MS
show two trends: 1) exploration of various new ionization
[
3]
Figure 1. Inductive ESI-MS on-line reaction monitoring system.
methods for reaction monitoring (see the Supporting
Information for a summary) and 2) insights into organic
reaction mechanisms through interception of reactive inter-
spray tip by a capillary under positive gas pressure (e.g.
helium as a protective gas if an air-/water-sensitive reaction is
involved) and ionized inductively. Note that inductive ESI is
[1]
mediates. Particular success in the latter endeavor has come
[
1a,b,e,k,l]
[4]
from electrospray ionization (ESI) monitoring.
How-
ever, limitations in existing MS monitoring systems still exist:
a) Off-line MS reaction monitoring becomes ineffective when
fast reaction kinetics and short-lived reaction intermediates
are involved. b) High-salt-containing sample solutions cannot
be handled in conventional electrospray ionization (ESI)
sources because of the likelihood of clogging of the ESI
emitter. c) Heated columns used to vaporize the solution in
a variant of ESI which provides several new capabilities: it is
characterized by a remarkable tolerance to matrix and to salt
[
4]
effects and has a high efficiency. Inductive ESI uses
a monopolar applied potential, not to be confused with
[
5]
alternating current (AC) electrospray, which uses an alter-
nating and directly applied potential. AC electrospray has
definite advantages, but they do not extend to the remote
application of the potential or the control of droplet creation,
nor do they provide the full immunity to the presence of high
salt concentrations or complex matrices seen in inductive ESI.
Sheath gas was used to aid in the nebulization process and to
minimize variations in droplet size. To allow rapid monitor-
ing, the delay time for sample transfer was reduced to a few
seconds by adding a sample splitter, which also minimized
contamination of the MS inlet.
[
3l]
some systems might expedite the reaction or lead to side
products. d) The open-air environment used in some on-line
[
*] X. Yan, E. Sokol, Dr. X. Li, G. Li, Dr. S. Xu, Prof. R. G. Cooks
Department of Chemistry, Purdue University
West Lafayette, IN 47907 (USA)
E-mail: cooks@purdue.edu
[
**] We acknowledge funding for this work by the National Science
Foundation (CHE 0848650 and CHE 1307264). We also acknowl-
edge funding for a precursor study by Pfizer, Inc. and the efforts of
Stephen Brune, Brian Marquez, George Perkins, Scott Bader,
Zhongli Zhang, Laura McAllister, Bill Farrell, Matthew Teague, Karen
Alsante, Justin Stroh, and Charles Cheng in that prior work.
Three reactions characteristic of many others important in
pharmaceutical synthesis (Scheme 1) were selected for mon-
itoring: a) reductive amination of 4-pyridinecarboxaldehyde
with 4-(aminomethyl)pyridine, b) Negishi cross-coupling of 3-
bromoquinoline with diethylzinc catalyzed by Pd-PEPPSI
(palladium-pyridine enhanced precatalyst preparation, stabi-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201310493.
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Angewandte
Communications
gas tee. The delay time in the splitter-equipped inductive ESI-
MS monitoring system was measured using optimized transfer
and splitter capillary dimensions (see Figure S4 in the
Supporting Information) as 0.2 min.
After validation of inductive ESI-MS based online
monitoring using the model reductive animation reaction,
we investigated reactions with more rigorous requirements.
The Negishi reaction—the palladium-catalyzed cross-cou-
pling of organohalides with organozinc reagents—is a selec-
tive and versatile method for the formation of CÀC bonds
which has been widely used in the development of medicinal,
[
6b]
agricultural, and organic materials. The reagents involved
are highly susceptible to water or oxygen, so the experiment
must be performed with their strict exclusion. Moreover, the
Negishi reaction is of additional interest because it appears to
occur via a series of cascaded reaction intermediates, the
instability and transience of which prevents their isolation. In
this study, the cross-coupling of 3-bromoquinoline with
diethylzinc catalyzed by Pd-PEPPSI-IPr in tetrahydrofuran
(THF; Scheme 1) was monitored by inductive ESI-MS (see
the Supporting Information for optimization of the ionization
when THF was used as the spray solvent).
Scheme 1. a) Reductive amination of 4-pyridinecarboxaldehyde;
b) Negishi cross-coupling of 3-bromoquinoline with diethylzinc cata-
lyzed by Pd-PEPPSI-IPr; c) Pd/C-catalyzed hydrogenolysis of 3,4-dime-
thoxybenzaldehyde.
[
6a]
lization, and initiation), and c) Pd/C-catalyzed hydrogenol-
ysis of 3,4-dimethoxybenzaldehyde.
The reductive amination of 4-pyridinecarboxaldehyde (2)
with 4-(aminomethyl)pyridine (1) was carried out using
a one-pot two-step procedure to produce bis((pyridin-4-
yl)methyl)amine (4). Selected ion chronograms (see Fig-
ure S1 in the Supporting Information) record the dynamic
changes in ion abundances of reagent 1, intermediate 3, and
product 4. (For the corresponding time-resolved mass spectra,
see Figure S2 in the Supporting Information.) The kinetic
progression of reductive amination can be clearly seen in this
data. The first condensation step occurs very fast: once 2 had
been added to the solution of 1, it took less than 1 min for the
reaction to reach equilibrium. The intermediate 3 was
generated simultaneously with the decrease of 1. The
second reduction step was not as fast as the first. The sodiated
The kinetics of the cross-coupling of 3-bromoquinoline
with diethylzinc is shown in Figure 2, which displays the
changing abundances of the ions corresponding to 3-bromo-
quinoline (m/z 208), the ligand of Pd-PEPPSI-IPr (m/z 389),
the reaction product 3-ethylquinoline (m/z 158), and several
intermediates (see below). Immediately after the injection of
3-bromoquinoline into the solution of Pd-PEPPSI at 8.4 min,
protonated 3-bromoquinoline was detected at m/z 208 (and
210 not shown). The injection of the diethylzinc reagent at
adducts of 3 appeared quickly upon addition of NaBH , thus
4
reflecting the change in the solution-phase matrix. The
product ion signal rose sharply in the first 0.5 min after
addition of the reducing agent, followed by a slower increase.
A corresponding decrease occurred in the signal correspond-
ing to intermediate 3, driving its equilibrium with 1 to the
right and depleting 1. Altogether, it took about 10 min under
the chosen conditions for product 4 to reach its highest
concentration, as judged by ion intensity. The total monitor-
ing time was 90 min without any clogging in the fused-silica
capillary at the high concentrations of reagents representative
of industrial interest.
The kinetic data obtained by continuous inductive ESI-
MS measurements of the reductive amination reaction were
1
verified by off-line H NMR spectroscopy (see Figure S3 in
the Supporting Information). Inductive ESI-MS provides
both continuous and more detailed information on the
reaction. This relatively simple reaction allowed validation
of the method.
The time lag between the sampling and measurement of
compounds in a reaction mixture is an important factor
because it affects how quickly an operator can respond to an
unexpected situation. However, when it is small, as it is here,
its uncertainty is even smaller, and the lag does not affect the
accuracy of the kinetic data. To decrease the amount of
sample entering the MS while maintaining a short delay time,
a three-way sample splitter was added before the nebulizing
Figure 2. Total ion chronogram and selective ion chronograms of 3-
bromoquinoline (m/z 208), ligand of Pd-PEPPSI (m/z 389), intermedi-
ates (m/z 407, 250, 379), and the product ethylquinoline (m/z 158) in
the Negishi cross coupling of 3-bromoquinoline with diethylzinc
catalyzed by Pd-PEPPSI in THF. I=relative abundance.
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1
1.6–14 min resulted in the cat-
alyst Pd-PEPPSI being acti-
II
0
vated from Pd to Pd , and
ions at m/z 389 derived from
the
N-heterocyclic
ligand
appeared at 12.2 min and
quickly increased. Protonated
3
-bromoquinoline
reagent
began to decrease at 12 min,
however, the reaction product
(
seen as protonated 3-ethylqui-
noline at m/z 158) did not
increase significantly until
min later. By scrutinizing
3
time-resolved mass spectra (see
Figure S5 in the Supporting
Information) and the corre-
sponding ion chronograms, we
discerned ions corresponding to
three intermediates at m/z 407,
3
79, and 250, which appeared
and reached their maxima
during that 3 min period
(
Figure 2). The intermediates
disappeared, while the product
Scheme 2. Proposed mechanism of the Pd-catalyzed Negishi cross-coupling of 3-bromoquinoline with
ions at m/z 158 reached their diethylzinc.
highest intensity at 25 min. The
ions at m/z 407, 379, and 250
[
8]
were assigned to quinoline coordinated with ethylzinc (see
Figure 2) on the basis of their m/z values, isotopic distribu-
tions, and confirmatory tandem MS (see Figures S6–S8 in the
Supporting Information).
in ESI to generate reaction products on the milligram scale
in contrast with the use of desorption electrospray ionization
(DESI)-MS as an effective tool for the interception of
[
1e–h]
reaction intermediates
(see the Supporting Information
Palladium-catalyzed Negishi cross-coupling is regarded as
following the pathway: oxidative addition of R X to Pd to
for further discussion). One advantage of the inductive ESI-
MS-based monitoring system is that it continuously samples
aliquots and allows the dynamic changes in the system to be
followed. The fact that a series of nested intermediates is
observed and that product is only observed as they disappear
is strong evidence that solution-phase reactions are being
followed. Nevertheless, caution needs to be exercised,
because intermediates observed in a reaction might not be
species that fall along the pathway that leads directly to
1
0
1
2
give a [PdR XL ] intermediate, transmetalation from [M]R
2
2
1
to give [PdR R L ], and reductive elimination to afford the
product R R and regeneration of the Pd catalyst (see
Scheme S1 in the Supporting Information).
intermediates without a precharged ligand have not previ-
2
1
2
0
[
6c]
Active Pd
[
7]
ously been seen by ESI-MS. However, interestingly, the
observation of intermediates of quinoline coordinated to
ethylzinc complexes suggests that in our experiment the zinc
reagent was not released from these complexes throughout
the catalytic cycle. A possible pathway consistent with this
data is given in Scheme 2 and is described in the Supporting
information. A by-product derived from the intermediate at
m/z 379 in this pathway was confirmed in the full-scan mass
[
9]
product.
Next, we challenged the inductive ESI-MS based reaction
monitoring system with a heterogeneous reaction. Pd/C-
catalyzed hydrogenation has been widely employed in
numerous organic transformations in both academic research
[10a–c]
and in industry.
The reaction commonly proceeds in a H2
1
spectrum and verified by H NMR spectroscopy after com-
atmosphere, which requires the reactor to be held at a positive
H2 pressure. Inductive ESI-MS reaction monitoring using
a sealed flask at positive pressure allows heterogeneous
reactions to be investigated. Here, the Pd/C-catalyzed hydro-
genolysis of 3,4-dimethoxybenzaldehyde was monitored by
inductive ESI-MS. Selected ion chronograms (Figure 3) and
time-resolved mass spectra (see Figure S15 in the Supporting
pletion of the reaction and its isolation and purification (see
Figures S9 and S10 in the Supporting Information). When the
reaction conditions were altered, Pd-containing intermediates
were detected in a related reaction (see the Supporting
Information).
A question existing in the investigation of intermediates
by MS is the extent to which an observed intermediate is the
product of the special conditions of the analysis (here small
evaporating droplets) versus an accurate representation of an
intermediate that occurs in the bulk solution-phase reaction.
This question is highlighted by reports on the use of reactions
+
Information) show ions [9 + H] at m/z 167, 0.48 min after
injection of reagent 9 into the Pd/C suspension in methanol.
Within 0.02 min, a new signal at m/z 191 appeared, which
reached its highest intensity within 0.45 min and disappeared
0.15 min later. Two other new signals at m/z 235 and 181 were
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Communications
assigned as sodiated adducts of dimethoxybenzenemethanol
21) and of dimethoxybenzaldehyde dimethyl acetal (23) and
(
as the hydride abstraction product of dimethoxybenzyl
methyl ether (22), respectively, as verified by tandem MS
and exact mass measurement (see Figure S17 and Table S1 in
the Supporting Information). In agreement with the classical
benzenemethanol pathway, 3,4-dimethoxybenzaldehyde is
first hydrogenated to give dimethoxybenzenemethanol (m/z
1
1
91), then converted into dimethoxybenzyl methyl ether (m/z
81), and finally the dimethoxytoluene (m/z 151) product is
produced. However, this sequence does not explain the
appearance of dimethoxybenzaldehyde dimethyl acetal (m/z
2
35). The observed sodiated adduct ions of dimethoxyben-
zaldehyde dimethyl acetal suggest a second pathway of
hydrogenlysis, in which benzaldehyde acetal is an intermedi-
ate instead of benzenemethanol. In the recent publication by
Figure 3. Selective ion chronograms of the reagent 9, intermediates
1), (2), and (3) assigned (see text) as 11, 12, and 13, and product 10
in the Pd/C-catalyzed hydrogenolysis of 3,4-dimethoxybenzaldehyde
over the time range 0–130 min (the arrows indicate when the reagent
and excess Pd/C were added).
(
[
10a]
Hu and co-workers,
a similar benzylaldehyde acetal
intermediate was separated and confirmed. The authors
noted that when lower alcohols such as methanol (as in our
case) and ethanol were used as solvents, only the benzylalde-
hyde acetal intermediate rather than benzenemethanol was
produced as an intermediate. We used the same solvent and
conditions as Hu and co-workers, but saw an intermediate,
benzenemethanol, which was not seen previously. This is not
surprising, as the lifetime of this intermediate was only 5 s, as
monitored by the inductive ESI-MS system. Transient inter-
mediates are easily missed in traditional studies of the
mechanism. Online inductive ESI-MS monitors reactions
continuously and so provides virtually real-time structural
information on the intermediates and products in the mixture.
As such, it should have great strength in capturing transient
intermediates. We suggest a new two-way three-stage path-
way involving three intermediates 21, 22, and 23 as shown in
Scheme 3. In this scheme, the functions of each reaction
intermediate are recognized.
In summary, inductive ESI-MS is a versatile method for
the direct and continuous monitoring of organic reactions
in situ while avoiding the need for physical contact of the high
voltage with the reaction solution. Sheath gas was used to
assist in the nebulization process and minimize size variation
in the droplets. Sample splitting decreased the time offset in
the measurement while avoiding contamination of the MS
inlet. Three important reactions with different features—
reductive amination, Negishi cross-coupling, and Pd/C-cata-
evident 0.34 min and 0.38 min, respectively, after that at m/z
1
91. Just 0.3 min later, the signal at m/z 235 had disappeared,
while the signal at m/z 181 dominated the reaction mixture
spectrum. At the same time, the deprotonated form of the
hydrogenolysis product 10 (m/z 151) began to appear, became
the base signal at 18 min, and dominated the spectrum of the
reaction product mixture at 75 min. Three separate inter-
mediates (m/z 191, 235, and 181) were evident during the
course of the reaction, as were two forms of the product (m/z
1
51 and 153 are the deprotonated and protonated forms of the
final product) which are favored at different times (see the
Supporting Information for a discussion of the observation of
+
both forms of [M Æ H] and the reasons for this in the time-
dependent composition of the total reaction mixture).
The detection of transient intermediates in the study of
reaction mechanisms is significant, especially because their
short lives challenge classical methods of monitoring reac-
tions. Online inductive ESI-MS monitors reactions continu-
ously and provides virtually real-time structural information
on the intermediates and products in the mixture, including
transient intermediates with half-lives as short as 5 s (see
Figure S16, part 1 in the Supporting Information) in reactions
that take several hours to complete. The selected ion chrono-
gram in the time interval 2.5–3.5 min (see Figure S16 in the
Supporting Information) suggests that the intermediate at
m/z 191 was the first of the three intermediates formed,
appearing at almost at the same time as reagent 9 was added.
Its signal maximized at 3 min. The intermediate ion at m/z 235
was followed by one at m/z 191 in the time range 2.9–3.2 min.
The full lifetimes of these two intermediates were both less
than 0.3 min. With the decrease of the former intermediates,
the intermediate ion at m/z 181 increased, and the conversion
of this intermediate into product 10 then occurred in what
appears to be the rate-limiting step.
Pd/C-catalyzed hydrogenolysis of benzaldehydes to meth-
ylbenzenes has been described as proceeding via a benzene-
[
10d,e]
methanol intermediate
because benzenemethanol has
been isolated as an intermediate or as a major by-product. In
Scheme 3. Two-way three-stage pathway of the Pd/C-catalyzed hydro-
our experiment, intermediate ions at m/z 191, 235, and 181 are
genolysis of 3,4-dimethoxybenzaldehyde in methanol.
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lyzed hydrogenolysis—were successfully monitored by using
this system. More interestingly, in the Negishi cross-coupling
and Pd/C-catalyzed hydrogenolysis, the observation of new
and some very short-lived intermediates and suggestion of
their interconnections may give new insights into inconclusive
mechanisms or supplement existing mechanisms. The induc-
tive ESI-MS on-line reaction monitoring system provides
a general and efficient way to investigate solution-phase
organic reaction mechanisms.
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Experimental Section
The configuration of a reaction monitoring system based on inductive
ESI is shown in Figure 1. The reaction solution in the sealed vessel
was pressurized by helium to ca. 3 psi to allow transfer continuously
through the capillary (i.d. 100 mm, length 40 cm) to the emitter-spray
tip. A gas bubbler filled with paraffin oil was used to monitor the
pressure in the reaction vessel. A tee was added at the front of the
capillary tip to introduce sheath gas. A three-way sample splitter was
added behind the sheath gas tee. An 8 cm long fused silica capillary
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outlet of the splitter was linked to a fused-silica capillary (i.d. 200 mm,
length 8 cm). A home-built power supply provided a positive pulsed
output of 2000 Hz and 860 V, which was supplied to an electrode that
surrounded the sheath gas line but did not make physical contact.
Strong electric fields were produced in the solution inside the emitter
and gave rise to bursts of droplets. This procedure resulted in the
pulsed emission of charged analytes from the reaction solution at
a controlled pulse rate. The spray was directed towards the inlet of the
MS, which was ca. 5 mm from the capillary tip. Although not used in
this study, the emitted droplets are predominantly positively charged
as the pulse is turned on and predominantly negatively charged as it is
turned off, thereby allowing rapid successive measurement of positive
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[
4]
and negative ion mass spectra. As indicated elsewhere, this has the
[
4a]
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spectrometer (LTQ, Thermo Fisher Scientific, San Jose, CA, USA)
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Received: December 4, 2013
Published online: April 17, 2014
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