Detection of Fleeting Amine Radical Cations and Elucidation of Chain Processes in Visible-Light-Mediated [3 + 2] Annulation by Online Mass Spectrometric Techniques

Article abstract of DOI:10.1021/jacs.7b06319

Visible-light-mediated photoredox reactions have recently emerged as a powerful means for organic synthesis and thus have generated significant interest from the organic chemistry community. Although the mechanisms of these reactions have been probed by a number of techniques such as NMR, fluorescence quenching, and laser flash photolysis and various degrees of success has been achieved, mechanistic ambiguity still exists (for instance, the involvement of the chain mechanism is still under debate) because of the lack of structural information about the proposed and short-lived intermediates. Herein, we present the detection of transient amine radical cations involved in the intermolecular [3 + 2] annulation reaction of N-cyclopropylaniline (CPA, 1) and styrene 2 by electrospray ionization mass spectrometry (ESI-MS) in combination with online laser irradiation of the reaction mixture. In particular, the reactive CPA radical cation 1^+?, the reduced photocatalyst Ru(I)(bpz)₃⁺, and the [3 + 2] annulation product radical cation 3^+? are all successfully detected and confirmed by high-resolution MS. More importantly, the post-irradiation reaction with an additional substrate, isotope-labeled CPA, following photolysis of 1, 2, and Ru catalyst provides strong evidence to support the chain mechanism in the [3 + 2] annulation reaction. Furthermore, the key step of the proposed chain reaction, the oxidation of CPA 1 to amine radical cation 1^+? by product radical cation 3^+? (generated using online electrochemical oxidation of 3), is successfully established. Additionally, the coupling of ESI-MS with online laser irradiation has been successfully applied to probe the photostability of photocatalysts.

Full text of DOI:10.1021/jacs.7b06319

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Article
Detection of Fleeting Amine Radical Cations and Elucidation
of Chain Processes in Visible Light-Mediated [3+2]
Annulation by Online Mass Spectrometric Techniques
Yi Cai, Jiang Wang, Yuexiang Zhang, Zhi Li, David Hu, Nan Zheng, and Hao Chen
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b06319 • Publication Date (Web): 08 Aug 2017
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Detection of Fleeting Amine Radical Cations and Elucidation
of Chain Processes in Visible Light-Mediated [3+2] Annulation
by Online Mass Spectrometric Techniques
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Yi Cai†§, Jiang Wang‡§, Yuexiang Zhang,†§ Zhi Li†, David Hu†, Nan Zheng*‡, and Hao Chen*†
†Department of Chemistry and Biochemistry, Center of Intelligent Chemical Instrumentation, Edison Biotechnology Instiꢀ
tute, Ohio University, Athens, OH 45701
‡Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701
ABSTRACT: Visibleꢀlight mediated photoredox reactions have recently emerged as a powerful means for organic synthesis and
thus have generated significant interest from the organic chemistry community. Although the reaction mechanisms have been
probed by a number of techniques such as NMR, fluorescence quenching, and laser flash photolysis and various degree of success
has been achieved, mechanistic ambiguity still exists (for instance, the involvement of the chain mechanism is still under debate)
due to lack of structural information about the proposed and shortꢀlived intermediates. Herein, we present the detection of transient
amine radical cations involved in intermolecular [3+2] annulation reaction of Nꢀcyclopropylaniline (CPA, 1) and styrene 2 by elecꢀ
trospray ionization mass spectrometry (ESIꢀMS) in combination with online laser irradiation of the reaction mixture. In particular,
+
the reactive CPA radical cation 1+., the reduced photocatalyst Ru(I)(bpz)3 , and the [3+2] annulation product radical cation 3+. are
all successfully detected and confirmed by high resolution MS. More importantly, the postꢀirradiation reaction with an additional
substrate, the isotopeꢀlabeled CPA following photolysis of 1, 2 and Ru catalyst provide strong evidences to support the chain mechꢀ
anism in the [3+2] annulation reaction. Furthermore, the key step of the proposed chain reaction, the oxidation of CPA 1 to amine
radical cation 1+. by product radical cation 3+. (generated using online electrochemical oxidation of 3) is successfully established.
Additionally, the coupling of ESIꢀMS with online laser irradiation has been successfully applied to probe the photostability of phoꢀ
tocatalysts.
light/dark experiments disapproved its involvement.6a,
Quantum yield measurements are in principle a more genꢀ
eral and sensitive method to differentiate the two competꢀ
6b
Introduction
ing processes. However, a wide range of quantum yields
from 1.3 to 77 across several types of photoredox reactions
have been reported,4gꢀi,6b which makes distinction of the
two processes more difficult, particularly for those with
quantum yields close to 1. Clearly, there is a strong need
for development of new tools that allow for explicit eluciꢀ
dation of photoredox reaction mechanisms including identiꢀ
fication of both the photoredox process and the chain
mechanism.
Photoredox catalysis has recently become a topic of inꢀ
tense study in the field of organic chemistry.1 The heightꢀ
ened interest in this topic is likely attributed to photoredox
catalysis’ versatility in generating radicals using light under
mild conditions, a specific mode of activation, which is
different from how radicals are produced under nonꢀphoto
conditions.2 As such, it provides means to explore radical
chemistry that is complementary to those under nonꢀphoto
conditions. Moreover, photoredox catalysis’ ability to
merge with other types of catalysis to form dual catalysis
further expands its utility far beyond the scope of traditionꢀ
al radical chemistry.3
Photoredox reactions pose a significant challenge to
chemists who are interested in studying their mechanisms.
They are typically fast and reversible, and the intermediates
are shortꢀlived. A variety of techniques such as NMR, EPR,
fluorescence quenching, quantum yield measurement, and
laser flash photolysis have been employed to study photoꢀ
redox reactions.4,6 However, these spectroscopic methods
usually lack structural information of the transient intermeꢀ
diates. Mass spectrometry (MS) has become a powerful
technique for detecting and characterizing shortꢀlived reacꢀ
tion intermediates as well as studying reaction mechanisms,
since the advent of soft ionization methods such as elecꢀ
trospray ionization (ESI)7 and desorption electrospray ioniꢀ
zation (DESI)8. The inherent high sensitivity and rich mass
In contrast to furious activity in method development,
mechanistic studies of photoredox catalysis have been raꢀ
ther scarce.4 In those published and limited results, there
exists controversy, such as whether photoredox reactions
involve chain processes. This is an important mechanistic
question in method development as different approaches
are required to optimize the two processes separately.
Light/dark experiments have been often used to differentiꢀ
ate them.4ꢀ6 However, there remains the ambiguity of interꢀ
preting light/dark experiments’ results, in which the chain
mechanism was established by other methods whereas
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Page 2 of 9
information provided by MS measurements distinguish it tolysis using a laser pointer (Figure 1a), but also enables
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from other commonly used methods. Moreover, in comparꢀ
ison to traditional spectroscopic approaches, it is a general
technique and does not need chromophoreꢀcarrying subꢀ
strates for investigating reaction mechanisms. However, the
probed species such as substrates, catalysts, intermediates,
or products must carry a charge, and sometimes the detecꢀ
tion can suffer from ion suppression effect due to the maꢀ
trix effect.
coupling with an online microreactor to study the reactiviꢀ
ties of the reaction intermediates. For instance, another
reagent such as CPAꢀd5 was introduced downstream via a
second channel (Figure 1b). In addition, for those intermeꢀ
diates that could not be generated photochemically (e.g.,
the radical cation of the [3+2] annulation product 3+.), elecꢀ
trolysis was employed as an alternative way to generate
radical cation 3+. whose reactivity could then be online
monitored by MS (Figure 1c). Combination of electroꢀ
chemistry (EC) with MS has been one of our research foꢀ
cuses which has applications for studying redox chemistry
of both small organic molecules and large protein moleꢀ
cules.8d,14 In this study, using the setup, we obtained uneꢀ
quivocal evidence to support the involvement of the chain
processes in the [3+2] annulation reaction. Since the setup
is flexible and modular, we believe that it can be easily
adopted to study other photoredox reactions.
9
We recently developed an intermolecular [3+2] annulaꢀ
tion of Nꢀcyclopropylanilines with alkenes by photoredox
catalysis (Scheme 1).9 This reaction displays some excelꢀ
lent features for a synthetic method such as broad functionꢀ
al group compatibility, 100% atom economy, and an overꢀ
all redoxꢀneutral process. The scope of this reaction was
later expanded to include various pi bonds.10 These results
have opened new avenues for the use of anilineꢀsubstituted
cyclopropanes as synthetic building blocks.11 Mechanistiꢀ
cally, these methods are all believed to proceed through
ring opening of the amine radical cations of Nꢀ
cyclopropylanilines. This process has been previously studꢀ
ied by EPR12a and electrochemical methods12b. However, it
has not been studied in the context of a complete catalytic
cycle, which is more relevant to our efforts in expanding
this reaction class to include other types of amineꢀ
substituted carbocycles. Therefore, we were eager to study
the complete catalytic cycle of the [3+2] annulation reacꢀ
tion.
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Scheme 1. The intermolecular [3+2] annulation of N-
cyclopropylaniline
Ru(II)(bpz)3(PF6)2.
1
and styrene
2
catalyzed by
Figure 1. a) Apparatus showing direct monitoring of the pho-
toredox reaction by online ESI-MS; b) apparatus allowing to
investigate the post-irradiation reaction event: a reaction mix-
ture is introduced into the silica capillary, photo-excited by
the laser pointer, and then mixed with an isotope-labeled new
substrate introduced via channel 2; c) apparatus for investi-
gating reactivity of radical cation generated via online elec-
trolysis: a thin-layer electrochemical flow cell is connected
with ion source and a substrate is introduced via channel 2 for
testifying the key electron transfer step involved in the chain
mechanism; AE, RE and WE represent auxiliary electrode,
reference electrode and working electrode, respectively.
Herein, we designed a series of online ESIꢀMS apparatus
(Figure 1) that allowed to directly detect the shortꢀlived
intermediates including the substrate radical cation 1+. and
the product radical cation 3+. from the visible lightꢀ
2+
mediated [3+2] annulation catalyzed by Ru(II)(bpz)3 (see
structures of 1+. and 3+. in Scheme 2).9 Although MS in
combination with online photolysis (e.g., using lamp or
laser to irradiate a reaction mixture prior to MS detection)
has been previously reported in literature,7q,13 this type of
setup has been rarely used to study the mechanism of visiꢀ
bleꢀlight triggered photoredox reactions.7q Moreover, none
of the reported MS studies provided any conclusive eviꢀ
dence for the chain reaction mechanism involved in photoꢀ
redox reactions. Our setup not only allows for the direct
detection of elusive reaction intermediates via online phoꢀ
Results and discussion
Apparatus. A high resolution Q Executive Plus hybrid
quadrupoleꢀOrbitrap mass spectrometer (Thermo Fisher
Scientific, San Jose, CA) was used in this study. As shown
in Figure 1a, to probe reaction intermediates, the commerꢀ
cial ESI ion source was removed to accommodate an inꢀ
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houseꢀmade ESI source. A piece of fused Silica capillary
As previously proposed (Scheme 2),9 upon irradiation,
2+
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(100 ꢁm i.d., 198 ꢁm o.d.) was used to deliver the reaction
mixture solution for online photolysis and online elecꢀ
trospray ionization (Figure 1a). An irradiation window on
the silica capillary (1 cm wide), located ca. 5 cm upstream
from the ESI emitter tip, was made by burning away the
organic capillary coating with flame. A laser pointer (403
nm, 50 mW, LaserPointerPro, HK) was employed as a light
source to irradiate the reaction solution in the capillary to
trigger the photoredox reaction as the solution flowed by
the irradiation window. The laser pointer was held about 5
cm away from the irradiation window. A high voltage +5
kV was applied to ionize the reaction mixture, with the
assistance of 170 psi N2 nebulization gas. The reaction soꢀ
lutions were all rigorously degassed with argon before irraꢀ
diation. The flow rate for infusing the reaction mixture soꢀ
lution through the silica capillary was 100 ꢁL/min. The
transportation time for the reaction mixture flowing from
the irradiation window to the ESI emitter tip was about 236
ms (dead volume= 0.393 μL, flow rate = 100 ꢁL/min).
Ru(II)(bpz)3 is promoted to the photoexcited triplet state
Ru(II)*(bpz)32+, which oxidizes CPA 1 to amine radical
+
cation 1+. with the concomitant formation of Ru(I)(bpz)3 .
Amine radical cation 1+. subsequently undergoes ring openꢀ
ing and then add intermolecularly to styrene 2 to produce
the [3+2] annulation product radical cation 3+.. Reduction
+
of 3+. by Ru(bpz)3 completes the catalytic cycle. Alternaꢀ
tively, a chain mechanism in which amine radical cation 3+.
oxidizes CPA 1 to a new radical cation 1+. while itself is
reduced to the product 3, allowing closure of the catalytic
cycle.
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Scheme 2. Proposed mechanism for the [3+2] annulation
reaction of N-cyclopropylaniline 1 and styrene 2 catalyzed
by Ru(II)(bpz)3(PF6)2.
To investigate the chain propagation process, the original
MS setup described in Figure 1a was modified to perform a
sequential reaction experiment (Figure 1b), in which a reacꢀ
tion mixture (e.g., a mixture of CPA 1, styrene 2 and
Ru(II)(bpz)3(PF6)2 4) was introduced into the silica capilꢀ
lary via channel 1 (50 ꢁL/min), photoꢀexcited by the laser
pointer, and then mixed with an isotopeꢀlabeled new subꢀ
strate (introduced via channel 2, 50 ꢁL/min). Upon mixing,
the added substrate reacted with the photoꢀexcited reaction
mixture in the downstream capillary served as a microreacꢀ
tor, prior to MS detection. Because the isotopeꢀlabeled subꢀ
strate was added after the photolysis of the reaction mixꢀ
ture, positive identification of the product derived from the
added isotopeꢀlabeled substrate could be used as evidence
to support the chain propagation process. MS’ inherent
high sensitivity enabled detection of the product in minute
amount, which made this apparatus far more sensitive than
dark/light experiments.
1+•
Redox
Process
3+•
To probe the above reaction mechanism, online irradiaꢀ
tion and detection experiments using the aforementioned
apparatus (Figure 1a) were first carried out. In this experiꢀ
ment, we started with the examination of the reaction beꢀ
tween Ru(II)(bpz)3(PF6)2 4 and CPA 1 under the photolyꢀ
sis condition. A mixture of [Ru(II)(bpz)3](PF6)2 4 (0.0004
mmol, 100 μM) and CPA 1 (0.02 mmol, 5 mM) in 4 mL of
CH3NO2 was infused at the flow rate of 100 ꢁL/min
through the silica capillary for ESIꢀMS detection after arꢀ
gon degassing. Without irradiating the reaction solution
flowing through the capillary by laser, an ESIꢀMS spectrum
was acquired (Figure 2a). The ions of m/z 134 (measured
m/z: 134.0966, theoretical m/z 134.0964, error +1.5 ppm)
and m/z 288 (measured m/z: 288.0408, theoretical m/z
288.0405, error ꢀ1.0 ppm) were detected, corresponding to
the protonated CPA [1+H]+ and Ru(II)(bpz)32+, respectiveꢀ
ly. We noticed that there was a small peak for 1+• (measꢀ
ured m/z: 133.0888, theoretical m/z 133.0886, error +1.5
ppm, Figure 2a inset) with intensity of 1.69E6 (manufacꢀ
turer arbitrary unit). We attributed the formation of 1+. to
inꢀsource oxidation of 1 during the ESI ionization proꢀ
cess,15 as it was still observed in the absence of the Ru cataꢀ
lyst 4. Furthermore, the reduced Ru(I) species was not obꢀ
served.
Alternatively, photolysis could be replaced by electrolyꢀ
sis to generate the amine radical cation of product 3. As
shown in Figure 1c, an electrochemical flow cell with a
magic diamond electrode (details shown in the text below)
was used in our experiment. Amine radical cation 3+. was
then mixed with CPA 1 introduced via channel 2 to examꢀ
ine its reactivity by online MS monitoring. In this case, no
high voltage was applied to the ESI source in order to avoid
the voltage conflict issue between the electrochemical cell
and the ion source. Photos for all of the experimental setꢀ
ups mentioned above are included in the Supporting Inforꢀ
mation (Figure S1).
Detection of Amine Radical Cations
Nꢀcyclopropylaniline (CPA) 1 and styrene 2 were chosen
as the model substrates (Scheme 1) to investigate the inꢀ
termolecular
[3+2]
annulation
catalyzed
by
Next, when the laser pointer was turned on to irradiate
the mixture in the capillary through the irradiation window,
the intensity of 1+. peak increased by 17 fold (Figure 2b
inset), which was ascribed to the photoꢀoxidation of 1.
Ru(II)(bpz)3(PF6)2 4 using the ESIꢀMS setꢀup with online
photolysis shown in Figure 1a. We selected this pair of
substrates because both were extensively studied in the
initial development of the annulation reaction.9,10
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Amine radical cation 1+. could undergo ring opening to
ciation (CID), the ion m/z 238 gave rise to a fragment ion
1
2
3
4
5
6
7
8
furnish the distonic radical cation. However, ESIꢀMS can’t
differentiate the two species because they have the same
mass. Additionally, the reduced Ru catalyst peak of
of m/z 145 by loss of C6H5NH2 (Figure S3ꢀa, Supporting
Information), consistent with its assigned structure. Furꢀ
thermore, the CID behavior of this ion was identical to that
of the protonated product at m/z 238 generated from ESI of
the authentic product compound 3 (Figure S3ꢀb, Supporting
Information), reinforcing the ion assignment. Although a
small peak for the CPA radical cation 1+• was seen (Figure
2c inset, its intensity similar to that seen in Figure 2a), it
was again probably due to the inꢀsource ESI oxidation of
the unreacted CPA 1. There were a few unassigned peaks
in Figure 2c, whose suggested chemical formulas were
included in the Supporting Information (Table S1, Supportꢀ
ing Information). Surprisingly, the product radical cation
3+• was not observed in the acquired MS spectrum under
this condition, which will be discussed further subsequently.
Notably, Ru(I)(bpz)3+ (m/z 576) could not been observed in
Figure 2c, presumably because it was consumed in the anꢀ
nulation reaction. This data supported the photoredox proꢀ
cess in which Ru(I)(bpz)3+ reduced the product radical catiꢀ
on 3+• to complete the catalytic cycle (Scheme 2). The two
processes, the photoredox process and the chain mechaꢀ
nism, likely competed against each other and intertwined
throughout the reaction.
+
Ru(I)(bpz)3 m/z 576 (measured m/z: 576.0815, theoretical
m/z: 576.0815, error 0.0 ppm) was also detected. The inset
in Figure 2b clearly showed the zoomedꢀin spectrum of
+
Ru(I)(bpz)3 at m/z 576 (in black), which matched well
with its theoretical isotopic peak distribution (in red). This
9
experiment result supported the photooxidation of CPA 1
2+ 2d
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by the photoexcited Ru(II)*(bpz)3
.
A control study in
which CPA 1 from the reaction mixture was replaced by
styrene 2 (Figure S2, Supporting Information) showed no
+
formation of Ru(I)(bpz)3 , excluding the possibility of the
redox reaction between Ru(II)*(bpz)32+ and styrene 2. Both
results were consistent with the Stern Volmer studies in
which CPA 1 was shown to be an effective quencher for
2+
Ru(II)*(bpz)3 but styrene 2 was not (Figure S14 and Figꢀ
ure S16, Supporting Information).
We encountered difficulties in detection of the product
radical cation 3+• during our studies of the online photolysis
of CPA 1 and styrene 2 in the presence of the Ru catalyst 4
(Figure 2c). We surmised that higher concentration of CPA
1 would result in a faster chain reaction between the prodꢀ
uct radical cation 3+• and CPA 1, and thus would shorten
the lifetime of 3+•. Alternatively, higher concentration of
CPA 1 could lead to higher concentration of Ru(I) via reꢀ
duction of the excited Ru(II) complex, which could also
shorten the lifetime of 3+• via the photoredox process
(Scheme 2).
To test this hypothesis and to observe the radical cation
3+•, we performed an ESIꢀMS monitoring experiment by
lowering the concentration of CPA 1 from 5 mM (0.02
mmol in 4 mL CH3NO2) to 10 ꢁM (0.04 μmol in 4 mL
CH3NO2) for the online photoredox reaction while mainꢀ
taining the concentrations of styrene 2 and Ru catalyst 4 as
those experiments shown in Figure 2 (0.1 M styrene 2 and
100 ꢁM Ru 4). Indeed, when CPA 1 was diluted to 100
ꢁM, the product radical cation 3+• at m/z 237.1512 (Figure
3c, measured m/z: 237.1512, theoretical m/z 237.1512, erꢀ
ror 0.0 ppm) was observed. The signal of 3+• appeared only
when the laser pointer was turned on, supporting that it was
a photochemical product. Upon further dilution of CPA 1,
the peak intensity of the CPA radical cation 3+• decreased
(Figure 3d). When the concentration of CPA 1 was lowered
to 10 ꢁM, the peak at m/z 237 was not observed (data not
shown), probably because the concentration of the resulting
3+. was below the detection limit of our MS instrument.
Notably, the observed 3+• was not an artifact of the inꢀ
source ESI oxidation product. In a control experiment, ESI
of the authentic product 3 did not give rise to observable
signal of 3+•. Furthermore, direct irradiation of 3 in the
presence of Ru catalyst 4 did not produce 3+•, either. All
these results not only showed the existence of the proposed
Figure 2. a) ESI-MS spectrum of Ru(II)(bpz)3(PF6)2 and CPA
in CH3NO2 acquired without light irradiation; b) ESI-MS
spectrum of Ru(II)(bpz)3(PF6)2 and CPA in CH3NO2 with
light irradiation; c) ESI-MS spectrum of Ru(II)(bpz)3(PF6)2,
CPA and styrene in CH3NO2 with light irradiation.
Then, we monitored the [3+2] annulation of CPA 1 and
styrene 2 in CH3NO2 with the Ru catalyst 4 using ESIꢀMS.
A degassed mixture of [Ru(bpz)3](PF6)2 4 (0.0004 mmol,
100 μM), CPA 1 (0.02 mmol, 5 mM), and styrene 2 (0.4
mmol, 0.1 M) in 4 mL CH3NO2 was irradiated inside the
capillary by the laser pointer, and the reaction was moniꢀ
tored online by ESIꢀMS. Under irradiation, the protonated
[3+2] annulation product [3+H]+ (m/z 238) (measured m/z:
238.1593, theoretical m/z 238.1590, error +1.2 ppm) was
clearly observed (Figure 2c). Upon collisionꢀinduced dissoꢀ
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product radical cation 3+• in the [3+2] annulation reaction,
In a control study when there was no light irradiation
1
2
3
4
5
6
7
8
but also verified our hypothesis that a low concentration of
(Figure 4a), m/z 134 and m/z 139 were observed, correꢀ
sponding to the protonated CPA [1+H]+ and CPAꢀd5 [1ꢀ
d5+H]+, respectively. When the laser pointer was turned on
for irradiation, the protonated [3+2] annulation product
[3+H]+ peak m/z 238 was clearly observed. More imꢀ
portantly, a new peak corresponding to the protonated
[3+2] annulation productꢀd5 [3ꢀd5+H]+ at m/z 243 was also
detected (measured m/z: 243.1900, theoretical m/z:
243.1904, error 1.6 ppm, Figure 4b inset). Moreover, beꢀ
fore adding CPAꢀd5 through channel 2 (only solvent was
introduced via channel 2), the product radical cation 3+• at
m/z 237 was observed (Figure 4b inset). After the mixing,
the product radical cation 3+• disappeared. The consumpꢀ
tion of the product radical cation 3+• with concurrent forꢀ
mation of the CPA productꢀd5 lent another strong evidence
to support the chain propagation.
To rule out the possibility that the observed [3ꢀd5+H]+ reꢀ
sulted from the oxidation of CPAꢀd5 by the preꢀexcited
photocatalyst, a second control experiment was carried out
in which a degassed solution of [Ru(bpz)3](PF6)2 4 (0.0004
mmol, 100 ꢁM) and styrene 2 (0.4 mmol, 0.1 M) was inꢀ
fused via channel 1 for irradiation (CPA 1 was omitted),
and the degassed solution of CPAꢀd5 (100 ꢁM) was infused
via channel 2. The injection flow rate for both channels was
kept as 50 ꢁL/min. The protonated CPAꢀd5 reaction prodꢀ
uct [3ꢀd5+H]+ at m/z 243 was not observed (Figure S6,
Supporting information). Presumably, because the lifetime
of the photoꢀexcited 4 is much shorter than the transportaꢀ
tion time for the reaction mixture to flow from the irradiaꢀ
tion window to the Tee mixer (0.74 µs1a vs. about 472 ms),
the photochemically preꢀexcited Ru catalyst 4 could be
deactivated before reaching CPAꢀd5.
CPA 1 would favor the observation of 3+•.
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Figure 3. Zoomed-in ESI-MS spectra showing the influence of
the CPA concentration on the observation of 3+•: a) 5 mM
CPA, b) 0.5 mM CPA, c) 100 µM CPA, and d) 25 µM CPA.
3+• was observed when the CPA concentration was lowered
down to 100 µM. Absolute intensity for m/z 237.1512 in Figure
2c and 2d are 2.35E5 and 1.43E5 (manufacturer arbitrary
unit), respectively. Note that no 1+. was observed in these ex-
periments probably due to the presence of excess amount of
styrene (except that a small peak of 1+. was seen for the case of
5 mM CPA due to in-source oxidation). Also, no Ru(I) species
was observed.
In order to further confirm the assignment of observed
3+• and [3+H]+ ions, styrene 2 was replaced by styreneꢀα, β,
βꢀd3 in the annulation reaction under otherwise identical
conditions. The protonated final productꢀd3 3ꢀd3 at m/z 241
(measured m/z: 241.1778, theoretical m/z 241.1779, error ꢀ
+•
0.4 ppm) and the productꢀd3 radical cation 3ꢀd3 at m/z
240.1699 (Figure S5b inset, measured m/z: 240.1699, theoꢀ
retical m/z 240.1700, error ꢀ0.4 ppm) were both observed
(Figure S5, Supporting Information).
2+
Ru(bpz)3
288
100
Chain Mechanism investigation
a) Light off
[1+H]+
50
0
a. Post-irradiation chain propagation
[1-d5+H]+
139
134
Encouraged by observing the dependence of detecting 3+•
on CPA 1 concentration, we decided to investigate the
chain propagation from a different angle, postꢀirradiation.
The original MS setup described in Figure 1a was modified
to perform a sequential reaction experiment (Figure 1b). A
mixing Tee was used to introduce CPAꢀd5 1ꢀd5 into the
silica capillary microreactor to further react with the irradiꢀ
ated reaction mixture of CPA 1, Ru(II) catalyst 4, and styꢀ
rene 2. A degassed solution of CPA 1 (100 μM),
[Ru(bpz)3](PF6)2 4 (0.0004 mmol, 100 μM), and styrene 2
(40 ꢁL, 0.4 mmol, 0.1 M) was infused via channel 1 for
irradiation. The degassed solution of CPAꢀd5 1ꢀd5 (100
μM) was infused via channel 2. The injection flow rate was
50 μL/min for both channels. This modified setup allowed
that the channel 1 reaction solution was first irradiated by
the blue laser pointer and then mixed with CPAꢀd5 1ꢀd5
from channel 2 without light irradiation. If the chain proꢀ
cess were involved, the radical cation intermediates 3+•
would induce CPAꢀd5 to participate in the [3+2] annulation
reaction to afford the annulation productꢀd5.
100
150
200
250
300
350
400
450
500
550
600
2+
Ru(bpz)3
288
[3-d5+H]+
243
100
Without
CPA-d5
b) Light on
3+.
[1+H]+
50
0
243.17
243.21
237
[1-d5+H]+
139
134
237.13
400
237.15
[3+H]+
238
100
150
200
250
300
350
450
500
550
600
m/z
Figure 4. ESI-MS spectra of post-irradiation reaction: a mix-
ture of degassed CPA 1 (100 µM), [Ru(bpz)3](PF6)2 4 (100
µM), and styrene 2 (0.1 M) in CH3NO2 was first irradiated,
then mixed with a degassed solution of CPA-d5 (100 µM) in
CH3NO2 introduced via channel 2 (see apparatus in Figure
1b), for testifying chain reaction mechanism. a) the light was
turned off. b) the light turned on. The inset shows zoomed-in
ESI-MS spectrum of irradiation without adding CPA-d5.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Oxidation of substrate 1 by 3+.
Page 6 of 9
b.
1
The remaining task in fully establishing the chain propaꢀ
gation process was to validate the oxidation of CPA 1 by
the radical cation of the annulation product 3+. (Figure 5a).
We initially attempted the generation of 3+. by photolysis of
the authentic reaction product 3 in the presence of Ru cataꢀ
lyst 4. The targeted 3+. was not observed, even though Stern
Volmer studies showed that product 3 was an effective
quencher for the photoexcited 4 albeit somewhat less effecꢀ
tive than CPA 1 (Figures S14 and S15, Supporting Inforꢀ
mation). We then attempted chemical oxidation of CPA 1
2
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using
a
singleꢀelectron
oxidant,
tris(4ꢀ
bromophenyl)ammoniumyl hexachloroantimonate. Altꢀ
hough 3+. was successfully generated, a large amount of the
oxidant remained. Because the unreactive oxidant could
directly oxidize 1 and thus interfere with the targeted oxiꢀ
dation of 1 by 3+., we had to abandon this approach, too.
Finally, we decided to focus on generation of 3+. using
electrochemical oxidation of 3. The setup described in Figꢀ
ure 1a was modified with addition of a thinꢀlayer electroꢀ
chemical flow cell to perform the electrochemical oxidation
(Figure 1c). A magic diamond electrode (12 x 30 mm) was
used with LiOTf as the supporting electrolyte. The flow
electrochemical cell was connected to a Tee mixer through
which CPA 1 was introduced. A solution of the annulation
product 3 (1 mM) and LiOTf (1 mM) in CH3CN was inꢀ
fused into the flow cell and CH3CN was first infused via
channel 2. A potentiostat was used to apply potential for
electroꢀoxidation. The injection flow rate for both channels
was 10 ꢁL/min. When a +3.0 V voltage was applied to the
flow cell to trigger the electrochemical oxidation of 3, the
targeted radical cation 3+. was observed (Figure 5b, black
line). When the solvent CH3CN, was replaced by CPA 1 in
CH3CN (100 ꢁM) in channel 2, the signal of 3+. decreased
(Figure 5b, red line) with concomitant formation of the
CPA radical cation 1+. (Figure 5c). This set of data validatꢀ
ed the oxidation of CPA 1 by the product radical cation 3+.,
which was also supported by our cyclic voltammetric
measurements of 1 and 3 (Figure S8, Supporting Inforꢀ
mation). Both have a very similar oxidation potential (ca.
0.8 V vs. SCE).
Figure 5. ESI-MS for monitoring of the oxidation of CPA 1 by
3+.: a degassed solution of product 3 (1 mM) and LiOTf (1
mM) in ACN was infused into the electrochemical flow cell to
generate 3+., which reacted with CPA 1 (introduced via chan-
nel 2). a) Chemical equation showing the reaction between the
3+. and 1. b) ESI-MS spectra (background subtracted) show-
ing the formation of the radical cation 3+. when the oxidation
potential was applied to the cell: black line (only solvent
ACN was introduced via channel 2) and red line (CPA 1 was
introduced via channel 2). c) ESI-MS spectrum (background
subtracted) showing the formation of CPA radical cation 1+.
when the cell was turned on and CPA 1 was introduced into
channel 2.
c.
Quantum yield measurement
To corroborate our MS studies on elucidation of the
chain mechanism, we measured the quantum yield of the
[3+2] annulation of 3,5ꢀdimethylcyclopropylaniline 5 and
styrene 2. Using potassium ferrioxalate as an actinometer
and a 300 W Xenon lamp (50% of light intensity, 439±5
nm bandpass filter high transmittance), we determined the
quantum yield over the time interval of 15 min, 30 min, and
60 min (Figure S9ꢀS12, Supporting Information).4g,4i,6b The
quantum yield was calculated to be 1.64, 1.68, and 1.44,
respectively, which maintained above one during the
course of the experiment and supported the chain mechaꢀ
nism. The low quantum yield on its own could lead to amꢀ
biguity in deciphering the chain mechanism,4g and thereꢀ
fore would require additional studies. However, our MS
studies provided unequivocal evidence to support the chain
mechanism.
To rule out that the observed CPA radical cation 1+. was
formed by reacting with other species in the oxidized solꢀ
vent, a control experiment was performed, in which only
LiOTf (1 mM) in CH3CN (without 3) was infused into the
cell for oxidation under the same condition and then mixed
with CPA 1 (100 ꢁM). In this control experiment, no CPA
radical cation 1+• was generated (Figure S7, Supporting
Information), indicating that no other species from the elecꢀ
trochemical cell except 3+. could oxidize CPA 1.
Based on the low quantum yield we obtained for the
[3+2] annulation, we anticipated that light/dark experiꢀ
ments might not reveal the chain mechanism. Not surprisꢀ
ingly, similar to Stephenson’s,6a Yoon’s,6b and others’4i,5
results, we observed that the annulation occurred only in
the presence of light and stalled when the light source was
off (Figure 6, details shown in Supporting Information).
Again as with other reports, this result revealed the limitaꢀ
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Journal of the American Chemical Society
tion of light/dark experiments to disapprove the chain remained intact (Figure 2c). This interesting observation
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mechanism. The failure of light/dark experiments in distinꢀ
guishing photoredox mechanisms from chain mechanisms
is presumably due to the premise that most of the reactions
under photoredox catalysis contain a short radical chain.
Unfortunately, light/dark experiments do not have response
fast enough to detect the radical chain. Our apparatus (Figꢀ
ure 1) not only possesses the inherently fast response of
online ESIꢀMS methods, but also enables coupling with an
online photo microreactor or an electrochemical cell to
monitor postꢀirradiation reaction products (e.g., the [3+2]
annulation product of CPAꢀd5 in the dark, Figure 4b; oxidaꢀ
tion of CPA 1 by electrochemically generated 3+., Figure
5). Both features make our apparatus a powerful tool to
detect chain processes in photoredox reactions
shed light on the premise that a less robust photocatalyst
such as Ru(bpz)3](PF6)2 4 could still be used as long as
there were viable reactions to be catalyzed.
Conclusions
The recent surge of activity in visible light photocatalyꢀ
sis has prompted organic chemists to study the mechanism
of various reactions under photoredox catalysis. However,
the mechanistic studies of these reactions prove challengꢀ
ing, as there is lack of analytic tools that are capable of
detecting transient intermediates in low quantity while also
providing rich structural information. The ESIꢀMS setꢀup
with online photolysis, which requires little amount of maꢀ
terials (e.g., 400 nanomoles of both [Ru(bpz)3](PF6)2 4 and
CPA 1) and possesses fast response and high detection senꢀ
sitivity, has shown to be a powerful tool to study visible
light photocatalysis mechanistically. The in situ ionization
capability of ESIꢀMS with online irradiation allows us to
detect key and short lived species such as amine radical
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+
cations and Ru(bpz)3 , and examine deactivation of photoꢀ
catalysts. Moreover, by combining electrochemistry with
MS, we are able to prove the viability of the oxidation of
CPA 1 by 3+., generated by electrochemical oxidation of 3.
This result along with the postꢀirradiation reaction study
provides conclusive experimental support for the involveꢀ
ment of the chain mechanism in the [3+2] annulation reacꢀ
tion. Finally, this study provides another good example of
using MS to detect elusive and transient reaction intermeꢀ
diates in low quantity.7,8 We believe that we have just
scratched the surface of ESIꢀMS with online irradiation’s
and online electrolysis’ potential in studying visible light
photocatalysis, and more new applications are anticipated
to come.
Figure 6. Light/dark experiments for the annulation
Photostability of catalyst
ASSOCIATED CONTENT
Supporting Information
Photostability is one of the key features for a good phoꢀ
tocatalyst. However, because of the presence of various in-
situ generated radical species, deactivation of photocataꢀ
lysts by adding one of these radical species to the catalyst’s
ligand is often encountered.16 Recently, the Stephenson
group delineated a deactivation pathway for Ir(ppy)3 via
ligand functionalization using a combination of kinetic,
synthetic, and spectroscopic tools.17 We were wondering
whether we could use the online irradiation MS to study the
potential deactivation pathway in the [3+2] annulation.
This is particularly relevant to the catalyst used in the annuꢀ
lation reaction, [Ru(bpz)3](PF6)2 4, which has shown to be
less stable than other Ru complexes based on our observaꢀ
tions. As shown in Figure 2b, in the absence of styrene 2,
the new peak at m/z 354 was observed, which was correꢀ
sponding to the Ru complex monoalkylated by CPA. Upon
CID (Figure S4, Supporting Information), this ion dissociꢀ
ated into fragment ions [CPAꢀH]+ (m/z 132), [354ꢀCPA]2+
(m/z 288), [354ꢀPhNHCH=CH2]2+ (m/z 295), [354ꢀ
PhNH2]2+ (m/z 308), and [Ru(bpz)2ꢀH]+ (m/z 417), which
indeed suggests that it is a covalentlyꢀbonded adduct ion of
CPA and Ru catalyst. However, ligand shedding to the catꢀ
alyst was not observed. In addition, to our surprise, in the
presence of both CPA 1 and styrene 2, the Ru complex 4
Experimental details, apparatus photos and additional MS,
MS/MS data and quantum yield experimental results The Supꢀ
porting Information is available free of charge on the ACS Publiꢀ
cations website.
AUTHOR INFORMATION
Corresponding Author
*nzheng@uark.edu
*chenh2@ohio.edu
Author Contributions
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the manuꢀ
script. §These authors contributed equally.
Funding Sources
This work was supported by NSF Career Award (CHEꢀ1255539)
and the National Institute of Health under grant number P30
GM103450 from the National Institute of General Medical Sciꢀ
ences to N.Z. as well as NSF IDBR (CHEꢀ1455554), NSF (CHEꢀ
1709075) and NSF MRI (CHEꢀ1428787) to H.C. Y.C. thanks the
Ohio Third Frontier Fund for research assistantship.
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Page 8 of 9
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(a) Wallentin, C.ꢀJ.; Nguyen, J. D.; Finkbeiner, P.;
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Cismesia, M. A.; Yoon, T. P. Chem. Sci. 2015, 6, 5426ꢀ5434.
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ACKNOWLEDGMENT
[7]
(a) Wilson, S. R.; Perez, J.; Pasternak, A. J. Am. Chem.
We thank Dr. Theresa H. Nguyen for early synthetic support and
Professor Bill Durham for advice on quantum yield measureꢀ
ments.
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