Mechanistic analysis of a copper-catalyzed C-H oxidative cyclization of carboxylic acids

Article abstract of DOI:10.1039/c7sc02240a

We recently reported that carboxylic acids can be oxidized to lactone products by potassium persulfate and catalytic copper acetate. Here, we unravel the mechanism for this C-H functionalization reaction using desorption electrospray ionization, online electrospray ionization, and tandem mass spectrometry. Our findings suggest that electron transfer from a transient benzylic radical intermediate reduces Cu(ii) to Cu(i), which is then re-oxidized to Cu(ii) in the catalytic cycle. The resulting benzylic carbocation is trapped by the pendant carboxylate group to give the lactone product. Formation of the putative benzylic carbocation is supported by Hammett analysis. The proposed mechanism for this copper-catalyzed oxidative cyclization process differs from earlier reports of analogous reactions, which posit a substrate carboxylate radical as the reactive oxidant.

Full text of DOI:10.1039/c7sc02240a

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Experimental evidence supports a
mechanism for oxidative conversion
of carboxylic acids to lactones that
initiates with C–H abstraction by
sulfate radical anion. The reaction is
found to proceed through a
carbocationic intermediate with redox
cycling of copper ion.

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Mechanistic Analysis of a Copper-Catalyzed C–H Oxidative
Cyclization of Carboxylic Acids
†
†
Shibdas Banerjee, Shyam Sathyamoorthi, J. Du Bois, and Richard N. Zare*
Received 00th January 20xx,
Accepted 00th January 20xx
We recently reported that carboxylic acids can be oxidized to lactone products by potassium persulfate and catalytic copper
acetate. Here, we unravel the mechanism for this C–H functionalization reaction using desorption electrospray ionization,
online electrospray ionization, and tandem mass spectrometry. Our findings suggest that electron transfer from a transient
benzylic radical intermediate reduces Cu(II) to Cu(I), which is then re-oxidized to Cu(II) in the catalytic cycle. The resulting
benzylic carbocation is trapped by the pendant carboxylate group to give the lactone product. Formation of the putative
benzylic carbocation is supported by Hammett analysis. The proposed mechanism for this copper-catalyzed oxidative
cyclization process differs from earlier reports of analogous reactions, which posit a substrate carboxylate radical as the
reactive oxidant.
DOI: 10.1039/x0xx00000x
www.rsc.org/
In order to elucidate the role of copper catalyst as well as to chart
the transformation of substrate into product, we have investigated
the mechanism of oxidative lactonization (Scheme 1) using a
combination of ambient ionization mass spectrometric techniques
and conventional physical-organic experiments. Desorption
electrospray ionization mass spectrometry (DESI-MS; Fig. 1a)12-15 and
Introduction
A detailed understanding of the mechanisms of reactions that
promote C–H bond functionalization is important for the continued
advancement of these technologies.1-5 We recently reported a
copper-catalyzed oxidative cyclization of aliphatic and aromatic
2 2 8
carboxylic acids using potassium persulfate (K S O ) as the terminal
1
6-
online electrospray ionization mass spectrometry (ESI-MS; Fig. 1b)
6
oxidant (Scheme 1). The reaction is performed open to air in a 1:1
mixture of acetic acid/water, uses low-cost copper acetate as a
catalyst, and furnishes lactone products in modest to good yields for
a variety of substrates. Results from kinetic isotope effect
experiments indicate that copper ion has no influence on the C–H
oxidation event.6 These findings coupled with other substrate
selectivity data and the absence of detectable products of
decarboxylation have led us to speculate that a sulfate radical anion
functions as the active oxidant in this reaction. Our conclusion differs
from prior literature reports7-11 for related processes, all of which
have suggested that intramolecular C–H abstraction by a carboxylate
radical initiates the cyclization event. In this study, we have
leveraged the power of mass spectrometry to obtain evidence in
support of our earlier proposal as well as additional mechanistic
insights that reveal the complex nature of this process.
2
0
have enabled direct capture of transient intermediates derived
from both substrate and copper catalyst, allowing us to posit a
possible mechanistic scheme for this cyclization reaction. Our
mechanistic hypothesis is corroborated by results from Hammett
experiments as well as from studies using substrate probes. All told,
these findings highlight the utility of mass spectrometry for the
analysis of complex, multicomponent reactions, particularly those
involving short-lived, redox-reactive species and kinetically labile
transition metal salts.
Figure 1a shows the experimental set up of DESI-MS, which is
used to monitor ion signals of intermediates formed during the
progress of the reaction. In this DESI-MS experiment, a spray of
charged
microdroplets,
generated
in
a
1:1
acetonitrile/dimethylformamide (ACN/DMF, v/v) solution, is
directed toward a glass sample plate on which the reaction mixture
is dispensed (Fig. S1, see Experimental section for details). When the
incident (primary) microdroplets impact the sample (reaction
mixture), reactants, intermediate species, and products are
extracted into secondary microdroplets. Subsequent solvent
evaporation from these secondary microdroplets generates gas-
phase analytes that are transferred into a high-resolution orbitrap
mass spectrometer for mass-to-charge ratio (m/z) analysis. The high
mass accuracy of this instrument allows for reliable identification of
fleeting intermediates. Typically, the average lifetime of
microdroplets in DESI or ESI is on the order of milliseconds.13,21
Accordingly, DESI-MS/ESI-MS can provide a ‘snapshot’ of reaction
progress under ambient conditions in the form of ion signals of
relevant species (substrate, catalyst, intermediate, and product).
Scheme 1 Copper-catalyzed oxidative cyclization of a typical carboxylic acid.
a.
Stanford University, Department of Chemistry, 333 Campus Drive, Stanford, CA
9
4305-4401 (USA), E-mail: zare@stanford.edu
†
These authors contributed equally to this work.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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unassigned signals mostly appear from impurities and background
2
–
can produce SO
4
•–, which is
artifacts. Thermal homolysis of S
capable of abstracting a hydrogen atom from 4-phenylbutyric acid to
generate benzyl radical 2 and HSO
–.23 The ion signal at m/z 259.0280
Fig. 2a) appears to correspond to the adduct of such a radical
2
O
8
4
(
•– 24
intermediate (2) with SO
4
.
This species has been characterized
with high mass accuracy (0.8 ppm error) and closely matches the
predicted isotopic distribution pattern (Fig. S4) for the sulfated
product.
Fig. 1 Schematic diagram of the (a) DESI-MS and (b) online ESI-MS setup for
intercepting species formed in the reaction mixture.
Results and Discussion
A. Mechanistic Scheme
Analysis of the overall rate of product formation in the oxidative
lactonization reaction (Fig. S2) shows that the process is rapid,
yielding maximal product within 5 min of initiation. Samples are thus
taken from the reaction mixture at 2 min post initiation for analysis
by DESI-MS. Results from these experiments (vide infra) and those in
6
our earlier report have led us to propose Scheme 2 as one plausible
mechanism for this Cu-catalyzed cyclization. Benzylic hydrogen
abstraction in phenylbutyric acid 1 by SO •–
affords a carbon radical
4
intermediate 2. One-electron oxidation of 2 by the Cu(II) catalyst
generates a resonance-stabilized carbocation 3 with concomitant
formation of a Cu(I) species. Intermediate 3 can then cyclize directly
to lactone product 4. If water traps the carbocation, alcohol 5 is
formed, which can either close to lactone 4 or undergo further
6
oxidation to ketone 6. In the presence of K
2
S
2
O
8
, Cu(I) is re-oxidized
to Cu(II), thus allowing for catalytic turnover.22 We have detected ion
signals corresponding to intermediates 2 (trapped by SO
•–), 3, 5,
products 4, 6, HSO – •–, and Cu(I) species in our
, active oxidant SO
4
4
4
experiments (Figs. 2 and 3). In most cases, characterization of these
species is further enabled by collision-induced dissociation (CID) (see
Figs. S5, S11, and 4).
Fig. 2 (a) Negative ion mode DESI mass spectrum for the (a) Cu(II)-catalyzed
oxidative cyclization of 4-phenylbutyric acid (Scheme 1). (b) CID-MS2 of the
mass selected ion at m/z 259.0280 [highlighted in yellow in (a)]. See Table S1
for the accuracy of the m/z measurement. (c) Online ESI-MS monitoring of
the formation of Cu(I) species in real time from the reaction mixture
(containing 4-phenylbutyric acid substrate) and control (reaction mixture
without substrate) at 75 °C. Inset shows the isotopic distribution of
I
3 2
Cu (CH CN)
]+. See the Experimental section and Fig. S10 in SI for details.
[
The CID-MS2 of the m/z 259.0280 analyte shows two major
–
fragments: HSO
4
and 4-hydroxy-4-phenylbutanoate (Fig. 2b).
Scheme 2 Proposed mechanism for the copper-catalyzed oxidative cyclization
of carboxylic acids to lactones.
Formation of 4-hydroxy-4-phenylbutanoate (m/z 179.0716, Fig. 2b)
3
is verified by mass selection followed by CID-MS on this species (Fig.
2
S5a), which matches the CID-MS (Fig. S5b) of standard 4-hydroxy-4-
–
B. Capturing Intermediates by Mass Spectrometry
phenylbutanoate or [5-H] in Fig. 2a. The structure of the analyte at
m/z 259.0280 (Fig. 2a) has been confirmed by comparing its CID (Fig.
Negative ion mode DESI-MS (Fig. 2a) of the reaction mixture detects
2
b) with that of a synthetic standard of 3-carboxy-1-phenylpropyl
sulfate (Fig. S6). Generation of the sulfated product can be ascribed
to reaction of the benzylic radical (i.e., 2) and K . It is also
possible that 3-carboxy-1-phenylpropyl sulfate (m/z 259.0280, Fig.
a) forms from sulfate trapping of carbocation 3; however, in light of
ion signals of hydrogen sulfate (HSO
and persulfate anion (S
2–) generated from decomposition of
. The detailed characterization of these species by their
4
–), sulfate radical anion (SO •–),
4
2
O
8
2 2 8
S O
2 2 8
K S O
isotopic distribution is given in Fig. S3. Please note that in Fig. 2 that
the intensity of different ion signals cannot be simply related to
concentrations of the corresponding species in bulk solution because
of differences in ionization efficiencies. Careful evaluation of the
mass spectra led us to identify a few among many detected signals
which formed the basis of the proposed mechanism. Other
2
the poor nucleophilicity of sulfate anion,25 this reaction pathway is
less likely.
We have demonstrated previously that cupric ion is required as
6
a catalyst for optimal reaction performance. From DESI-MS, we have
been unable to identify any type of organocopper complex derived
2
| J. Name., 2012, 00, 1-3
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from 1. A weak signal, however, has been detected in positive ion catalyzed oxidation of ethylbenzene. See the experimental section in SI for
I
+
details and Table S1 for the accuracy of the m/z measurement.
3 2
mode DESI-MS for Cu(I) complexed with acetonitrile ([Cu (CH CN) ] )
at m/z 144.9827 (Fig. S7). It is possible that this species results from
reduction of Cu(II) ion in the spray ionization process.26,27 To
determine if Cu(I) is generated under our reaction conditions, we
I
]+ in real time by an
have monitored the formation of [Cu (CH
3
CN)
2
on-line ESI-MS setup (Figs. 1b and S8) in which the reaction mixture
continuously flows through a capillary to the ESI source. Figure 2c
I
]+ as a function of reaction
depicts the ion abundance of [Cu (CH
3
CN)
2
time. This ion chronogram reflects a clear increase in Cu(I)
abundance over the course of the reaction with 4-phenylbutyric acid
1, as compared to a control experiment in which only 1 is excluded.
A similar ion chronogram recording is obtained using an alternative
substrate, 4-methylvaleric acid (Fig. S9). Oxidative cyclization of this
carboxylic acid yields the corresponding lactone, albeit less
efficiently than for a substrate such as 1.
Figure 3a presents the positive ion mode DESI mass spectrum for
the Cu(II)-catalyzed cyclization of 4-phenylbutyric acid 1 (Scheme 1).
The reaction products, lactone 4 and ketone 6, are detected as
6
protonated, sodiated, and potassiated species, as expected. Figures
+
+
S11 and 4c present CID data for [6+H] and [4+H] , respectively. The
peak at m/z 163.0756 can be attributed to either protonated product
[
4+H]+ or carbocation intermediate 3. These two analytes are
isomeric and thus cannot be distinguished on the basis of m/z alone.
Participation of the carbocation 3 as an active intermediate is well
supported by the Hammett Analysis (vide infra). However, in
separate experiments employing ethylbenzene, DESI-MS analysis of
an aliquot of the reaction mixture (2 min) unambiguously identifies
the ion signal of the corresponding benzylic carbocation (Fig. 3b).
These findings establish that carbocation formation can indeed occur
under our reaction conditions and that such an intermediate (see Fig.
S12 also) is detectable on the timescale of the DESI-MS experiment.
2
From the reaction with 4-phenylbutyric acid 1, CID on m/z 163.0756 Fig. 4 CID-MS spectrum of the species at m/z 163.0756 detected from (a) the
establishes that this species undergoes 98% dissociation in the gas reaction mixture at 2 min (Fig. 2a), (b) the reaction mixture at 15 min, (c) the
phase at 15% normalized collision energy (NCE)28, 29 (Fig. 4a). By
contrast, analysis of a pure sample of lactone 4 shows that [4+H] is
protonated 4 (standard) at 35 % normalized collision energy (NCE28, 29), and
+
(d) the protonated 4 (standard) at 15 % NCE. (e) The CID of 3 or [4+H]+
produces the same product ions A and B, whose most plausible structures are
postulated here. The theoretical m/z values of the corresponding species are
presented in red. (f) A breakdown curve of standard [4+H]+ species is also
plotted to show its NCE-dependent dissociation profile.
98% dissociated at 35% NCE (Figs. 4c and 4f). These data suggest that
the ion at m/z 163.0756 (Fig. 3a) is likely a mixture of both benzylic
+
carbocation 3 and protonated lactone [4+H] . Thus, we would expect
+
the analyte at m/z 163.0756 to require less energy than [4+H] to
undergo the same extent of dissociation (Fig. 4) given the intrinsic
reactivity of the benzylic carbocation.30 Notably, when the reaction
mixture is analyzed at a later time point (15 min), the CID on m/z
163.0756 appears similar to that of a pure sample of 4 (Fig. 4).
+
Fig. 5 Plot of log (kAr/kPh) vs. Hammett-Brown substituent constant σ from the
competition experiments between 4-phenylbutyric acid and para-substituted
4
-phenylbuytric acids for the oxidative cyclization reaction.
C. Hammett Analysis
Further support for the proposed intermediacy of a benzylic
carbocation intermediate 3 follows from Hammett analysis data.31
series of competition experiments between 4-phenylbutyric acid and
A
Fig. 3 Positive ion mode DESI mass spectrum for the (a) Cu(II)-catalyzed
oxidative cyclization of 4-phenylbutyric acid (Scheme 1), and (b) Cu(II)-
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para-substituted 4-phenylbutyric acid derivatives shows a clear We have investigated the mechanism of a Cu-catalyzed oxidative
preference for oxidation of electron-rich arene substrates. Fig. 5 cyclization of carboxylic acids using a combination of DESI-MS, online
presents
a
plot of log(kAr/kPh
)
against the Hammett-Brown ESI-MS, tandem mass spectrometry, Hammett analysis, and
substrate probes. This mechanistic study is not based solely on mass
+
substituent constant σ . The linear relationship between log(kAr/kPh
)
+
+
2
and σ yields a ρ value of –0.87 with an R of 0.96. Plots of this data spectrometry but also relies on evidence gathered from NMR
against either the para-substituent constant σ or the Creary radical analysis, which is not subject to possible artifacts from mass
constant σ
· do not give linear correlations (Fig. S13).32 These results spectrometry. The evidence found from our mass spectrometric
p
c
implicate a transition state with significant partial positive charge in analysis is fully consistent with that from the NMR analysis. Although
the rate-determining step, consistent with the formation of it is only possible to disprove a proposed mechanism and not prove
intermediate 3.
it, the weight of all evidence supports a pathway for lactone
formation that initiates through benzylic C–H abstraction by SO •
and proceeds through an intermediate carbocation, which is trapped
by the pendant carboxylic acid (or by H O). An alternative route
Scheme S1) following through the intermediacy of an alkyl sulfate
–
4
D. Mechanistic Analysis Using Substrate Probes
2
(
Reported studies of C–H oxidative lactonization reactions have
posited reaction mechanisms that occur by way of carboxylate
radical generation and subsequent 1,6-H-atom abstraction.7
order to query if such a carboxylate radical is responsible for
formation of 4 and 5, Barton ester 7 was prepared33,34 and heated for
may account for lactone production in the absence of a Cu salt. High
resolution mass spectrometry has allowed us to obtain a rather
complete mechanistic picture of this reaction, including the role of
Cu(II) as an outer-sphere oxidant. Using collision-induced
dissociation, we were able to assign the structures of several of the
observed species, which we believe are part of the catalytic cycle.
Despite remarkable sensitivity, mass spectrometry remains an
under-utilized tool for the analysis of reaction mechanisms.37,38 The
present study highlights the power of mass spectrometric techniques
when combined with more conventional physical organic
experiments for elucidating complex catalytic processes.
-10
In
2
h in BrCCl
thermal conditions to give transient radical species. Analysis of the
reaction mixture of 7 with BrCCl (Fig. S14a) shows the formation of
-membered lactone 9 as a major product (30%) and 6-membered
lactone 8 as a minor constituent (4%) (Scheme 3a). Similarly, when
carboxylic acid 10 is treated with PhI(OAc) and I , a reagent
3
(Scheme 3a). Substrates of this type can fragment under
3
5
2
2
combination reported to promote lactone formation through an
intermediate carboxylate radical35,36, five-membered lactone 9 is
again the major product (44%) (Scheme 3b, Fig. S14b). In sharp
contrast to these two results, the isomeric 6-membered lactone 8 is Experimental
the predominant product under our Cu-catalyzed protocol (Scheme
All chemicals were purchased from Sigma-Aldrich (St. Louis,
MO). HPLC grade solvents were purchased from Fisher Scientific
3c, Fig. S14c), confirming that the mechanism of this latter reaction
does not operate through a carboxylate radical.
(
Nepean, ON, Canada). Reactions were performed using
glassware that was oven-dried. Air- and moisture-sensitive
liquids and solutions were transferred via syringe or stainless
steel cannula. Organic solutions were concentrated under
reduced pressure (~15 Torr) by rotary evaporation. Solvents
were purified by passage under 12 psi through activated
alumina columns. Detailed procedures for synthesis of
substrate probes and reactions for Hammett analysis are
provided in the Supporting Information (SI). DESI-MS studies
were performed on a high-resolution mass spectrometer
(
Thermo Scientific LTQ Orbitrap XL Hybrid Ion Trap-Orbitrap
mass spectrometer) using a homebuilt DESI source. The details
of DESI-MS experiments are described in the SI. The online ESI-
MS experiment for real time monitoring of the Cu(I) species was
performed using the pressurized infusion method originally
described by McIndoe and coworkers.20 See the SI for complete
experimental details.
Acknowledgements
This work was supported by National Science Foundation under
the CCI Center for Selective C–H Functionalization (CHE-
1
205646) and Air Force Office of Scientific Research through
Basic Research Initiative grant (AFOSR FA9550-16-1-0113).
Scheme 3 (a) Fragmentation of Barton ester 7 produces five-membered
lactone 9 as the major product. (b) Formation of 9 predominates under
PhI(OAc)
2
/I
2
conditions. (c) The Cu-catalyzed reaction favors formation of the Notes and references
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| J. Name., 2012, 00, 1-3
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Potassium persulfate can re-oxidize Cu(I) to Cu(II) and, in
this regard, we have found that cyclization of 1 occurs in 50
%
yield using 25 mol % CuCl as a catalyst.
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