Mechanistic insight into the photoredox catalysis of anti-markovnikov alkene hydrofunctionalization reactions

Article abstract of DOI:10.1021/ja506228u

We describe our efforts to understand the key mechanistic aspects of the previously reported alkene hydrofunctionalization reactions using 9-mesityl-10-methylacridinium (Mes-Acr⁺) as a photoredox catalyst. Importantly, we are able to detect alk

Full text of DOI:10.1021/ja506228u

Article
pubs.acs.org/JACS
Mechanistic Insight into the Photoredox Catalysis of Anti-
Markovnikov Alkene Hydrofunctionalization Reactions
Nathan A. Romero and David A. Nicewicz*
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, United States
S
* Supporting Information
ABSTRACT: We describe our efforts to understand the key
mechanistic aspects of the previously reported alkene hydro-
functionalization reactions using 9-mesityl-10-methylacridinium
(Mes-Acr+) as a photoredox catalyst. Importantly, we are able to
detect alkene cation radical intermediates, and confirm that
phenylthiyl radical is capable of oxidizing the persistent acridinyl
radical in a fast process that unites the catalytic activity of the
photoredox and hydrogen atom transfer (HAT) manifolds.
Additionally, we present evidence that diphenyl disulfide ((PhS)2)
operates on a common catalytic cycle with thiophenol (PhSH) by way of photolytic cleaveage of the disulfide bond. Transition
structure analysis of the HAT step using DFT reveals that the activation barrier for H atom donation from PhSH is significantly
lower than 2-phenylmalononitrile (PMN) due to structural reorganization. In the early stages of the reaction, Mes-Acr+ is
observed to engage in off-cycle adduct formation, presumably as buildup of PhS− becomes significant. The kinetic differences
between PhSH and (PhS)2 as HAT catalysts indicate that the proton transfer step may have significant rate limiting influence.
INTRODUCTION
■
Alkenes are one of the most versatile chemical feedstocks and are
key components of innumerable synthetic transformations. A
particularly active field of catalysis utilizes alkene reactants in
hydrofunctionalization reactions such as olefin hydroalkoxyla-
tion and hydroamination reactions.1−3 A vast majority of these
alkene hydrofunctionalization reactions proceed with Markovni-
kov selectivity. In the past decade and a half, there have been
significant efforts by a number of research laboratories to develop
catalytic protocols to access the opposite regioisomeric hydro-
functionalization adducts;4−6 however, a more general catalytic
platform has yet to be identified.
To address this, our laboratory has recently developed a
number of methods for alkene hydrofunctionalization7−12 that
have demonstrated the unique synthetic control accessible
through systems which rely upon the well-defined redox cycles of
a photoredox catalyst.13 These methods display complete anti-
Markovnikov selectivity, employing a catalytic quantity of the
organic dye 9-mesityl-10-methyl acridinium14−29 (Mes-Acr+)30
as a photooxidant along with a cocatalyst proposed to be a redox-
Figure 1. Anti-Markovnikov hydrofunctionalization using Mes-Acr+ as a
photoredox catalyst and PMN, PhSH, or (PhS)2 as viable HAT
catalysts.
active hydrogen atom donor (Figure 1).
One initial report from our group featured the use of Mes-
AcrClO4 as a catalytic photooxidant along with 50−200 mol % 2-
phenylmalononitrile (PMN) as an H atom transfer (HAT)
reagent in a hydroetherification reaction that proceeds with
complete regioselectivity.7 This is particularly noteworthy in the
context of oxidative alkene functionalizations, which often result
in overoxidation and subsequent difunctionalization.31−34
Further optimization of this and related transformations
identified thiophenol (PhSH) and, intriguingly, diphenyl
disulfide ((PhS)2) as competent HAT catalysts, and these
second-generation conditions have allowed for improved yields
and drastically shortened reaction times. The increased efficiency
rendered by arenethiol-based cocatalysts has enabled extension
Received: June 20, 2014
© XXXX American Chemical Society
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Scheme 1. Proposed Mechanism for Anti-Markovnikov Hydroetherification
of this anti-Markovnikov methodology to include a diverse array
of nucleophiles, including carboxylic acids,8 amines,9,10 mineral
acids such as HF, HCl, and MsOH,11 as well as propargylic and
allylic alcohols and acids in a tandem addition-cyclization
sequence.35,36 This demonstration of an efficient and broadly
applicable complement to Markovnikov-selective protocols is a
testament to the value of the alkene cation radical as an
intermediate accessible via single electron transfer (SET).
As these transformations are all believed to proceed by a
similar mechanism, we were eager to establish a more intimate
understanding of the reaction mechanism in order to further
expand the synthetic utility of this reaction class. We viewed the
intramolecular hydroetherification of alkenols as a model
transformation for this study. Our current mechanistic
hypothesis is depicted in Scheme 1, using alkenol hydro-
etherification as a representative example. Following single
electron transfer from the alkene (1) to the electronically excited
Mes-Acr+, the pendant alcohol undergoes intramolecular
nucleophile addition to the alkenyl cation radical (2).
Deprotonation of distonic cation radical 3 and subsequent
hydrogen atom transfer (HAT) furnishes the cyclic ether (5). In
the excited state, Mes-Acr+* is thought to undergo one electron
reduction from the alkene; however, exciplex-mediated cycliza-
tion has been implicated in similar systems.37−43 The HAT
catalyst is believed to operate in a concomitant redox cycle where
HAT generates phenylthiyl radical (PhS·), which serves as a one
electron oxidant for the acridine radical (Mes-Acr·). In this way,
regeneration of ground state Mes-Acr+ and proton transfer to
the resulting thiolate (7) completes a net redox-neutral cycle.
catalytic systems is notoriously challenging. To understand the
interdependent nature of dual catalyst cycles requires an in-depth
inquiry beyond macroscopic study of overall rate and reaction
order. Thus, we sought to conduct kinetic studies on the
elementary steps in the proposed reaction mechanism toward
elucidation of the rate limiting factors. We took a tandem
approach in our study of the mechanism: steady state and
transient absorption and emission spectroscopies were employed
in determining rate constants for steps 1−2 and 5−6, while
computational methods were utilized to offer complementary
insight where spectroscopic study was impracticable (step 4).
RESULTS AND DISCUSSION
■
Oxidative Activity of Excited State Mes-Acr+. To address
the photocatalytic activity of Mes-Acr+, we focused on the use of
transient spectroscopic methods. Although Mes-Acr+ has been a
well-studied, yet contentious chromophore in recent years,
photophysical studies have been mainly directed toward
characterization of its excited state topology (Scheme 2).
Verhoeven et al. report that the first singlet excited state of
Mes-Acr+, localized on the acridinium system (hereafter referred
to as the locally excited singlet state or LES) undergoes rapid
intramolecular charge transfer from acridinium to the mesityl
substituent to form the singlet CT state (CTS).26 LES and CTS
are understood to be in thermal equilibrium, and fluorescence
from both singlet states is measured on the nanosecond time
scale. Moreover, both Fukuzumi and Verhoeven identify a long-
lived transient species that is observed to decay on the order of
microseconds following laser excitation. Much of the debate has
centered on the identity of this microsecond transient species,
suggested by Fukuzumi to possess CT character and an excited
state reduction potential (E*red) of +1.88 V vs SCE,14 while
Verhoeven provides evidence that the species is the locally
excited triplet state with E*red = +1.45 V vs SCE.26 In the absence
of unambiguous evidence that the triplet state is comprised of
two distinct states or that it is singly a CT or LE triplet, we will
simply refer to this long-lived intermediate as the triplet (T),
noting that T may denote CTT (charge transfer triplet) or LET
(locally excited triplet), or both.
The efficacy of the arenethiol-based HAT catalysts has been
red
1/2
attributed in part to the oxidizing nature of PhS· (E = +0.16 V
vs SCE),44 which is expected to be an excellent redox partner for
oxidation of Mes-Acr· (E = −0.55 V vs SCE).11
red
1/2
While many photoredox reactions feature additives that can
greatly improve reaction efficacy through redox activity in
parallel with the photosensitizer, few examples are truly catalytic
with respect to the additive. In contrast, our system constitutes an
interesting example where a redox active H atom donor seems to
be catalytically relevant in both electron and proton transfer
steps. However, mechanistic analysis of such multicomponent
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Scheme 2. Excited State Energy Diagram Adapted from
Verhoeven26 and Fukuzumi15
Table 1. Mes-Acr+ Fluorescence Quenching by Alkenes and
HAT Catalysts
In the course of our investigation, additional questions arose as
to the photophysical nature of the excited state Mes-Acr+ in the
midst of previous reports which draw varying conclusions from
spectroscopic data. A crucial difference in our work was the use of
nonpolar solvents such as 1,2-dichloroethane (DCE) rather than
acetonitrile (MeCN), which was the medium employed in prior
studies. Herein we share new evidence regarding the photo-
physical characteristics of Mes-Acr+ and its ET behavior in
oxidation reactions with alkenes.
a
KSV: Stern−Volmer Constant; error <5% (estimated from multiple
b
trials). k1: bimolecular quenching constant (i.e., kq) where k1 = KSV/
τo; error <6% (error in τo = 0.5%). V vs SCE. Irreversible half wave
c
potential measured by cyclic voltammetry (sweep rate = 100 mV/s).
d
Xyl-Acr+ as the fluorophore.
Fluorescence Quenching: Rate of Primary Electron Transfer
k1. Of the reports where Mes-Acr+ is used as a preparative
photolytic oxidant, the long-lived transient (T) has been
primarily implicated in inquiries of its excited state oxidative
capacity.16,19−21,23,24,45 Although Fukuzumi presents evidence
that T is responsible for oxidation of arenes with moderate
oxidation potentials (e.g., anthracene; Eox = +1.19 vs SCE16), the
oxidation potentials of many substrates employed in our
methodology (e.g., 9−11, Table 1) approach or exceed the
excited state reduction potential of T (E*red), which is estimated
to lie between +1.45 and +1.88 V vs SCE based on the values
reported by Verhoeven and Fukuzumi, respectively. Thus, while
we acknowledged the possibility T could undergo reduction from
more oxidizible alkenes (e.g., 8, 9, and 1b in Table 1 could be
oxidized by CTT), it seemed unlikely that T-mediated oxidation
could be general with respect to all alkenes used in our system, on
the grounds that SET from alkenes 1 to T is endergonic in the
cases where Ep/2 of the alkene exceeds +1.88 V. We considered
the possibility that a viable pathway for oxidation is through SET
to a singlet excited state of Mes-Acr+ (both LES and CTS are
estimated to have excited state reduction potentials exceeding
+2.0 V vs SCE).26 Since both singlet states are fluorescent, we
elected to measure the rate of electron transfer by Stern−Volmer
analysis of Mes-Acr+ fluorescence quenching.46
order rate constant (9.9 0.1 × 109 M−1 s−1) near the diffusion
limit, while even the poorly oxidizable alkenoic acid 11 quenches
Mes-Acr+* with a rate constant of 6.1 0.2 × 108 M−1 s−1.
Significantly, quenching of fluorescence is not observed for
PMN, whereas both PhSH and (PhS)2 are competent quenchers
at rates competitive with the alkenes studied.
Figure 2 shows the quenching constant, k1, plotted against the
thermodynamic driving force ΔGo calculated from one electron
oxidation potentials (Ep/2) of each quencher and the excited state
reduction potential for Mes-Acr+ (E*red(LES) = +2.12 V vs SCE;
Employing Time-Correlated Single Photon Counting
(TCSPC), we measure a fluorescence lifetime of 6.40 0.03
ns for Mes-AcrBF4 in DCE.47 Stern−Volmer analysis was carried
out on the observed quenching of fluorescence lifetime at
increasing concentration of the quenchers given in Table 1.
Anethole (8) quenches Mes-Acr+* most efficiently with a second
Figure 2. Rehm−Weller plot for k1 as determined by Stern−Volmer
analysis of Mes-Acr+ fluorescence quenching where [Mes-Acr+] = 16
μM in DCE. Dashed blue line represents the diffusion limit in DCE (kdif
≈ 9.5 × 109 s−1) estimated using the modified Debye equation.49
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Supporting Information Figure S3). The trend of this Rehm−
Weller plot reveals a plateau in the rate of quenching as k1
approaches the diffusion limit, characteristic of a mechanism of
quenching which proceeds via electron transfer.46,48 Further-
more, these results indicate that alkene oxidation by way of the
singlet excited states of Mes-Acr+ is a feasible pathway for all
substrates examined.
= 9-mesityl-10-methylacridinium tetrafluoroborate),50 which
does not form a CT state in DCE,51 yet is seen to undergo
fluorescence quenching (see Table 1, footnote d). The emission
spectrum of Mes-Acr+ in MeCN shows a strong emission band
centered around 570 nm that confirms the existence of a CTS
state previously observed.52,53 CTS is in equilibrium with LES,
with emission centered around 500 nm (Figure 3a). Variable
temperature emission spectra for Mes-Acr+ reveal a decrease in
CTS fluorescence at elevated temperature as thermal repopula-
tion of the LES becomes more significant, seen also as an increase
in the LES emission component (Figure 3a).26 In DCE, the
emission spectrum for Mes-Acr+ exhibits features of both LES
and CTS states, but differs from the spectrum in MeCN in that
the LES appears more pronounced (Figure 3b). In contrast, Xyl-
Acr+ exhibits a comparatively narrow emission band and lacks
CT fluorescence on the low-energy side as seen in Mes-Acr+
(Figure 3c). Variable temperature studies on Xyl-Acr+ reveal no
change in the shape of fluorescence, and only a decrease in
quantum yield (Supporting Information, Figure S6) is seen as
temperature is increased, leading to the conclusion that the
locally excited singlet state of Xyl-Acr+ is most prominent in
DCE.
Emission Spectroscopy: Role of LES and CTS States in
Oxidative Activity of Mes-Acr+. Although the above fluo-
rescence quenching analysis clarifies that photoinduced electron
transfer can be effected by a singlet state, it does not explicitly
address whether the singlet state responsible for alkene oxidation
is LE or CT in nature. At the wavelength of detection for
fluorescence decay (515 nm), the contribution from CT
emission is expected to be minimal (see Supporting Information,
Figure S3), a finding consistent with the records reported by
Verhoeven.26 Yet, because LES and CTS exist in equilibrium, a
feature emphasized by the variable temperature emission spectra
shown in Figure 3, the particular behavior of each individual
Having confirmed that Xyl-Acr+ exhibits no discernible CT
fluorescence, we compared the rate of fluorescence quenching in
Xyl-Acr+ to that of Mes-Acr+. We discovered that Xyl-Acr+
exhibits an enhanced fluorescence lifetime of 17 0.8 ns, and is
quenched by β-methylstyrene (9) with an even larger rate
constant (k1 = 7.8 0.3 × 109 M−1 s−1) than is Mes-Acr+ (6.9
0.3 × 109 M−1 s−1). Because emission from Xyl-Acr+ occurs
primarily from an LES state, this finding demonstrates that the
CTS is not required for productive quenching. Furthermore,
s
observation of a significantly longer fluorescence lifetime (τLE
)
for Xyl-Acr+ emphasizes that CTS is formed by intramolecular
quenching of LES in Mes-Acr+.26,52,53 That Xyl-Acr+* undergoes
SET from alkenes faster than Mes-Acr+* suggests that the CTS is
an unnecessary photophysical pathway for catalysts of this type.
In fact, formation of CTS may decrease the likelihood of alkene
oxidation by competitive quenching of the longer-lived LES.
While this example does not preclude that the active oxidant in
Mes-Acr+ is the CTS, it does reveal that an intramolecular charge
transfer state is not essential to the oxidative activity of this
acridinium class. We view these results as having important
implications for catalyst development through future modifica-
tions to the currently deployed scaffold.
Laser Flash Photolysis: Detection of Cation Radical
Intermediates. While absorbance spectra for styrenyl cation
radicals have been reported upon generation in a solid matrix,54
key studies by Johnston and Schepp elucidated the solution
phase spectra and kinetic behavior of styrenyl cation radicals
when reacted with various nucleophiles.55−59 In light of this
precedent, we felt confident that we could observe cation radicals
(2) as intermediates upon Laser Flash Photolysis (LFP) with
Figure 3. Variable temperature fluorescence spectra of Mes-Acr+ in (a)
MeCN and (b) DCE and of (c) Xyl-Acr+ in DCE (λex = 450 nm).
Spectra normalized to 530 nm to show decrease in CT and increase in
LE components with increasing temperature.
singlet state is not easily extracted. Although seemingly a trivial
question, we recognized that this detail has important
implications in the design of more powerful photooxidants
based on the mesityl-acridinium template. For example, if the
active oxidant is a CTS state, then the oxidizing power of any
mesityl-acridinium possessing a CTS state is approximately
limited to the redox potential of the mesityl- cation radical.
Alternatively, if the active oxidant is the LES state, then
development of more oxidizing acridinium catalysts should
focus on suppressing intramolecular charge transfer as a
superfluous pathway.
Mes-Acr+, given that the absorption for the cation radical (λmax
=
590−600 nm) was expected to be spectrally separated from the
transient signal for both T (λmax = 500 nm) and Mes-Acr· (λmax
520 nm).
=
Laser flash photolysis was first performed on a 50 μM solution
of Mes-AcrBF4 in DCE in order to determine the transient
absorption spectrum for T and to establish a point of reference
with prior photophysical studies. Although the transient
absorption spectrum for the triplet matches the previously
reported spectra closely, the observed microsecond transient
decays with complicated kinetics (Supporting Information,
To investigate this behavior, we compared the fluorescence
properties of Mes-Acr+ to that of the 9-xylyl analogue (Xyl-Acr+
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Figures S10 and S11). The kinetic model used to achieve a best fit
to the signal decay at 480 nm contained a first-order exponential
(τT = 36 μs) and a second-order term (τT = 0.25 μs). The lifetime
of the first order decay constant is similar to that calculated by
Verhoeven in MeCN, while a second-order decay component
has been by observed by Fukuzumi, who determined that
bimolecular decay results from formation of a T···T dimer.22
When laser flash photolysis is performed on Mes-Acr+ with
anethole (8), the anethole cation radical 8+· is detected by a new
feature at 600 nm in the transient absorption spectrum after laser
excitation of Mes-Acr+ at 430 nm (Figure 4a). The absorption
corresponding absorbance for free alkenol 1b is observed with a
maximum at the same wavelength, though this signal is
significantly lessened at the 20 ns time delay.
Comparison between the lifetime of each cation radical 1b and
9 allows for estimation of the rate of cyclization (k2). Single
wavelength kinetic decay (Supporting Information, Figures
S12−14b) of the signal at 590 nm for TBDMS-protected
alkenol 14 persists well into the microsecond regime (τ = 5.9 μs),
while a signal for cation radical 1b cannot be detected at 590 nm
at a time delay of 40 ns. We interpret this comparison to signify
consumption of the styrenyl cation radical by nucleophilic
addition of the tethered oxygen-nucleophile in 1b. On the basis
of the observation that cation radical 1b cannot be detected
beyond 40 ns, the first-order rate constant for intramolecular
nucleophile addition is estimated to have an approximate lower
limit of 2.5 × 107 s−1 for this class of alkenols.61
Triplet or Singlet? While quenching of singlet state Mes-
Acr+* is observed for all substrates in Table 1 with large
bimolecular rate constants k1, we noted that the efficiency of
fluorescence quenching is generally low due to the short
fluorescence lifetime of 6.4 ns. For example, when alkene 9 is
the quencher, roughly 20% of fluorescence is quenched at a
concentration of [9] = 6.0 mM (Supporting Information, Figure
S9). In combination with a poor quantum yield of fluorescence
(ΦF = 8%; Supporting Information, Figure S7), this corresponds
to an oxidation quantum yield of roughly 1.6% at this
concentration. Under the conditions where cation radical 9+·
was detected by transient absorption spectroscopy (Figure 4b;
[9] = 6.0 mM, [Mes-AcrBF4] = 0.050 mM), the estimated
maximum concentration of both 9+· and Mes-Acr· is 0.8 μM
following quenching of the singlet. However, based on the
absorption for Mes-Acr· at 20 ns (Supporting Information,
Figure S12), the actual concentration of Mes-Acr· (and 9+·) is
2.4 μM. Thus, regarding singlet Mes-Acr+* as the sole oxidant is
inconsistent with the ca. 3-fold greater formation of 9+· than is
predicted. This disparity leads us to believe that the singlet
manifold of Mes-Acr+ is not the exclusive pathway for oxidation in
the case of 9.
As previously noted, the triplet state T may be sufficiently
oxidizing to undergo reduction by 9 (and other alkenes with less
positive oxidation potentials). Indeed, given that the singlet
excited states are insufficient to explain the degree of cation
radical formation in Figure 4b, it is our conclusion that 9 can be
oxidized by both the singlet and triplet excited states of Mes-
Acr+. However, in our attempt to address the dynamics of alkene
oxidation, we discovered that Mes-Acr+ forms ground state
donor−acceptor complexes with alkenes (eq 1; see also
Supporting Information, Figures S23 and S24), resulting in
some degree of preassociation of the quencher with Mes-Acr+.
For the portion of Mes-Acr+ complexed with the alkene as [Mes-
Acr···9]+, excitation of the acridinium chromophore to LES can
be followed by rapid electron transfer, likely faster than diffusion
or excited state deactivation by fluorescence or intersystem
crossing.62 Thus, if the efficiency of this electron transfer is
assumed to be unity, the concentration of 9+· generated from
irradiation of [Mes-Acr···9]+ can be estimated as the
concentration of the complex [Mes-Acr···9]+ upon determi-
Figure 4. Detection of alkenyl cation radicals by Laser Flash Photolysis
where [Mes-Acr+] = 50 μM in DCE. (a) The differential absorption
spectrum for 8+· (yellow) obtained by subtraction of Mes-Acr· from the
transient absorption spectrum at 500 ns. (b) The differential absorbance
spectra for cation radicals 1b+·, 14+·, and 9+· (orange, red and blue,
respectively) obtained by subtraction of Mes-Acr· and LET from the
transient absorption spectrum recorded 20 ns after the laser pulse. OD =
optical density, or absorbance.
spectrum for the anethole cation radical is calculated by
subtraction of the contribution from Mes-Acr·, which was
determined by spectroelectrochemical analysis (Supporting
Information, Figures S1 and S10). The anethole cation radical
8+· possesses a maximum near 600 nm, and is in close agreement
with the spectrum reported previously.55 Styrenyl cation radicals
were also detected at a 20 ns time delay for β-methylstyrene (9),
alkenol 1b and TBDMS-protected alkenol 14 using the same
method of Laser Flash Photolysis (Figure 4b; see Supporting
Information Figures S12−14a for curve fitting procedure).
Centered roughly at 590 nm, these spectra likewise match the
absorption spectra for β-alkyl cation radicals reported in the
literature.54,60 The difference spectrum for protected alkenol
cation radical 14 exhibits a maximum at 590 nm, and a
nation of the equilibrium constant KDA
.
Mes‐Acr+ + 9 ⇌ [Mes‐Acr⋯9]+
(1)
Using the Benesi−Hildebrands method,63 we estimate the
equilibrium constant KDA to be 0.96 M−1. When applied to the
conditions used in the spectroscopic analysis of Figure 4b, an
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additional 0.3 μM 9+· can be accounted for as originating from a
donor−acceptor complex. In combination with the 0.8 μM
generated by diffusion-limited quenching of the singlet state, we
estimate that singlet Mes-Acr+ is responsible for roughly 45%
(1.1 μM) of 9+· shown in Figure 4b, while the other 55% is most
likely formed by reductive quenching of a triplet T. In this case,
ET to LET would be disfavored, so the probable identity of T is
CTT according to the assignment by Fukuzumi (E*red = +1.88 V
vs SCE for CTT).
Scheme 3. Disulfide Crossover Experiment Probing
Mechanism of Disulfide Homolysis
Importantly, we note that the preparative reactions are carried
out at drastically higher concentrations than those used in
spectroscopic studies (see Scheme 1). At higher concentrations,
the proportion of [Mes-Acr···9]+ approaches that of free Mes-
Acr+, which has the effect of increasing the efficiency of 9+·
formation, even though the solutions are optically dense (i.e.,
Absorbance450 nm ≫ 2.0). Thus, while increasing the overall
concentration does not increase the number of photons
absorbed, it may increase the efficiency of oxidative quenching
due to increased donor−acceptor complexation. Interestingly,
the photochemical quantum yield of reaction (ΦR) was
determined to be ∼1.7% at full conversion for the reaction of
1b with 0.1 equiv PhSH as the H atom donor.64 At earlier time
points (t < 20 min), ΦR is slightly higher (∼2.3%), consistent
with additional efficiency conferred by complexation when the
substrate concentration is highest. Notably, the overall quantum
efficiency of the reaction is compatible with the degree of
fluorescence quenching observed for this substrate, supporting
our mechanistic hypothesis for alkenes with high oxidation
potentials.
Disulfide Exchange Experiments. Our lab has reported
the use of diphenyl disulfide (PhS)2 as a HAT cocatalyst in place
of PhSH. Although initially puzzling, we proposed that the
activity of (PhS)2 could be understood to operate on the same
mechanistic landscape as PhSH if either PhS· or PhS− was
generated in situ from the disulfide (step 6). In this respect, it is
important to note that (PhS)2 can be isolated as a minor
byproduct when PhSH is used as an HAT catalyst. Conversely,
significant amounts of PhSH are detected in reactions employing
(PhS)2, implicating a possible equilibrium between the two
species. Thus, we were eager to understand how the activity of
the (PhS)2 and PhSH might be mechanistically related.
Under conditions directly analogous to the preparative
reaction conditions (i.e., total disulfide concentration = 25
mM), the rate of exchange was monitored by GC−MS. Under
irradiation of an equimolar solution of (PhS)2, (12), (4-MePhS)2
(15) and Mes-AcrBF4 (13 mM in each) with a blue LED lamp
(Condition A), we observed disulfide crossover, with 16 formed
in a ratio of 2:1:1 with respect to the symmetrical disulfides after
approximately 120 min (Supporting Information, Figure S20).
We were surprised to find that irradiation in the absence of Mes-
AcrBF4 (Condition B) gave rise to disulfide 16, with apparent
zero-order behavior until the equilibrium disulfide amounts were
reached. Dark control experiments show no exchange within the
analytical limits of the experiment at both room temperature and
heating to 40 °C. Although we are unaware of any precedent
where an aryl disulfide was cleaved with such low energy
radiation, the spectral overlap between the disulfide solution and
the emission output of the LED lamp is evident (Supporting
Information, Figure S22).
These results indicate that the aryl disulfide bond can be
homolytically cleaved directly in a light-dependent reaction,
consistent with the zero-order behavior seen when Mes-Acr+ is
absent. Presumably, the mechanism of disulfide exchange is
different in the presence of the Mes-Acr+, as the mixed disulfide
16 forms with more complicated kinetics under Condition A.
Considering that (PhS)2 quenches Mes-Acr+* fluorescence
+
(Table 1), oxidation of (PhS)2 to the cation radical (PhS)2 ·
followed by sulfur−sulfur cleavage seems like a plausible
mechanistic step. Additionally, triplet sensitization and sub-
sequent homolysis is also possible. However, as it relates to the
preparative reactions, we observe that Mes-Acr+ bleaches after
approximately 3 min (vide infra) before the disulfide undergoes
significant exchange. Thus, because Mes-Acr+ is not present in a
photoactive form for a majority of the reaction, direct photolytic
homolysis is the most mechanistically relevant possibility.
Laser Flash Photolysis: Direct Observation and Rate of
Mes-Acr· Oxidation (k5) by PhS·. We viewed the photo-
oxidant regeneration step 5 as vital in understanding the efficacy
of the HAT catalyst and how the rate of this step affects the
overall kinetics. Although there is literature precedent suggesting
that the phenyl-thiyl radical PhS· would be capable of oxidizing
the crucial intermediate Mes-Acr·,44,74 a fast dimerization
process (Step 6) might be expected to compete with electron
transfer (Step 5). Having characterized Mes-Acr· in isolation by
spectroelectrochemical methods, we were optimistic that we
could take advantage of the persistence of this acridinyl radical in
a kinetic study of the regeneration event described by the rate
constant k5. We anticipated that laser-induced generation of PhS·
by LFP44,71,75−79 would allow us to monitor the oxidation of
Mes-Acr· by transient absorption spectroscopy. To this end, we
successfully prepared Mes-Acr· by chemical reduction with
Given the sulfur−sulfur bond dissociation energy of (PhS)2,65
we reasoned that a homolytic mechanism was more likely than
reductive cleavage in a redox system which lacks a strong
reductant, given the highly negative reduction potential of
(PhS)2 (Ep = −1.65 V vs Ag/AgCl).66,67 Both oxidative68−70 and
triplet-sensitized71 mechanisms of S−S cleavage have been
proposed for aryl- and alkyl-disulfides. While direct homolytic
mechanisms are well-known in the literature,72 we were unaware
of any previous report where an aryl disulfide is cleaved by
irradiation with visible light. In order to evaluate the possibility of
homolytic disulfide cleavage, we designed a crossover experiment
with disulfide (4-MePhS)2 (15) as a “labeled” analogue to
(PhS)2.71 Disulfide 15 was selected as a suitable “labeled”
phenyl-disulfide as it affords a tractable difference in chromato-
graphic mobility and mass-spectral signature without possessing
a significant difference in dissociative behavior.65,73 In the event
of homolysis, crossover of the arylthiyl units would be observed
(whether by radical−radical recombination or by a homolytic
substitution mechanism), which could be detected by gas
chromatography as the symmetrical disulfides 12 and 15
exchange to form mixed disulfide 16 (Scheme 3).
F
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Scheme 4. Chemical Reduction of Mes-Acr+ and Reoxidation via PhS· by Laser Flash Photolysis of (PhS)2
stoichiometric CoCp2 (Scheme 4).80−82 The acridinyl radical
Mes-Acr· was indefinitely persistent at room temperature under
dark, anaerobic conditions (Supporting Information, Figure
S16).
To generate PhS· by photolysis of (PhS)2 while minimizing
excitation of Mes-Acr·, we selected a laser excitation wavelength
of λex = 410 nm, where Mes-Acr· absorption is at a minimum. We
confirmed that PhS· could be generated under these conditions,
decaying by second order kinetics (2kr = 2.7 × 106 M−1 s−1,
Supporting Information Figure S18a)78 independent of pump
wavelength. When Mes-Acr· was prepared in a solution
containing (PhS)2 and subjected to laser photolysis at 410 nm,
a bleach in the signal at 520 nm was observed concomitant with a
recovery of the Mes-Acr+ absorption at 445 nm. The bleach at
520 nm can be fit to a monoexponential curve with an observed
rate constant k = 2.5
0.4 × 105 s−1 (Figure 5a). At this
wavelength, absorbance due to PhS· is insignificant. However,
the kinetics of Mes-Acr+ appearance at 445 nm are more complex
due to the absorption of PhS· in this wavelength range (ε ≈ 2000
M−1 cm−1 at 460 nm).83
As shown in Figure 5a, the transient signal at 445 nm is a
combination of Mes-Acr+ growth and PhS· decay84 from an
initial maximum of ∼2.5 mΔOD (OD = optical density, or
absorbance). After taking PhS· decay into account,75,85−88
a
single exponential fit describes the growth of Mes-Acr+ with an
observed rate constant k = 2.5 × 105 s−1, confirming that Mes-
Acr+ grows in at the same rate that Mes-Acr· disappears. To a
reasonable approximation, the concentration of Mes-Acr+ at t <
50 μs matches the amount of Mes-Acr· consumed, as determined
from the ΔOD at 445 and 520 nm, respectively. Comparison of
the transient spectrum at 30 μs with the predicted differential
absorption spectrum (i.e., the opposite of the Mes-Acr· transient
difference spectrum) yields strong similarity, further validating a
direct conversion of Mes-Acr· to Mes-Acr+. In control
experiments excluding (PhS)2, we are unable to observe any
significant transient signal exceeding baseline absorbance
(Supporting Information, Figure S17), supporting our inter-
pretation that the radical PhS· is an oxidant for Mes-Acr·.89
To obtain a second-order rate constant k5, a pseudo-first-order
kinetic study90 was conducted. The low photolytic yield of PhS·
with laser photolysis at 410 nm precluded consistent generation
of the thiyl radical over a range of Mes-Acr· concentrations. LFP
was instead performed with 355 nm laser excitation.77 At this
wavelength, photolysis of (PhS)2 is consistent over a range of
Mes-Acr· concentration, and the concentration of PhS·
generated in a 3 mM solution of (PhS)2 is estimated to be less
than 6 μM. Varying the concentration of Mes-Acr· under
pseudo-first-order conditions results in a linear increase in the
rate of oxidation, measured as the rate of disappearance of the
signal at 520 nm (Figure 6a). The second order rate constant k5 is
taken as the slope of the line fit to the pseudo-first order plot in
Figure 6b, and is calculated at 3.1 0.5 × 109 M−1 s−1. The
Figure 5. Direct observation of Mes-Acr· turnover by PhS· generated
during LFP with excitation at 410 nm. (a) Bleach in absorbance at 520
nm (blue) corresponding to consumption of Mes-Acr·; fit to a
monoexponential curve (dashed red) with an observed rate constant of
2.5
0.4 × 105 s−1; growth of the signal at 445 nm (light blue)
corresponds to appearance of Mes-Acr+ and decay of PhS· and is fit to a
curve (dashed yellow) consisting of a single exponential describing Mes-
Acr+ appearance (dashed red) and mixed-order decay of PhS· (dashed
black). (b) Transient difference spectrum at a 30 μs time delay. The
dashed red trace is the predicted difference spectrum for 1:1 conversion
of Mes-Acr· to Mes-Acr+.
magnitude of k5 is on the same order as k1 (kET), consistent with
the expectation that ET between Mes-Acr· and PhS· is
significantly exothermic.91 Control experiments under condi-
tions where Mes-Acr+ and (PhS)2 are respectively excluded
show no significant bleaching at 520 nm. We believe this
experiment offers further evidence in support of our mechanistic
proposal that Mes-Acr· is oxidized by PhS· in a key step that
unites the cooperative activity of the photoredox and HAT
cocatalysts.
Computational Results: Rate of HAT (k4). We viewed
steps 3 and 4 (proton transfer and HAT, respectively) more
difficult to address experimentally. Thus, we turned to
computational methods for estimating the rates of these steps.
Although Arnold disclosed an ab initio study on the regioselective
G
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likely reflecting the requirements for structural reorganization in
PMN. This difference in activation barrier corresponds to a ca.
104-fold difference in rate, where HAT with PhSH is estimated to
proceed with a rate constant of approximately 6.2 × 105 M−1 s−1
at 298 K (cf. k4 with PMN computed at 5.0 × 101 M−1 s−1). The
calculated rate constant k4 is in good agreement with
experimentally determined rates for HAT between PhSH and
alkyl and benzylic radicals (e.g., k = 3.13 × 105 for PhCH2· in
hexane).108,109 Moreover, the drastic lowering in activation
energy for HAT with PhSH over PMN is likely to contribute to
the enhanced efficacy of PhSH as an HAT cocatalyst.
Figure 6. Determination of the second-order rate constant k5 describing
oxidation of Mes-Acr· to Mes-Acr+ by PhS·. (a) Normalized
monoexponential fitting for Mes-Acr· disappearance at 520 nm where
[Mes-Acr·] ranges from 25 to 250 μM. (b) The observed rate constants
for Mes-Acr· disappearance plotted against [Mes-Acr·]; the second
order rate constant k5 is determined from the slope of the linear
regression as 3.1 0.5 × 109 M−1 s−1 (error estimated from regression
statistics).
addition of methanol to alkene cation radicals,92 we wanted to
model the intramolecular reaction using modern DFT methods.
We recognized that a number of post-Hartree−Fock method-
ologies suffer from systematic errors in describing open shell
systems where charge and spin localization are required, as in a
cation radical.93−95 For this reason, we could not obtain
meaningful information from inquiries into cation radicals 3
using the (U)B3LYP methodology.31,96−101 Thus, we focused
our attention on step 4 (HAT) with calculations performed at the
UB3LYP/6-311+G(d) level of theory.102−107
The lowest energy configuration of radical 4/PhSH (structure
17) following deprotonation is shown in Figure 7 to possess a
hydrogen-bonding interaction between O and S−H groups.
Radical 4 and PMN possess a similar H-bonded conformation
(structure 19). In both cases, this structural configuration lies on
the reaction coordinate for suprafacial HAT. The lowest energy
transition structures computed for PhSH and PMN both exhibit
geometries where the phenyl ring of the cocatalyst is
perpendicular to the bond undergoing cleavage in the transition
state (structures 18‡ and 20‡). For both H atom donors, this
requires ca. 90 deg rotation of the dihedral angle, which, owing to
double −CN substitution in PMN, is less energetically costly for
PhSH. Additionally, the benzylic carbon atom of PMN is seen to
undergo a change in hybridization in the transition state. The
calculated activation free energy barrier (ΔG‡) for HAT is 9.5
kcal mol−1 for PhSH, as compared with 15.1 kcal mol−1 for PMN,
Figure 7. Computed structures for HAT between PhSH (17, 18‡) or
PMN (19, 20‡) and benzylic radical 4. Structures 17 and 19 are local
minima; structures 18‡ and 20‡ are transition states for HAT.
Preparative Scale Reaction Kinetics. The kinetic studies
reported above predict fast alkene oxidation and intramolecular
O-addition with catalyst turnover occurring on the nanosecond
time scale. Furthermore, computational analysis predicts HAT to
be relatively fast when PhSH is the H atom donor. Yet, the rate to
completion of the preparative reaction is empirically slow.
Therefore, we aimed to identify a resting state in both catalytic
cycles in order to understand the key rate limiting factors.
1. HAT Catalyst Resting State and Substrate Conversion:
Gas Chromatography (GC). Kinetic analysis of alkenol 1b
conversion (as shown in Figure 8) was conducted by sampling
the mixture over the course of the reaction. A side-by-side
comparison of PhSH and (PhS)2 as HAT catalysts reveals a
marked difference between the activity of PhSH and (PhS)2.
When the HAT catalyst is PhSH (Condition C), alkenol
consumption and ether formation are approximately linear until
reaction completion. In contrast, the overall rate of ether
formation is significantly faster when (PhS)2 is employed
(Condition D), and the reaction goes to completion after 4 h,
but only after an induction period where the rate of product
formation is somewhat delayed. Notably, the yield of ether 5b at
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Figure 8. Reaction progress for hydroetherification of alkenol 1b under conditions C or D (scale: approximately 0.5 mmol alkenol 1b). (a and b)
Conversion of 1b to 5b (PhSH and (PhS)2 also shown in units of mol % relative to [1b]o) as determined by gas chromatography with dodecane as an
internal standard. (c and d) Monitoring Mes-Acr+/Mes-Acr· during reaction by UV−vis. Highlighted spectral traces: red = 0 min, orange = 1 min,
yellow = 2 min, cyan = 3 min. Time traces of absorbance at 450 and 520 nm are highlighted in blue. Absorbance cut off above 1.75 absorbance units.
full conversion is roughly 10% less (91% yield) for the reaction
with (PhS)2 than with PhSH (essentially quantitative yield),
possibly reflecting a bias toward reduction of the disulfide bond
by 2H+/2e−.
Condition C (HAT catalyst = PhSH), absorption at both 450
and 520 nm begin to return at ca. 6 h, corresponding to
reappearance of Mes-Acr+ and Mes-Acr·, respectively. For
Condition D (HAT catalyst = (PhS)2), both absorptions
increase from baseline after only 1 h, reaching significant levels
after ca. 4 h. Although the absorptions for both Mes-Acr+ and
Mes-Acr· disappear early in the reaction, the kinetics in Figure 8
clearly indicate steady product formation during this period,
verifying that the catalytic activity is not depleted.
Given that Mes-AcrBF4 can be isolated after the reaction is
complete, we considered the possibility that the period when
Mes-Acr+/Mes-Acr· absorbance is not detectable represents
formation of a reversible adduct110−113 as a resting state. Shown
in Scheme 5, we postulated that the PhS− could add to Mes-Acr+
following oxidation of Mes-Acr·. If this addition is reversible, a
steady state concentration of Mes-Acr+ is available for immediate
excitation and photoinduced ET with alkene 1b. In support of
this hypothesis, we observe reappearance of the Mes-Acr+
Monitoring the relative quantities of PhSH and (PhS)2 as the
reactions proceed lends important insight into the resting state of
the HAT catalyst. Under Condition C (Figure 8a), the amount of
PhSH present (yellow) changes very little, and is maintained at
approximately 17−19 mol % when PhSH is the HAT catalyst. In
these cases, the remaining molar balance can be accounted for as
(PhS)2 (orange), formed in roughly 1 mol % over the course of
the reaction. In contrast, when 10 mol % (PhS)2 is employed, the
disulfide is progressively converted to PhSH as the reaction goes
to completion (Figure 8b, yellow/orange traces). This
conversion is correlated with the formation of ether 5b, and in
both reactions (Conditions C and D), the final amounts of PhSH
and (PhS)2 are ca. 18 mol % and 1 mol % respectively, further
evidence that (PhS)2 and PhSH share a common catalytic role.
2. Mes-Acr Resting State: UV−Vis Time Evolution. When
Mes-Acr+ (13 mM) with alkenol 1b (250 mM) and either PhSH
(Condition C) or (PhS)2 (Condition D) were continuously
irradiated in a cuvette with 450 nm LEDs while monitored by
UV−vis, the absorption for Mes-Acr· quickly grew in (λmax = 520
nm), but then decayed sharply, disappearing entirely by t = 4 min
when PhSH is the HAT catalyst (Condition C) or t = 3 min
when (PhS)2 is used (Condition D). Under the preparative
conditions, the absorbance for 13 mM Mes-Acr+ is too intense to
be measured; however, this absorption band (λ = 400−460 nm)
likewise disappeared after only 3 min of irradiation. In the case of
Scheme 5. Proposed Adduct Formation between PhS− and
Mes-Acr+
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absorption in the dark when irradiation is ceased after reaching
depletion of Mes-Acr+/Mes-Acr· absorbance under Conditions
C (Figure 9). Absorbance for Mes-Acr+ at 450 nm returns slowly,
CONCLUSION
■
Through the use of transient and steady state spectroscopic
techniques, we have addressed the rate constants describing the
elementary steps in our proposed mechanism for anti-
Markovnikov alkene hydrofunctionalization, using an alkenol
as an intramolecular model system. Detection of alkene cation
radical intermediates validates that the mechanism proceeds by
electron transfer rather than by formation of an exciplex between
the catalyst an alkene as has been postulated in prior alkene
hydrofunctionalization reactions involving photocatalysts. We
found that all alkenes examined are oxidized on the nanosecond
time scale by a singlet Mes-Acr+* state, while alkenes with
moderate oxidation potentials can also be oxidized by the triplet
state. Moreover, direct observation of Mes-Acr· turnover by PhS·
supports the intermediacy of a key step which unites the parallel
catalytic cycles of photoredox and HAT catalysts. Exchange
studies reveal that disulfides are competent HAT catalysts which
operate on the same cycle as the corresponding thiophenols by
way of photolytic thiyl radical generation. We estimate the rate of
HAT to be fast, with PhSH reacting at a rate ca. 104 times faster
than PMN. Given that the rate constants addressed explicitly
herein are estimated to be fast, our working hypothesis is that
deprotonation may be rate limiting in some capacity.
Observation that Mes-Acr+ is engaged in an off-cycle equilibrium
is consistent with buildup of thiolate PhS− and further suggests
the possibility that reversible adduct formation might have
additional rate limiting influence. Many of the insights gained
through this mechanistic analysis can be applied to other anti-
Markovnikov hydrofunctionalizations reported by our group,
although reaction specific considerations are the subject of an
ongoing research program, along with current efforts toward
photoredox catalyst development based on the acridinium
scaffold.
Figure 9. Recovery of Mes-Acr+ absorbance at 450 nm under dark
conditions after bleaching at t = 5 min.
validating that Mes-Acr+ is catalytically relevant even after
apparent bleaching. Similar behavior is observed when 0.1 eq.
(PhS)2 is employed (Condition D); however, Mes-Acr+
reappears faster in this case (Figure 9). In both experiments,
absorbance at 520 nm remains at baseline, indicating that Mes-
Acr· is not formed. Attempts to observe a thiolate-acridinium
adduct by 1H NMR or to isolate an adduct (e.g., 21) synthetically
were unsuccessful, but efforts to characterize the resting state
behavior of the Mes-Acr+ manifold are ongoing.
DISCUSSION: RATE LIMITING FACTORS
■
ASSOCIATED CONTENT
We believe the difference in overall reaction rate when
comparing PhSH and (PhS)2 is consistent with deprotonation
(step 3, Scheme 1) having rate limiting influence. Because
(PhS)2 does not depend on HAT for generation of thiyl radical
PhS· in the early stages of reaction (i.e., before ca. 50%
conversion), fast oxidation of Mes-Acr· results in a higher steady
state concentration of PhS−, leading to a higher rate of
deprotonation. On the other hand, PhSH is required to
encounter radical 4 before generating PhS· at all points in the
reaction. Although HAT is expected to be fast, concentration of
radical 4 is in turn limited by the rate of deprotonation, to the
effect of decreased PhS− concentration, and thus, a slower overall
rate.
■
S
* Supporting Information
Experimental procedures and spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
nicewicz@unc.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
One consequence of the overlap between the catalytic cycles of
Mes-Acr+ and HAT reagent is that the effect of a single rate
limiting step could be amplified by preventing formation of
intermediates crucial in the turnover of either cycle. Thus, the
rate limiting step may change as the reaction progresses. If proton
transfer is rate limiting as we suggest, the expected buildup of
PhS− is consistent with the observation that Mes-Acr+ is
occupied in an off-cycle intermediate. We acknowledge the
possibility that such a step might also result in a rate limiting
equilibrium. Pending current investigations into the rate of
deprotonation (k4) and the putative equilibrium of the Mes-Acr+
catalyst and an as yet unidentified adduct, it is plausible that both
steps have a combined limiting effect on the overall reaction rate
when PhSH or (PhS)2 is employed as the hydrogen-atom donor
catalyst.
A portion of this work was performed in the UNC-EFRC
Instrumentation Facility established by the UNC EFRC (Center
for Solar Fuels, an Energy Frontier Research Center funded by
the U.S. Department of Energy, Office of Science, Office of Basic
Energy Sciences under Award Number DE-SC0001011). This
work was also supported by Award No. R01 GM098340 from the
National Institute of General Medical Sciences. N.A.R. also
acknowledges an NSF Predoctoral Fellowship. We are grateful to
Dr. M. Kyle Brennaman, Prof. Alex Miller, and Prof. Jillian
Dempsey for insightful conversations and assistance with
spectroscopic measurements.
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L
dx.doi.org/10.1021/ja506228u | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX