Mechanistic Investigation and Optimization of Photoredox Anti-Markovnikov Hydroamination

Article abstract of DOI:10.1021/jacs.1c03644

The reaction mechanism and the origin of the selectivity for the photocatalytic intermolecular anti-Markovnikov hydroamination of unactivated alkenes with primary amines to furnish secondary amines have been revealed by time-resolved laser kinetics measur

Full text of DOI:10.1021/jacs.1c03644

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Mechanistic Investigation and Optimization of Photoredox Anti-
Markovnikov Hydroamination
Yangzhong Qin, Qilei Zhu, Rui Sun, Jacob M. Ganley, Robert R. Knowles,* and Daniel G. Nocera*
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ABSTRACT: The reaction mechanism and the origin of the selectivity for the
photocatalytic intermolecular anti-Markovnikov hydroamination of unactivated alkenes
with primary amines to furnish secondary amines have been revealed by time-resolved
laser kinetics measurements of the key reaction intermediates. We show that back-
electron transfer (BET) between the photogenerated aminium radical cation (ARC) and
reduced photocatalyst complex (Ir(II)) is nearly absent due to rapid deprotonation of the
ARC on the sub-100 ns time scale. The selectivity for primary amine alkylation is derived
from the faster addition of the primary ARCs (as compared to secondary ARCs) to
alkenes. The turnover of the photocatalyst occurs via the reaction between Ir(II) and a thiyl radical; the in situ formation of an off-
cycle disulfide from thiyl radicals suppresses this turnover, diminishing the efficiency of the reaction. With these detailed mechanistic
insights, the turnover of the photocatalyst has been optimized, resulting in a >10-fold improvement in the quantum yield. These
improvements enabled the development of a scalable flow protocol, demonstrating a potential strategy for practical applications with
improved energy efficiency and cost-effectiveness.
with aminium radical cations (ARCs). ARCs add to the alkenes
in an anti-Markovnikov fashion to form product radicals27 that
then react with thiols through hydrogen atom transfer (HAT)
to deliver the final product (Scheme 1).28 The utility of this
methodology has been demonstrated for the formation of
tertiary amine products from their respective secondary amines
with IrA (IrA = [Ir(III)(dF(Me)ppy)2(dtbbpy)]PF6 and
INTRODUCTION
■
Light-driven photoredox catalysis has emerged as a powerful
strategy to perform organic synthesis under mild conditions by
taking advantage of photons to generate highly reactive
intermediates that are otherwise difficult to access with
traditional methods.1−7 Photoredox reactions, however, may
confront back-reactions and undesired side-reactions as a result
of the high reactivity of the photogenerated intermediates,8−11
leading to a diminished energy efficiency.10,11 These back-
reactions must be overcome to enable the sustainable
adaptation of photoredox methods, which includes the use of
solar light as an energy input.12−14 Accordingly, photoredox
catalysis performed under batch reaction conditions may
require intense light sources (e.g., high-power LED lamps) and
extended reaction times (e.g., days) to achieve appreciable
yields of product.2−7 Therefore, flow setups are usually
preferred15−17 to achieve high throughput for photocatalysis.
As has been shown recently by our groups9−11,18,19 and
others,20−24 detailed mechanistic studies provide critical
insight for improving energy efficiency and the scope of
photocatalysis methods. The formation of C−N bonds via
intramolecular hydroamidation photocatalysis has particularly
benefitted from the detection of reactive intermediates and an
understanding of their chemistry.11 Recently C−N bond
formation has been achieved under mild photocatalytic
conditions by hydroamination reactions between alkylamines
and unactivated alkenes,25,26 demonstrating an atom-economic
strategy to furnish both secondary and tertiary amine products.
These photocatalytic hydroamination reactions have relied on
photoexcited iridium complexes (Ir(III)) to oxidize amines,
generating reduced photocatalyst complexes (Ir(II)) along
Scheme 1. Previously Proposed Mechanism for the
Intermolecular Hydroamination of Unactivated Alkenes
with Primary or Secondary Amines under Photoredox
Conditions
Received: April 7, 2021
Published: June 30, 2021
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10232

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S1A). The flow experiments were performed by using a custom flow
setup with two Kessil lamps illuminating the reaction tubing from
both sides (Figure S1B). UV−vis absorption spectra were obtained by
using a Cary 5000 spectrophotometer (Agilent). NMR spectra were
obtained by using a Bruker Avance Neo (400 MHz) spectrometer.
The product yields were determined by gas chromatography (GC,
Agilent 5975C) with dibenzyl ether as the internal standard. Isolated
yields were obtained for large-scale reactions (section M, Supporting
Information).
dtbbpy = 4,4′-di-tert-butyl-2,2′-dipyridyl) as the photocatalyst
(Figure 1C).25 Strikingly, when the analogous reactions are
Quenching Studies. Steady-state emission spectra were meas-
ured by using a QM4 fluorometer (Photon Technology Interna-
tional). Steady-state quenching studies were performed by using the
averaged steady-state emission intensity (I) ranging from 550 to 600
nm, with excitation at 400 nm. Dynamic quenching studies were
based on lifetimes (τ) measured by the emission decay at 600 nm
with pulsed excitation at 355 nm. The Stern−Volmer quenching
constant (Ksv) and quenching rate constant (kq) were obtained by
using the relations I0/I or τ0/τ = 1 + Ksv × [quencher] and kq = Ksv/
τ0, where I0 and τ0 are the emission intensity and emission lifetime,
respectively, for a sample in the absence of quencher.
Electrochemical and Spectroelectrochemical Studies. All
electrochemical studies were performed by using a Model 760D
potentiostat from CH Instruments. Cyclic voltammetry (CV)
measurements were undertaken by using a glassy carbon working
electrode, Pt wire counter electrode, and Ag+/Ag reference electrode
on solutions purged with N2. All CVs were referenced to the
ferrocenium/ferrocene (Fc+/Fc) redox couple measured under the
same conditions. Spectroelectrochemical measurements were per-
formed in a N2-filled glovebox and under similar conditions as above,
except that a thin Pt mesh working electrode was placed into a 0.5
mm path length cuvette. The absorption spectra under an applied
potential were obtained by using an Ocean Optics spectrometer and
OceanView software.
Quantum Yield Measurement. The quantum yield (QY) was
measured by using a custom setup. Monochromic light was generated
by a Kessil lamp (PR160-440nm) and a 435 nm band-pass filter
(FWHM = 10 nm). Passing through a lens (f = 40 mm), the light was
focused onto the reaction solution (Figure 1A), which was contained
in a 1 cm cuvette. The QY was determined via the following equation:
Figure 1. Product yields and selectivity achieved by different
photocatalysts for photoredox hydroamination reactions starting
from (A) primary amine 1 and (B) secondary amine 2. (C)
Structures and redox potentials of IrA and IrB photocatalysts and
HAT catalyst (TripSH). The redox potentials are referenced to Fc+/
Fc.
performed on primary amines with a stronger photooxidant
IrB (IrB = [Ir(III)(dF(CF3)ppy)2(4,4′-d(CF3)bpy)]PF6), the
secondary amine products are selectively obtained with little
over-reaction to produce tertiary amines (Figure 1A).26 Such
photocatalyst-dependent chemoselectivity is intriguing and
provides an imperative for a detailed mechanistic under-
standing to improve the photochemical efficiency and enable a
scalable protocol for large-scale synthesis.
Here, we present comprehensive mechanistic studies to
uncover the origins of this chemoselectivity, as such insight
aids in further reaction development, optimization, and
application. We find that the chemoselectivity for the
formation of secondary amine originates from the faster
addition of the primary ARCs to the alkenes as compared to
secondary ARCs. We have identified that rapid deprotonation
of the ARCs, arising from their augmented acidity compared to
the parent amine, is a significant nonproductive side-reaction.
In addition, two critical intermediates (Ir(II) and thiyl radical)
have been observed and found to be essential to the turnover
of the photocatalyst and, hence, the overall reaction efficiency.
With these mechanistic insights, an optimization strategy has
been developed to improve the reaction efficiency, which
enables relatively large-scale syntheses under scalable flow
conditions for practical synthetic applications.
number of product molecules
number of photons absorbed
cV
ϕt
QY =
=
(1)
where c is product concentration, V is the volume of the reaction
solution, ϕ is the photon flux, and t is the reaction time. For each QY
measurement, 1.2 mL of the reaction solution was used. The reaction
time (t) varied from 30 to 300 min depending on the reaction rate.
The photon flux was calibrated to be 2.56 × 10−7 mol/s
(corresponding to a power of 62.1 mW) based on a published
procedure.29 The product concentration (c) was determined by GC
with dibenzyl ether as an internal standard.
Time-Resolved Laser Spectroscopy. The laser spectroscopic
setup was described in detail previously.30 Excitation pulses at 355 nm
were generated by a Quanta-Ray Nd:YAG laser (SpectraPhysics) with
a repetition rate of 10 Hz and a pulse width of ∼8 ns. Continuous
white light, generated by a xenon-arc lamp (PTI, Model A1010), was
used as the probe for the transient absorption (TA) measurements.
To measure the time-resolved emission decay, the excitation laser
beam was focused onto the sample contained in a 1 cm path length
cuvette. The resulting emission was collected by a pair of lenses (f =
20 cm), passed through a monochromator (Triax 320) to select the
wavelength, and then detected with a photomultiplier tube (PMT).
To measure the TA kinetics, the sample was flowed through a 2 mm
path length micro flow cell (Starna Cells 583.65-Q-2/Z15), and both
excitation and probe beams were focused onto the same spot on the
sample. The transmitted probe beam was directed to the spectrometer
and detected by the PMT. The signal of the PMT was recorded on a 1
GHz oscilloscope (LeCroy, Model 9384CM). To measure the
broadband TA spectra, the probe beam passing through the
spectrometer was detected by a CCD camera (Andor Technology).
EXPERIMENTAL SECTION
■
General Considerations. All samples were prepared in a N2-filled
glovebox unless otherwise stated. Solvents were dried with 3 Å pre-
activated molecular sieves. All commercial chemicals were purchased
from Sigma-Aldrich or TCI Chemicals and used as received.
Photoreagents and model substrates for mechanistic studies were
synthesized (section A, Supporting Information) with their purity
verified by NMR spectroscopy. For batch reactions, the solution was
typically placed in a 2-dram glass vial, which was then sealed with
electrical tape and illuminated with a single blue LED Kessil lamp
(PR160-440 nm) under constant stirring and fan cooling (Figure
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Custom software was used for controlling the apparatus and data
processing. Details of TA data analysis are provided in section B of the
Supporting Information.
TripSH showed no appreciable increase in the presence of
amine (Figure S5). Surprisingly, the quenching of primary
amine 1 exhibits a solvent dependence whereas the secondary
amine 2 and TripSH did not (Figure 2A). The 4−5-fold
increase in kq for the quenching of 1 from benzonitrile
(PhCN) to 1,4-dioxane and isopropyl acetate (iPrOAc) is also
accompanied by a significant increase in the product yield of 2
RESULTS
■
Hydroamination Selectivity. Figure 1A shows the results
for the reaction between cyclohexylamine (1) and methylene-
cyclopentane, with the IrB photocatalyst. As previously
observed,26 the secondary amine (2) is the predominant
product. To further confirm this chemoselectivity, the
secondary amine product (2) was subjected to the same
photoreaction conditions with the IrA and IrB photocatalysts
(Figure 1B). We note that the oxidizing power of the
photoexcited *IrB relative to *IrA (E1/2(IrB(*III/II)) =
1.27 V and E1/2(*IrA(III/II)) = 0.59 V)26 is greater, and thus
*IrB should be able to photogenerate the secondary ARCs
(step 1, Scheme 1) with greater facility. Nevertheless, the
tertiary amine 3 is obtained in only 20% yield for IrB, whereas
a product yield of 87% is obtained for the IrA photocatalyst
(Figure 1B).
i
(26% in PhCN, 76% and 79% in 1,4-dioxane and PrOAc,
respectively) (Table S1, entries 1 and 2). To gain further
1
insight into this solvent-dependent quenching behavior, H
NMR spectra of 20 mM 1 were measured in the presence of
various concentrations of 1,4-dioxane. The broadening and
shift of the NH2 peak likely suggest a H-bonding interaction
between 1 and 1,4-dioxane (Figure 2B). Under similar
conditions, much less broadening and peak shift were observed
for diethylamine (Figure S6). Nevertheless, the quenching of
the *IrB by the secondary amine is higher than by the primary
amine, suggesting that the secondary amine product may
inhibit the primary amine reaction upon its formation in situ.
To test this inhibition effect, we performed the primary amine
hydroamination reaction with and without 20 mol % 2 as
shown in Table S1. A dramatically attenuated initial rate was
observed after 1 h of illumination in the presence of pre-added
product 2 (35% yield compared to 64% yield without
secondary amine product 2, entries 5 and 6, respectively).
Back-Electron Transfer, Deprotonation, and Addi-
tion. The stronger quenching of *IrB by 2 than by 1 (Figure
2A) suggests that the selectivity for the primary amine (Figure
1A) cannot result from the differences in the generation of the
ARCs by excited-state electron transfer (step 1, Scheme 1). We
therefore turned our attention to probing the back-electron
transfer (BET) between the ARCs and the reduced photo-
catalyst, IrB(II), by examining the TA spectrum upon laser
photoexcitation. Because of a weak long-lasting background
signal after photoexciting IrB in 1,4-dioxane (Figure S7A), all
Quenching Rate and Solvent Dependence. To assess
the reactivity of *IrB with primary and secondary amines (step
1, Scheme 1), Stern−Volmer quenching experiments were
performed on IrB in various solvents in the presence of 1, 2, or
TripSH (TripSH = 2,4,6-triisopropylbenzenethiol) (Figure 2A
and Figures S2−S4). In 1,4-dioxane, 1 displays a quenching
rate constant, kq, comparable to that of TripSH, whereas 2
displays a kq that is 2−3 times larger. In addition, quenching by
i
TA spectroscopic studies were performed in PrOAc, in which
*IrB decays completely to the ground state (τ0 = 212 ns)
(Figure S7B) while maintaining similar yields and chemo-
selectivities as observed in 1,4-dioxane (Table S1, entry 2).
Figure 3A shows the TA spectrum (λexc = 355 nm) when 200
i
mM substrate 1 or 100 mM substrate 2 is added to a PrOAc
solution of 0.2 mM IrB. The high concentration of substrate
ensures that *IrB is efficiently quenched, allowing a sufficient
concentration of the quenching products to be captured in the
TA spectrum. The formation of IrB(II) is observed
immediately after initial quenching, indicating the oxidation
of the amine substrates. However, TA features of ARCs (1•+ or
2•+) are not detected as these species absorb in the UV region
(<300 nm),31 which is beyond the detection range of our
instrument. The spectrum of IrB(II) was confirmed
independently by spectroelectrochemistry (Figure S8C).
Surprisingly, IrB(II), probed at 520 nm, shows no appreciable
decay up to 450 μs after the initial quenching event (Figure
3A, inset). Similarly, when *IrA was quenched by the
secondary amine 2, the resulting IrA(II) signal also remained
for a long time (Figures S8C and S9). These results indicate
that BET between IrA(II) or IrB(II) and the primary or
secondary ARCs is insignificant.
Figure 2. (A) Stern−Volmer quenching rate constant for the excited
state *IrB by substrates 1, 2, and TripSH in benzonitrile (PhCN),
1,4-dioxane, and isopropyl acetate (iPrOAc). Primary amine 1 exhibits
an enhanced quenching rate in 1,4-dioxane and iPrOAc. (B) 1H NMR
spectra of 20 mM substrate 1 in benzene-d6 with various
concentrations of 1,4-dioxane. The dashed gray box highlights the
peak broadening and shift for the protons on the NH2 group,
indicating their H-bonding with 1,4-dioxane.
The insignificant BET may result from a fast deprotonation
of the ARCs. To further verify the deprotonation pathway, we
performed a photoredox deuteration reaction using the
conditions shown in Figure 3B based on a published method.32
We found 37% deuteration on the Cα of substrate 1 and 90%
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Figure 3. (A) TA spectra at 2.5 μs of a solution containing 0.2 mM IrB and 200 mM primary amine 1 (black) or 100 mM secondary amine 2
(blue). The inset shows the corresponding kinetic traces probed at 520 nm exhibiting nearly no decay, suggesting the absence of direct BET
between photogenerated intermediates. (B) Deuteration reactions under photoredox conditions suggest that deprotonation can happen at the Cα,
where the deuterated product yields are shown accordingly. (C) TA spectra at 2.5 μs of a solution containing 0.2 mM IrB and 200 mM substrate 1
in the absence (black) and presence (red) of 50 mM 1,1-diphenylethylene. The arrow highlights the TA feature centered at 329 nm, showing the
intermediate after ARCs (1•+) add to 1,1-diphenylethylene. The addition kinetics (probed at 329 nm) are shown in the inset with various
concentrations of 1,1-diphenylethylene (12 mM (black), 24 mM (red), and 36 mM (blue)). (D) Correlations between the addition product signal
and the concentration of 1,1-diphenylethylene. Different slopes (kprod) suggest that 1•+ adds to alkenes more effectively than 2•+.
1
deuteration on both two Cα’s of substrate 2 based on the H
NMR spectra (Figure S10). In addition, on the basis of the
oxidation potential and the bond dissociation energy (BDE),
we estimated the pKa(NH) and pKa(CαH) of ARCs (Scheme
S1 and section K in the Supporting Information). With
ethylamine as an example, pKa(NH) and pKa(CαH) were
calculated to be 14 and 6 in MeCN (Scheme S1A),
respectively, significantly lower than the pKa of ethyl-
ammonium (pKa = 18). For diethylamine, pKa(NH) and
pKa(CαH) were calculated to be 20 and 15 (Scheme S1B),
respectively, in contrast to a pKa of 19 for diethylammonium.
The addition of ARCs to alkenes (step 2, Scheme 1) was
probed by TA spectroscopy using solutions containing IrB,
primary amine 1, and 1,1-diphenylethylene. Figure 3C shows
the TA spectra obtained at 2.5 μs for solutions containing 0.2
mM IrB and 200 mM 1 with and without 50 mM 1,1-
diphenylethylene. An additional TA feature at ∼330 nm was
observed for the solution with 1,1-diphenylethylene (Figure
3C, red) when compared to the one without (Figure 3C,
black). This 330 nm feature is characteristic of the
corresponding diphenylmethine radical31 resulting from the
addition of ARC to the olefin (step 2, Scheme 1). Control
experiments show that 1,1-diphenylethylene itself does not
quench *IrB (Figure S11A) or contribute to the TA spectrum
observed in Figure 3C (Figure S11B). To gain further kinetic
information about the addition process, single-wavelength TA
traces were monitored at 329 nm, where IrB(II) shows an
isosbestic point with the spectrum of IrB(III) (Figure S8B).
However, because of the residual signal of *IrB and potential
scattering, the TA traces show a background signal up to ∼200
ns (Figure S12, black trace). To remove this background
signal, the TA trace for the solution without 1,1-diphenyl-
ethylene (0.2 mM IrB and 200 mM 1) was subtracted from the
TA traces for similar solutions containing 1,1-diphenylethylene
(Figure S12). The background-corrected TA traces are shown
in the inset of Figure 3C. The product signal at 329 nm
emerges at ∼100 ns and increases with increasing concen-
trations of 1,1-diphenylethylene (12, 24, and 36 mM).
However, no clear rising feature was observed before 100 ns
(Figure 3C, inset). These results suggest that the deprotona-
tion of the ARCs occurs extremely fast on the sub-100 ns time
scale. Because of the fast deprotonation, residual signal of *IrB,
and scattering, we were unable to measure the addition rate
constant for the ARCs. Because deprotonation can occur from
both CαH and NH groups (Scheme S1), tert-butylamine,
which does not possess Cα-hydrogens, was also used to study
the addition process. Similar results were obtained showing
that the product radicals emerged at ∼100 ns (Figure S13)
with no clear rising features below 100 ns. These results
indicate that deprotonation occurs primarily from the NH
group for primary amines.
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Figure 3D plots the signal of the addition product (average
signal from 200 ns to 2.0 μs at 329 nm for traces in the inset of
Figure 3C) as a function of the concentration of 1,1-
diphenylethylene. Linear fitting (Figure 3D, solid lines) allows
for the extraction of the product radical formation rate
constant (kprod) as a function of concentrations of 1,1-
diphenylethylene, which effectively reflects the addition rate
of the ARCs. As shown in Figure 3D, kprod was found to be
∼75 times higher for primary ARCs (1•+, kprod = 166.5 5.3
at 490 nm in addition to IrB(II) features at 385 and 520 nm.
Laser excitation at 355 nm of a 15 mM Trip2S2 solution
produces the same TA feature (Figure S14A), establishing
TripS• as the origin of the 490 nm transient absorption.
Additionally, the IrB(II) features decayed significantly for the
solutions containing TripSH (Figure 4A), in contrast to the
case when TripSH is absent (Figure 3A). These results
implicate the reaction of TripS• with IrB(II), likely with a
subsequent proton transfer to re-form IrB(III) and TripSH.26
Accordingly, the reaction involving thiyl radical opens another
pathway to turn over the photocatalyst, which would otherwise
persist as IrB(II) (Figure 3A).
mOD/M) than for secondary ARCs (2•+, kprod = 2.2
0.2
mOD/M). Therefore, the selectivity for primary amine (Figure
1A) correlates with a faster addition rate of the primary ARCs.
Accordingly, any other photocatalyst that can oxidize primary
amine should show a selectivity similar to that of IrB. Indeed,
this is the case. When a metal-free organic photocatalyst,
MesAcr (MesAcr = 9-mesityl-3,6-di-tert-butyl-10-phenylacri-
dinium tetrafluoroborate and E1/2(MesAcr*/MesAcr−) = 1.68
V vs Fc+/Fc),33 was used, the primary amine reaction proceeds
with similar chemoselectivity as that observed for IrB
photocatalyst (Table S1, entries 3 and 4).
Photocatalyst Turnover Mediated by a Thiyl Radical.
To close a photocatalytic cycle, the reduced photocatalyst
Ir(II) must return to Ir(III) (Scheme 1). To assess whether
TripSH can facilitate the regeneration of the Ir(III) photo-
catalyst, TA studies were performed on a solution containing
0.2 mM IrB, 100 mM 2, and 30 mM TripSH (Figure 4). The
TA spectrum at 200 ns in Figure 4A shows a prominent signal
The decay of the TripS• at 490 nm occurs on a faster time
scale than IrB(II) (Figure 4A). After 100 μs, TripS•
completely disappears whereas ∼28% IrB(II) remains. The
faster decay of TripS• is likely due to its dimerization to form
disulfide Trip2S2. When IrB is replaced with IrA (0.2 mM IrA,
100 mM 2, and 30 mM TripSH), similar spectral profiles are
observed, albeit with faster decay kinetics (Figure S15). To
compare the indirect BET between TripS• and the reduced
photocatalyst (IrA(II) or IrB(II)), single-wavelength TA
traces were probed at 520 nm (Figure 4B). Consistent with
the spectral evolution, the TA traces show that IrA(II) decays
faster than IrB(II). On a longer time scale (>100 μs), the TA
traces do not decay to zero (Figure 4A and Figure S15) as a
result of the prevalence of Ir(II) resulting from the formation
of the disulfide. To quantify the kinetics of the ET reaction
between Ir(II) and TripS•, TA studies were performed on a
solution containing 0.2 mM IrB, 100 mM pyridine, and 30
mM TripSH (Figure S16), allowing us to determine the
difference extinction coefficient (Δε) of TripS• (Figure S16C
and section B.1, Supporting Information). With a known Δε
for TripS• and Ir(II) (Figure S8C), we extracted the ET rate
constants (kET) of (2.1 0.1) × 1010 and (8.1 0.1) × 109
M−1 s−1 for IrA(II) and IrB(II), respectively (section B.2,
Supporting Information).
Disulfide Formation and Accumulation of Ir(II). The
formation of disulfide has a significant impact on photocatalyst
turnover if it cannot be reduced by Ir(II); in this case Ir(II)
will accumulate and become the resting state. This is more
likely to happen for reactions with IrB due to its mild reducing
potential (E1/2 = −1.18 V vs Fc+/Fc), which is significantly
lower than the half-wave reduction potential of Trip2S2 (Ep/2
=
−2.25 V vs Fc+/Fc) determined by CV (Figure S17C). The
TA result of residual Ir(II) in the presence of disulfide, Trip2S2,
can be recapitulated with UV−vis spectroscopy of reaction
solutions of IrB, which quickly turn from yellow to dark red
under blue light illumination (Figure 5, inset). To quantify this
color change, UV−vis absorption spectra were monitored as a
function of time for the standard reaction solution (Figure 1A)
contained within a screw-capped cuvette (2 mm path length).
As shown in Figure 5, the absorption spectra evolve over 40
min to furnish a profile with maxima at 385 and 520 nm, which
match the absorption spectrum of IrB(II) (Figure S8B). This
dark red color of the IrB(II) remains stable in the sealed
cuvette once generated. Subsequently exposing the solution to
air causes the prompt disappearance of the dark red color as a
result of the aerobic oxidation of IrB(II).
Figure 4. (A) TA spectra of a solution containing 0.2 mM IrB, 100
mM substrate 2, and 30 mM TripSH. (B) TA kinetics probed at 520
nm for a solution containing 100 mM substrate 2, 30 mM TripSH,
and 0.2 mM photocatalyst IrA or IrB. The faster decay for the
solution with IrA compared to that with IrB indicates a faster
photocatalyst turnover (see text). The scatter plots show the
experimental data, and the solid lines show the model fittings
(section B, Supporting Information), which allowed for the extraction
of the rate constant (kET) for the reaction between Ir(II) and TripS•.
To determine whether IrB(II) can react with Trip2S2,
IrB(II) was generated photochemically (Figure 5) under
standard reaction conditions (Figure 1A), after which 15 mM
Trip2S2 was added to the photolyzed solution. The signature
absorption of IrB(II) at 520 nm showed nearly no change after
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Figure 5. UV−vis absorption spectra of the primary amine reaction
solution during 40 min of illumination under blue light. The reaction
solution changed from an initial yellow contour to dark red, as shown
by the inset, due to the accumulation of IrB(II). The reaction
conditions were kept identical with those shown in Figure 1A, except
that the solution was stored in a 2 mm path length screw-capped
cuvette for UV−vis measurements.
several hours in the dark following the addition of Trip2S2
(Figure S18A, dark red and orange), suggesting little to no
reaction between IrB(II) and Trip2S2 under the standard
reaction conditions. IrB(II) was also generated by shining blue
light on a solution containing 0.06 mM IrB and 50 mM 2 for 1
min (Figure S18B, dark red). Adding 15 mM Trip2S2 in the
dark to this photolyzed solution resulted in no color change.
Further illumination of this solution with additional disulfide
results in the disappearance of the IrB(II) (Figure S18B, pink).
In contrast, when a similar experiment was performed with IrA
and 2 under standard conditions (Figure 1B), IrA(II) was not
observed (Figure S18C). Alternatively, IrA(II) was generated
photochemically by shining blue light on a solution containing
0.1 mM IrA and 50 mM 2 for 1 min (Figure S18D, blue).
Adding 15 mM Trip2S2 to the illuminated solution resulted in
an immediate disappearance of the IrA(II) signal (Figure
S18D, orange). To further confirm the reaction between
IrA(II) and Trip2S2, IrA(II) was chemically synthesized by the
treatment of IrA(III) with sodium amalgam (section A.4,
Supporting Information). The absorption spectrum of the
resulting solution (Figure S19, blue) matched that of IrA(II)
obtained spectroelectrochemically (Figure S8A, blue). When
Trip2S2 was added to this IrA(II) solution, the signature
absorption feature of IrA(II) at 530 nm disappeared (Figure
S19, orange). Thus, Trip2S2 can be reduced by IrA(II) but not
by IrB(II).
Reaction Optimization and Flow Chemistry. Recogniz-
ing that TripS• dimerizes to Trip2S2, which IrB(II) is unable to
reduce to regenerate the ground state IrB(III), an optimization
strategy was focused on increasing the concentration of TripS•.
Under the original conditions of 1 mM IrB (Figure 1A),26 the
maximum possible concentration of Trip2S2 is 0.5 mM.
Because of the limited absorption of Trip2S2 in the visible
region (Figure S14B), this concentration does not enable
TripS• to be generated substantially in the standard reaction
condition (Figure 1A). Accordingly, reaction conditions were
examined with the addition of excess Trip2S2 with the desire to
increase TripS• upon photocleavage of the disulfide. Figure 6
summarizes quantum yields (QYs) of the secondary amine
product 2 with different concentrations of thiol and/or
disulfide. The QY obtained for the standard conditions of 30
mol % (15 mM) TripSH is 0.20 0.02%. Replacing 30 mol %
TripSH with 30 mol % Trip2S2 causes a 3× increase in the QY
Figure 6. (A) Quantum yield (QY) measurements of the primary
amine reaction as shown in Figure 1A. Varying the loading of TripSH
and/or Trip2S2 results in significant increases in the QY. Standard
deviations were obtained from experiments in triplicates. (B)
Optimized reaction efficiency with additional disulfide allows for
large scale (50 mL, 2.5 mmol) reactions to be performed under
i
scalable flow conditions. A binary solvent of 1,4-dioxane and PrOAc
(80:20 vol/vol) was used to solubilize IrB. Multiple substrates were
tested on a large scale to demonstrate the general applicability of the
optimized reaction strategy. Isolated yields were obtained via flash
chromatography of the secondary-amine-product-derived benzamide.
Yields in parentheses correspond to the secondary amines or their
HCl salts, obtained from acid−base treatment of the postillumination
reaction mixture (section M, Supporting Information).
(0.61 0.01%), which is also higher than that obtained for 60
mol % TripSH (QY = 0.44 0.01%). With both TripSH and
Trip2S2 at 20 mol %, the QY further improved to 1.55
0.13%, reflecting that both TripSH and Trip2S2 are important
to the reaction efficiency. Indeed, further boosting both the
concentrations of TripSH and Trip2S2 to 30 mol % led to a QY
of 2.43
0.04%, which is 12× greater than the original
reaction conditions (Figure 1A) for this photoredox process.
Further optimization examined the effect of the absence and
presence of additional disulfide with reduced loadings of
photocatalyst and alkene (Table S2). Under the standard
conditions of Figure 1A, decreasing the photocatalyst loading
from 2 mol % to 0.5 mol % slightly reduced the product yield
from 75% to 67% (Table S2, entries 1−3). Under similar
conditions with the addition of 30 mol % (15 mM) disulfide,
the product yield increased from 70% to 81% with a
concomitant decrease in the photocatalyst loading (Table S2,
entries 4−6). The slightly lower product yield observed with
additional disulfide (Table S2, entry 4) when compared to that
without (Table S2, entry 1) is possibly due to over-reaction
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Figure 7. Complete reaction cycle for photoredox hydroamination. ET = electron transfer; BET = back-electron transfer; PT = proton transfer;
HAT = hydrogen atom transfer.
after 20 h of blue light illumination. Significantly, the yield of
product is maintained with 3-fold lower alkene loadings (2
equiv). Whereas a modest decrease in yield is observed in the
absence of Trip2S2 (Table S2, entries 1 and 8), in the presence
of Trip2S2, the yield increases from 70% to 78% (Table S2,
entries 4 and 10). Interestingly, high yields hold for
photocatalysts other than IrB. Using MesAcr at 4 mol %
loading in the presence of Trip2S2 leads to appreciable product
yield of the secondary amine (87%) with no detectable tertiary
amine (Table S1, entry 4). These results together establish that
the presence of disulfide allows the photoinduced hydro-
amination to be performed under reduced loadings of
photocatalyst and alkene. Additionally, we also monitored
the progress of the reaction with IrB in the presence of 30 mol
% Trip2S2 and in the absence of TripSH. The photoreaction
delivered the highest product yield of 2 (85%) in 7 h; further
illumination resulted in a drop in yield of 2 from 85% to 69%
with the concomitant formation of tertiary amine product 3
(Table S4).
The optimized conditions allowed the primary amine
hydroamination reaction to be performed efficiently on larger
scale under flow conditions. A flow reaction setup was
designed comprising two Kessil lamps (440 nm) that
illuminated both sides of a sample flowing through a PTFE
tube (Figure S1B). The improved reaction efficiency induced
by disulfide was verified for the flow setup (see section C in the
Supporting Information). For the primary amine reaction
(Figure 1A) performed in the presence of 30 mol % Trip2S2,
60% and 73% product yields were achieved in 5 and 10 min,
respectively (Table S3). In contrast, only 11% and 14% yields
were obtained after 5 and 10 min, respectively, for the
photocatalysis under the original conditions (Figure 1A).
Further illuminating the solution for 80 min delivered product
in just 51% yield (Table S3). Large-scale synthesis was
demonstrated by using the conditions shown in Figure 6B, top
(section C, Supporting Information), where the photocatalyst
loading was halved compared to the previously reported
conditions.26 Multiple primary amine and alkene subtrates
were tested and showed moderate to high isolated yields
(Figure 6B, bottom). All reactions were complete in 9 h on a
2.5 mmol (50 mL) scale. The flow setup may easily
accommodate larger scale reactions if so desired.
DISCUSSION
■
A complete reaction cycle for the photoredox hydroamination
reaction between primary amines and alkenes is proposed in
Figure 7. The excited-state photocatalyst *Ir(III) oxidizes the
amine to generate Ir(II) and ARC with a quenching rate
constant approaching the diffusion-controlled limit (Figure
2A). The generation of Ir(II) is established by the transient
absorption at 385 and 520 nm (Figure 3A). At this juncture,
the ARC may react along three possible pathways: (A)
addition to alkene in a productive reaction (Figure 7, left,
productive cycle), (B) direct BET with Ir(II), and (C)
deprotonation to form a neutral radical (Figure 7, right,
nonproductive cycle). As previously elucidated, ARC propagat-
ing along pathway A establishes the productive hydro-
amination.25,26 The addition of ARC to the alkene is
conveniently examined by using 1,1-diphenylethylene as its
radical cation absorbs at 330 nm,31 which we have detected in
the TA spectrum (Figure 3C). The resulting product radical
cation can engage in a facile HAT reaction with TripSH (∼108
M
−1 s−1)34 to form the product ammonium cation and TripS•,
which then undergoes a reduction by Ir(II) and proton
transfer to afford the desired product and regenerate both
TripSH and Ir(III) (ET/PT reactions). The selectivity in this
cycle originates from a difference in the kinetics between
primary and secondary amines along pathway A. Pathway C
enters an off-cycle reaction and is the determinant of
photocatalyst turnover, which is specific to the redox
properties of the Ir photocatalyst.
Origin of Chemoselectivity in the Primary Amine
Reaction. A merit of this photoredox hydroamination method
is its chemoselectivity toward the formation of secondary
amine with minimal overalkylation.26 Figure 1A reproduces the
selectivity for this reaction of the primary amine by using IrB
photocatalyst. To investigate the origin of this chemo-
selectivity, we examined the Stern−Volmer quenching of
*IrB by the primary amine (1) and secondary amine (2). The
enhanced quenching rate constant of IrB* by 2 as compared to
1 (Figure 2A) excluded the possibility that the chemo-
selectivity is associated with the initial quenching process
(forward ET). TripSH was also observed to quench *IrB, but
the quenching is insignificant considering its lower concen-
tration (15 mM) as compared to that of the amine substrate
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(50 mM) under the standard reaction conditions (Figure 1A).
Even in the presence of amine substrate (1 or 2), the
quenching by TripSH only increased slightly (Figure S5),
suggesting that proton-coupled electron transfer (PCET) does
not contribute to the initial quenching to any significant
extent.19,35,36 The primary amine 1 shows a quenching
predominantly deprotonate from the NH group on the sub-
100 ns time scale, which is also consistent with previous
reports of a short lifetime (40 ns) for primary ARCs.39 The
presence of fast deprotonation of the primary ARCs diverts the
system to pathway C and also accounts for the absence of
significant BET along pathway B in Figure 7. Additionally, the
secondary ARCs are also short-lived under photoredox
conditions based on similar observations showing the absence
of direct BET after the initial quenching (Figure 3A, blue
plots). This is in stark contrast to the reported lifetime of a few
microseconds for the secondary alkyl ARCs in acidic solution31
and likely suggests that the secondary amine substrate
significantly accelerates the deprotonation of ARCs under
photoredox reaction conditions by acting as a base.
Pathway C diverts the system into a reaction off-cycle
(Figure 7, right) because the neutral aminyl radicals formed
after deprotonation are not observed to add efficiently to the
alkene, as no additional rise in signal of the product radical is
observed beyond 100 ns by TA spectroscopy (Figures 3C,
inset, and Figure S13). This is in line with the several orders of
magnitude slower addition reported for nucleophilic aminyl
radicals when compared to electrophilic ARCs.40 The carbon-
centered radical formed after deprotonation from the CαH
group should not react with alkene either, since the alkylation
byproduct is not observed. Under the photoredox conditions
shown in Figure 1A, the neutral aminyl and carbon radicals are
expected to be reduced rapidly by TripSH via HAT (Figure 7,
right cycle), as both reactions have been reported to proceed
with rate constants of ∼108 M−1 s−1.34 Following HAT, TripS•
and the starting materials (amines) are generated, the latter of
which prevent side reactions from consuming the amine
substrates.
i
efficiency 4−5-fold higher in 1,4-dioxane and PrOAc than in
PhCN, likely due to the H-bonding interaction between
primary amine and 1,4-dixoane as reflected by a peak shift and
broadening of the NH2 signal in the 1H NMR spectra shown in
Figure 2B. Considering the strong and potentially deleterious
competitive quenching from 2 and TripSH (Figure 2A), this
increased quenching for primary amine (1) may play an
essential role in delivering the high product yields of 2 in 1,4-
i
dioxane (76% in Figure 1A) and PrOAc (79% in Table S1,
entry 2).
Pathway B may engender selectivity for the primary amine if
IrB(II) reacts with 2•+ by back-electron transfer (BET) much
faster than with 1•+, hence extending the lifetime of 1•+ for
addition to the olefin (pathway A). However, the TA spectrum
of IrB(II) persists over long times for both the primary and
secondary amine quenching reaction (Figure 3A, inset, and
Figure S9), indicating that BET is not a dominant reaction
pathway and moreover is not the origin of chemoselectivity.
These quenching results together suggest that chemoselectivity
arises from differential addition rates of the primary versus
secondary ARC to alkene. Indeed, as shown in Figure 3D, the
primary ARC adds to the alkene at a rate (kprod) that is ∼76
times greater than that for the corresponding secondary ARC.
Moreover, these results suggest that the chemoselectivity for
the primary amine shown in Figure 1A and Table S1 (entry 2)
is inherent to the primary ARC and is not photocatalyst-
specific. This contention is confirmed by the observation that
chemoselectivity was maintained (Table S1, entries 3 and 4),
when the primary amine reaction was performed by using the
organic photocatalyst MesAcr in place of IrB.
Deprotonation of ARCs. ARCs are known to undergo
facile deprotonations from NH or CαH groups to form neutral
radicals,27,37 as deduced primarily for secondary ARCs.38 The
pKa calculations shown in Scheme S1 suggest that deprotona-
tion is favored from both NH and CαH groups for primary
ARCs, and only from the CαH group for secondary ARCs,
indicated by the lower pKa values of the ARCs than their
corresponding ammonium cations. To probe if deprotonation
from the CαH group does occur, ARCs were generated under
photoredox conditions in the presence of D2O and TripSH.
Deprotonation from the CαH group is supported by the results
of Figure 3B and Figure S10, which show 37% and 90%
deuteration at Cα for primary amine 1 and secondary amine 2,
respectively. These results are consistent with the pKa
calculations and confirm that deprotonation from the CαH
group indeed occurs.
Photocatalyst Turnover. Beyond its function as a HAT
catalyst to facilitate product formation (Figure 7, left cycle)
and the recovery of the amine substrate (Figure 7, right cycle),
TripSH plays a critical role in mediating photocatalyst
turnover.
For photoredox reactions involving IrB, TripSH provides a
source of TripS• to drive photocatalyst turnover to IrB(III).
The reaction between TripS• and IrB(II) was studied by
observing the time evolution of the TA features for IrB(II) at
385/520 nm and TripS• at 490 nm, respectively (Figure 4A).
Moreover, the reaction between IrB(II) and TripS• offers an
ET/PT pathway for the photocatalyst to turnover as both
IrB(II) and TripS• decay significantly (Figure 4), in contrast
to nearly no decay of IrB(II) in the absence of TripSH (Figure
3A, inset). The TripS• radical can also dimerize to form a
disulfide (Trip2S2), resulting in an accelerated decay of TripS•
relative to IrB(II) decay and a residual TA signal for IrB(II)
(Figure 4A). The formation of the Trip2S2 will negatively affect
photocatalyst turnover if IrB(II) cannot react with Trip2S2.
Indeed, photolysis of IrB(III) in the presence of primary
amine, TripSH, and alkene leads to the generation of IrB(II)
as monitored by UV−vis spectroscopy (Figure 5). Addition of
Trip2S2 to this photolyzed solution of IrB(II) results in little
change to the absorption profile, confirming the absence of
reaction between IrB(II) and Trip2S2. However, as shown in
Figure S18C, when the solution of IrB(II) and Trip2S2 was
further subjected to illumination, IrB(II) can turnover due to
the reaction between IrB(II) and the photogenerated thiyl
radical. Therefore, for primary amine substrates, the reaction
between IrB(II) and TripS• provides the only plausible path
for photocatalyst turnover to IrB(III). To this end, the
TA spectroscopic studies suggest that deprotonation of the
primary ARCs is faster than 100 ns. Figure 3C shows that the
TA signal of the product radical cation appears promptly at
100 ns regardless of varying concentrations of 1,1-diphenyl-
ethylene (Figure 3C, inset). To determine if the fast
deprotonation is associated with CαH group or the NH
group, TA kinetics studies were also performed by using tert-
butylamine, which is absent of CαHs. As shown in Figure S13,
the product cation radical also appears in <100 ns, indicating
that fast deprotonation occurs from the NH group. On the
basis of these results, we conclude that primary ARCs
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regeneration of TripS• by Trip2S2 photocleavage22 is essential
for the primary amine reaction. Figure S14 shows that Trip2S2
photocleavage is a facile process as the TripS• is formed
promptly after laser excitation.
working in concert as HAT catalysts (Figure 7, left and right
cycles). Though it has been shown that disulfide plays an
important role in catalyst turnover in a number of radical-
mediated transformations,22 thiol and disulfide together can
enhance catalysis by working in concert. Whereas thiol is
responsible for reducing the carbon-centered radical because of
its rapid HAT dynamics (left cycle, Figure 7), the disulfide
plays an essential role in turning over the photocatalyst. The
benefit of thiol/disulfide cooperativity is apparent in the
enhanced yield shown in Figure 6A (orange and dark green
bar).
Batch reactions typically face challenges in scale-up using
large reaction vessels42 because photoexcitation is confined to
absorption of incident light at the surface of the reactor. The
absorbance is particularly problematic for the primary amine
reaction because of the accumulation of the IrB(II) (Figure 5),
which absorbs light more strongly than IrB(III) (Figure S8B)
and thus manifests a strong inner filter effect as the photoredox
reaction proceeds. Under flow conditions, the inner filter effect
may be attenuated by irradiating the same quantity of solution
in unit time as a batch reactor but over a shorter path length.
Additionally, the quantum yield of the overall reaction of IrB
with primary amine is significantly increased with the addition
of Trip2S2. This increased quantum yield allows the photo-
reaction to proceed with a shortened residence time under flow
conditions as demonstrated in Table S3, which lists product
yields of the photoredox reaction performed in the flow reactor
for given time periods of irradiation. Together, the shortened
path length enabled by the flow reactor and the increased QY
with additional Trip2S2 permitted a relatively large-scale
synthesis to be performed with reduced loading of the
photocatalyst as shown in Figure 6B.
For photoredox reactions involving IrA, photocatalyst
turnover may be driven by reaction with TripS• as well as by
direct reaction with Trip2S2. Unlike the result in Figure 5 for
IrB(II), IrA(II) does not build up for the photolysis of a
solution containing IrA(III), secondary amine, TripSH, and
alkene (Figure S18C). This result suggests superior turnover
ability for IrA compared to IrB, as is observed for the faster TA
decay kinetics of Ir(II) and TripS• for IrA (Figure S15) as
compared to IrB (Figure 4A). Kinetic modeling of the decay
signal at 520 nm for the two photoredox reactions yields the
rate constants of kET = (2.1 0.1) × 1010 M−1 s−1 vs kET = (8.1
0.1) × 109 M−1 s−1, respectively (Figure 4B), for the ET/PT
reaction following the generation of TripS• from TripSH by
HAT. Moreover, unlike IrB(II), IrA(II) can directly react with
Trip2S2 to furnish IrA(III) as was verified in Figures S18D and
S19, where the disappearance of IrA(II) was observed when
Trip2S2 was added to an IrA(II) solution prepared either
photochemically (Figure S18D) or chemically (Figure S19).
Hence, in IrA photoredox reaction with secondary amine
substrates, the regeneration of TripS• from Trip2S2 via
photolysis is not essential for photocatalyst turnover.
The differences in the turnover between IrA and IrB stem
from the redox potentials of the reduced photocatalysts. Using
CV (Figure S17), we determined IrB(II) to be much less
reducing than IrA(II) (E1/2 = −1.18 and −1.80 V vs Fc+/Fc
for IrB(III/II) and IrA(III/II), respectively). Hence, IrA(II)
can react directly with Trip2S2 and also react with TripS• more
efficiently than IrB(II) to result in photocatalyst turnover. We
note that the half-peak potential for RSSR reduction (Figure
S17), Ep/2 = −2.25 V vs Fc+/Fc, is a poor approximation of the
standard potential for disulfides. In disulfides, the reduction is
accompanied by irreversible bond breaking that results in a
shift of Ep/2 that is 300−600 mV more negative than the
standard potential.41 Accordingly, as shown in Figures S18B
and S18D, IrA(II) is able to reduce disulfide while IrB(II) is
not and IrA(II) is able to turn over by direct reduction of the
disulfide. This additional dark reaction for IrA(II) enhances
turnover and accounts for the photocatalyst dependence in the
secondary amine reactions (Figure 1B), where 87% tertiary
amine product 3 was obtained by using IrA, in contrast to the
20% yield obtained by using IrB. Moreover, as demonstrated
in Table S1 (entries 5 and 6), the pre-addition of 2 decreases
the primary amine reaction efficiency. This inhibition is caused
by the formation of the secondary amine product due to
quenching of the *IrB photocatalyst (Figure S5), thus sending
the system into the off-cycle pathway (Figure 7, right).
CONCLUSION
■
A detailed mechanistic study of the photoredox anti-
Markovnikov hydroamination of alkenes reveals that the
reaction selectivity for primary amines over their secondary
amine products is inherent to the addition kinetics of ARCs to
the alkene. For primary amines, the rate of addition is nearly 2
orders of magnitude faster than that of secondary ARCs. The
BET between photogenerated species (Ir(II) complexes and
ARCs) is circumvented by the fast deprotonation (<100 ns) of
the ARCs. Instead, a reaction between Ir(II) and thiyl radical
was discovered to be essential in facilitating photocatalyst
turnover. This process is retarded by the formation of disulfide,
which must be photolyzed to form thiyl radicals to turn over
the photocatalyst. Finally, we optimized the photocatalyst
turnover and achieved a quantum yield increase in excess of an
order of magnitude compared to the previously reported
conditions. This further allowed us to demonstrate efficient
large-scale reactions under scalable flow conditions. Our results
show that mechanism-informed optimization strategies can
benefit practical applications of photoredox hydroamination of
primary amines and potentially other hydrofunctionalizations
as well.
Mechanism-Informed Reaction Optimization. The
detailed mechanism reveals that the efficiency of the primary
amine hydroamination reaction by IrB is compromised by
photocatalyst turnover, implying that a potential optimization
strategy is to increase the concentration of thiyl radicals
generated via photolysis of the disulfides. As shown in Figure 6,
additional disulfide results in the improvement of the quantum
yield by over an order of magnitude and allows for lower
loadings of photocatalyst or alkene (Table S2). We note that a
HAT catalyst that cannot undergo side reactions such as
dimerization may also facilitate photocatalyst turnover though
TripSH remains the best HAT catalyst known to date. This is
likely due to the multiple roles served by thiol and disulfide
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c03644.
Materials and methods, data analysis, quantum yield
measurements, photoredox catalysis setups, quenching
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optimizations, product isolation (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Daniel G. Nocera − Department of Chemistry and Chemical
Biology, Harvard University, Cambridge, Massachusetts
02138, United States; orcid.org/0000-0001-5055-320X;
Email: dnocera@fas.harvard.edu
Robert R. Knowles − Department of Chemistry, Princeton
University, Princeton, New Jersey 08544, United States;
orcid.org/0000-0003-1044-4900; Email: rknowles@
princeton.edu
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Coupling Using Modified Carbon Nitride. Chem. Sci. 2020, 11,
7456−7461.
Authors
Yangzhong Qin − Department of Chemistry and Chemical
Biology, Harvard University, Cambridge, Massachusetts
02138, United States; orcid.org/0000-0002-2450-521X
Qilei Zhu − Department of Chemistry and Chemical Biology,
Harvard University, Cambridge, Massachusetts 02138,
United States; orcid.org/0000-0002-6360-9820
Rui Sun − Department of Chemistry and Chemical Biology,
Harvard University, Cambridge, Massachusetts 02138,
United States; orcid.org/0000-0002-3894-8425
Jacob M. Ganley − Department of Chemistry, Princeton
University, Princeton, New Jersey 08544, United States;
orcid.org/0000-0001-7705-2886
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Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c03644
Funding
This work was supported by the National Science Foundation
under Grant CHE-1855531 (D.G.N.) and the National
Institutes of Health under Grant R35-GM134893 (R.R.K.).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Dr. Adam Rieth for helpful discussions and
mechanistic insights.
■
REFERENCES
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