General Strategy for Improving the Quantum Efficiency of Photoredox Hydroamidation Catalysis

Article abstract of DOI:10.1021/jacs.8b09109

The quantum efficiency in photoredox catalysis is the crucial determinant of energy intensity and, thus, is intrinsically tied to the sustainability of the overall process. Here, we track the formation of different transient species of a catalytic photoredox hydroamidation reaction initiated by the reaction of an Ir(III) photoexcited complex with 2-cyclohexen-1-yl(4-bromophenyl)carbamate. We find that the back reaction between the amidyl radical and Ir(II) photoproducts generated from the quenching reaction leads to a low quantum efficiency of the system. Using transient absorption spectroscopy, all of the rate constants for productive and nonproductive pathways of the catalytic cycle have been determined, enabling us to establish a kinetically competent equilibrium involving the crucial amidyl radical intermediate that minimizes its back reaction with the Ir(II) photoproduct. This strategy of using an off-pathway equilibrium allows us to improve the overall quantum efficiency of the reaction by a factor of 4. Our results highlight the benefits from targeting the back-electron transfer reactions of photoredox catalytic cycles to lead to improved energy efficiency and accordingly improved sustainability and cost benefits of photoredox synthetic methods.

Full text of DOI:10.1021/jacs.8b09109

Subscriber access provided by The University of Texas at El Paso (UTEP)
Article
General Strategy for Improving the Quantum
Efficiency of Photoredox Hydroamidation Catalysis
Serge Ruccolo, Yangzhong Qin, Christoph Schnedermann, and Daniel G. Nocera
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b09109 • Publication Date (Web): 16 Oct 2018
Downloaded from http://pubs.acs.org on October 16, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 13
Journal of the American Chemical Society
1
2
3
4
5
6
General Strategy for Improving the Quantum Efficiency of Photore-
dox Hydroamidation Catalysis
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
†
†
Serge Ruccolo , Yangzhong Qin , Christoph Schnedermann, and Daniel G. Nocera*
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138–2902
ABSTRACT: The quantum efficiency in photoredox catalysis is the crucial determinant of energy intensity and thus is intrinsically tied to the
sustainability of the overall process. Here, we track the formation of different transient species of a catalytic photoredox hydroamidation reac-
tion initiated by the reaction of an Ir(III) photoexcited complex with 2-cyclohexen-1-yl(4-bromophenyl)carbamate. We find that the back
reaction between the amidyl radical and Ir(II) photoproducts generated from the quenching reaction leads to a low quantum efficiency of the
system. Using transient absorption spectroscopy, all the rate constants for productive and non-productive pathways of the catalytic cycle have
been defined, enabling us to establish a kinetically competent equilibrium involving the crucial amidyl radical intermediate that minimizes its
back reaction with the Ir(II) photoproduct. This strategy of using an off-pathway equilibrium allows us to improve the overall quantum effi-
ciency of the reaction by ×4. Our results highlight the benefits from targeting the back-electron transfer reactions of photoredox catalytic cycles
to lead to improved energy efficiency and accordingly improved sustainability and cost benefits of photoredox synthetic methods.
Introduction
rate-limiting and non-productive pathways, both of which will sig-
1
1–13
nificantly affect the quantum efficiency of the reaction.
Such rate
Photoredox catalysis has emerged as a prominent methodology
for highly selective, high throughput synthesis. A photoredox syn-
thetic strategy allows for the straightforward generation of high en-
ergy and reactive radical intermediates resulting from electron trans-
fer with a photocatalyst excited state, thereby unlocking reaction
pathways that are difficult or even impossible to access using tradi-
constant data have not been characterized in most reports of photo-
redox catalytic systems to date; insight into reaction mechanisms
have relied primarily on the redox potentials of the photocatalyst and
1
4,15
16,17
reagents,
bond dissociation energies
and steady-state Stern-
1
8
Volmer quenching rate constants, which provide information on
the initial photoinduced redox event but not on ensuing reactions.
Information pertaining to the productive pathways involving sub-
strate and photoproduct intermediates, appearing after the initial
photoinduced electron transfer, are the crucial determinants of the
overall quantum efficiency of the synthetic method. In this regard, a
major loss channel inherent to all photochemical processes and par-
1
tional routes. As with any current methodological development,
photoredox synthetic pathways are accentuated when the design ef-
fort incorporates sustainability. To this end, the Process Mass In-
tensity (PMI = quantity of raw materials input (kg)/quantity of bulk
active pharmaceutical ingredient output (kg)) has been adopted as
2
3
a metric for the implementation of green chemistry and engineering
in modern synthetic design strategies. Whereas reagents and sol-
vents are PMI targets of opportunity as raw materials inputs, the
value of the energy input has been appreciated to a lesser extent even
though it may be the overriding determinant of sustainability with
regard to the environmental manufacturing footprint and the cost of
the overall synthetic pathway. Accordingly, in addition to PMI, En-
ergy Intensity (EI = total process energy (J)/mass of final product)
is an emerging metric of importance in the design of new synthetic
1
9,20
ticularly to photoredox catalysis is back electron transfer (BET),
which circumvents the forward propagation of the desired reaction
sequence (see Scheme 1). Mechanistic insights pertaining to BET
and other non-productive pathways may be furnished by time-re-
solved spectroscopy, which allows intermediates to be identified and
rate constants to be determined. With this information in hand,
competitive reaction pathways may be defined and subsequently
1
8,21–23
manipulated.
Such information is valuable for the rational op-
4
,5
timization of the quantum efficiencies of photoredox catalytic reac-
tions.
methods. In the context of EI, photoredox (as well as electrore-
6
dox ) catalysis has the attractive attribute that its energy input may
7
We now demonstrate an improved synthetic methodology for
hydroamination by exploiting the knowledge garnered from com-
prehensively defining the reaction mechanism. Hydroamidation re-
actions are important but challenging transformations that generate
C–N bonds from olefins with readily available amides, carbamates
be a solar source, which by its nature has significant virtue with re-
gard to sustainability, and in view of the declining cost of solar gen-
8
,9
eration, has a cost benefit as well. However, to fully realize these
attributes of a light energy input, the photoredox catalysis must oc-
cur at high quantum efficiency (Φ = product out/photons in).
Whereas reaction scope and new methodologies for photoredox
catalysis are rapidly expanding, quantum efficiencies to date have
been typically overlooked and not optimized. Rational design prin-
ciples to optimize Φ relies on extracting rate constants for photo-
chemical steps and ensuing reaction rate constants pertaining to
p
2
4
or ureas; the functionalized amide and lactam products are omni-
present in pharmaceuticals, natural products and biological sys-
2
5,26
1
0
tems,
and also appear in bulk commodity chemicals such as N-
methyl-2-pyrrolidone and N-vinyl-2-pyrrolidone, which are cur-
rently produced on kilotons scale for their applications as solvents or
p
2
7
plastic precursors. Successful hydroamidation methods typically
invoke nitrogen-centered amidyl radicals as pivotal intermediates, as
ACS Paragon Plus Environment

Journal of the American Chemical Society
ported in ppm relative to SiMe
Page 2 of 13
(δ = 0) and were referenced inter-
4
Scheme 1
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
nally with respect to the protio solvent impurity (δ = 5.32 for
40 13
CDHCl
2
). C NMR spectra are reported in ppm relative to SiMe
4
(
δ = 0) and were referenced internally with respect to the solvent (δ
=
53.84 for CD
2
2
Cl ). Coupling constants are given in Hz. UV-vis
spectra were recorded at 293 K in tightly sealed 1 cm quartz cuvettes
on a Cary 5000 spectrometer (Agilent), and were blanked against
the appropriate solvent. 2,4,6-Trimethylphenylthiol (MesSH) was
purchased from Alfa Aesar or Santa Cruz Biotech and distilled be-
Bu
fore use. Tributylmethylammonium dibutyl phosphate (Pi ) was
purchased from Sigma Aldrich and dried under high vacuum for 24
h before use. 4-Bromophenyl isocyanate, cyclohexanol, sodium hy-
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
dride, tetrabutylammonium hexafluorophosphate (TBAPF ), and
6
camphorquinone (CQ) were purchased from Sigma Aldrich and
41
used without purification. [Ir(dF(CF
3
)ppy)
2
(bpy)]PF
6
,
2-cyclo-
42
hexen-1-yl(4-bromophenyl)carbamate 1a, 2-cyclohexen-1-yl(4-
cyanophenyl)carbamate 1b, di(2,4,6-trimethylphenyl) disulfide
43
44
45
2
8,29
(MesSSMes) and 2,4,6-trimethylbenzenesulfenyl chloride were
prepared according to literature procedures. The synthesis and char-
acterization of cyclohexyl(4-bromophenyl)carbamate (3) and N-
(2,4,6-trimethylphenylthyil)2-cyclohexen-1-yl(4-bromophenyl)
carbamate (4) are detailed in the supporting information.
they can rapidly add to olefins in an anti-Markovnikov manner.
However, the formation of the key amidyl radical intermediate is of-
ten nontrivial and involves the use of either synthetically challenging
3
0,31,32
33
precursors such as chloroamides, thioamides,
aryloxy amides
3
4
35
or strong oxidants. As pioneered by Knowles and co-workers,
photoredox catalysis has engendered a simple and reliable strategy
to deliver the amidyl radical by photoinduced proton-coupled elec-
Quantum Efficiency Measurements. Typical photoredox hy-
droamidation reactions were performed using the procedure re-
35
3
6–38
ported by Knowles and co-workers with the appropriate amide
tron transfer (PCET)
between the excited state of an Ir(III) pho-
substrates and [Ir(dF(CF
3
)ppy)
2
(bpy)]PF
6
(dF(CF )ppy = 2-(2,4-
3
tocatalyst and the corresponding amide in the presence of a dibu-
tylphosphate base and a thiol hydrogen atom donor. This successful
synthetic hydroamidation method applies to a wide range of amide,
carbamates, ureas and olefin substrates but as we report here occurs
at low efficiency owing to facile BET of the photogenerated amidyl
radical. We now show that the entire hydroamidation cycle encom-
passes seven rate constants, two of which involve quenching the
amidyl radical by BET with the Ir(II) photocatalyst and hydrogen
atom transfer with the thiol. Both of these reactions return the amide
starting reactant before cyclization of the amidyl radical may occur
to produce the desired hydroamidation product. Using transient ab-
sorption spectroscopy, the rate constants of the complete hydroam-
idation cycle have been determined, allowing us to design an off-cy-
cle equilibrium that traps the amidyl radical with a disulfide as sche-
matically indicated in Scheme 1. The trapping reaction attenuates
BET of the photogenerated amidyl radical, which may be returned
to the catalytic cycle via the equilibrium. Knowledge of the cycliza-
tion rate constant in comparison to the rate constants for BET and
HAT enables the equilibrium to be tuned to allow the cyclization re-
action to prevail. Through this strategy, the photoinduced hydroam-
ination reaction may be optimized to result in a significant increase
in the quantum efficiency of the synthetic method.
difluorophenyl)-5-(trifluoromethyl)-pyridinyl, bpy = 2,2´-bipyri-
dine) as a photoredox catalyst (PC) in a 2 mol% loading,
–
Bu
2
[
OP(O)(OBu)
2
] (Pi
) as a base in a 20 mol% loading and 2,4,6-
trimethylphenylthiol (MesSH) as an H-atom donor or MesSSMes
in a 10 mol% loading (unless stated otherwise) in CH Cl . All reac-
2
2
tions were carried out under constant illumination provided by a
A160WE Tuna Blue light source. The light source used for quantum
yield measurements was a 150 W Xe arc lamp (Newport 67005 arc
lamp housing) with a Newport 69907 universal arc lamp power sup-
ply. This latter light source was equipped with a a 310 nm long pass
filter and a second Hg line filter (380 nm or 435 nm) to generate a
wavelength-selective irradiation beam. Photon fluxes were deter-
mined by chemical actinometry against a potassium ferrioxalate
46
standard (0.006 M for 380 nm and 0.15 M for 435 nm). All meas-
urements were conducted to an average conversion of 15%, and the
illumination times were adjusted accordingly.
Electrochemical Studies. Electrochemical measurements were
performed on a CH Instruments (Austin, Texas) 760D Electro-
chemical Workstation using CHI Version 10.03 software. Cyclic
voltammetry (CV) experiments were conducted in a N
box on a CH Cl solution at 293 K containing 0.2 mM of PC, 0.1 M
tetrabutylammonium hexafluorophosphate (TBAPF ) using a CH
2
-filled glove-
2
2
6
Instruments glassy carbon button working electrode (area = 0.071
Experimental
2
cm ), BASi Ag/AgNO
3
(0.1 M) reference electrode, and Pt wire
was dried prior to use. CVs were rec-
General Considerations. All reactions and samples were pre-
-filled glovebox unless stated otherwise. Anhydrous sol-
vents were obtained from drying columns and stored over activated
counter electrode. TBAPF
6
pared in a N
2
orded with compensation for solution resistance and were refer-
+
enced to the ferrocenium/ferrocene (Fc/Fc ) couple by recording
3
9
molecular sieves. NMR spectra were recorded at the Harvard Uni-
versity Department of Chemistry and Chemical Biology NMR facil-
ity on a Varian Mercury400 spectrometer operating at 400 MHz or
the CV of the complexes in the presence of a small amount of ferro-
cene. Spectroelectrochemical measurements were conducted in a
small volume, 0.5 mm path length spectroelectrochemical cell
1
a Varian Unity/Inova500 spectrometer operating at 500 MHz for H
+
equipped with a Pt mesh working electrode, a nonaqueous Ag/Ag
acquisitions, and Varian Unity/Inova500C spectrometer operating
at 126 MHz for C acquisitions. H NMR chemical shifts are re-
reference electrode, and a Pt auxiliary electrode, all purchased from
Bioanalytical Systems. A fiber-coupled light source (Ocean Optics
DT-MINI-2GS) illuminated the sample and the transmitted light
1
3
1
ACS Paragon Plus Environment

Page 3 of 13
Journal of the American Chemical Society
was coupled into an optical fiber and sent to an Ocean Optics
USB4000) spectrometer. Absorption spectra were recorded with
OceanView 1.4.1 software.
Scheme 2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Optical Characterization. Steady-state emission spectra were
measured on a Photon Technology International (PTI) QM4 fluo-
rimeter coupled to a 150 W Xe arc lamp as an excitation light source.
The emitted photons were detected by a Hamamatsu R928 photo-
multiplier tube (PMT) cooled to –70 °C. Samples were placed in
tightly sealed 1 cm path length quartz cuvettes. Steady-state Stern-
Volmer (SV) quenching experiments monitored the emission inten-
sity at 500 nm generated by excitation at 370 nm, while dynamic
quenching experiment followed emission decay at 500 nm after laser
excitation at 355 nm. For all SV quenching experiments, the sample
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Bu
contained PC (25 μM), Pi
2
(0.25 mM) and different concentration
of quenchers 1a and MesSH. Before each series of experiments, the
lifetime of PC was measured in absence of quencher; the lifetime of
PC* varied from τ = 1.70 to 1.82 ꢀs, in good agreement with previ-
0
ously reported lifetimes for analogous iridium polypyridyl com-
optimizations were carried out on an ultrafine grid with the conver-
gence criterion: RMS(Force) < 3 × 10 (iop1/7 = 30). Frequency
47
Bu
–6
plexes. Stock Pi
2
solutions of PC and quencher were prepared and
mixed to give the desired concentration of quencher (with the con-
centration of PC held at 25 μM). All Stern-Volmer experiments were
conducted under identical experimental conditions in less than 1 h,
ensuring that oxygen contamination was minimized (as verified by
calculations verified the nature of the optimized structure; local min-
ima displayed no negative frequencies, while transition states indi-
cated one negative frequency associated with the excepted IRC.
Gibbs free energies for each compound were obtained at T = 298.15
K and the corresponding cyclization rates were approximated by
transition-state theory according to the following,
the minimal variation in τ ).
0
Detailed information about the nanosecond transient absorption
48
(
TA) spectroscopy setup has been provided previously. Briefly, an
rd
ꢂꢃꢄ
ꢅ
∆ꢇⱡ
Quanta-Ray Nd:YAG laser (SpectraPhysics) provides 3 harmonic
laser pulses at 355 nm with a repetition rate of 10 Hz and maximum
output of 3 W. The laser output was directed to a MOPO (Spec-
traPhysics) to produce tunable pump pulses from the UV to the vis-
ible spectral region. The excitation energy at the sample was set to 1
mJ/pulse. White light generated by a 75 W Xe-arc lamp (Photon
Technologies Incorporated A1010 arc lamp) was partly selected
with a pinhole to serve as probe light. Both pulses were focused and
overlapped on the sample with a crossing angle of ~15°. Samples
were flowed through a 1 cm path length flow cell (Starna Cells) to
avoid photodamage. The transmitted probe was directed to a spec-
trometer (Triax 320) and detected either by a PMT (Hamamatsu)
or a CCD camera (Andor Technology). Single-wavelength TA
traces were recorded by the PMT coupled to a 1 GHz oscilloscope
ꢀꢁ
=
exp ꢆ−
ꢈ
(1)
ꢂꢃꢄ
where k
B
is Boltzmann’s constant, T is temperature, h is Planck’s con-
ⱡ
stant and ∆ꢉ is the Gibbs free energy barrier for cyclization.
UV-vis absorption transitions for 1a• and 2a• were computed us-
4
9
ing time-dependent DFT (TD-DFT) in Gaussian 16 at the same
level of theory. The number of excited states included in the calcula-
tion was set to 8.
Results
Photoredox Hydroamidation Quantum Yield. The photore-
dox hydroamidation of 1a was performed using the procedure re-
ported by Knowles and co-workers (Scheme 2). In this cycle, the
3
5
+
[
Ir(dF(CF
3
)ppy)
2
(bpy)] photocatalyst (PC) is quenched by the
(LeCroy 9384CM), while spectra were acquired by the CCD cam-
amide to produce the amidyl radical. This quenching reaction occurs
by PCET, and hence is promoted by the presence of the dibu-
tylphosphate base, Pi . After cyclization, MesSH serves as a hydro-
gen atom donor to the cyclized radical intermediate to furnish the
final product. Using a ferrioxalate actinometer (λexc = 380 nm), we
find that the desired cyclized carbamate product 2a is obtained in
era. All setups were synchronized either to the TTL pulse of the Q-
switch signal or the pump pulse detected by a photodiode. Time de-
lays were generated by an SRS DG535 delay generator (Stanford Re-
search Systems). The solution used to record kinetic traces typically
Bu2
Bu
contained PC (0.1 mM), Pi
2
(1 mM), the amide substrate (10
mM), and when necessary, MesSH or MesSSMes (2 mM). The ex-
periments were conducted in succession to ensure the same experi-
mental conditions. The pump wavelength was set to 355 nm or 440
nm to ensure exclusive absorption by PC. The fitting procedures of
the kinetic traces are detailed in the SI.
86% yield with a quantum efficiency of 4.7(4)% ([MesSH] = 2
mM). The influence of the arylthiol concentration on the quantum
efficiency was evaluated by conducting the photoredox hydroami-
dation of 1a in the presence of various concentrations of MesSH
(0.2, 1, and 4 mM), which furnished quantum yields of 2.1, 3.4 and
DFT Calculations. Quantum mechanical calculations were per-
formed using density functional theory (DFT) as implemented in
6
.5%, respectively. The hydroamidation of para-cyano substrate 1b
49
into product 2b under standard conditions proceeded with a quan-
titative yield and showed an increase in quantum yield to 5.8(4)%,
as expected as a result of the presence of an electron-withdrawing
group (EWG), which leads to faster cyclization rate through desta-
bilization of the electrophilic amidyl radical intermediate.
The hydroamidation of 1a with MesSSMes in place of MesSH
proceeds in 91% yield and with an enhanced quantum efficiency of
Gaussian 16. All geometry optimizations were carried out at the
UB3LYP/cc-pVTZ level of theory in combination with the conduc-
tor-like polarizable continuum model (C-PCM) to implicitly ac-
count for solvation of the molecules in CH
2
2
Cl . Transition states
3
4
were obtained with the QST3 algorithm and intrinsic reaction coor-
dinate calculations (IRC, backward and forward direction) resulted
in the expected reactant and product species. In all cases, geometry
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 13
Bu
Bu 51
2
]/Δδ against [Pi
2
]. The retrieved value for the
from a plot of [Pi
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Bu
2
–1
binding constant between PC and Pi
is K = 549(24) M (Figure
S1b). Additionally, a shift in the NH resonance of 1a is observed
Bu
upon increasing concentrations of Pi
Pi to 1a via a hydrogen bonding interaction (Figure S1c). The
equilibrium constant for the interaction between Pi
2
, suggesting association of
Bu
2
Bu
2
and 1a may
be obtained from similar titration studies, furnishing a binding con-
-1
stant of K = 25(1) M (Figure S1d).
Bu
The association of 1a to Pi
2
is consequential to excited state
35
quenching. 1a alone does not quench the excited state of the PC,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Bu
2
however, in the presence of Pi
, a steady-state SV quenching con-
–1
stant of KSV = 939 M was observed (Figure S5), in agreement with
Knowles’ previous studies. Moreover, a similar Ksv value of 890 M
Figure 1. Emission spectra of PC (25 ꢀM) without (▬) and with PiBu
(2 mM) (▬). Emission profile obtained upon the addition of 20 mM
TBAPF (▬). Inset: Emission decay of PC (25 ꢀM) without (▬) and
35
-1
2
is obtained from dynamic quenching measurements (Figure S5).
6
These quenching results are consistent with a shift in the redox po-
Bu
Bu
2
with Pi
2
(2 mM) (▬). Decay trace (▬) obtained upon the addition
tential of 1a upon its association to Pi , as confirmed by cyclic volt-
of 20 mM TBAPF
6
.
ammetry measurements. The cyclic voltammogram (CV) of 1a
alone shows an irreversible wave at +1.3 V (Figure S2a). In the pres-
ence of base, a new cathodic peak appears at +0.77 V (Figure S2b).
With an oxidation potential for PC* of +0.85 V (based on the stand-
1
1.9(8)%. When the excitation wavelength was changed to λexc = 435
nm, a similar quantum yield of 13.9(10)% was measured. The con-
stancy between the quantum yields at these different wavelengths
ensures that the increased quantum efficiency observed for MesSS-
Mes is not a result of its direct photolysis, as MesSSMes has no ab-
sorption at 435 nm (Figure S11). The photoredox hydroamidation
of 1a with both MesSH (10 mol%) and MesSSMes (10 mol%) pro-
ceeds with a quantum efficiency (13.5(10)%) similar to that of
MesSSMes alone (Table S1). As observed previously for the para-
cyano substrate 1b, the quantum efficiency for hydroamidation in-
creases (to 20.0(9)%) when MesSH is replaced with MesSSMes.
–
ard potential of the redox couple PC/PC and the maximum emis-
15
sion wavelength of PC* of 500 nm), whereas the direct oxidation
Bu
of 1a by PC* is not possible, the oxidation of 1a associated to Pi
thermodynamically accessible.
2
is
Bu
MesSH is also capable of quenching PC* in the presence of Pi .
2
Steady-state and dynamic SV quenching measurements yield Ksv
=
–1
–1
2
K
1
29 M and 232 M , respectively (Figure S6). Based on the relative
SV of 1a as compared to that of MesSH, we deduce that 10 mM of
a will quench the PC* emission by 89.9%, and thus 1a is the pri-
mary quencher under the experimental synthesis conditions. As KSV
= k where τ is the natural (unquenched) lifetime of PC* (τ (PC*)
1.7 and 1.82 ꢀs, respectively), the rate constants for quenching by
Quenching Studies. Stern-Volmer (SV) quenching experi-
Bu
τ
q o
o
o
ments were conducted to evaluate the reaction of PC* with Pi
2
,
=
MesSH and the amide substrate.
8
–1 –1
8
–1 –1
Bu
1a and MesSH are 5.2 × 10 M s and 1.3 × 10 M s , respectively.
The former represents rate for the PCET reaction (kPCET1) of the am-
ide with PC*.
The presence of Pi
2
nominally affects the photophysics of PC*.
Addition of base prompts the appearance of fine structure on the
PC* emission profile (Figure 1), though the overall integrated emis-
sion intensity is unchanged. The lifetime of PC increases marginally
Bu
Transient Species. The PCET reaction between PC* + Pi
2
+
Bu
1
a generates the amidyl radical 1a•, HPi
2
and the reduced Ir(II)
from 1.78 (black trace, Figure 1 inset) to 2.01 ꢀs (red trace, Figure 1
–
Bu
species PC . Transient absorption (TA) spectroscopy was under-
taken to characterize these species and their reaction rate constants.
TA spectra of photocycle intermediates were generated from the
inset) with the addition of 2 mM Pi
2
(Figure 1, inset). The emis-
Bu
sion intensity and lifetime do not change for the addition of Pi
2
concentrations down to 0.5 mM (Figure S4). These results are sug-
, as has been observed to occur
when cationic polypyridyl complexes are in the presence of monoan-
Bu
2
and PC + MesSH
, as the quenching studies (vide infra) showed that both 1a and
Bu
two initial quenching photoevents: PC + 1a + Pi
gestive of ion-pair formation, PC:Pi
2
Bu
2
+
Pi
MesSH can react with PC* in the presence of Pi
Figure 2A (black trace) shows the TA spectrum at 2.5 ꢀs after
Bu
2
.
5
0
ionic species such as chloride. Addition of an excess TBAPF
solution of PC and Pi
6
to a
Bu
2
recovers the native lifetime of PC (blue
trace, Figure 1 inset), and the fine structure on the emission profile
Bu
photoexcitation (λexc = 355 nm) of PC + 1a + Pi
2
in CH
2
2
Cl . At this
–
Bu
time delay, PC and 1a• only contributes to the TA signal, as PC* is
of PC is lost, consistent with the separation of a PC:Pi
2
ion pair at
removed by quenching and the base shows no visible absorption.
increased ionic strength of the solution.
–
1
Both the absorption spectra of PC and 1a• may be determined in-
An ion-pair complex is reflected in the H NMR spectrum of PC
Bu
dependently. Because the CV of PC (Figure 3, inset) shows a reversi-
in the presence of increasing concentrations of Pi
methane. Addition of Pi
2
in dichloro-
to PC causes a shift in the CH ligand res-
onance at 8.61 ppm (Figure S1a). The equilibrium constant for the
–
+
Bu
ble PC/PC redox couple a wave at –1.64 vs Fc/Fc , the absorption
2
–
spectrum of PC may generated by spectroelectrochemistry (Figure
3, red spectrum). As both PC and PC are present in the TA spec-
–
Bu
binding between Pi
2
and PC may be obtained from the chemical
Bu
trum, the spectrum of consequence is the difference spectrum of PC
shift (δ) of this resonance upon titration of PC by Pi
relationship,
2
, using the
–
and PC (Figure 3, orange spectrum), which is provided by subtract-
ing the PC absorption profile of Figure 3 (black spectrum) from the
–
ꢃꢌꢍ
ꢃꢌꢍ
]
PC absorption profile of Figure 3 (red spectrum). The absorption
[
ꢊꢋ
]
ꢏ
[ꢊꢋ
=
−
(2)
∆
ꢎ
ꢐ∆ꢎꢑꢒꢓ
∆ꢎꢑꢒꢓ
spectrum of 1a• may be determined independently with the use of
the radical initiator camphorquinone (CQ) to generate 1a• by HAT
between CQ* and 1a, as the excited state CQ* is known to abstract
where Δδ = δ(PC) – δobs, and Δδmax is the maximum value of Δδ. Spe-
cifically, the equilibrium constant, K (= slope/intercept), is provided
52
hydrogens from a variety of substrates. The advantage of CQ as a
ACS Paragon Plus Environment

Page 5 of 13
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 3. UV-vis spectroelectrochemistry of PC and reduced PC– in
+
CH
2
Cl
2
. Applying a potential of –1.66 V vs Fc/Fc converts PC (▬)
–
into PC (▬). The difference extinction coefficient (▬) between PC
–
and PC is shown according to the right axes. Inset: CV of a solution of
with 0.1 M TBAPF
at a scan rate 0.01 V s–
1
PC (0.2 mM) in CH
and referenced vs Fc/Fc .
2
Cl
2
+
6
Scheme 3
Figure 2. A TA spectrum (▬) taken 2.5 μs after photoexciting (λexc
=
Bu
3
55 nm) a CH
2
Cl
2
solution of PC (0.1 mM), Pi
2
(1 mM) and 1a (10
mM). TA spectrum (▬) taken 20 μs after photoexciting (460 nm) a
Bu
the PC + MesSH + Pi
2
quenching reaction in CH
2
Cl . The TA
2
Bu
CH
2
Cl
2
solution of camphorquinone (CQ) (10 mM), Pi
2
(1 mM)
spectrum for the MesS• (Figure 2B, purple line) was independently
obtained from laser excitation (λexc = 355 nm) of di-(2,4,6-trime-
thylphenyl) disulfide, MesSSMes, in CH
sorption at λmax = 493 nm is characteristic of arylthyil radicals. The
sum (Figure 2A, red line) of the PC/PC difference spectrum (Fig-
ure 2B, orange line) and the MesS• absorption spectrum (Figure 2B,
purple line) perfectly matches the TA spectrum (Figure 2B, blue
line) obtained for PC + Pi
–
and 1a (10 mM). The absorption spectrum of PC (▬), generated by
spectroelectrochemistry (see Figure 3). The spectrum shown in red
2
2
Cl (Figure 2B); the ab-
–
(
▬) is generated by adding the spectrum of PC (▬) and 1a• (▬);
this spectrum reproduces the TA spectrum at 2.5 μs (▬). B TA spec-
trum (▬) taken 5.2 μs after photoexciting (440 nm) a CH Cl solution
(1 mM) and MesSH (10 mM). TA spectrum
▬) obtained after photolysis (λexc = 355 nm) of a CH Cl solution of
5
3,54
–
2
2
Bu
of PC (0.1 mM), Pi
(
2
2
2
Bu
2
+ MesSH, confirming that PC* in the
–
MesSSMes (1 mM). The absorption spectrum of PC (▬), generated
presence of base is quenched by MesSH in an photoinduced elec-
tron transfer event.
by spectroelectrochemistry (see Figure 3). The spectrum shown in red
–
(
▬) is generated by adding the spectrum of PC (▬) and MesS• (▬);
Figure S9 summarizes the absorption spectra of the key photore-
this spectrum reproduces the TA spectrum at 5.2 μs (▬).
–
dox intermediates, PC , 1a• and MesS• and shows their difference
molar absorptivity coefficients, which are valuable for modelling
photosensitizer is its weak excited state absorption together with the
weak absorption of the CQH• photoproduct in the 400 to 600 nm
spectral range (Figure S7), thus allowing for baseline-free detection
of the radical signature of 1a• at λmax = 435 nm (Figure 2A, green
line). To further confirm that the spectral feature has N• parentage,
we examined the photoreaction of CQ with 3, which is an analog of
transient absorption kinetics (vide infra). The difference extinction
coefficient for PC was determined from the spectroelectrochemical
–
spectrum in which a sufficient number of Coulombs were passed to
–
ensure complete conversion to PC . The difference extinction coef-
ficient for 1a• was determined from TA spectrum at 2.5 ꢀs after pho-
Bu
toexcitation (λexc = 355 nm) of a solution of PC + 1a + Pi
2
. At this
–
1a without the olefin functionality, for which the cyclization step is
early time, PC and 1a• are generated in equimolar amounts by the
impossible (Scheme 3). The TA spectrum recorded after 2.5 ꢀs laser
PCET quenching. Therefore, the difference extinction coefficient of
Bu
–
excitation (λexc = 355 nm) of a solution of either PC + Pi
ure S8a) as well as CQ + Pi
2
+ 3 (Fig-
1a• is provided by deconvoluting the signal into the signal of PC
Bu
–
2
+ 3 (Figure S8b) is the same as that
and 1a•, and then referencing to the molar absorptivity of PC . The
obtained when 1a is the substrate, confirming that the spectral fea-
same method furnishes the difference extinction coefficient for
MesS• shown in Figure S9.
ture at 435 nm belongs exclusively to the amidyl radical species. As
–
shown in Figure 2A, the sum (red line) of the PC/PC difference
Figure S10 displays the TA spectra recorded on solutions con-
Bu
taining PC + Pi
2
+ MesSH in the presence of either 1a or 3. At long
spectrum (Figure 2A, orange line) and the 1a• spectrum (Figure 2A,
green line) matches the TA spectrum (Figure 2A, black line) ob-
times after excitation (21.5 ꢀs), a significant signal arising from
MesS• is observed. The Stern-Volmer quenching results indicate
that the amount of MesS• generated by quenching PC* with MesSH
is insignificant (owing to the dominance of substrate quenching aris-
ing from its higher concentration ([1a] = 10 mM, [MesSH] = 2
Bu
tained for solutions of PC, Pi
2
and 1a, confirming that PC* reacts
with 1a in the presence of base by photoinduced electron transfer to
–
form PC and 1a•.
Figure 2B shows the results of a similar series of experiments for
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 13
unimolecular cyclization reaction furnishes a cyclization rate con-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
4 –1
stant k = 2.4 × 10 s .
c
After cyclization, the radical product 2a• can engage in two reac-
tions: (i) HAT with MesSH to give the hydroamidation product 2a
–
Bu
Bu
2
and MesS•, and (ii) PCET with PC , HPi
2
to regenerate PC:Pi
and produce 2a. We were able to extract the rate of HAT between
a and MesSH by following the appearance of MesS•, which was fit-
2
8
–1 –1
ted to a value of kHAT2 = 1.8 × 10 M s . Although this rate is subject
to error because of the low signal of MesS• at the later stages of the
reaction, the fitted number is consistent with reported rate constants
of HAT between thiols and secondary alkyl radicals, which are well
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
8
–1 –1 56
documented to be in the order of 10 M s . We cannot determine
–
Bu
2
the rate of the PCET between PC , HPi
and 2a• because 2a• does
not exhibit an appreciable visible absorption signature. Nonetheless,
Figure 4. Single wavelength kinetic traces recorded at 425 nm after
we believe that the this PCET reaction is minor as compared to HAT
Bu
photoexcitation (355 nm) of a solution of PC, Pi
2
and 3 in the absence
–
because the concentration of PC is significantly lower than that of
(
○, experimental data; ▬, fit) and presence (○: experimental data, ▬:
–
Bu
MesSH, such that kPCET3[PC ] << kHAT2[MesSH]. In evidence of the
model fit) of MesSH, compared to a solution of PC, Pi , substrate 1a
2
insignificance of this pathway, no product is observed in the absence
of MesSH.
in the absence (○: experimental data, ▬: model fit) and presence (○:
experimental data, ▬: model fit) of MesSH. Inset: early time dynamics.
Note, the orange and green traces are overlapped with each other.
The MesS•, generated from both HAT reactions involving 1a•
–
Bu
2
and 2a•, may react with PC and HPi
by PCET to complete the
photocycle. Fitting the decay of MesS• formed after photoexcitation
mM) and larger quenching rate constant k ). Accordingly, the ob-
q
Bu
(
λ
exc = 355 nm) of a solution of PC + Pi
2
+ 3 + MesSH yields a rate
servation of MesS• at long times is indicative of reactions subsequent
to the substrate quenching reaction with PC*. It is noteworthy that
the production of MesS• is more prevalent when the substrate is 1a
than 3, presaging its important role in the complete photoredox hy-
droamidation process.
Kinetics Rate Constants for the Photoinduced Catalytic Hy-
droamination Cycle. Because substrate 3 eliminates the possibility
of cyclization, it isolates the reaction kinetics for generation of the
amidyl radical and its return to the amide reactant by BET or HAT
9
–1 –1
constant of kPCET2= 5.4 × 10 M s for the reaction of MesS• with
–
Bu
2
PC in the presence of HPi
.
The orange trace in Figure 4 shows the decay at 425 nm of the
Bu
complete system, i.e. PC + Pi
2
+ 1a + MesSH and as a reference in
Bu
the absence of cyclization, PC + Pi
2
+ 3 + MesSH (Figure 4, green
trace). The decay traces for both solutions are identical, a result that
is in line with a cyclization rate constant that is small as compared to
k
BET and kHAT1. The rate constants and standard deviations from fits
of the time-dependent data are listed in Table S2.
(with MesSH). The single wavelength kinetic trace of the amidyl
DFT Calculations. Further support for the assignment of the
visible absorption features observed in the nanosecond transient ab-
sorption measurements is offered by time-dependent density func-
tional theory (TD-DFT). Figure 5 shows the absorption line spec-
trum of 1a• calculated from TD-DFT. After Gaussian broadening
radical 3• monitored at 425 nm after photoexcitation (λexc = 355 nm)
Bu
of a solution of PC + Pi
2
+ 3 was measured first in the absence of
MesSH to allow the BET kinetics between the amidyl radical and
–
PC to be defined without interference of cyclization. The monitor-
ing wavelength of 425 nm was selected slightly to the blue of the
maximum absorption of the radical so as to be outside the window
of residual PC* emission. In the absence of a hydrogen atom donor,
the decay of the TA signal in Figure 4 (red trace) is a result of the
(
see methods) and scaling of the simulated spectrum of 1a• by a fac-
tor of 0.47, we observe excellent agreement with the experimentally
deduced absorption spectrum. As expected for an aliphatic carbon
radical, cyclized radical 2a• absorbs almost exclusively in the UV
spectral region, inaccessible to our laser excitation wavelength (Fig-
ure 5). We can therefore confidently exclude cyclized radical signa-
tures in our transient absorption data and subsequent photoinduced
chemistry of the cyclized radical species.
–
BET reaction between PC and 3• and accordingly is governed by
bimolecular kinetics. Fitting the decay trace (see SI) furnishes kBET
=
9
–1 –1
7.4 × 10 M s . The green trace in Figure 4 is the observed decay of
the amidyl radical when MesSH is added to the reaction mixture.
The faster disappearance of the amidyl radical 3• in the presence of
MesSH is a consequence of HAT between the amidyl radical and
MesSH to produce 3 and the thiyl radical MesS• species. The re-
The cyclization reaction of 1a• to 2a• was also investigated using
DFT calculations (Figure 6A). The product radical 2a• is lower in
–1
energy by ΔGstab = 3.5 kcal mol compared to 1a•, indicating a ther-
7
–1 –1
trieved rate constant of kHAT1 = 7.9 × 10 M s is in the range of
modynamically favorable reaction. However, the transition state for
5
5
reported values for HAT between amidyl radicals and thiols. We
‡
–1
the cyclization is energetically uphill by ΔG = 12.57 kcal mol ,
note that though kHAT1 is two orders of magnitude slower than kBET
,
3
which translates to a cyclization rate constant of kc,DFT = 3.75 × 10
s , in good agreement with the experimental value of 2.4 × 10 s as
the former reaction pathway is manifest in the photocycle owing to
the high concentration of MesSH (2 mM) in the reaction mixture.
Next, we explored the contribution of the cyclization reaction (in
-1
4 –1
measured by TA kinetics. The associated rate constants for the re-
–1
verse cyclization (2a• → 1a•) computes to 10.2 s , rendering the
the absence of MesSH) to the decay kinetics by examining the ki-
intramolecular cyclization essentially irreversible. To examine the
effect of the para substituent on the cyclization rate, the activation
barriers were calculated for the following para-substituted groups: –
Bu
netic trace at 425 nm of a solution of PC + Pi
2
+ 1a. We observe a
marginally faster decay signal compared to the same solution con-
taining substrate 3. This difference is attributed to the presence of
the cyclization reaction pathway, which also consumes 1a• (Figure
NO
2
, –CN, –CF
3
, –H, –Br and –OMe and correlated with the corre-
57
sponding Hammett parameter, i
p
(Figure 6B, top). We find a gen-
4, blue trace). Kinetics analysis with the added contribution of the
ACS Paragon Plus Environment

Page 7 of 13
Journal of the American Chemical Society
Scheme 4
1
2
3
4
5
6
7
8
9
-1
mol ) indicating the thioamide to be a stronger trap with an equilib-
rium that remains thermally accessible. We therefore investigated
the photoredox hydroamidation cycle employing MesSSMes in
place of MesSH.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The single wavelength kinetic trace at 425 nm after photoexcita-
Bu
tion (λexc = 440 nm) of a solution of PC + Pi
2
+ MesSSMes + 1a
Figure 5. Simulated absorption line spectrum for 1a• and 2a• (or-
ange and blue, respectively, right y-axis) overlaid with the experi-
mentally retrieved 1a• spectrum (black, left y-axis). Simulated ab-
showed a higher concentration of both 1a• and MesS• after 21.5 μs
Figure 7). Photoexcitation was conducted at 435 nm or 440 nm to
avoid direct photolysis of MesSSMes; unlike photoredox cycles re-
(
sorption line spectra were scaled by 0.47 and broadened to 0.25 eV
2
1
–1
lying on direct photolysis of the disulfide, direct photolysis is neg-
ligible at 380 nm. Indeed, based on the extinction coefficients of PC
and MesSSMes at 380 nm (Figure S11), only ~5% of the incident
photons are absorbed by MesSSMes and at 435 nm, MesSSMes does
not absorb light. In view of the similar quantum efficiencies for 435
nm (13.9%) and 380 nm (11.9%) excitation, direct photolysis of di-
sulfide is not responsible for the production of MesS• observed in
Figure 7.
(
2016 cm , at half-width half height) to match the amplitude of the
experimentally retrieved 1a• spectrum (orange and blue shaded,
left y-axis).
‡
eral decrease in ∆G for increasing strength of the electron withdraw-
ing substituents. The decreased activation barrier directly translates
into a faster cyclization rate with the fastest calculated rate constant
NO
5
–1
for NO
2
(k
c
2
= 2.2 × 10 s ) and the slowest calculated rate con-
c
To define the role of thioamide 4 in the photocycle, the photore-
dox chemistry was performed with 4 as the only potential source of
amidyl radical. The thioamide was prepared through the sequence
of reactions consisting of deprotonation of 1a with 1 equiv of NaH
followed by addition of MesSCl. When solutions of PC + MesSH +
OMe
1 –1
stant for OMe (k
= 3.2 × 10 s ). The observed trend for the ac-
tivation barrier is mirrored in the trend for the stabilization Gibbs
free energy of the product radical compared to the substrate radical
(Figure 6B, bottom).
Disulfide Trapping. With the insights provided by the kinetics
measurements, we sought to trap the photogenerated amidyl radical
4
were photolyzed, 1a and 2a are quantitively produced (in a 1:0.2
ratio). Direct irradiation of 4 in the presence or absence of PC leads
to an intractable mixture of products over hours with negligible for-
mation of 2a, thereby confirming that the amidyl radical/thioamide
equilibrium of Scheme 4 results in a clean conversion cycle.
–
to minimize its back reaction with PC . Energetic considerations led
us to deliver a masked MesS• to amidyl radical 1a• by reacting
MesSSMes with 1a• to form the thioamide species 4 via the equilib-
rium depicted in Scheme 4. DFT calculations show that the energy
difference for the reaction between 1a• and MesSSMes to produce
–
The reaction between PC and MesSSMes was examined as a
possible side reaction. Figure S3 shows the CV for the electrochem-
ical reduction of PC in the presence of MesSSMes. A S-waveform is
0
–1
4 and MesS• is slightly favorable at ΔG DFT = –1.19 kcal mol . A
0
more favorable reaction is obtained for 1b (ΔG DFT = –2.59 kcal
Figure 6. Calculated cyclization reaction properties. (a) Reaction diagram depicting the cyclization 1a• → 2a• with associated optimized
–1
structures. Values in parentheses are relative Gibbs free energies in kcal mol . The inset illustrates the ring-delocalization of the nitrogen-
centered radical in the singly-occupied molecular orbital. (b) Computed Gibbs free energy activation barriers (top, black circles) and linear fit
top, orange, dashed) and product stabilization Gibbs free energies (bottom) for different para-substituents on the phenyl ring correlated with
(
2
the Hammett parameter, σ
p
. The R values for the linear fits are also shown.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 13
constants were determined from eq (3) for CVs taken at scan rates
of 0.02 V s for solutions containing PC (0.2 mM) + MesSSMes at
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
–1
concentrations of 2, 5, 10 mM; the averaged rate constant of kcat
=
–1 –1
4
8(3) M s is too slow to account for the fast kinetics observed in
transient absorption experiments. Thus, the observed transient and
kinetics observed in Figure 7 is a direct result of the amidyl radi-
cal/thioamide equilibrium.
Discussion
Scheme 5 shows the complete photoredox hydroamidation cy-
cle. The solid black pathway was originally identified by Knowles
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
5
and co-workers, and the results described herein are in complete
agreement with this pathway. The electrochemical, quenching and
transient kinetics studies reported in this study allow us to further
elaborate the cycle with the addition of the red, blue and dotted path-
ways and all rate constants for the primary photoredox event and
subsequent reactions of intermediates. The photoredox hydroami-
dation of substrate 1a, despite being quantitative, proceeds with a
low quantum efficiency of 4.7% (±0.4) (Figure 8). Critical to the
overall efficiency of the photoredox cycle are the red reaction path-
ways involving the photogenerated amidyl radical and its subse-
quent reaction kinetics.
Figure 7. TA decay trace (▬) recorded at 425 nm after photoexciting
440 nm) a solution of PC (0.1 mM), PiBu
(1 mM), 1a (10 mM)
and MesSSMes (1 mM). The normalized blue trace (▬) is from Figure
(
λ
exc
=
2
4
, which results from photoexciting (
λ
exc
= 355 nm) a solution of PC
Bu
(
0.1 mM), Pi
2
(1 mM) and 1a (10 mM). Inset: TA spectra taken at
2
1.5 μs after photoexcitation.
observed, characteristic of a rate-limiting catalytic reaction that is
5
8
not limited in substrate. For this case, the plateau current directly
5
9,60
yields the reaction rate constant
from,
Overall there are five critical reaction intermediates (i.e. PC*
–
(
Ir(III) photosensitizer), PC (Ir(II) photoproduct), 1a•, 2a• and
ꢘ
ꢘ
ꢔ = Fꢕꢖ √ꢙꢚꢀꢖ
(3)
ꢗ
ꢛ
MesS•), characterized by 7 rate constants, that define the complete
catalytic cycle comprising the following steps: (i) absorption of a
photon by PC to produce the excited state PC*, and (ii) PCET be-
where i represent the plateau current, F the Faraday constant, S the
ꢘ
electrode surface, ꢖ the PC concentration, D the diffusion coeffi-
Bu
ꢗ
2
tween PC* and the amide that is hydrogen bonded to Pi to yield
ꢘ
cient of PC, k the rate constant of the reaction and ꢖ the concen-
Bu
–
ꢛ
2
an amidyl radical, HPi and the reduced species PC . At this
tration of MesSSMes. The diffusion coefficient D of PC was calcu-
lated using,
branchpoint, three separate reaction paths are available to the pri-
Bu
mary photoproducts: (iii) BET between the amidyl radical, HPi
2
–
and the reduced species PC to regenerate the starting reagents, (iv)
HAT between the amidyl radical and MesSH to produce the amide
reactant and MesS•, and (v) cyclization by addition of the amidyl
radical to the double bond to form a carbon centered radical. Fol-
lowing cyclization, (vi) HAT between the C-centered radical and
MesSH generates the final hydroamidation product and MesS•. The
ꢟꢠ
ꢘ
ꢘ
ꢔ = 0.446ꢝꢕꢖ √ꢙꢞ
(4)
ꢜ
ꢗ
ꢡꢄ
ꢘ
where ꢔꢜ represent the peak current of PC in the absence of MesSS-
Mes, v the scan rate, R the gas constant, and T the temperature. Rate
Scheme 5
ACS Paragon Plus Environment

Page 9 of 13
Journal of the American Chemical Society
highlighted by the singly-occupied molecular orbital (SOMO, Fig-
1
2
3
4
5
6
7
8
9
ure 6A, inset). Following cyclization, product 2a is most easily
formed by HAT between 2a• and MesSH. To determine this rate
constant, we monitored the transient absorption decay of a solution
Bu
of PC + Pi
2
+ 1a + MesSH (orange trace, Figure 4). As the presence
of the cyclization reaction consumes 1a• to form 2a•, a faster decay
might be expected for the system when 1a is present vs 3 (green
trace, Figure 4). However, we observe almost identical decays for
these two systems. This result is due to the fact that there is addi-
tional absorption arising from the presence of MesS• that is pro-
duced by HAT between the cyclized radical 2a• and MesSH. Fitting
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
the kinetics of the decay of the orange trace with the known kBET
,
k
1
HAT1 and k
c
rate constants (section G4 in SI) furnishes kHAT2 = 1.8 ×
8
–1 –1
–
Bu
0 M s . Finally, the cycle is closed by PCET between PC , HPi
2
Figure 8. Quantum yield values for the photoredox hydroamidation of
Bu
and MesS• to regenerate PC:Pi
2
and MesSH. The kinetics for this
substrates 1a and 1b in different reaction conditions. Pink bars corre-
reaction is provided by the observed decay of MesS• in the transient
Bu
spond to non-optimized conditions (PC (2 mol%), Pi
2
(20 mol%),
Bu
absorption experiment of a solution of PC + Pi
2
+3 and MesSH.
MesSH (10 mol%)), while blue bars depict optimized conditions (PC
9
–1 –1
The observed decay renders a value of kPCET2 = 5.4 × 10 M s (sec-
tion G2 in SI).
Bu
(
2 mol%), Pi
2
(20 mol%), MesSSMes (10 mol%)). Error bars corre-
spond to one standard deviation.
The rate constants of the complete photoredox cycle reveal the
BET and the HAT reactions as the major non-productive pathways.
The rate constants allow the concentration profiles for the interme-
diate species formed during the reaction to be simulated, including
the product radical 2a•. If no BET or HAT1 were present, 100% con-
version of 1a• to 2a• is expected. When the BET pathway is added
c
–
Bu
2
cycle is closed by (vii) PCET among PC , HPi
generate PC:Pi
and MesS• to re-
Bu
2
and MesSH. Alternatively, the cycle is closed di-
rectly by the PCET reaction of the C-centered radical with PC and
–
Bu
HPi
2
. We now progress through each step of the catalytic cycle, be-
ginning with the PCET quenching step.
into the simulation (i.e., kBET and k added to the simulation), we ob-
Based on measured redox properties, PC* is not capable of oxi-
serve that only 29.6 % of 1a• converts to 2a•; 71.4% of 1a• engages
in BET reaction. With the addition of the HAT1 pathway to the sim-
ulation, the overall conversion yield of 1a• to 2a• is further reduced
to 8.4%. Thus, the combination of BET and HAT1 pathways con-
sume 91.6% of 1a• after the initial PCET quenching event. Noting
that the initial quenching event has a yield of 89.9%, the upper limit
for the photoredox product quantum yield is 7.6%.
dizing the substrate alone but can oxidize the amide when hydrogen
Bu
bonded to a base such as Pi
2
. Such hydrogen-bonded PCET events
are common for a multitude of redox-based organic transfor-
6
1–64
mations.
Both steady state and dynamic quenching experiments
indeed show that the PCET quenching between PC* and 1a is effi-
Bu
cient only when Pi
2
is present, and the PCET quenching event pro-
8
ceeds with a rate constant of k
M s . Additionally, the PCET nature of the quenching event is con-
q
(= kPCET1 in Scheme 5) = 5.2 × 10
With the major loss pathways of BET and HAT1 established, we
explored optimization strategies aimed at minimizing these reac-
tions. Because the cyclization rate for 1a• is slow as compared to the
BET and HAT rates (Scheme 5), we first sought to use substrates
with faster cyclization rates that could kinetically compete with the
fast BET and HAT reactions. The para substituent of the aniline
group of 1a provides a straightforward handle on the cyclization rate
of the corresponding amidyl radical, since electron-withdrawing
groups (EWG) lead to faster cyclization rate through destabilization
-1 –1
firmed by transient absorption spectra, which shows the decay of
–
PC* with the attendant formation of PC and the prompt formation
of PCET product 1a• upon the laser excitation of a solution of PC +
Bu
Pi
2
+ 1a (Figure 2A). Importantly, the high rate of quenching con-
firms that the low quantum efficiency of the system is not limited by
the initial photoredox event.
After photoinduced electron transfer, the amidyl radical may re-
act by BET, HAT and cyclization defined by rate constants kBET
65
,
of the π-delocalized amidyl radical. DFT calculations indeed sup-
k
HAT1 and k
c
, respectively, in Scheme 5. In determining these rate
port that cyclization rates correlate with the nature of the para sub-
stituent on the aniline group, with stronger EWG groups leading to
increasingly faster cyclization rates due to smaller activation barrier
(Figure 6B). The quantum yield for hydroamidation of the para-cy-
ano substrate 1b into product 2b under standard photoredox condi-
tions does indeed show an increase from 4.7(4)% to 5.8(4)% (Fig-
ure 8). However, as reflected in this modest increase in efficiency,
cyclization alone is too slow to kinetically compete with the BET and
HAT1 reactions.
constants, substrate 3, which cannot cyclize, is useful as it allows the
bimolecular BET reaction to be isolated. Bimolecular kinetics analy-
sis of the red trace in Figure 4 (section G1 in SI) gives kBET = 7.4 ×
9
–1 –1
10 M s . When MesSH is present, back reaction to the amide start-
ing material is enhanced by HAT, as shown by the faster decaying
green trace in Figure 4. With the value of kBET in hand, kinetics anal-
ysis (section G2 in SI) of the decay of the transient absorption signal
Bu
for solutions of PC + 3 + Pi
k
2
+ MesSH (green trace, Figure 4) yields
7
–1 –1
HAT1 = 7.9 × 10 M s . By switching to substrate 1a, the cyclization
Of the two pathways, BET is the most important to the overall
efficiency of the photocycle as (i) the rate constant for this reaction
is highest and (ii) it is effectively enhanced because the primary pho-
reaction kinetics is introduced into the system. This additional ki-
netics pathway is reflected in a faster decay rate (blue trace, Figure
11,66
4
) as compared to that for substrate 3 (red trace, Figure 4). Analysis
toproducts may geminately recombine within a solvent cage. Ac-
of the blue trace using kBET (section G3 in SI) directly furnishes the
cordingly, we turned our attention to directly intruding on this reac-
tion path to markedly increase the efficiency of the photoredox cy-
cle. In the initial quenching reaction, the concentrations of the initial
photoproducts are equal and small (sub-micromolar). Since the
4
–1
rate of cyclization, k = 2.4 × 10 s . The slow intramolecular cycliza-
c
tion rate is a consequence of the delocalization of the unpaired elec-
tron over the phenyl group of the aniline in the amidyl radical 1a•, as
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 13
BET reaction is bimolecular, further reduction in the concentration
of PC or amidyl radical can markedly affect the rate of the reaction.
atom donor as the sources for a reduction in the overall quantum ef-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
–
ficiency of the photoredox cycle of 95.3%. By adopting the strategy
outlined in Scheme 1, an off-cycle equilibrium removes the radical
from the solvent cage formed from the primary photoreaction, thus
attenuating BET and allowing the radical to be released at a later
stage of the photoredox cycle. We believe that this strategy of off-
pathway equilibria may be generalized and will be useful to increas-
ing the quantum efficiency of many other photoredox systems be-
yond hydroamidation. Such increases in quantum efficiency will be
better appreciated as the energy input is recognized as a major deter-
minant in the environmental manufacturing footprint and cost asso-
ciated with photoredox synthetic pathways.
We settled on a strategy to intercept the amidyl radical by reversibly
trapping it, and in doing so, removing it from the solvent cage of the
primary photoproducts, thereby disrupting BET. We found that
–
–1 –1
MesSSMes does not react with PC (k = 48 M s ) and is thus avail-
able to successfully trap the transient amidyl radical 1a• to form thi-
oamide 4 via the equilibrium reaction shown in Scheme 4. Diffusion
–
of the thioamide 4 away from PC impedes the bimolecular BET re-
action. Because of the nearly thermoneutral amidyl radical/thioam-
ide equilibrium, the amidyl radical may be released at a later stage to
re-enter the catalytic cycle and undergo productive cyclization. In
support of this contention, the transient absorption decay of a solu-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Bu
ASSOCIATED CONTENT
Supporting Information
tion of PC, Pi , MesSSMes and 1a shows a higher concentration of
2
both 1a• and MesS• at later stages of the reaction (Figure 7). We
note that independently prepared thioamide 4 in the presence of
MesS• (generated by irradiation of PC and MesSH) promptly and
cleanly produces a mixture of 1a and 2. Conversely, irradiation of
thioamide 4, whether in the presence or absence of PC, leads to an
intractable mixture of products over hours, thereby establishing that
1
Synthetic details for compounds 3 and 4, H NMR binding studies, ad-
ditional details on quantum yield measurements, laser experiments, fit-
ting strategies and a complete author list for ref. 49.
AUTHOR INFORMATION
1a• can only be cleanly generated from thioamide 4 when MesS• is
Corresponding Author
dnocera@fas.harvard.edu
present. These results further support the reversibility of the amidyl
radical/thioamide reaction. By perturbing BET with the side-equi-
librium involving the amidyl radical, when MesSSMes is introduced
in place of MesSH, the hydroamidation quantum yield of 1a is in-
creased to 11.9(8)%; for the faster cyclizing para-cyano substrate 1b,
a quantum efficiency of 20.0(9)% is achieved.
Author Contributions
†These authors contributed equally.
Notes
The authors declare no competing financial interest.
Conclusion
ACKNOWLEDGMENT
The reactions governing the quantum efficiency of the photore-
dox hydroamidation of olefins are elucidated by transient laser and
electrochemical methods. Determination of the rate constants for
the reactions involving five intermediates in the cycle identify the en-
ergy-wasting and non-productive back reaction of the photogener-
ated amidyl radical with the reduced photosensitizer and hydrogen
This work was supported by a grant from the NSF (CHE-1464232). C.
Costentin, A. G. Maher, S. J. Hwang are acknowledged for helpful dis-
cussions. C. N. Brodsky is thanked for helping with spectroelectrochem-
ical measurements. Kate Maldjian is thanked for helping with the
graphics. The computations in this paper were run on the Odyssey clus-
ter supported by the FAS Division of Science, Research Computing
Group at Harvard University.
REFERENCES
(11) Kavarnos, G. J.; Turro, N. J. Photosensitization by Reversible Electron
Transfer: Theories, Experimental Evidence, and Examples. Chem. Rev. 1986, 86,
(1) Shaw, M. H.; Twilton, J.; MacMillan, D. W. C. Photoredox Catalysis in
Organic Chemistry J. Org. Chem. 2016, 81, 6898–6926.
(2) Tucker, J. L. Green Chemistry, a Pharmaceutical Perspective. Org. Process
Res. Dev. 2006, 10, 315–319.
4
01–449.
12) Fox, M. A. Photoinduced Electron Transfer in Organic Systems: Control
of Back Electron Transfer. In Advances in Photochemistry; John Wiley: New York,
(
(
3) Jimenez-Gonzalez, C.; Constable, D. J. C.; Ponder, C. S. Evaluating the
1986; pp 237–327.
‘
Greenness’ of Chemical Processes and Products in the Pharmaceutical Industry-
(13) Narra, S.; Nishimura, Y.; Witek, H. A.; Shigeto, S. Mechanism of Back
Electron Transfer in an Intermolecular Photoinduced Electron Transfer
Reaction: Solvent as a Charge Mediator. ChemPhysChem 2014, 15, 2945–2950.
a Green Metrics Primer. Chem. Soc. Rev. 2012, 41, 1485–1498.
(4) Oelgemöller, M. Solar Photochemical Synthesis: From the Beginnings of
Organic Photochemistry to the Solar Manufacturing of Commodity Chemicals.
Chem. Rev. 2016, 116, 9664–9682.
(
14) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Visible Light Photoredox
Catalysis with Transition Metal Complexes: Applications in Organic Synthesis.
Chem. Rev. 2013, 113, 5322–5363.
(15) Romero, N. A.; Nicewicz, D. A. Organic Photoredox Catalysis. Chem.
Rev. 2016, 116, 10075–10166.
(
5) Francisco García, C. Sustainable Chemistry Metrics. ChemSusChem
009, 2, 905–919.
6) Horn, E. J.; Rosen, B. R.; Baran, P. S. Synthetic Organic Electrochemistry:
2
(
An Enabling and Innately Sustainable Method. ACS Cent. Sci. 2016, 2 , 302–308.
(7) Nocera, D. G. Solar Fuels and Solar Chemicals Industry. Acc. Chem. Res.
(
16) Blanksby, S. J.; Ellison, G. B. Bond Dissociation Energies of Organic
Molecules. Acc. Chem. Res. 2003, 36, 255–263.
17) Waidmann, C. R.; Miller, A. J. M.; Ng, C.-W. A.; Scheuermann, M. L.;
2
017, 50, 616–619.
8) Fu, R.; Chung, D.; Lowder, T.; Feldman, D.; Ardani, K.; Fu, R.; Chung,
(
(
Porter, T. R.; Tronic, T. A.; Mayer, J. M. Using Combinations of Oxidants and
Bases as PCET Reactants: Thermochemical and Practical Considerations. Energy
Environ. Sci. 2012, 5, 7771–7780.
D.; Lowder, T.; Feldman, D.; Ardani, K. U.S. Solar Photovoltaic System Cost
Benchmark: Q1 2017 U.S. Solar Photovoltaic System Cost Benchmark: Q1 2017.
NREL 2017, No. September, 1–66.
(9) Powell, D. M.; Winkler, M. T.; Choi, H. J.; Simmons, C. B.; Needleman,
D. B.; Buonassisi, T. Crystalline Silicon Photovoltaics: A Cost Analysis Frame-
work for Determining Technology Pathways to Reach Baseload Electricity Costs.
Energy Environ. Sci. 2012, 5, 5874–5883.
(
18) Arias-Rotondo, D. M.; McCusker, J. K. The Photophysics of Photoredox
Catalysis: A Roadmap for Catalyst Design. Chem. Soc. Rev. 2016, 45, 5803–5820.
19) William, R. A.; Artur, O.; Fabrice, R. Back‐reactions, Short‐circuits, Leaks
and Other Energy Wasteful Reactions in Biological Electron Transfer: Redox
Tuning to Survive Life in O . FEBS Lett. 2012, 586, 603–616.
(
2
(
10) Cismesia, M. A.; Yoon, T. P. Characterizing Chain Processes in Visible
Light Photoredox Catalysis. Chem. Sci. 2015, 6, 5426–5434.
ACS Paragon Plus Environment

Page 11 of 13
Journal of the American Chemical Society
(
43) Xu, F.; Zhu, L.; Zhu, S.; Yan, X.; Xu, H. C. Electrochemical
Intramolecular Aminooxygenation of Unactivated Alkenes. Chem. Eur. J. 2014,
0, 12740–12744.
44) Goto, K.; Holler, M. Synthesis and Crystal Structure of an Arenesulfenyl
Iodide with Unprecedented Stability. Chem. Commun. 1998, 3, 1915–1916.
45) Hicks, R. G.; Nodwell, M. B. Synthesis and Electronic Structure
(
20) Ponseca, C. S.; Chábera, P.; Uhlig, J.; Persson, P.; Sundström, V.
Ultrafast Electron Dynamics in Solar Energy Conversion. Chem. Rev. 2017, 117,
0940–11024.
21) Romero, N. A.; Nicewicz, D. A. Mechanistic Insight into the Photoredox
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
1
(
(
Catalysis of Anti- Markovnikov Alkene Hydrofunctionalization Reactions. J. Am.
Chem. Soc. 2014, 136, 17024–17035.
(
Investigations of Α,ω- Bis(arylthio)oligothiophenes toward Understanding Wire-
Linker Interactions in Molecular-Scale Electronic Materials. J. Am. Chem. Soc.
(
22) Pitre, S. P.; McTiernan, C. D.; Scaiano, J. C. Understanding the Kinetics
and Spectroscopy of Photoredox Catalysis and Transition-Metal-Free
Alternatives. Acc. Chem. Res. 2016, 49, 1320–1330.
2
000, 122, 6746–6753.
46) Hatchard, C. G.; Parker, C. A. A New Sensitive Chemical Actinometer.
(
(
23) Koyama, D.; Dale, H. J. A.; Orr-Ewing, A. J. Ultrafast Observation of a
II. Potassium Ferrioxalate as a Standard Chemical Actinometer. Proc. R. Soc. A
Math. Phys. Eng. Sci. 1956, 235, 518–536.
(47) Lowry, M. S.; Goldsmith, J. I.; Slinker, J. D.; Rohl, R.; Pascal, R. A.; Mal-
liaras, G. G.; Bernhard, S. Single-Layer Electroluminescent Devices and Photoin-
duced Hydrogen Production from an Ionic Iridium(III) Complex. Chem. Mater.
Photoredox Reaction Mechanism: Photoinitiation in Organocatalyzed Atom-
Transfer Radical Polymerization. J. Am. Chem. Soc. 2018, 140, 1285–1293.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
24) Gooßen, L. J.; Huang, L.; Arndt, M.; Gooßen, K.; Heydt, H. Late
Transition Metal-Catalyzed Hydroamination and Hydroamidation. Chem. Rev.
2015, 115, 2596–2697.
2
005, 17, 5712–5719.
48) Holder, P. G.; Pizano, A. A.; Anderson, B. L.; Stubbe, J.; Nocera, D. G.
(
25) Pattabiraman, V. R.; Bode, J. W. Rethinking Amide Bond Synthesis.
Nature 2011, 480, 471–479.
26) Roughley, S. D.; Jordan, A. M. The Medicinal Chemist’s Toolbox: An
Analysis of Reactions Used in the Pursuit of Drug Candidates. J. Med. Chem.
(
Deciphering Radical Transport in the Large Subunit of Class I Ribonucleotide
Reductase. J. Am. Chem. Soc. 2012, 134, 1172–1180.
(
(49) Gaussian 16, Revision B.01, M. J. Frisch, G. W. Trucks, H. B. Schlegel, G.
E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, G. A. Peters-
son, H. Nakatsuji, X. Li, M. Caricato, A. V. Marenich, J. Bloino, B. G. Janesko, R.
Gomperts, B. Mennucci, H. P. Hratchian, J. V. Ortiz, A. F. Izmaylov, J. L. Sonnen-
berg, D. Williams-Young, F. Ding, F. Lipparini, F. Egidi, J. Goings, B. Peng, A.
Petrone, T. Henderson, D. Ranasinghe, V. G. Zakrzewski, J. Gao, N. Rega, G.
Zheng, W. Liang, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M.
Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, K. Throssell, J. A.
Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. J. Bearpark, J. J. Heyd, E. N. Broth-
ers, K. N. Kudin, V. N. Staroverov, T. A. Keith, R. Kobayashi, J. Normand, K.
Raghavachari, A. P. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, J. M.
Millam, M. Klene, C. Adamo, R. Cammi, J. W. Ochterski, R. L. Martin, K.
Morokuma, O. Farkas, J. B. Foresman, and D. J. Fox, Gaussian, Inc., Wallingford
CT, 2016.
2
011, 54, 3451–3479.
(27) Harreus, A. L.; Backes, R.; Eichler, J.-O.; Feuerhake, R.; Jäkel, C.; Mahn,
U.; Pinkos, R.; Vogelsang, R. 2-Pyrrolidone. In Ullmann’s Encyclopedia of
Industrial Chemistry; Wiley-VCH Verlag GmbH: Weinheim, 2000.
(28) Nguyen, L. Q.; Knowles, R. R. Catalytic C-N Bond-Forming Reactions
Enabled by Proton-Coupled Electron Transfer Activation of Amide N-H Bonds.
ACS Catal. 2016, 6, 2894–2903.
(29) For a recent example of an olefin hydroamidation method which does
not involve amidyl radicals, see: Zhou, Y.; Engl, O. D.; Bandar, J. S.; Chant, E. D.;
Buchwald, S. L. CuH‐Catalyzed Asymmetric Hydroamidation of Vinylarenes An-
gew. Chem. Int. Ed. 2018, 57, 6672
(
30) Zard, S. Z. Recent Progress in the Generation and Use of Nitrogen-
Centred Radicals. Chem. Soc. Rev. 2008, 37, 1603–1618.
(31) Carestia, A. M.; Ravelli, D.; Alexanian, E. J. Reagent-Dictated Site Selec-
tivity in Intermolecular Aliphatic C-H Functionalizations Using Nitrogen-Cen-
tered Radicals. Chem. Sci. 2018, 9, 5360–5365.
(50) Ward, W. M.; Farnum, B. H.; Siegler, M.; Meyer, G. J. Chloride Ion-
Pairing with Ru(II) Polypyridyl Compounds in Dichloromethane. J. Phys. Chem.
A 2013, 117, 8883–8894.
(
32) Xiong, T.; Zhang, Q. New Amination Strategies Based on Nitrogen-
Centered Radical Chemistry. Chem. Soc. Rev. 2016, 45, 3069–3087.
33) Davies, J.; Svejstrup, T. D.; Fernandez Reina, D.; Sheikh, N. S.; Leonori,
(51) Fielding, L. Determination of Association Constants (K ) from Solution
a
NMR Data. Tetrahedron 2000, 56, 6151–6170.
(
(52) Monroe, B. M.; Weiner, S. A.; Hammond, G. S. Mechanisms of
D. Visible-Light-Mediated Synthesis of Amidyl Radicals: Transition-Metal-Free
Hydroamination and N-Arylation Reactions. J. Am. Chem. Soc. 2016, 138, 8092–
Photochemical Reactions in Solution. LII. Photoreduction of Camphorquinone.
J. Am. Chem. Soc. 1968, 90, 1913–1914.
8095.
(
53) Nakamura, M.; Ito, O.; Matsuda, M. Substituent Effect on the Rate
(
34) Nicolaou, K. C.; Baran, P. S.; Kranich, R.; Zhong, Y. L.; Sugita, K.; Zou,
Constants for the Reactions between Benzenethiyl Radicals and Stable Free
Radicals Estimated by Flash Photolysis. J. Am. Chem. Soc. 1980, 102, 698–701.
N. Mechanistic Studies of Periodinane-Mediated Reactions of Anilides and
Related Systems. Angew. Chem. Int. Ed. 2001, 40, 202–206.
(35) Miller, D. C.; Choi, G. J.; Orbe, H. S.; Knowles, R. R. Catalytic Olefin
Hydroamidation Enabled by Proton-Coupled Electron Transfer. J. Am. Chem.
Soc. 2015, 137, 13492–13495.
(
54) Dénès, F.; Pichowicz, M.; Povie, G.; Renaud, P. Thiyl Radicals in Organic
Synthesis. Chem. Rev. 2014, 114, 2587–2693.
55) Homer, J. H.; Musa, O. M.; Bouvier, A.; Newcomb, M. Absolute Kinetics
(
of Amidyl Radical Reactions. J. Am. Chem. Soc. 1998, 120, 7738–7748.
(56) Franz, J. A.; Bushaw, B. A.; Alnajjar, M. S. Absolute Rate Expressions for
the Abstraction of Hydrogen by Primary, Secondary, and Tertiary Alkyl Radicals
from Thiophenol. J. Am. Chem. Soc. 1989, 111, 268–275.
(
36) Cukier, R. I.; Nocera, D. G. Proton-Coupled Electron Transfer. Annu.
Rev. Phys. Chem 1998, 49, 337–369.
37) Miller, D. C.; Tarantino, K. T.; Knowles, R. R. Proton-Coupled Electron
(
Transfer in Organic Synthesis: Fundamentals, Applications, and Opportunities.
Top. Curr. Chem. 2016, 374, 1–59.
(
57) Hansch, H. C. Substituent Constants for Correlation Analysis in Chemistry
and Biology; John Wiley: New York 1979.
58) Savéant, J.-M. Molecular Catalysis of Electrochemical Reactions. In
(
38) Wenger, O. S. Proton-Coupled Electron Transfer with Photoexcited
Metal Complexes. Acc. Chem. Res. 2013, 46, 1517–1526.
39) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers,
(
Elements of Molecular and Biomolecular Electrochemistry; John Wiley: New York,
2006; pp 251–297.
(
F. J. Safe and Convenient Procedure for Solvent Purification. Organometallics
1996, 15, 1518–1520.
(
59) Rountree, E. S.; McCarthy, B. D.; Eisenhart, T. T.; Dempsey, J. L. Evalu-
ation of Homogeneous Electrocatalysts by Cyclic Voltammetry. Inorg. Chem.
014, 53, 9983–10002.
60) Costentin, C.; Savéant, J.-M. Multielectron, Multistep Molecular Catal-
(
40) Fulmer, G. R.; Miller, A. J. M.; Sherden, N. H.; Gottlieb, H. E.;
2
Nudelman, A.; Stoltz, B. M.; Bercaw, J. E.; Goldberg, K. I. NMR Chemical Shifts
of Trace Impurities: Common Laboratory Solvents, Organics, and Gases in
Deuterated Solvents Relevant to the Organometallic Chemist. Organometallics
(
ysis of Electrochemical Reactions: Benchmarking of Homogeneous Catalysts.
ChemElectroChem 2014, 1, 1226–1236.
2
010, 29, 2176–2179.
(41) Singh, A.; Teegardin, K.; Kelly, M.; Prasad, K. S.; Krishnan, S.; Weaver,
(
61) Turek, A. K.; Hardee, D. J.; Ullman, A. M.; Nocera, D. G.; Jacobsen, E.
N. Activation of Electron-Deficient Quinones through Hydrogen-Bond-Donor-
Coupled Electron Transfer. Angew. Chem. Int. Ed. 2016, 55, 539–544.
J. D. Facile Synthesis and Complete Characterization of Homoleptic and
Heteroleptic Cyclometalated Iridium(III) Complexes for Photocatalysis. J.
Organomet. Chem. 2015, 776, 51–59.
(
62) Morris, W. D.; Mayer, J. M. Separating Proton and Electron Transfer
Effects in Three-Component Concerted Proton-Coupled Electron Transfer Re-
actions. J. Am. Chem. Soc. 2017, 139, 10312–10319.
(
42) Zhu, L.; Xiong, P.; Mao, Z. Y.; Wang, Y. H.; Yan, X.; Lu, X.; Xu, H. C.
Electrocatalytic Generation of Amidyl Radicals for Olefin Hydroamidation: Use
of Solvent Effects to Enable Anilide Oxidation. Angew. Chem. Int. Ed. 2016, 55,
(63) Hammes-Schiffer, S. Theory of Proton-Coupled Electron Transfer in
Energy Conversion Processes. Acc. Chem. Res. 2009, 42, 1881–1889.
2226–2229.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 12 of 13
Cyclizations: Generality, Scope, and Mechanism. J. Am. Chem. Soc. 2002, 124,
233–2244.
66) Gould, I. R.; Ege, D.; Mattes, S. L.; Farid, S. Return Electron Transfer
within Geminate Radical Ion Pairs. Observation of the Marcus Inverted Region
J. Am. Chem. Soc. 1987, 109, 3794–3796.
(
64) Greene, B. L.; Taguchi, A. T.; Stubbe, J.; Nocera, D. G. Conformation-
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
ally Dynamic Radical Transfer within Ribonucleotide Reductase. J. Am. Chem.
Soc. 2017, 139, 16657–16665.
(
(
65) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Barluenga, S.; Hunt, K. W.;
Kranich, R.; Vega, J. A. Iodine(V) Reagents in Organic Synthesis. Part 3. New
Routes to Heterocyclic Compounds via O-Iodoxybenzoic Acid-Mediated
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ACS Paragon Plus Environment

Page 13 of 13
Journal of the American Chemical Society
1
2
TOC
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ACS Paragon Plus Environment