Decarboxylative Alkyl Coupling Promoted by NADH and Blue Light

Article abstract of DOI:10.1021/jacs.0c09678

Photoexcited dihydronicotinamides like NADH and analogues have been found to generate alkyl radicals upon reductive decarboxylation of redox-active esters without auxiliary photocatalysts. This principle allowed aliphatic photocoupling between redox-activ

Full text of DOI:10.1021/jacs.0c09678

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Decarboxylative Alkyl Coupling Promoted by NADH and Blue Light
Rajdip Chowdhury,$ Zhunzhun Yu,$ My Linh Tong, Stefanie V. Kohlhepp, Xiang Yin,
and Abraham Mendoza*
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ABSTRACT: Photoexcited dihydronicotinamides like NADH and
analogues have been found to generate alkyl radicals upon
reductive decarboxylation of redox-active esters without auxiliary
photocatalysts. This principle allowed aliphatic photocoupling
between redox-active carboxylate derivatives and electron-poor
olefins, displaying surprising water and air-tolerance and unusually
high coupling rates in dilute conditions. The orthogonality of the
reaction in the presence of other carboxylic acids and its utility in
the functionalization of DNA is presented, notably using visible
light in combination with NADH, the ubiquitous reductant of life.
the potential of redox-active esters to be introduced through
strategies unavailable to the parent carboxylic acids.
During our synthetic studies with redox-active carbenes,12
we recognized that the coupling of redox-active esters and
Michael acceptors8a,b,f−l could significantly expand its capa-
bilities with a suitable biocompatible reductant (Scheme 1B).
The reduced nicotinamide adenine dinucleotide (NADH)
would be ideal because it is a native component of biological
systems.
INTRODUCTION
■
Visible light is a prime stimulus to control the conformation of
chemical bonds,1 or their cleavage.1a,2 The phototriggered
formation of chemical bonds can enable frontier research in
medicine and biology,3 but their development is still a
challenge in comparison to thermal click reactions4 due to
the slower rate and the need for UV-light and/or photo-
catalysts.5 On one hand, photo-cross-linking methods still rely
on unstable precursors like azirines or cyclopropanones.5a,6 On
the other hand, recent C−C coupling reactions using
photobiocatalytic systems have shown great promise but
these are still limited to activated substrates with auxiliary
photosensitizers and electron donors.7 As such, developments
in self-sensitized, phototriggered, and fast C−C photocoupling
between simple functionalities are still highly sought after
(Scheme 1A).8,9 Aliphatic linkages are particularly attractive
due to their small size, robustness, and flexibility, which
maximize the chances to obtain functional and metabolically
stable conjugates.8
Decarboxylative radical addition reactions (Scheme 1A)
have recently emerged as prime tools to create aliphatic
ligations in biomolecules.8,9 These methods take advantage of
the abundance of carboxylic acids8,10 and the various
technologies developed with Michael acceptors.1b,11 Despite
their success, radical addition reactions are slow (6−12 h) and
require additional catalysts, inorganic reducing suspensions,
and/or additives that are not native to biological systems.8 The
abundance of endogenous carboxylic acids in biomolecules or
biomatrices poses a selectivity challenge for carboxylic acid
substrates (1), due to their similar oxidation potentials.8c−e In
contrast, the N-hydroxyphthalimide (NHPI) esters (2) can be
orthogonally activated in the presence of other carboxylates via
single-electron reduction.8a,b,f−l Recent methods based on
desymmetrization8n and late-stage carbene transfer12 illustrate
The redox potential of NADH and its analogs (Eox{5} =
0.57 V vs Ag/Ag+) is insufficient to activate redox-active esters
(Ered{2} ∼ − 1.1
0.1 V vs Ag/Ag+).13 These
dihydronicotinamides are potent single-electron reductants in
the excited state (Eox*{5} = −2.60 V vs Ag/Ag+),14,15 but their
short lifetimes in solution (τ{5*} ∼ 0.7 ns)16 have limited their
application as autonomous photoreductants.14,17,18 At the
onset of our work, these reagents required additional
(photo)catalysts8f−l,18,19 or enzymes20 under rigorously anhy-
drous and degassed conditions to drive reductive couplings.
We reasoned that the short-lived excited states of these systems
would have a minimal impact in photoinitiated reactions21 and
would avoid side-reactions in the presence of dioxygen derived
from triplet-sensitization. The transient generation of the
powerful photoreductant 5* would effectively circumvent the
incompatibility with oxygen and moisture of other ground state
super electron donors.22 Importantly, the expected byproducts
of the reaction would be biocompatible: the cofactor NAD+
Received: September 15, 2020
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© XXXX American Chemical Society
A

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Scheme 1. Approach Towards Aliphatic Photo-Coupling
with Native NADH Bio-Photoreductant
Scheme 2. Discovery of the Photo-Coupling Promoted by
BuNAH (10) and NADH (11)
a
a
Determined by 1H NMR using 1,1,2,2- tetrachloroethane as internal
b
c
standard. 3 equiv used. 10 equiv used.
a
NAD, Nicotinamide Adenine Dinucleotide; PET, Photoinduced
This result can be rationalized by the slightly more reductive
character of BuNAH (10)26 than the N-benzyl- and N-aryl-
dihydronicotinamides 5,8. Moreover, the performance of
BuNAH (10) is only marginally affected by concentrations
as low as 1 mM (entry 8). The system tolerates water as
cosolvent (50% v/v; entry 9) and air atmosphere (entry 10).
These are unique features that contrast with sensitive ground-
state organic reductants22a,4b,c,24,25 and other photocatalyzed
reactions.8f,h,18,19c,d Interestingly, BuNAH (10) can be
prepared in multigram amounts, stored indefinitely as a solid,
and handled for more than a week as a DMSO stock solution
(see SI), thus enabling microdosing in high-throughput
studies.
These results led us to explore the performance of NADH
(11) due to its relevance as the native reductant in biological
systems. The photophysics of NADH (11) have additional
challenges due to its shorter excited state lifetime (τ{NADH}
∼ 0.4 ns) and the interaction between its dihydronicotinamide
and adenine moieties.27 To our delight, the commercial
NADH disodium salt (11) promoted the coupling reaction in
a dilute mixture of water and DMSO (1−10 mM; entries
11,12). Unlike that of BuNAH (10), it was found that the use
of NADH (11) required inert atmosphere and larger amounts
for optimal results, probably due to its higher sensitivity and/or
less favorable photophysic properties.
Electron Transfer; 5 − R = Ph, R’= H.
(or analogues thereof), CO2, and phthalimide (LD50{rat oral}
> 5 g/kg).23
RESULTS AND DISCUSSION
■
Toward this end, the reaction of the NADH model BNAH (5)
with the redox-active ester 2a and the acrylate acceptor 3a was
studied under blue light illumination (λ = 450 nm) without
photocatalysts or additives (Scheme 2).8f−l To our delight, the
desired decarboxylative coupling product 4a was obtained in
high yield using DMSO as solvent (entry 1). The reaction was
found to be surprisingly fast, reaching 66% yield after 5 min of
illumination (entry 2). Given the importance of maximizing
the reaction rate for its implementation at higher dilu-
tion,3,4,4c−i we explored related photoreductants. It was
found that the dihydronicotinamide moiety is essential for
high activity (entry 3) as well as the appropriate substitution at
the heterocyclic nitrogen (entries 4,5). In line with seminal
studies by Overman8h and recent work by Shang,24 the
dihydropyridine 9 was found to promote the reaction, but it
was slower and less efficient than the more biocompatible
dihydronicotinamides (entry 6).25 Interestingly, the N-butyl
dihydronicotinamide BuNAH (10), which is the closest
structural homologue to NADH among the photoreductants
explored, was optimal both in terms of yield and rate (entry 7).
We set out to explore the scope of the photocoupling using
artificial BuNAH (10; conditions A) or natural NADH (11;
conditions B) as photoreductants in aqueous (50% H2O in
B
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⧧
Scheme 3. Scope Study
⧧
Yields were determined by 1H NMR using an appropriate internal standard; for isolated yields at preparative concentrations, see SI. HE; Hantzsch
a
b
c
d
ester (9). Ar atmosphere. 100 mM concentration. DMSO was used as solvent. Dihydropyridine 9 was used instead of BuNAH (10) for
comparison. 20 mM concentration.
e
DMSO) and dilute conditions (1 mM; Scheme 3) most
relevant in Chemical Biology. Alternatively, preparative scale
reactions can be undertaken at higher concentrations in
DMSO (see SI for details). Various Michael acceptors bearing
electron-withdrawing groups such as ester (4a,b), amide
(4c),11c aldehyde (4d), ketone (4e), nitrile (4f), or sulfone
(4g) were accommodated. Among these, acrolein was
significantly less efficient as an acceptor, probably due to
degradation of the sensitive aliphatic aldehyde product 4c. The
maleimide scaffold (4h) that is common in bioconjugation
reactions1b,5e,11a,b was found to be very efficient. In stark
contrast, no coupling product was obtained using the
dihydropyridine 9,24,25 thus illustrating the superior reactivity
of BuNAH (10) or NADH (11) as photoreductants.24,25 High
yields and fast reactions also occur across a wide range of
redox-active esters. Tertiary sites are coupled efficiently, thus
allowing interesting structures to be functionalized, including
bicyclic (4i), adamantyl (4j), piperidine (4k), cyclopropane
(4l), and more complex scaffolds such as the drug gemfibrozil
(4m,n). Secondary radical precursors are equally effective in
the reaction (4o,q).
Interestingly, the products 4q,q’ demonstrate that the
norbornenyl−nortricyclyl radical equilibrium28 can be estab-
lished before their capture by the Michael acceptor. Primary
C
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Scheme 4. Alkyl Photo-Coupling on DNA
a
b
c
d
Reaction time 2 h. Reaction time 4 h. Buffer pH 5.5. Coupling product was detected by MS but could not be quantified due to insufficient
chromatographic resolution. ND, Not Determined.
carboxylate derivatives led to the products (4r−u) featuring
robust and flexible alkyl-ligations. These include the cross-
coupling of indole (4r), D-biotin (4s), a fatty acid (4t), and
pyridine (4u) derivatives. Among those, the biotinylated
product 4s displays an easily oxidizable thioether, a polar
urea, a secondary amide, and an anomerically activated sugar.29
Moreover, the reaction was proven to be useful in the late-
stage functionalization of natural products, including the
peptide model derived from alanine (4w), and various densely
functionalized terpenes with unprotected ketone, enone, olefin,
diene, alcohol, and ester functions (4v,x-aa). The orthogon-
ality between redox-active esters and unprotected carboxylic
acids is demonstrated on the products 4n,aa. These substrates
would lead to mixtures of products and/or polymers through
existing coupling reactions based on oxidative decarboxyla-
tion.8c−e Furthermore, the coupling reactions were complete in
10−75 min. This is substantially faster than previous methods
despite the dilute conditions. Particularly sensitive or apolar
substrates were understandably less efficient in the standard
dilute aqueous media of the reaction (i.e., 4d,s,u,v,y,z,aa). In
these cases, coupling efficiencies are enhanced simply by using
higher concentration, inert atmosphere, and DMSO as solvent.
However, in more favorable substrates, the reaction could
operate even in pure water as solvent with similar results
(4r,w).
facilitating mixing in small reaction volumes (<300 μL). These
features are characteristic of this system and can facilitate the
future implementation of this reaction in automatic platforms.
The kinetic time-profile of the reaction with BuNAH (10)
was obtained using in situ no-D NMR monitoring.30
Nondeuterated DMSO was used to prevent any potential
artifacts due to solvent isotopic effects in the propagation of
the radical chain. However, it was found that the reaction
proceeds similarly in DMSO and DMSO-d6, without any
solvent-derived byproducts (see SI). This way it was possible
to confirm that the reaction can be completed in 4.3 min at
100 mM concentration (Scheme 5A; gray).8f−l Moreover, 10-
Scheme 5. Kinetic Profiling of the Photo-Coupling by No-D
1H NMR
The features of this system in terms of rate, concentration,
water tolerance, and solubility of its components made it an
ideal candidate for the in vitro alkyl photocoupling on polar
biomacromolecules. To benchmark the performances of
BuNAH (10) and NADH (11) in this context against
comparable decarboxylative coupling methods, we set out to
explore coupling reactions on DNA.8b,d These are important in
the synthesis of DNA-encoded libraries (DEL)8b,d,9e yet
challenging due to the complex functionality of the substrates
and low scale at which these reactions need to occur. To our
delight, DEL headpieces 12a,b were coupled efficiently using
either BuNAH (10) or NADH (11) and blue light at 10 nmol-
scale to deliver “on-DNA”-functionalized products 13aa-ae,ba-
be (Scheme 4). These reactions are generally completed in 1 h
with excellent yields despite the micromolar concentrations
(100 μM) in buffered media. Importantly, all the components
in this system can be handled as dilute solutions, thus
D
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fold (10 mM) and even 100-fold (1 mM) dilutions resulted in
a surprising rate acceleration (Scheme 5A; blue traces). The
reaction is completed in just 80 s of illumination at 1−10 mM
with identical efficiency. To discern the origin of the
acceleration, a control experiment was run in the least
favorable concentration (100 mM) using a thinner reactor
tube (1.25 mm diameter) to minimize the light path on the
system. This resulted in significantly faster kinetics (Scheme
5A; red). This result demonstrates that the acceleration
observed upon dilution stems from the attenuation of the inner
filter effect.31 With the usage of NADH (11) as photo-
reductant, the reaction is slower (Scheme 5B) but faster than
previous decarboxylative coupling reactions.8,24 The reaction is
completed in 60 min (>80% in less than 25 min). These results
are remarkable considering the dilute conditions (20 mM) in
the presence of only 1.5 equiv of the acceptor 3a and NADH
(11). Importantly, the system is stable in the absence of light
(Scheme 5C). After a long dark period, the system was
illuminated obtaining an identical kinetic profile to that of a
standard experiment, as evidenced by the time-shifted overlay
(Scheme 5D). This demonstrates the absence of static
deactivation in the dark, which may be relevant in cases
where other equilibria need to be established before the C−C
coupling event is phototriggered.3,5,6
Scheme 6. Mechanistic Studies
Absorption spectroscopy revealed that the light absorption
of BuNAH (10) is similar to those of other dihydronicotina-
mides,16 featuring a strong band at 350 nm that extends into
the visible region (Scheme 6A, left). In the presence of the
redox-active ester 2a, which only absorbs below 350 nm, the
absorption increases marginally at 450 nm using concen-
trations as high as 0.1 M (12% increase; Scheme 6A, right),
which may indicate the formation of a donor−acceptor
complex (EDA).32,33 Thus, we set out to study the relevance
of this possible EDA interaction in the photoactivation of this
reaction. Stern−Volmer studies evidenced a linear quenching
of the steady-state fluorescence of BuNAH (10; Scheme 6B;
blue) with increasing concentrations of the redox-active ester
2a. Nevertheless, the linear decrease in luminescence intensity
is not a definitive proof of the mechanism by which this
phenomenon occurs.34 Therefore, the fluorescence lifetime of
the excited state 10* (τ0(10*) = 1.08 ns) was measured using
Time-Correlated Single Photon Counting (TCSPC). This
study revealed a decrease in the lifetime of excited BuNAH
(10*, Scheme 6B; purple) upon increase of the concentration
of redox-active ester 2a. However, the significantly different
slopes of the steady-state and lifetime Stern−Volmer plots
were not consistent with a conventional dynamic quenching
scenario.34 Instead, the data supports the formation of a
nonemissive EDA complex 10·2 in equilibrium with the free
10 (Scheme 6B; right). The corresponding equilibrium
constant could be estimated through fitting of the steady-
state and lifetime data (Keq ∼ 7; see SI).34 Consistently, no
additional luminescence bands corresponding to the EDA
complex 10·2 could be observed in either excitation or
emission spectra (see SI). At this point, it is unclear which of
these coexisting dynamic and static interactions between
BuNAH (10) and the redox-active ester 2 are most important
for the reactivity. However, it is known that the formation of
EDA complexes is affected by changes in the substrate, solvent,
concentration, and/or temperature.32 The fact that the
reaction is not inhibited in dilute conditions disfavors the
EDA complex to be critical in the photoactivation of this
system.24 In this sense, the direct reduction by photoexcited
dihydronicotinamides without engagement in donor−acceptor
complexes32,33 has been documented but only in the context of
more activated alkyl halide substrates.17b
The expected intermediacy of free-diffusing alkyl radicals
was demonstrated by the different ratios of the products
4ab,ab’ that were obtained using the 5-hexenyl radical clock
precursor 2ab at different initial concentrations (Scheme 6C).
To discern the fate of the radical intermediate that would result
from the addition of the alkyl radical into the electron-deficient
olefin, we conducted a series of experiments with the
dideuterated BuNAH derivative 10-d2 (Scheme 6D). These
experiments revealed that hydrogen atom transfer (HAT) from
BuNAH (10) is the main process to quench the putative
radical addition product.8g,h,19c−e Further control experiments
confirmed that the solvents (DMSO and H2O) do not
exchange with 10-d2 under the reaction conditions and do not
have any relevant role in the HAT process (see SI). The
involvement of a radical chain mechanism was studied
measuring the average quantum yield. This was determined
in triplicate at 20−25% conversion of 2a, obtaining a value of
2.9 0.5, which points to the propagation of a radical chain.31
The mechanistic proposal in Scheme 7 comprises the
electron−proton−electron transfer manifold that is typical in
radical reductions mediated by dihydronicotinamides14,17,35
and our own experiments (Schemes 5 and 6). Photoinduced
electron and proton transfer from dihydronicotinamide 10 to
E
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Sweden; orcid.org/0000-0001-9199-6736;
Email: abraham.mendoza@su.se
Scheme 7. Proposed Mechanism
Authors
Rajdip Chowdhury − Department of Organic Chemistry,
Arrhenius laboratory, Stockholm University, 10691 Stockholm,
Sweden; orcid.org/0000-0001-5515-4371
Zhunzhun Yu − Department of Organic Chemistry, Arrhenius
laboratory, Stockholm University, 10691 Stockholm, Sweden
My Linh Tong − Department of Organic Chemistry, Arrhenius
laboratory, Stockholm University, 10691 Stockholm, Sweden;
orcid.org/0000-0003-4305-3295
Stefanie V. Kohlhepp − Department of Organic Chemistry,
Arrhenius laboratory, Stockholm University, 10691 Stockholm,
Sweden; orcid.org/0000-0003-3433-4642
Xiang Yin − Department of Organic Chemistry, Arrhenius
laboratory, Stockholm University, 10691 Stockholm, Sweden
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c09678
Author Contributions
the redox-active ester 2 through the dynamic and/or static
mechanisms discussed above (Scheme 6B) produces the
carbon centered radical 14, a nicotinyl radical 15, phthalimide
(16), and CO2. The radical 14 adds to the olefin 3 to produce
the radical 17, which after concerted8g or stepwise35 HAT
yields the coupling product 4 and the nicotinyl radical 15.8g
The latter could reduce the redox-active ester 2 to produce the
pyridinium salt 18, CO2, and the alkyl radical 14 that
propagates the chain reaction (see Scheme 6C,D).8g The
formation of the pyridinium salts 18 derived from BuNAH
(10) and NADH (11) and their kinetic correlation with the
formation of the product 4 has also been evidenced by in situ
NMR monitoring (see SI).
$These authors contributed equally.
Funding
Financial support from the Knut and Alice Wallenberg
Foundation (KAW2016.0153), and the European Research
Council (714737) is gratefully acknowledged.
Notes
The authors declare no competing financial interest.
Raw data for this article can be downloaded from Zenodo
DOI: 10.5281/zenodo.4106400.
ACKNOWLEDGMENTS
■
We are indebted to the personnel of AstraZeneca Gothenburg
and the Dept. of Organic Chemistry at Stockholm University
for unrestricted support. The authors particularly thank Dr F.
CONCLUSIONS
■
Herein, we report that the dihydronicotinamides BuNAH (10)
and NADH (11) promote the photocoupling of redox-active
esters and Michael acceptors upon illumination with blue light.
These reactions do not require external photocatalysts or
additives, have no detectable background reactivity, can run in
water, and have an unusually high rate even at low
concentration. This system has demonstrated its utility in the
functionalization of DNA macromolecules in extremely dilute
conditions. The mechanistic experiments demonstrate the
multifaceted role of these dihydropyridines as photoinitiators,
reductants, and hydrogen-atom donors to drive this fast
photocoupling using a minimal homogeneous system. This
work introduces NADH (11) as an autonomous photo-
reductant and opens prospects for new artificial coupling
reactions that our group is currently investigating.
́
́
Julia-Hernandez for fruitful discussions, and Prof. E. Borbas
and S. Kiraev (Uppsala U.) for assistance with early stage
fluorescence measurements.
REFERENCES
■
(1) (a) Ankenbruck, N.; Courtney, T.; Naro, Y.; Deiters, A.
Optochemical Control of Biological Processes in Cells and Animals.
Angew. Chem., Int. Ed. 2018, 57 (11), 2768−2798. (b) Fehrentz, T.;
̈
Schonberger, M.; Trauner, D. Optochemical Genetics. Angew. Chem.,
́
Int. Ed. 2011, 50 (51), 12156−12182. (c) Albert, L.; Vazquez, O.
Photoswitchable Peptides for Spatiotemporal Control of Biological
Functions. Chem. Commun. 2019, 55 (69), 10192−10213. (d) Szy-
́
manski, W.; Beierle, J. M.; Kistemaker, H. A. V.; Velema, W. A.;
Feringa, B. L. Reversible Photocontrol of Biological Systems by the
Incorporation of Molecular Photoswitches. Chem. Rev. 2013, 113 (8),
6114−6178. (e) Heinrich, B.; Bouazoune, K.; Wojcik, M.; Bakowsky,
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c09678.
■
́
U.; Vazquez, O. ortho-Fluoroazobenzene Derivatives as DNA
sı
Intercalators for Photocontrol of DNA and Nucleosome Binding by
Visible Light. Org. Biomol. Chem. 2019, 17 (7), 1827−1833.
(f) Broichhagen, J.; Trauner, D. The in vivo Chemistry of
Photoswitched Tethered Ligands. Curr. Opin. Chem. Biol. 2014, 21,
121−127.
Experimental procedures, characterization, and other
data (PDF)
̌
́
(2) (a) Klan, P.; Solomek, T.; Bochet, C. G.; Blanc, A.; Givens, R.;
Rubina, M.; Popik, V.; Kostikov, A.; Wirz, J. Photoremovable
Protecting Groups in Chemistry and Biology: Reaction Mechanisms
and Efficacy. Chem. Rev. 2013, 113 (1), 119−191. (b) Kolarski, D.;
Sugiyama, A.; Breton, G.; Rakers, C.; Ono, D.; Schulte, A.; Tama, F.;
Itami, K.; Szymanski, W.; Hirota, T.; Feringa, B. L. Controlling the
AUTHOR INFORMATION
Corresponding Author
Abraham Mendoza − Department of Organic Chemistry,
Arrhenius laboratory, Stockholm University, 10691 Stockholm,
■
F
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Circadian Clock with High Temporal Resolution through Photo-
dosing. J. Am. Chem. Soc. 2019, 141 (40), 15784−15791.
Kinetically guided radical-based synthesis of C(sp3)−C(sp3) linkages
on DNA. Proc. Natl. Acad. Sci. U. S. A. 2018, 115 (28), E6404−
E6410. For decarboxylative radical additions with carboxylic acids in
biomolecules, see: (c) McCarver, S. J.; Qiao, J. X.; Carpenter, J.;
Borzilleri, R. M.; Poss, M. A.; Eastgate, M. D.; Miller, M. M.;
MacMillan, D. W. C. Decarboxylative Peptide Macrocyclization
through Photoredox Catalysis. Angew. Chem., Int. Ed. 2017, 56 (3),
(3) Devaraj, N. K. The Future of Bioorthogonal Chemistry. ACS
Cent. Sci. 2018, 4 (8), 952−959.
(4) For examples of nonlight regulated bioorthogonal reactions, see:
(a) Sletten, E. M.; Bertozzi, C. R. Bioorthogonal Chemistry: Fishing
for Selectivity in a Sea of Functionality. Angew. Chem., Int. Ed. 2009,
48 (38), 6974−6998. (b) Patterson, D. M.; Nazarova, L. A.; Prescher,
J. A. Finding the Right (Bioorthogonal) Chemistry. ACS Chem. Biol.
2014, 9 (3), 592−605. (c) Whiting, M.; Muldoon, J.; Lin, Y.-C.;
Silverman, S. M.; Lindstrom, W.; Olson, A. J.; Kolb, H. C.; Finn, M.
G.; Sharpless, K. B.; Elder, J. H.; Fokin, V. V. Inhibitors of HIV-1
Protease by Using In Situ Click Chemistry. Angew. Chem., Int. Ed.
2006, 45 (9), 1435−1439. (d) Fang, Y.; Zhang, H.; Huang, Z.; Scinto,
S. L.; Yang, J. C.; Am Ende, C. W.; Dmitrenko, O.; Johnson, D. S.;
Fox, J. M. Photochemical Syntheses, Transformations, and Bio-
orthogonal Chemistry of Trans-Cycloheptene and Sila Trans-Cyclo-
heptene Ag(I) complexes. Chem. Sci. 2018, 9 (7), 1953−1963. (e) An,
P.; Lewandowski, T. M.; Erbay, T. G.; Liu, P.; Lin, Q. Sterically
Shielded, Stabilized Nitrile Imine for Rapid Bioorthogonal Protein
Labeling in Live Cells. J. Am. Chem. Soc. 2018, 140 (14), 4860−4868.
(f) Blackman, M. L.; Royzen, M.; Fox, J. M. Tetrazine Ligation: Fast
Bioconjugation Based on Inverse-Electron-Demand Diels−Alder
Reactivity. J. Am. Chem. Soc. 2008, 130 (41), 13518−13519.
(g) Patterson, D. M.; Nazarova, L. A.; Xie, B.; Kamber, D. N.;
Prescher, J. A. Functionalized Cyclopropenes As Bioorthogonal
Chemical Reporters. J. Am. Chem. Soc. 2012, 134 (45), 18638−
18643. (h) Sachdeva, A.; Wang, K.; Elliott, T.; Chin, J. W. Concerted,
Rapid, Quantitative, and Site-Specific Dual Labeling of Proteins. J.
Am. Chem. Soc. 2014, 136 (22), 7785−7788. (i) Laughlin, S. T.;
Baskin, J. M.; Amacher, S. L.; Bertozzi, C. R. In Vivo Imaging of
Membrane-Associated Glycans in Developing Zebrafish. Science 2008,
320 (5876), 664−667.
(5) For examples of light-regulated bioorthogonal reactions:
(a) Tasdelen, M. A.; Yagci, Y. Light-Induced Click Reactions.
Angew. Chem., Int. Ed. 2013, 52 (23), 5930−5938. (b) Chen, R. T.;
Marchesan, S.; Evans, R. A.; Styan, K. E.; Such, G. K.; Postma, A.;
McLean, K. M.; Muir, B. W.; Caruso, F. Photoinitiated Alkyne−Azide
Click and Radical Cross-Linking Reactions for the Patterning of PEG
Hydrogels. Biomacromolecules 2012, 13 (3), 889−895. (c) Singh, K.;
Fennell, C. J.; Coutsias, E. A.; Latifi, R.; Hartson, S.; Weaver, J. D.
Light Harvesting for Rapid and Selective Reactions: Click Chemistry
with Strain-Loadable Alkenes. Chem. 2018, 4 (1), 124−137. (d) Kaur,
G.; Singh, G.; Singh, J. Photochemical Tuning of Materials: A Click
Chemistry Perspective. Mater. Today Chem. 2018, 8, 56−84.
(e) Bordoni, A. V.; Lombardo, M. V.; Wolosiuk, A. Photochemical
radical thiol−ene click-based methodologies for silica and transition
metal oxides materials chemical modification: a mini-review. RSC Adv.
2016, 6 (81), 77410−77426. (f) Ramil, C. P.; Lin, Q. Photoclick
chemistry: a fluorogenic light-triggered in vivo ligation reaction. Curr.
Opin. Chem. Biol. 2014, 21, 89−95.
̈
728−732. (d) Kolmel, D. K.; Loach, R. P.; Knauber, T.; Flanagan, M.
E. Employing Photoredox Catalysis for DNA-Encoded Chemistry:
Decarboxylative Alkylation of α-Amino Acids. ChemMedChem 2018,
̈
13 (20), 2159−2165. (e) Bloom, S.; Liu, C.; Kolmel, D. K.; Qiao, J.
X.; Zhang, Y.; Poss, M. A.; Ewing, W. R.; MacMillan, D. W. C.
Decarboxylative alkylation for site-selective bioconjugation of native
proteins via oxidation potentials. Nat. Chem. 2018, 10, 205−211. For
photocatalyzed coupling of redox-active esters and Michael acceptors,
see: (f) Brandhofer, T.; Mancheno, O. G. Versatile Ru-Photoredox-
̃
Catalyzed Functionalization of Dehydro-Amino Acids and Peptides.
ChemCatChem 2019, 11 (16), 3797−3801. (g) Okada, K.; Okamoto,
K.; Morita, N.; Okubo, K.; Oda, M. Photosensitized decarboxylative
Michael addition through N-(acyloxy)phthalimides via an electron-
transfer mechanism. J. Am. Chem. Soc. 1991, 113 (24), 9401−9402.
(h) Pratsch, G.; Lackner, G. L.; Overman, L. E. Constructing
Quaternary Carbons from N-(Acyloxy)phthalimide Precursors of
Tertiary Radicals Using Visible-Light Photocatalysis. J. Org. Chem.
2015, 80 (12), 6025−6036. (i) Schnermann, M. J.; Overman, L. E. A
Concise Synthesis of (−)-Aplyviolene Facilitated by a Strategic
Tertiary Radical Conjugate Addition. Angew. Chem., Int. Ed. 2012, 51
̈
(38), 9576−9580. (j) Schwarz, J.; Konig, B. Metal-free, visible-light-
mediated, decarboxylative alkylation of biomass-derived compounds.
Green Chem. 2016, 18 (17), 4743−4749. (k) Muller, D. S.; Untiedt,
̈
N. L.; Dieskau, A. P.; Lackner, G. L.; Overman, L. E. Constructing
Quaternary Stereogenic Centers Using Tertiary Organocuprates and
Tertiary Radicals. Total Synthesis of trans-Clerodane Natural
Products. J. Am. Chem. Soc. 2015, 137 (2), 660−663. (l) Jamison,
C. R.; Overman, L. E. Fragment Coupling with Tertiary Radicals
Generated by Visible-Light Photocatalysis. Acc. Chem. Res. 2016, 49
(8), 1578−1586. for a related decarboxylative alkynylation, see:
(m) Yang, J.; Zhang, J.; Qi, L.; Hu, C.; Chen, Y. Visible-light-induced
Chemoselective Reductive Decarboxylative Alkynylation under
Biomolecule-compatible Conditions. Chem. Commun. 2015, 51,
5275−5278. (n) Chen, T. − G.; Barton, L. M.; Lin, Y.; Tsien, J.;
Kossler, D.; Bastida, I.; Asai, S.; Bi, C.; Chen, J. S.; Shan, M.; Fang, H.;
Fang, F. G.; Choi, H. − W.; Hawkins, L.; Qin, T.; Baran, P. S.
Building C(sp3)-rich complexity by combining cycloaddition and C−
C cross-coupling reactions. Nature 2018, 560, 350−354.
(9) For other types of photochemical radical couplings in
biomolecules, see: (a) Aycock, R. A.; Pratt, C. J.; Jui, N. T.
Aminoalkyl Radicals as Powerful Intermediates for the Synthesis of
Unnatural Amino Acids and Peptides. ACS Catal. 2018, 8 (10),
̈
9115−9119. (b) Kolmel, D. K.; Meng, J.; Tsai, M.-H.; Que, J.; Loach,
R. P.; Knauber, T.; Wan, J.; Flanagan, M. E. On-DNA Decarboxylative
Arylation: Merging Photoredox with Nickel Catalysis in Water. ACS
Comb. Sci. 2019, 21 (8), 588−597. (c) Garreau, M.; Le Vaillant, F.;
Waser, J. C-Terminal Bioconjugation of Peptides through Photoredox
Catalyzed Decarboxylative Alkynylation. Angew. Chem., Int. Ed. 2019,
(6) (a) Li, G.; Liu, Y.; Liu, Y.; Chen, L.; Wu, S.; Liu, Y.; Li, X.
Photoaffinity Labeling of Small-Molecule-Binding Proteins by DNA-
Templated Chemistry. Angew. Chem., Int. Ed. 2013, 52 (36), 9544−
9549. (b) Herner, A.; Lin, Q. Photo-Triggered Click Chemistry for
Biological Applications. Top. Curr. Chem. 2016, 374 (1), 1.
(7) Lee, S. H.; Choi, D. S.; Kuk, S. K.; Park, C. B. Photobiocatalysis:
Activating Redox Enzymes by Direct or Indirect Transfer of
Photoinduced Electrons. Angew. Chem., Int. Ed. 2018, 57 (27),
7958−7985.
(8) For decarboxylative radical additions with redox-active esters in
biomolecules, see: (a) Qin, T.; Malins, L. R.; Edwards, J. T.;
Merchant, R. R.; Novak, A. J. E.; Zhong, J. Z.; Mills, R. B.; Yan, M.;
Yuan, C.; Eastgate, M. D.; Baran, P. S. Nickel-Catalyzed Barton
Decarboxylation and Giese Reactions: A Practical Take on Classic
Transforms. Angew. Chem., Int. Ed. 2017, 56 (1), 260−265. (b) Wang,
J.; Lundberg, H.; Asai, S.; Martín-Acosta, P.; Chen, J. S.; Brown, S.;
Farrell, W.; Dushin, R. G.; O’Donnell, C. J.; Ratnayake, A. S.;
Richardson, P.; Liu, Z.; Qin, T.; Blackmond, D. G.; Baran, P. S.
̈
58 (24), 8182−8186. (d) Bottecchia, C.; Noel, T. Photocatalytic
Modification of Amino Acids, Peptides, and Proteins. Chem. - Eur. J.
2019, 25 (1), 26−42. (e) Phelan, J. P.; Lang, S. B.; Sim, J.; Berritt, S.;
Peat, A. J.; Billings, K.; Fan, L.; Molander, G. A. Open-Air Alkylation
Reactions in Photoredox-Catalyzed DNA-Encoded Library Synthesis.
J. Am. Chem. Soc. 2019, 141 (8), 3723−3732.
́
(10) (a) Bratt, E.; Suarez-Pantiga, S.; Johansson, M. J.; Mendoza, A.
Mechanism and regioselectivity of the anionic oxidative rearrange-
ment of 1,3-diketones towards all-carbon quaternary carboxylates.
Chem. Commun. 2019, 55 (60), 8844−8847. (b) Colas, K.; dos
Santos, A. C. V. D.; Mendoza, A. i-Pr2NMgCl·LiCl Enables the
Synthesis of Ketones by Direct Addition of Grignard Reagents to
Carboxylate Anions. Org. Lett. 2019, 21 (19), 7908−7913.
G
https://dx.doi.org/10.1021/jacs.0c09678
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
(11) (a) Renault, K.; Fredy, J. W.; Renard, P.-Y.; Sabot, C. Covalent
Modification of Biomolecules through Maleimide-Based Labeling
Strategies. Bioconjugate Chem. 2018, 29 (8), 2497−2513. (b) Spicer,
C. D.; Pashuck, E. T.; Stevens, M. M. Achieving Controlled
Biomolecule−Biomaterial Conjugation. Chem. Rev. 2018, 118 (16),
7702−7743. (c) Lee, Y.-J.; Wu, B.; Raymond, J. E.; Zeng, Y.; Fang, X.;
Wooley, K. L.; Liu, W. R. A Genetically Encoded Acrylamide
Functionality. ACS Chem. Biol. 2013, 8 (8), 1664−1670.
(12) (a) Yu, Z.; Mendoza, A. Enantioselective Assembly of
Congested Cyclopropanes using Redox-Active Aryldiazoacetates.
ACS Catal. 2019, 9 (9), 7870−7875. (b) Montesinos-Magraner,
M.; Costantini, M.; Ramírez-Contreras, R.; Muratore, M. E.;
Johansson, M. J.; Mendoza, A. General Cyclopropane Assembly by
Enantioselective Transfer of a Redox-Active Carbene to Aliphatic
Olefins. Angew. Chem., Int. Ed. 2019, 58 (18), 5930−5935.
(13) (a) Horner, L.; Jordan, M. Studien zum Vorgang der
Wasserstoffubertragung, 53. Beitrag zur Kenntnis der elektroreduk-
̈
tiven Spaltung von Hydroxylaminderivaten. Justus Liebigs Ann. Chem.
1978, 1978 (9), 1518−1525. (b) Li, H.; Breen, C. P.; Seo, H.;
Jamison, T. F.; Fang, Y.-Q.; Bio, M. M. Ni-Catalyzed Electrochemical
Decarboxylative C−C Couplings in Batch and Continuous Flow. Org.
Lett. 2018, 20 (5), 1338−1341.
(14) Fukuzumi, S.; Inada, O.; Suenobu, T. Mechanisms of Electron-
Transfer Oxidation of NADH Analogues and Chemiluminescence.
Detection of the Keto and Enol Radical Cations. J. Am. Chem. Soc.
2003, 125 (16), 4808−4816.
compounds. J. Am. Chem. Soc. 1981, 103 (21), 6495−6497.
(d) Lackner, G. L.; Quasdorf, K. W.; Overman, L. E. Direct
Construction of Quaternary Carbons from Tertiary Alcohols via
Photoredox-Catalyzed Fragmentation of tert-Alkyl N-Phthalimidoyl
Oxalates. J. Am. Chem. Soc. 2013, 135 (41), 15342−15345. For
radical couplings using nonredox-ester phthalimide derivatives, see:
(e) Ito, Y.; Kimura, A.; Osawa, T.; Hari, Y. Photoredox-Catalyzed
Deformylative 1,4-Addition of 2′-Deoxy-5′-O-phthalimidonucleosides
for Synthesis of 5′-Carba Analogs of Nucleoside 5′-Phosphates. J. Org.
Chem. 2018, 83 (18), 10701−10708. (f) Deng, Y.; Nguyen, M. D.;
Zou, Y.; Houk, K. N.; Smith, A. B. Generation of Dithianyl and
Dioxolanyl Radicals Using Photoredox Catalysis: Application in the
Total Synthesis of the Danshenspiroketallactones via Radical Relay
Chemistry. Org. Lett. 2019, 21 (6), 1708−1712. (g) Zhang, J.; Li, Y.;
Zhang, F.; Hu, C.; Chen, Y. Generation of Alkoxyl Radicals by
Photoredox Catalysis Enables Selective C(sp3)−H Functionalization
under Mild Reaction Conditions. Angew. Chem., Int. Ed. 2016, 55 (5),
1872−1875.
(20) Emmanuel, M. A.; Greenberg, N. R.; Oblinsky, D. G.; Hyster,
T. K. Accessing non-natural reactivity by irradiating nicotinamide-
dependent enzymes with light. Nature 2016, 540, 414−417.
(21) Studer, A.; Curran, D. P. Catalysis of Radical Reactions: A
Radical Chemistry Perspective. Angew. Chem., Int. Ed. 2016, 55 (1),
58−102.
(22) (a) Tsurugi, H.; Mashima, K. Salt-Free Reduction of Transition
Metal Complexes by Bis(trimethylsilyl)cyclohexadiene, -dihydropyr-
azine, and −4,4′-bipyridinylidene Derivatives. Acc. Chem. Res. 2019,
52 (3), 769−779. (b) Tsurugi, H.; Mashima, K. A New Protocol to
Generate Catalytically Active Species of Group 4−6 Metals by
Organosilicon-Based Salt-Free Reductants. Chem. - Eur. J. 2019, 25
(4), 913−919. (c) Broggi, J.; Terme, T.; Vanelle, P. Organic Electron
Donors as Powerful Single-Electron Reducing Agents in Organic
Synthesis. Angew. Chem., Int. Ed. 2014, 53 (2), 384−413. (d) Murphy,
J. A.; Khan, T. A.; Zhou, S.-z.; Thomson, D. W.; Mahesh, M. Highly
Efficient Reduction of Unactivated Aryl and Alkyl Iodides by a
Ground-State Neutral Organic Electron Donor. Angew. Chem., Int. Ed.
2005, 44 (9), 1356−1360. (e) Murphy, J. A.; Garnier, J.; Park, S. R.;
Schoenebeck, F.; Zhou, S.-z.; Turner, A. T. Super-Electron Donors:
Bis-pyridinylidene Formation by Base Treatment of Pyridinium Salts.
Org. Lett. 2008, 10 (6), 1227−1230.
(15) For photocatalysis based on NAD+ excitation, using UV light
and sacrificial electron donors, see: Kim, J.; Lee, S. H.; Tieves, F.;
Paul, C. E.; Hollmann, F.; Park, C. B. Nicotinamide adenine
dinucleotide as a photocatalyst. Sci. Adv. 2019, 5 (7), eaax0501.
(16) Martens, F. M.; Verhoeven, J. W.; Gase, R. A.; Pandit, U. K.; de
Boer, T. J. On the question of one-electron transfer in the mechanism
of reduction by NADH-models. Tetrahedron 1978, 34 (4), 443−446.
(17) For seminal work on the photochemistry of NADH analogues,
see: (a) Fukuzumi, S.; Mochizuki, S.; Tanaka, T. Photoreduction of
phenacyl halides by NADH analogues. Origins of different
mechanistic pathways. J. Chem. Soc., Perkin Trans. 2 1989, 2 (10),
1583−1589. (b) Fukuzumi, S.; Hironaka, K.; Tanaka, T. Photo-
reduction of alkyl halides by an NADH model compound. An
electron-transfer chain mechanism. J. Am. Chem. Soc. 1983, 105 (14),
4722−4727. (c) Fukuzumi, S.; Koumitsu, S.; Hironaka, K.; Tanaka, T.
Energetic comparison between photoinduced electron-transfer
reactions from NADH model compounds to organic and inorganic
oxidants and hydride-transfer reactions from NADH model
compounds to p-benzoquinone derivatives. J. Am. Chem. Soc. 1987,
109 (2), 305−316.
(18) For a related radical fragmentation of photoexcited 4-alkyl-
dihydropyridines, see: (a) van Leeuwen, T.; Buzzetti, L.; Perego, L.
A.; Melchiorre, P. A Redox-Active Nickel Complex that Acts as an
Electron Mediator in Photochemical Giese Reactions. Angew. Chem.,
Int. Ed. 2019, 58 (15), 4953−4957. (b) Buzzetti, L.; Prieto, A.; Roy,
S. R.; Melchiorre, P. Radical-based C-C Bond-Forming Processes
Enabled by the Photoexcitation of 4-Alkyl-1,4-dihydropyridines.
Angew. Chem., Int. Ed. 2017, 56 (47), 15039−15043. (c) Bonet, A.
G.; Tellis, J. C.; Matsui, J. K.; Vara, B. A.; Molander, G. A. 1,4-
Dihydropyridines as Alkyl Radical Precursors: Introducing the
Aldehyde Feedstock to Nickel/Photoredox Dual Catalysis. ACS
Catal. 2016, 6, 8004−8008.
(19) For related photocatalyzed reactions of redox-active esters, see:
(a) Okada, K.; Okamoto, K.; Oda, M. A new and practical method of
decarboxylation: photosensitized decarboxylation of N-acyloxyphtha-
limides via electron-transfer mechanism. J. Am. Chem. Soc. 1988, 110
(26), 8736−8738. (b) Okada, K.; Okubo, K.; Morita, N.; Oda, M.
Reductive decarboxylation of N-(acyloxy)phthalimides via redox-
initiated radical chain mechanism. Tetrahedron Lett. 1992, 33 (48),
7377−7380. (c) Pac, C.; Ihama, M.; Yasuda, M.; Miyauchi, Y.;
Sakurai, H. Tris(2,2’-bipyridine)ruthenium(2+)-mediated photore-
duction of olefins with 1-benzyl-1,4-dihydronicotinamide: a mecha-
nistic probe for electron-transfer reactions of NAD(P)H-model
̈
(23) Lorz, P. M.; Towae, F. K.; Enke, W.; Jackh, R.; Bhargava, N.;
Hillesheim, W., Phthalic Acid and Derivatives. In Ullmann’s
Encyclopedia of Industrial Chemistry; Wiley: New York, 2007.
(24) Zheng, C.; Wang, G.-Z.; Shang, R. Catalyst-free Decarbox-
ylation and Decarboxylative Giese Additions of Alkyl Carboxylates
through Photoactivation of Electron Donor-Acceptor Complex. Adv.
Synth. Catal. 2019, 361 (19), 4500−4505.
(25) During our scope studies, it has been independently disclosed24
similar reactions promoted by the dihydropyridine 9, albeit only
under strictly deoxygenated and anhydrous conditions, and with lower
efficiency and rate. The dihydronicotinamide BNAH (5) was declared
unsuitable for this reaction,24 in clear contrast with our results
(Scheme 2, A; entry 5).
(26) (a) Brewster, M. E.; Simay, A.; Czako, K.; Winwood, D.; Farag,
H.; Bodor, N. Reactivity of biologically important reduced pyridines.
IV. Effect of substitution on ferricyanide-mediated oxidation rates of
various 1,4-dihydropyridines. J. Org. Chem. 1989, 54 (15), 3721−
3726. (b) Paul, C. E.; Gargiulo, S.; Opperman, D. J.; Lavandera, I.;
́
Gotor-Fernandez, V.; Gotor, V.; Taglieber, A.; Arends, I. W. C. E.;
Hollmann, F. Mimicking Nature: Synthetic Nicotinamide Cofactors
for C=C Bioreduction Using Enoate Reductases. Org. Lett. 2013, 15
(1), 180−183.
(27) Scott, T. G.; Spencer, R. D.; Leonard, N. J.; Weber, G.
Synthetic spectroscopic models related to coenzymes and base pairs.
V. Emission properties of NADH. Studies of fluorescence lifetimes
and quantum efficiencies of NADH, AcPyADH, [reduced acetylpyr-
idineadenine dinucleotide] and simplified synthetic models. J. Am.
Chem. Soc. 1970, 92 (3), 687−695.
H
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Journal of the American Chemical Society
pubs.acs.org/JACS
Article
(28) (a) Alnajjar, M. S.; Kuivila, H. G. Free-radical and anion
intermediates in the reactions of 5-halo-2-norbornenes and 3-
halonortricyclenes with (trimethyltin)sodium. J. Org. Chem. 1981,
46 (6), 1053−1057. (b) Walborsky, H. M.; Topolski, M. The surface
nature of Grignard reagent formation. J. Am. Chem. Soc. 1992, 114
(9), 3455−3459. (c) Wong, P. C.; Griller, D. A kinetic EPR study of
the norbornenyl-nortricyclyl radical rearrangement. J. Org. Chem.
1981, 46 (11), 2327−2329.
(29) We have also detected the successful coupling of the fully
unprotected sugar, but only trace amounts could be isolated.
(30) Hoye, T. R.; Eklov, B. M.; Ryba, T. D.; Voloshin, M.; Yao, L. J.
No-D NMR (No-Deuterium Proton NMR) Spectroscopy: A Simple
Yet Powerful Method for Analyzing Reaction and Reagent Solutions.
Org. Lett. 2004, 6 (6), 953−956.
(31) Buzzetti, L.; Crisenza, G. E. M.; Melchiorre, P. Mechanistic
Studies in Photocatalysis. Angew. Chem., Int. Ed. 2019, 58 (12),
3730−3747.
(32) (a) Rosokha, S. V.; Kochi, J. K. Fresh Look at Electron-Transfer
Mechanisms via the Donor/Acceptor Bindings in the Critical
Encounter Complex. Acc. Chem. Res. 2008, 41 (5), 641−653.
(b) Lima, C. G. S.; Lima, T. M.; Duarte, M.; Jurberg, I. D.; Paixao,
M. W. Organic Synthesis Enabled by Light-Irradiation of EDA
Complexes: Theoretical Background and Synthetic Applications. ACS
Catal. 2016, 6 (3), 1389−1407. (c) Foster, R. Electron donor-
acceptor complexes. J. Phys. Chem. 1980, 84 (17), 2135−2141.
(33) Cao, Z.-Y.; Ghosh, T.; Melchiorre, P. Enantioselective radical
conjugate additions driven by a photoactive intramolecular iminium-
ion-based EDA complex. Nat. Commun. 2018, 9 (1), 3274.
(34) (a) Lakowicz, J. R. Principles of Fluorescence Spectroscopy,
Plenum: New York, 1983, ch. 9;. (b) Fraiji, L. K.; Hayes, D. M.;
Werner, T. C. Static and Dynamic Fluorescence Quenching
Experiments for the Physical Chemistry Laboratory J. J. Chem. Educ.
1992, 69, 424−428.
(35) Martens, F. M.; Verhoeven, J. W.; Varma, C. A. G. O.;
Bergwerf, P. Photo-oxidation of 1,4-dihydropyridines by various
electron acceptors: a laser flash photolysis study. J. Photochem. 1983,
22 (2), 99−113.
I
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J. Am. Chem. Soc. XXXX, XXX, XXX−XXX