Innovative catalytic EDA complex
Literature seminar ̲ 2023,2,2
B4, Takeshi Inoue

Contents

n Introductionn Catalytic electron donor ; NaI + PPh3n Catalytic electron acceptor ; Tetrachlorophthalimiden Summary & perspective

2

Contents

n Introductionn Catalytic electron donor ; NaI + PPh3n Catalytic electron acceptor ; Tetrachlorophthalimiden Summary & perspective

3

Photo-redox chemistry4• Photo-redox catalysts• Synthetically elaborated organic dyes.
• Metal complexes with polyheteroaryl ligands.
• Exogenous compounds.

Paixao et al. ACS Catal. 2016, 6, 1389-1407.

Electron donor-acceptor complex (EDA complex); Electron rich,
Low ionization potential( i.e., reductant, nucleophile )5; Electron poor,
high electron affinity( i.e., oxidant, electrophile )• Generating radical species without exogenous photo-redox catalysts or metals.
• Induce various radical reaction under mild condition.
• Expand the chemical space. (new selectivity and substrate scope, etc)
Melchiorre et al. J. Am. Chem. Soc. 2020, 142, 5461-5476.

Theoretical background[Charge transfer band of EDA complex]

6[Back electron transfer (BET)]

BET• EDA complex exhibits new absorption
band in longer wavelength.

• Competition with BET is unavoidable
problem in EDA complex.

Paixao et al. ACS Catal. 2016, 6, 1389-1407.

t are needed tophotochemistry.

Kornblum, Kochi, and others showed that the EDA
complex photochemistry could trigger synthetically usefulradical processes under mild reaction conditions (Figure 2).

Pioneering synthetic applications

YNTHETIC

strong color on
The observation
ons in diﬀerent
his phenomenon
pan of about 40
ns showed thatof considerable
f studies, amongose a quantummation of thesee-transfer theory,
donor D with aectron-accepting
ectronic aﬃnity,
ex in the groundg the association
Electronysical properties;
f the donor
separated
bitals are formed
frontier orbitals
Acceptor;
is characterizednd, the charge→ ΨES electronic
with ground and7

Irreversible fragmentation(Leaving groups)→ Avoid unproductive BET.

Figure2. Seminal Enamine,
examples reporting the use of Alkyl
EDA complex
Enamine,Anisoleresidue.
photochemistry
Enolate for synthetic
Amineapplications. RF: perﬂuoroalkyl
stannene

Speciﬁcally,
Bunnett investigated theOrgano Cantacuzene and Tetranitro
Nitroarene
participation of enaminesand enolates (structure 1)TCNE
as donors
iodidemethanein charge-transfer interactions with aryl and perﬂuoroalkyl
iodides of type 2, to form an EDA aggregate (EDA-1, Figure2a).17,18 Following the mechanistic pattern depicted in Figure(a) Cantacuzene et al. J. Chem. Soc., Perkin Trans. 1 1977, 1365-1371.
Bunnett. Acc. Chem. Res. 1978, 11, 413-420.
(b) Russell et al. J. Org. Chem. 1987, 52, 3102-3107.
Kornblum et al. J. Org. Chem. 1991, 56, 3475-3479.
(c) Kochi et al. J. Am. Chem. Soc. 1987, 109, 7824-7838.
Kochi et al. J. Am. Chem. Soc. 1979, 101, 5961-5972.

PHOTOCHEMISTRY(the charge-transfer band hνCT). Irradiation of the colored
Synthetic
oflaboratory
EDA26 complex
EDA complexphotochemistry(EDA-5), followed by irreversible extrusion of8
In 2013, independentrenaissanceeﬀorts by Chatani25 and ouraryl iodide, generated the radical intermediates I and II, whichrevisited and reintroduced EDA complex photochemistry as afurnished the C2-arylated product 11a.29
useful radical generation strategy for chemical synthesis• Pyrrole and iodonium cation• Concomitantly,
Enamine andbenzyl bybromideprompted
the interest in asymmetric(Figure3). To better contextualize these studies and provide
30
organocatalysis, our laboratory had been investigating thedirect α-alkylation of aldehydes 12 with electron-deﬁcient alkyl
bromides 13, including benzyl and phenacyl bromides,
catalyzed by the chiral amine 14 (Figure 3b).26 Previous
studies27a on similar reactivity established the need for a
photoredox catalyst to generate radicals via reductive cleavageof the alkyl bromide 13. However, a control experiment
revealed that, for speciﬁc substrates 13, the reaction could
eﬃciently proceed in a stereoselective fashion without anexternal photoredox catalyst.26 The chemistry did not proceed
at all without light illumination, and evidence was collectedsupporting a radical manifold. Mechanistic studies revealed the
Chatani et al. Chem. Lett. 2013, 42, 1203-1205.
et al. Nat. Chem. 2013, 5, 750-756.
ability of the electron-richMelchiorre
chiral enamines
III, generated upon
Figure 3. (a) Visible-light-induced C2-arylation of pyrroles in thecondensationof the amine
catalyst
14 uponwith association
aldehyde 12,
toabsenceof a photocatalyst:
EDA-5
formedof twotrigger the formation
visible-light-absorbing
EDA
complexes
stoichiometricsubstrates.of(b)Enantioselective catalytic
α-alkylationof(EDA-6)
with electron-deﬁcient
Serendipitous observation (linked
to control
aldehydes
enabledby experiment).
irradiation of an dinitrobenzyl
enamine-based and
EDA phenacyl
complex:bromides13. Anupon
intracomplex
irradiationof
EDA-6
formedassociationSET,
of ainduced
transientbycatalytic
chiral→ Reintroduced EDA complexintermediate
photochemistry.
III with
13. LED:light-emitting
diode; CFL:
EDA-6,
aﬀordedthesubstratechiral radical
ion pairIV. By facilitatingancompact
ﬂuorescentlamp;
EWG: electron-withdrawing
group;
irreversible
cleavage ofthe carbon−halogen
bond, the bromide
MTBE:
methyltert-butyl
ether; TMS: BET
trimethylsilyl.
ﬁlledtogray
within IV
avoidedan unproductive
securingThe
accessthecirclerepresentsabulky
substituent
onthechiralorganic
catalyst.
reactive open-shell intermediate V. Optical absorption
spectroscopic studies conﬁrmed the formation of theimportance as it is a rare example where both thermal andelectron spin resonance, ESR), while irradiation under a shorter
dinitrobenzyl
bromide fragmen
underphotochemical
mild reactionmechanisms
conditionscan
2).
of (Figure
theEDA
complexactivation
strategy
is based
light- the same
be separately identiﬁed andwavelength,
262on
nm,theproducesradical species but with 9
Stoichiometric
EDAcoupling
complexthanvisible-lightthe van derirradiation
Waals separat
drivenofsubstrates, thedonor higher
and theacceptorstudied. Physicochemical parameters,
includingthetwowavelengtha slightly
quantumyield. UnderÅ),36 whichis consonant
the corresponding
CT bands,of absorption maxima (λmax) from
(Figure4a). The viabilityof the resulting
processes
is to observe(again atradical
436 nm),attempts
alkyl radicals
using witof stoichiometric
donor
and(K
acceptor]
at work
in similar
the solid st
the [Coupling
equilibrium constantsof EDA complex
formation
Et4Sn, iBu4Sn, and secBu4Sn were being
unfruitful.
Under
EDA),
and molar absorptivities (εEDA) were measured. All CT bands
compacterror,
ﬂuorescencelamp (Creaction conditions, inside the experimental
the photowere observed to fall at least in some extent in the visible region
the radical
VI, whichemical
reaction of Et2SnMe2 withofTCNE
exhibitsion
thepairsame
ACS Catalysis(with 345 nm ≤ λmax ≤ 437 nm). In addition, low formation
selectivity for Et/Me addition in respect
the uponcorresponding
and toVIII
extrusion of
constants (KEDA ≤ 7.7) and molar absorptivity (εEDA ≤ 500
thermalSchemeprocess.
16. EDA Complex-Photoinduced
quantumArylation
yield of ofthe process
(S
−1
−1
70a
M cm ) were observed, which was attributed to the weak
Overall,Using
theseIodonium
previous Salts,
observations(added to withothers),Arenesunder
Irradiation
White
combination
could
be respoTainteraction between the σ HOMO of R4Sn 3 and the π*
allowedthe= establishment
complexindole
5, derived
LEDs (λ400−750 nm)of the EDA
alkylated
18. from
Similar phL
LUMO of TCNE 4 (Scheme 7).
the combination of R4Sn 3 and processes
TCNE 4, haveas a beencommondeveloped
intermediate in both processes, thermal and 37
photochemical.
aromatics. For example, K
Both reaction pathways have been remarked to proceed via the
Scheme 7. Study on the Thermal and Photochemical
EDA complex
same general mechanism, that is, photoactive
an electron-transfer
event (EDElectron Transfer between Tetraalkyltin Derivatives 3 andof byanilinederivatives 19
leading to a radical ion pair 7, followed
the fragmentationof andTCNE 42
2
to forgea C(sp )−C(sp)
unstable tin radical cation (this one20,
being
characterized
as a37a4c). triad 8 combines to“dark” process) to aﬀord triad 8. Finally,
aﬀord the addition product 6 (Schemeα-Ketoacids
9).
of type 22 h
The authors corroborated the involvementof thesuitable donors
for EDA
productive
complex 5 in the electron-transferdiﬀerent
event (as acceptors,
opposed toincludinga39kinetic dilemma ofparticipation as a spectator
species, cf.
2013InKochi et al. J. Am. Chem. Soc. 1979, 101, 5961-5972.
Chatani et al. Chem.acids.
Lett.the, 42,particular,1203-1205. the latter
Scheme 5), because the rate for theaddition
overall transformation
kT systetothecarbonyll examples reporting the use of EDA complex
correlates with the constant of formation KEDA, and the fact that
Electrondonor
andacceptor
finally
end up in product scaffold.
•synthetic applications. RF: perﬂuoroalkyl residue.
an intimate relationship is noted between both the photo• Electronically biased substrates. chemical and thermal activations in the electron-transfer event(Scheme 10).
ntacuzene and Bunnett
investigatedthe→ Low applicability in synthesis.
Based on the same selectivities observed for the insertion of
namines and enolates (structureFigure1) as donors
mixed
alkyl tin
R1 SnR2 into TCNE 4 (e.g., in the
4. (a) General strategy for the
couplingof derivatives
electron-richsacriﬁcial
donor
compounds
EDA bycomplex
oxidized
38 to deliver cyclic imines 36 andfragmentation needed for radical
formation.
Generally,
simple that beelicit
(RA,
blue
circleinFigure8a)andleavinggroup.
The(EDA-13) andgeneratedradicalssubstrates
XII and
XIII, withformation
bywhichaggregation
with electron-poor
substrates(Figurerespectively.
This
iminyl radical generation fromeasily available
adornednativefunction10 di
Sacrificial
donor
and
redox
auxiliary
substrate’s
main
core
does
not
need
to
be
electronicallybiasedUponradicalthe resulting
substituted
aryl openoximes was also used to synth(mostlyradical
halides coupling.
within 7a).
acceptors)
werethis formation,
products alities
30 upon
Thelight-induced
mildused for
48aimidazoles,
cyclic sulfonimides,48b phenanthridines,
purpose.
Thephotochemicaluse of native fragmenting
is advantageous
ntal conditionsof thisprocessgroups
securedquinolines.48c Further studies highlighted the abilit
in
terms
of
the
availabilityofthereagents,but
itrequiresthentfunctional
group
tolerance,
as demonstrated by thective
EDA complexes,
formedupon in situ
potassium carbonate to participate as donor in similar
EDA complex
formation to be elicited exclusively by theunterpartfrom weakly polarized
substrates, remedy hydrochlor48dfunctionalizationofdiuretic
complexes
toform
amidylradicals.
electronic
properties
ofthesubstrate’s
main
core.
This
means
uction of C−C (a−c) and C−S bonds (d),(structure 30a
Figure6d).
The main advantage of installing suitable redox auxiliarthat inonly
highlyresidue.polarized radicals can be generated. For
uanidine; RF: perﬂuoroalkyl
the possibility of generating unbiased radicals, not bearin
example,in the previous contribution
reported in Figure 7, it is
g Structural
Constrictions:
Using Sacriﬁcialstabilizing/activating functionality. Often, the redox auxili
theAuxiliaries.
electron-poor
naturemethodsof the perﬂuoralkyl
fragment within
andhighlighted
asked Redox
an electron-richenolate, The
whicheasily installedon auxiliary]
readily available substrates. Chen’s g
RFI that securesthe formation of the EDA complex, while the[Redoxpon facile
deprotonationof α-cyanoable
the couplingoftwosubstrates,
which
are
also
implemented a protocol for generating alkyl radicals
iodideis a merefragmenting group. The resulting perﬂuorear
highlyEDA
acidicproton.
The formation.
enolatein a thecomplex
Therefore,
thealcohol precursors, simply by adorning the native hydoalkyl uponradicalassociationis therefore electronically biased (highly
complex (EDA-10)
ofthe reaction
products
is somehow
restrictedby theproved useful
moiety of the substrate with a N-phthalimide fragment (Felectrophilic).
In
an alternative
strategy, whichRFrﬂuoroalkyl iodides(RFI, where
49a
9a).
The aromatic ring of the resulting N-(alktoexpandthesynthetic
potentialof
EDA
complexphotoselecthighlypolarized
reagents
with
donor
and
lkyl fragment). The photoactivity ofchemistry,a reaction
partnerwith a purposely
properties,
which
eventually
up isin decorated
the productrophilic
perﬂuoroalkyl
radicals(RFend·),activatinggroup,
which serves as both redox-auxiliarytedarylinstalledmoietyof substrate
25limitation
Oneby thestrategy
to
evade
this
is to
use group. The(RA, (HAS)
blue circle
in Figure 8a) andleaving
matic
substitution
pathway.
donor compounds
thatelicitnot EDA
corenm)does
need to complex
be electronically biased precursor
mination (Φ substrate’s= 3.8, λ main
= 400
by mechanism
aggregationelectron-poor(Figureain
as withthe mainreaction substrates
Figure 7. (a) General strategy for radical formation based on the use
nhelight-induced
radical formation,
openEDA complex photoactivity
served the ofresulting
a stoichiometric sacriﬁcial donor to drive EDA complex formation.
SET

The structure of the radical trap, which is not involved in the radical
odides are particularly prone to EDA
formation process, ends up in the ﬁnal product. (b) Photochemical== NEt
ey have been extensively
used
asFigure 8.
generationof perﬂuoroalkyl
radicalstheof quinoxalines;(a) General
representationof theforuseof synthesisa redox auxiliary3
radicalNO2
t representative example isO a photo-,that drives
residue. of an EDA complex and, upon
RF: perﬂuoroalkyl
both the formation
Figure 9. (a) N-phthalimide as aphotoexcitation and fragmentation, the generation of an electronicallyLeonori et al. Angew. Chem., Int.
Ed
. 2015, 54, 14017-14021.
5465
https://dx.doi.org/10.1021/jacs.0c01416
alcohols and forms an EDA complex
unbiased radical. (b) Photochemical generation of nitrogen-centered
NO2

J. Am. Chem. Soc. 2020, 142, 5461−5476

Catalytic EDA complex• Quinuclidine + Tetrachlorophthalimide

11• Eosin Y + Pyridinium

Bach et al. ACS Catal. 2019, 9, 9103­9109.

Lakhdar et al. J. Am. Chem. Soc. 2016, 138, 7436­7441.

• Specific pair of electron donor and acceptor.
⟺ Limited to selected substrates.

Contents

n Introductionn Catalytic electron donor ; NaI + PPh3n Catalytic electron acceptor ; Tetrachlorophthalimiden Summary & perspective

12

Catalytic electron donor ; NaI + PPh3

Giese radical addition,
R Journal of the American Chemical Society
Minisci reaction ···Acceptor
Figure 15. (a) General
strategy Ph
for catalysisF3C in EDA complex
O O
RI
photochemistry: a donor
catalyst that can photochemicallygenerate
=
O N
O
R N
Ph
R
radicals and then be turned over. (b)Photocatalytic
radical alkylations,,
Ph
O combinationO
mediated by the catalyticof triphenylphosphineandTogni’s reagent
Pyridinium
active ester
sodium iodide; TFA:Redox
triﬂuoroacetic
acid.

ca

13
Figure 16. Use of 3-acetox
catalyst for visible-light-me
Cformation; q-OAC: 3-aceto
le
yl.

in
pubs.acs.org/JA
7
EDA-24. Blue-lightirra
from the catalyst (q-Othcascadesequence:
moiety,leading
to deca2wTC(sp)-centered
rad
amino
radicalXXXIII.

leading
to cyclohex
by thecatalyst
radicalturnsintermediate
the catalyst overantransfeex+•
trappedthe previo
to deliver,
afte
73 by
anionthe43,catalytic
deliveringthepT
cycle.
quantumyield (Φ =with
0.0
was consonantexcycle withnoradicalThe reported cat
geOverall,q-OAc the69 trigg
expandingsynacts photochemistry.
ﬁrst as a donor forel
moiety in 47a produced the catalyst radical cation XXXI and,F
complex,
and
then
can
upon CO2 extrusion, the open-shell intermediate XXI. Radicals
example, driven bygcompound(PPh3 + NaI)
warks as 65
catalytic
donor.
• Combination
XXXIII. The crucial asp
XXIof
aresimple
then interceptedby acid-activatedheteroarenes
in ageneral catalyst tur
geometricallyconstraine
Minisci
manifold.
The
crucial
step
of
this
mechanism
istheE• EDA complex formation with several acceptors.
electron
acceptors.
dine core, which precatalyst turnover: the radical cation XXXII, generated uponp
EDA throughComplex• Visible light.
proceeding
α-d
C−C bond formation, is reduced by the Ph3P−I· intermediate+•, 363, 1429‒1434.
Fu et al. Science. 2019
Enzymatic
XXXI, which was proposed to be a persistent radical.68 This
q-OAc
, XXXIV.CatalycaBackground[Aryl triflate]

14[Hypervalent iodine]

Li et al. J. Am. Chem. Soc. 2017, 139, 8621­8627.

•

Iodide is known to reduce various organic molecules.

✕ UV irradiation or high temperature is required.

Studer et al. Angew. Chem. Int. Ed. 2013, 52, 10792-10795.

This work→ Reduction of RAE via EDA complex.
→ Visible light excitation with PPh3.

gain in spin on phosphorus on going from R3P-Br tods
On the other hand, organophosphine was found to andbe correspondingan(MeO),(S)P-Br-.
This suggests that the effective electronegativity of phosphorus
to Delocalized
eﬃcient electron donor.
Given theirbetween
excellent performanceinradicaliodideandis considerably
reducedin the PPhmethoxy derivative.
This is most unexpected because
3
3
ASPECTS
OF
M
E
C
H
A
N
I
S
M
of the greater electronegativity of the ligands, which is exemplified in the decrease in.
organic chemistry, especially in transition metal-catalyzed
p :s ratio on phosphorus for the methoxy derivative. This inconsistency in trend
the13
ere tworeactions,majorroutestotheo*radicalsstudies
in
this
work,
as and
shown
is
most
curiousrequiresin
further study.
exploitation
of
their
new
featureshas
attracted[Observation of Ph3P­I· by ESR]
ic
for theintense
phosphorus: reaction catalyzed by organo-TABLE3 .-ORBITAL POPULATIONS ESTIMATED FROM E.S.R. PARAMETERS',
interest.derivatives
Normally, thengradical
atom
total
a:
4
phosphine species wasproceeded
via a nucleophilic process,
R3P--+
R3Po++e(5)R,P*-CI
P
0.164
0.58
0.744
al
and rare examples of radical chemistry were reported.14 We
Cl
0.0131
0.26
0.291
R3P.+ hal- --+ R3P-hal,
ng
P
0.136
0.46
0.596
(6)Br
envisioned that the catalytic amount of organophosphine R3P---Br
0.386
0.36
0.026
ed
0.59
P
0.180
0.77
would combine with ethyl iododiﬂuoroacetate to form a
Br
0.022
0.32
0.34
of
hal+
halo
+
eRSP*-I
P
0.48
0.468
0.148
noncovalent interaction,
which
could
inducearadical
(7)
B
A
I
0.030
0.38
0.410
on
O
intermediate, R3P
thus leading
toOR,P.-hal.
theO discovery of unprecedented R2S*-CI
CI
0.050
0.30
0.35
O
halo
3
(8) Brwo
R2S*-Br
0.43
0.026
0.456
Ph
transformations (Scheme 1).
R2S-I
N
0.43
0.463
0.033
I
N
yl
Ph
alkyl
O
alkyl
O
To verify this hypothesis and study the organophosphine
Calculated
from
the J.
following
estimatedfromthe wavefunctions
given by FroesePetersenetPal.
Chem.parameters,
Soc. Faraday
Trans.
II. 1979, 75, 210‒219.
a
O(J. Chern. Phys., 1966, 45,1417).
O
catalysis reaction, we chose alkenes and ICF2COOEt as A" (3fP)/G = 3664, (35Cl) = 1666, ("Br) = 8341, (12'1) = 7294.5’s+Published on 01 January 1979. Downloaded by The University of Tokyo on 1/23/2023 10:38:55 AM.

+

1= 201.4 ("Cl) = 100.7 (81Br)= 493.5 (12'1) = 453.2of the values given in tables 1 and 2.
Calculated
fromaveragesO

O
Scheme 1. Reaction Design Based on the Noncovalent Also,N
weshould relate[Complexation
the present results withof
thoseassigned
toPPh
the radical[Reaction between
example]
NaI
and
3]
alkyl
Interactions
P and the C−I BondO
Me$-Brby
LuckenandMa~eline.~*Thisradicalwas
detectedinX-irradiatedO

dimethyl(9-fluoreny1)sulphonium bromide, the presence of two methyl groups being
Phsplitting of x 9 G .
establishedby the observation of a nearly isotropic multiplet
PhPhG) indicate
NaI
Curiously, the 81Brhv
hyperfine tensor components(366.2, 85.8 and 85.8
PP
a considerably smaller spin-density on bromine+ than we have obtained for similarradicals. One possibility is that this species is formed from the parent sulphur cation,
PPh 3 the increase in s-character in theR(Me),S-+, to give [R(Me),S*-Brlf.
However,
Na I
Na I
orbital on sulphur should lead to a marked increase in spin-density on bromine
relative to the R,S*-Br radicals, which is opposite to the observed change. Thus
Phthat the Me,S--Br formulation is to be preferred. This work was perwe agree
He et al. Org. Lett. 2019, 21, 6705­6709.
formedtentatively suggest that some libratory
Ph at room Itemperature ; we thereforeO
Exergonic
motion has P
caused partial averaging ofOthe tensor
components.by 4.6 kcal/mol

Ph

NaI
+
PPh 3

Received: July 4, 2019
Published: August 12, 201915

Na
2B" I("P)

•

ng
in
ch
nd
ex
ic
eon
ee
yl
he

9. Proposed Full Catalytic Cycles

•

Ph

e–

Na

N

OM E C Halkyl
ASPECTS OF
ANISM
O

e–

O
N
O

P
Ph

P

T

in acetonitrile
through thedelocalized
and(22)
PPh3 is exergonic
theticallyelaborateorganic
which
used
as 10).
a principle
to construct
redox
photoredox
catalysts
indyescurrentuse
aretransfer
is appliedin organic
photovoltaics
0.44 and
0.42,
respectively(Fig. 1B). The
calcunTheorganic
photovoltaics
(22)
0.44
andhave0.42,
respectively
(Fig.
1B).
Thea catalytic
calcurecent
progressin(16),
photoredox
catalysis(9,
Such
irradiation-induced
intermolecularchargeand spindensities
acrossI and P arecation-pinteraction(exergonicby
4.6
kcal/mol).
charge-separated
excitedstates(17–19)accessible
cycle
for
organicsynthesis.
lyprecious
metalcomplexes(11–15)andsynandtraditional
photochemistry
(23)
but
is
seldomlationsalsosuggestedthatcomplexationofNaI
ochemistry (23) but
seldom catalysts
lations alsosuggestedthat complexationof NaI
Theisphotoredox
in current
use aretransfer is appliedin organic photovoltaics (22)0.44 and 0.42, respectively (Fig. 1B). The calcuThe assembly of NaI and PPh3 with the RAE
by absorption of visible light (Fig. 1A). PhotoWe posited that a photoredox catalytic cycle
is exergonicinacetonitrile
through the of NaI
and PPh3 lations
callyelaborateorganic
dyes(16),transfer
which
have
used
asinlight-induced
aacetonitrile
principle
tothroughconstructa catalyticN-(cyclohexanecarbonyl)phthalimide
redox
exergonic
theelectron
and PPho constructaintermolecularcatalytic
redox
precious
metalcomplexes(11–15)and onsynand traditional
photochemistry(23)
but is seldom
alsotosuggested
that complexation
3 isform ainducedmostly
chargethroughbasedintermolecularinteraction
4.6 kcal/mol).
ge-separated
excitedstates(17–19)accessible
cyclehavefororganicsynthesis.
exergonic
acetonitrile
through theandviaPPhtheticallyorganic
dyesinteraction
(16),
used
as
a principle
constructcharge
a catalytic
redox
cation-p(exergonicby
4.6
kcal/mol).
thesis.
3 is(exergonictransfercation-p
complex (CTC)
coulombic
inter- inby
assemblyof donorelaborate
and acceptor
molecules
by whichtransfer
without
directexcitationof thetocatalyst
cation-p(exergonic
by 4.6kcal/mol).
charge-separated
states(17–19) andaccessible
cycle
for
synthesis.
is calculated
be exergonic
byinteraction
3.8 kcal/mol
noncovalentinteractions
is(Fig.
aexcitedwell-known
process
substrates
obviatetheneedfor expenRAE
The toassemblyof
NaI
and PPhofvisiblelight
1A).
Photopositedthata organic
photoredox
catalyticaction
cycle
with
the
RAE
The
assemblyof We
NaIand couldPPhabsorption
photoredox
catalytic
cycle
3 with the3
The assembly of NaI and PPhto
by absorption
oftransfer
visiblelight(Fig. 1A).
PhotoWe positedthat aa photoredox
catalyticN-(cyclohexanecarbonyl)phthalimide
cycle
form thea RAE
ced intermolecularchargethroughbased
on light-induced
intermolecularelectron
N-(cyclohexanecarbonyl)phthalimide
toform
3 withintermolecularelectron
N-(cyclohexanecarbonyl)phthalimide
to form a
inducedchargetransfer
transferthrough(CTC)
basedon light-induced
charge transfer
complex (CTC) via coulombic intermblyof donor
acceptorby complex
transfer
without
excitation
the catalyst electron
chargevia direct
coulombic
inter- ofintermolecular
ect excitation
ofand
theintermolecularcatalyst molecules
charge transfer(CTC)
viakcal/mol
coulombic interassembly
andacceptor
molecules
byexergonictransfer
without
directexcitationof the catalyst
action is calculated
to be complex
exergonic
by 3.8adonorwell-known
process
andtosubstrates
could
obviatethe needfor expenaction
is calculatedbeby 3.8kcal/moldovalent
obviateinteractions
theneed forisof
expen-

Simulations of charge transfer energetics

noncovalent interactions is a well-known process[DFT calculation]and substrates could obviate the need for expen-

action is calculated to be exergonic by 3.8 kcal/mol[Spin delocalization]=
Fig. 1. Redox catalysis based on light-induced

duced
intermolecular electron transfer from sodium
dium iodide to redox-active ester. (A) Light-

induced intramolecular charge transfer(CT) and light-induced intermolecular donor(D)–acceptor (A) charge transfer throughor self-assembly via noncovalent interactions.
L, ligand; M, metal. (B) Estimated Gibbs
energy Fig.
changeof intermolecular3
1. Redox
catalysiselectron
based on light-induced
1.. Redox
catalysis
based
on light-induced
transfer from NaI and NaI/PPh
3 component
intermolecular electron transfer from sodium
to aliphatic
N-(acyloxy)phthalimide
to deliver an alkyl radical, and a possible iodide/phosphine redox cycle. (C) Photoactivation of assembled
molecular
electrontransfer from(NPhth)sodiumiodidetoredox-active
ester.
(A)of N-(acyloxy)phthalimide
with NaI and LightPPh3 through coulombic and cation-p interactions. SET, single electron transfer. 3
e to complex
redox-active
ester. (A) Light-

PPh stabilizes the iodide radical.

→ Relatively favorable formation of PhP ­I· radical.

induced intramolecular charge transfer

ced intramoleculartransferandcharge
light-induced
intermolecular donor
nt Fu et al.,(CT)Science363,
1429–1434(2019) donor
29 March 2019and light-induced
intermolecular(D)–acceptor (A) charge transfer through1 of 616

T

The photoredox catalysts in current use aremostly precious metal complexes (11–15) and synthetically elaborate organic dyes (16), which havecharge-separated excited states (17–19) accessible
by absorption of visible light (Fig. 1A). Photoinduced intermolecular charge transfer throughassembly of donor and acceptor molecules bynoncovalent interactions is a well-known processtransfer is applied in organic photovoltaics (22)and traditional photochemistry (23) but is seldom
used as a principle to construct a catalytic redox
cycle for organic synthesis.
We posited that a photoredox catalytic cycle
based on light-induced intermolecular electrontransfer without direct excitation of the catalyst
and substrates could obviate the need for expen-

0.44 and 0.42, respectively (Fig. 1B). The calculations also suggested that complexation of NaI
and PPh3 is exergonic in acetonitrile through thecation-p interaction (exergonic by 4.6 kcal/mol).
The assembly of NaI and PPh3 with the RAE
N-(cyclohexanecarbonyl)phthalimide to form acharge transfer complex (CTC) via coulombic interaction is calculated to be exergonic by 3.8 kcal/mol

Simulations of charge transfer energetics[The energy barrier of charge transfer]

Coulombic interaction+
Cation-" interaction
Fig. 1. Redox catalysis based on light-induced(w/ LiIelectron; ー1.1kcal/mol,w/ KI ; ー2.9kcal/mol)intermoleculartransfer from sodium
iodide to redox-active ester. (A) Lightinduced intramolecular charge transfer
3(CT) and light-induced intermolecular donor(D)–acceptor (A) charge transfer throughself-assembly via noncovalent interactions.
L, ligand; M, metal. (B) Estimated Gibbs
energy change of intermolecular electrontransfer from NaI and NaI/PPh3 component
to aliphatic N-(acyloxy)phthalimide (NPhth) to deliver an alkyl radical, and a possible iodide/phosphine redox cycle. (C) Photoactivation of assembled
complex of N-(acyloxy)phthalimide with NaI and PPh3 through coulombic and cation-p interactions. SET, single electron transfer.

PPh lowers energy barrier of charge transfer.
→ SET with visible light.

17

ansoiety
rcus
enThe
transemoiety
abrrier
Marcustary
onens one.
Theheab0-todetobarrierh anentaryonds
ies onbasis
S0-toeddideatohotoith an
npondsree basis
ored aters
photobox-reon
n in
n to
eters
ered
arboxblue
wn3in
PPh
ion
le S1to
vered
ction
er
blue
orm
o) PPhin- 3
bleuan-S1
actionalyst
otion.
formsoanyinquanthe
atalystvail-

3 However, highly electrongave
tricyclohexylphosphineloweredtheassterically bulky triarylphosphine ligand
deficient
did basisthefercomparable
process from yields.
iodideto the phthalimide moiety
to atris(4-pentafluorophenyl)phosphine
wavelength of 436 nm(fig. S3).
Onyield,
the
of
86.5
kcal/mol
(Fig.
1C;
see
supplementary
deficienttris(4-pentafluorophenyl)phosphinedidthe stericallybulkytriarylphosphine
ligandawas completely
ineffective,
probably
due to we
its explored2-(diphenylphosphino)biphenyl,
which likely
was estimatedto be 61.2 kcal/mol using Marcusof theabove
theoreticalanalysis,materials).
onelectron-donating capacity to facilitate
wastheory,completely
probably
dueentostudies
itslack 2-(diphenylphosphino)biphenyl,
which
likelyofhindered
formation
of
the
CTC
(Fig.
2A). All
within ineffective,
1.5 Further
kcal/mol computationalofthe photon
simple combination of NaI and PPh3 as a photoexcitedof capacity
thecanCTC
assigned
S0-totransferformationof the iodideuse(Fig.
of 2A).
threeAll
components—phosphine, sodium iodide,
ergy
that
456-nm state
blue LEDs
provide.
The theelectron
lackof theelectron-donating
to facilitate
hindered
ofsalt.
theTheCTC
redox
catalyst
for decarboxylative
alkylation
reanalogous
electrontransfer
process
intheabS
excitation
toelectrontransferfromiodideto1electrontransferoftheiodide
salt.
The
use
of
three
components—phosphine,sodiumiodide,gave comparable yields. However, highly electron- actions
tricyclohexylphosphinelowered the yield, as(31, 32).
a higher barrier
sencetheof PPh3 must overcomep*orbitalof the phthalimide
moiety with an
deficienttris(4-pentafluorophenyl)phosphinedidthestericallybulkytriarylphosphine
ligandof 86.5 kcal/mol (Fig. 1C; see supplementary
excitationenergy
of
2.85
eV,
which
corresponds
Investigationofkey
reactionparameterswascompletely
ineffective,
probablydue
2-(diphenylphosphino)biphenyl, which likely
materials).
Furthercomputational
studies
on to its
toawavelength
of
436
nm
(fig.
S3).
On
the
basis
lack
of electron-donating
capacity
toS0facilitate
hindered
formation
the CTC for(Fig.
2A). All-tothe excitedstate of the CTC assigned
theThe
optimized
reactionofconditions
decarboxof theabove
theoreticalanalysis,
we
exploreda
S1 excitation
to electrontransferfromiodidetouseelectrontransferoftheiodidesalt.
Theof ylative
threecomponents—phosphine,sodiumiodide,inalkylation using NaI/PPh3 are shownasaphotoof NaI
andwithPPhan
the p*simple
orbital combinationof the phthalimide
moiety3
Fig. 2. Decarboxylative cyclohexyl addition to
excitationof 2.85
which corresponds
redoxenergy
catalyst
foreV,
decarboxylative
alkylation retrimethyl[(1-phenylvinyl)oxy]silane delivered
to a wavelength
of
436
nm
(fig.
S3).
On
the
basis
actions (31, 32).
a-cyclohexylacetophenone in 82% yield under blueof the above theoretical analysis, we explored a
LED irradiation of 20 mole percent (mol %) PPh3
simplecombination of NaI
and PPh
3 as a photoInvestigationof keyreactionparametersand 150 mol % NaI in acetonitrile (see table S1
redox catalyst for decarboxylative alkylation reThe
optimized
reactionconditionsfordecarboxactions (31, 32).
for details of optimization) (33, 34). The reaction
ylative alkylation using NaI/PPh3 are shown inrequires further desilylation by a base to form
Investigationof key reactioncyclohexyl
parametersaddition to
Fig. 2. Decarboxylative
the a-alkylated ketone. Because NaI is so inThe optimized
reaction conditions for decarbox- delivered
trimethyl[(1-phenylvinyl)oxy]silane
expensive, it was used in superstoichiometric quanare82%
shown
in under blue
ylativealkylation using NaI/PPh3 in
a-cyclohexylacetophenoneyield
tity (1.5 equivalent) both as electron-transfer catalyst
Fig. 2. Decarboxylative cyclohexyl addition to
LED irradiation of 20 mole percent (mol %) PPhand
3base to trap the trimethylsilyl (TMS) cation.
trimethyl[(1-phenylvinyl)oxy]silane delivered
and
150
mol
%
NaI
in
acetonitrile
(see
table
S1
Extremelypure(99.999%) NaI without any
a-cyclohexylacetophenone in 82%✕yield
under blue interaction
Cation
with
RAE.
for
detailsof
optimization)
(33,
34).
The
reaction
LED irradiation of 20 mole percent (mol %) PPh3
metal contamination was tested and gave therequiresdesilylationa baseand 150
mol % further
NaI in acetonitrile(see bytable
S1 to form
same results observed with the commonly availfor detailsof optimization)(33, 34).Because
The reaction
the a-alkylated
ketone.
NaI is so inable reagent-grade material (purity >99.0%). The
requiresfurther itdesilylation
bysuperstoichiometrica base to form
expensive,
was used inquanresults of testing other alkali halides are shown in
the a-alkylated ketone. Because NaI is so intity (1.5 equivalent) both as electron-transfer catalyst
Fig. 2A. Lithium and potassium iodide were much
expensive, it was used in superstoichiometric quanand
base
to
trap
the
trimethylsilyl(TMS)
cation.
less effective than NaI, and a soluble quaternarytity (1.5 equivalent) both as electron-transfer catalyst
pure (99.999%)
without any
ammonium iodide was entirely ineffective. The
and baseExtremely
to trap the trimethylsilyl(TMS)NaI
cation.
metal
contamination
wastestedandgavetheExtremely pure (99.999%) NaI without any
observed alkali metal cation effect revealed thatmetalsame
contamination
was tested
and
gave
the
results observedwiththecommonly
availthe sodium cation has an important role in thesameableresults
observedwiththecommonly
availreagent-grade material (purity >99.0%). The
electron transfer activation step, as indicated by✕ Electron donating capacity.
able reagent-grade
material(purity>99.0%).
The
results of testing other alkali halides are shown in
DFT study in Fig. 1C (formation of the CTC by LiI,
results of testing other alkali halides are shown in
Fig. 2A. Lithium and potassium iodide were much
NaI, and KI is exergonic by 1.1 kcal/mol, 3.8 kcal/
Fig. 2A. Lithium and potassium iodide were much Sterichinderance.
lesseffective
than
NaI,
and
a
solublequaternarymol, and 2.9 kcal/mol, respectively, as indicatedless effective than NaI, and a soluble quaternaryammonium
was ineffective.
entirely ineffective.
The
by DFT calculation). Other sodium halides (fluoammonium
iodide iodide
was entirelyThe
observedalkali metal
revealed
observedalkalication
metaleffectcationeffectthat
revealed thatride, chloride, and bromide) were also ineffective.
the sodium
cation cation
has an importantrole in the role in the As noted above, phosphine is crucial to facilitate
the sodium
has an important

Investigation of key reaction parameters18moietyarcus
n en. Thee abarrier
ntary
es on
S0-toide to
th an
ponds
basis
red a
hotoon re-eters

rboxwn in
on to
vered
r bluePPh3
ble S1
actionform
so inquanatalyst
ation.
t any
e theavail). The
wn in
much
rnary
e. Thed thatn thedeficient tris(4-pentafluorophenyl)phosphine
did the sterically bulky triarylphosphine ligand
the a-alkylated
ketone. Because NaI iswhich
so in- likely
was completely ineffective, probably due to its
2-(diphenylphosphino)biphenyl,
expensive,
it was usedin superstoichiometricquanlack of electron-donating capacity to facilitate
hindered
formationof the CTC (Fig.
2A). Alltity (1.5threeequivalent)both as electron-transfer
catalystiodide,electron transfer of the iodide salt. The use ofcomponents—phosphine,sodiumand base to trap the trimethylsilyl (TMS) cation.
Extremely pure (99.999%) NaI without any
metal contamination was tested and gave thesame results observed with the commonly available reagent-grade material (purity >99.0%). The
3 shown in
3 halides are
results of testing other alkali
Fig. 2A. Lithium and potassium iodide were muchless effective than NaI, and a soluble quaternaryammonium iodide was entirely ineffective. The
observed alkali metal cation effect revealed thatthe sodium cation has an important role in theelectron transfer activation step, as indicated by
DFT study in Fig. 1C (formation of the CTC by LiI,
NaI, and KI is exergonic by 1.1 kcal/mol, 3.8 kcal/
mol, and 2.9 kcal/mol, respectively, as indicatedby DFT calculation). Other sodium halides (fluoride, chloride, and bromide) were also ineffective.
As noted above, phosphine is crucial to facilitate
intermolecular charge transfer and stabilizes theiodine radical as a R3P–I• species (30). Thus, we
also screened a series of phosphines with different
electronic and steric properties (Fig. 2A, secondrow). The results showed that the electronic properties of triarylphosphines did not significantly affectthe reaction efficiency, as using tris(4-fluorophenyl)
phosphine and tris(4-methoxyphenyl)phosphine

UV-vis spectroscopy

19

Stock solutions
2, ,4,NaI
PPhand, NaI
TFA
were preparedsame concentration
Stock solutionsof 1, 2, of
4, 1,
PPh
TFAandwere
preparedwith the withsametheconcentration

used in used
the reaction.
The solutions
were preparedin the presenceof air using
CHusingsolvent.
in the reaction.
The solutions
were preparedin the presenceof airCH
3CN as3CN as solvent.

1

Hefei National Laboratory for Physical Sciences at theMicroscale, CAS Key Laboratory of Urban Pollutant
Conversion, Anhui Province Key Laboratory of Biomass Clean
Energy, iChEM, University of Science and Technology ofChina, Hefei, Anhui 230026, China. 2Department ofChemistry, School of Science, University of Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

Fig. 2. Key reaction-controlling parameters of NaI and PPh3–catalyzed decarboxylative
alkylation. (A) Parameters affecting decarboxylative alkylation of silyl enol ethers. (B) Parameters
affecting decarboxylative alkylation of N-heteroarenes. (C and D) UV-Vis absorption spectraof reactant mixtures. Concentration of each substance in UV-Vis measurement is identical tothe concentration used in reactions. Me, methyl; TFA, trifluoroacetic acid.

*Corresponding author. Email: rui@chem.s.u-tokyo.ac.jp (R.S.);
Red
shift wasobserved.
Figure Figure
S1: UV/vis
absorption(Y.F.) spectra of the combination between different startingS1: fuyao@ustc.edu.cn
UV/visabsorption spectra of the combination between different starting

materials
recordedrecordedin →CHFormation
as solventofcomplexbetween NaI/PPh3 and RAE.
3CN
Fu
etin
al., Science363,
1429–1434(2019)
29 March 2019
materialsCH
as EDAsolvent
3CN

2 of 6

decarboxylative
Minisci-typeAcrossalkylation(36, 37)usedalkylation,
PPh3, quantities
in irradiation
NaI, irradiation,a Brønsted
and highlights the important roleactionof PPh3onin catalytic(5 andto 20
mol %; seewavelength.
thethe decarboxylative Minisci alkyl(40of 4-methylquinoline (Fig. 2B) gave results simkeeping the iodine radical trapped as the putativeacid additive to increase the electrophilicity of themetable S4 for a detailed parameter study). Severspectrum (Fig. 2A and table S1), green LEDs
was measured to be 0.15, a valu
ilar to those observed for the alkylation of silyl
persistent R3P–I• species. The classic CTC I2•PPh3
N-heteroarene were all essential (Fig. 2B). Onceas t
closed catalytic cycle rather than
was also ineffective.
enol ether (Fig. 2A), except that for the Minisci
again, addition of 10 mol % of iodine completely
whprocess initiated by electron tra
We next explored the dependence of the rereaction, both sodium iodide and PPh3 could be
suppressed the reaction. The quantum yield of
norused in catalytic quantities (5 to 20 mol %; see
action on irradiation wavelength. Across thethe decarboxylative Minisci alkylation (Fig. 2B)
Cyclohexyl iodide was not detec
abstable S4 for a detailed parameter study). Severspectrum (Fig. 2A and table S1), green LEDs
was measured to be 0.15, a value suggesting aaction mixtures of the silyl eno
eno
closed catalytic cycle rather than a radical chainsor
N-heteroarene,andacontrol
exp
process initiated by electron transfer (38, 39).
cyclohexyl iodide as alkylationredr
Cyclohexyl iodide was not detected in the rearo
action mixtures of the silyl enol ether or theyield any desired alkylation pro
est
N-heteroarene, and a control experiment using
To provide further understandme
cyclohexyl iodide as alkylation reagent did notchaphotoredox
system,
we
measu
PPh
3
yield any desired alkylation products.
red(UV-Vis) absorption spectra. Rea
To provide further understanding of the NaI/
no
tration effects on the UV-Vis absor
PPh3 photoredox system, we measured UV-visible
Ho(UV-Vis) absorption spectra. Reactant concenin a light-induced intermolecular
onsd
tration effects on the UV-Vis absorption spectrum
LEcharge-transfer reaction were repo
in a light-induced intermolecular donor-acceptorPPhand co-workers for C–S coupling
charge-transfer reaction were reported by Miyake
est(40). We performed a UV-Vis absor
and co-workers for C–S coupling of aryl halidescha(40). We performed a UV-Vis absorption measurement using a solution of the samePPhment using a solution of the same concentration
as the real reaction mixture (Fig.tur
2,
as the real reaction mixture (Fig. 2, C and D), fromwhich it was apparent that neit
which it was apparent that neither NaI, PPh3,Ap
nor the combination of NaI and
nor the combination of NaI and PPh3 has any
eth
absorption in the visible region (Fig. 2D). Silylabsorption in the visible regionNeenol ether and 4-methylquinoline showed abenol ether and 4-methylquinolinsynsorption features only in the UV (<350 nm). The
eno
sorptionfeatures
only
in
the
UV
(
redox-active ester showed an absorption onset
groredox-active ester showed an abaround 390 nm. The mixture of redox-active
minaround 390 nm. The mixtureamo
ester (1) with either silyl enol ether (2) or 4methylquinoline (4) did not show any significant
ester (1) with either silyl enolbroechange of the absorption onset compared with(30
methylquinoline (4) did not show
redox-active ester (1) alone, which suggests thatchange of the absorption onset(34cno intermolecular charge transfer took place.
com
redox-active ester (1) alone, which
However, an obvious redshift of absorption
iou
onset, tailing into the wavelength range of blue
no intermolecularcharge transf
acti
Fig. 3. Scope for decarboxylative alkylation of silyl enol ether. Reaction
conditions: redox-active
LED irradiation, was observed when the NaI/
yiel
ester (0.2 mmol, 1.0 equiv), silyl enol ethers (0.4 mmol), NaI (0.3 However,mmol), PPh3 an(20 obvious
mol %), redshift
PPh3 component was mixed with redox-active
stra
CH3CN (2 ml),
15 hours, room temperature (r.t.), 456-nm blue LEDs.
Isolatedyieldsarereported.
onset, tailing into the wavelength
ester. This redshift supports the formation of a
*Reaction on 8.0 mmol scale. Boc, tert-butyloxycarbonyl.
LED irradiation, was observedrivaw
charge-transfer complex (41, 42) between NaI/

Substrate scope of decarboxylative alkylation of silyl enol ether

20

ered
blue
PPh3
e S1
tion
orm
o inuanalyst
tion.
any
the
vailThe
n in
much
nary
The
that
the
d by
LiI,
kcal/
ated
fluotive.
itate
the
, we
rent
ond
operffect
enyl)
hine

Clean

.S.);

Minisci-type addition to heterocycle

21

Proposed mechanism

Control experiment.
Fig. 6. A proposed full catalytic
cycle of NaI/PPh3 photoredox catalysis.
Catalytic cycle of decarboxylative
alkylation with N-heteroarene isdemonstrated as an example.
See fig. S4 for proposed full catalytic
cycles for reactions with silyl enol
ether and alkene.

Quantum yield = 0.15
→ Closed catalytic cycle rather than radical
Fu et al., Science
363, 1429–1434 (2019)29 March 2019
chain
processparameters of NaI and PPh –catalyzed
Fig. 2.
Key reaction-controlling
decarboxylative
3

alkylation. (A) Parameters affecting decarboxylative alkylation of silyl enol ethers. (B) Parameters
affecting decarboxylative alkylation of N-heteroarenes. (C and D) UV-Vis absorption spectraof reactant mixtures. Concentration of each substance in UV-Vis measurement is identical tothe concentration used in reactions. Me, methyl; TFA, trifluoroacetic acid.

5 of 6

spanned redox-active esters derived from secduced to 5 mol % of NaI and 5 mol % of PPh3 tog of4-methyl
alkylation
product
62 in 80%
ondary (46,49)
andacids,
tertiary(50–53)
aliphatic
yield.2.78
Besidesquinoline,
other subsystem is appealing for industrial application
tocarboxylic
a-aminoacids (54–59),
a-hydroxy give

Substrate scope of minisci-type radical addition
system
is appealinglarge-scale
syntheses.for industrial application tolarge-scale
syntheses.
The scope of Minisci-type alkylation (Fig. 4A)
The scopeof Minisci-type(Fig. sec4A)
spannedredox-active
estersalkylation
derived fromspannedredox-active
esters derived
secondary (46,49) and tertiary(50–53)from
aliphatic
ondary (46, 49) and tertiary (50–53) aliphatic

carboxylic
acids,anda-aminoacids(54–59),a-hydroxyacids (47, 48),
peptides(63)(36). The
catalyst
acids
(47,
48),
and
peptides
(63)
(36).
The
catalyst
loading for a gram-scale reaction could be reloadinga gram-scale
reaction
could
be3retoduced tofor
5 mol% of NaI and
5 mol %of PPhduced2.78
to 5gmolof NaI and
5 mol %62
of PPhgiveof %alkylation
product
in 80%
3 togive 2.78 g of alkylation product 62 in 80%

yield.
Besides
4-methyl
stitutedquinolines
were quinoline,
also reactiveother(64, sub70).
stitutedquinolines
were
also
reactive(64,
70).
Alkylation took place on the C4 position of the
Alkylation
tookwhenplaceC2-substitutedon the C4 positionof thequinoline ringquinolines
quinoline
ring
when
were tested(65,71).C2-substituted
Isoquinolinesquinolines(66–68),
were tested (65, 71). Isoquinolines (66–68),

Fig. 4. Minisci-type decarboxylative alkylation. (A) Scope for Miniscitype decarboxylative alkylation of N-heteroarenes. Reaction conditions:N-heteroarenes (0.2 mmol, 1.0 equiv), redox-active ester (0.3 mmol),NaI (10 mol %), PPh3 (20 mol %), TFA (0.2 mmol), acetone (2 ml),
15 hours, r.t., 456-nm blue LEDs. Isolated yields are reported.
*PhCF 3 as solvent. †N-heteroarenes (8.0 mmol, 1.0 equiv),
redox-active ester (8.8 mmol, 1.1 equiv), NaI (5 mol %), PPh3
(5 mol %), TFA (8.0 mmol), acetone (40 ml), 15 hours, r.t., 456-nm
blue LEDs. ‡(±)-1,1′-binaphthyl-2,2′-diyl hydrogenphosphate(5.0 mol %) instead of TFA (0.2 mmol). (B) Merging NaI/PPh3
photoredox catalysis with chiral phosphoric acid (PA) catalysis
for enantioselective Minisci-type a-aminoalkylation. Reaction
conditions: N-heteroarenes (0.1 mmol, 1.0 equiv), redox-active
ester (0.15 mmol), NaI (20 mol %), PPh 3 (20 mol %), chiral PA

quinoline ring whewere tested (65, 7

22(5.0 mol %), 1,4-dIsolated yields are
determined by hig(C) Scope of enana-aminoalkylation
anion catalysis. Re
1.0 equiv), redox-a
PPh3 (10 mol %),15 hours, r.t., 456enantiomeric excestereochemistry o*N-heteroarenes ((20 mol %), PPh3
Et, ethyl; t-Bu, ter

Alkylationplace
on theloading
for a gram-scale
could Alkylation
be re- took
place ontook
the C4
positionof C4
the position of theng
for a gram-scale
reaction reaction
could be retoquinolinering
when
C2-substituted
quinolines
duced
mol
of NaI
mol3 %
to of PPhquinolinering
when
C2-substituted
quinolines
to 5 molto%5of
NaI%and5 moland% of5 PPh
3
2.78
g
of
alkylation
product
62
in
80%
were
tested(65,
71).
Isoquinolines(66–68),give 2.78 g of alkylation product 62 in 80%
were tested (65, 71). Isoquinolines (66–68),

Enantioselective minisci-type reaction

23

R ES E A RC H | R E PO R T

their deprotonation could play important roles
in determining product enantioselectivity.
We elected to use RAEs derived from aminoacids as precursors to N-acyl a-amino alkyl radicals (Fig. 2A, radical generation), which areprochiral, nucleophilic radicals that possesshydrogen bond donor functionality. It is wellestablished that facile alkyl radical generation
occurs from RAEs upon acceptance of a single electron (38–40), and there are a number ofrecent examples of photoredox catalysts being
used as electron donors for this purpose, including in conjunction with RAEs derived fromN-acyl amino acids (20, 41, 42) and to achieve
Minisci-type additions (20). In line with theseprevious studies, we envisaged a reductive photoredox cycle, in which fragmentation of the RAE
is induced via electron transfer from an Ir(II)species generated off-cycle (see figs. S1 to S4 forfluorescence-quenching studies). After regeneration of Ir(III) and subsequent excitation, thecatalyst should function as the single-electronoxidant required to rearomatize the heteroarene(Fig. 2A, III to 3).
To assess whether asymmetric induction could
be achieved, we selected 4-methylquinoline asa test substrate. Irradiation from blue LEDs in
the presence of 2 mole percent (mol %) of photocatalyst [Ir(dF(CF3)ppy)2(dtbpy)]PF6 and 5 mol %of chiral Brønsted acid catalyst (R)-TRIP in
ethyl acetate enabled efficient coupling of
4-methylquinoline (2a) and the RAE derived
from N-acetyl-L-phenylalanine (1a) to give 3a in
94% yield after 14 hours (Fig. 2B). The enantiomeric excess of the product was determined to[Reaction mechanism][Substrate scope]

Phipps et al. Science. 2018, 360, 419‒422.

Fig. 2. Reaction development. (A) Hypothesis for enabling enantioselective Minisci-type addition.

EDA complex formation with other acceptors
EDA complex with pyridinium

EDA complex with Togniʼs reagent

Fig. 6. A proposed full catalytic
cycle of NaI/PPh3 photoredox catalysis.
Catalytic cycle of decarboxylative
alkylation with N-heteroarene isdemonstrated as an example.
See fig. S4 for proposed full catalytic
cycles for reactions with silyl enol
ether and alkene.

• Applicable to various electron acceptors.
→ Wide substrate activation.

24

Other applications of NaI/PPh3 system
1. Iododecarboxylation using LiI/PPh3[Reaction mechanism]

Shang et al. Org. Lett. 2020, 22, 8572­8577.

[Investigation of key reaction parameters]

25

aniline formation from substituted nitroarenes especially with
reducible functional groups (Scheme 2). The substrates

Other applications of NaI/PPh3 systemb

2. Decarboxylative cross-coupling

Table 2yield (%)

aVariations ofentry
α,β-unsaturated
carboxylic(1)PR3
reductant acidssolvent

2a3aScheme 2. NaI/PPh3-Mediated Photochemical Reduction of
3.
Reduction of nitroarene
Nitroarenes

PhSiH3
DCM
60
trace
1
PPh3
2
PPh3
PhSiH3
Et2O
45
trace
3
PPh3
PhSiH3
EtOAc
90
nd
4
PPh3
PhSiH3CHCl398
nd
Scheme 2 Control experiments.
5
P(o-tol)3
PhSiH3
CHCl3
trace
trace
6
P(p-FPh)3
PhSiH3
CHCl3
80
trace
Reactionmechanism
7
P(PMP)3
PhSiH3
CHCl3
75
trace
8
PCy3
PhSiH3
CHCl3
trace
trace
9
PPh3
TEOA
CHCl3
12
trace
10
PPh3
TEA
CHCl3
trace
trace
11
PPh3
Et3SiH
CHCl3
10
trace
c
12
PPh3
PhSiH3
CHCl3
<20
nd
d
13
PPh3
PhSiH3
CHCl3
nd
nd
14
PhSiH3
CHCl3
24
nd
e
PPh3
PhSiH3
CHCl3
trace
nd
Organic 15Letterspubs.acs.org/OrgLett
f
16
PPh3
CHCl3
16
52
17f NaI/PPh
PPh3 -Mediated Photochemicallydioxane
8Reductive
82 (78)
Scheme 3.
3
e,f
18
PPh3
dioxanetrace
14

LetterAminationof 2-NitrobiarenesaReaction conditions: 1a (0.2 mmol), NaI (40 mol %), PPh3 (20 mol%), reductant (2 equiv), solvent (2.0 mL), irradiation with a 35 W
blue LEDs at 60 °C for 72 h under argon atmosphere; bYield
determined by GC analysis of the crude reaction mixture using 1,3,5trimethylbenzene as the internal standard, and yield in parentheses
indicates isolated yield. cNaCl, NaBr, KI, or NH4I instead of NaI.
dReactionin dark. eWithout NaI. f2.5 equiv of PPh3.
Scheme 3 Possible
mechanism.

.),
/Z

a

Reaction conditions: 1a (0.2mmol),
2a (0.3mmol),
NaI(1.5 equiv.),
al. Org. Biomol.
Chem. 2020, 18to, 5589‒5593.
donor
was
found
be eﬀective for the
PhSiH3Liaset hydrogen
he PPh3 (20 mol%), DMA (2 mL), room temperature, argon, and 10 h. E/Z •a

Isolated yield of 10 mmol scale reaction.

bearing either electron-withdrawing or electron-donating
et al. Org.aﬀord
Lett. 2021
, 5349­5353.
groups worked well Huang
to exclusively
the, 23
corresponding26

Short summary

27

Catalytic electron donor; NaI + PPh3
O
N OH
R1

OH
O

R1

O

O

NPhth

O

DIC , DMAP
Ph
Ph

R2

NH2

Ph

O

Ph
R2

Figure 1
catalyst
formatio
yl.

Ph
N
Ph

CF3
I
O
O

Figure 15. (a) General strategy for catalysis in EDA complex
photochemistry: a donor catalyst that can photochemically generateradicals and then be turned over. (b) Photocatalytic radical alkylations• Combination of the simple compounds (NaI + PPh3).
mediated by the catalytic combination of triphenylphosphine and→ Application to large-scale synthesis.
sodium iodide; TFA: triﬂuoroacetic acid.
• PPh3 enables SET from iodide to acceptors by visible light irradiation.

moiety in 47a produced the catalyst radical cation XXXI and,• Wide substrate activation.
upon CO2 extrusion, the open-shell intermediate XXI. Radicals

EDA-24from thmoiety,amino rby theturns thtrappedanion 4
quantum
cycle w
Overall,
acts ﬁrs
complex

Contents

n Introductionn Catalytic electron donor ; NaI + PPh3n Catalytic electron acceptor ; Tetrachlorophthalimiden Summary & perspective

28

ochemistry
the allowed
potential
plex catalytic has
platform
us to develop mechanistically distinct radical reactions,areunavailable
toconvend catalytic
system. Quantum
yield measurementsto
establishedthat a closed catalytic
cycle
Generalstrategy
suppressback
electron transfer
tetrachlorophthalimides
to readily turn over and govern each catalytic cycle.
ause the chemical reactivity
diﬀers fundamentally from
[General strategy]ite
its
potential,−acceptorintrinsic
(EDA)
long
specialized area
adicalstime
underamild2
becauseg, interest
masteredby only a few
of activating
silitysituation
has changed
genous photoredox
mical
methods
e couplingof two have been
Incorporationgroupsin electron
to suppress
BET.
Figureof1. leaving(a) Classical
EDA complex
theory acceptor
and the factors
thatynthetic
toolbox of modern
trates.3 Recently,
complicate synthetic applications. (b) A general strategy to make theimplementing
the spurred byhasmainly been→
Requiresequivalentamountof electron
acceptor.
alyticthus
constant for
EDA
complex synthetically
productive.
KEDA: association
reliesregime,on theuse of colored
rotocols relied on, kBET, kP: kinetic constants;
the formation
the EDA complex;
kSETacceptor.
of ofcatalytic
electron⟺ Few examples
gyof visibleupon
light to activate
ex formation
ΨGS: wave function associated with the ground state; ΨES: wave
bstrates
and a to generate
adorned withfunction associated with the excited state; SET: single-electron. A photoinduced
reactionconditions.6
transfer;
LG: leaving group.
This work; Tetrachlorophthalimide
as a catalytic electron acceptor.
ated radicals
that
unity
has
recognized
theprocesses.
achintrinsicallydiﬀerstyof thatdevelopinganot Specifrely on the use of
xdoes
catalysis.
however, the EDA complex photochemistry has attracted thec Thisacceptors
could exploits thestrategyinterest of a growing number of chemists,
providingacceptor
fresh
substrates not
Catalytic
11 ü
rh(Figuresubstrate
A
and
a
donor
opportunities in synthetic chemistry.
1b). Theses,
respectively)tobringof the catalyst via
Effective
turnoverWith this Perspective, we will criticallyüassess
the synthetic, arising fromtheolecularaggregationin thepotential of EDA complex photochemistry.
We willsubstrateprovide a activation
Wide
ü
plex.
A
few
recentn donor−acceptor (EDA)
possible rationale for why this photochemical approach was
cit EDA complex
omponents
A
and
D
may
useful to activatees,butlimited
the resulting
EDA
reforetoMelchiorre et al. J. Am. Chem. Soc. 2022, 144, 8914­8919.
Received: February 5, 2020
n triggers an intramolecular29

Background30• Quinuclidine + Tetrachlorophthalimide• NaI/PPh3 and Phthalimide

Fig. 1. Redox catalysis based on light-induced
intermolecular electron transfer from sodium
iodide to redox-active ester. (A) Lightinduced intramolecular charge transfer(CT) and light-induced intermolecular donor(D)–acceptor (A) charge transfer throughself-assembly via noncovalent interactions.
Fu et al. Science. 2019, 363, 1429‒1434.
L, ligand; M, metal. (B) Estimated Gibbs
energy change of intermolecular electrontransfer from NaI and NaI/PPh3 component
to aliphatic N-(acyloxy)phthalimide (NPhth) to deliver an alkyl radical, and a possible iodide/phosphine redox cycle. (C) Photoactivation of assembled
complex of N-(acyloxy)phthalimide with NaI and PPh3 through coulombic and cation-p interactions. SET, single electron transfer.

• DHP and Phthalimide

Fu et al., Science 363, 1429–1434 (2019)

1 of 629 March 2019

Bach et al. ACS Catal. 2019, 9, 9103­9109.

Molander et al. Adv. Synth. Catal. 2021,363, 3507‒3535.

Phthalimide effectively forms EDA complex with various electron donors.

pubs.acs.org/JACS
Communication
Properties
ofacceptor
catalysts
pubs.acs.org/JACS
Communication

31[Redox active ether]
O

O
R

N O

O
SET

O

O

O
R

N O

N + CO2 + ROO[acceptor catalysts]
O
N
O

SET

O

O

N

N +

O

O

Reduced catalyst B is kinetically stable.
→ Effective turn over.

Electron donors as radical source[Trifluoroborate]32[silicate]

4CzIPN

Li et al. Adv. Synth. Catal. 2018, 360, 2781­2795.
Fensterbank et al. Chem. Soc. Rev., 2022, 51, 1470‒1510.

[Dihydropyridine]
O

R

EtO
Me

O

O
OEt

N
H

Me

SET

R

EtO
Me

O

O
OEt

N

Me

O

EtO
Me

OEt
N

Me

+

R

UV-visspectroscopyCommunication
pubs.acs.org/JACS

Red shift was observed. → EDA complex formation.

33

Screening of acceptor catalysts
Journal of the American Chemical Society
Journalof the American
ChemicalSocietypubs.acs.org/JACS[Giese-typeradicaladdition]34
pubs.acs.org/JACS

Communication

Communication

Journal of the American Chemical Society

pubs.acs.org/JACS• Catalyst B and C afforded product in high yield.
• Radical generation via EDA complex. (entry 8~10)
Figure 2. Initial explorations. (a) Model reaction and catalysts tested. (b) Optimization studies: reactions performed on a 0.1 mmol scale at 40 °C

tivity (entries 11 and 12, respectively).
We then evaluated the scope of the Giese addition protocol
using diﬀerent radical precursors and electron-poor oleﬁns(Figure 3a). In contrast to other methods,11 there is no need

Mechanistically,
weI (E
proposethat forthecatalyst
GieseB)reaction
redof the radical anion= −0.84
and radical radic
proceeds
via
aredox-neutral
catalytic
cycle(Figure3c).upon(S)-7-Chloro-1-cinnamyl-4-(cyclopropylethynyl)-4-(trifluorometh
red
35
woul
III (e.g., E = −0.54 vs SCE for the radical generated
Excitation of the
EDA complex12formed between the acceptor
1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one(6x):
Synthesradical trap from fumarate). To corroborate this mechanistic The
catalyst B oraccording
C andtothe
electron-rich
substrate
would
GeneralProcedure E using
DHP 1s1(116.0
mg, 0.2 mmol
therm
proposal,wemeasuredthequantum
yield
(Φ)
of
the
reaction[Substratescope]
generate the equiv.)
alkyl radical
II
along
with
the
catalyst
radicaland styrene
1.0
mmol,
An of
E/Zth
of 1a and 2a catalyzed
by B, (104.0
which mg,wasas low
as 5.00.04equiv.).
(λ = 460
1
anion I (path ofdetailedin Figure1b).byInterceptionof II Theby the>20:1 wasdetermined
HasNMR
crudeseemixtureIII (nm, using potassium
ferrioxalate
theanalysis.
actinometer;
electron-poor purified
oleﬁn 2bywould
lead tochromatography
the reactive electrophilic
flash column
onsilicaindicatesgel (15% radic
AcOE
section
D.4
in
Supporting
Information).
This
resultradical III. SET
reduction
of
III
by
the
catalyst
radical
anion
I
prop
hexanes asprocesseluent) toisafford
6x (54.5
mg, 63% yield)
as a white
solid
that
a
radical-chain
unlikely,
conﬁrmingtheabilityofwould then aﬀord product 3 while closing the catalytic cycle.
of 1a
1
donor
turn3) overandtriggerH
NMR which
(400
MHz,
CDCl
δfor
7.59
– 7.51repeatedly(m,1H), 7.42(m,ThethelastEDA
SETcatalytic
event,
istocrucial
catalyst
turnover,is– 7.27nm,
radical1H),
formation.
7.25 thermodynamically– 7.22(m,6.98 (d, feasible
J = 8.8 Hz,= 16.1,
1.7 properties
Hz, 1H), 6.18 (dt,sectio
J=1
on1H),
the 6.58
basis(dt,ofJthe
redox
our
goals
identify
acatalyst
generalacceptor
catalyst
red
5.6 Hz,4.79of– 4.59(m,
2H),
1.40=to(tt,
J = 8.3,
Hz, 1H),B)0.99(m, 4H). that aof 1H),
theOneradicalanion
I (Ewas−0.84
for5.1
and– 0.78
radical13the3) δdesignofformechanisticallydistinctradicalthe 12E
C NMR(101 MHz,148.2,
136.0,
135.4,
133.4, 131.6,
129.1,upon
128.8,
128.3,
III suitable(e.g.,
Eredfor=CDCl−0.54
vs SCEthe radical
generated
12
processes.
Speciﬁcally,
weTo8.91,
soughtour EDA radic
122.1,
117.8,
115.8,from
95.8,
66.4, 46.9, 8.94,-0.5. to integrate
radicaltrap
fumarate).
corroborate
this mechanistic
complexplatformwitha (Φ)
cobalt-based
catalytic On
19
F NMR(376 MHz,CDCl3) δ -80.20.
proposal,
we catalytic
measuredthe quantum
yieldof the reaction
process.
Thea+):few
reportson(λtheuse of suitaof 1aand 2afor
catalyzed
B,contains
which
was
as
low
as 0.04= 460
HRMS:
calculated
C23literature
H17ClFby454.0792,
found
454.0800.
3NNaO
2 (M+Na
proce
complexes
to generateradicals
feed a metal-based
nm,EDAusing
potassium
ferrioxalate
as theandactinometer;see
13[Reaction mechanism]
catalytic
cycle.
The synergyof EDAand metal compsection
D.4Substrates
inSupporting
Information).
Thiscatalysis
result indicates
C4. Unsuccessfulproce
was successfully
implemented
by thecombining
thatcatalysis
a radical-chain
process is unlikely,
conﬁrming
ability of14the EDA
the EDA
acceptor
C andcobaloxime
7 toUnsuccessful
substrates
theaction
EDA ofcatalytic
donor
to turncatalyst
over andrepeatedly
triggercatal
performthe Heck-type coupling of radical precursors 1 withradicalformation.
catal
15
styrenederivatives(Figure4a).
Oneof ourgoals was5 toidentify
a general acceptor catalyst
actio
The
generality
of
this
dual
catalytic
protocol,which
aﬀordedsuitable for the design of mechanistically distinct radical
perfo
productsSpeciﬁcally,
6, was ﬁrst we
investigatedwithintegrate
respect tostyrene styre
processes.
sought toourtheEDA
component.
Electron-poor(products6b−g) and electron-rich
Figure 3. (a) Substrate scope for the Giese reaction catalyzed by EDA complex
catalytic
platform witha cobalt-based
catalyticTh
acceptors. Reactions were performed on a 0.2 mmol scale using 1.5 process.
(adducts
and 6i)contains
styrenesa bearing
ortho-,
The6h
literature
few reports
on meta-,the useorofpara- prod
equiv of 1. Catalyst B was used for DHP substrates, and C was used EDA
substituents
onto thearylforring
reactedsmoothlyprovide comp
Figure3. (a) Substratescope
the allGiesereaction
catalyzed
bytoEDA
complexes
generate
radicalsandfeed
a metal-based
13
for silicates and triﬂuoroborates. Yields refer to isolated products 3 catalytic
acceptors.
Reactions
wereperformed
a 0.2 catalysis
mmol
scaleand
using
1.5
(add
theQuantum
corresponding
disubstituted
alkeneproducts
in metalmoderate
cycle.
The
synergyof onEDAyield= 0.04#+(average of two runs per substrate). Using K as cation of the silicate. catalysis
equiv
of
1.
Catalyst
B
was
used
for
DHP
substrates,
and
C
was
used
to goodwas
yields.
Vinyl heteroarenes,
bearinga pyridine (6j)successfully
implemented
by combining
the or a subst

Substrate scope of Giese-type radical addition

Heck-type reaction with cobaloxime

Journal of the American Chemical Society

pubs.acs.org/JACS[Reaction design]

Figure 4. Dual photochemical EDA complex−cobalt catalytic system for the Heck-type reaction. (a) Scope of the Heck-type process. Reactions
were performed on a 0.2 mmol scale using 5 equiv of 5 and 1 equiv of 1. Yields refer to isolated products 6 after puriﬁcation (average of two runs).
E/Z ratio was determined by 1H NMR analysis of the crude mixture. #Using K+ as cation of the silicate. (b) Proposed mechanism, with the cobalt
and EDA catalytic cycles intertwined.

(6w), and efavirenz (6x) scaﬀold within the Heck-type
products.

MeCN)16 to aﬀord the Co(II) species V while turning over the
EDA acceptor catalyst. The cobalt-based catalytic cycle would

36

Communicat

SubstrateJournal
scopeof Heck-type reactionof the American Chemical Society

pubs.acs.org/JACS

Communication(S)-7-Chloro-1-cinnamyl-4-(cyclopropylethynyl)-4-(trifluoromethyl)1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one(6x):
Synthesizedaccording to General Procedure E using DHP 1s (116.0 mg, 0.2 mmol, 1.0
equiv.) and styrene (104.0 mg, 1.0 mmol, 5.0 equiv.). An E/Z ratioof >20:1 was determined by 1H NMR analysis. The crude mixture waspurified by flash column chromatography on silica gel (15% AcOEt inhexanes as eluent) to afford 6x (54.5 mg, 63% yield) as a white solid.
1

H NMR (400 MHz, CDCl3) δ 7.59 – 7.51 (m, 1H), 7.42 – 7.27 (m, 5H),
7.25 – 7.22(m, 1H), 6.98 (d, J = 8.8 Hz, 1H), 6.58 (dt, J = 16.1, 1.7 Hz, 1H), 6.18 (dt, J = 16.1,
5.6 Hz, 1H), 4.79 – 4.59 (m, 2H), 1.40 (tt, J = 8.3, 5.1 Hz, 1H), 0.99 – 0.78 (m, 4H).
13
C NMR (101 MHz, CDCl3) δ 148.2, 136.0, 135.4, 133.4, 131.6, 129.1, 128.8, 128.3, 126.6,
122.1, 117.8, 115.8, 95.8, 66.4, 46.9, 8.94, 8.91, -0.5.
19
F NMR (376 MHz, CDCl3) δ -80.20.
HRMS: calculated for C23H17ClF3NNaO2 (M+Na+): 454.0792, found 454.0800.
C4. Unsuccessful Substrates

Unsuccessful substrates

Quantum yield = 0.01

37

Contents

n Introductionn Catatlytic donor ; NaI + PPh3n Catalytic acceptor ; Tetrachlorophthalimiden Summary & perspective

38

Summary & perspective[NaI and PPh3]• Tricomponent EDA complex.
• Industrial application to large-scale synthesis.
• Applicable to wide range of electron acceptor.

[Tetrachlorophthalimide]• One of the few examples of catalytic acceptors.
• Applicable to wide range of electron donors.
• Combination with metal-based catalytic system.

39Perspective

40[Redox auxiliary]• Relying on existing redox auxiliaries.
→ Investigation of new EDA-active structure(redox auxiliary).

• Radical generation without conversion to redox auxiliary.
O
N OH
R1

OH
O

R1

O

O

NPhth

SET

O

DIC , DMAP
Ph
Ph

R2

NH2

Ph

O

Ph
R2

Ph
N
Ph

EDA complex

Perspective

41[Redox auxiliary]• Relying on existing redox auxiliaries.
→ Investigation of new EDA-active structure(redox auxiliary).

• Radical generation without conversion to redox auxiliary.
O
N OH
R1

OH
O

R1

O

O

NPhth

SET

O

DIC , DMAP
Ph
Ph

R2

NH2

Ph

O

Ph
R2

Ph
N
Ph

EDA complex