C-H activation via Multiple-site
Concerted Proton-Electron Transfer

Literature Seminar #1
2023/8/24
M1 Arii

Outline
Outline1. Introduction
1-1. PCET and CPET ・ Marcus Cross Relation
1-2. Example of Canonical HAT, Separated CPET,
Multi-Site CPET
1-3. Importance of Hydrogen Bond in MS-CPET
2. Contents
2-1. Intramolecular C-H activation via MS-CPET
2-2. Intramolecular C-H activation with photocatalyst
via MS-CPET
2-3. Intermolecular C-H activation via MS-CPET
3. Summary1Outline
Outline1. Introduction
1-1. PCET and CPET ・ Marcus Cross Relation
1-2. Example of Canonical HAT, Separated CPET,
Multi-Site CPET
1-3. Importance of Hydrogen Bond in MS-CPET
2. Contents
2-1. Intramolecular C-H activation via MS-CPET
2-2. Intramolecular C-H activation with photocatalyst
via MS-CPET
2-3. Intermolecular C-H activation via MS-CPET
3. Summary

2

PCET and CPET

1-1

Introduction

PCET : Proton-Coupled Electron Transfer
Reaction which proton transfer (PT) and electron transfer (ET)CPET : Concerted Proton Electron Transfer
Reaction in which one proton and one electron transfer concertedly
・ CPET with different mechanisms exist.
・ However, their classification is ambiguous and continuous.

H

Ph

H

e-

HO

O

N

N

O
N

O
N

e-

N

H

N
Ru
N

N

N
Ph

Fe

eN

N
O
N

N

N

Ox+

N

H

Ph

N

All the reactions listed above are CPET.

3

Illustration of CPET

1-1

Introduction

Although there is no clear classification, CPET can be divided into three main categories.
① Canonical HAT② Separated CPET

ET
X H

PT

ET
A

H A

X

eH
H
▶ Proton and electron transfer as hydrogen atom.

X H

PT

A

X

H A

▶ Proton and electron transfer
to another atom in the same molecule.

➩ Protons and electrons transfer into the same bond.
③ Multiple Site CPET
ET
Ox+

X H

PT

Base

Ox

X

H Base+▶ Proton and electron transfer to completely separate molecules.
Darcy, J. W.; Koronkiewicz, B.; Parada, G. A.; Mayer, J. M., Acc. Chem. Res. 2018, 51, 2391−23994

constants, following the Brønsted catalysis law (eframework. These solution reactions
the Eyring‡equation, thisis equivalent to correlatin
singof the1-1free energies (ΔG°) instead◦
Marcus
Cross
Relation
◦
∂(∆G
)
2(∆G
+
λ)
1
∆G
ΔG°
(eq
3).
These
two
equationsgive
the same ue typical of HAT discussions, because
α=
=
=
+
◦)
4λ
2
2λ Introduction∂(∆G
α. To go beyond this LFER, many CPET studies
ected with equilibrium constants, linear
Marcuscrossoverequationcan 5be used
to understand the reactiontreatment
rate of CPET.
Marcus−Hush−Levitch-likeof rate ve
LFERs),and versionsof Marcus
theory.
force
1, eq 4). Speciﬁcally, we have fous are Whenoften small
but canproceeds
be substantial|∆G◦ | (Figure! λ is established.
thereactioninCPET,
mplexes.5 ΔG° for a HAT reaction is thee two bond dissociation free energies,= α log(Keq ) + β① log(k)DFE(Y−H).
Solution BDFEs
can be12
Brønsted
catalysis(Scheme2A).law
tion pKa and E° values
are schemebe ◦ +drawn
for the= α∆Gβ"② ∆G‡cand and a reductantEyring(Scheme2B), giving
equation
12,13
even thoughan “eﬀective BDFE”,◦(∆G when+ λ)2 the proton‡ cleaveds homolytically③ ∆G =
4λ reagents. Yetm diﬀerent sites or diﬀerent
foratheof parabolas
andnalysis is the same:Equation
the sum ofpKaintersection‡∂(∆G) manner
2(∆G◦to+ derive
λ)an be used αin=thesame
1 + ∆G◦==④
4λ
2λ∂(∆G◦ ) that transfersn MS-CPET reaction
a2
ent. The use of BDFEeff therefore allows"◦ "◦ theory
comparisons 1of! concerted
1e1 − /1H!+
description of reactions where th∆G∆G◦ Figure 1. Marc!
∵ |∆G | " λ ⇔"1⑤ α= 2 1+ λ2
λ reactant and product free energy surfa
their form.
of the parabolic
free energy of the transition state (ΔG‡) in terms ofan be obtained from diﬀerent combinaintrinsic inbarrierλ, eq
4. an α of 0.5
Basically,andthe reactions
CPET
have
on oxidant/reductant
acid/base that proceed
es a thermochemical tunability
thatKoronkiewicz,
canDarcy, J. W.;
B.; Parada, G. A.; Mayer, J. M., Acc. Chem. Res. 2018, 51, 2391−2399135However, there are inherent reagent
Marcus cross relation predicts the rate constants
James M. Mayer, et al., J. Org. Chem. 2022, 87, 2997−3006

Outline
Outline1. Introduction
1-1. PCET and CPET ・ Marcus Cross Relation
1-2. Example of Canonical HAT, Separated CPET,
Multi-Site CPET
1-3. Importance of Hydrogen Bond in MS-CPET
2. Contents
2-1. Intramolecular C-H activation via MS-CPET
2-2. Intramolecular C-H activation with photocatalyst
via MS-CPET
2-3. Intermolecular C-H activation via MS-CPET
3. Summary

6

nium−Oxo Complex. The oxidation of C−H bond[(bpy)2(py)RuIVO]2+ (RuIVO2+, bpy = bipyridine, ppyridine) was discovered in the 1980s by Thomas M
one of the founders of the ﬁeld of PCET.15Introduction
Our later stshowed that this reaction proceeds by rate limiting
16,17
･
2A).
One
signiﬁcant piece of evidence
Alkane(Figureoxidationby t-BuO
radical−+concerted e and H transfer was a linear correlation of

Example of Canonical HAT

1-2
radical-chain chlorination
ET
H 3C H

ET

Cl
PT

CH3

H Cl

R H

O

R

HO

PT
Darcy, J. W.; Koronkiewicz, B.; Parada, G. A.; Mayer, J. M., Acc. Chem. Res. 2018, 51, 2391−2399

Hydrogen atom abstraction by a Ruthenium−oxo complex

Evidence of progress in CPET mechanism
H

H

H

H

e-

O
N

N
N
RuⅣ
N
N

H
H
O

MeCN
N

N
RuⅢ

N

N
N

Bryant, J. R.; Mayer, J. M., J. Am. Chem. Soc. 2003, 125, 10351−10361

2. (A) HAT is
fromtoluene to RuIVreduced.
O2+. (B) Graph showin
・ Electron may have transferred to ruthenium asFigure
ruthenium
ultimately
dependence of rate constants (ln(kHAT)) on driving force (ln(・ However, since the electrons are in Ru-O π* orbital,
theof transferred
electrons
IV 2+
O . Data from ref 16.
for oxidationshydrocarbons by Ru
may also form O-H bond.
7

Example of Separated CPET

1-2

Introduction

Alkane oxidation by compound I in Cytochrome P450se-

the mixture of porphyrin radical cation and thiyl radical

Yosca, T. H., et al., Science, 2013, 342, 825.

・ The proton adds to the oxo forming a hydroxo ligand.
・ The electron transfers a “hole”(= porphyrin radical cation or thiyl radical)
away from the oxo.

Separated CPET
8Example of Separated CPET

1-2

Introduction

CPET with the long distance between redox and baisic site
ET
O
O

O

O
N

RuⅡ

PT

N

O 4.2

O

MeCN

N

O

O

RuⅢ

NH

N

HO

N

O

Å

N

N

Wu, A.; Masland, J.; Swartz, R. D.; Kaminsky, W.; Mayer, J. M., Inorg. Chem. 2007, 46, 11190−11201
O
N
O

O

O
N

RuⅢ
N
O
N

11.
2

O
Å

O

H O

MeCN

O

N

O

N
RuⅡ
N
O
N

N

ET

O

N

O

PT

OH

Manner, V. W.; Mayer, J. M., J. Am. Chem. Soc. 2009, 131, 9874−9875
N

ET
O

N
N

ⅢN
N Fe
N

O

N

H O N

N

PT
MeCN

N

14 Å

N
N

ⅡN
N Fe
N

OH
O

O

N

N
N

Warren, J. J.; Menzeleev, A. R.; Kretchmer, J. S.; Miller, T. F.; Gray, H. B.; Mayer, J. M., J. Phys. Chem. Lett. 2013, 4, 519−523

Concerted proton electron transfer proceeds although the reduction and base fields
are too far apart to interact with each other.
9

Example of Multi-Site CPET

1-2

Introduction

One-Electron Oxidation of a Phenol Coupled with an Intramolecular Amine-Driven Proton Transfer
ET

N

H
O

PT

H
O

NH2
Ph
Ph

NH2
Ph
Ph

N

Mayer, J. M.; Rhile, I. J., J. Am. Chem. Soc. 2004, 126, 12718-12719.

Evidence of progress in CPET mechanism

ET1

HOAr-NH2 ，X
CPET

HOAr-NH2 ，X+① A primary kinetic isotope effect
kH/kD = 2.4±0.2
PT2☞ Protons are involved in the rate-limiting step.

OAr-NH3 ，X

OAr-NH3 ，X+② The reaction rate is too fast to go through a high-energy
intermediate. (→ Appendix)③ α = ΔΔG‡/ΔΔG゜= 0.53

PT1

ET2

PT

ET
CPET
10

Journal of CPET
the American Chemical Society
Example of Multi-Site

1-2

Scheme 3. Square Scheme Showing Free Energies
of Proton
Introduction
for the Termolecular MS-CPET TEMPOH Oxidation withThree-Component MS-CPET Reactions
OH
N

O
N

N
Fe
Rn

Fe
Rn

Fe
Rn

Rn
ET

H
N

hydrogen
bond
N
H
O
PT
N

Rn

Rn

⧧
The
diagonal
the ΔGfromthe measured
k2 and the Eyring
Morris, W. D.; Mayer, J.
M.,
J. Am.gives
Chem.
Soc.
2017,
139, 10312−10319.
aEvidence of progress in CPET mechanism① ΔG゜ET1 and ΔG゜PT2 are each larger than ΔG‡.
☞ The reaction is not via ET1, PT2. (→ Appendix)② α = ΔΔG‡/ΔΔG゜ = ln(k2) / ln(Keq) = 0.46
Changing the E of the oxidant or the pKa of the basewill result in an α of 0.5. (→ Appendix)

11
Figure 3. Plot of ln (k2) vs ln (Keq) for TEMPOH oxidations
by thecombination of a pyridine base with [Cp2Fe]BF4 (blue squares)

Outline
Outline1. Introduction
1-1. PCET and CPET ・ Marcus Cross Relation
1-2. Example of Canonical HAT, Separated CPET,
Multi-Site CPET
1-3. Importance of Hydrogen Bond in MS-CPET
2. Contents
2-1. Intramolecular C-H activation via MS-CPET
2-2. Intramolecular C-H activation with photocatalyst
via MS-CPET
2-3. Intermolecular C-H activation via MS-CPET
3. Summary12

Importance of Hydrogen Bond in MS-CPET

1-3

Introduction

MS-CPET requires fixing the reaction coordinates of a proton in advance.

Hydrogen bond is the key
H

ET

O

PT
NH2

hydrogen
bond

Ph
Ph

N

ET
Fe
Rn

hydrogen
bond
N
H
O
PT
N

Rn

Tyrosine oxidation in Photosystem Ⅱ
His190

P680
Tyr161N H
ET

N

His190MS-CPET

N H

P680

N
H

H PT
O hydrogenbond

Tyr161O

J. L. Dempsey, J. R. Winkler, H. B. Gray, Chem. Rev. 2010, 110, 7024–7039.

Enzymes also use hydrogen bond to proceed MS-CPET.
C-H bond cannot form hydrogen bonds.

C-H activation using MS-CPET is difficult.

However, what if we could fix the C-H bond on the PT reaction coordinates in advance?
13

Outline
Outline1. Introduction
1-1. PCET and CPET ・ Marcus Cross Relation
1-2. Example of Canonical HAT, Separated CPET,
Multi-Site CPET
1-3. Importance of Hydrogen Bond in MS-CPET
2. Contents
2-1. Intramolecular C-H activation via MS-CPET
2-2. Intramolecular C-H activation with photocatalyst
via MS-CPET
2-3. Intermolecular C-H activation via MS-CPET
3. Summary

14

2-1

Design of Molecules by DFT Calculations

Conditions for molecules designed by DFT calculations

Intramolecular C-H activation via MS-CPET☞ A base positioned near a relatively weak C–H bond2-(9H-fluoren-9-yl)benzoate
OO

H

Steric interactions between the rigid fluorene and the benzoate
Keeping the rings nearly perpendicular
Positioning the base near the weak benzylic C–H bondMarkle, T. F.; Darcy, J. W.; Mayer, J. M., Sci. Adv. 2018, 4, eaat5776
15

2-1

Lactone Formation in C-H activation via MS-CPET
Intramolecular C-H activation via MS-CPET

HO

O

O
Oxidant (2.0 eq)
Base (2.0 eq)

H

O

MeCN (0.01 M)

Ox+
Base
Base
Ox+
ET

Ox+

O
H PT

HO

O

O

MS-CPET: aminium (NAr3•+) , ferrocenium (Fc+)

Base: DBU, TBAOH

Markle, T. F.; Darcy, J. W.; Mayer, J. M., Sci. Adv. 2018, 4, eaat5776
16

Comparison with Regioisomers

2-1

Intramolecular C-H activation via MS-CPETHOOOOxidant (2.0 eq)
Base (2.0 eq)

H

O

MeCN (0.01 M)

HOOOxidant (2.0 eq)
Base (0 eq)

H

MeCN (0.01 M)

NR
No oxidant consumption

H
Oxidant (2.0 eq)
Base (2.0 eq)
OH
O

MeCN (0.01 M)

NR
No oxidant consumption

Monitoring the disappearance of the colored oxidants
Markle, T. F.; Darcy, J. W.; Mayer, J. M., Sci. Adv. 2018, 4, eaat5776

The presence and positioning of the base are crucial for MS-CPET.
17

Mechanism Analysis

2-1Intramolecular C-H activation via MS-CPET

Stepwise reaction = (ET + PT) vs One-step reaction = MS-CPET
O

O

H

ΔG
°M

ET

O

Ox+

MS

ET

-CP
ET
PE
for T ~ 0 k
FeC calp* + mo -1
l
2

S-C

O

Evidence of progress in MS-CPET

O

PT

Ox+

ΔG°ET ~
+38 kcal mol-1
for FeCp*2+

HO

ΔG°PT ~ +19 kcal mol-1

HOO① Reaction proceeds at anoxidant with ΔG゜MS-CPET near0, and no further decrease inoxidizing power will preventthe reaction from progressing.

H
Ox

Ox
PT

Proceeding via MS-CPET

Eox〔V〕*2 kMS-CPET 〔M-1 s-1〕 KIE (kH/kD)

entry

Oxidant*1

1

N(ArBr)3•+

0.67

7.2×105〜4.5

2

N(ArOMe)(ArBr)2•+

0.48

5.4×104­

3

N(ArOMe)2(ArBr)•+

0.32

1.9×104

2.4

4

N(ArOMe)3•+

0.16

9.5×103

3.7

5FeCp2+

0.00

1.9×103−

6FeCp*Cp+−0.27

3.8×102

1.6

7FeCp*2+−0.48

2.3×101−

8

CoCp2+

−1.33

NR

n/a

*1 ArX = p-C6H4-X*2 E1/2 = versus FeCp2+/0 in MeCN

② kMS-CPET is dependent on
the strength of oxidant = Eox＆
H/D substitution
ET and PT occurringin the rate-limiting step.

18
Markle, T. F.; Darcy, J. W.; Mayer, J. M., Sci. Adv. 2018, 4, eaat5776

Mechanism Analysis

2-1Intramolecular C-H activation via MS-CPET

Stepwise reaction = (ET + PT) vs One-step reaction = MS-CPET③ The value of α = ΔΔG‡/ΔΔG゜ = Δln(k2) / Δln(Keq)
Determining Keq
HO
H

①

O
②

H

O

H

H

④

Ox+
O
H

MS-CPET ☞ Combination of acid-base and oxidation reactions
HO
BDEC-H

e-

−pKa

CG
Eox

H

H

Ox+

ΔG°MS-CPETO

ΔG°MS-CPET = BDEC-H − 1.37pKa − 23.06Eox − CGΔlog(Keq) = ­ΔG°MS-CPET /2.303RT
Δlog(kMS-CPET) = αΔlog(Keq)

e-

Ox
HO

O

O
H

HO

O

③

HAT reaction ☞ the difference in BDEs

O
Ox

Markle, T. F.; Darcy, J. W.; Mayer, J. M., Sci. Adv. 2018, 4, eaat5776
Julia W. Darcy, Scott S. Kolmar, and James M. Mayer, J. Am. Chem. Soc. 2019, 141, 10777−10787
19

C–H Bond Cleavage by Proton-Coupled Electron Transfer

Darcy, Kolmar, and Mayer

Mechanism Analysis

2-1

3.3

Tabulated Brønsted α values with varying oxidants

The value for the Brønsted α varies with the oxidant, as shown in Figure 1 in the main text. Table
S3.5 shows how these values change with oxidant strength. Not every oxidant was measured withevery substrate due to general oxidant/base incompatibilities described above. The number of data
points is indicated in the far right column. The linear fits of these data are shown graphically in
Figure S3.2 and given numerically in Table S3.5 (uncertainty from the fit of the lines in Figure
C–H Bond Cleavage by Proton-Coupled Electron TransferS2.3).

Intramolecular C-H activation via MS-CPET③ The value of α = ΔΔG‡/ΔΔG゜ = ln(k2) / ln(Keq)

Chemical Society Ox+
O
H

ΔBDEC-H (CO2-)〔kcal mol-1〕
3.3 Tabulated
Oxidant
Brønsted α Brønsted α values with varying oxidants
−0.06
•+
+0.8
NH2
N(ArBr)3 22.0 0.64
The•+value for the Brønsted α varies with the oxidant, as shown in Figure 1 in
N(ArOMe)(ArBr)2
S3.521.5
shows0.54how these values
0.22Not every oxidan+0.3change with oxidant strength.
OMe N(Ar ) (Ar•+
0.36 ± 0.07
OMe 2
Br)
every
substratedue
togeneraloxidant/baseincompatibilities
described above
N(ArOMe)3•+0.48 ± 0.05
0 right column. The linear fits0 of these data are sH
21.2
pointsisindicated
in
the
far
FeCp2+
0.58 ± 0.10
FigureS3.2 and given numerically in Table S3.5 (uncertainty from the fit o+
0.83
FeCp*Cp−0.9
CF320.30.61 ± 0.09
S2.3).
+

Table S3.5. Brønsted α calculations with ferrocenium and aminium oxidants. The error is taken
entryH) expt ΔpKa(CO2H) expt
2Articlefrom the error of the linearRfit shownpKa(COin Figure S3.2.

Ox
HO

O

O

1
2

0.2〜0.4 % MeOH

3

MeCN
R

R

αET ： Fixed substituents, changing reduction potential

4

FeCp*20.99 ± 0.12

S3.5.reduction
Brønsted α potential,
calculations changing
with ferrocenium
and aminium oxidant
Brønsted αTable： Fixedsubstituentsfrom the error of the linear fit shown in Figure S3.2.
Oxidant
N(ArBr)3

Brønsted α•+N(ArOMe)(ArBr)2

0.64
•+

0.54

•+

0.36 ± 0.07

N(ArOMe)2(ArBr)
N(ArOMe)3•+

FeCp2+

0.48 ± 0.05
0.58 ± 0.10+

FeCp*Cp

0.61 ± 0.09+

0.99 ± 0.12

FeCp*2scheme for the oxidation of Flr(R)CO2− substrates. Reactions were performed with an excess of carboxylate,Figure S3.2. The Brønsted α with each oxidantthe
are shown as the linear fits.
as a solution
ETin MeOH). Absorbance spectra were monitored on a stopped-ﬂow following the disappearance ofox
um oxidants. (B) Representative absorbance versus time data set monitoring the reaction of N(ArOMe)3•+ with
- S16 ws the absorbance at the λmax of the oxidant, 752 nm, versus time, and the ﬁt to an exponential functionusingC) Plot of the logarithm of the MS-CPET rate constants (kMS‑CPET = k2/2) versus changes in driving force for all
ts. Δlog(Keq) = −ΔΔG°rxn/2.303RT and ΔΔG°rxn = ΔBDFECH(CO2H) − 1.37ΔpKa(CO2H) − 23.06Eox (see text
or the reaction of the R = H compound with FeCp*2+ has been set
a equal to zero,12 and all other values are relative
FECH and pKa,COOH (see the Supporting Information for all values). Uncertainty in the last decimal is shown in
PET rate constants versus changes in driving force for the four substrates with a single oxidant (FeCp2+).

・ α = 0.19〜0.22 ☞ Not sensitive to changes in E
・ Brønsted α = about 0.50 ☞ Sensitive to changes in substituents
Changing substituentswere performed with various pararX •+ ) and ferrocenium (Fc+)

pK ⇦ large effect(→ Appendix)
BDE ⇦ small effectJulia W. Darcy, Scott S. Kolmar, and James M. Mayer, J. Am. Chem. Soc. 2019, 141, 10777−10787
Information section 3). These incompatibilities can be20
mitigated by using the weaker ferrocenium oxidants,
astheseJames M. Mayer, et al., J. Org. Chem. 2022, 87, 2997−3006

2-1

DFT Calculated Potential Energy Surfaces
Intramolecular C-H activation via MS-CPET

Comparison of changes in IRC between PT and MS-CPET
IRC = Internal Response Coordinates
O

O

O

O

HO

O

HO

O

H
PT

Ox+

MS-CPET

ET

Ox

H PT

Ox+

： N(ArBr)3•+

PT coordinate : the distance between the fluorenyl proton and carboxylate oxygen
the extent of ET (only MS-CPET) : the change on the nitrogen atom of the oxidant
Julia W. Darcy, Scott S. Kolmar, and James M. Mayer, J. Am. Chem. Soc. 2019, 141, 10777−10787
21

2-1

DFT Calculated Potential Energy Surfaces(A)・(B) : IRC and TS

l of the American Chemical Society

Intramolecular C-H activation via MS-CPET(C)・(D) : IRC and Distance of protons to oxygen
ArticleC–H Bond Cleavage by Proton-Coupled Electron Transfer

Dar

The extent of ET

Figure S4.3. NBO charge versus
internal
reaction
coordinate for the MS-C
□ : thechargefor nitrogen
Flr(H)CO2- and N•+(ArBr)3. The
for nitrogenshown bycarbon
blue squares◇ :charge
the charge
for theisfluorenyl
fluorenyl carbon is shown by red diamonds.

To assess the extent of charge transfer throughout the reaction NBO calculation
along the internal reaction coordinate. The NBO charge of nitrogen starts at the•+(ArBr)3 (-0.315 units), and stays constant up until the approximate TS. At the・ “PT in MS-PCET” is slower than PT inNtheTS.
Thenegative,
electrontransfer"switch"is Br)3 (N becomes more
and remains
at the value
for isolated N(Aris consistent withelectron transferby
occurring
the transitionof
stateabut electronic
・ PT precedes ET in MS-PCET.
triggered
the attransfer
Flr(H)CO2– lagging significantly behind the transfer of the proton. The NB・ In MS-CPET, ET occurs at once in TS.
to negativea transition
fluorenyl carbonproton
becomes moreas the protonstate.
gets further away, thenmore positive as the electron transfers at the transition state, then
22becomes
electronic
reorganization
andJ. protontransfer
progress
the10777−10787
remainder of thJulia W. Darcy, Scott S. Kolmar,
and James
M. Mayer,
Am. Chem.
Soc.
2019,for141,

Outline
Outline1. Introduction
1-1. PCET and CPET ・ Marcus Cross Relation
1-2. Example of Canonical HAT, Separated CPET,
Multi-Site CPET
1-3. Importance of Hydrogen Bond in MS-CPET
2. Contents
2-1. Intramolecular C-H activation via MS-CPET
2-2. Intramolecular C-H activation with photocatalyst
via MS-CPET
2-3. Intermolecular C-H activation via MS-CPET
3. Summary

23

C-H activation with Photocatalysis via MS-CPET

2-2

Intramolecular C-H activation with photocatalyst via MS-CPET

CF3

F
HO

O

H

R

[IrⅢH] (10 mol%)Co(acac)3 (1.2 eq.)
TBAOAc (0.8 eq.)O

MeCN (3-5 mM)
410 nm LED

N

O
F
F

N

Ir
N
N

1

1-lac

Omitting the light, photocatalyst, terminal oxidant, or added base results in no or only trace lactone.

F

R
CF3

[IrⅢR]

Two possible iridium catalytic pathways
Net oxidation conditions

Net neutral conditions

CoⅢ(acac)3
Ⅲ*[Ir ]

1-lac[IrⅢ ], hv 1

10

hν

-1
-1 s
6 M

1−

10

8 M

=

1

=

-1
-1 s

kq

CoⅡ(acac)2[IrⅣ] k q

1−

[IrⅡ]

1

[IrⅢ]
1−

・ *[IrⅢ] reacts rapidly with Co(acac)3.
・ Reaction cannot proceed without Co(acac)3.

Lactone-forming reactions occur
in the red pathway(= Net oxidation conditions).

Maraia E. Ener, Julia W. Darcy, Fabian S. Menges, and James M. Mayer, J. Org. Chem. 2020, 85, 7175−718024Markers of Iridium-Catalyzed C-H Activation

2-2

Intramolecular C-H activation with photocatalyst via MS-CPET

However, the blue path (Net neutral conditions) also occurs in the system.
HO
H

O

HO

[IrⅢH] (10 mol%)TBAOAc (0.8 eq.)

DO

CD3OD (2 %v/v)
CD3CN (3-5 mM)
410 nm LED*[IrⅢ]
O

O

H

entry

[IrⅢH]

410 nm LED

1-d Substituent 〔%〕

1

­

−

0

2

＋

＋

80

[IrⅡ]

MeOD
O

OH

[IrⅡ]

MeOH
O

OD

[IrⅢ]
O

O

D

Deuterium incorporation can be used as a marker for transient C−H activation by *[IrⅢ].
Maraia E. Ener, Julia W. Darcy, Fabian S. Menges, and James M. Mayer, J. Org. Chem. 2020, 85, 7175−7180
25

2-2

Substrate Scope of Iridium-Catalyzed C-H Activation
Intramolecular C-H activation with photocatalyst via MS-CPET
O
O

O

O

1
75 % D, +ox

O

O

O

O

5
45 % 1D, 6 % 2D
+ox

O

O

2
80 % D, +oxOO3
100 % D, +oxOO

686 % D, +oxOO7
20 % D

O

8
8%D
O

O

OH
O

OH

4
ND, +oxOOO S NHO

962 % D10
30 % 1D, 5 % 2D

O
N

O
O

11
0%D

O

12
0%D

13
0%D

14
0%D

+ox : Lactone is also formed when catalyst and oxidant are added

Photoredox C−H activation occurs for a variety of benzylic substrates with internalcarboxylates.

26
Maraia E. Ener, Julia W. Darcy, Fabian S. Menges, and James M. Mayer, J. Org. Chem. 2020, 85, 7175−7180

CPET under these aceticPhotoredox
acid-tuned conditionsconditions(Figure 3). For
ansient
absorption
experimentsshow
theformationofsubstrate 7 (toluate), which
has one of theMS-CPET
strongest C−H a
2-2
accomplish
5−1 −1,
II
bonds
in
Table
1,
the
k
=
4
×
10
M
s
suggeststhat ET/
Table 2.photosensitizer
Measured and Estimated([IrReductionq
duced]) Potentials
in thevs presence
of
a
+/0
+/0
opening
new avenues
HAT
is a likelyC-H
mechanism
forwithC−H
activation.
Ferrocene (Fc ) in MeCN
Intramolecular
activation
photocatalyst
via MS-CPETtote, further supporting this possibility. This stepwise
The substrates in Table 1 span the range of bond strengths
concertedmechanism.
redox couple
E1/2 (V)references
betweenthatoxidizeof 1 and 7 andare expected to
span
the transitionFo
[Ir
]
can
carboxylates
directly.
Ranism Emay
IVbeIII expected to outcompete a concerted one∼1.38
estimated here
1/2 (IrH /IrH )between mechanisms. Trityl
substrates 2,are
3, andpossible
4 have similarun
pathways
a
IV
III
E
(Ir
/Ir
)
∼1.35
estimated
here
tBu
bond strengths to 1 and probably follow an MS-CPET
PET) 1/2fortBusubstrates
with stronger C−Hb bonds,C−H
in whichduring
E1/2 (*IrHIII/IrHII)∼1.05
estimated heremechanism, while phenylgenerated
toluate (5) may
undergo photore
predombII
II to be slower (conceptually
ET isE1/2expectedillustratedin(*IrtBu /IrtBu )∼0.95
estimated here
inantly ET/HAT
or a combinationof bothmechanisms.
tion
with
the
two-steppatSomemolecules
may
proceedwith The
E1/2 (RCO2•/RCO2−)∼0.9
3a, 4a, 19
limitedsolubilityof
these
substrates
(<20
mM)
has
precluded3).aQuasi-reversible waves by cyclic voltammetry; see Supporting“ET+HAT”analysis.
insteadofHAT,
MS-CPETrapid
which
hasnotb
Stern−Volmer
Similarly,
the available
data dob
Information, Section 4.1. See discussion of the optical E0−0 energies
allow drawing mechanistic conclusions for the reduction of the
stepwise ET/HAT pathin Supporting Information, Section 4.2.
ﬂuorenyl radical, the last part of the isotope exchange pathway(Scheme2, Supporting Information
Section 6.2).
carboxylate
and by st
MS-CPET
Information Section 4). These values show that the groundindependent→
the C−H bondis weak of the C−H
state [IrIV] species are capable of oxidizing carboxylates by
CONCLUSIONS
outer-sphere electron transfer, and very likely the excited states
thepresented
protonabove
acceptoristhatbasic
andcan bfavoredwhen
the C−H
The results
demonstrate
photoredox
as well. This is consistent with Glorius’ report that *[IrtBuIII]be useddifficult
as a mild, toversatile
method for base-directed C−H
oxidize.
(typicallycarboxylate hereoxidizes benzoate to PhCO2•, which then activates a variety ofactivation, deuterium incorporation, and functionalization.
4aaliphatic C−H bonds by intermolecular HAT (Scheme 1B).
Photoredox conditions hope
can replacetothat thermal
these oxidants
insights
Our transient absorption experiments show the formation ofaccomplish MS-CPET at the ﬂuorenyl C−H bond in 1,“ET+HAT”
the reduced photosensitizer ([IrII]) in the presence offor activating
opening new avenues tostrategies
probe fundamental
aspects of this C
benzoate, further supporting this possibility. This stepwise→ themechanism.
C−H bondisthe
strongerconcertedFor
many
substrates,
two mechanistic
intofundamental
aspe
mechanism may be expected to outcompete a concerted one
pathwaysarepossibleunderthehighlyoxidizingconditions
the proton acceptor is easy to(MS-CPET) for substrates with stronger C−H bonds, in which
generated during photoredox. MS-CPET is likely in competiMS-CPET is expected to be slower (conceptually illustrated inoxidize.
tion withthe two-step pathway of rate-limiting ET followed by
Figure 3).
rapid HAT, which has been reported in other studies.4a The
stepwise ET/HAT path is favoredby a moreeasily oxidized
Materials.
Substrates
1(
carboxylate and by stronger C−H bonds, since it is1-d),2, S15,MS-CPETand 6 maywere
independent of the C−Hbond strength.
befavored when the C−H bondis weak, andprotonacceptor
Substrate
3 thewassynthesize(typicallycarboxylate
here)
basic
and diﬃcult
to 7175−7180
oxidize. We
Maraia E. Ener,
Julia W.concerted
Darcy, Fabianand
S. Menges,
and James
M. Mayer,
J. is
Org.
Chem.
2020, 85,
3. Conceptual transition
betweenstepwiseC−
were
obtainedfrohope that these insights chemicals
will facilitate further
developmentof27
ation mechanisms with a single oxidant. Boxedstrategies
numbers
for activating C−H
bonds
and deeper explorations
further
puriﬁcation
unless ot
estimates of the E0−0 energies (Table 2, Supporting“ET + HAT” vs MS-CPET■■

EXPERIMENTAL SE

Outline
Outline1. Introduction
1-1. PCET and CPET ・ Marcus Cross Relation
1-2. Example of Canonical HAT, Separated CPET,
Multi-Site CPET
1-3. Importance of Hydrogen Bond in MS-CPET
2. Contents
2-1. Intramolecular C-H activation via MS-CPET
2-2. Intramolecular C-H activation with photocatalyst
via MS-CPET
2-3. Intermolecular C-H activation via MS-CPET
3. Summary

28

Intermolecular Aliphatic C-H Activation via MS-CPET

2-3

R1

SO2Ph

IrⅢ catalyst 1 (2 mol%)

H

SO2Ph

(1.5-3.0 eq.)
SO2Ph
DCM, blue LEDs, rt, 24 h

N

SO2Ph

NBu4OP(O)(OBu)2 (5 mol%)
R2Intermolecular C-H activation via MS-CPET
CF3
F
CF3

R1

R2

F
F

Ir

N
N

N
CF3
CF3

F

transition state
ET

CF3
CF3

F

R1

*

R2
H

IrⅢ

N
N

O
H
H

O

N
F

CF3
CF3

P

OBu
OBu

MS-CPET

R2

CF3
CF3

F

PT

N
F
F

R1

H
O

N
F
F

IrⅡ

N
N

N
F

O

P

OBu
OBu

CF3
CF3

Ir-phosphate Complex
Carla M. Morton, et al., J. Am. Chem. Soc. 2019, 141, 13253−13260

Intermolecular aliphatic C-H activation via MS-CPET was achieved.
29

Development of Conditions for C-H Alkylation

2-3

Intermolecular C-H activation via MS-CPET
O
H

SO2Ph
SO2Ph
1.5 eq.

IrⅢ catalyst 1 (x mol%)
NBu4OP(O)(OBu)2 (5 mol%)
DCM, blue LEDs, rt, 24 h
O O
tBu
S
N
H
sulfonamide(y eq.)
MeO

O

SO2Ph
SO2Ph

entry

x mol%

y eq.

yileld〔%〕

1

5

1.0

75

2

5

0

66

3

2

0

92

The mechanism that the authors were designing
O O
tBu
S
*[IrⅢ]N
H
ET MS-CPET(N-H)
MeO
MeO
O
PT
hyderogen
O P
bond
OBu
OBu

O O
[IrⅡ]
tBu
S
N
ET
HAT(C-H)
O
PT
O
HO P
OBu
H
OBu

O O
tBu
S
N
H
MeO

O

HO

[IrⅡ]
O
P

OBu
OBu

SO2Ph
SO2Ph

O

SO2Ph
SO2Ph

The authors' initial approach was to generate heteroatom-centered radicals via
MS-CPET, followed by HAT of hydrocarbons.

However, alkylation proceeded without sulfonamide, as represented in entry 3.
30Carla M. Morton, et al., J. Am. Chem. Soc. 2019, 141, 13253−13260

Substrate Scope / Alkene Scope

2-3

SO2Ph

IrⅢ catalyst 1 (2 mol%)
NBu4OP(O)(OBu)2 (5 mol%)H
R1Intermolecular C-H activation via MS-CPET

Alkene Scope

Substrate Scope

SO2Ph

R2

SO2Ph
R1

(1.5-3.0 eq.)

O

H

R2

H

6
n = 1, 55 %n = 2, 45 %7
n = 1, 48 %n = 2, 50 %

Me

H

H

16
40 %

H

H

8
80 %

9
58 %

Me

H
10
64 %

H

92 %

Ph
CO2Me

COMe

COPh

47 %

60 %

50 %

Substrate Scope

Me Me
H

OAc

X
X = H (11), 83 %X = Br (12), 83 %
H

SO2Ph

PhthN

SO2Ph

n

EWG

DCM, blue LEDs, rt, 24 h
AcO

n

O

EWG (1.5-3.0 eq.)

SO2Ph
DCM, blue LEDs, rt, 24 h

H

IrⅢ catalyst 1 (2 mol%)
NBu4OP(O)(OBu)2 (5 mol%)

Reaction proceeds selectively withweaker C-H bonds as seen in HAT.

Me
13
85 %

O

H

17
92 %

14
89 %
O
O
18
57 %

H

15
60 %

Alkene Scope
H

Boc
N
H

O
19
65 %

Reactions with alternative alkenes
also proceeded in moderate yields.

20
67 %

Carla M. Morton, et al., J. Am. Chem. Soc. 2019, 141, 13253−13260
31

2-3

Mechanism Analysis (Formation of Complex)
Intermolecular C-H activation viaAppendix
MS-CPET① : The association of the phosphate base and iridium photocatalyst
Titration of the base into a solution containing the IrⅢ catalyst☞ Downfield shifts in the 1H NMR spectrum of all protons of the bipyridine ligand
Especially, 3,3′-protons
entry

Ir photocat.

Eox (V vs. Fc+/Fc)

Keq〔M-1〕

yield〔%〕15,5’-d(CF3)bpy

1.30(7.8 ± 0.6) × 103

73

2

bpy

0.94

(1.0 ± 0.1) × 103

37

34,4’-dtbbpy

0.83(3.4 ± 0.2) × 102

45

43,3’-F-5,5’-d(CF3)bpy

1.59

−

−

5

3,3’-d(CO2CH3)bpy

1.28

−

−

Keq = (7.8±0.6)×103 M-1

CF3

F
N

3,3′-protons binds
to the phosphate base

The crystal structure of the IrⅢ catalyst
and diphenyl phosphate base

F
F

Ir

N
N

N
F

Loss of 3,3'-proton prevents
R binding to phosphate baseR

CF3

Carla M. Morton, et al., J. Am. Chem. Soc. 2019, 141, 13253−13260

tra of Ir photocatalyst upon phosphate base titration, exhibiting downﬁeld shifting of the resonanc
20
ligand; X-ray crystal structure of the iridium-phosphate complex rendered using CYLView;d32withdrawn from the vial, and yield was monitored by GC.

Mechanism Analysis (Formation of Complex)

2-3

Table S24: Initial Rate Kinetics with Increasing Fluoride Loading

Intermolecular C-H activation via MS-CPET① : The association of the phosphate base and iridium photocatalyst
2 mol % Ir(III) catalyst 1
5 mol % Bu4NOP(O)(OBu)2
X mol % TBAF
α-phenyl methacrylate (1 equiv)

CF3
CF3

F

Experimentally, it was found that the Keq is comparable to thatCH Cl , blue LEDs, rt
3 M^-1of phosphate bases. Keq =(1 (6.9±0.4)×10
equiv)
O

N

2

2

Ph

CO2Me

O

was allowed to stir underN blue LED irradiation. At each timepoint, 5 µL of solution was

H

F

F

H monitored by GC.
withdrawn
from theIrvial, N
and yield wasFNCompetitive experiments confirm the need for complex.

able S24: Initial Rate Kinetics
CF3 with Increasing Fluoride LoadingF
IrⅢ catalyst 1 (2 mol%)

CF32 mol % Ir(III) catalyst 1
5 mol % Bu4NOP(O)(OBu)O
H2
X mol % TBAF
α-phenyl methacrylate (1 equiv)O(1 equiv)

CH2Cl2, blue LEDs, rt

NBu4OP(O)(OBu)2 (5 mol%)
TBAF (x mol%)
Ph

O

CO2Me

Ph
CO2Me

(1.0 eq.)

Ph

CO2Me
DCM, blue LEDs, rt
O

Reaction efficiency was maintained when TBAF was added to the N-H PCET reaction.
☞ Complex is required for C-H activation.
S55

33
Carla M. Morton, et al., J. Am. Chem. Soc. 2019, 141, 13253−13260

2-3

Mechanism Analysis (Formation of Complex)② : ET also requires substrate

Intermolecular C-H activation viaAppendix
MS-CPETA signal
forphosphate.
monoreduced
Ir could becomplex
observed
by eﬀecttransientnding
Keq with(B) Iridium-ﬂuoride
and theof absorption spectroscopy.
competitive binder has an inverse ﬁrst-order concentration dependence.
Ⅱ

The formation of IrⅡ can determine if electron transfer has occurred.

・ Electron transfer is occurring only
when both substrate and phosphatebase are present.
・ Electron transfer is proportional tosubstrate concentration.
MS-CPET proceeds only when all
three elements are present.

34

a solution of Ir photocatalyst and phosphate base byCarla
ethylbenzene
andM. Morton, et al., J. Am. Chem. Soc. 2019, 141, 13253−13260

Outline
Outline1. Introduction
1-1. PCET and CPET ・ Marcus Cross Relation
1-2. Example of Canonical HAT, Separated CPET,
Multi-Site CPET
1-3. Importance of Hydrogen Bond in MS-CPET
2. Contents
2-1. Intramolecular C-H activation via MS-CPET
2-2. Intramolecular C-H activation with photocatalyst
via MS-CPET
2-3. Intermolecular C-H activation via MS-CPET
3. Summary

35

Summary
Summary

・ By designing the molecule, intramolecular C-H activation proceeded via MS-CPET,
which normally requires hydrogen bond.
OOH・ By using mechanism analysis experiments and computational
chemistry, it was also confirmed that ET and PT proceed
concertedly.
・ The introduction of the photocatalyst facilitated the study of C-H activation via MSCPET and expanded the substrate.
CF3
F

HO
H

O

[IrⅢH] (10 mol%)Co(acac)3 (1.2 eq.)
TBAOAc (0.8 eq.)

R
O

N

O
F
F

MeCN (3-5 mM)
410 nm LED
1

N

Ir
N
N

1-lac

F

R
CF3

[IrⅢR]HO
H

O[IrⅢH] (10 mol%)TBAOAc (0.8 eq.)

HO
D

O

CD3OD (2 %v/v)
CD3CN (3-5 mM)
410 nm LED

36

Summary
Summary・ A system for C-H activation via intermolecular MS-CPET has been discovered andcan be applied to many aliphatic C-H bond.
CF3
CF3

F

H
R1

SO2Ph

IrⅢ catalyst 1 (2 mol%)
NBu4OP(O)(OBu)2 (5 mol%)
R2

N

SO2Ph

SO2Ph

R1

(1.5-3.0 eq.)
SO2Ph
DCM, blue LEDs, rt, 24 h

F
F

R2

Ir

N
N

N
F

CF3
CF3

transition state
ET
CF3
CF3

F

R1

*

R2
H

PT

N
F
F

IrⅢ

N
N

O
H
H

O

N
F

P

OBu
OBu

CF3
CF3
Ir-phosphate Complex
37

Appendix

AppendixExample of Multi-Site CPET

1-2

Appendix

ET

PT

H
O

H
O

NH2
Ph
Ph

N

k = 105 M-1s-1
N

NH2
Ph
Ph

Mayer, J. M.; Rhile, I. J., J. Am. Chem. Soc. 2004, 126, 12718-12719.

Evidence of progress in CPET mechanism ② : high-energy intermediates
back ET : kET-1 = 1017 M-1s-1
ΔG‡ = 11 kcal mol-1
ΔG=+16.4 kcal mol-1
Keq= 10-12
ET1
HOAr-NH2 ，X+
PT2
KPT2 < 10-4

HOAr-NH2 ，X

PT1

CPET
OAr-NH3 ，X+

OAr-NH3 ，XET2

no evidence for the zwitterion
39

Example of Multi-Site CPET

1-2

Appendix

Three-Component MS-CPET Reactions
OH
N

Fe

ΔG゜ET1 = +16 kcal mol-1
ΔG゜PT1 = +31 kcal mol-1

Rn

＞

ET

Rn

(ΔG is given from the measured k2 and the Eyring equation.)

H
N
Fe
Rn

Rn

Fe

ΔG‡ = 10 kcal mol-1

‡

O
N

N

hydrogen
bond
N
H
O
PT
N

Rn

Rn

☞ The reaction is not via ET1, PT2.
OH
N

N

ΔG°PT2 = +31 kcal mol-1
Fe

NMe2
ΔG°ET1ΔG ‡= +16 kcal mol-1

OH
N

NMe2

Fe
NMe2

=1

0k

ca

lm

ΔG°ET2 = −45 kcal mol-1

ol -1

O
N

N
Fe

O
N

H
N

ΔG°PT1 = ­30 kcal mol-1

H
N
Fe
NMe2

Morris, W. D.; Mayer, J. M., J. Am. Chem. Soc. 2017, 139, 10312−10319.
40

Example of Multi-Site CPET

1-2

Three-Component MS-CPET Reactions

AppendixOHN

α = ΔΔG‡/ΔΔG゜

O
N

N
Fe
Rn

ET
Fe

entry

oxidant

base

Rn

a

1

[Cp2Fe]BF4

py

2[Cp2Fe]BF4

4-Me-py3[Cp2Fe]BF4

4-MeO-py

4[Cp2Fe]BF4

4-Me-py5[Cp2Fe]BF4

2,6-lutidine

6[Cp2Fe]BF4

4-Me2N-py

7[(MeCp)2Fe]PF6py

8[Cp(Cp*)Fe]PF6py

9[Cp(Cp*)Fe]PF64-Me-py10[Cp(Cp*)Fe]PF64-MeO-py

11[Cp(Cp*)Fe]PF6

4-Me2N-py

Fe
Rn

Rn

= ln(k2) / ln(Keq) = 0.46

HNhydrogen
bond
N
H
O
PT
N

Rn

Rn

The diagonal gives the ΔG⧧ from the measured k2 and the Eyring equMorris, W. D.; Mayer, J. M., J. Am. Chem. Soc. 2017, 139, 10312−10319.
Figure 3. Plot of ln (k2) vs ln (Keq) for TEMPOH oxidations41by the

combination of a pyridine base with [Cp2Fe]BF4 (blue squares),2-1

Lactone Formation in C-H activation via MS-CPET
Appendix

HO
H

O

HO

O
Oxidant (1.0 eq)
DBU (1.0 eq)

O

O

H

MeCN (0.01 M)

0.5 eq0.5 eqMarkle, T. F.; Darcy, J. W.; Mayer, J. M., Sci. Adv. 2018, 4, eaat5776

42

Mechanism Analysis

2-1

Appendix③ The value of α = ΔΔG‡/ΔΔG゜ = ln(k2) / ln(Keq)Society

Ox+
O
H

Ox
HO

O
0.2〜0.4 % MeOH
MeCN

R

R

O

ArticleΔpKa(CO2H) expt
pKa(CO2H) exptΔBDEC-H (CO2-)〔kcal mol-1〕

entry

R

1

NH2

22.0

+0.8

−0.06

2

OMe

21.5

+0.3

0.22

3

H

21.2

0

0

4

CF3

20.3

−0.9

0.83

①
Compare entry1 and 4
ΔpKa = 1.7 → ΔG゜= 2.3 kcal mol-1-1② ΔBDEC-H = 0.9 kcal mol☞ ΔpKa has a greater impact.
・ The R = OMe compound reacts 3 times faster thanthe R = H compound.
・ The R = OMe have a slightly stronger C−H bond.
☞ The difference of BDE isn’t the major contributor.

the oxidation of Flr(R)CO2− substrates. Reactions were performed with an excess of carboxylate,
Julia W. Darcy,
Scott S. Kolmar,
andtheJames
M. Mayer,ofJ.theAm. Chem. Soc. 2019, 141, 10777−10787
in MeOH). Absorbance spectra were monitored
on a stopped-ﬂow
following
disappearance•+James
et al., J. Org. Chem. 2022, 87, 2997−3006)3 with(B) Representative absorbance versus time data set monitoring the reaction of
N(ArM.
OMeMayer,bance at the λmax of the oxidant, 752 nm, versus time, and the ﬁt to an exponential function using
43
he logarithm of the MS-CPET rate constants (kMS‑CPET = k2/2) versus changes in driving force for all) = −ΔΔG° /2.303RT and ΔΔG° = ΔBDFE (CO H) − 1.37ΔpK (CO H) − 23.06E (see text

The imbalance of the proton transfer in Flr(H)CO2− is
2-1 in Figure 3A by a traditional More O’Ferrall−Jencks
illustrated

are quite strong. Again, PT is farther along the reaction
coordinate than would be expected from the Hammond
postulate. Electronic reorganization within the ﬂuorene lag
Appendixbehind the proton transfer.
One way to visualize MS-CPET in the Bernasconi PNS
formalism is to represent the two electronic states as two Mor
O’Ferrall−Jencks planes, as shown in Figure 3B. The bottom
plane shows the nuclear reorganization to arrive at thtransition state. Electron transfer for the MS-CPET reaction
is shown by a “jump” from one plane to another, because i
occurs instantaneously on the time scale of nuclear motion(the Franck−Condon principle).5a,30,31 This takes the system
to the upper plane where the nuclear reorganization icompleted to form the product. This description is supportedby the DFT calculations, which show that the NBO charge on
the nitrogen atom of the oxidant sharply changes at thtransition state, while the nuclear motions proceed smoothl
before and after the transition state.
The late position of proton transfer along the reaction
coordinate provides a rationale for the larger Brønsted α uponchanging the substituent than the oxidant. It is, however, mor
challenging to use this model to understand the smadependence of the rate constants on the reduction potentia
of oxidant (αET = 0.2). In a simple Marcus theory formalism,
small α would normally indicate a strongly exoergic reaction
with −ΔG° approaching λ. This is not consistent with ou
estimates that MS-CPET is close to isoergic for the oxidationof Flr(H)CO2− with FeCp*2+.12 In addition, this explanation
would require curvature of the log(kMS‑CPET) versus log(Keq‑MS‑CPET) plots, which is not seen in Figure 1C. The TS fo
the MS-CPET is early only in the “electronic reorganization
coordinate, and this refers to π bond rearrangement in th
44 to thFigure 3. (A) A More O’Ferrall−Jencks plot for intramoleculardeveloping ﬂuorenyl radical, not electron transfer−
Figure
3.
(A)
A
More
O’Ferrall−Jencks
plot
for
intramolecular
progressof the ScottprotonS.transfer
proton transfer in Flr(H)CO2 . TheJulia
W. Darcy,
Kolmar, and James
Mayer, J. Am. Chem.
Soc. 2019,
141,requires
10777−10787
oxidant.M.Understanding
the small
α likelya mor

DFT Calculated Potential Energy Surfacesspectra were typically taken on the sealed reaction mixture without workup unless otherwise
2-2 noted.

C-H activation with phyocatalysis via MS-CPET
Appendix

Figure S2. Red: Substrate 1 (deprotonated in situ). The singlet at 6.67 ppm corresponds to the fluorenyl proton.
Green: Crude reaction mixture after overnight irradiation. Initial reaction mixture: 6 mM 1 with 0.8 eq TBAOAc, 7mM Co(acac)3, 75 µM [IrH], in d3-MeCN. Blue: 1-lac generated by photoredox oxidation. The crude reaction
mixture was filtered through a silica plug.
45

approximate rate constant for photoredox C−H bond cleavage
2-2 Iridium-Catalyzed
in 1 by *[IrtBuIII]C-H
ﬁts thissame correlation(FigureActivation
Proceedsvia2),
MS-CPET
bond
18
Appendix
supportinganMS-CPETmechanism.
(ortho-nternalterium11 andon foror 14,
NMR
toluatehin thelectivery to airectedMaraia E. Ener, Julia W. Darcy, Fabian S. Menges, and James M. Mayer, J. Org. Chem. 2020, 85, 7175−7180

carbonFigure 2. Plot of the rate constant vs oxidant strength for oxidation of
5acondiThe fact thatthecircles
photocatalytic
systemalso onthe thermal
correlation
theMS-CPET
cyan star is
1. Redand trendlines
are isthermaloxidations;
thylpiline suggeststhat iridium-catalyzed
C-Hwork).
activation
by MS-CPET.
The also
star proceeds
size encompasses
oxidation
by *[IrtBuIII] (thisuncertainty in kMS‑CPET and E (oxidant).
hers as7177

https://dx.doi.org/10.1021/acs.joc.0c00333
J. Org. Chem. 2020, 85, 7175−7180
46

2-3

Substrate Scope / Alkene Scope
Journal of the American Chemical Society

Appendix

catalyst and diphenyl p
the oxygen atom of the
bipyridyl ligand (Figur
UV/vis titrations, the epairing of the Ir(III) ca
calculated to be (7.8
indicative of the format
We would note that pha range of structurallythat vary in their substi
bipyridine ligand (Figu
To demonstrate thethe photocatalyst for
catalysts with the H-bo
ligand substituted with
(Figure 5A). Reaction
catalysts did not yieldalkylation product. T
Figure3. Catalyticproduced
C−H alkylation
complex substrates.
Yields areshowed
The oxygen-centeredradicalsby ofphosphate
oxidationlowsubstitution of the bipof isolated product.
regioselectivity. Therefore, it is thought that a different mechanism is atproperties
work. of the com
performed a previously
Carla M. Morton, et al., J. Am. Chem. Soc. 2019, 141, 13253−13260
47

2-3

Reaction Mechanism

Journal of the American Chemical Society

ArticleAppendix48
Figure 7. Proposed reaction mechanism for the catalytic C−H alkylation involving an intermolecular multisite-PCET via an iridium-phosphate
Carla M. Morton, et al., J. Am. Chem. Soc. 2019, 141, 13253−13260
complex.