Testing the limits of radical-anionic CH-amination: A 10-million-fold decrease in basicity opens a new path to hydroxyisoindolines via a mixed C-N/C-O-forming cascade

Article abstract of DOI:10.1039/c9sc06511c

An intramolecular C(sp3)-H amidation proceeds in the presence of t-BuOK, molecular oxygen, and DMF. This transformation is initiated by the deprotonation of an acidic N-H bond and selective radical activation of a benzylic C-H bond towards hydrogen atom transfer (HAT). Cyclization of this radical-anion intermediate en route to a two-centered/three-electron (2c,3e) C-N bond removes electron density from nitrogen. As this electronegative element resists such an oxidation , making nitrogen more electron rich is key to overcoming this problem. This work dramatically expands the range of N-anions that can participate in this process by using amides instead of anilines. The resulting 107-fold decrease in the N-component basicity (and nucleophilicity) doubles the activation barrier for C-N bond formation and makes this process nearly thermoneutral. Remarkably, this reaction also converts a weak reductant into a much stronger reductant. Such reductant upconversion allows mild oxidants like molecular oxygen to complete the first part of the cascade. In contrast, the second stage of NH/CH activation forms a highly stabilized radical-anion intermediate incapable of undergoing electron transfer to oxygen. Because the oxidation is unfavored, an alternative reaction path opens via coupling between the radical anion intermediate and either superoxide or hydroperoxide radical. The hydroperoxide intermediate transforms into the final hydroxyisoindoline products under basic conditions. The use of TEMPO as an additive was found to activate less reactive amides. The combination of experimental and computational data outlines a conceptually new mechanism for conversion of unprotected amides into hydroxyisoindolines proceeding as a sequence of C-H amidation and C-H oxidation.

Full text of DOI:10.1039/c9sc06511c

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Testing the Limits of Radical-Anionic CH-Amination: a 10-Million-Fold Decrease in
Basicity Opens a New Path to Hydroxyisoindolines via a Mixed C-N/C-O-Forming Cascade
Quintin Elliott, † Gabriel dos Passos Gomes, †, ‡ Christopher J. Evoniuk, † and Igor V. Alabugin*†
† Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida
32306, United States
‡ current address: Department of Chemistry and Department of Computer Science, University of
Toronto, Toronto, Ontario, Canada
Abstract:
An intramolecular C(sp3)-H amidation proceeds in the presence of t-BuOK, molecular oxygen,
and DMF. This transformation is initiated by the deprotonation of an acidic N-H bond and selective
radical activation of a benzylic C-H bond towards hydrogen atom transfer (HAT). Cyclization of
this radical-anion intermediate en route to a two-centered/three-electron (2c,3e) C-N bond removes
electron density from nitrogen. As this electronegative element resists such an “oxidation”, making
nitrogen more electron rich is key to overcoming this problem. This work dramatically expands
the range of N-anions that can participate in this process by using amides instead of anilines. The
resulting 107-fold decrease in the N-component basicity (and nucleophilicity) doubles the
activation barrier for C-N bond formation and makes this process nearly thermoneutral.
Remarkably, this reaction also converts a weak reductant into much a stronger reductant. Such
“reductant upconversion” allows mild oxidants like molecular oxygen to complete the first part of
the cascade. In contrast, the second stage of NH/CH activation forms a highly stabilized radical-
anion intermediate incapable of undergoing electron transfer to oxygen. Because the oxidation is
unfavored, an alternative reaction path opens via coupling between the radical anion intermediate
and either superoxide or hydroperoxide radical. The hydroperoxide intermediate transforms into
the final hydroxyisoindoline products under basic conditions. The use of TEMPO as an additive
was found to activate less reactive amides. The combination of experimental and computational
data outlines a conceptually new mechanism for conversion of unprotected amides into
hydroxyisoindolines proceeding as a sequence of C-H amidation and C-H oxidation.
Introduction
Due to their abundance, C(sp3)-H bonds offer an excellent starting point for the
1
functionalization of organic compounds. However, the productive use of C-H bonds is
2
complicated due to the difficulties associated with their selective activation. These challenges
prompt chemists to search for new approaches for utilizing C-H bonds as a reactive organic
3
functionality.
C-H amination couples C-H activation with the concomitant formation of a C-N bond and
4
opens new avenues for the synthesis of nitrogen-containing organic compounds. This approach
has evolved into a versatile group of reactions that overcome the challenges with C-H activation
and C-N bond formation. Depending upon nitrogen’s participation in C-H activation and C-N bond
formation, one can broadly classify C-H amination reactions within the following four approaches:
a) C-H activation directly coupled with C-N bond formation (direct activation), b) C-H activation
with delayed C-N bond formation, c) N-assisted C-H activation, and d) independent C-H/N-H
activation (Scheme 1).

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b) C-H Activation with Delayed C-N Bond Formation
a) Direct Activation
Nitrogen is responsible for C-H activation
Additional reagent needed for C-N bond formation
Usually, remote intramolecular activation
Nitrogen Centered Radical
Nitrogen is responsible for C-H activation
Nitrogen is responsible for C-N and N-H bond formation
Singlet Nitrene
R
C-H
Insertion
R
H
N
R
H
R
H
N
N
2) -e
1) HAT
N
C
N
R
N
C
C
3) -H+
H
R
R
C
C
H
Conjugated Nitrogen Centered Radical Cation
Triplet Nitrene
R
Radical
Rebound
R
R
H
1) -H+
R
H
N
3) -e
4) -H+
H
HAT
N
N
H
N
C
N
R
N
H
2) HAT
H
c) Nitrogen-Assisted C-H Activation
Nitrogen is not directly involved in C-H activation
d) Independent N-H/C-H Activation
Two independently formed reactive intermediates: N- and C-centered
Nitrogen may play a secondary role as directing group
Dianion
"Reductive Elimination without a metal"
Strong
Base
Transition Metal C-H activation
-2 e-
H
R
R
H
N
N
[M]H
R
R
N
N
[M]
H
1) [MX]
R
R
H
N
H
R
N
N
2) -H+
-X-
This work
Radical-anion
Reductive Elimination
R
H
N
R
N
-e
HAT
Scheme 1. Selected examples of the four approaches to C-N bond formation via C-H activation.
All carbons are tetravalent, the non-participating C-H bonds are omitted for clarity.
In direct activation (Scheme 1a), nitrogen is responsible for the activation of C-H bonds
and the formation of both the C-N and the N-H bonds. This mode of activation works with highly
coordinatively unsaturated species, e.g., nitrenes and nitrenium ions, where nitrogen can insert into
5
a C-H bond in either a stepwise or concerted manner.
In C-H activation with delayed C-N bond formation (Scheme 1b), nitrogen assists in C-H
activation by breaking the C-H bond, but the C-N bond forming step needs an additional
participant (e.g., an external oxidant). This process also requires an electron-deficient nitrogen-
6
7
centered intermediate, i.e., a radical or a radical-cation. If placed in proximity to a C-H bond, a
nitrogen-centered radical can abstract a hydrogen atom, forming a carbon centered radical. A C-N
bond is formed by trapping this radical. Alternatively, activation of a C-H bond can be achieved
by deprotonation of a nitrogen radical-cation, prepared by oxidation of an amine. Although such
deprotonation usually proceeds at the α-position where it can provide a stabilized C-centered α-
8
radical. Activation of a remote C-H bond becomes possible in conjugated radical-cations, even
,
9 10
when the activating NH2 moiety and the activated CH2 group are five bonds away.
In N-assisted C-H activation reactions (Scheme 1c), nitrogen does not directly participate
in the C-H activation step but can trap the C-centered reactive species once they are formed. An
external reagent, such as an appropriately chosen transition metal, is used for C-H activation. An
appealing strategy is to use nitrogen as a directing group, guiding the transition metal to the
,
11 12
targeted C-H bond and facilitating C-N bond formation afterwards. A new C-N bond can be
13
formed via reductive elimination at the transition metal.

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The fourth, conceptually different approach is to activate both the N-H and the C-H bonds
by independently converting them into reactive intermediates (Scheme 1d). By decoupling the two
steps, this approach potentially becomes the most flexible, but the conditions for selective and
independent N-H/C-H activation are not always easy to achieve. The possible situations here
involve: i) formation of N- and C- centered radicals, ii) formation of a radical and an anion
(usually, C-radical and N-anion), and iii) formation of an N-anion and a C-anion. The latter two
paths must be terminated by 1e and 2e oxidations, respectively, to yield the “normal” two-
centered/two-electron (2c,2e) C-N bond.
Productive combination of two reactive intermediates is efficient only when one of these
14
intermediates is relatively persistent. From this perspective, formation of stable N-anions
(approaches ii and iii) is attractive (Scheme 1d).
Sarpong and coworkers illustrated that a C, N dianion, formed in the presence of strong
15
base can form a C-N bond upon two-electron oxidation with I2 (iii). This approach, which can be
conceptually considered “reductive elimination without a metal”, allows C-N bond formation
without the need for preoxidized coupling partners via the formal loss of H2. Formation of five-,
six-, and seven-membered rings was found to proceed even in conformationally unbiased
substrates.
In our work, we explore the advantage of a three-electron approach (ii).10 Because the three
electron radical/anion interactions are potentially stabilizing, they can lead to favorable C/N
precoordination which leads to instantaneous C-N bond formation upon oxidation. In contrast, the
4e anion/anion interactions are repulsive, and hence, the C,N-dianion may adopt a conformation
that is not conducive to bond formation.
We have recently illustrated the value of the radical-anionic approach in an intramolecular
C(sp3)-H amination.10 This method relies on a sequence of N-H deprotonations and selective H-
atom transfers (HAT) from C-H bonds to generate a radical-anion intermediate (Scheme 3a). This
intermediate forms a thermodynamically favored two-center/three-electron (2c, 3e) “half bond”,
where one of the electrons is forced to occupy a high energy antibonding orbital (“electron
16
upconversion”, Scheme 2). The newly formed radical-anion can then be readily oxidized into a
“normal” 2c,2e bond by a mild oxidant, such as molecular oxygen. By generating a radical anion
in situ, we effectively take a weak reductant and evolve it into a more potent reductant. Such
16
“electron upconversion” allows for the effective use of a mild oxidant such as molecular oxygen.
By avoiding stronger oxidants, we prevented undesired product oxidation in our cascade reactions
that yield expanded N-doped polyaromatic systems.
2-center, 3-electron "half-bond"
upconverted
electron
R
R
2c,3e
R
N
*C-N
3. -e
NH
H
N
1. -H+
2. -H
R'
R'
R'
n
n
n
C
Radical-anion
N
C-N
Scheme 2. Steps in the proposed C-H/N-H activation and the mechanism of electron upconversion.
In this manuscript, we push the limits of this approach by using amides, a drastically less
nucleophilic nitrogen source (Scheme 3b). We will show how this structural modification diverts
17
the cascade towards incorporation of a late C-O bond forming step and opens a synthetic route to
18
3-hydroxyisoindolinones. Recently, Xiao et al. independently developed a mechanistically
different version of 3-hydroxyisoindolinone synthesis from secondary amides (Scheme 3c). An
interesting feature of Xiao’s work is that the same catalyst is used in two different ways to promote

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the two cascade stages. In the first ground state stage, eosin Y acts as a radical redox catalyst which
is oxidized to a radical-cation by reaction with a stoichiometric amount of an external oxidant
(SelectFluor). Without light, the reaction stops at the first step (C-N bond formation). The second
step (the formation of the C-O bond) is achieved by using eosin Y as a photocatalyst in the presence
of oxygen. The overall transformation had a good scope for the aromatic substituents but was only
reported for N-monosubstituted amides (N-methoxy, N-aryl, N-alkyl).
a) Previous work:
6-membered aromatic heterocycles
NH2
NH
Ar
N
NH
Ar
t-BuOK
DMF, O2
Ar
Ar
2c,3e
H = -11.0
G = -8.9
C=N bond formation
starts with anilines
b) Current work:
Less nucleophilic amide
5-membered non-aromatic heterocycles
O
O
NH
O
O
NH2
NH
NH
Ar
t-BuOK
DMF, O2
Ar
Ar
Ar
OH
2c,3e
Isoindolinone
H = -5.0
C-N/C-O bond formation
G = -3.6
starts with benzamides
c) Xiao and coworkers, Chem. Eur. J,
2018
, 16895:
O
O
NHR
O
Select-
Fluor
O
NHR
O2, hv
eosin Y
NR
NR
Ar
OH
Ar
Ar
Ar
eosin Y
excited state: photoredox
ground state: radical redox
Scheme 3. Expanding previous work to utilize less nucleophilic amides, as well as the formation
of non-aromatic five membered heterocycles, and C-N/C-O bond formation. All energies are in
kcal/mol.
It is clear that our approach and the approach of Xiao are very different mechanistically
(anionic vs. cationic) and, hence, should provide complementary reactivity patterns for future
synthetic designs. Our work presents an alternative route that proceeds in the ground state and does
not require additional oxidants besides molecular oxygen. In addition, it avoids formation of a
cationic species, a feature which can be beneficial to substrates that are sensitive to oxidative
conditions. Furthermore, as we will show below, our conditions are applicable for primary amides.
The successful use of amides as nucleophilic partners in a base-promoted oxidative C(sp3)-
H amidation yields isoindolinones under transition-metal free conditions. Because the presence of
metal impurities should be minimized in pharmaceutics,19 a transition-metal free alternative is an
attractive choice for the synthesis of isoindolinones related to the antihypertensive agent
Chlortalidone,20 inhibitors of MDM2-p53 interactions,21 and selected natural products.22
Furthermore, a variety of post-synthetic modifications of the core hydroxyisoindoline structure are
possible (Scheme S5 in Supporting Information) including transformations mediated by chiral
-
23 24
25
phosphoric acids and by transition metal catalysts.

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Results and discussion
We began by subjecting amide 1a (0.01 mmol) to the previously optimized conditions,
(i.e., DMF, 4 Å-molecular sieves (MS), O2 atmosphere, and 3 equivalents of t-BuOK at room
temperature) for 4 hours.9 To our delight, 2a was formed in an excellent yield, 87% (Table 1, entry
1). When DMSO and THF were used in place of DMF, the yields of 2a were lower (36% and 47%,
entries 2 and 5) along with the formation of undesired side products. Furthermore, when DMF was
replaced with acetonitrile, toluene, or DCM, 2a was not observed (entry 3-4, 6). These results
prompted us to perform the rest of our studies in DMF.
We then tested five additional bases (entry 7-11). The tert-butoxide salts produced 2a in
the highest yields. Interestingly, the size of the counterion impacts the conversion of 1a into 2a.
While the difference was small for the sodium and potassium tert-butoxide salts (87% vs 79%
respectively), a noticeable difference in yield was observed between the K, Na, and Li hydroxides
(55%, 31%, <1% respectively). Fewer than 3 equivalents of base (entry 12-13) were insufficient
for the full consumption of the starting material. More than 3 equivalents of base (entry 14-15)
were found to be unnecessary as there was no improvement in yield.
We then varied the reaction time (entry 16-18) and observed full consumption of starting
material within one hour. Finally, when the reaction vial was charged with air instead of oxygen,
2a was produced in 75% yield (entry 19). However, the rate of the reaction was slower and not all
of 1a was consumed.
Table 1. Optimization Table
O
O
NH2
NH
Conditions
OH
2a
1a
Entry
Solvent
DMF
DMSO
MeCN
Toluene
THF
DCM
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Base
Eq Atm
Time
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
3 h
2 h
1 h
1 h
Yield %
87 %
36 %
< 1%
< 1%
47 %
< 1%
79 %
55 %
31 %
< 1%
< 1%
55 %
68 %
85 %
88 %
85 %
82 %
84 %
75 %
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuONa
KOH
3
3
3
3
3
3
3
3
3
3
3
1
2
4
5
3
3
3
3
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
Air
NaOH
LiOH
K2CO3
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
Reaction conditions: All reactions performed in a 20 mL scintillation via, 1a (0.025M), 2.5 mL of solvent,
4 Å-molecular sieves (MS), and room temperature (22 ˚C). All yields determined by 1H NMR using internal
standard.

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We then explored the scope of substituents that are compatible with the reaction conditions.
Variation in the pendant aryl ring revealed that heterocyclic substrates, as well as the substrates
with ortho, meta, and para electron withdrawing groups produced the target products in good to
excellent yields. On the other hand, electron donating groups were only tolerated in the meta
position. Lower conversions to the corresponding isoindolinone were observed (39% and 48%
respectively) for the reactions of 4-methoxy and 4-methyl substrates. However, substrate 2c with
a para tert-butyl group underwent the desired transformation in high yield (84%).
Table 2. Amide scope for C(sp3)-H amidation and hydroxylation.
R
NH
O
R
O
t-BuOK, DMF, O2
4Å-MS, 4 h, rt
N
Ar
OH
Ar
1
2
O
O
O
O
O
O
NH
NH
OH
NH
OH
NH
OH
O
O
OH
2c,
2a,
2b,
84%
87%
65%
2d,
39%
O
O
Br
Br
NH
NH
OH
NH
S
NH
OH
OH
OH
O
2f,
70%
2e,
2g,
85%
81%
2h,
75%
CF3
CF3
O
O
O
O
O
NH
NH
NH
NH
F
OH
OH
90%
OH
OH
O
F3C
2i,
O
2j,
83%
2l,
68%
2k,
O
Cl
89%
O
O
F3C
NH
NH
O
Br
Br
NH
CF3
OH
OH
O
OH
2m,
66%
2o,
94 %
2n,
78%
F3C
O
R
O
O
Br
NH
N
NH
Ar
OH
OH
OH
R=
CH3
2q,
48%
2p,
86%
2r,
30%
2s,
OCH3
0%
Reaction conditions: benzamide (0.025M), t-BuOK (3 eq.), 4Å MS, DMF, O2 balloon and the reactions
were allowed to stir for 4 hours at rt. Unless stated otherwise, the yield is of the isolated product.
Substitution in the amide ring had a smaller effect – the reaction tolerated both electron
donating and withdrawing groups, ortho, meta, and para to the amide. The overall transformation
remained unaffected with halogens (i.e., Br, Cl, and F) on either the amide ring or pendant aryl
ring, allowing for the introduction of a useful synthetic handle for future modifications.
We also investigated the possibility of introducing additional substituents at the amide
nitrogen. The N-methyl amide 2r underwent the desired transformation sluggishly (30% yield,
74% based on reclaimed starting material) under the standard conditions. On the other hand, a N-
methoxy amide remained unreactive under our standard conditions (vide infra).

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Mechanistic studies
A series of studies designed to gain insight into the reaction mechanisms were performed
and are listed below (Scheme 4). First, the C-H bond strength is critical for the reaction success.
A BDE ≤ 85 kcal/mol was needed and simple benzylic or alkylbenzylic C-H bonds remained
unreactive under our conditions (eq. 1).
(1) Role of C-H Bond Strength
O
H2N
O
NH
H
t-BuOK, DMF
O2, rt, 4h
4Å mol. sieves
HO
2a,
87%
BDE = 85 kcal/mol
1a
Ph
Ph
H
O
H2N
O
H2N
O
H
NH
H
t-BuOK, DMF
O2, rt, 4h
OH
4Å mol. sieves
Not observed
1w
, 93%
1w
CH3
CH3
H
BDE = 88 kcal/mol
O
H2N
O
H2N
O
H
H
t-BuOK, DMF
O2, rt, 4h
NH
4Å mol. sieves
OH
1x,
97%
Not observed
1x
H
H
H
BDE = 92 kcal/mol
(2) Role of Oxygen
O
O
NH
NH2
t-BuOK, DMF
Ar
1a,
82%
, rt, 4h
4Å mol. sieves
HO
1a
2a,
15%
O
(3) Singlet Oxygen
O
NH2
NH
t-BuOK, DMF
CF3
Dark
4Å mol. sieves
O2,
, rt, 4h
HO
CF3
1i
2i
, 79%
Scheme 4: Mechanistic tests for the C-H bond strength and for the participation of oxygen. All
energies are reported in kcal/mol.
When the reaction is performed under an inert atmosphere (Ar), the consumption of 1a is
greatly diminished (eq. 2), confirming the importance of O2 as the oxidant.
We have also considered the possible involvement of singlet oxygen. Singlet oxygen has
been shown to be synthetically useful in the oxidation of heteroatoms, cyclization reactions, and
26
the synthesis of hydroperoxides. However, 1i was fully consumed even in the absence of light,
producing 2i in 79% yield (eq. 3). Reactivity in the dark indicates that singlet oxygen is not
involved in the main path of this reaction.
Under these oxidative conditions, one could suggest that the reaction occurs via an
27
oxidation of the CH2 moiety to a carbonyl intermediate. This intermediate could then close the
cycle via nucleophilic attack of the amide onto the carbonyl under basic conditions. We have

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eliminated benzylic C-H oxidation in our early work by using N-Me substituted anilines, which
yield products that clearly could not originate from the ketone.10 Obtaining such direct evidence
in the present case is problematic because, unlike the aniline cascade, the present amide cascade
is terminated by C-O bond formation that renders the C/N radical-anion coupling and the carbonyl
pathway products identical.
Cascade Interruption
a) Amide Cascade Interruption
O
H = -7.2
G = -5.1
O
O
t-BuOK, DMF
NHOCH3
NHOCH3
O
O2, rt, 4h
4Å mol. sieves
NOCH3
OH
Ph
Not observed
Ph
Ph
N.R.
1s
b) Aniline Cascade Interruption
MeHN
t-BuOK, DMF
NHMe
O2, rt, 4h
4Å mol. sieves
N
N
OH
Ph
2017
Ph
57%
Ph
Ph
JACS,
, 16210
8%
6%
MeHN
or
N
O
HO Ph
Ph
Not observed
c) Isoindolinone Conversion
O
O
NH
NH
t-BuOK, DMF
O2, rt, 4h
H
HO
4Å mol. sieves
83%
Scheme 5. Interruption of the amide and aniline cascades
To test for the possible formation of a carbonyl intermediate, we wanted to use an
unreactive amide in order to avoid the cyclization, while still allowing for the benzylic carbon to
remain reactive enough to be oxidized into a ketone. However, no reaction was observed when
amide 1s was exposed to the standard conditions. Calculations show that if a ketone intermediate
were formed, its cyclization would be thermodynamically favorable (ΔG = -5.1 kcal/mol).
Assuming that this substitution at nitrogen does not directly change reactivity at the remote
benzylic position, the lack of benzylic oxidation suggests that the carbonyl intermediate is not
10
formed under our conditions (Scheme 5). We have also found that an isoindolinone is readily
converted into the respective 3-hydroxyisolindolinone under these conditions, a process that is
unlikely to proceed through a carbonyl intermediate.
Computational Data
Calculations were carried using the meta-hybrid (U)M06-2X functional28 and the 6-
31+G(d,p) basis set for all atoms, with an ultrafine integration grid (99,590 points). A broken-spin
approach was applied when necessary. The implicit SMD29 solvation model was used to simulate
the effects of N,N-dimethyl-formamide (DMF) throughout the calculated structures. Grimme’s D3
version (zero damping) for empirical dispersion30 was also included. Unless otherwise noted, all
results presented are at the (SMD=DMF)/(U)M06-2X(D3)/6-31+G(d,p)/int=ufine level of theory.
Frequency calculations were carried out for all structures to confirm them as either a minimum or

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a TS. All calculations were performed with the Gaussian 09 software package.31 Structural
drawings and orbital plots were produced with CYLView 1.0.132 and Chemcraft 1.8.33
Radical Cascade Mechanism
Guided by these experimental results, we turned to computations for identifying the key
intermediates of this transformation. A full thermodynamic landscape for the proposed reaction
cascade is shown in Scheme 6. Each step in this cascade is thermodynamically favorable. In
subsequent individual sections, we will discuss the individual steps along with their activation
barriers and the respective experimental evidence.
O
O
NH2
O
H
NH
O
NH
tBuO
DMF
O2
NH
H
SET
Ph
Ph
Ph
Ph
tBuO
DMF
O2
H = -5.0
G = -3.6
H = -29.6
G = -29.1
H = -16.1
G = -17.2
H = -10.7
G = -10.0
A1
A2
O
NH
H
A3
Ph
O
O
O
O
HOO
DMF
NH
tBuO
N
N
N
Ph
OH
Ph
Ph
Ph
OOH
DMF
H
tBuO
H
H = -37.6
G = -24.4
H = -31.1
G = -30.4
H = -17.3
G = -17.7
A6
A5
A4
Scheme 6. Proposed mechanism and calculated reaction thermodynamics for the individual steps
in the N-H/C-H amidation. All energies are in kcal/mol.
Generation of DMF radical
We suggest that the chemical species responsible for the formation of the bis-benzylic C-
centered radical is DMF radical (C(O)N(CH3)2). The formation of this radical under these
conditions is well-documented. Yan et al. used them in a variety of interesting transformations that
34
combined C-H activation and C-C bond formation. However, the mechanism by which the DMF
radical is generated is not fully established. A commonly suggested path that involves oxidation
of DMF anion by DMF is highly thermodynamically unfavorable (ΔG = +54.0 kcal/mol, Scheme
7).10
While we were unable to find the pKa of t-BuOH in DMF, literature reports35 the pKa of
1-butanol in DMF to be 33.3. It is reasonable to estimate the pKa of t-BuOH in DMF to be ca. 34-
35. The pKa of DMF in DMF (38),35 makes it approximately 3-4 pKa units less acidic than t-
BuOH. Although it makes the initial deprotonation of H-C(O)NMe2 uphill, a small amount of
DMF anion is still formed at equilibrium. Calculations show that although this deprotonation is
endergonic by 11.2 kcal/mol, the activation barrier for the deprotonation of DMF is relatively low
(12.6 kcal/mol, Scheme 7), and equilibrium should be reached quickly.
1
13
Indeed, Drapeau and co-workers noted a formamide proton shift, via H and C NMR,
when t-BuOK was added to wet DMF-d7.36 Their computational work additionally highlighted two
interesting points regarding the impact of counter ions. First, the cation stabilizes the DMF anion,

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assisting in deprotonation. Second, a cation of a certain size (e.g., Li) can stabilize the DMF anion
and increase the barrier for its oxidation to DMF radical.36 Our experimental results also suggest
that reaction is slow in the presence of Na and, to a greater extent, Li counterions (Table 1, Entry
1, 7-10).
Our calculations show that the oxidation of DMF anion by oxygen is slightly exergonic
(with the inclusion of K+, Scheme 7). This makes the combined deprotonation and oxidation of
DMF endergonic by ~10 kcal/mol, which would allow only small quantities of DMF radical to be
present at a given time. If the propagation step of the cascade is fast, then the initial penalty of
forming the DMF radical is a small price to pay when all sequential steps in the cascade reactions
are favorable and efficient. Overall, the generation of DMF radical imposes a ~10 kcal/mol penalty
needed to initiate an otherwise exergonic sequence. Interestingly, calculations suggest that the
activation barrier for proton abstraction from DMF is almost entirely entropic (enthalpy of
activation is only 2.2 kcal/mol). The TS Gibbs energy (12.6 kcal/mol) is only 1.4 kcal/mol higher
than the Gibbs energy of the product, suggesting that the deprotonation should be rapidly
reversible.
DMF-anion formation
tBuO H
O
O
O
N
N
H
H‡ = +2.2
G‡ = +12.6
H = +12.0
G = +11.2
DMF-radical formation vis Single Electron Transfer (SET)
O
Unfavorable SET
N
H
O
O
H = +53.7
G = +54.0
N
DMF
O
N
K+O2
K+
H = +0.3
G = -0.4
N
O2
Favorable SET
Scheme 7. Formation of DMF radical. All energies reported in kcal/mol.
Deprotonation/ H-Atom Transfer
The unusual nature of our intramolecular C-H amination stems from the generation of a
radical and an anion in situ. To achieve this, two criteria must be met. First, an acidic proton is
needed for a deprotonation that produces a persistent N-anion. Second, the substrates should have
a sufficiently weak C-H bond that undergoes HAT with the formation of a C-radical.
The cascade mechanism begins with the exergonic deprotonation of the mildly acidic
benzamide by tert-butoxide (ΔG = -17.2 kcal/mol, Scheme 6, A1). Once a persistent nitrogen anion
is quickly generated, the slowly produced DMF radical (see the SI for discussion of DMF radical
formation) can engage the sufficiently weak bis-benzylic C-H bond (BDE = 85 kcal/mol) in a HAT
step (ΔG = -10.0 kcal/mol, Scheme 6, A2). This step yields the initial acyclic radical-anion
intermediate. While the HAT ΔG‡ and ΔG are slightly lower for the neutral amide than the
deprotonated amide (ΔG‡ = 17.6 vs 19.1, ΔG = -10.9 vs -10.0 kcal/mol), the high concentration of

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base and the highly favorable thermodynamics for the deprotonation step should result in the
majority of HAT occurring after deprotonation (Scheme 8).
37
While tert-butoxide can deprotonate the benzylic C-H bond of diphenylmethane (pKa =
32.2 in DMSO), the benzamide’s N-H bond is far more acidic (pKa = 23.3 in DMSO). The nine
orders of magnitude difference in acidity leaves no doubt that the N-H bond should be
deprotonated preferentially. In our previous work, we explored the possibility of t-BuOK
deprotonating the benzylic C-H bond and found that ΔG for this process is also favorable (-3
kcal/mol) suggesting that C-H deprotonation is feasible as well. However, once the initial nitrogen
anion is formed, the second deprotonation would form a dianion. Although the possibility of a
dianionic process cannot be completely eliminated at the present stage, we favor the radical HAT
path for the C-H activation because of the coulombic penalty associated with the formation of
multiply charged species.
The transition state for the initial HAT is interesting. At the stage where the benzylic C-H
bond begins to break to form the C-centered radical, the benzylic C-H is misaligned with the
aromatic π-system. Hence, the forming radical finds itself in alignment only with the pendant
aromatic ring. One might expect that as this radical would prefer to be in a close alignment with
both aromatic rings to take advantage of stereoelectronic stabilization. This finding explains why
the pendant aryl group is necessary – although the CH2 groups in substrates 1w and 1x are formally
“benzylic” (Scheme 4), the core aryl group does not directly contribute to their C-H activation.
Under these intramolecular stereoelectronic constraints, their relatively low BDE values are
somewhat misleading.
Furthermore, the amide is rotated out of conjugation the aromatic π-system in a nearly
orthogonal geometry.38 The twisted geometry may provide an explanation to why amide
deprotonation does not activate the ortho-benzylic C-H bond towards H-abstraction. Steric
hindrance between the two relatively large ortho-substituents contributes to this geometric
preference. On the other hand, the amide -system may engage in through-space interactions with
the back lobe of the anti-bonding orbital of the breaking C-H bond. In this scenario, the amide may
be assisting in the C-H activation process by helping to stabilize the newly forming radical via a
through-space interaction.
O
NH2
O
NH2
H‡ = 6.7
G‡ = 17.6
Ph
H = -10.8
G = -10.9
Ph
O
NH
O
NH
H‡ = 7.4
G‡ = 19.1
H = -10.7
G = -10.0
Ph
Ph
Scheme 8. Reaction energy profiles and twisted transition states for C-H activation in neutral and
deprotonated substrates. All energies are in kcal/mol.

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Radical-Anionic Cyclization and C-N Bond Formation
In the key step of the overall cascade, the N-anion and the C-centered radical in A2 react
to form a 2c,3e “half” bond, also making a cyclic radical-anion in the process. Interestingly, this
process occurs without the apparent loss of amide resonance since it is the 2nd “in-plane” lone pair
of nitrogen that is involved in the N-C coupling. On the other hand, the radical center rotates out
of conjugation with the central aryl ring as well. The latter stereolectronic penalty is likely to
contribute to a relatively high, 17.2 kcal/mol, Gibbs barrier and the low thermodynamic driving
force, ΔG = -3.6 kcal/mol, for this seemingly trivial step (Scheme 9). These values are significantly
less favorable than the analogous values for the C-N bond formation from deprotonated anilines
(8.5 and -27.8 kcal/mol, respectively) reported in our earlier work. This dramatic difference
highlights the importance of N-partner basicity/donor ability for this process. We will discuss this
factor further in the conclusions section of this manuscript.
O
O
NH
NH
H
H‡ = 16.2
G‡ = 17.2
Ph
Ph
H = -5.0
G = -3.6
O
O
N
N
H‡ = 1.6
G‡ = 12.4
H = -31.1
G = -30.4
Ph
Ph
H
Scheme 9. Transition states for the C-N bond formation and second HAT.
Additionally, the three non-bonding electrons of the radical and anion reacting partners
have to find “a new home” in this step. Two of these electrons are accommodated in the newly
formed σ orbital of the C-N bond. The third electron avoids its apparent destiny of ending up at
the high energy σ*C-N orbital by “hopping” to a lower energy π* orbital of the aromatic ring
39
(Scheme 10). This state crossing, not unusual for radical-anionic reactions, stabilizes the product
by creating a delocalized π-type radical-anion.
Energy
*
(nC-nN)
*
*
mix
avoided
crossing
nC
nN


Reactant
Product

(nN+nC)
Reaction coordinate
Scheme 10. State crossing avoids populating the high energy σ*C-N orbital.

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Nevertheless, the reacting system evolved from a mild reductant (electron in a non-bonding
orbital) into a more potent reductant (electron is an antibonding orbital). The high reducing power
of the cyclic product allows its reaction with a mild oxidant, such as molecular oxygen. This
reaction (i.e., single electron transfer) removes the antibonding electron, converting a 2c,3e-bond
into a normal 2c,2e C-N bond. This step simultaneously forms superoxide in a thermodynamically
favorable way with ΔG = -29.1 kcal/mol (Scheme 6, A3).
After the benzamide is cyclized into an isoindolinone, the cyclic intermediate is
deprotonated to give anion A4 (Scheme 6, ΔG = -17.7 kcal/mol). The -C-H bond in this anion is
sufficiently weakened to form a stabilized radical-anion A5 ( ΔG = -30.4 kcal/mol after a HAT to
DMF radical).
Diverting from C=N to C-O bond formation
From the stabilized radical intermediate A5, one can envision two possible mechanisms
for the formation of the C-O bond (Scheme 11). The first is similar to what we reported in our
10
previous work , in which the intermediate is oxidized a second time by molecular oxygen to form
the C=N moiety of an imine intermediate. This intermediate may then be intercepted by a suitable
nucleophile generated in situ, such as superoxide or hydroxide. In particular, superoxide is known
40
to undergo disproportionation to give O2 and hydroxide under aqueous conditions. It is possible
that a similar process to generate hydroxide could occur under the conditions of our C-H amination
reaction, whereas t-BuOH would serve as the proton source instead of H2O. The second possibility,
is that a radical coupling partner such as superoxide or hydroperoxyl radical couples to the C-
centered radical making a hydroperoxide intermediate.
Nucleophilic Addition to
Michael Acceptor
O
OH
N
O2
Ar
O2
O
O
N
NH
Ar
Ar
OH
HOO-
O
NH
Ar
OOH
O2 /HOO
Radical Coupling with
Superoxide/Hydroperoxide
Scheme 11. Possible routes to product from stabilized radical-anion intermediate.
We initially tested to see if the addition of an external nucleophile could be used to trap the
plausible imine intermediate. The addition of either sodium or potassium methoxide hinders the
reaction, with no methoxy product observed in these experiments (Scheme 12).

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Imine Trapping
O
O
t-BuOK,
NH
NH2
CF3
MeOM (1.5eq)
HO
DMF, O2, 4h, rt
4Å mol. sieves
CF3
2i
1i
M
1i
2i
3i
0%
Na
K
67% 28%
45% 49% 0%
O
O
NH
CF3
N
CF3
MeO
3i
Not observed
Scheme 12. Attempting to trap the hypothetical imine intermediate.
Our calculations show the oxidation of radical-anion A5 by O2 is thermodynamically uphill
(ΔG = +10.0 kcal/mol, Scheme 13). While this is not a prohibitive price to pay, it is worth noting
that this oxidation step is 39.1 kcal/mol more endergonic than the initial oxidation step. This
substantial increase stems from several factors, including lack of aromatic stabilization in the N-
heterocyclic part of the product as well as the additional radical and charge stabilization in the
reactant, not only through the bis-phenyl groups, but additionally through the nitrogen and
carbonyl.
This finding contrasts our previous work with anilines where the second oxidation step was
favorable (ΔG = -16.6 kcal/mol) due to the formation of an aromatic system.10 In the present case,
the situation is different, and this differences manifests itself in a divergent reaction pathway
(formation of a C-O bond instead of C=N moiety). To understand this step better, we explored the
possibility of radical coupling being responsible for the final C-O formation.
Second Oxidation in Benzamide Cascade
O
O
O2
N
N
SET
O2
Ph
Ph
H = +9.8
G = +10.0
Second Oxidation in Aniline Cascade
O2
N
SET
O2
N
Ph
Ph
H = -17.3
G = -16.6
Scheme 13. Contrasting thermodynamics (kcal/mol) for the C=N forming oxidations in the amide
and aniline cascades.
A series of studies designed to gain insight into the possible radical coupling of A5 were
performed and are listed below (Scheme 14).

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We then employed two common radical trapping agents, attempting to either trap a radical
intermediate or to inhibit the reaction. TEMPO, caused a slight decrease in isolated yield (87% vs
76%) but no TEMPO trapped product or recovered starting material was observed (eq. 1). This
finding is consistent with the radical mechanism if intramolecular radical trapping (i.e., the
cyclization) is faster than the intermolecular trapping, or if TEMPO can play an alternative role by
promoting the C-H activation step. More detailed discussion on the possible role of TEMPO will
be given in a subsequent section.
We also tested the effect of a common radical and peroxide trapping agent, 3,5-di-tert-4-
butylhydroxytoluene (BHT), at the standard reaction conditions (eq. 2). The phenol moiety of BHT
is often used to halt the autoxidation of organic molecules with oxygen, analogous to that of
vitamin E. BHT can deactivate two (usually peroxy) radicals – the first one by a hydrogen atom
41
transfer and the second one by reaction at the cycle.
We found that the reaction is partially inhibited (2i was isolated in a 47% yield, starting
material recovered in 27% isolated yield. Furthermore, BHT-OH was additionally isolated in 25%
yield. Low yields are a result of isolation difficulties. Formation of this product further suggests
that a radical pathway is involved.
(1) TEMPO Trap
O
O
NH
t-BuOK,
TEMPO (1.2 eq)
NH2
DMF, O2, 4h, rt
4Å mol. sieves
HO
2a,
1a
76%
(2) Inhibiting Radical Reaction
O
O
O
t-BuOK,
NH2
BHT (1.5 eq)
NH
CF3
1i
, 23%
CF3
DMF, O2, 4h, rt
4Å mol. sieves
HO
1i
HO
BHT-OH,
2i
25%
, 47%
Scheme 14. Radical coupling mechanistic studies.
Addition of Superoxide/Hydroperoxyl Radical to the Radical-Anion A5
It is unlikely that the OH group in the final product is a result of radical coupling with
hydroxide radical, as it is highly reactive and will likely abstract a hydrogen atom from the solvent
42
or t-BuOH before reaching the reactant. This consideration led us to explore the possibility of
43
radical coupling with superoxide or with its conjugate acid, the hydroperoxyl radical (HOO•).
Our calculations show this to be a favorable path for forming the C-O bond (Scheme 15).
In particular, radical addition to intermediate A5 via HOO• was found to be highly exergonic, ΔG
= -23.6 kcal/mol. Addition of superoxide (the precursor of HOO•) to A5 was favorable, ΔG = -
11.0 kcal/mol. On the other hand, the addition of molecular oxygen was found to be endergonic,
ΔG = +7.5 kcal/mol. It is worth noting that all three of these proposed pathways are
thermodynamically more favorable than an oxidation of A5 by O2 (ΔG = +10.0 kcal/mol).

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K+
O
O
NH
O
N
Ph
OH
Ph
O
OH
H = –37.2
G = –23.6
H = -45.5
G = -32.5
OOH
OOH
K+
K+
O
O
O
O
tBuO
H
3O2
N
NH
O
3O2
NH
N
Ph
O
Ph
Ph
Ph
H = -9.6
G = +1.4
tBuO K+
H = –23.6
G = –23.5
H = –4.2
G = +7.5
O
O
H = -30.4
G = -19.1
H = –23.2
G = –11.0
O2
O2
O
K+
O
NH
N
Ph
O
Ph
O
O
O
Scheme 15. Computational thermodynamic data for the addition of molecular oxygen, superoxide,
and hydroperoxyl radical to the stabilized radical intermediate. Energies in kcal/mol.
Superoxide has been shown to act as a Brønsted base in aprotic media and deprotonate
44
weak acids such as 1-butanol in DMF (pKa = 33.3 in DMF) . It is therefore possible, that
superoxide may deprotonate t-BuOH (estimated pKa ≈ 34-35 in DMF) generated in situ, forming
HOO•. Hence, both HOO• and superoxide may couple with A5.
The evidence that we have presented up to this point suggests that formation of a
45
hydroperoxide intermediate should be considered (Scheme 6, A6). To explore this possibility, we
prepared this intermediate and tested its properties as described in the following section.
Hydroperoxide Intermediate
The hydroxy group of 2p was converted into hydroperoxy group of 3p (Scheme 16, Eq 1)
by acid-catalyzed reaction with H2O2. The reference spectra contained the characteristic broad
46
downshifted peak of a hydroperoxide that readily underwent deuterium exchange. After
subjecting 3p to our standard conditions, the formation of 2p was observed by TLC within five
minutes. In half an hour, 2p was formed in 88% yield (Scheme 16, Eq 2). The lack of 3p reactivity
in the absence of t-BuOK (Scheme 16, Eq 2) indicates the important role of t-BuOK in the
reduction of the hydroperoxide intermediate into the final product.
Because of the rapid consumption of hydroperoxide in the presence of base, we anticipate
its existence in situ to be fleeting. The existence of transient hydroperoxide intermediates, that
convert to OH-bearing final products, has previously been reported in O2-mediated oxidations of
3
1
47
C(sp )-H bonds. Indeed, in several experiments, H NMR of the reaction mixtures showed a
broad downshifted singlet, potentially indicative of the hydroperoxide, (See Supporting
Information for additional details). Although this intermediate was too unstable to persist and to
be reliably detected under the reaction conditions, these findings suggest that a hydroperoxide
intermediate (Scheme 6, A6) is formed transiently and reduced by t-BuOK/t-BuOH into the final
isoindolinone product. The hydroperoxide may also be involved in the radical chain propagation
by serving as a possible source of O-centered radicals that can assist in the C-H activation step.

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(1) Preparing Hydroperoxide
O
O
NH
NH
10M H2SO4
H2O2 30% 10 eq
Ether, 4h, rt
OH
Br
O
HO
Br
2p
3p
, 68%
(2) Peroxide Stability
O
O
O
O2, MS,
DMF, rt, 30 min
NH
NH
NH
t-BuOK, 3eq
OH
Br
O
HO
Br
HO
Br
O2, MS,
DMF, 30min, rt
N.R.
Not Observed
2p
, 88%
3p
Scheme 16. Preparation and instability of the suggested hydroperoxide intermediate.
Secondary Amides
We were intrigued by the sluggish reactivity of the secondary amides. Since we isolate
unreacted starting material, the reaction is interrupted in the initial stages. Yet our calculations find
that each of the three initiation steps, i.e., the deprotonation (ΔG = -16.0), HAT (ΔG = -9.3), and
the radical-anion cyclization (ΔG = -5.9), for 1r are thermodynamically favorable (Scheme 17).
secondary amides
CH3
NH
CH3
N
CH3
N
O
O
O
H
tBuO
CH3
DMF
O
N
Ph
Ph
H = -7.1
G = -5.9
Ph
tBuO
Ph
DMF
H = -9.8
G = -9.3
H
H = -15.4
G = -16.0
Scheme 17. Calculations for the deprotonation, HAT, and radical-anion cyclization of 1r. All energies are
reported in kcal/mol.
We used computed activation barriers to understand why the secondary amides are
unreactive (See Supporting Information). Our analysis suggests that the barrier for the H-
abstraction is about 1.2 kcal/mol higher for the secondary amides than it is for the primary amides.
This difference should lead to a ca. 10-fold rate decrease for this step, providing a possible
explanation for the low reactivity of the secondary amide substrates under the reaction conditions.
Conversely, the calculated barrier for the C-N bond formation is lower for the secondary
amides, indicating that this step is unlikely to be the cascade bottleneck (Scheme 18). Aimed by
these observation, we have concentrated our attention on the H-transfer step.
secondary amides
CH3
O
CH3
O
N
N
H‡ = 12.5 (16.2)
G‡ = 13.4 (17.2)
H = -7.1 (-5.0)
G = -5.9 (-3.6)
Ph
Ph
H

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Scheme 18. Computed activation and reaction enthalpies and Gibbs energies for the cyclization of
secondary amide 1r. Numbers in parentheses are for primary amide 1a. All numbers reported in
kcal/mol.
Indeed, focus on C-H activation allowed us to solve the problem of secondary amides as
described below. Recalling that TEMPO had no detrimental effect on our radical reaction, we
considered the possibility of TEMPO assisting in C-H activation.
Indeed, literature suggests that TEMPO can be a useful additive to the oxidation of benzylic
C(sp3)-H bonds. For example, TEMPO can be oxidized into an oxoammonium salt (TEMPO+) in
the presence of hydroperoxyl radical, peroxyl radicals, or a secondary oxidant (e.g. NaOCl) as
48
shown in Scheme 19a. The latter has been shown to act as an oxidant that may facilitate the
49
forward progression of redox reactions. In particular, TEMPO+, generated in situ, from TEMPO
3
50
was used as a cocatalyst in the aerobic oxidation of benzylic C(sp )-H into carbonyls. Even if the
carbonyl intermediate is formed in this case, it would, as we previously discussed in Scheme 5,
readily cyclize under basic conditions into our isoindolinone product.
51
Additionally, TEMPO+ has been suggested to facilitate benzylic hydride transfers. It is
plausible that in our case, a concerted C-N bond formation and benzylic hydride transfer to
TEMPO+ occurs generating TEMPOH and our cyclized product (Scheme 19b). Alternatively, one
can consider a hydride transfer to TEMPO+ forming a benzylic carbocation that is immediately
trapped intramolecularly via cyclization (Scheme 19c).
a) Redox activation of TEMPO
O2
HOO
HOO
"H
"
O
O
N+
OH
N
N
TEMPO+
TEMPO
TEMPOH
b) Concerted Cyclization and Hydride Transfer
O
O
OH
N
R
N
O
N
N
R
H
Ph
R
Ph
c) Hydride Transfer and Zwitterion Cyclization
O
O
O
R
N
H
N
O
N
N
R
Ph
Ph
Ph
-TEMPO
H
Scheme 19. Potential pathways for TEMPO assistance in C-H activation.
Although the exact mechanistic path for C-H activation in our system is so far unknown,
the combination of possible attractive scenarios motivated us to test the effect of TEMPO on the
reaction. To our delight, we observed the nearly full consumption when secondary amide 1r was
subjected to the optimized conditions along with TEMPO. Interestingly, no TEMPO-trapping
product was present in the reaction mixture. Instead, 2r was obtained in 74% isolated yield a
dramatic improvement over the standard conditions (30% without TEMPO vs. 74% with TEMPO,

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DOI: 10.1039/C9SC06511C
Scheme 20). Motivated by this finding, we tested reactivity of 1s in the presence of TEMPO.
Gratifyingly, the reaction affords 2s, albeit in a moderate yield of 31% (the majority of reaction
mixture is unreacted 1s). Furthermore, substrates 1t, 1u, and 1v also showed a substantial increase
in reactivity with the addition of TEMPO and the products 2t, 2u, and 2v were isolated in 87%,
54%, and 55% respectively.
O
O
R
N
t-BuOK, DMF
O2, 4Å-MS, 4h, rt
N
R
H
TEMPO
(1 eq)
Ph
HO
Ph
Substrate
Product
Yield, %
Me
30a, 74b, 86c
0a, 31b, 94c
49a, 87b, 87
2r
1r
OMe
1s
2s
2t
n-Bu
t-Bu
1t
33a, 54b, 71c
2u
2v
1u
t-Bu
25a, 55b, 87c
1v
Scheme 20. Improved C-H activation with TEMPO as an additive. Reaction conditions:
Secondary benzamide (0.025 M), t-BuOK (3 eq), DMF (2 mL), 4Å MS, O2 balloon, reactions
stirred at r.t. overnight. (a) Isolated yields for reaction performed under standard conditions. (b)
Isolated yields for reactions with the addition of TEMPO. (c) Yields based of reclaimed starting
materials with the addition TEMPO.
Nitriles
As we explored the reactivity of amides under our oxidative C-H amination conditions, we
decided to take advantage of the electrophilic nature of benzonitriles, a common precursor in our
amide synthesis. In the presence of a suitable nucleophile, anionic addition to the electrophilic
carbon on nitriles will result in formation of a nitrogen anion. This anion may then trap a carbon
radical, forming a C-N bond upon oxidation.
Indeed, nitrile 4a was found to transform into 2a in good yield (72%) in the presence of t-
BuOK and O2 in DMF (Scheme 21). Two interesting side products were isolated as well. The
rearranged product 5a is a result of C-H and C-C activation. Because product 6a was not reported
previously, we have confirmed its structure by single crystal X-ray crystallography (see Supporting
Information). Although the mechanism and scope of these transformations will have to be explored
further in the future work, this finding does illustrate that the scope of the present approach to C-
H activation extends beyond amide and aniline couplings.
O
N
O
H
t-BuOK (3 eq), O2
DMF (0.025M)
O
N
NH
Ph
OH
HN
O
O
4Å mol. sieves
rt, 1.5h
Ph
Ph
Ph
4a
2a,
5a,
6a,
11%
72%
12%
Scheme 21. C-H activation and cyclization of a nitrile substrate.

Chemical Science
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DOI: 10.1039/C9SC06511C
Conclusion
We have developed a direct non-photochemical method for converting C(sp3)-H bonds into
C-N and C-O bonds under mild conditions with the aid of base, molecular oxygen, and DMF. Each
component of the overall reaction plays a pivotal role in a coordinated sequence of deprotonation,
H-atom transfer, and electron transfer that forges the C-N bond. The base has three main functions:
1) to deprotonate the N-H bond, 2) to provide an adequate concentration of DMF carbamoyl anion
to be converted to DMF radical, and 3) to convert the hydroperoxide intermediate into the final
hydroxyl product. The DMF radical performs selective HAT at the di-benzylic C(sp3)-H to form a
C-centered radical. The C-N bond is formed initially through a 2c,3e interaction between the N-
anion and C-radical. Oxidation of the radical-anion intermediate by oxygen completes the C-N
bond forming sequence. Computational data suggest that the stabilized radical anion formed after
the second HAT could not be oxidized by molecular oxygen. Instead, the radical couples with
either superoxide or hydroperoxide species to generate a hydroperoxide intermediate that
ultimately decomposes to form the hydroxide product. Addition of TEMPO opens the door for the
use of secondary amides and improves the performance of some insufficiently reactive primary
amides. This process allows for the formation of functionalized N-heterocycles in an operationally
simple and robust fashion.
Importantly, this work dramatically expands the range of N-anions that can participate in
the three-electron approach to C-N bond formation. In general, 2c,3e-bonds are weaker than their
classic 2c,2e-counterparts. Hence, limitations for their formation are much more severe. For
example, the C-N bond formation in the radical cyclization with anilines is uphill by >20 kcal/mol.
One of the reasons why this deceivingly simple transformation is unfavorable is that it leads to the
development of cationic character at nitrogen. Trading the lone pair of nitrogen for a 2c,3e-bond
removes electron density from the N atom – an “oxidation” process that this electronegative
element generally resists. Making nitrogen more electron rich, preferably anionic, is key to
overcoming this problem.10
In the present work, we have increased N-H bond acidity by seven orders of magnitude
from our earlier studies by switching from anilines10 (pKa~30 in DMSO) to amides (pKa~23 in
DMSO). Such deactivation of the conjugated nitrogen base increases the activation barrier for C-
N bond formation from 8.510 to 17.2 kcal/mol and decreased reaction exergonicity from 2810 to 4
kcal/mol. Thus, the present use of a stabilized N-anion provided important “bracketing”
information on the thermodynamic limits of three-electron C-N bond formation. Although the
initial correlations presented in Scheme 22 are crude, considering the small number of points and
differences in the formed ring size, they should provide the first approximate guidelines for the
design of such reactions.

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DOI: 10.1039/C9SC06511C
Scheme 22. Testing for the effect of N-H component acidity on the kinetics and thermodynamics
of three-electron C-N bond formation
Furthermore, even though the C-N bond formation from deprotonated benzamides is still
efficient despite the additional kinetic and thermodynamic penalties, the next step, i.e., the C=N
moiety formation, is not favorable anymore! Here, the cyclized radical-anion is so stable that it
does not undergo one-electron oxidation under the reaction conditions. Instead, a new reactivity
pattern becomes available and the reaction sequence culminates in the formation of a C-O bond
instead of a C=N moiety.
These observations can guide the choice of N-H components in future reactions that form
2c,3e bonds. There is a broad range (pKa~20-32 in DMSO) of N-H bonds that can be deprotonated
by potassium tert-butoxide but do not form an overstabilized and unreactive conjugate base. For
such N-H partners, a variety of possible C-H bonds may be used for generating a suitable C-radical
for the three-electron C-H aminations. One can sufficiently weaken the C-H bond (BDEs in the
range of 80-90 kcal/mol) by placing heteroatoms or non-aromatic π-systems next to the methylene
carbon.
The N-deprotonated benzamides presented in this work are close to the “pKa limit” for
three-electron bond formation from benzylic radicals. In order to expand this limit to less reactive,
more stabilized nitrogen bases, one has to use more reactive, less stabilized radical partners. We
hope that our report will encourage broad investigation of new strategies for unconventional C-N
bond formation.
Conflicts of Interest
The authors declare no conflicts of interest.
Acknowledgments:
The fundamental and synthetic aspects of this study were supported by donors of the ACS
Petroleum Research Fund (PRF#57377-ND4) and by the National Science Foundation (CHE-
1465142). We appreciate the allocation of computational resources from FSU RCC and the NSF
1
13
XSEDE (TG-CHE160006) and assistance in acquiring H and C NMR spectra from the NMR
Facility of FSU Department of Chemistry and Biochemistry.
Footnote
Electronic supplementary information (ESI) available: Experimental details, compound
characterization, and computational details for all calculated structures. See DOI:
10.1039/x0xx00000x
AUTHOR INFORMATION
Corresponding Author
*alabugin@chem.fsu.edu
TOC Graphic:

Chemical Science
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DOI: 10.1039/C9SC06511C
Radical-Anionic C(sp3)-H Amidation: C-N/C-O Bond Formation
O
O
NH
O
O
NH2
NH
NH
t-BuOK
DMF, O2
Ar
OH
Ar
Ar
2c,3e
Ar
Isoindolinone
2-center, 3-electron
"half-bond"
R
R
N
upconverted
electron
R
NH
*C-N
3. -e-
N
1. -H+
2. -H
H
R'
R'
R'
C
2c,3e
N
Radical-anion
C-N
Transition Metal Free
C-H Functionalization
Uses Mild Oxidants
References
1 (a) Wencel-Delord, J.; Glorius, F. Nat. Chem., 2013, 5, 389-375. (b) Lu, Q.; Glorius, F. Angew. Chem. Int. Ed.,
2017, 56, 49-51. (c) Choi, G.; Zhu, Q.; Miller. D.C.; Gu, C.; Knowles, R. R. Nature, 2016, 539, 268–271. (d) Chu,
J.C.K.; Rovis, T. Nature, 2016, 539, 272–275. (e) Burg, M. Sc.; Gicquel, M.; Breitenlechner, S.; Pöthig, A.
Angew. Chem. Int. Ed., 2018, 57, 2953-2957. (f) Chu, J.K.; Rovis, T. Angew. Chem. Int. Ed., 2018, 57, 62-101.
2
(a) Peng, B.; Maulide, N. Chem. Eur. J., 2013, 19, 13274-13287. (b) Xie, J.; Pan, C.; Abdukader, A.; Zhu, C.
Chem. Soc. Rev., 2014, 43, 5245-5256. (c) Park, Y.; Kim, Y.; Chang, S. Chem. Rev., 2017, 117, 9247-9301. (d)
Thansandote, P.; Lautens, M. Chem. Eur. J., 2009, 15, 5874-5883.
3
(a) Chen, M.S.; White, C. Science, 2010, 327, 566-571. (b) Murahuashi, S.; Komiya, N.; Nake, T. J. Am. Chem.
Soc., 2003, 125, 15312-15313. (b) Dangel, B.; Godula, K.; Won Youn, S.; Sezen, B.; Sames, D. J. Am. Chem. Soc.,
2002, 124, 11856-11857. (c) Shabashov, D.; Daugulis, O. J. Am. Chem. Soc., 2010, 132, 3965-3972. (d)
Zatolochnaya, O.V.; Gevorgyan, V. Nat. Chem., 2014, 6, 661-663. (e) Timsina, Y.N.; Gupton, B.F.; Ellis, K.C. ACS
Catal., 2018, 8, 5732-5776. (f) Dhakshinamoorthy, A.; Asiri, A.; Garcia, H. ACS Catal., 2019, 9, 1081-1102. (g)
Zhou, Z.; Kürti, L. Synlett., 2019, 30, 1525-1535.
4 (a) Hazelard, D.; Nocquet, P.; Compain, P. Org. Chem. Front., 2017, 4, 2500-2521. (b) Collet, F.; Dodd, R.H.;
Dauban, P. Chem. Commun., 2009, 34, 5061-5074. (c) Ramirez, T.A.; Zhao, B.; Shi, Y. Chem. Soc. Rev., 2012, 41,
921-942. (d) Gutekunst, W.R.; Baran, P.S. Chem. Soc. Rev., 2011, 40, 1976-1991. (e) Jeffrey, J. L.; Sarpong, R.
Chem. Sci., 2013, 4, 4092-4106.
5 (a) Arai, A.; Ueda, Y.; Morisaki, K.; Furuta, T.; Sasamori, T.; Tokitoh, N.; Kawabata T. Chem. Commun., 2018, 54,
2264-2267. (b) Kono, M.; Harada, S.; Nemoto, T. Chem. Eur. J., 2017, 23, 7428-7432. (c) Rauser, M.; Ascheberg,
C.; Niggemann, M. Angew. Chem. Int. Ed., 2017, 56, 11570-11574. (d) Starkov, P.; Jamison, T.F.; Marek, I. Chem.
Eur. J., 2015, 21, 5278 – 5300. (e) Ramierez, T.A.; Zhao, B.; Shi, Y. Chem. Soc. Rev., 2012, 41, 931–942. (f) Collet,
F.; Lescot, C.; Dauban, P. Chem. Soc. Rev., 2011, 40, 1926–1936. (g) Bois, J.D. Org. Process Res. Dev., 2011, 15,
758–762. (h) Aguila, J. B.; Badiei, Y. M.; Warren, T. H. J. Am. Chem. Soc., 2013, 135, 9399- 9406. (i) Zhang, X.;
Xu, H.; Liu, X.; Phillips, D.L.; Zhao, C. Chem. Eur. J., 2016, 22, 7288 – 7297.
6 (a) Hu, X.; Qi, X.; Chen, J.; Zhao, Q.; Wei, Q.; Lan, Y.; Xia, W. Nat. Commun., 2016, 7, 11188-11200. (b)
Nicolaou, K.C.; Baran, P.S.; Zhong, Y.-L.; Barluenga, S.; Hunt, K.W.; Kranich, R.; Vega, J.A. Iodine. J. Am. Chem.
Soc., 2002, 124, 2233-2244. (c) Wang, Y.; Chen, H.; Zhu, X.; Chiba, S. J. Am. Chem. Soc., 2012, 134, 11980-
11983. (d) Cecere, G.; König, C.M.; Alleva, J.L.; MacMillan, D.W.C. J. Am. Chem. Soc., 2013, 135, 11521-11524.
(e) Allen, L. J.; Cabrera, P. J.; Lee, M.; Sanford, M. S. J. Am. Chem. Soc., 2014, 136, 5607-5610. (f) Tranatino,
K.T.; Miller, D.C.; Callon, T.A.; Knowles, R.R. J. Am. Chem. Soc., 2015, 137, 6440-6443.
7 (a) Hofmann, A. W. Ber. Dtsch. Chem. Ges., 1879, 12, 984-990. (b)Wolff, M. Chem. Rev., 1963, 63, 55–64.
8 (a) McManus, J.B.; Onuska, N.P.R.; Nicewicz, D.A. J. Am. Chem. Soc., 2018, 140, 9056-9060. (b) Margrey, K. A.;
Leven, A.; Nicewicz, D.A. Angew. Chem. Int. Ed., 2017, 56, 15644-15648. (c) Shaw, M.H.; Shurtleff, V. W.;
Terrett, J. A.; Cuthbertson, J.D.; MacMillan, D.W.C. Science, 2016, 352, 1304-1308. (d) Jeffrey, J.L.; Petronijević,
F.R.; MacMillan, D.W.C. J. Am. Chem. Soc., 2015, 137, 8404-8407. (e) Prier, C.K.; MacMillan, D.W.C. Chem. Sci.,
2014, 5, 4173-4178. (f) Bartling, H.; Eisenhofer, A.; König, B.; Gschwind, R.M. J. Am. Chem. Soc., 2016, 138,
11860-11871.
9 Evoniuk, C. J.; Hill, S. P.; Hanson, K.; Alabugin, I. V. Chem. Commun., 2016, 52¸7138-7141.
10 Evoniuk, C. J.; Gomes, G. P.; Hill, S.; Satoshi, F.; Hanson, K.; Alabugin, I. V. J. Am. Chem. Soc., 2017, 139,
16210-16221.

Page 23 of 25
Chemical Science
View Article Online
DOI: 10.1039/C9SC06511C
11 (a) Yang, M.; Su, B.; Wang, Y.; Chen, K.; Jiang, X.; Zhang, Y.; Zhang, X.; Chen, G.; Cheng, Y.; Cao, Z.; Guo,
Q.; Wang, L.; Shi, Z. Nat. Comm., 2014, 5, 4707-4713. (b) Timsina, Y.; Gupton, F.; Ellis, K. ACS Catal., 2018, 8,
5732-5776. (c) Wang, Z.; Ni, J.; Kuninobu, Y.; Kanai, M. Angew. Chem. Int. Ed., 2014, 53, 3496 –3499. (d) He, G.;
Zhang, S.; Nack, W.; Li, Q.; Chen, G. Angew. Chem. Int. Ed., 2013, 52, 11124 –11128. (e) Wu, X.; Zhao, Y.; Ge, H.
Chem. Eur. J., 2014, 20, 9530 – 9533. (f) Neumann, J. J.; Rakshi, S.; Dröge, T.; Glorius, F. Angew. Chem. Int. Ed.,
2009, 48, 6892 –6895.
12
Labinger, J. A.; Bercaw, J. E. Nature, 2002, 417, 507−514.
13 (a) Tan, Y.; Hartwig, J. F. J. Am. Chem. Soc., 2010, 132, 3676−3677. (b) Youn, S. W.; Bihn, J. H.; Kim, B. S.
Org. Lett., 2011, 13, 3738−3741. (c) Hartwig, J. F. Inorg. Chem., 2007, 46, 1936−1947. (d) Jordan-Hore, J. A.;
Johansson, C. C. C.; Gulias, M.; Beck, E. M.; Gaunt, M. J. J. Am. Chem. Soc., 2008, 130, 16184−16186.
14 Studer, A. Chem. Eur. J., 2001, 7, 1159-1164.
15 (a) West, S.P.; Bisai, A.; Lim, A.D.; Narayan, R.R.; Sarpong, R. J. Am. Chem. Soc., 2009, 131, 11187-11194 (b)
Gruver, J.M.; West, S.P.; Collum, D.B.; Sarpong, R. J. Am. Chem. Soc., 2010, 132, 13212-13213. (c) Jeffrey, J.L.;
Bartlett, E.B.; Sarpong, R. Angew. Chem. Int. Ed., 2013, 52, 2194-2197.
16 (a) Syroeshkin, M. A.; Kuriakose, F.; Saverina, E. A.; Timofeeva, V. A.; Egorov, M. P.; Alabugin, I. V. Angew.
Chem. Int. Ed., 2019, 58, 5532-5550. (b) Studer, A.; Curran, D. P. Nat. Chem., 2014, 6, 765-773.
17 For the general review of dehydrogenative C–O bond formation, see: Krylov, I. B.; Vil’, V A. Terent’ev, A. O.
Cross-dehydrogenative Coupling for the Intermolecular C-O Bond Formation. Beilstein J. Org. Chem., 2015, 11,
92–146.
18 Yan, D.-M; Zhao, Q.-Q.; Rao, L.; Chen, J.-R.; Xiao, W.-J. Chem. Eur. J., 2018, 24, 16895-16901.
19 U. S. Department of Health and Human Services Food and Drug Administration (2015). Q3D Elemental
Impurities Guidance for Industry.
20 Topliss, J.G.; Konzelman, L.M.; Sperber, N.; Franklin, E.R. J. Med. Chem., 1964, 7, 453–456.
21 (a) Hardcastle, I. R.; Ahmed, S. U.; Atkins, H.; Farnie, G.; Golding, B. T.; Griffin, R. J.; Guyenne, S.; Hutton, C.;
Källblad, P.; Kemp, S. J.; Kitching, M. S.; Newell, D. R.; Norbedo, S.; Northen, J.; Reid, R. J.; Saravanan, K.;
Willems, H. M.; Lunec, J. J. Med. Chem., 2006, 49, 6209-6221. (b) Riedinger, C.; Endicott, J.A.; Kemp, S.J.;
Smyth, L.A.; Watson, A.; Valeur, E.; Golding, B.T.; Griffin, R.J.; Hardcastle, I.R.; Noble, M.E. ; McDonnell J.M. J.
Am. Chem. Soc., 2008, 130, 16038-16044. (c) Hardcastle, I. R.; Liu, J.; Valeur, E.; Watson, A.; Ahmed, S. U.;
Blackburn, T. J.; Bennaceur, K.; Clegg, W.; Drummond, C.; Endicott, J. A.; Golding, B. T.; Griffin, R. J.; Gruber,
J.; Haggerty, K.; Harrington, R. W.; Hutton, C.; Kemp, S.; Lu, X.; McDonnell, J. M.; Newell, D. R.; Noble, M. E.;
Payne, S. L.; Revill, C. H.; Riedinger, C.; Xu, Q.; Lunec, J. J. Med. Chem., 2011, 54, 1233-1243. (d) Watson, A.F.;
Liu, J.; Bennaceur, K.; Drummond, C.J.; Endicott, J.A.; Golding, B.T.; Griffin, R.J.; Haggerty, K.; Lu, X.;
McDonnell, J.M.; Newell, D.R.; Noble, M.E.M.; Revill, C.H.; Riedinger, C.; Xu, Q.; Zhao, Y.; Lunec, J.;
Hardcastle, I.R. Bioorg. Med. Chem. Lett., 2011, 21, 5916-5919. (e) Grigoreva, T.A.; Novikova, D.S.; Petukhov,
A.V.; Gureev, M.A.; Garabadzhiu, A.V.; Melino, G.; Barlevv, N.A.; Tribulovich, V.G. Bioorg. Med. Chem. Lett.,
2017, 27, 5197-5202.
22 (a) Fajardo, V.; Elango, V.; Cassels, B. K.; Shamma, M. Tetrahedron Lett., 1982, 23, 39–42. (b) Kamauchi, H.;
Shiraishi, Y.; Kojima, A.; Kawazoe, N.; Kinoshita, L.; Koyama, K. J. Nat. Prod., 2018, 81, 1290–1294.
23 Chen, M.-W.; Chen, Q.-A.; Duan, Y.; Ye, Z.-S.; Zhou, Y.-G. Chem. Comm., 2012, 48, 1698-1700.
24 Kang, Z.; Zhang, D.; Shou, J.; Hu, W. Org. Lett., 2018, 20, 983-986.
25 (a) Nishimura, T.; Nagamoto, M.; Ebe, Y.; Hayashi, T. Chem. Sci., 2013, 4, 4499-4504, (b) Sharma, S.; Oh, Y.;
Mishra, N.K.; De, U.; Jo, H.; Sachan, R.; Kim, H.S.; Jung, Y.H.; Kim, I.S. J. Org. Chem., 2017, 82, 3359–3367. (c)
Nagamoto, M.; Nishimura, T. Chem. Comm., 2014, 50, 6274 - 6277. (d) Nishimura, T.; Noishiki, A.; Ebe, Y.;
Hayashi, T. Angew. Chem. Int. Ed., 2013, 52, 1777-1780.
26 (a) Wasserman, H. H.; Ives, J. l. Tetrahedron, 1981, 37, 1825-1852. (b) Ogilby, P. R. Chem. Soc. Rev., 2010, 39,
3181-3209. (c) Ghogare, A. A.; Greer, A. Chem. Rev., 2016, 116, 9994-10034.
27 (a) Gao , Y.; Hu, G.; Zhong, J.; Shi, Z.; Zhu, Y.; Su, D.; Wang, J. Angew. Chem. Int. Ed., 2013, 52, 2109-2113.
(b) Urgoita, G.; SanMartin, R.; Herrero, M.T.; Domínguez, E. Chem. Commun., 2015, 51, 4799-4802. (c) Ma, J.;
Hu, Z.; Li, M.; Zhao, W.; Hu, X.; Mo, W.; Hu, B.; Sun, N.; Shen, Z. Tetrahedron, 2015, 71, 6733-6739. (d) Wang,
H.; Wang, Z.; Huang, H.; Tan, J.; Xu, K. Org. Lett., 2016, 18, 5680-5683. (e) Guo, C.; Zhang, Y.; Zhang, Y.; Wang,
J. Chem. Commun., 2018, 54, 3701-3704. (f) Sterckx, H.; Morel, B.; Maes, B.U.W. Angew. Chem. Int. Ed., 2019,
58, 7946-7970.
28 The M06-2X functional has demonstrated to provide good thermodynamic data for organic reactions. For more
details, see: (a) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc., 2008, 120, 215-241. (b) Zhao, Y.; Truhlar, D. G. Acc.
Chem. Res., 2008, 41, 157-167.

Chemical Science
Page 24 of 25
View Article Online
DOI: 10.1039/C9SC06511C
29 Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B, 2009, 113, 6378-6378.
30 Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. J. Chem. Phys., 2010, 132, 154104.
31 Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.;
Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.;
Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.;
Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.;
Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari,
K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, M. J.; Klene, M.; Knox, J. E.;
Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador,
P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J.
Gaussian, Inc., Wallingford CT, 2009.
32 CYLview, 1.0b; Legault, C. Y., Université de Sherbrooke, 2009 (http://www.cylview.org)
33 ChemCraft 1.8 http://www.chemcraftprog.com, accessed in February 2016.
34 (a) Chen, Y.-Y.; Zhang, X.-J.; Yuan, H.-M.; Wei, W.-T.; Yan, M. Chem. Commun., 2013, 49, 10974-10976. (b)
Wang, W.-J.; Zhao, X.; Tong, L.; Chen, J.-H.; Zhang, X.-J.; Yan, M. J. Org. Chem., 2014¸ 79, 8557-8565. (c) Chen,
Y.-Y.; Zhang, N.-N.; Ye, L.-M.; Chen, J.-H.; Sun, X.; Zhang, X.-J.; Yan, M. Rsc. Adv., 2015, 5, 48046-48049. (d)
Wei, W.-T.; Cheng, Y.-J.; Hu, Y.; Chen, Y.-Y.; Zhang, X.-J.; Zou, Y.; Yan, M. Adv. Synth. Catal., 2015, 357, 3474-
3478. (e) Chen, Y.-Y.; Chen, Z.-Y.; Zhang, N.-N.; Chen, J.-H.; Zhang, X.-J.; Yan, M. Eur. J. Org. Chem., 2016, 3,
599-606.
35
Nanni Jr., E. J.; Stallings, M. D.; Sawyer, D. T. J. Am. Chem. Soc., 1980, 102, 4481- 4485.
36 Pichette Drapeau, M.; Fabre, I.; Grimaud, L.; Ciofini, I.; Ollevier, T.; Taillefer, M. Angew. Chem., Int. Ed., 2015,
54, 10587-10591.
37 Li, J.-S.; Yang, F.; Yang, Q.; Li, Z.-L.; Chen, G.-Q.; Da, Y.-D.; Huang, P.-M.; Chen, C.; Zhang, Y.; Huang, L.-Z.
Synlett, 2017, 28, 994-998.
38 For the effect of such geometric changes on stability and reactivity, see: Komarov, I. V.; Yanik, S.; Ishchenko, A.
Y.; Davies, J. E.; Goodman, J. M.; Kirby, A. J. J. Am. Chem. Soc., 2015, 137, 926–930. Hutchby, M.; Houlden, C.
E.; Haddow, M. F.; Tyler, S. N. G.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. Angew. Chem., 2012, 124, 563–
566. Szostak, M.; Aube, J. Chem. Rev., 2013, 113, 5701–5765. Vatsadze, S. Z.; Loginova, Y. D.; Gomes, G.;
Alabugin, I. V. Chem. Eur. J., 2017, 23, 3225-3245.
39 Peterson, P.; Shevchenko, N.; Breiner, B.; Manoharan, M.; Lufti, F.; Delaune, J.; Kingsley, M.; Kovnir, K.;
Alabugin, I. V. J. Am. Chem. Soc., 2016, 138, 15617–15628.
40 Cotton, F.A.; Wilkinson, G.; Murillo, C.A.; Bochmann, M. Advanced Inorganic Chemistry (6th ed.).; Wiley: New
York, 1999, p. 461.
41 Burton, G.W.; Ingold, K.U. J. Am. Chem. Soc., 1981, 103, 6472-6477.
42 (a) Bothe, E.; Schuchmann, M. N.; Schulte-Frohlinde, D.; Sonntag, C. Z. Naturforsch. B: J. Chem. Sci., 1983, 38,
212−219. (b) Song, W.; Xu, T.; Cooper, W. J.; Dionysiou, D. D.; Cruz, A. A. de la; O’Shea, K. E. Environ. Sci.
Technol., 2009, 43, 1487−1492. (c) Dorfman, L. M.; Adams, G. E. Reactivity of the Hydroxyl Radical in Aqueous
Solutions; U.S. National Bureau of Standards: Washington, DC, 1973.(d) Chen, H.; Lin, L.; Lin, Z.; Guo, G.; Lin, J.
M. J. Phys. Chem. A, 2010, 114, 10049−10058.
43 (a) Nanni, E. J.; Sawyer, D. T.; Ball, S. S.; Bruice, T. C J. Am. Chem. Soc., 1981, 103, 2797−2802. (b) Sawyer, D.
T.; Nanni, E.J.; Roberts, Jr., J. L. Electrochemical and Spectrochemicla Studies of Biological Redox Components,
1982, 585-600. (c) Hayyan, M.; Hasim, M. A.; AlNashef, I. M. Chem. Rev., 2016, 116, 3029-3085.
44 (a) Nanni Jr., E. J.; Stallings, M. D.; Sawyer, D. T. J. Am. Chem. Soc., 1980, 102, 4481- 4485. (b) Chin, D-H.;
Chiericato Jr., G.; Nanni Jr, E. J.; Sawyer, D. T. J. Am. Chem. Soc., 1982, 104, 1296-1299.
45 Note that the peroxide moiety in this molecule would engage in the anomeric nO*C-N interaction. Such
interactions were shown to significantly stabilize peroxides with geminal acceptor groups: (a) Gomes, G. P.; Vil’,
V.; Terent’ev, A.; Alabugin, I. V. Chem. Sci., 2015, 6, 6783 – 6791. (b) Vil’, V. A.; Gomes, G. P.; Ekimova, M. V.;
Lyssenko, K. A.; Syroeshkin, M. A.; Nikishin, G. I.; Alabugin, I. V.; Terent’ev, A. O. J. Org. Chem., 2018, 83,
13427–13445. c) Juaristi, E.; Gomes, G. P.; Terent’ev, A. O.; Notario, R.; Alabugin, I. V. J. Am. Chem. Soc., 2017,
139, 10799–10813. (d) Gomes, G. P.; Yaremenko, I. A.; Radulov, P. S.; Novikov, R. A.; Chernyshev, V. V.;
Korlyukov, A. A.; Nikishin, G. I.; Alabugin, I. V.; Terent’ev, A. O. Angew. Chem. Int. Ed., 2017, 56, 4955–4959.
46 Swern, D.; Clements, A. H.; Lung, T. M. Anal. Chem., 1969, 41, 412-416.

Page 25 of 25
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View Article Online
DOI: 10.1039/C9SC06511C
47 (a) Schultz, D.M.; Levesque, F.; DiRocco, D.A.; Reibarkh, M.; Ji, Y.; Joyce, L.A.; Dropinski, J.F.; Sheng, H.;
Sherry, B.D.; Davies, I.W. Angew. Chem. Int. Ed., 2017, 56, 15274-15278. (b) Tsang, A.S.-K.; Kapat, A.;
Schoenebeck, F. J. Am. Chem. Soc., 2016, 138, 518-526. (c) Liu, K.-J.; Duan, Z.-H.; Zeng, X.-L.; Sun, M.; Tang, Z.;
Jiang, S.; Cao, Z.; He, W.-M. Fast, ACS Sustainable Chem. Eng., 2019, 7, 10293-10298. (d) Lesieur, M.; Genicot,
C.; Pasau, P. Org. Lett., 2018, 20, 1987-1990.
48 (a) Griesser, M.; Shah, R.; Van Kessel, A. T.; Zilka, O.; Haidasz, E. A.; Pratt, D. A. J. Am. Chem. Soc., 2018, 140,
3798-3808. (b) Samuni, A.; Krishna, C. M.; Riesz, P.; Finkelstein, E.; Russo, A. J. Biol. Chem., 1988, 263,
17921−17924. (c) Mitchell, J. B.; Samuni, A.; Krishna, M. C.; DeGraff, W. G.; Ahn,M. S.; Samuni, U.; Russo,
Biochemistry, 1990, 29, 2802−2807. (d) Krishna, M. C.; Grahame, D. A.; Samuni, A.; Mitchell, J. B.; Russo, A.
Proc. Natl. Acad. Sci. U. S. A., 1992, 89, 5537−5541.(e) Krishna, M. C.; Russo, A.; Mitchell, J. B.; Goldstein, S.;
Dafni,H.; Samuni, A. J. Biol. Chem., 1996, 271, 26026−26031.
49
(a) Bobbit, J. M.; Brückner, C.; Merbouh, N. Org. React., 2009, 74, 103. (b) Richter, H.; Mancheño, O. G.. Eur.
J. Org. Chem., 2010, 2010, 4460-4467. (c) Neel, A. J.; Hehn, J. P.; Tripet, P. F.; Toste, F. D. J. Am. Chem. Soc.,
2013, 135, 14044-14047. (d) Tarantino, K. T.; Miller, D.C.; Callon, T. A.; Knowles, R. R. J. Am. Chem. Soc., 2015,
137, 6440- 6443.
50 Zhang, Z.; Gao, Y.; Liu, Y.; Li, J.; Xie, H.; Li, H.; Wang, W. Org. Lett., 2015, 17, 5492-5495.
51 (a) Semmelhack, M. F.; Schmid, C. R.; Cortes, D. A. Tetrahedron Lett., 1986, 27, 1119−1122. (b) Hamlin, T.A.;
Kelly, C.B.; Ovian, J.M.; Wiles, R.J.; Tilley, L.J.; Leadbeater, N.E. J. Org. Chem., 2015, 80, 8150-8167. (c) Richter,
H.; Mancheño, O.G. Eur. J.Org. Chem., 2010, 4460-4467. (d) Dong, J.; Xia, Q.; Yan, C.; Song, H.; Liu, Y.; Wang,
Q. J. Org. Chem., 2018, 83, 4516-4524.