Mechanism of Ni-catalyzed oxidations of unactivated C(sp3)-H Bonds

Article

Mechanism of Ni-Catalyzed Oxidations of Unactivated C(sp )−H

Bonds

Yehao Qiu and John F. Hartwig*

Cite This: https://dx.doi.org/10.1021/jacs.0c09157

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sı Supporting Information

ABSTRACT: The Ni-catalyzed oxidation of unactivated alkanes,

including the oxidation of polyethylenes, by meta-chloroperbenzoic

acid (mCPBA) occur with high turnover numbers under mild

conditions, but the mechanism of such transformations has been a

subject of debate. Putative, high-valent nickel-oxo or nickel-oxyl

intermediates have been proposed to cleave the C−H bond, but several

studies on such complexes have not provided strong evidence to support

such reactivity toward unactivated C(sp )−H bonds. We report

mechanistic investigations of Ni-catalyzed oxidations of unactivated

C−H bonds by mCPBA. The lack of an eﬀect of ligands, the formation

of carbon-centered radicals with long lifetimes, and the decomposition of

mCPBA in the presence of Ni complexes suggest that the reaction occurs

through free alkyl radicals. Selectivity on model substrates and deuterium-labeling experiments imply that the m-chlorobenzoyloxy

radical derived from mCPBA cleaves C−H bonds in the alkane to form an alkyl radical, which subsequently reacts with mCPBA to

aﬀord the alcohol product and regenerate the aroyloxy radical. This free-radical chain mechanism shows that Ni does not cleave the

C(sp )−H bonds as previously proposed; rather, it catalyzes the decomposition of mCPBA to form the aroyloxy radical.

INTRODUCTION

1890s, Fenton reported the iron(II)-catalyzed oxidation of

■

tartaric acid by hydrogen peroxide. Later, the Gif-Barton

Oxidation of aliphatic C−H bonds is an important chemical

transformation that is widely practiced in nature and in synthetic

chemistry. In most living organisms, cytochrome P450 enzymes

catalyze the hydroxylation of saturated C−H bonds, and, in

methanotrophic bacteria, methane monooxygenases (MMOs)

system, which utilizes iron catalysts and tBuOOH or H O as

,13,14

oxidants, the Pt(II) catalytic system by Shilov and Periana,

and the Ru porphyrin system by Groves and others

15−17

were

developed to achieve the oxidation of alkanes with high turnover

numbers (TONs). More recently, white reported a selective

oxidation of aliphatic C−H bonds in complex molecules with

catalyze the hydroxylation of methane to produce methanol. In

synthetic chemistry, the oxidation of feedstock alkanes is a

promising way to make valuable products, such as alcohols and

ketones, from inexpensive starting materials. However, a high-

yielding, selective oxidation of unactivated aliphatic C−H bonds

is challenging because the large bond dissociation energies

BDEs) near 100 kcal/mol and high highest occupied

molecular orbital (HOMO)−lowest unoccupied molecular

orbital (LUMO) gaps make them inert to many chemical

18,19

and iron catalysts containing nitrogen-based ligands.

Compared to these methods that involve group 8 transition-

metal catalysts, Ni-catalyzed oxidations of alkanes are less

explored but have been reported to occur with high TONs. Itoh

and others have reported the hydroxylation of cyclohexane and

adamantane with mCPBA and nickel catalysts containing

tetradentate, nitrogen-based ligands, such as tris(2-

(

20−22

reactions and because the ubiquity of C(sp )−H bonds in

pyridylmethyl)amine (TPA).

Our group achieved selective

organic molecules makes it necessary to distinguish between

similar, but inequivalent sites. In addition, oxidized products,

such as alcohols and alkyl halides, are generally more reactive

than the starting unfunctionalized alkanes, so overoxidation may

hydroxylation of polyethylenes with mCPBA and Ni catalysts

containing phenanthroline-based (Phen-based) ligands. This

oxidation occurred with loadings of nickel as low as 0.1 mol %,

required mild conditions (50 °C under air), and aﬀorded the

occur, leading to undesired byproducts.

Despite these challenges, many methods have been developed

Received: August 26, 2020

in the past century for the oxidation of aliphatic C−H bonds.

7,8

Several organic reagents, such as ozone, dioxiranes, and

aromatic peracids,

,10

were found to oxidize saturated hydro-

carbons with high selectivity for tertiary C−H bonds. The

oxidation of aliphatic C−H bonds catalyzed by transition-metal

complexes also has been developed extensively. As early as the

XXXX American Chemical Society

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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with hundreds of TONs (Figure 1 A).

Article

mono-oxidized product (alcohol rather than ketone or ester)

Ni-oxygen intermediate cleaved the C−H bonds in hydro-

carbons, the identity of the ancillary ligands that possess varied

electronic and steric properties should aﬀect the selectivity of the

catalytic reaction. Therefore, Ni complexes (1a−1h, Figure 2)

that contain a series of nitrogen-based, bidentate or tetradentate

ligands (L1−L8) were synthesized and used for the catalytic

oxidation of cyclohexane (2 ) and adamantane (3 ).

Figure 1. (A) Ni-Catalyzed hydroxylation of cyclohexane, adamantane,

and polyethylenes by mCPBA. (B) Previously proposed pathway for

Ni-catalyzed oxidation of aliphatic C−H bonds. (C) This work: free-

radical chain mechanism of Ni-catalyzed oxidation of C(sp )−H bonds

by mCPBA.

The Ni-catalyzed oxidation of saturated hydrocarbons by

mCPBA has been proposed to occur by forming a transient Ni-

oxyl or Ni-oxo intermediate (hereafter called a Ni-oxygen

0,25,26

species) that cleaves the C−H bond (Figure 1B).

Hikichi

reported the isolation and characterization of a Ni complex of

mCPBA containing a trispyrazolylborate-based (Tp-based)

ligand. Several other Ni-oxygen species containing macro-

cyclic, nitrogen-based ligands also have been characterized

Figure 2. Structures of ligands L1−L8 and Ni catalysts 1a−1h.

6,28−34

spectroscopically.

These nickel intermediates oxidize

activated C−H bonds (BDE < 90 kcal/mol) in substrates such

The results of the oxidation of cyclohexane (2) catalyzed by

this series of nickel complexes are shown in Table 1A.

Cyclohexanol (4a) was formed as the major product together

with small amounts of cyclohexanone (4b), ε-caprolactone (4c),

and chlorocyclohexane (4d). The formation of 4c can be

attributed to the uncatalyzed Baeyer−Villiger oxidation of 4b.

The ratio of alcohol to ketone and lactone, that is, A/(K + E),

deﬁned as the ratio of the yield of 4a to the combined yields of

4b and 4c, reﬂects the selectivity for mono-oxidation.

Our data show that the identity of the ligand aﬀects the rate of

the oxidation process. Reactions in the presence of complexes

1a−1e, which contain sterically unhindered ligands L1−L5,

reached full conversion of mCPBA within 1−1.5 h (Table 1A,

entries 1−5), whereas those in the presence of 1f and 1g, which

contain sterically encumbered ligands L6 and L7, required 2 and

3 h to reach greater than 90% conversion, respectively (Table

1A, entries 6 and 7). The conversion of the reaction with

complex 1h, which contains the most sterically hindered ligand

L8, in which two methyl groups ﬂank the phenanthroline

moiety, was low even after 4 h of heating (Table 1A, entry 8).

Time courses further conﬁrmed that the rates of the reactions in

the presence of complex 1a were signiﬁcantly higher than those

in the presence of Ni complexes containing sterically hindered

ligands, such as 1h (see the Supporting Information).

27,28,33

as 9,10-dihydroanthracene (DHA) and xanthene,

but the

reactivity of such intermediates with unactivated C−H bonds

(

BDE ≈ 100 kcal/mol) has not been convincingly established.

This trend in reactivity is inconsistent with the results of the

catalytic reactions, in which the strong C−H bonds in

cyclohexane and polyethylenes undergo hydroxylation under

mild conditions. Studies that address this issue of the reactivity

of Ni-oxo or Ni-oxyl complexes with C−H bonds and

mechanisms of Ni-catalyzed oxidation reactions are crucial to

understanding the role of Ni in the catalytic system and to

improving the eﬃciency and selectivity of these reactions

further.

In this work, we report mechanistic investigations of the Ni-

catalyzed oxidation of unactivated aliphatic C−H bonds. We

provide evidence that, contrary to the previously proposed

reaction pathways, Ni complexes are not involved in the cleavage

of C−H bonds; rather, they catalyze the decomposition of

mCPBA to generate an aroyloxy radical that cleaves the C−H

bond via hydrogen atom abstraction (HAA). The resulting alkyl

radical then reacts with mCPBA to form the hydroxylated

product and regenerates the aroyloxy radical. Thus, the catalytic

reaction proceeds via a free-radical chain mechanism (Figure

C) in which the rate of initiation is determined by the

concentration and identity of the nickel complex, but the nickel

complex does not control the regioselectivity of the oxidations.

However, the data in Table 1 also show the lack of a

pronounced eﬀect of the ligand on the yield of oxidized products

or on the A/(K + E) ratio. All reactions in the presence of

complexes 1a−1g gave product 4a in 31%−39% yield and

products 4b, 4c in 10%−11% combined yield; the A/(K + E)

ratios of these reactions range from 3.1 to 3.5, which is well

within experimental error. The oxidation of cyclohexane in the

RESULTS AND DISCUSSIONS

. Eﬀect of Ligands on Selectivity. To understand the role

of Ni complexes in the catalytic reaction, we studied the eﬀect of

■

varying the ligands on the selectivity of oxidation. If a transient

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Article

Table 1. Results of the Oxidation of (A) Cyclohexane and (B)

Adamantane in the Presence of Diﬀerent Catalysts

eﬀect of ligands on both product distribution and selectivity for

mono-oxidation, along with the similar yield of products and

selectivity of the catalytic reactions conducted without ligands, is

inconsistent with the previously proposed pathway in which a

Ni-oxygen species cleaves the C−H bond.

Although the chemoselectivity for the formation of alcohol,

ketone, and lactone products 4a−4c provided preliminary

evidence that a ligated nickel complex is not involved in the

cleavage of C−H bonds, the ketone and ester are likely to be

secondary products. Therefore, the distribution of these

products could be envisioned to depend on several factors

besides the identity of the species that cleaves the C−H bond. A

more rigorous test would involve the measurement of the initial

products. In addition, measuring the selectivity for tertiary

versus secondary (or primary) C−H bonds in a model alkane is

important to identify the species that cleaves the C−H bond and

to understand the mechanism of Ni-catalyzed oxidations of

hydrocarbons. Thus, we also measured the regioselectivity for

the oxidation of adamantane.

The results of the oxidations of adamantane (3) catalyzed by a

series of nickel complexes are shown in Table 1B. 1-

Adamantanol (5a) was the major product; 2-adamantanol

(

5b), 2-adamantanone (5c), and 1- and 2-chloroadamantane

5d and 5e) were the minor products. Like the reactions of

cyclohexane, the rates of the reactions of adamantane depended

on the ligand bound to nickel. Reactions catalyzed by Ni

complexes 1a−1e reached greater than 90% conversion of

mCPBA within 1−1.5 h (Table 1B, entries 1−5), whereas those

catalyzed by 1f and 1g, which contain sterically encumbered

ligands L6 and L7, required 2 and 3 h to reach similar levels of

conversion (Table 1B, entries 6 and 7). The reaction in the

presence of complex 1h, which contains the most sterically

hindered ligand L8, did not reach 90% conversion, even after 4 h

of heating (Table 1B, entry 8).

Despite the diﬀerent rates of reactions catalyzed by these

complexes, all of the reactions catalyzed by complexes 1a−1g

furnished product 5a in 24.9%−38.5% yield, the combination of

products 5b and 5c in 2.4%−3.1% yield, product 5d in 2.4%−

.2% yield, and product 5e in 2.4%−5.0% yield. The ratio of the

combination of products from functionalization at the tertiary

positions (5a and 5d) to the combination of those at the

secondary position (5b, 5c, and 5e), which is denoted 3°/2°,

reﬂects the regioselectivity of this reaction. These 3°/2° ratios

were between 4.4 and 6.9 and well within the experimental error

of each other. In addition, the oxidation of adamantane catalyzed

by ligandless NiCl and CoCl furnished the combination of

products 5a and 5d in 32.6% and 29.9% yield and the

combination of products 5b, 5c and 5e in 5.9% and 4.9%

yield, corresponding to 3°/2° ratios of 5.5 and 6.1, respectively,

which are indistinguishable from those of reactions catalyzed by

the ligated Ni complexes 1a−1g. The lack of dependence of the

product distribution and regioselectivity of the oxidation of

adamantane on this series of Ni complexes containing diﬀerent

ligands and on ligandless metal chlorides, again, is inconsistent

with the hypothesis that a Ni-oxygen species cleaves unactivated

C−H bonds in alkanes.

2. Formation of Carbon-Centered Radicals with Long

Lifetimes. Determining whether carbon-centered radicals are

formed and, if so, estimating the lifetime of these radicals is

crucial to understanding the mechanism of oxidations of C−H

bonds. The formation of chlorinated products 5d and 5e in high

yields in a Ni-catalyzed oxidation of adamantane with 1 equiv of

Conditions: 0.125 mmol mCPBA, 7.5 equiv of 2 or 2 equiv of 3, 0.1

mol % catalyst, DCM/MeCN (3:1, 0.125 M), 50 °C under air. All

yields were based on mCPBA and reported as the arithmetic mean of

three repeated experiments. Time required to reach greater than 90%

conversion of mCPBA unless noted otherwise. Low conversion of

mCPBA even after 4 h of reaction. Conversion too low to determine.

In the presence of CCl (1 equiv).

presence of ligandless NiCl (Table 1A, entry 9) formed product

4a in 31% yield and products 4b and 4c in 13% combined yield,

corresponding to an A/(K + E) ratio of 2.4 ± 0.6. This ratio is

comparable to those of reactions catalyzed by ligated Ni

complexes 1a−1g. Similar results were observed for the

oxidation of 2 catalyzed by CoCl , although the cobalt-catalyzed

reaction was faster than the nickel-catalyzed one and reached full

conversion within 1.5 h (Table 1A, entry 10). The negligible

CCl (Table 1B, entry 12) strongly suggests the formation of

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complex 1a under standard conditions (Figure 3 A). Chlor-

Article

carbon-centered radicals and subsequent trapping by CCl₄.

Substrates that react as radical clocks are often employed to

study the lifetime of carbon-centered radicals and the rate of the

Table 2A, the oxidation of cis-6 in the presence of a series of Ni

complexes, including the ligandless NiCl , formed the tertiary

alcohols with a cis-fraction ranging from 42.6% to 48.9%. These

results indicate that the lifetime of the carbon-centered radical

formed in these reactions is long enough that complete

epimerization occurs before the formation of the C−O bond.

The cis fraction from the Ni-catalyzed oxidation of trans-6,

summarized in Table 2B, ranged from 36.9% to 41.7%. The

lower fraction of the cis product from reactions catalyzed by 1e−

formation of C−O bonds during the oxidation of C−H bonds.

For example, several radical clocks based on cyclopropanes were

used to study the mechanism of the hydroxylation of saturated

C−H bonds catalyzed by P450 enzymes. In this work, we used

the well-known cis- and trans-1,2-dimethylcyclohexane (cis- and

trans-6) as radical clocks to investigate the lifetime of carbon-

centered radicals formed in the Ni-catalyzed oxidation reaction.

The Ni-catalyzed oxidation of cis-6, which occurred

predominantly at the tertiary position, generated the tertiary

alkyl radical 7, which is known to epimerize rapidly (ﬁrst-order

1g and NiCl , which are slower than the reactions catalyzed by

1a−1c (Table 2B, entries 4−7), is likely due to a competing

background, uncatalyzed hydroxylation by mCPBA. Uncata-

lyzed oxidation of alkanes by mCPBA is known to occur with

−1 36

rate constant k ≈ 10 s ), and aﬀorded tertiary alcohols 8a

retention of conﬁguration. These results are also consistent

and 8b as major products (Table 2A). The fraction of the cis

with the Ni-catalyzed reactions occuring through a long-lived

alkyl radical before the step that forms the C−O bond.

Table 2. Results of the Ni-Catalyzed Oxidation of (A) cis-6

3. Ni-Catalyzed Decomposition of mCPBA and a

Callback to Fenton Chemistry. Our attempts to isolate Ni-

oxygen intermediates or Ni-mCPBA adducts ligated by

phenanthrolines have simply led to the decomposition of

mCPBA. In the absence of alkanes, mCPBA was consumed

completely to form meta-chlorobenzoic acid (mCBA) in 72%

yield and chlorobenzene (9) in 15% yield in the presence of Ni

and (B) trans-6

Figure 3. (A) Results of Ni-catalyzed decomposition of mCPBA in the

absence of alkanes. (B) Formation of chlorobenzene in Ni-catalyzed

oxidation of 2 by mCPBA.

obenzene, which was formed in ∼51% yield in the catalytic

oxidation of cyclohexane (Figure 3B), would arise from the

decarboxylation of the meta-chlorobenzoyloxy radical (10).

Moreover, our data show that the rate of decomposition of

mCPBA is dependent on the identity of the ligand in the Ni

catalyst. Time courses indicate that the rate of decomposition in

the presence of complex 1a is signiﬁcantly higher than that in the

presence of complex 1h, which contains sterically hindered

ligands (see the Supporting Information).

Conditions: 0.125 mmol of mCPBA, 7.5 equiv of cis- or trans-6, 0.1

mol % [Ni], DCM/MeCN (3:1, 0.125 M), 50 °C under air, 1−4 h.

All yields were based on mCPBA and reported as the arithmetic mean

of three repeated experiments.

This Ni-catalyzed decomposition of an aromatic peracid that

involves free-radical intermediates is reminiscent of the classic

39,40

Fenton chemistry (Scheme 1),

in which an iron(II) cation

catalyzes the decomposition of hydrogen peroxide to generate

the hydroxyl radical (11) (eq 1−1). If an alkane is present in the

reaction system, the highly reactive radical 11 abstracts a

hydrogen atom from a C−H bond to form water and an alkyl

radical, which can subsequently form alcohol (eq 1−2). If no

alkane is present, H O will decompose to release O and water

through either a radical chain (eqs 1−3 and 1−4) or a nonchain

pathway (eqs 1−1, 1−3, and 1−5). The decomposition of

mCPBA in the presence of Ni complexes, the lack of an eﬀect of

the ligands on the selectivity of catalytic reactions, and the

product (ratio of the yield of 8a to the combined yield of 8a and

b) reﬂects the rate of the epimerization of 7 versus that of the

formation of a C−O bond. If the formation of the C−O bond

occurs much faster than the epimerization, then the cis product

8a would be formed predominantly. When the step that forms

the C−O bond occurs more slowly than the epimerization of 7,

the products 8a and 8b have been observed in similar amounts,

36,38

corresponding to a cis-fraction close to 50%.

As shown in

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Article

Scheme 1. Mechanism of Fenton Reactions of H O₂

formation of long-lived carbon-centered radicals led us to

propose an alternative reaction pathway in which the Ni species

does not cleave the C−H bond; instead, it reacts with mCPBA to

generate free radicals that abstract a hydrogen atom from the

C(sp )−H bond. However, because the nickel-catalyzed

reaction occurs with mCPBA instead of H O , the identity of

the species that cleaves the C−H bond in such a scenario was

unclear.

. Identity of the Free Radical Responsible for C−H

Bond Cleavage. To identify the radical that cleaves the C−H

bond during the reactions with mCPBA containing catalytic

amounts of nickel complex, we conducted the reactions of

mCPBA and Ni complexes with deuterium-labeled cyclohexane

(

2-d ) and adamantane (3) and compared the selectivity of

these reactions to the known selectivities for the reactions

involving abstraction of the hydrogen atom in a C−H bond by

various radicals. Figure 4A shows four mCPBA-derived free

radicals that might be formed in the reaction system containing

nickel: the 3-chlorobenzoyloxy radical (10), the hydroxyl radical

(

11), the 3-chlorophenyl radical (12), which can be formed by

decarboxylation of 10, and the 3-chlorobenzoylperoxy radical

13).

The selectivity of hydroxyl radical (11) for the oxidation of

(

Figure 4. (A) Free radicals derived from mCPBA that might cleave C−

H bonds in the catalytic reaction. (B) Tertiary to secondary selectivity

of free radicals for the oxidation of 3. (C) Photomediated formation of

adamantane is low. The 3°/2° ratios from oxidations of 3 that

involve cleavage of C−H bonds by radical 11 range from 0.4 to

benzoylperoxy radical from benzil under an atmosphere of O . (D)

.3 (Figure 4B, entries 1−3). These values are much smaller

Results of Ni-catalyzed oxidation of 2-d .

than those of Ni-catalyzed oxidation of 3 by mCPBA, which

range from 4.4 to 6.9. Thus, hydroxyl radical 11 is unlikely to be

the species that cleaves the C−H bond in this reaction.

If 3-chlorophenyl radical (12) were the major species that

cleaves the C−H bond in Ni-catalyzed oxidations of alkanes,

then the oxidation of deuterated cyclohexane (2-d ) would

observed that 87% of the chlorobenzene that formed contained

the deuterium label (see the Supporting Information). These

results further support our hypothesis that chlorobenzene (9) is

formed primarily by hydrogen atom transfer from solvent

molecules to radical 12.

aﬀord deuterated cyclohexanol (4a-d ) and deuterated cyclo-

hexanone (4b-d ) as the major products, along with a

The benzoylperoxy radical (13′) can be generated by the

stoichiometric amount of deuterated chlorobenzene (9-d ).

photomediated homolysis of benzil under an atmosphere of O

42,43

However, H NMR spectra of the reaction of 2-d with mCPBA

(Figure 4C).

To measure the selectivity of radical 13′ for the

and a catalytic amount of Ni complex 1a showed that this

reaction formed 4a-d₁₁and 4b-d₁₀in 26% and 8% yields,

oxidation of adamantane (3), we conducted the photochemical

oxidation of 3 with benzil and O in 1,2-dichloroethane (DCE).

respectively, but produced 9-d in only 2% yield (Figure 4D).

The 3°/2° ratios derived from the products of these reactions

range from 11.2 to 12.1 (Figure 4B, entry 4), which is higher

than those from Ni-catalyzed oxidations of 3 conducted in the

same solvent (Figure 4B, entry 5). Given the similar structures of

radicals 13 and 13′, it is likely that the 3°/2° selectivity for the

oxidation of 3 by these two radicals is similar. Therefore, the 3-

chlorobenzoylperoxy radical (13) is unlikely to be the species

that cleaves C−H bonds in Ni-catalyzed oxidations of alkanes.

Thus, the aroyloxy radical 10 is the most likely radical to

cleave the C−H bond. The BDE of the O−H bond in mCBA was

This result indicates that aryl radical 12 cannot be the major

intermediate that cleaves C−H bonds in hydrocarbons. The

large amount of byproduct 9 observed in the catalytic oxidations

of 2 and 3 (Figure 3B) was most likely formed by hydrogen atom

transfer (HAT) from solvent molecules, such as dichloro-

methane (DCM), to 12. This hypothesis is supported by the

detection of 1,1,2,2-tetrachloroethane in the reaction mixture,

which is the homocoupling product of dichloromethyl radicals

(

CHCl ·) that would form by hydrogen atom transfer from

DCM to 12. We also conducted the Ni-catalyzed oxidation of

reported to be 107.3 kcal/mol, which is higher than those of

cyclohexane by mCPBA with DCM-d as the solvent and

unactivated C−H bonds in alkanes and makes HAT from

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yield, corresponding to a 2 °/1 ° ratio of 1.9 ± 0.4 (Figure 6 A).

Article

alkanes to radical 10 thermodynamically favorable. The second-

order rate constant for the abstraction of a hydrogen atom from

adamantane is not a suitable substrate for this experiment (see

the Supporting Information).

by 4-methoxybenzoyloxy radical (14) was measured to be on

The reaction of peroxide 15 with alkane 16 in the presence of

−1 −1

the order of 10 M s , whereas the ﬁrst-order rate constant for

2 equiv of CBr furnished 17a in 10.4% yield and 17b in 5.5%

−1 44

decarboxylation of 14 was measured to be 10 −10 s . Given

the similarity between the structures of m-chloro- and p-

methoxy-substituted benzoyloxy radicals 10 and 14, it is likely

that the rate constants for abstraction of a hydrogen atom from

an unactivated C(sp )−H bond by these two radicals are similar

and that the rate of abstraction of a hydrogen atom by 10 would

be similar to that of the decarboxylation. This prediction based

on the literature values ﬁts with the observed oxidation process

and formation of chlorobenzene.

However, reliable data on the selectivity of aroyloxy radical 10

for the abstraction of hydrogen atoms from alkanes were needed

to assess more precisely whether this radical cleaves the C−H

bonds in Ni-catalyzed oxidations. Thus, we generated radical 10

in situ via the thermal decomposition of bis(3-chlorobenzoyl)-

peroxide (15), measured its selectivity for hydrogen-atom

abstraction of a model alkane, 2,2,4,4-tetramethylpentane (16),

and compared the selectivity of the metal-free bromination of 16

by peroxide 15 to that of Ni-catalyzed reactions (Figure 5 ). All

Figure 6. Illustration of the GC experiment for the detection of alkyl

hydroperoxide intermediates designed by Shul’pin.

The Ni-catalyzed bromination of 16 by mCPBA formed 17a in

35.2% yield and 17b in 17.9% yield, corresponding to a 2°/1°

ratio of 2.0 ± 0.2 (Figure 6B). The similarity between the

selectivity of the bromination reactions with diaroyl peroxide 15

and the process with the nickel complex and mCPBA strongly

suggests that radical 10 is the species that cleaves the C−H bond

in the catalytic system.

To assess further our proposal that the aroyloxy radical

derived from the aromatic peracid is the species that cleaves the

C−H bond in the catalytic reaction, we conducted reactions

with a diﬀerent peracid. We envisioned that the selectivity for

the Ni-catalyzed bromination of 16 would be diﬀerent for

reactions with aromatic peracids bearing diﬀerent substituents

than the chloride in mCPBA. Indeed, the Ni-catalyzed

bromination of 16 by 3,5-bis(triﬂuoromethyl)perbenzoic acid

(

18) furnished 17a in 14.7% yield and 17b in 13.4% yield,

corresponding to a 2°/1° ratio of 1.1 ± 0.1 (Figure 6C). This

ratio is lower than those from reactions involving m-

chlorobenzoyloxy radical 10 (Figure 6A,B) and further

corroborates our hypothesis that aroyloxy radicals derived

from aromatic peracids cleave the C−H bonds of alkanes in the

catalytic system.

5. The C−O Bond Formation Step. Having identiﬁed the

free radical responsible for C−H bond cleavage, we investigated

the step that forms the C−O bond. Three possible pathways can

lead to the formation of a C−O bond from the carbon-centered

radical generated by hydrogen-atom abstraction of the alkane by

Figure 5. Bromination of alkane 16 by (A) peroxide 15, (B) mCPBA

and Ni complex 1a, and (C) peracid 18 and Ni complex 1a. Conditions:

aroyloxy radical 10 (Scheme 2): (1) trapping by O to generate

(

A) 0.0625 mmol of 15, 10 equiv of 16, 4 equiv of CBr , DCM (0.0625

an alkylperoxy radical, which subsequently decomposes to form

alcohol and ketone products (eq 2−1); (2) trapping by a

putative nickel(III) hydroxide species, which would be

generated by the oxidation of the Ni(II) complex by mCPBA,

to form the alcohol product and a Ni(II) species (eq 2−2); (3)

trapping by mCPBA to aﬀord the alcohol product and radical 10

(eq 2−3).

M), 80 °C under N ; (B) 0.125 mmol of mCPBA, 5 equiv of 16, 2 equiv

of CBr , 0.1 mol % 1a, DCM (0.125 M), 50 °C under N . (C) 0.125

mmol of 18, 5 equiv of 16, 2 equiv of CBr , 1 mol % 1a, DCM (0.125

M), 50 °C under N . Average of eight repeated experiments. Average

of three repeated experiments.

reactions were conducted in the presence of CBr , which is well-

known to trap carbon-centered radicals rapidly. In this case, the

distribution of products 17a and 17b from bromination at the

secondary and primary C−H bonds accurately reﬂects the

selectivity in the hydrogen-atom transfer step. The model

substrate 16 was chosen because radicals derived from CBr₄,

The decomposition of alkylperoxy radicals usually forms the

corresponding alcohol and ketone products in an ∼1:1 ratio,

whereas the Ni-catalyzed oxidation of 2 gave A/(K + E) ratios

between 3.1 and 3.5 (Table 1A). Furthermore, the yield and

selectivity of the catalytic oxidations of 2 and 3 under an

such as CBr ·, do not cleave the strong primary and secondary

atmosphere of N were similar to those of the reactions under

air. These straightforward observations suggest that the

C−H bonds in alkane 16 and, therefore, do not interfere with

the measurement of the selectivity of hydrogen-atom abstraction

by aroyloxy radical 10. The tertiary C−H bonds in adamantane,

formation of the C−O bond does not involve O and that the

steps in eq 2−1 are unlikely to be the major ones forming the C−

however, can be cleaved by these radicals derived from CBr , so

O bond in the Ni-catalyzed oxidations. Nonetheless, we decided

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society

Article

Scheme 2. Three Possible Pathways for the Formation of C−O Bonds

to assess more precisely whether trapping of alkyl radicals by O₂

occurred and, if so, what percentage of the oxidized products

were formed from O₂.

To assess this pathway further, we determined the amount of

alkylperoxy intermediates in the product mixture that would

potential formation of alcohol by reaction of the alkyl radical

with a nickel hydroxide species (Scheme 2, eq 2−2). If the C−O

bonds were formed by this species, then the cis fraction of the

alcohols formed from the reactions of 1,2-dimethylcyclohexanes

would be expected to depend on the electronic and steric

properties of the nickel species, which in turn would depend on

the identity of the ligand.

form by the trapping of the alkyl radical with O . Shul’pin et al.

6,47

reported an experiment for this purpose (Figure 6).

Alkylperoxy intermediates, such as cyclohexyl hydroperoxide

19), decompose by gas chromatography (GC) to generate the

Having ruled out the two pathways described above, we

considered that the trapping of carbon-centered radicals by

mCPBA (Scheme 2, eq 2−3) would be the major pathway for

the formation of the C−O bond. Indeed, the reaction of an alkyl

radical with an aliphatic peracid by a free-radical chain process

has been well-established by many examples of decarboxylative

(

corresponding alcohol and ketone products 4a and 4b in a ∼1:1

ratio. Treatment of a reaction mixture containing alcohol 4a,

ketone 4b, and intermediate 19 with an excess of reductants,

such as PPh , reduces 19 to 4a in quantitative yield without

aﬀecting the amount of alcohol or ketone formed before the

formation of alcohols from aliphatic peracids.

addition of PPh . Thus, if intermediate 19 is present in a reaction

6. The Free-Radical Chain Mechanism. Having inves-

tigated both the C−H bond-cleaving and the C−O bond-

forming steps, we propose a free-radical chain mechanism for the

Ni-catalyzed oxidation of unactivated C(sp )−H bonds by

mCPBA (Scheme 3). Contrary to the hypotheses in the

mixture, the ratios of alcohol to ketone (A/K) derived from the

GC trace of the mixture before and after the treatment with PPh₃

will be diﬀerent. Moreover, the percentage of 19 in the total

amount of oxidized products can be calculated from these ratios.

The A/K ratio derived from GC traces of the mixture from the

Ni-catalyzed oxidation of 2 under an atmosphere of N after 5

Scheme 3. Free-Radical Chain Mechanism of Ni-Catalyzed

Oxidation of Unactivated C(sp )−H Bonds

min before the addition of PPh was identical to that after the

addition of PPh (Table 3, entries 1 and 2). This result indicates

Table 3. GC Results of the Ni-Catalyzed Oxidation of

Cyclohexane under N and Air

entry

N /air

treatment with PPh₃

A/K

yes

4.6 ± 0.1

4.5 ± 0.0

6.1 ± 0.8

4.2 ± 0.7

N₂

air

Conditions: 0.125 mmol mCPBA, 7.5 equiv 2, 0.1 mol % 1a, DCM/

MeCN (3:1, 0.125 M), 50 °C, 5 min. Arithmetic mean of three

repeated experiments.

20,25,26

literature

that Ni-oxygen intermediates cleave C−H

that intermediate 19 was not formed and that molecular O was

bonds, our data suggest that the Ni complex catalyzes the

reaction of mCPBA to generate the 3-chlorobenzoyloxy radical

(10) among other products (eq 3−1). Equation 3−1 likely

consists of several redox reactions, but our data do not allow

conclusions about the mechanism of this step. Radical 10

abstracts a hydrogen atom from the alkane to form the mCBA

byproduct and a carbon-centered radical (eq 3−2), which then

reacts with mCPBA to aﬀord the alcohol product and regenerate

radical 10 (eq 3−3), thus propagating the radical chain. As

not generated in situ during the reaction under N . The A/K

ratio derived from GC traces of the reaction conducted under air

before the addition of PPh was 4.2 ± 0.7, and the ratio after the

addition of PPh was 6.1 ± 0.8 (Table 3, entries 3 and 4). The

small diﬀerence between these ratios suggests that some amount

of intermediate 19 was formed under air by the pathway shown

as eq 2−1 in Scheme 2. However, the percentage of 19 in the

total amount of oxidized species (4a + 4b + 19) was estimated to

be only 10% based on these two ratios (see the Supporting

Information for details of the calculation). Thus, the trapping of

discussed previously, the trapping of alkyl radicals by O is a

minor side reaction under air (eq 3−4). Decarboxylation of

radical 10 to generate the 3-chlorophenyl radical 12, which

captures a hydrogen atom from solvent molecules to form the

chlorobenzene byproduct (eq 3−5), competes with the reaction

of 10 with a C−H bond (eq 3−2).

alkyl radicals by O , even under air, was not the major pathway

for the formation of the C−O bond in the catalytic reactions.

The lack of eﬀect of the ligands on the yield and selectivity of

the Ni-catalyzed oxidation of alkanes does not support the

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society

California, Berkeley, California 94720, United States;

Article

On the basis of this mechanism, the identity of the Ni complex

inﬂuences the rate of decomposition of mCPBA and hence the

rate of formation of radical 10, but it does not change the

selectivity for reaction at one C−H bond over another. This

conclusion is consistent with our observation that reactions

catalyzed by Ni complexes with more sterically hindered ligands

are slower, but the selectivities of these reactions are similar to

those catalyzed by complexes with less hindered ligands. This

radical chain mechanism, in which the C−H bond is not cleaved

by a nickel complex, reconciles the combination of low reactivity

X-ray crystallographic data for complex 1g (CIF )

X-ray crystallographic data for complex 1h (CIF)

AUTHOR INFORMATION

Corresponding Author

■

John F. Hartwig − Department of Chemistry, University of

orcid.org/0000-0002-4157-468X ; Email: jhartwig@

berkeley.edu

of Ni-oxygen species toward strong C(sp )−H bonds and the

Author

well-documented formation of oxidation products in high yield

from Ni-catalyzed oxidations occurring at strong aliphatic C−H

bonds.

Yehao Qiu − Department of Chemistry, University of California,

Berkeley, California 94720, United States; orcid.org/0000-

002-2650-0703

Alexanian and co-workers achieved tunable, selective

Complete contact information is available at:

https://pubs.acs.org/10.1021/jacs.0c09157

chlorination of C(sp )−H bonds via free-radical pathways by

49,50

modifying the substituents on the N-chloroamide reagents.

The free-radical mechanism we propose for the Ni-catalyzed

oxidation of unactivated alkanes suggests that novel, substituted

aromatic peracids, likewise, could modify the selectivity of the

oxidation of C(sp )−H bonds in complex molecules and

polymers.

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

This work was supported by the Director, Oﬃce of Science, of

the U.S. Department of Energy under Contract No. DE-

AC0205CH11231. We gratefully acknowledge Dr. H. Celik for

assistance with the NMR experiments, Dr. N. Settineri for the X-

ray crystallography, Dr. M. Zhang in the LBL Catalysis Facility

for the IR and ESI HRMS experiments, Dr. E. Kreimer for the

elemental analysis, and Dr. R. Chatterjee for the EPR analysis.

Instruments in the CoC-NMR are supported in part by NIH

S10OD024998. Y.Q. thanks Dr. A. Bunescu, Dr. L. Chen, and

Dr. P.-f. Ji for helpful discussions.

CONCLUSION

In conclusion, we report detailed mechanistic investigations of

the oxidation of unactivated C(sp )−H bonds by mCPBA

■

catalyzed by Ni complexes coordinated by nitrogen-based

ligands. We show the absence of an eﬀect of the ligand on the

yield and selectivity of this reaction, as well as a clear correlation

between reaction rates and the steric hindrance of the ligands.

Experiments with radical clocks indicate that this reaction

generates a carbon-centered radical that is suﬃciently long-lived

to epimerize before the formation of the C−O bond.

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