Catalytic Oxidative Cleavage Reactions of Arylalkenes by tert-Butyl Hydroperoxide - A Mechanistic Assessment

Article abstract of DOI:10.1021/acs.joc.9b03346

Oxidative cleavage reactions of arylalkenes by tert-butyl hydroperoxide that occur by free radical processes provide access to carboxylic acid or ketone products. However, the pathway to these cleavage products is complex, initiated by regioselective oxygen radical addition to the carbon-carbon double bond. Subsequent reactions of the initially formed benzyl radical lead eventually to carbon-carbon cleavage. Thorough investigations of these reactions have identified numerous reaction intermediates that are on the pathways to final product formation, and they have identified a new synthetic methodology for the synthesis of peroxy radical addition-induced hydroperoxide formation.

Full text of DOI:10.1021/acs.joc.9b03346

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Article
Catalytic Oxidative Cleavage Reactions of Arylalkenes
by tert-Butyl Hydroperoxide – A Mechanistic Assessment
Yong-liang Su, Luca De Angelis, Linh Tram, Yang (Kevin) Yu, and Michael P Doyle
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03346 • Publication Date (Web): 28 Jan 2020
Downloaded from pubs.acs.org on February 2, 2020
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Catalytic Oxidative Cleavage Reactions of Arylalkenes by tert-Butyl Hydroperoxide – A Mechanistic
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Assessment
Yong-Liang Su,‡ Luca De Angelis,‡ Linh Tram, Yang Yu, and Michael P. Doyle*
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Department of Chemistry, The University of Texas at San Antonio, San Antonio, Texas 78249, United
States
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E-mail: michael.doyle@utsa.edu
OOtBu
HOO
M+
O2
+
Z
TBHP
O
O
OH
or
Z
Z
Z
Intermediates
OOtBu
OOtBu
M+
+
TBHP
Z
ABSTRACT: Oxidative cleavage reactions of aryl-alkenes by tert-butyl hydroperoxide that occur by free
radical processes provide access to carboxylic acid or ketone products. However, the pathway to these
cleavage products is complex, initiated by regioselective oxygen radical addition to the carbon-carbon
double bond. Subsequent reactions of the initially formed benzyl radical lead eventually to carbon-carbon
cleavage. Thorough investigations of these reactions have identified numerous reaction intermediates
that are on the pathways to final product formation, and they have identified a new synthetic
methodology for the synthesis of peroxy radical addition induced hydroperoxide formation.
INTRODUCTION
The oxidation of alkenes is a complex area for investigation.1 Extensive studies have been directed to
epoxidation2 and dihydroxylation,3 as well as to allylic oxidation4 and oxidative cleavage.5 The preferred
oxidant is molecular oxygen, but its hydroperoxide counterparts often overcome the mechanistic
difficulties associated with the activation of molecular oxygen. Of the hydroperoxides that have been
employed, hydrogen peroxide is the preferred reagent, but tert-butyl hydroperoxide (TBHP) is more stable
and is a suitable replacement for hydrogen peroxide in investigations of peroxidation reactions.6 The
formation and reactions of the relatively selective tert-butylperoxy radical are integral to understanding
the associated free radical processes.7
An increasing number of investigations have utilized TBHP in addition reactions with styrenes.8 Addition
occurs by either the combination of TBHP with another oxidant, as with iodine and TBHP to produce tert-
butyl hypoiodide,9 or via a generally presumed catalyst-dependent free radical pathway involving the tert-
butylperoxy radical. In the free radical pathway the tert-butylperoxy radical facilitates formation of a new
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radical, generally by hydrogen atom abstraction, that undergoes initial addition to styrene, and the
resulting radical either produces a mixed peroxide8c,8f or the corresponding ketone that is presumably
formed by the Kornblum-DeLaMare reaction10 of the mixed peroxide (Scheme 1). Formation of the mixed
peroxide product can occur by the combination of the benzyl and tert-butylperoxy radicals8c,f or by
oxidation of the initially formed benzyl radical to the corresponding benzyl cation followed by its
nucleophilic trapping by TBHP.9 Alternatively, with transition metal catalysts, the possibility exists of
peroxy radical transfer from a metal peroxide-ligated intermediate that would form the observed
product.8b However, none of these considerations address the question of when or how carbon-carbon
cleavage occurs.
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Scheme 1. Oxidative Reactions of Styrenes Involved in TBHP
Kornblum-DeLaMare
tBuOO
Ar
R
O
R
tBuOO
reaction
R
R
Ar
Ar
Ar
RESULTS AND DISCUSSION
Rhodium(II) caprolactamate [Rh2(cap)4] has been our preferred catalyst for the generation of the tert-
butylperoxy radical because of its low oxidation potential11 and a catalytic cycle that generates tBuOOꞏ
by both oxidation and reduction of Rh2(cap)4 (Scheme 2). The amount of catalyst used determines the rate
for generation of tBuOOꞏ so that a low catalyst loading is generally used. This catalyst has been preferred
for allylic and propargylic oxidations,12 benzylic,13 and phenolic oxidations,14 as well as the oxidative
Mannich reaction,15 and the mechanistic details of these transformations have been elaborated.4b,16
Copper halides have also been used effectively for allylic oxidation17 and the oxidative Mannich reaction.18
Scheme 2. Catalytic Formation of the tert-Butylperoxy Radical
H2O
MLn
tBuOOOOtBu
tBuOOH
tBuOO
tBuOO
+
O2
tBuOOtBu
tBuOOH
HO-MLn
tBuOH
tBuOO
tBuO
tBuOOH
A recent report by Liu and coworkers on the TBHP oxidation of styrene in chloroform claimed the
formation of dichloromethyl/tert-butylperoxy radical addition products in high yield without the
involvement of a metal catalyst (Scheme 3, a).19 The authors report that this reaction occurred by a free
radical process. However, our attempts to repeat this reaction were unsuccessful, and we were unable to
obtain the reported product under the specified reaction conditions, or to detect any reaction of TBHP
with styrene at room temperature without a metal catalyst over very long reaction times. Instead, we
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discovered that the combination of substituted styrenes, chloroform, and TBHP in the presence of
diisopropylethylamine with catalytic amounts of copper iodide or Rh2(cap)4 forms -peroxy-,-
dichloropropylbenzene products in high yield (Scheme 3, b).20 The formation of an -aminoradical from
DIPEA by the tert-butylperoxy radical circumvents preferential hydrogen atom transfer from chloroform
in favor of halogen atom transfer by the -aminoradical, thereby releasing the halomethyl radical for
addition to alkenes. Without the tertiary amine this combination of reactants produced a complex mixture
of products that lead to oxidative cleavage of the carbon-carbon double bond, and this process is the
subject of this investigation.
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Scheme 3. Selective Chlorine Atom Abstraction from Chloroform to Form α-Peroxy-β,β-
dichloropropylbenzenes.
Liu' work:
TBHP (3.0 eq)
OOtBu
w and w/o catalyst
CHCl2
a
( )
+
CHCl3
Ph
Ph
rt, solvent
62% yield (reported)
0% yield (found)
Our previous work:
tBuOO
R1
CuI (1 mol %)
CHCl2
b
(
)
Z
Z
TBHP (5.0 eq.), DIPEA (5.0 eq.)
CHCl3:acetone (1:1, 0.2 M), rt
R1
R1 = H or alkyl
61-97% yield
The reactions of styrenes with TBHP in the presence of free radical generating catalysts were
investigated to determine their reaction pathways. Products were isolated from reactions performed on
a large scale at room temperature. Rhodium(II) caprolactamate was selected as the catalyst for initial
studies because of its solubility in polar and low polarity solvents.4a Treatment of p-methylstyrene with T-
HYDRO (70% aqueous TBHP) in solvents of different polarity at room temperature, catalyzed by 1 mol%
dirhodium caprolactamate, produced a complex mixture of oxidation products (Scheme 4), each member
of which was individually isolated and characterized, and their presence in reaction mixtures was
1
determined by HPLC and/or H NMR analyses.21 Several of these products (3a, 8a, and 9a) were
unexpected but were confirmed in multiple separate experiments.
Scheme 4. Products Formed from p-Methylstyrene in Rh2(cap)4 Catalyzed Reactions with TBHP in
Various Solvents
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OOH
OOtBu
OOtBu
OOtBu
OtBu
OOtBu
4
5
6
7
8
9
Me
Me
Me
Me
Me
Me
2a
3a
4a
O
OH
O
OOtBu
T-HYDRO (5.0 eq)
OOtBu
Me
Rh2(cap)4 (1 mol%)
Solvent, rt, 18 h
Me
1a
5a
6a
7a
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O
O
OH
OH
O
N
OH
Rh
Rh
Me
Me
8a
9a
10a
Rh2(cap)4
A majority of the products described in Scheme 4 were obtained from TBHP reactions at room
temperature in chloroform catalyzed by Rh2(cap)4 (entries 1 and 2, Table 1), and they were confirmed by
spectral and chromatographic analysis. Percent conversion was greater with the use of T-HYDRO [(70%
TBHP in water, (entry 1, Table 1)] than with anhydrous TBHP (entry 2, Table 1). The loss of reactant p-
methylstyrene due to polymerization or related processes was not determined, but the total yield
obtained from multiple experiments under the same conditions does accurately reflect the molar amount
of oxidized reactant. The same reactions performed in chloroform or water with CuI as the catalyst under
the same conditions were much more sluggish (entries 11-14, Table 1) and incomplete even after a
reaction time of 7 days due to the limited solubility of CuI in these solvents. Percent conversion is based
on reacted p-methylstyrene, and total yield refers to the experimentally determined amounts of oxidation
products. No reaction occurred without catalyst. Bis-peroxide 2a was a major product, and this compound
was previously formed from the Mn(OAc)3 catalyzed reaction of TBHP in acetonitrile at room temperature
(63% yield).8b Compounds 4a and 5a were inseparable by HPLC, but their copresence was confirmed by
1H NMR spectra of the reaction mixtures and, for an accurate and distinctive identification, HRMS spectra
confirmed both 4a and 5a (see SI for more information). A surprising and unexpected product was epoxide
8a whose presence was confirmed spectrally and chromatographically, but also by the presence of vicinal
diol 9a.
Table 1. Solvent Dependence on the Catalytic Oxidation of p-Methylstyrene by TBHPa
Entry
Solvent
Conv.(%)b 2a (%) 4a/5a (%) 6a (%) 7a (%) 8a (%) 9a (%) 10a (%) Total yield
(%)c
Reactions catalyzed by Rh2(cap)4:
1
2
3
4
CHCl3
CHCl3
DCM
DCE
75
58
94
99
15
11
4
18
4
3
8
13
21
2
1
2
60
36
69e
76
d
nd
13
14
nd
8
nd
1
nd
20
33
8
3
5
8
7
6
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Hexane
68
2
5
5
4
nd
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2
2
4
6
24
30
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44
71
50
51
40f
56g
6
Cyclohexane 72
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3
11
2
10
10
nd
nd
nd
7
MeCN
Acetone
MTBE
H2O
60
4
18
4
7
8
97
3
7
11
9
24
8
9
60
14
23
nd
3
3
10
100
2
nd
17
9
Reactions catalyzed by CuI:
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CHCl3
CHCl3
H2O
H2Oh
H2Oi
33
44
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60
6
nd
nd
nd
nd
nd
nd
10
12
6
nd
nd
nd
nd
nd
nd
nd
nd
nd
7
10
19
nd
5
nd
nd
nd
11
nd
3
nd
nd
nd
nd
nd
nd
20
31
6
h
5
28
4
4
nd
nd
H2Oh,i
70
2
nd
nd
5
aReaction conditions: T-HYDRO (2.0 mmol) was added dropwise to a pre-sonicated solution of 1a (0.4 mmol), catalyst (1.0 mol%)
and 2.0 mL of solvent, and the reaction was continued for 18 h at rt. The yield of each product was determined by HPLC analysis
and calibrated by1H-NMR spectral analysis of the reaction mixture with 1,3,5-trimethoxybenzene as the internal standard. Values
b
provided in this table are from multiple experiments, and the yields are averaged (+/- 1-5%). Percent conversion is based on
reacted p-methylstyrene. cThe sum of product yields for products listed in Scheme 3. dUsing TBHP in decane. eIncludes 13% 3a.
fIncludes 2% 3a. gIncludes 5% 3a. hReaction time was 7 days. iUsing DIPEA (1.1 eq). nd = not detected
We anticipated that the reactions of TBHP with p-methylstyrene would be solvent dependent. The data
in Table 1 show that p-methylstyrene is fully consumed or nearly so in DCE, DCM, acetone, and water with
catalysis by Rh2(cap)4, but not in hydrocarbon solvents, probably due to fast decomposition of TBHP in
hydrocarbon solvents. Rapid evolution of oxygen was observed after TBHP was added when hexane and
cyclohexane were used as the solvents. Coordination by acetonitrile to rhodium(II) caprolactamate at its
axial coordination sites accounts for the low percent conversion in this polar solvent.11,22 The major
products in Rh2(cap)4-catalyzed reactions, with few exceptions, are the vicinal bis-tert-butylperoxide 2a
and p-toluic acid 10a. Surprisingly, 2-(tert-butoxy)-1-(tert-butylperoxy)-1-(p-toluyl)ethane (3a) was
identified in those reactions where H2O or MTBE were used as solvents in less than 5%, but its regioisomer
was not detected. This compound presumably arises by addition of the initially formed tert-butoxy radical
to p-methylstyrene in competition with its favored hydrogen atom abstraction from TBHP (Scheme 5).23
Unexpectedly, styrene oxide 8a and diol 9a were observed as minor products (generally < 5%) by both
NMR and HPLC analyses, but in higher amounts in CHCl3, DCE and acetone. Although unexpected,
epoxidation of styrene is not an uncommon process in metal-catalyzed reactions of TBHP.8d Although
oxygen transfer from peroxides is generally attributed to metal-oxo intermediates,24 this is unlikely with
Rh2(cap)4, and the mechanism for epoxide formation in the reactions reported in Table 1 is uncertain.
Scheme 5. Formation of 3a in the Rh2(cap)4 Catalyzed Oxidation of 1a by TBHP
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OOtBu
OtBu
OtBu
tBuOOH
Rh2(cap)4
tBuOO
Me
Me
tBuO
tBuOOH
3a
Rh2(cap)4OH
Me
1a
tBuOH
tBuOO
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With CuI as the catalyst (1.0 mol %) the rate of oxidation of p-methylstyrene by TBHP in water and
chloroform was slow compared with reactions catalyzed by Rh2(cap)4. Only 10% 4a/5a and 10% 8a were
detected after 18 h from the reaction in chloroform with two-thirds of the starting material remaining
(entry 11, Table 1), and percent conversion did not increase significantly when the reaction time was
extended to 7 d (entry 12, Table 1). Doubling the amount of TBHP had no effect on percent conversion or
on the yield of oxidation products. A similar slow conversion was observed in water even using DIPEA (1.1
eq) as a ligand to solubilize CuI (entries 13-16, Table 1). The contrasting behavior between CuI and
Rh2(cap)4 suggests an intrinsically different outcome from their reactions with TBHP.
To determine the reaction pathways in product formation, the time courses for reactions in chloroform
and water were performed using Rh2(cap)4 as catalyst (Figure 1 and 2). Anticipating that the formation of
2a and 4a/5a were competitive, these products were monitored from the reaction performed in
chloroform; and Figure 1 shows the complementary buildup of both products; the formation of 4a/5a is
faster than formation of bis-tert-butyl peroxide 2a which is probably related to the initial sequestering of
available oxygen in the reaction solution that is unavoidable with TBHP.
Figure 1. Yield
curves for 2a and 4a/5a in CHCl3. T-HYDRO (2.0 mmol) was added dropwise to 1a (0.4 mmol), Rh2(cap)4 (1 mol%) in CHCl3 (2.0
mL) and the reaction was monitored the first 30 minutes and every hour for 18 h at room temperature. The yield of each product
was determined by HPLC analysis.
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In water, by contrast, p-methylstyrene 1a is consumed rapidly, and just after 4 h its molar amount is
less than 5% (Figure 2). The initial rapid consumption of 1a occurs with the formation of the bis-tert-
butylperoxide 2a and styrene oxide (8a) as major products. After 3 h the amount of 2a remains at 25%,
whereas the amount of epoxide 8a increases initially then decreases to less than 5% after 3 h. The
formation of p-toluic acid 10a occurs late in the reaction, reaching a maximum amount of 17% at 18 h.
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Figure 2. Percentage profiles of 1a, 2a, 8a and 10a in H2O. T-HYDRO (2.0 mmol) was added dropwise to a pre-sonicated solution
of 2.0 mL H2O, 1a (0.4 mmol), and Rh2(cap)4 (1 mol%). The reaction was monitored the first 30 minutes and every hour for 18 h
at room temperature. The yield of 1a and each product was determined by HPLC analysis.
Fascinated by the competing oxygenation reaction described in Figure 1, the oxidation reaction was
performed under an atmosphere of oxygen instead of air (Scheme 6). Under these conditions, bis-
peroxide 2a was not formed, and hydroperoxide 4a was formed in 85% yield. Under these conditions a
variety of hydroperoxide compounds 4 were prepared in high isolated yields, suggesting the generality of
this process. Thus, the benzyl radical that is formed by tert-butylperoxy radical addition to styrene reacts
competitively with either dioxygen or the tert-butyl peroxy radical in the first stage of the oxidative
cleavage reaction. Dioxygen is an effective trap for the benzyl radical, even with -cyclopropylstyrene
whose benzyl radical is subject to cyclopropylcarbinyl radical ring opening.25
Scheme 6. Synthesis of hydroperoxide products 4a
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R2
R2
Rh2(cap)4 (0.25 mol%)
OOtBu
OOH
3
4
5
6
7
8
9
Ar
1 or 14
OOH
Ar
T-HYDRO (5.0 eq), O2 (1 atm)
CHCl3, rt
4
OOH
OOH
OOtBu
OOtBu
OOtBu
OOtBu
OOtBu
CF3
Me
MeO
b
b
b
4a
4b
4c
: 78%
: 85%
: 86%
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OOH
OOH
Me
OOH
OOtBu
4d
4e
4f
: 70%
: 91%
: 90%
aConditions: T-HYDRO (2.0 mmol), Rh2(cap)4 (0.25 mol%), 1 or 14 (0.4 mmol), CHCl3 (4.0 mL), O2 (1 atm), rt. Isolated yield.
bRh2(cap)4 (0.25 mol%), T-HYDRO (4.0 mmol).
Shyu and coworkers have reported the copper(II) chloride-catalyzed TBHP oxidation of styrene and
geminal disubstituted alkenes to carbonyl compounds at room temperature from which moderate to
good yields of the corresponding cleavage products were obtained.26 However, benzaldehydes were
reported as the only products in reactions with styrenes, and formation of the corresponding benzoic
acids was not reported. Yet in reactions catalyzed by Rh2(cap)4 and CuI, the carboxylic acid cleavage
product is a major product, and p-tolualdehyde is a minor product (Table 1). When the reaction
temperature is increased to 80C, the overall yield of carboxylic acid 10a increased (Table 2). The optimum
solvent was found to be water for reactions catalyzed by Rh2(cap)4 (entry 10, Table 2). CuI also catalyzed
the formation of p-toluic acid 10a in moderate yields (entries 12-13, Table 2). Using CuCl2 as the catalyst
instead of CuI, p-toluic acid 10a was formed in low yield (entry 14, Table 2) and p-tolualdehyde was not
detected. When the reaction catalyzed by Rh2(cap)4 was conducted under an oxygen atmosphere, the
yield of p-toluic acid was increased to 76% (entry 11, Table 2).
Table 2. Screening reaction condition for the catalytic oxidation of 1aa
O
Rh2(cap)4 (1 mol%)
OH
T-HYDRO (5.0 eq), solvent, 80oC, 24 h
Me
Me
1a
10a
Entry
Solvent
CHCl3
Catalyst
Rh2(cap)4
Rh2(cap)4
Rh2(cap)4
Rh2(cap)4
Rh2(cap)4
Rh2(cap)4
Rh2(cap)4
Rh2(cap)4
Rh2(cap)4
Rh2(cap)4
Yield (%)b
48
1
2
3
4
5
6
7
8
9
DCM
DCE
55
58
62
61
45
57
35
64
Hexane
Cyclohexane
MeCN
Toluene
MTBE
H2O
H2O
10c
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H2O
CHCl3
H2O
Rh2(cap)4
CuI
CuI
CuCl2
76e
51e
18e
38e
H2O
5
aReaction conditions: T-HYDRO (2.0 mmol) was added to a pre-sonicated solution of 1a (0.4 mmol), catalyst (1 mol%) and 2.0
mL solvent, and the reaction was continued for 24 h at 80oC. bUnless indicated otherwise, isolated yields are reported. c4.0 eq
NaOH was added as the additive. dThe reaction was conducted under an oxygen atmosphere. eThe yield of the p-toluic acid was
determined by HPLC analysis.
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A series of experiments was performed to elucidate the mechanism of this oxidative cleavage reaction.
1-[1,2-Bis(tert-butylperoxy)ethyl]-4-methylbenzene 2a, 1-[2-(tert-butylperoxy)-1-hydroperoxyethyl]-4-
methyl-benzene 4a, and 2-(tert-butylperoxy)-1-(p-tolyl)ethan-1-one 6a were separated from the reaction
mixture, and they were separately subjected to the reaction conditions to determine if these compounds
were intermediates in the formation of p-toluic acid (Schemes 7-13). Bis-peroxide 2a was treated with T-
HYDRO in water at 80℃ with catalysis by Rh2(cap)4, and oxidative cleavage accounted for the majority of
product formation (Scheme 7). However, nearly 20% of reactant remained after 18 h, and only 41% of
reacted 2a was converted to p-toluic acid. In contrast, with CuI as the catalyst α-keto peroxide 6a was
formed, but p-toluic acid 10a was produced in less than 20% yield, suggesting the possible limitations of
unligated CuI. Using 1.1 eq of DIPEA to solubilize CuI, caused conversion of bis-peroxide 2a to p-toluic acid
10a in more than 70% of yield. Hydrogen atom abstraction from the benzylic position of 2a followed by
cleavage of the O-O bond, similar to that previously reported for allylic oxidations by TBHP,12c accounts
for the formation of α-keto peroxide 6a, but its subsequent oxidative cleavage to p-toluic acid is not
mechanistically evident in these experiments but could arise from initial cleavage of the O-O bond.
Scheme 7. Oxidation Products of Bis-peroxide 2aa
O
O
OOtBu
OOtBu
O
catalyst (1 mol%)
OOtBu
OH
+
T-HYDRO (5.0 eq), H2O, 80oC, 18 h
+
Me
Me
Me
Me
6a
7a
10a
2a
Rh2(cap)4
CuI
19%
37%
<1%
3%
<1%
2%
41%
19%
72%
24%
<1%
CuI, DIPEA (1.1 eq)
1%
aConditions: T-HYDRO (2.0 mmol), 2a (0.4 mmol), catalyst (1 mol%), water (2.0 mL), 80 oC, 18 h. The percentage of each compound
compared with the initial amount of 2a was determined by HPLC analysis. The values below the starting material are the
percentage of the remaining 2a after the reaction was done.
Hydroperoxide 4a, formed by dioxygen trapping of the benzyl radical intermediate, undergoes initial O-
O cleavage similar to that of TBHP with Rh2(cap)4 as the catalyst at room temperature (Scheme 2), and the
products formed by this catalytic reaction are solvent dependent (Scheme 8). In chloroform, less than 50%
of hydroperoxide 4a is converted to products, but in water ketoperoxide 6a and oxidative cleavage
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product 10a are the major products at room temperature. At 80℃, hydroperoxide 4a is converted to p-
toluic acid in 73% of yield. This is an example of a secondary alkoxy radical acting as a hydrogen atom
acceptor (giving 5) and a hydrogen atom donor (giving 6)27 or undergoing C-C cleavage to form p-
tolualdehyde28 and, subsequently, p-toluic acid (Scheme 9). In contrast, oxidative cleavage of the O-O
bond of 4a is very slow with CuI as the catalyst until an organic base (DIPEA) is added, and only then does
4a react at a reasonable rate. In water the major product is alcohol peroxide 5a, but in chloroform
oxidative cleavage product 7a is the major product. The origin of 9a is uncertain.
9
10
11
12
13
14
15
16
17
18
19
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Scheme 8. Oxidation Products of the Hydroperoxide 4aa
OH
O
O
OH
O
OOH
catalyst (1mo%)
T-HYDRO (5.0 eq)
OOtBu
+
OOtBu
OH
OOtBu
OH
+
+
+
rt, 18h
Me
Me
Me
Me
Me
Me
4a
5a
6a
7a
9a
10a
Rh2(cap)4, CHCl3
Rh2(cap)4, H2O
57%b
9%b
15%b
21%c
<1%c
<1%b
<1%c
8%b
<1%b
7%c
1%b
7%c
<1%c
<1%c
17%b
58%c
<1%c
<1%c
38%b
<1%c
22%c
73%c
7%b
Rh2(cap)4, H2O, 80 °C
<1%c
<1%c
12%b
<1%c
CuI, DIPEA (1.1 eq), CHCl3 5%b
CuI, DIPEA (1.1eq), H2O
<1%c
12%c
aConditions: T-HYDRO (1.0 mmol), 4a (0.2 mmol), catalyst (1 mol%), solvent (2.0 mL), 18 h. The values below the starting material
are the percentage of the remaining 4a after the reaction was done. bThe percentage of each compound compared with the initial
1
amount of 4a was determined by H-NMR spectral analysis of the reaction mixture using 1,3,5 trimethoxybenzene as internal
standard. cThe percentage of each compound compared with the initial amount of 4a was determined by HPLC analysis.
Scheme 9. Oxidative Decomposition of Secondary Hydroperoxide 4
OH
OOtBu
S
Ar
H
5
SH
OH
O
O
O
OOtBu
OOtBu
OOtBu
Ar
Ar
Ar
H
H
MLn LnM-OH
S
SH
6
4
O
CH2OOtBu
+
Ar
H
S = Substrate
7
Treatment of ketoperoxide 6a with T-HYDRO in water with Rh2(cap)4 and CuI catalysis gave the results
described in Scheme 10. T-HYDRO efficiently converts 6a to p-toluic acid under catalysis by Rh2(cap)4 and
CuI in water at room temperature. At 80 ℃ percent conversion is higher, as is the yield of p-toluic acid,
with both catalysts. Oxidative cleavage of 6a occurs at a much slower rate without catalyst. In contrast,
the oxidation of 6a in chloroform or cyclohexane by TBHP at room temperature under catalysis by
Rh2(cap)4 produces hemiketal 11a in 15% and 28% yield respectively. 11a was also identified through HR-
MS from the oxidative reaction of 1a. Increasing the temperature at 80℃ in chloroform, the percent
conversion of ketone peroxide 6a to the p-toluic acid is 75%. The oxidation of 6a occurs by hydrogen atom
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abstraction to form an intermediate α-keto radical, which is trapped by molecular oxygen, then hydrogen
atom capture to form a hydroperoxide that undergoes O-O cleavage catalyzed by Rh2(cap)4 to form the
hemiketal 11a (Scheme 11).
Scheme 10. Oxidation Products of the Ketoperoxide 6aa
8
9
O
O
O
O
OOtBu
OH
catalyst (1 mol%)
OOtBu
OH
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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41
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43
44
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53
54
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60
T-HYDRO (5.0 eq), H2O, temp., 24 h
Me
Me
Me
Me
10a
7a
11a
6a
25%b
5%c
<1%b
<1%c
<1%f
6%f
63%b
70%c
8%f
<1%b
<1%c
15%f
3%f
Rh2(cap)4, rt
Rh2(cap)4, 80°C
62%f
<1%f
<1%f
7%f
Rh2(cap)4, CHCl3, N2, rtd
Rh2(cap)4, CHCl3, N2, 80°Cd
Rh2(cap)4, cyclohexanee
CuI, DIPEA (1.1eq), rt
CuI, DIPEA (1.1 eq), 80°C
no catalyst, 80°C
75%f
42%f
76%f
91%f
14%b
<1%f
<1%f
<1%f
<1%b
28%f
<1%f
<1%f
<1%b
<1%f
80%b
aConditions: Unless indicated otherwise, T-HYDRO (2.0 mmol), 6a (0.4 mmol), catalyst (1 mo%), water (2.0 mL), 18 h. The values
b
below the starting material are the percentage of the remaining 6a after the reaction was done. The percentage of each
1
compound compared with the initial amount of 6a was determined by H-NMR spectral analysis of the reaction mixture using
1,3,5-trimethoxybenzene as internal standard. cIsolated percentage of each compound. dTBHP in decane. eRh2(cap)4 , 0.25 mol%,
4d. fThe percentage of 6a, 7a, 10a and 11a compared with the initial amount of 6a was determined by HPLC analysis.
Scheme 11. Oxidative Decomposition of Ketoperoxide 6
SH
O
O
O2
O
O
OOtBu
OOtBu
OOtBu
OH
OOtBu
Ar
Ar
Ar
Ar
S
SH
MLn
LnM-OH
OH
11
S
O
6
S = Substrate
tert-Butyl p-methylperbenzoate was investigated as a possible intermediate formed from hemiketal 6a
produced by addition of TBHP, but this compound was not detected (<1%) in the reaction mixture, and
the perester was determined to be stable under the reaction conditions. However, hemiketal peroxide
11a, which was determined by spectral and HRMS to be a reaction product from the oxidation of 6a by T-
HYDRO in chloroform or cyclohexane at room temperature with Rh2(cap)4 as the catalyst, was
independently synthesized from phenylglyoxal.29 Treatment of 11a with T-HYDRO and catalyst gave the
results as shown in Scheme 12. The catalytic oxidation of 11a with TBHP is solvent dependent. Reaction
with TBHP catalyzed by CuI with DIPEA in H2O converts hemiketal peroxide 11a to p-toluic acid 10a in 94%
yield, whereas no reaction occurred in CHCl3. Oxidation of 11a by TBHP in water with Rh2(cap)4 as the
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catalyst at room temperature produced p-toluic acid in only 10% yield. However, by increasing the
temperature to 80 oC the yield of p-toluic acid 10a increased to 65% (isolated yield).
Scheme 12. Oxidation Products of the Hemiketal 11aa
O
O
OOtBu
OH
catalyst (1mol%)
OH
T-HYDRO (5.0 eq), rt, 18 h
9
Me
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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10a
11a
Rh2(cap)4, CHCl3
Rh2(cap)4, H2O
94%
71%
<1%
10%
Rh2(cap)4, H2O, 80°C
7% (5%)
95%
62% (65%)
<1%
CuI, DIPEA (1.1 eq), CHCl3
CuI, DIPEA (1.1 eq), H2O
<1%
94%
aConditions: T-HYDRO (1.0 mmol), 11a (0.2 mmol), catalyst (1 mol%), 2.0 mL of solvent, 18 h. The percentage of 11a and 10a
compared with initial amount of 11a was determined by HPLC analysis. Isolated percentage is in parenthesis. The values below
the starting material are the percentage of the remaining 11a after the reaction was done.
A plausible mechanism for this oxidation involves initial nucleophilic addition by water, then hydrogen
atom abstraction from one of the hydroxyl groups on the benzylic position to form an alkoxy radical that
effects cleavage of the C-C bond and formation of the p-toluic acid and tert-butylperoxy methanol 12
which was detected by HRMS (Scheme 13A). However, another pathway through aryl acyl radical (13)30
could not be excluded (Scheme 13B).
Scheme 13. Oxidative Decomposition of Hemiketal Peroxide 11
O
OH
OH
OOtBu
O
O
H2O
OH
OOtBu
OOtBu
(A)
(B)
Ar
OH
Ar
Ar
Ar
S
SH
10
OH
OH
11
OH
HO
OOtBu
HO
OOtBu
SH
S
12
O
OOtBu
O
O
O
O
OOtBu
OOtBu
Ar
Ar
Ar
Ar
OH
OH
S
SH
13
O
10
11
S = Substrate
Oxidative cleavage with TBHP and Rh2(cap)4 as the catalyst at 80oC was investigated with substituted
styrenes 1 and geminal-disubstituted ethylenes 14 (Scheme 14). The styrenes formed the corresponding
benzoic acids in moderate yields (56-72%), and ketones could also be obtained in good yields from
geminal-disubstituted ethylenes. Even performing the oxidation reaction of (1-cyclopropylvinyl)benzene
14c at room temperature provided cyclopropyl phenyl ketone 15c in 94% isolated yield, demonstrating
that capturing the benzyl radical by the tert-butylperoxy radical or molecular oxygen is faster than
cyclopropylcarbinyl ring-opening.25 Indeed, when the oxidative cleavage reaction was performed with -
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methyl styrene 14e at room temperature in DCM, an intermediate to the oxidative cleavage product was
isolated and characterized (Eq 1); in addition, hydroperoxide 4e was converted to 15e in 43% with catalysis
of Rh2(cap)4 (Eq 2). Hydroperoxide 4e underwent O-O cleavage in a similar way as 4a in Scheme 9, but
forming a tertiary alkoxy radical that undergoes C-C cleavage to form ketone 15 (Scheme 15).
Scheme 14. Oxidation Products of Substituted Styrenes 1 and Geminal-Disubstituted Ethylenes 14
9
R2
10
11
12
13
14
15
16
17
18
19
20
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O
O
Rh2(cap)4 (1 mol%)
or
T-HYDRO (5.0 eq), solvent, 80oC, 12 h
Ar
OH
10
Ar
15
R
O
Ar
1 or 14
O
OH
Z
Z
d
14b
14c
15b
: 65%
O
b
1a:
10a
10b
10c
10d
10e
Z = p-Me
: Z = p-OMe
: Z = p-Ph
: Z = H
: 72%
c
1b
1c
1d
1e
: 52%
c
c
: 62%
e
15c
: 94%
O
: 56%
c
: Z = p-Br
: Z = m-Cl
: 68%
c
c
1f
1g
10f
: 67%
14d
14e
d
15d
: 69%
O
10g
: Z = p-CF3
: 62%
O
Me
Me
c
e
14a
15a
: 80%
15e
: 81%
aCondition: T-HYDRO (2.0 mmol), 1 or 14 (0.4 mmol), Rh2(cap)4 (1 mol%) and 2.0 mL of solvent. Isolated yield. bWater as solvent
and NaOH (4.0 eq) as the additive. cWater as solvent. dCyclohexane as solvent. eRh2(cap)4 (0.25 mol%), cyclohexane as solvent,
room temperature and 2 days
Rh2(cap)4 (0.25 mol %),
Me
Me
Me
TBHP (70 wt. % in H2O)
DCM, rt, 48h
+
(1)
(2)
OOt-Bu
OOH
Ph
Ph
Ph
15e,
O
14e
4e
, 52%
44%
Me
Me
Rh2(cap)4 (1 mol%)
DCM, rt, 72h
OOt-Bu
Ph
Ph
15e,
O
OOH
43%
4e
Scheme 15. Oxidative Decomposition of Tertiary Hydroperoxide 4
OH
O
O
S
SH
O
OOtBu
HO
OOtBu
OOtBu
+
OO-tBu
H2C
Ar
R
Ar
Ar
LnM-OH
MLn
R
4
R
S = Substrate
15
12
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Scheme 16. Proposed Mechanism for the Overall Oxidative Cleavage of C=C Bonds.
3
4
5
6
OOtBu
OH
O
TBHP
Z
Z
Z
MLn
7
8
9
+
OOtBu
OOtBu
O
HO
OOtBu
O
HOO
TBHP
MLn
TBHP
MLn
rt
trapped by O2
fast
OOtBu
Z
Z
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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32
33
34
35
36
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41
42
43
44
45
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47
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49
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51
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53
54
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60
tBuOO
OOtBu
TBHP
MLn
Z
Z
tBuOO
TBHP
MLn
trapped by tBuOO
TBHP
MLn, 80oC
Z
O
slow
OH
O
OH
Minor products/intermediates:
OH
O
Z
Z
+
Z
+
Z
Conclusion. Free radical oxidative cleavage of a C=C is a process whose complexity31 is often
overlooked. A general mechanism is proposed for this reaction that uses tert-butyl hydroperoxide as the
oxidant and either dirhodium(II) caprolactamate or copper iodide as catalysts (Scheme 16). The reaction
is initiated by peroxy radical addition to the carbon-carbon double bond that forms the more stable radical
intermediate. In the case of styrene and substituted styrenes the resultant benzyl radical combines with
either the tert-butylperoxy radical or dioxygen in solution, and using a saturated oxygen solution the
hydroperoxide product is exclusive (Scheme 6). There is a noticeable dependence of trapping by the tert-
butylperoxy radical or dioxygen on the solvent and catalyst. These competitive reactions, occurring at
room temperature and dependent on the flux of the tert-butylperoxy radical (Scheme 2) and the
concentration of dioxygen provide the major pathways that lead to oxidative cleavage. From this point
the oxidative pathways diverge. Hydroperoxide 4 undergoes oxidative O-O bond cleavage at room
temperature to form an alkoxy radical that produces at least three major products (Scheme 9) that are
further oxidized with the eventual formation of a benzoic acid (or ketone from an ,-disubstituted
alkene). In contrast, the vicinal di-tert-butylperoxide product is resistant to further oxidation at room
temperature, but at 80 C undergoes benzylic hydrogen atom abstraction to form the ketoperoxide 6 or
oxidative cleavage to produce benzaldehyde and/or benzoic acid. Ketoperoxide 6 undergoes oxidative
cleavage, one pathway for which is through its oxidized arylglyoxal hemiacetal 11 (Scheme 11). The
hemiacetal peroxide 11 is further oxidized to the final product p-toluic acid 10. A survey of styrenes and
related geminal-disubstituted ethylenes has shown the generality of the oxidative cleavage process.
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General Information. Reactions, unless noted, were performed in oven-dried (120 °C) glassware with
magnetic stirring under air atmosphere. Unless otherwise noted, all commercially available compounds
were used as purchased without further purification. Analytical thin layer chromatography (TLC) was
carried out using silica gel plates; visualization was accomplished with UV light (254 nm). Column
chromatography was performed on CombiFlash®Rf200 and Rf+ purification systems using normal phase
10
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1
disposable columns. H NMR spectra were recorded on 500 MHz and 300 MHz spectrometers, and
chemical shifts were reported in ppm. The peak information was described as br = broad, s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, comp = composite; coupling constant(s) in Hz. The number
of protons (n) for a given resonance was indicated by nH. Coupling constants were reported as J-values in
Hz. CDCl3 was used as a reference (7.26 ppm) for all spectra. 13C NMR spectra were recorded on a 126 MHz
spectrometer with complete proton decoupling. Chemical shifts are reported in ppm utilizing the central
resonance of the CDCl3 absorption as a reference (77.16 ppm). High-performance liquid chromatography
(HPLC) analysis were conducted using an Agilent 1220 Infinity HPLC system with a Poroshell 120 EC-C18
column and water/acetonitrile as eluent. High-resolution mass spectra (HRMS) were performed on a
Bruker Q-TOF-ESI mass spectrometer with an ESI resource using an ion calibration solution as the
standard. Melting points (mp) were measured uncorrected on an Electro Thermo Mel-Temp DLX 104
device.
Rh2(cap)4(MeCN)2 was prepared according to the literature procedure.32 The purity of TBHP was
1
13
monitored by NMR spectroscopy. All previously unreported products were characterized by H and C
NMR, as well as HRMS. Spectra of compounds 2a,8b 7a, 8a, 9a, 10a, 10b, 10c, 10d, 10e, 10f, 10g, 15a, 15b,
15c, 15d and 15e, agree with published information.33
Catalytic Oxidation of p-Methylstyrene 1a. A 8.0 mL 6-dram screw-cap vial containing a stirring bar was
charged sequentially with 1a (47.3 mg, 0.4 mmol, 1.0 equiv.), catalyst (1.0 mol%) and 2.0 mL of the
designated solvent. The mixture was sonicated for 1 min to facilitate the maximum dissolution of the
metal catalyst, after which T-HYDRO (TBHP 70% in water, 270 μL, 2.0 mmol) was added dropwise into the
vial. The reaction solution was sealed with a cap and stirred for 18 h at the selected temperature then
transferred to a 20.0-mL 6-dram screw-cap vial with 10.0 mL of acetone. From the diluted solution, a
measured amount was taken and transferred to 10.0 mL volumetric flask for quantitative analysis. The
flask was then brought to 10.0 mL of volume with acetonitrile, and the solution was analyzed by HPLC
with water/acetonitrile (1:4) as the eluent.
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Isolation of Compounds 2a-8a from Reaction Catalyzed by Rh2(cap)4 in CHCl3. T-HYDRO (11.2 mL, 100.0
mmol) was added dropwise to a pre-sonicated 100.0 mL round-bottom flask containing a magnetic stirring
bar, 30.0 mL of CHCl3, 1a (20.0 mmol, 2.36 g) and Rh2(cap)4 (16.4 mg, 0.1 mol%) at room temperature. The
solution was stirred for 18 h at room temperature after which the volume was reduced under reduced
pressure, and the residue was purified by column chromatography (silica gel, AcOEt/hexane = 5%).
Fractions containing the products were combined, and the solvent was evaporated under reduced
pressure followed by additional drying under high vacuum for 20 min (0.09 Torr, room temperature) to
afford 2a (888.1 mg, 15%), 3a (56.1 mg, 1%), 4a (672.6 mg, 14%), 5a (89.6 mg, 2%), 6a (133.2 mg, 3%), 8a
(188.2 mg, 7%).
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1
1-[2-(tert-Butoxy)-1-(tert-butylperoxy)ethyl]-4-methylbenzene, 3a: colorless oil; H NMR (300 MHz, ,
CDCl3) δ 7.26 (d, J = 7.9 Hz, 2H), 7.15 (d, J = 7.9 Hz, 2H), 4.98 (dd, J = 7.4, 4.8 Hz, 1H), 3.67 (dd, J = 10.4, 7.4
13
Hz, 1H), 3.47 (dd, J = 10.4, 4.8 Hz, 1H), 1.25 (s, 9H), 1.16 (s, 9H). C{1H} NMR (126 MHz, CDCl3) δ 137.5,
136.5, 129.0, 127.2, 86.0, 80.9, 73.4, 64.6, 27.6, 26.6, 21.4. HRMS (ESI) calculated for C17H28NaO3 [M+Na]+:
303.1931; found: 303.1928. The structure of 3a was confirmed by the comparison of the CH2 chemical
shift of 3a with 2a, 4a/5a, as well as the similar structure reported in Ref 23a.
1
1-(2-(tert-Butylperoxy)-1-hydroperoxyethyl)-4-methylbenzene, 4a: colorless oil; H-NMR (500 MHz,
CDCl3) δ 8.57 (br, 1H), 7.26 (d, J = 7.7 Hz, 2H), 7.19 (d, J = 7.7 Hz, 2H), 5.30 (dd, J = 8.5, 3.3 Hz, 1H), 4.25
(dd, J = 13.1, 8.5 Hz, 1H), 4.15 (dd, J = 13.1, 3.3 Hz, 1H) 2.36 (s, 3H), 1.28 (s, 9H). 13C{1H} NMR (126 MHz,
CDCl3) δ 138.6, 134.1, 129.5, 127.2, 85.2, 81.2, 76.9, 26.4, 21.3. HRMS (ESI) calculated for C13H24NO4
[M+NH4]+: 258.1700; found: 258.1704.
2-(tert-Butylperoxy)-1-(p-tolyl)ethan-1-ol 5a: colorless oil; 1H NMR (500 MHz, CDCl3) δ 7.28 (d, J = 8.0
Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 5.05 (dd, J = 9.0, 2.5 Hz, 1H), 4.07 (dd, J = 12.6, 2.5 Hz, 1H), 3.94 (dd, J =
13
12.6, 9.0 Hz, 1H), 2.34 (s, 3H), 1.29 (s, 9H). C{1H} NMR (126 MHz, CDCl3) δ 137.7, 137.1, 129.3, 126.3,
81.1, 80.9, 72.4, 26.5, 21.3. HRMS (ESI) calculated for C13H24NO3 [M+NH4]+: 242.1751; found: 242.1758.
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2-(tert-Butylperoxy)-1-(p-tolyl)ethan-1-one, 6a: colorless oil; H NMR (300 MHz, CDCl3) δ 7.88 (d, J =
8.3 Hz, 2H), 7.26 (d, J = 8.3 Hz, 2H), 5.06 (s, 2H), 2.41 (s, 3H), 1.24 (s, 9H). 13C{1H} NMR (126 MHz, CDCl3) δ
195.0, 144.5, 132.8, 129.3, 128.5, 81.2, 77.6, 26.4, 21.9. HRMS (ESI) calculated for C13H22NO3 [M+NH4]+:
240.1594; found: 240.1596.
Catalytic Oxidation of 1-[1,2-Bis(tert-butylperoxy)ethyl]-4-methylbenzene 2a. In a pre-sonicated 8.0
mL 6-dram screw-cap vial containing a magnetic stirring bar, catalyst (1.0 mol%) 2a (118.6 mg, 0.4 mmol)
and 2.0 mL of solvent, T-HYDRO (270.0 μL, 2.0 mmol) was added dropwise. After stirring for 18 h at the
selected temperature, the reaction solution was transferred to a 20.0-mL 6-dram screw-cap vial with 10.0
mL of acetone. From the diluted solution a measured amount was taken and transferred to a 10.0 mL
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volumetric flask for quantitative analysis. The flask was then brought to 10.0 mL with acetonitrile, and the
solution was analyzed by HPLC with water/acetonitrile as the eluent.
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Catalytic Oxidation of 1-[2-(tert-Butylperoxy)-1-hydroperoxyethyl]-4-methylbenzene 4a, HPLC. T-
HYDRO (135.0 μL, 1.0 mmol) was added dropwise to a pre-sonicated 8.0 mL 6-dram screw-cap vial
containing a magnetic stirring bar, catalyst (1.0 mol%), 4a (48.0 mg, 0.2 mmol), 2.0 mL of solvent. The
solution was stirred for 18 h at the designated temperature, after which it was analyzed by HPLC as
described previously.
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Catalytic Oxidation of 1-[2-(tert-Butylperoxy)-1-hydroperoxyethyl]-4-methylbenzene 4a, NMR. T-
HYDRO (135.0 μL, 1.0 mmol) was added dropwise to a pre-sonicated 8.0-mL 6-dram screw-cap vial
containing a magnetic stirring bar, 2c (48.0 mg, 0.2 mmol), catalyst (1.0 mol%), 1,3,5 trimethoxybenzene
(33.6 mg, 0.2 mmol) used as the internal standard, and 2.0 mL of CDCl3. The reaction solution was stirred
for 18 h at room temperature, and the residue was analyzed by 1H-NMR spectroscopy. The percent yield
of product was determined from the integral values of the internal standard (s, 6.11 ppm), the benzylic
proton of 4a (dd, 5.32-5.30), the benzylic proton of 5a (dd, 5.08-5.06) and the α-alkyl protons of 6a (s,
5.09 ppm), and the α-proton of 7a (s, 9.92 ppm), the benzylic proton of 9a (dd, 4.84-4.81), and the
aromatic ortho-protons of 10a (d, 8.02 ppm).
Catalytic Oxidation of 2-(tert-Butylperoxy)-1-(p-tolyl)ethan-1-one 6a. T-HYDRO (270.0 μL, 2.0 mmol)
was added dropwise to a pre-sonicated 8.0-mL 6-dram screw-cap vial containing a magnetic stirring bar,
Rh2(cap)4 (2.7 mg, 1.0 mol %) 6a (88.8 mg, 0.4 mmol) and 2.0 mL of water. The reaction solution was
heated at 80 ℃ in oil bath and stirred for 18 h then cooled at room temperature and transferred to a 50.0
mL round bottom-flask with 20.0 mL of AcOEt. The volume of the solution was reduced under reduced
pressure, and the resulting residue was purified by column chromatography (silica gel, DCM/MeOH =
20:1). Fractions containing the product were combined, and the solvent was evaporated under reduced
pressure followed by additional drying under high vacuum for 20 min (0.09 Torr, room temperature) to
afford p-toluic acid 10a in 70% yield.
Catalytic Oxidation of 2-(tert-Butylperoxy)-1-(p-tolyl)ethan-1-one 6a, NMR. T-HYDRO (270.0 μL, 2.0
mmol) was added dropwise to a pre-sonicated 8.0-mL 6-dram screw-cap vial containing a magnetic stirring
bar, 6a (88.8 mg, 0.4 mmol), Rh2(cap)4 (2.7 mg, 1.0 mol%) and 2.0 mL of water. The reaction solution was
stirred for 18 h at the selected temperature, then cooled to room temperature and transferred to a 50.0
mL round bottom-flask with 20.0 mL of AcOEt. 1,3,5-Trimethoxybenzene (67.3 mg, 0.4 mmol), used as
internal standard, was added; and the volume of the reaction solution was reduced under reduced
pressure. The resulting residue was dissolved in CDCl3 and analyzed by 1H-NMR spectroscopy. The percent
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yields of products were determined from the integral values of internal standard (s, 6.11 ppm) and α-alkyl
protons of 6a (s, 5.09 ppm) and the aromatic protons of 10a (d, 8.02 ppm).
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Catalytic Oxidation of 2-(tert-Butylperoxy)-1-(p-tolyl)ethan-1-one 6a, HPLC. T-HYDRO (270.0 μL, 2.0
mmol) was added dropwise to a pre-sonicated 8.0-mL 6-dram screw-cap vial containing a magnetic stirring
bar, metal catalyst (1.0 mol%), 6a (88.8 mg, 0.4 mmol), 2.0 mL of solvent and DIPEA when it was required
(77.0 μL, 0.44 mmol). The reaction solution was brought to the selected temperature and stirred for 18 h,
then cooled to room temperature and transferred to a 20.0 mL 6-dram screw-cap vial with 10.0 mL of
acetone. From the diluted solution a measured amount was transferred to a 10.0 mL volumetric flask for
quantitative analysis. The flask was then brought to 10.0 mL in a volumetric flask with acetonitrile and
analyzed by HPLC with water/acetonitrile as the eluent.
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Catalytic Oxidation of 2-(tert-Butylperoxy)-2-hydroxy-1-(p-tolyl)ethan-1-one 11a. T-HYDRO (270.0 μL,
2.0 mmol) was added dropwise to a pre-sonicated 8.0-mL 6-dram screw-cap vial containing a magnetic
stirring bar, Rh2(cap)4 (2.7mg, 1.0 mol%) 11a (95.2 mg, 0.4 mmol) and 2.0 mL of water. The reaction
solution was heated at 80 ℃ in oil bath and stirred for 18 h then cooled at room temperature and
transferred to a 50.0 mL round bottom-flask with 20.0 mL of AcOEt. The volume of the solution was
reduced under reduced pressure, and the resulting residue was purified by column chromatography (silica
gel, DCM/MeOH = 20:1). Fractions containing the products were combined, and the solvent was
evaporated under reduced pressure followed by additional drying under high vacuum for 20 min (0.09
Torr, room temperature) to afford p-toluic acid 10a in 65% (35.0 mg) and hemiketal peroxide 11a in 5%
(5.0 mg)
Catalytic Oxidation of 2-(tert-Butylperoxy)-2-hydroxy-1-(p-tolyl)ethan-1-one 11a, HPLC. T-HYDRO
(135.0 μL, 1.0 mmol) was added dropwise to a pre-sonicated 8.0-mL 6-dram screw-cap vial containing a
magnetic stirring bar, catalyst (1.0 mol%), 11a (47.6 mg, 0.2 mmol) in 2.0 mL of solvent. The reaction
solution was stirred for 18 h at room temperature, after which it was analyzed by HPLC as described
previously.
Kinetic Measurements of Rh2(cap)4 Catalyzed Oxidations of 4-Methylstyrene by T-HYDRO in H2O. T-
HYDRO (270.0 μL, 2.0 mmol) was added dropwise at room temperature to a pre-sonicated 8.0-mL 6-dram
screw-cap vial containing a magnetic stirring bar, 2.0 mL of water, 1a (47.3 mg, 0.4 mmol) and Rh2(cap)4
(2.6 mg, 1.0 mol%). The reaction solution was sealed with a cap and stirred. Aliquots were removed after
the first 30 minutes and then every hour until the 18th hour, transferred to a 10.0 mL volumetric flask, and
brought to 10.0 mL of volume with acetonitrile, then analyzed by HPLC (Poroshell 120 EC-C18 column)
with water/acetonitrile (80/20) as the eluent.
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Kinetic Measurements of Rh2(cap)4 Catalyzed Oxidation of 4-Methylstyrene by T-HYDRO in CHCl3. T-
HYDRO (270.0 μL, 2.0 mmol) was added dropwise to a pre-sonicated 8.0-mL 6-dram screw-cap vial
containing a magnetic stirring bar, 2.0 mL of CHCl3, 1a (47.3mg, 0.4 mmol) and Rh2(cap)4 (2.6 mg, 1.0
mol%) at room temperature. The reaction solution was sealed with a cap and stirred and analyzed after
the first 30 minutes and then every hour until the 18th hour as described above.
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Synthetic Procedure for Hydroperoxide Compounds 4. A 25 mL round-bottom flask was charged
sequentially with a stir bar, Rh2(cap)4 (0.67 mg, 0.25 mol%, or 1.4 mg, 1.0 mol%), alkene derivate (0.4
mmol) and 4.0 mL of CHCl3. Then the round-bottom flask was sealed with a robber septum which two
needles were inserted. The solution was charged with oxygen for 10 minutes, then the outlet needle was
removed, and the inlet needle was replaced with a balloon containing oxygen. T-HYDRO (235.0 μL, 2.0
mmol, or 540.0 μL, 4.0 mmol) was added dropwise to the mixture with a syringe. The reaction was
monitored by TLC, and every 12h, T-HYDRO (270.0 μL) was added until the reaction was complete. The
reaction solution was passed through a 3-cm silica gel plug using DCM as the eluent. Then the volume of
the solution was reduced under reduced pressure, and the resulting residue was purified by column
chromatography on silica gel using hexanes/ethyl acetate (20:1) as the eluent. Fractions containing the
product were combined, and the solvent was evaporated under reduced pressure followed by additional
drying under high vacuum for 20 min (0.09 Torr, room temperature) to afford the corresponding
hydroperoxide product 4.
1-(2-(tert-Butylperoxy)-1-hydroperoxyethyl)-4-methylbenzene 4a: (81.0 mg, 85%). 1H NMR (500 MHz,
CDCl3) δ 8.57 (s, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 5.33 (dd, J = 8.3, 3.3 Hz, 1H), 4.27 (dd,
J = 13.0, 8.3 Hz, 1H), 4.17 (dd, J = 13.0, 3.3 Hz, 1H), 2.38 (s, 3H), 1.30 (s, 9H). 13C{1H} NMR (126 MHz, CDCl3)
δ 138.4, 134.0, 129.4, 127.1, 85.1, 81.1, 76.8, 26.3, 21.2. HRMS (ESI) calculated for C13H24NO4 [M+NH4]+:
258.1700; found: 258.1704.
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1-(2-(tert-butylperoxy)-1-hydroperoxyethyl)-4-methoxybenzene 4b, colorless oil (103.0 mg, 86%). H
NMR (500 MHz, CDCl3) δ 8.76 (br, 1H), 7.29 (d, J = 8.7 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 5.26 (dd, J = 8.2, 3.5
Hz, 1H), 4.25 (dd, J = 12.8, 8.2 Hz, 1H), 4.14 (dd, J = 12.8, 3.5 Hz, 1H), 3.79 (s, 3H), 1.26 (s, 9H). 13C{1H} NMR
(126 MHz, CDCl3) δ 159.8, 129.3, 128.6, 114.1, 84.8, 81.1, 76.6, 55.4, 26.4. HRMS (ESI) calculated for
C13H24NO5 [M+NH4]+: 274.1649; found: 274.1649.
[1-(2-(tert-Butylperoxy)-1-hydroperoxyethyl)-4-(trifluoromethyl)]benzene 4c, colorless oil (92.0 mg
78%). 1H NMR (500 MHz, CDCl3) δ 8.53 (br, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 8.1 Hz, 2H), 5.42 (dd, J
= 7.8, 3.6 Hz, 1H), 4.24 (dd, J = 13.2, 7.8 Hz, 1H), 4.17 (dd, J = 13.2, 3.6 Hz, 1H) 1.30 (s, 9H). 13C{1H} NMR
(126 MHz, CDCl3) δ 141.2, 130.6 (q, 2JCF = 32.6 Hz), 127.2, 125.5 (q, 3JCF = 3.8 Hz), 123.9 (q, 1JCF = 272.2 Hz),
84.6, 81.2, 76.2, 26.2. HRMS (ESI) calculated for C13H21F3NO4 [M+NH4]+: 312.1417; found: 312.1415.
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[2-(tert-butylperoxy)-1-cyclopropyl-1-hydroperoxyethyl]benzene, 4d, colorless oil (96.8 mg, 91%). 1H
NMR (500 MHz, CDCl3) δ 8.86 (s, 1H), 7.41 – 7.27 (m, 5H), 4.64 (d, J= 22 Hz, 1H), 4.60 (d, J= 22 Hz, 1H), 1.42
– 1.37(m, 1H), 1.31 (s, 9H), 0.47 – 0.40 (m, 2H), 0.28 – 0.25 (m, 1H), 0.06 – 0.03 (m, 1H). 13C{1H} NMR (126
MHz, CDCl3) δ 137.8, 128.1, 127.8, 126.9, 88.1, 82.0, 77.3, 26.5, 15.9, 1.2, 1.1. HRMS (ESI) calculated for
C15H26NO4 [M+NH4]+: 284.1856; found: 284.1851.
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[1-(tert-butylperoxy)-2-hydroperoxypropan-2-yl]benzene, 4e, colorless oil (86.4 mg, 90%). H NMR
(500 MHz, CDCl3) δ 8.49 (br, 1H), 7.45 (d, J = 7.5 Hz, 2H), 7.38 (dd, J = 7.5, 6.9 Hz, 2H), 7.34 – 7.27 (m, 1H),
4.44 (d, J = 12.8 Hz, 1H), 4.33 (d, J = 12.8 Hz, 1H), 1.59 (s, 3H), 1.28 (s, 9H). 13C{1H} NMR (126 MHz, CDCl3)
δ 141.9, 128.4, 127.7, 125.6, 85.4, 81.6, 78.0, 26.3, 22.4. HRMS (ESI) calculated for C13H24NO4 [M+NH4]+:
258.1700; found: 258.1701.
1-[(tert-butylperoxy)methyl]-1-hydroperoxy-2,3-dihydro-1H-indene, 4f, colorless oil (70.6 mg, 70%).
1H NMR (500 MHz, , CDCl3) δ 8.44 (s, 1H), 7.51 (d, J = 7.4 Hz, 1H), 7.31 (td, J = 7.4, 1.2 Hz, 2H), 7.28 – 7.25
(m, 1H), 7.23 (t, J = 7.4 Hz, 1H), 4.51 (d, J = 12.5 Hz, 1H), 4.32 (d, J = 12.5 Hz, 1H), 3.10 (ddd, J = 16.2, 8.4,
7.0 Hz, 1H), 2.87 (ddd, J = 16.2, 8.9, 4.4 Hz, 1H), 2.40 (ddd, J = 14.0, 8.4, 4.4 Hz, 1H), 2.26 (ddd, J = 14.0,
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8.9, 7.0 Hz, 1H), 1.29 (s, 9H). C{1H} NMR (126 MHz, CDCl3) δ 145.3, 140.7, 129.6, 126.5, 125.4, 125.2,
94.2, 81.6, 76.5, 32.6, 29.8, 26.5. HRMS (ESI) calculated for HRMS (ESI) calculated for C14H24NO4 [M+NH4]+:
270.1700; found: 270.1694.
Synthetic Procedure for 2-(tert-Butylperoxy)-2-hydroxy-1-(p-tolyl)ethan-1-one 11a. 2-Oxo-2-(p-
tolyl)acetaldehyde was prepared according to the reported procedure.34 2-(tert-Butylperoxy)-2-hydroxy-
1-(p-tolyl)ethan-1-one 11a was prepared with modification from reference 29. T-HYDRO (510.0 μL, 3.6
mmol) was added dropwise to a 50.0 mL round bottom flask a 10.0 mL solution of water containing 2-
oxo-2-(p-tolyl)acetaldehyde (300.0 mg, 1.8 mmol), after which the reaction solution was stirred for 12 h
at room temperature, and a white precipitate was formed. The precipitate was filtered under vacuum,
collected in a 6-dram screw-cap vial and dried further under high vacuum for 20 min to afford the
1
corresponding product 11a as a white solid (372.9 mg, 87%). mp: 72-74 ℃. H NMR (500 MHz, CDCl3) δ
8.03 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 6.08 (d, J = 9.5 Hz, 1H), 5.02 (d, J = 9.5 Hz, 1H), 2.45 (s, 3H),
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1.19 (s, 9H). C{1H} NMR (126 MHz, CDCl3) δ 191.6, 145.8, 130.7, 129.9, 129.6, 94.8, 81.0, 26.7, 22.0.
HRMS (ESI) calculated for C13H18KO4 [M+K]+: 277.0837; found: 277.0827.
Catalytic Oxidation of Substituted Styrenes, 1a. A 8-mL 6-dram screw-cap vial containing a stirring bar
was charged sequentially with p-methylstyrene (0.4 mmol, 1.0 equiv.), Rh2(cap)4 (2.7 mg 1.0 mol%), 2.0
mL of water and NaOH (64.0 mg, 1.6 mmol). The mixture was sonicated for 1 min to facilitate the
maximum dissolution of the metal catalyst, after which T-HYDRO (TBHP 70% in water, 270.0 μL, 2.0 mmol)
was added dropwise into the vial. The reaction solution was sealed with a cap and stirred for 18 h at 80
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℃ in oil bath. After the reaction was complete, the reaction solution was transferred to a separatory
funnel and 10.0 mL of NaOH (1M) were added. The aqueous layer was rinsed with three portions of DCM
(10.0 mL), after which the aqueous layer was acidified with 20.0 mL HCl (1M), and a precipitate was
formed. The white precipitate was filtered under vacuum, collected in a 6-dram screw-cap vial and dried
further under high vacuum for 20 min to afford the corresponding p-toluic acid 10a (39.2 mg 72%).
Catalytic Oxidation of Substituted Styrenes, 1b-g. A 8.0 mL 6-dram screw-cap vial containing a stirring
bar was charged sequentially with 1 (0.4 mmol, 1.0 equiv.), Rh2(cap)4 (2.7 mg 1.0 mol%), 2.0 mL of water.
The mixture was sonicated for 1 min to facilitate the maximum dissolution of the metal catalyst, after
which T-HYDRO (TBHP 70% in water, 270.0 μL, 2.0 mmol) was added dropwise into the vial. The reaction
solution was sealed with a cap and stirred for 18 h at 80 ℃ in oil bath. After that, the volume of the
solution was reduced under reduced pressure, and the resulting residue was purified by column
chromatography on silica gel using DCM/methanol (20:1) as eluent. Fractions containing the product were
combined, and the solvent was evaporated under reduced pressure followed by additional drying under
high vacuum for 20 min (0.09 Torr, room temperature) to afford the corresponding benzoic acid product
10. p-Toluic acid 10a (39.2 mg, 72%). 4-Methoxybenzoic acid 10b (32 mg, 52%). 4-Biphenyl-carboxylic acid
10c (49.2 mg, 62%). Benzoic acid 10d (27 mg, 56%). 4-Bromobenzoic acid 10e (54.7 mg, 68%). 4-
Chlorobenzoic acid 10f (41.2 mg, 67%). 4-Trifluoromethyl benzoic acid 10g (47.1 mg, 62%).
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General Procedure for the Catalytic Oxidation of Geminal-Disubstituted Ethylenes, 14. A 8.0 mL 6-
dram screw-cap vial containing a stirring bar was charged sequentially with 14 (0.4 mmol, 1.0 equiv.),
Rh2(cap)4 (2.7 mg 1.0 mol%) and 2.0 mL of cyclohexane. The mixture was sonicated for 1 min to facilitate
the maximum dissolution of the metal catalyst, after which T-HYDRO (TBHP 70% in water, 270.0 μL, 2.0
mmol) was added dropwise into the vial. The reaction solution was sealed with a cap and stirred for 18 h
at 80 ℃ in oil bath. After completion of the reaction, the reaction solution was passed through a 3 cm
silica gel using DCM as the eluent. Then the volume of the solution was reduced, and the resulting residue
was purified by column chromatography on silica gel using hexanes/ethyl acetate (20:1) as eluent.
Fractions containing the product were combined, and the solvent was evaporated under reduced pressure
followed by additional drying under high vacuum for 20 min (0.09 Torr, room temperature) to afford the
corresponding ketone product 15. Benzophenone 15a (58.3 mg, 80%). 2,3-Dihydro-1H-inden-1-one 15b
(34.4 mg, 65%). Cyclopropyl(phenyl)methanone 15c (55.0 mg, 94%). Cyclohexyl(phenyl)methanone 15d
(52.0 mg, 69%). Acetophenone 15e (38.4 mg, 81%).
Catalytic Oxidation of -Methylstyrene in DCM
Rh2(cap)4 (0.66 mg, 1.0x10-3 mmol) was added to a solution of 14e (47.3 mg, 0.40 mmol) and TBHP (70
wt. % in H2O, 259.4 mg, 2.0 mmol) in 2.0 mL DCM at room temperature. The color of the reaction became
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pink immediately. The reaction was terminated after stirring for 48 h. After the reaction was complete,
the reaction solution was passed through a 3-cm silica gel plug using DCM as the eluent. The volatiles
were removed in vacuo. The crude products were purified by flash column chromatography (SiO2,
hexane/ethyl acetate, 20:1) to afford compound 15b (22.1 mg, 44% yield) and compound 4e (54.9 mg,
52% yield).
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Catalytic Oxidation of [1-(tert-Butylperoxy)-2-hydroperoxypropan-2-yl]benzene, 4e
Rh2(cap)4 (1.5 mg, 2.2x10-3 mmol) was added to a solution of 4e (50.0 mg, 0.22 mmol) in 1 mL
dichloromethane at room temperature. The color of the reaction became pink immediately indicating the
conversion of the catalyst to rhodium (II,III) caprolactamate. The reaction was terminated after 3 days.
The volatiles were removed in vacuo. The crude products were purified by flash column chromatography
(SiO2, hexane/ethyl acetate, 20:1). Fractions containing the product were combined, and the solvent was
evaporated under reduced pressure followed by additional drying under high vacuum for 20 min (0.09
Torr, room temperature) to afford acetophenone 15e (8.0 mg, 43% yield).
ASSOCIATED CONTENT
The Supporting Information is available free of charge on the ACS Publications website at DOI:
Experimental tables, copies of 1H and 13C NMR spectra of compounds 2a, 3a, 4a-4f, 5a, 6a and 11a, copies
of 1H NMR spectra of compounds 10a-10g and 15a-15e, HPLC trace and calibration curve for compounds
1a-11a, HPLC trace of a crude reaction solution, HR-MS data of compounds 2a-6a, 8a, 11a and 12, HR-MS
spectra of compounds 2a-5a.
AUTHOR INFORMATION
Corresponding Author
*michael.doyle@utsa.edu
Author Contributions
‡Y.-L. S. and L. D. A. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Support for this research from the Welch Foundation (AX−1871) is gratefully acknowledged. We thank
W. G. Griffith for extensive mass spectral analyses.
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