Interplay of method development and mechanistic studies - From aerobic oxidative coupling to radical reactions via alkenyl peroxides

Article abstract of DOI:10.1055/s-0035-1560706

This account summarizes how scientific advances were made in the authors' research group by combining method development in organic synthesis with detailed mechanistic studies. The discovery of an unexpected autoxidative coupling reaction led, by virtue of an ever increased understanding of its mechanism, to a strategy for green C-H functionalization reactions, novel modes of radical generation, addition reactions of ketones to alkenes and new insights into an old reaction, the Baeyer-Villiger oxidation. 1 Introduction 2 Aerobic Oxidative Coupling Reactions with Benzylic C-H Bonds 2.1 The Autoxidative Coupling with Xanthene 2.2 With a Little Help from Light - CHIPS 2.3 Related Autoxidative Coupling Reactions 3 How Does the Autoxidative Coupling Work? 3.1 An Excursion: Formation of Alkenyl Peroxides from Criegee Intermediates in the Atmosphere 3.2 How do Alkenyl Peroxides Form in Solution? Meet Criegee Again 3.3 The Full Mechanism of the Autoxidative Coupling Reaction 4 Previous Indications for Solution Chemistry of Alkenyl Peroxides 4.1 What Might Alkenyl Peroxides be Good for? 5 Concluding Remarks.

Full text of DOI:10.1055/s-0035-1560706

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© Georg Thieme Verlag Stuttgart · New York
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M. Klussmann, B. Schweitzer-Chaput
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Interplay of Method Development and Mechanistic Studies –
From Aerobic Oxidative Coupling to Radical Reactions via Alkenyl
Peroxides
Martin Klussmann*
Bertrand Schweitzer-Chaput1
Max-Planck-Institut für Kohlenforschung,
Kaiser-Wilhelm-Platz 1, 45470 Mülheim an
der Ruhr, Germany
klusi@mpi-muelheim.mpg.de
Received: 29.07.2015
Accepted after revision: 04.09.2015
Published online: 26.11.2015
tional additives and very high temperatures. It is thus desir-
able to develop reactions that can utilize simple and cheap
oxidants such as elemental oxygen or air which produce be-
nign waste products like water.3
DOI: 10.1055/s-0035-1560706; Art ID: st-2015-a0587-a
Abstract This account summarizes how scientific advances were
made in the authors’ research group by combining method develop-
ment in organic synthesis with detailed mechanistic studies. The dis-
covery of an unexpected autoxidative coupling reaction led, by virtue of
an ever increased understanding of its mechanism, to a strategy for
green C–H functionalization reactions, novel modes of radical genera-
tion, addition reactions of ketones to alkenes and new insights into an
old reaction, the Baeyer–Villiger oxidation.
R1
R1
R1
R2
R2
R2
R1
R1
R1
R2
R2
R2
[cat.]
H
H
+
Ox
OxH2
Scheme 1 Catalytic oxidative coupling reactions forming new C–C
bonds from two C–H bonds
1
2
Introduction
Aerobic Oxidative Coupling Reactions with Benzylic C–H Bonds
2.1 The Autoxidative Coupling with Xanthene
2.2 With a Little Help from Light – CHIPS
2.3 Related Autoxidative Coupling Reactions
Our research group has committed itself to the develop-
ment of oxidative coupling reactions that do not require ex-
tensive amounts of synthetic oxidants and additives. We
are also intrigued by the mechanisms of these reactions,
which are often not well understood. Our motivation to in-
vestigate oxidative coupling reactions is thus twofold: dis-
covering synthetic methods and principles of chemical re-
activity.
In this account, the development of a research project is
outlined that illustrates the fruitful interplay of method de-
velopment and mechanistic studies. It thus largely follows a
chronological order and not a thematic one, and discusses
results from our own group, but not without putting these
into context with related topics.
3
How Does the Autoxidative Coupling Work?
3.1 An Excursion: Formation of Alkenyl Peroxides from Criegee Inter-
mediates in the Atmosphere
3.2 How do Alkenyl Peroxides Form in Solution? Meet Criegee Again
3.3 The Full Mechanism of the Autoxidative Coupling Reaction
4
Previous Indications for Solution Chemistry of Alkenyl Peroxides
4.1 What Might Alkenyl Peroxides be Good for?
Concluding Remarks
5
Key words homogeneous catalysis, green chemistry, oxygen, perox-
ides, radicals, reaction mechanisms, C–H functionalization
1 Introduction
Oxidative coupling reactions enable the formation of
C–C bonds by functionalizing one or even two C–H bonds,
which can obviously reduce the number of steps in a syn-
thesis and allows simple starting materials to be utilized
(Scheme 1).2 Performing such reactions in a catalytic fash-
ion is thus very attractive for green chemistry and explains
the interest these reactions have received in recent years.
However, many of the methods that have been developed
require stoichiometric amounts of synthetic oxidants, addi-
2 Aerobic Oxidative Coupling Reactions
with Benzylic C–H Bonds
In 2009, we started a project to develop a cross-coupling
reaction that would functionalize benzylic C–H bonds by
using oxygen as an oxidant. Several oxidative coupling reac-
tions employing oxygen already existed at the time, for ex-
ample with tertiary amines as substrates.4 However, ben-
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zylic C–H bonds that are not stabilized by an adjacent nitro-
gen atom appeared to be significantly more difficult to
cleave by oxidation.
Conducting such transformations with oxygen remains
a challenge even today. As one of the few developments be-
sides this and the ones discussed below, Zhang et al. have
developed a palladium-catalyzed method for benzyl ester
formation using toluene.7
In 2010 – and ahead of us – the Li group reported the
first aerobic oxidative coupling method for benzylic com-
pounds. It enabled the coupling of diarylmethanes and in-
dane with various 1,3-dicarbonyl nucleophiles at 105 °C
(Scheme 2).5 They used a triple catalytic system of two
transition-metal salts as well as N-hydroxyphthalimide
(NHPI), an organic hydrogen atom transfer (HAT) mediator,
as a variation of a system they had previously developed for
the aerobic oxidative coupling of benzylic ethers.6
2.1 The Autoxidative Coupling with Xanthene
So, before the method shown in Scheme 2 had been
published, we had set out to find substrates and conditions
that would allow such an aerobic oxidative coupling reac-
tion. Instead of high temperatures, we tried an approach of
using elevated pressure, although the flammability of most
organic solvents and substrates restricts such experiments
to about 10 bar of oxygen, without more sophisticated
equipment. The – perhaps somewhat naïve – rationale be-
hind this approach was the assumption that if with oxygen
as the oxidant the desired reactions would not run, more
oxygen might help. After numerous screening experiments
with various substrate and catalyst combinations, we found
that xanthene (1) could be oxidatively coupled with simple
ketones using transition-metal salts as catalysts together
with a strong acid, and running the reactions at ambient
temperature and at 10 bar partial pressure of oxygen. Some
representative results are shown in Table 1. Commonly
used redox-active metal chlorides were not very active (Ta-
ble 1, entries 1–3), but palladium and nickel salts, for exam-
ple, appeared as promising catalysts (Table 1, entries 4 and
5). Only later was a control experiment performed to study
the reaction in the absence of a catalyst. Being very confi-
Cu(OTf)2 (5 mol%)
FeCl2 (5 mol%)
NHPI (20 mol%)
O
O
O
O
R2
Ar
R3
+
Ar
R1
O2, neat, 105 °C
overnight
R2
R3
R1
O
O
O
O
Ph
OEt
OMe
O
O
OH
Ph
Ph
Ph
55%
Ph
N
Ph
Ph
O
O
94%
Ph
83%
OMe
NHPI
Scheme 2 Oxidative coupling reactions with benzylic C–H bonds using
oxygen as the terminal oxidant
Biographical Sketches
Martin Klussmann leads a re-
search group at the Max-Planck-
Institut (MPI) für Kohlenfor-
schung, Mülheim an der Ruhr,
which develops synthetic meth-
ods with a focus on oxidative
coupling reactions and green
chemistry and investigates reac-
tion mechanisms. He obtained
his Ph.D. in the group of Profes-
sor M. Reggelin at the Tech-
nische Universität Darmstadt,
Germany,
and
afterwards
worked as a postdoctoral re-
searcher with Professor D. G.
Blackmond at Imperial College
London, UK.
Bertrand Schweitzer-Cha-
put was born in Sèvres, France,
in 1986. He received his bache-
lor’s degree from Versailles-
degree from Paris XI University,
France, in 2010. He then joined
the Klussmann group at the MPI
für Kohlenforschung for his doc-
toral studies. After staying there
for an additional year as a post-
doctoral researcher to reap
(more of) the fruits of his dis-
coveries, he moved to Tarrago-
na, Spain, to take up
a
Saint-Quentin
University,
postdoctoral position with
Paolo Melchiorre.
France, in 2008 and his master’s
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dent of the failure of this experiment, we were all the more
surprised when the yield of the coupling product 2 actually
improved (Table 1, entry 6).8
OOH
H+
O2
1
– H2O2
O
O
Table 1 Discovery of the Acid-Catalyzed Autoxidative Coupling
4
5
+ 4
– H+
O
O
– H+
[cat.] (1 mol%)
O
O
O
O
MsOH (7 mol%)
O
neat, r.t., 24 h
+
2
100 bar
(N2/O2 = 90:10)
O
O
3
1
2
Scheme 3 An initial working model of the autoxidative coupling reac-
tion, including the formation of the observed by-product 3
Entry
Catalyst
Yield (%)a
1
2
3
4
5
6
CuCl2
FeCl2
MnCl2
NiCl2
PdCl2
–
0
0
rangement reactions in the presence of strong acids, a pro-
cess which is utilized in the industrial synthesis of phenol,
for example.9 However, it was also known from a few re-
ports that hydroperoxides (including 4) can be substituted
under the right conditions, mediated by Brønsted or Lewis
acids.10
18
62
78
85
a Determined by 1H NMR spectroscopy
Obtaining a more refined model of the reaction mecha-
nism turned out to take some time, but we will come back
to that later. In the meantime, we turned our attention to
exploring the synthetic possibilities of this discovery. We
found that we could perform the reaction at ambient pres-
sure under an atmosphere of oxygen, or even air, with only
slightly reduced reaction rates, which could be improved by
increasing the temperature a little to 40 °C. Under these
conditions, the coupling product 2 was isolated in 90% yield
and various other ketones could also be coupled with xan-
thene (Scheme 4).8,11
Obviously, this unexpected result was repeated and we
wondered whether trace impurities of transition metals
were responsible for the outcome. However, the experi-
ment could be reliably reproduced and analysis by atomic
adsorption spectroscopy indicated that the reagents were
clean within the detection limit. Moreover, the addition of
copper and iron salts actually inhibited the reaction (Table
1, entries 1 and 2) and so the seemingly positive effect of
palladium and nickel salts obviously has to be attributed to
their low activity as inhibitors. Accordingly, we believe that
this reaction does not require any metal catalyst.
Under these circumstances, it was all the more intrigu-
ing to find out how the reaction worked, as it was undoubt-
edly an oxidative reaction that converted all of the starting
material at ambient temperature within 24 hours, in the
absence of any redox-active catalyst. During the screening
of suitable acid catalysts, we observed the precipitation of
xanthenyl peroxide 3 when using trifluoroacetic acid (TFA),
an acid that was too weak to give high yields of the desired
product. As a working model, we thus assumed that xan-
thene was activated by autoxidation, leading to a hydroper-
oxide 4, which could be activated toward nucleophilic sub-
stitution by the acid catalyst, forming a stabilized xanthyli-
um cation intermediate 5. This could react with the enol
form of a ketone to give 2 or with another hydroperoxide to
yield 3 (Scheme 3).
O
R1
R2
O
MsOH (5–7 mol%)
O
2 (balloon)
R2
1
+
neat, 40 °C, 5–64 h
R1
O
O
R
O
n
Ph
O
R
O
O
O
R = Me, 34%
R = Ph, 49%
R = Me, 95%
R = n-Bu, 93%
n = 1 (2), 90%
n = 2, 94%
n = 3, 67%
n = 4, 80%a
Scheme 4 Representative products from the autoxidative coupling re-
actions of ketones with xanthene at ambient pressure. a TfOH was used
as the catalyst
A hydroperoxide group is not usually regarded as a leav-
ing group in nucleophilic substitution reactions, especially
as organic hydroperoxides are known to undergo rear-
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Interestingly, acetone performed rather poorly, but in
general, both acyclic and cyclic ketones could be coupled
with xanthene under surprisingly simple conditions: stir-
ring them neat in the presence of oxygen and a catalytic
amount of a simple sulfonic acid.
At ambient pressure, only reactions with ketones gave
reasonable product yields. Using other carbonyl derivatives
was sometimes moderately successful, while all the other
compounds tested did not show any reactivity. This indi-
cates that high nucleophilicity12 alone does not make a
good substrate in this reaction. Again, by applying elevated
pressure and temperature, we were able to broaden the
product scope somewhat (Scheme 5).8,11 Malonates, alde-
hydes and electron-rich benzenes could be used as nucleo-
philes. In the case of aldehydes, the isolated products
turned out to be the over-oxidized carboxylic acids.
O
R1
R2
O
MsOH/TfOH (5–7 mol%)
O2 (5–10 bar)
R2
+
neat, r.t.
60–128 h
R1
O
O
O
O
Ph
O
F
N
R
N
31%
Cbz
82%
(54:46 dr)
R = Ph, 74%
R = Me, 72%
O
O
O
R = Cbz, 77%
N
Ph
Nu
TfOH (5–7 mol%)
O
2 (6–10 bar)
35%
42%
O
1
+
Nu–H
OMe
CH2Cl2 or EtOAc
OMe
O
Scheme 6 Representative products from the autoxidative coupling re-
action with other benzylic compounds at elevated pressure
O
O
O
OOH
O
MeO
MeO
R
OH
6
O
O
O
Figure 1 Isochromane-derived hydroperoxide 6
42% (128 h, r.t.)
80% (R = OMe, 24 h, 70 °C)
65% (R = H, 72 h, 90 °C)
78% (48 h, r.t.)
Scheme 5 Representative products with non-ketone nucleophiles us-
ing elevated pressure and temperature
any extension of the substrate and product scope would re-
quire to accelerate the autoxidation rate.
Later studies revealed that the aerobic autoxidation of
xanthene into peroxide 4 proceeds very well in ketones
(and DMSO), but much less efficient in all the other sol-
vents investigated.13 This interesting solvent effect can ex-
plain the observed preference for ketone nucleophiles, but
its nature remains unclear.
At ambient pressure of oxygen, xanthene was the only
benzylic hydrocarbon substrate that we found to react with
reasonable yields, with the exception of some acridanes.
The latter, as well as a few other compounds with benzylic
C–H bonds, reacted much better at elevated partial pres-
sures of oxygen (Scheme 6).8,11 As can be seen, the sub-
strates are restricted to heterocycles. Diarylmethanes, how-
ever substituted, showed no reactivity under these condi-
tions.
2.2 With a Little Help from Light – CHIPS
The synthesis of hydroperoxides by reaction with sin-
glet oxygen, generated by photochemical methods, is well-
known.14 We therefore investigated a strategy to combine
their intentional synthesis with the acid-catalyzed substi-
tution with nucleophiles, which would result in a two-step
C–H functionalization via Intermediate PeroxideS (CHIPS),
requiring only oxygen, visible light and catalysts and initia-
tors, respectively. Related approaches had been investigated
before but were generally limited to very few products.15
We were able to achieve a proof-of-concept with tetrahy-
drocarbazoles 7 and N-nucleophiles (Scheme 7).16
The oxidation to the hydroperoxide 8 proceeds quanti-
tatively by irradiation with visible light and rose Bengal as a
sensitizer.16a,17 Subjecting the isolated peroxide to acid in
the presence of electron-poor anilines or related nucleo-
philes gave products 9 after short reaction times. Depending
on the substrate, the reaction conditions of the second step
can be varied to achieve optimum results.16a Some of the
products, for example 9c, have potent antiviral properties.18
The observation of the isochromane-derived hydroper-
oxide 6 as an intermediate (Figure 1) supported the original
working model of autoxidation and nucleophilic substitu-
tion.11 However, it was also obvious from these results that
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position products catalyzing the substitution of intermedi-
ate hydroperoxides.
HOO
hν, [rose Bengal]
O2
Jeganmohan and More reported the oxidative coupling
of diarylmethylketones with electron-rich arenes, by simply
stirring the substrates in air in the presence of an acid.22
The addition of potassium persulfate (K2S2O8) was found to
be beneficial for the yield, but was not essential (Scheme
8b).
Possibly related reactions involving tetrahydrofuran,
benzylic ethers and N-aryl tetrahydroisoquinolines have
been reported, some of which required additives that could
act as radical initiators to increase the rate of the autoxida-
tion.23 The concept of generating activated intermediates by
autoxidation for the subsequent addition to double bonds is
also interesting in this context, which shows that such a
simple process can be utilized synthetically in many ways.24
toluene, r.t., 3 h
quantitative
N
N
H
8
7
a) CF3CO2H (10 mol%), MeOH
or b) AcOH
R1
R2
8
+
HN
NR1R2
r.t., 2 h
N
H
9
Ph
Br
N
NH
NH
N
H
N
H
N
H
Ph
9a
95%
9b
67%
(91:9 dr)
9c
60%
O2N
O2N
Scheme 7 Synthesis of substituted tetrahydrocarbazoles by CHIPS
3 How Does the Autoxidative Coupling
Work?
The transformation of tetrahydrocarbazoles 7 into the
products 9 can also be achieved in a one-pot reaction, but
with reduced yields.16a The mechanism of this reaction in-
cluding the remarkable shift of the hydroperoxide moiety at
position 4a to the N-substituent at position 1 was found to
proceed via an acid-mediated tautomerization of 8.19
As inspiring as the autoxidative coupling with xanthene
is in the context of green chemistry, the accessible products
have (so far) not been of any synthetic use. A much better
understanding of the reaction mechanism became highly
desirable to us to provide a foundation for further develop-
ments.
2.3 Related Autoxidative Coupling Reactions
Thus, the reaction of xanthene with cyclopentanone
was chosen as a model system for more detailed mechanis-
tic studies.13 Indeed, performing the reaction in the absence
of acid resulted in an autoxidation, yielding hydroperoxide
4 as the major product, as well as xanthone 10 and xant-
hydrol 11 (Figure 2). The latter two only formed in larger
amounts at higher conversions of xanthene, indicating that
they are secondary products formed from 4.
The autoxidative coupling reaction with xanthenes also
inspired research projects by other groups. For example,
supported sulfonic acids were shown to be useful catalysts
for the reaction and an asymmetric advancement was de-
veloped using a chiral organocatalyst for the coupling with
aldehydes.20
Huo et al. reported the autoxidative coupling of N-aryl-
glycine derivatives with indoles (Scheme 8a).21 The reaction
conditions simply involve stirring both substrates in 1,2-di-
chloroethane (DCE) under an atmosphere of oxygen at
40 °C. Freshly distilled DCE gave reduced yields in contrast
to older batches, which supported the role of acidic decom-
OOH
O
OH
O
O
O
O
O
4
10
11
12
Figure 2 Oxidized compounds formed during the autoxidation of xan-
thene or during autoxidative coupling reactions
a)
O
H
R2
N
Ar
R1
O
In reactions with cyclopentanone, δ-valerolactone (12)
was also observed as a by-product in up to 25% yield, sug-
gesting that a Baeyer–Villiger oxidation had taken place –
we will discuss this later.
O2
H
N
+
Ar
R1
MeCN, DCE
40 °C, 4–60 h
30–83%
N
H
NH
R2
29 products
The working model for the reaction mechanism
(Scheme 3) seemed to be fully in line with these observa-
tions, and that could have been the end of it, if we had not
put it into our minds to also study the kinetics of the reac-
tion a little bit. The autoxidation of 1 in the absence of acid
proceeds with remarkable speed compared with most
known autoxidation reactions (Scheme 9). At 40 °C, a 25%
b)
O
OMe
OMe
MeO
O2
O
Ph
+
CF3CO2H
r.t., 24 h, 55%
MeO
Ph
Ph Ph
Scheme 8 Related autoxidative coupling reactions
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M. Klussmann, B. Schweitzer-Chaput
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yield of 4 is obtained after two hours, and nearly full con-
version of 1 is achieved after 24 hours. If the hydroperoxide
4 is subjected to acid catalysis in cyclopentanone, it is
quickly converted into product 2 in about two minutes.
Thus, the autoxidation step seems to be rate-determining.
But to our surprise, the coupling reaction itself actually
proceeded faster than that! For example, after two hours,
75% of xanthene is converted into 2 compared with only
25% conversion in the autoxidation.
anesulfonic acid (MsOH) were added. As expected, com-
pound 4 readily formed the substitution product 2. More
slowly however, about 50% of 13 was converted into the
coupling product 14 (Scheme 10).
O
OOH
MsOH (7 mol%)
cyclopentanone
Ar, 40 °C
O
O
O
2
4
O
+
MsOH (7 mol%)
cyclopentanone, O2, 40 °C
O
2 h: 75%
no H2O2 detected
O
O
O
1
2
13
14
O2, 40°C
cyclopentanone
MsOH (7 mol%)
cyclopentanone
r.t.
OOH
Scheme 10 Oxidative coupling of xanthene 13 with cyclopentanone
by H2O2 formed in situ from the reaction with 4
2 h: 25%
2 min, quant.
H2O2 detected
O
This clearly showed that the byproduct H2O2 is a compe-
tent oxidant under these reaction conditions mediating the
oxidative coupling of xanthenes with ketones by acid catal-
ysis, and explains why no H2O2 could be detected in the re-
action mixtures of the autoxidative couplings. However, the
mechanism of this transformation remained puzzling since
the reaction still does not contain any redox-active cata-
lysts.
To avoid the above-mentioned solubility problems asso-
ciated with aqueous hydrogen peroxide, we instead used
solutions of tert-butyl hydroperoxide (t-BuOOH) in decane,
and found it to be a suitable substitute for further studies. It
turned out that oxidative coupling reactions such as that
forming 14 shown above displayed a remarkable solvent ef-
fect. Significant yields were achieved with the combination
of acid catalysis, t-BuOOH or hydrogen peroxide and ke-
tones, in contrast to all other solvents, regardless of their
polarity.
There have been reports on the activation of hydrogen
peroxide purely by acids, yet these concern superacidic me-
dia or gas-phase reactions, and propose ionic mechanisms
triggered by full protonation of the peroxide.26 In contrast,
the C–H functionalization in the autoxidative coupling ap-
pears to be a radical process: the reaction as such does not
proceed at all if catalytic amounts of 3,5-di-tert-4-butylhy-
droxytoluene (BHT), a common radical inhibitor, are add-
ed.8 Additionally, in the experiment shown in Scheme 10,
the formation of 14 is suppressed completely in the pres-
ence of BHT, while the formation of 2 is not.13
4
Scheme 9 Differences in the autoxidation versus the autoxidative cou-
pling of xanthene
Obviously, the mechanism cannot be correct if the reac-
tion proceeds faster than the proposed rate-controlling
step. Since the evidence still pointed toward the involve-
ment of an intermediate hydroperoxide, we wondered if
the addition of the acid catalyst or the formation of the re-
action product 2 were responsible for the increase in the re-
action rate. The addition of 2 had been shown before to ac-
tually decrease the reaction rate.8 Acids had been reported
to influence autoxidation rates, but in systems not directly
applicable to the reaction we studied.25 When we investi-
gated the addition of weaker acids on the autoxidation
without significantly converting the hydroperoxide 4 into
2, there was no effect, only acetic acid actually decreased
the rate. The rate increase must therefore have another ex-
planation.
Another difference between autoxidation and the au-
toxidative coupling concerns hydrogen peroxide. As expect-
ed, it was detected as a by-product by spectroscopic analy-
sis of the reaction from isolated 4 to 2, while it was not
found in the reaction starting from 1 (Scheme 9).13
Attempts with aqueous solutions of hydrogen peroxide
(H2O2) to study its effect on the reaction proved to be diffi-
cult due to solubility problems in presence of the relatively
large amounts of water. A key experiment was performed
with hydrogen peroxide formed in situ: an equimolar mix-
ture of xanthenyl hydroperoxide (4) and the dimethyl xan-
thene 13 were dissolved under argon – in order to prevent
aerobic autoxidation of 13 – and catalytic amounts of meth-
To gain more information regarding the nature of the
radicals involved, we tried to carefully characterize all the
products formed in the reactions of the hydroperoxides, ke-
tones and acids. In the presence of xanthene, we discovered
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the dimer 15 as a by-product and tert-butyl peroxide 16 as
a transient intermediate (Scheme 11a).13 Both products
suggest the involvement of xanthenyl and peroxyl radicals.
3.1 An Excursion: Formation of Alkenyl Peroxides
from Criegee Intermediates in the Atmosphere
Ozonolysis of alkenes leads to primary ozonides, which
decompose into a carbonyl compound and a carbonyl oxide
or Criegee intermediate 22.30 In contrast to ozonolysis in
solution, these products rapidly dissociate in the gas phase
and the reactions of the Criegee intermediate play an im-
portant role in atmospheric chemistry.31 One reaction path-
way is the intramolecular proton transfer to form an alkenyl
hydroperoxide 23, a highly unstable compound that rapidly
decomposes via O–O bond homolysis into a hydroxyl and a
carbonyl radical (24) (Scheme 12).
O
a)
OOt-Bu
15
O
16
O
b)
O
O
p-TsOH (10 mol%)
t-BuOOH (4 equiv)
Ph
Ph
+
MeCN, Ar
50 °C, 4–22 h
OOt-Bu
R1
O
OH
17, 72%
O
O
O
O
O3
– R1CHO
~H+
O
O
O
H
H
Ot-Bu
OOt-Bu
R2
R1
R2
R2
R2
22
23
+
+
Criegee intermediate
18, 12%
19, 5%
O
O
OH
Ot-Bu
c)
H
H
O
O
O
17
18
19
R2
R2
24
Scheme 12 Formation of alkenyl peroxides in the atmosphere by ozo-
20
nolysis of alkenes
21
t-BuOO
t-BuO
Since this reaction also proceeds in the dark, it is be-
lieved to be the major source of atmospheric hydroxyl radi-
cals in the night time.32
t-BuOH t-BuOOH
Scheme 11 (a) Oxidized by-products formed in reactions of xanthene
with cyclopentanone, t-BuOOH and MsOH. (b) Products formed from
reactions of styrene with cyclohexanone. (c) Retrosynthetic analysis
leading to a putative intermediate
Due to their instability, alkenyl peroxides have not been
characterized directly. Instead, they have been the focus of
many theoretical studies in the context of atmospheric
chemistry.33 Various substituted vinyl and alkenyl perox-
ides have been investigated and found to generally possess
very labile O–O bonds, the ease of homolytic decomposition
being rationalized by the resonance stabilization of the car-
bonyl radical 24. It has been suggested that alkenyl, alkynyl
and aryl peroxides in general do not exist as stable com-
pounds under ambient conditions.33b
Particularly revealing were experiments in the presence
of styrene as a trapping agent (Scheme 11b). We found high
yields of γ-peroxyketones such as 17,27 and later, we also
characterized the oxygenated ketones 18 and 19 as by-
products.28 In something like a retrosynthetic analysis,
these products could be traced back to a ketone-radical 20,
a tert-butyl peroxyl and an oxyl radical (Scheme 11c). The
tert-butyl peroxyl radical is well known to form in a very
fast reaction by hydrogen atom transfer (HAT) between an
oxyl radical and excess t-BuOOH.29 Thus, it can probably be
assumed that products 17–19 could arise from 20 and an
oxyl radical alone. These, in turn, might have formed from a
structure such as 21, an alkenyl peroxide, by homolytic O–O
bond cleavage. Not knowing about the properties of this
putative intermediate, we looked for prior reports. Howev-
er, we did not find such a structure in the synthetic chemis-
try literature, but instead did so in reports from an unex-
pected area.
3.2 How do Alkenyl Peroxides Form in Solution?
Meet Criegee Again
We rationalized that alkenyl peroxides could form in
solution by a condensation reaction between ketones and
hydrogen peroxide or hydroperoxides, catalyzed by acids
(Scheme 13). While this mechanism is fundamentally dif-
ferent from the atmospheric one, it is interesting to note
that it is once more connected with Rudolf Criegee: nucleo-
philic addition of a peroxide to the carbonyl group would
first form a tetrahedral intermediate 25, also known as a
Criegee intermediate or adduct.34 Under acidic conditions,
this could form a peroxycarbenium ion35 26 by protonation
and loss of water, followed by loss of a proton to generate
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197
M. Klussmann, B. Schweitzer-Chaput
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the alkenyl peroxide 27. Alternatively, acids might catalyze
the concerted elimination of water. The alkenyl peroxide
would in either case decay into a stabilized ketone radical
28 and an oxyl radical.
[H+]
H+
– H+
O
O
HO
O
OR
HO
O
OR
H
+ R–OOH
O
25
Criegee adduct
+ R-OH
[H+]
+ R–OOH
Scheme 14 Baeyer–Villiger oxidation by acid-catalyzed reaction of ke-
tones with peroxides, shown with acetone as an example
OR
+ H+, – H2O
O
O
HO
O OR
26
25
[H+]
– H2O
reaction pathways leading from three different Criegee ad-
ducts to alkenyl peroxides and esters, respectively.28 We
took peracetic acid as a model for peracids, preferred in the
Baeyer–Villiger oxidation, hydrogen peroxide and tert-butyl
hydroperoxide, preferred in our radical reactions, and
methanesulfonic acid as a catalyst in all cases. The transi-
tion states TS1 for the Baeyer–Villiger rearrangement were
found to be quite close to each other, the barrier being low-
est for peracetic acid, in line with the experimental prefer-
ence. However, the barriers for the use of H2O2 and t-BuOOH
were still easily accessible, indicating that both of these re-
agents should be suitable for the reaction per se (Figure 4).
Criegee adduct
– H+
OR
O
O
O
OR
28
27
Scheme 13 Formation of alkenyl peroxides by acid-catalyzed conden-
sation, shown with acetone as an example
Some observations support this proposal. If an aqueous
solution of t-BuOOH is utilized in the addition reaction to
styrene (Scheme 11b above), the reaction to afford 17 pro-
ceeds at a reduced rate. In contrast, in the presence of mo-
lecular sieves, the reaction does not take place and we ob-
served the formation of geminal bisperoxide 29 instead
(Figure 3), apparently resulting from condensation of cyclo-
hexanone with two molecules of t-BuOOH.28 These results
are in agreement with a series of equilibria involving the
peroxycarbenium ion: large amounts of water shift them
toward the starting materials and thereby suppress the
overall reaction rate, while its complete removal favors the
condensation to give 29.
t-BuOO OOt-Bu
Figure 4 Energy diagram for the calculated reaction pathways of the
Baeyer–Villiger oxidation and alkenyl peroxide formation from Criegee
adducts 25; enthalpy values are given in kcal/mol.28 Calculated using
the ωB97XD functional with the 6-31++G(d,p) basis set (geometries
and frequencies), the aug-cc-pV(T+d)Z basis set (energies) and the IEF-
PCM solvent model (acetone). The total enthalpies contain the enthalpy
of one molecule of methanesulfonic acid and methanesulfonate, re-
spectively.
29
Figure 3 Geminal bisperoxide 29
But that was not the end of this mechanistic investiga-
tion yet. Criegee adducts 25 are intermediates in the Baeyer–
Villiger oxidation that transforms ketones into esters and
lactones by reaction with a peroxide under acidic condi-
tions, being in fact very similar conditions to the radical
generation that we found.34,36 For the Baeyer–Villiger oxida-
tion, electron-poor peracids display the highest reactivities,
but hydrogen peroxide is the reagent of choice with regard
to atom economy. The generally accepted mechanism of the
Baeyer–Villiger oxidation involves formation of the Criegee
adduct 25 and subsequent rearrangement, both steps of
which can be acid catalyzed (Scheme 14).34
For the alkenyl peroxide formation, the concerted path-
way of water elimination via TS2 (Figure 4) was found to be
favorable compared with the stepwise mechanism via per-
oxycarbenium ions 26. Now, the barrier was lowest for
t-BuOOH and the three barriers differed more strongly in
energy. Comparison of TS1 and TS2 for each peroxide can
explain general trends for the two reactions. For peracetic
acid, the Baeyer–Villiger rearrangement is favored over
alkenyl peroxide formation by 5.6 kcal/mol, meaning that
the latter will basically not be observed. For t-BuOOH, it is
the other way around and alkenyl peroxide formation is fa-
vored by 3.0 kcal/mol. For H2O2, both barriers differ by only
1.1 kcal/mol in favor of the elimination. This provides an
additional or alternative explanation for the choice of
So what factors decide the fate of the Criegee adduct?
We asked a theoretical chemist for help and looked at the
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M. Klussmann, B. Schweitzer-Chaput
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peracids in Baeyer–Villiger oxidations: these reagents have
the lowest barriers for the rearrangement, but additionally
disfavor the formation of alkenyl peroxides. For H2O2 and t-
BuOOH, the Baeyer–Villiger oxidation is in principle also fa-
vorable, but they face strong competition from the elimina-
tion pathway. This, and not the often perceived leaving
group ability of the peroxides could be the best rationaliza-
tion for the performance of peroxides in Baeyer–Villiger ox-
idations.
Obviously, one should be able to influence these kinetic
barriers by the choice of catalyst and ketone substrate. In-
deed, it has been shown that an immobilized Sn–salen com-
plex can utilize t-BuOOH for very selective Baeyer–Villiger
oxidations with cyclohexanone, which gave no observable
trace of the lactone with sulfonic acid catalysts.28,37 Non-
enolizable ketones will also not be able to form alkenyl per-
oxides. We found that under conditions that generate radi-
cals from cyclohexanone (Scheme 11b above), adamanta-
none (30) (Figure 5) underwent cleanly the Baeyer–Villiger
oxidation with t-BuOOH to give the corresponding lactone,
and not much slower than when m-chloroperoxybenzoic
acid was used.28
to the generally accepted mechanism38 via the xanthenyl
radical 31, which in the presence of oxygen rapidly forms
the peroxyl radical 32. This in turn forms the observable
hydroperoxide 4 after HAT, most likely from another mole-
cule of xanthene (1) in a radical-chain reaction. In the pres-
ence of an acid of sufficient strength,13 hydroperoxide 4 is
protonated and liberates one molecule of hydrogen perox-
ide upon formation of the xanthenyl cation 5. Reaction with
cyclopentanone, for example via its enol form, then leads to
the main product 2. The observed by-products, xanthone
10, xanthyl peroxide 3 and xanthydrol 11, are formed from
the hydroperoxide 4 and the cation 5, respectively. Hydro-
gen peroxide can now react with cyclopentanone under
acid catalysis forming the Criegee adduct 33, which partial-
ly proceeds to the (observed) lactone 12 via Baeyer–Villiger
rearrangement, and to the alkenyl hydroperoxide 34. The
latter will rapidly decompose into radicals, which accelerate
the autoxidation of xanthene by forming additional
amounts of radical 31 via HAT. If this reaction is run under
argon, 31 dimerizes into 15, which has sometimes been ob-
served.
O
3.3 The Full Mechanism of the Autoxidative Cou-
pling Reaction
30
Figure 5 Structure of adamantanone (30)
Now we can outline the state-of-the-art mechanism of
the autoxidative coupling reaction of xanthene with cyclo-
pentanone (Scheme 15). Autoxidation proceeds according
OO
15
1
(Ar)
(O2)
O
O2
10
1
OOH
O
32
O
31
4
O
O
O
H2O
2
H+
O
1
OH
O
O
OH
[H+]
H2O2
OOH
HO OOH
O
5
[H+]
O
33
34
3, 11
[H+]
H2O
O
O
12
Scheme 15 State-of-the-art reaction mechanism of the autoxidative coupling reaction of xanthene (1) with cyclopentanone
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M. Klussmann, B. Schweitzer-Chaput
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4 Previous Indications for Solution Chemis-
try of Alkenyl Peroxides
instability (Scheme 16a). At –10 °C, the compounds slowly
decomposed to the tert-butyl ethers 37 and 38. Indications
from NMR studies led them to propose intermediate radi-
cals such as 39, which form the ethers by geminate recom-
bination.
Although the chemistry of alkenyl peroxides was appar-
ently only studied by atmospheric chemists in recent years,
the fact that radical reactions start from the simple mixture
of hydroperoxides, ketones and acids did not go entirely un-
noticed. In addition, alkenyl peroxides have been discussed
by synthetic chemists before, but these rare reports proba-
bly never received much attention.
A few groups had intentionally studied the synthesis of
alkenyl peroxides, speculating about their instability due to
the failure to observe them.39 They suggested that the re-
sulting decomposition products had formed by a sigma-
tropic rearrangement, while we consider homolytic decay
and geminate recombination more likely.
Pavlinec and Lazar discovered that the radical polymer-
ization of methyl methacrylate can be initiated at unusually
low temperatures (40 °C) with t-BuOOH, if ketones and sul-
furic acid are used as additives, but they did not consider
the formation of alkenyl peroxides.40 Solyanikov et al. have
studied the decomposition of organic hydroperoxides in
acidic media and found that the addition of ketones and al-
dehydes significantly accelerated the reaction.41 A radical
mechanism was proposed and suggested to proceed via
O–O bond cleavage of Criegee adducts or related com-
pounds.
When we stirred compound 35a in the presence of sty-
rene and t-BuOOH at 50 °C overnight, the addition product
40 was obtained in 12% yield along with 37a and the re-
duced product 41 in 42% and 40% yields, respectively
(Scheme 16b, see the Supporting Information). This further
supports the assumption by Kropf and Ball, as reduction
product 41 would have formed by HAT from t-BuOOH to
the intermediate radical 39, which also added to styrene
forming 40 after subsequent reaction with a tert-butyl per-
oxyl radical. The analogous recombination product of a per-
oxyl radical and 39 was not observed, but this compound is
once more an aryl peroxide and would thus not be stable
under the reaction conditions.
4.1 What Might Alkenyl Peroxides be Good for?
Intrigued by the mechanistic discoveries we had made,
we also turned our eye to synthetic applications. As it has
already been indicated above, the radicals formed by decay
of alkenyl peroxides can mediate oxidative coupling reac-
tions (Scheme 10) and add to styrene (Scheme 11b). In both
cases, we could apply this chemistry to obtain a variety of
products. Oxidative cross-coupling reactions between sub-
strates bearing benzylic C–H bonds and nucleophiles
worked more generally than just with xanthene, as shown
by the products in Scheme 17.13 Presumably, the radicals
formed activate the benzylic substrate by HAT, ultimately
generating cationic intermediates.
Apparently the only known case of isolable alkenyl per-
oxides was reported by Kropf and Ball.42 They synthesized
the three heteroarene-peroxides 35a,b and 36 by base-me-
diated nucleophilic aromatic substitution and noted their
a)
OOt-Bu
O
O
Ot-Bu
–10 °C, ca. 30 d
petroleum ether
N
HN
N
MsOH (10 mol%)
t-BuOOH (2–3 equiv)
Nu
R
N
R
N
R
N
Nu–H
+
Ar
R
ketone, 40 °C
Ar
R
35a, R = H
35b, R = Cl
37a, R = H, 80%
37b, R = Cl, 85%
39
NH
OOt-Bu
O
O2N
O
N
Cbz
EtO2C
Cl
EtO2C
Ot-Bu
–10 °C, ca. 30 d
MeO
OMe MeO
OMe
petroleum ether
56%
N
36
Cl
N
H
38
O
OMe
OMe
b)
OOt-Bu
O
Scheme 17 Oxidative cross-coupling reactions mediated by ketones, t-
Ph
(2 equiv)
BuOOH and acid-catalysis
N
HN
t-BuOOH (4 equiv)
37a
42%
+
41
40%
Ar, MeCN, 50 °C, 12 h
N
35a
N
Directly utilizing the ketone radicals derived from the
alkenyl peroxides is synthetically interesting because effi-
cient catalytic approaches to simple ketone radicals are lim-
ited.43 We found the addition of ketones to styrenes to be
more general and could utilize cyclic and open-chain ke-
tones alike, as well as trisubstituted styrenes (Scheme 18).27
O
Ph
OOt-Bu
HN
40
12%
+
N
Scheme 16 Isolable heteroarene-peroxides and their decomposition
reactions
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M. Klussmann, B. Schweitzer-Chaput
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R1
O
t-BuOO
R1
Ar
R3
O
MsOH (2–10 mol%)
t-BuOOH (4 equiv)
R4
R1
R1
R4
+
Ar
O
[R-SO3H]
t-BuOOH
MeCN, 50 °C
overnight
R2
R3
R2
O
O
R4
+
50 °C, 12–24 h
N
R2
N
R2
O
R3
OMe
OOt-Bu
OOt-Bu
OOt-Bu
O
O
Ph
Ph
Ph
60%
O
O
O
O
74%
44%
O2N
OOt-Bu
OOt-Bu
O
O
Ph OOt-Bu
N
N
Ph
Ph
Ph
61%
O
Bn
N
O
Ph
O
O
68%
27%
Scheme 18 Acid-catalyzed addition of ketones to styrenes
Scheme 20 Acid-catalyzed cascade reaction for the synthesis of oxin-
doles bearing ketone side chains
The resulting γ-peroxyketones were mostly unknown
compounds, but turned out to be synthetically very useful,
as the peroxide residue can easily be interconverted by
Kornblum–DeLaMare rearrangement44 or catalytic hydro-
genation (Scheme 19). In this way, 1,4-diketones, homoal-
dol products or alkyl ketones are accessible.27 The group of
Zhiping Li has also recently developed direct, acid-catalyzed
transformations of γ-peroxycarbonyl compounds into sub-
stituted furans or carbazoles.45
5 Concluding Remarks
The outlined progress of research in our group started
with the unexpected discovery of an aerobic autoxidative
coupling reaction that did not require any redox-active cat-
alysts and ended with the discovery of the solution chemis-
try of alkenyl peroxides, which can be easily synthesized via
the condensation of ketones and hydroperoxides, and
which rapidly decompose into radicals. Along the way, new
strategies for oxidative cross-coupling reactions were de-
veloped that utilize only acid catalysts as well as oxygen
and hydroperoxides, respectively.
In retrospect, these discoveries could in principle have
been predicted based on a very small number of less re-
garded reports from the last fifty years. As is so often the
case, there is a lot of hidden wealth in old publications. In-
stead, they rely on dedicated mechanistic studies of the
originally discovered autoxidative coupling reaction, in-
cluding kinetic measurements, product studies, trapping
experiments and theoretical calculations. The insight won
this way allowed us to rationalize the old reports men-
tioned and gave us the inspiration for new research projects
that we would not have devised otherwise. Without dedi-
cated co-workers and an environment that supports the in-
vestigation of an obscure reaction for the sake of generating
knowledge, this would not have been possible. Only the fu-
ture will tell whether alkenyl peroxide chemistry can actu-
ally be considered useful, but we think so.
R2
R2
[Pd/C], H2
MeCN
[Pd/C], H2
MeOH
OH
R1
R1
Ar
Ar
[H+]
O
O
R2
t-BuOO
R2
R1
Ar
[base]
R1
O
R1
R2
O
O
Ar
O
N
H
R2
[H+]
N
R1
H
Scheme 19 Synthetic transformations of γ-peroxyketones
The addition of ketone radicals to N-aryl acrylamides
generates oxindoles by a radical cascade reaction (Scheme
20). This reaction was developed simultaneously by the
group of Xia and ours,46 based on the aforementioned work
with styrenes and on the known oxindole formation by rad-
ical cyclization.47
Further applications of alkenyl peroxides can be easily
imagined, given that they can be used in various ways: as a
form of activated carbonyl compounds (e.g., Schemes 18
and 20) and arenes (e.g., Scheme 16), or as mediators of re-
actions without becoming incorporated into the products
(e.g., Scheme 17). In addition, different synthetic approach-
es to make them besides the acid-catalyzed procedure from
ketones and hydroperoxides discussed here are possible, as
has been shown previously.39a,42a
Acknowledgment
We thank our previous co-workers and colleagues for their work and
motivation, the MPI für Kohlenforschung for continuous support, as
well as the DFG (Heisenberg scholarship to M.K., KL 2221/4-1, and KL
2221/3-1).
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Supporting Information
(23) (a) Gunduz, H.; Kumbaraci, V.; Talinli, N. Synlett 2012, 23, 2473.
(b) Tanoue, A.; Yoo, W.-J.; Kobayashi, S. Org. Lett. 2014, 16, 2346.
(c) Ueda, H.; Yoshida, K.; Tokuyama, H. Org. Lett. 2014, 16, 4194.
(d) Huo, C.; Wu, M.; Chen, F.; Jia, X.; Yuan, Y.; Xie, H. Chem.
Commun. 2015, 51, 4708.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560706.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
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2010, 2, 592. (b) Lu, Q.; Zhang, J.; Zhao, G.; Qi, Y.; Wang, H.; Lei,
A. J. Am. Chem. Soc. 2013, 135, 11481.
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