Oxidase catalysis via aerobically generated hypervalent iodine intermediates

Article abstract of DOI:10.1038/nchem.2873

The development of sustainable oxidation chemistry demands strategies to harness O'2 as a terminal oxidant. Oxidase catalysis, in which O'2 serves as a chemical oxidant without necessitating incorporation of oxygen into reaction products, would allow diverse substrate functionalization chemistry to be coupled to O'2 reduction. Direct O'2 utilization suffers from intrinsic challenges imposed by the triplet ground state of O'2 and the disparate electron inventories of four-electron O'2 reduction and two-electron substrate oxidation. Here, we generate hypervalent iodine reagents - a broadly useful class of selective two-electron oxidants - from O'2. This is achieved by intercepting reactive intermediates of aldehyde autoxidation to aerobically generate hypervalent iodine reagents for a broad array of substrate oxidation reactions. The use of aryl iodides as mediators of aerobic oxidation underpins an oxidase catalysis platform that couples substrate oxidation directly to O'2 reduction. We anticipate that aerobically generated hypervalent iodine reagents will expand the scope of aerobic oxidation chemistry in chemical synthesis.

Full text of DOI:10.1038/nchem.2873

ARTICLES
PUBLISHED ONLINE: 16 OCTOBER 2017 | DOI: 10.1038/NCHEM.2873
Oxidase catalysis via aerobically generated
hypervalent iodine intermediates
Asim Maity, Sung-Min Hyun and David C. Powers
*
The development of sustainable oxidation chemistry demands strategies to harness O2 as a terminal oxidant. Oxidase
catalysis, in which O2 serves as a chemical oxidant without necessitating incorporation of oxygen into reaction products,
would allow diverse substrate functionalization chemistry to be coupled to O2 reduction. Direct O2 utilization suffers from
intrinsic challenges imposed by the triplet ground state of O2 and the disparate electron inventories of four-electron O2
reduction and two-electron substrate oxidation. Here, we generate hypervalent iodine reagents—a broadly useful class of
selective two-electron oxidants—from O2. This is achieved by intercepting reactive intermediates of aldehyde autoxidation
to aerobically generate hypervalent iodine reagents for a broad array of substrate oxidation reactions. The use of aryl
iodides as mediators of aerobic oxidation underpins an oxidase catalysis platform that couples substrate oxidation directly
to O2 reduction. We anticipate that aerobically generated hypervalent iodine reagents will expand the scope of aerobic
oxidation chemistry in chemical synthesis.
is a readily available, environmentally benign, thermody- m-chloroperbenzoic acid11–13,16. There are no methods available
namically strong oxidant. The development of chemical for the direct synthesis of hypervalent iodine compounds from
O2 strategies to couple O2 reduction directly to substrate oxi- O2. (Liu and co-workers have suggested O2-coupled generation of
dation would enable sustainable synthetic methods1–3. However, I(V) intermediates during aerobic alcohol oxidation17, but the
selective and efficient utilization of O2 is challenging due to the active oxidant in this chemistry has subsequently been reassigned
triplet ground state of O2, which imposes substantial kinetic barriers as Br2; ref. 18.) We were attracted to aerobic oxidation of aryl
to O2 reduction and gives rise to poorly selective radical chem- iodides based on the hypothesis that the resulting hypervalent
istry4,5, and due to the disparity between the electron inventories iodine reagents, in conjunction with ligand exchange at iodine,
of four-electron O2 reduction and two-electron substrate oxi- could provide a new platform for oxidase chemistry. Here, we inter-
dation6,7. Broadly, there are two approaches to O2 utilization: (1) cept aldehyde autoxidation intermediates to prepare a family of
oxygenase chemistry, in which O2 serves as both an oxidant and hypervalent iodine reagents using O2 as the terminal oxidant, and
the source of oxygen content in organic reaction products; and demonstrate the utility of aerobic oxidation of aryl iodides in
(2) oxidase chemistry, in which O2 serves as a proton and electron oxidase catalysis to functionalize a variety of substrate classes.
acceptor but is not incorporated into the organic reaction products
(Fig. 1)8. Oxidase chemistry is synthetically attractive because Results and discussion
many desirable oxidation reactions do not require substrate oxygen- Intercepting aldehyde autoxidation for aerobic oxidation of aryl
ation. To achieve oxidase chemistry, small-molecule mediators that iodides. Aldehyde autoxidation chemistry, which converts aldehydes
participate in facile redox chemistry with O2 to generate two-elec- to carboxylic acids under the action of O2, is among the earliest
tron oxidants (such as hydroquinone oxidation to benzoquinone) reactions of O2 with organic molecules to be characterized19. In
have been utilized9,10. The application of available mediators, 1832, Wöhler and Liebig reported the autoxidation of
however, is currently limited by either the generation of weak oxi- benzaldehyde to benzoic acid20. Bäckström advanced the now-
dants or limited substrate scope.
accepted radical chain mechanism for aldehyde autoxidation in
In the absence of broadly applicable strategies for O2 utilization, 1927 (Fig. 2), which involves hydrogen-atom abstraction (HAA)
synthetic chemists have developed myriad reagents that participate from aldehyde A to generate acyl radical B, reaction of B with O2
in selective two-electron oxidation chemistry. For example, hyper- to generate acyl peroxy radical C, and HAA to generate an
valent iodine reagents are a broadly useful class of selective two- equivalent of peracid D and the acyl radical chain carrier B21.
electron chemical oxidants based on 3-centered, 4-electron (3c–4e) Subsequent Baeyer–Villiger reaction via intermediate E generates
iodine–ligand bonds11–13. These reagents find application in two equivalents of acid F22. The synthetic utility of autoxidation
diverse chemical settings, including C–H hydroxylation and amin- intermediates in reaction development has been realized23–27. For
ation, olefin functionalization, oxidative dearomatization, and as example, aerobically generated acyl radical intermediates have been
group-transfer reagents in catalysis. The broad utility of hypervalent intercepted for olefin addition chemistry and aerobically generated
iodine reagents derives from the facile ligand exchange chemistry peracids have been utilized for oxygen-atom transfer chemistry28–32
available at iodine. Ligand exchange reactions allow hypervalent We initiated our investigation of aerobic oxidation of aryl iodides
.
iodine reagents to be utilized in oxidative oxygen-, nitrogen-, by examining the viability of the oxidation of PhI with O2 in the
halogen- and hydrocarbyl-transfer chemistry11,14,15. The current presence of a variety of simple aldehydes in 1,2-dichloroethane
liabilities of hypervalent iodine reagents include the frequent (DCE) at 23 °C (Table 1). We found that, although benzaldehyde
need for stoichiometric quantities of these compounds and the was ineffective in promoting the oxidation of iodobenzene
synthesis of these reagents from wasteful metal-based oxidants (Table 1, entry 1), isobutyraldehyde and butyraldehyde led to the
such as KMnO4, NaIO4 and oxone, or organic peracids such as observation of 2% and 6% yield of I(III) bis-esters, respectively
Department of Chemistry, Texas A&M University, College Station, Texas 77843, USA. e-mail: david.powers@chem.tamu.edu
*
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2873
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(TFA)2 and PhI(OBz)2 in 52 and 48% yields, respectively. Aldehyde-
promoted oxidation of 2-iodobenzoic acid, 2-(2-iodophenyl)propan-
2-ol and 1,1,1,3,3,3-hexafluoro-2-(2-iodophenyl)propan-2-ol affords
I(III) compounds 4, 5 and 6, respectively. Benziodoxole-based hyper-
valent iodine reagents, in which the ortho-substituent chelates to the
oxidized iodine centre (that is, 4–6), are widely utilized in atom-
and group-transfer chemistry14. The developed conditions also
provide access to bis-I(III) compound 738, by four-electron oxidation
of 1,2-diiodobenzene, in 90% yield. Finally, we examined oxidation
of 2-tert-butylsulfonyliodobenzene to access 2-tert-butylsulfonyl-
iodosylbenzene, a hypervalent iodine derivative that has found appli-
cation in hydroxylation catalysis due to its substantially increased
solubility versus unsubstituted iodosyl benzene39. Unlike the afore-
mentioned oxidation reactions, which generate I(III) derivatives in
high yield, oxidation of 2-tert-butylsulfonyliodobenzene affords I(V)
derivative 8. The unanticipated overoxidation in this case is probably
due to disproportionation of an initially formed I(III) derivative.
Consistent with this hypothesis, treatment of independently prepared
2-tert-butylsulfonyliodosylbenzene with AcOH, which is generated as
a by-product of autoxidation, resulted in the immediate disproportio-
a Oxygenase chemistry
O2, 2e–, 2 H+
subred
sub(O)
H2O
H2O
+
Hydroxylation by methane monooxygenase (MMO)
MMO, NADH, H+
CH4
O2
CH3OH
+
+
–NAD+
b Oxidase chemistry
½ O2 (O2), 2H+
subred
subox
+
H2O (H2O2)
Glucose oxidation by glucose oxidase
OH
OH
O
O2
O
+
HO
HO
HO
HO
H2O2
Glucose
oxidase
HO
HO
O
OH
Figure 1 | Oxygenase versus oxidase aerobic oxidation chemistry. a, In
oxygenase chemistry, O2 functions both as the electron acceptor as well as
the source of oxygen content during substrate functionalization. For
example, in the hydroxylation of methane by methane monooxygenase
(MMO), the oxygen content in methanol is derived from O2. b, In oxidase
chemistry, O2 functions only as a proton and electron acceptor and is not
incorporated into the oxidized substrate. An example of biological oxidase
chemistry is the aerobic oxidation of glucose by glucose oxidase. For
synthetic chemistry, oxidase strategies are attractive because they allow a
broad range of substrate functionalization modes to be coupled to O2 as the
terminal oxidant.
1
nation to I(I) and I(v) derivatives (see Supplementary Fig. 2 for H
NMR of disproportionation).
Application of aerobic oxidation of aryl iodides to oxidase
chemistry. Access to chemical platforms for oxidase chemistry, in
which O2 is utilized as the terminal oxidant without participating
in substrate oxygenation, would provide an approach to coupling
diverse modes of substrate oxidation directly to O2 reduction. Here,
we demonstrate that aerobic oxidation of aryl iodides can be used to
couple O2 reduction to 1,2-difunctionalization of olefins, carbonyl
(entries 2 and 3). Use of acetaldehyde afforded PhI(OAc)2 (1a) in α-functionalization, oxidative dearomatization chemistry and direct
42–91% yield (yields obtained from five identical reactions, entry 4). C–H amination chemistry (Fig. 3). For each of the transformations
We speculated that the variability of oxidation efficiency was illustrated in Fig. 3, control reactions in the absence of aryl iodides
due to inconsistent initiation of radical autoxidation chemistry. resulted in no conversion to the illustrated oxidation products.
Addition of a sub-stoichiometric amount of various metal salts
Aerobic oxidation of aryl iodides can be utilized in substrate oxy-
(1 mol%) that have been demonstrated to initiate autoxidation genation. Aerobic 1,2-bis-acetoxylation of styrene derivatives40, illus-
(entries 5–7)33,34 led to identification of CoCl2·6H2O as a highly trated by the conversion of 4-fluorostyrene (9) to bis-acetate 10 in
effective autoxidation initiator, leading to PhI(OAc)2 in 99% yield. 88% yield, can be accomplished via a one-pot procedure (Fig. 3a).
AcOH is the only by-product of aldehyde-promoted PhI oxidation, In the specific case of styrene functionalization, a one-pot, two-step
and PhI(OAc)2 can be isolated as a pure compound following a protocol, in which PhI(OAc)2 is prepared prior to styrene addition,
simple aqueous extraction to remove Co salts (see Supplementary was necessary. The incompatibility of radical chain autoxidation of
1
Fig. 1 for the crude H NMR spectrum). Using CoCl2·6H2O as PhI with the presence of styrene is consistent with the facility of
radical chain initiator, PhI oxidation can be accomplished with air radical addition to styrenes. One-step aerobic carbonyl α-oxidation
as the O2 source (63% yield). Aerobic oxidation of PhI to generate reactions proceed readily. Acetophenone (11) undergoes α-
PhI(OAc)2 could be carried out on gram scale (97% yield, 1.59 g iso-
O
O
O
O
O2
O2
A
lated product). The developed aerobic oxidation is compatible with
a broad range of organic solvents. In addition to DCE, high yields
are obtained in coordinating solvents, such as CH3CN (entry 8),
and protic solvents, such as AcOH (entry 9). In contrast, PhI oxi-
dation does not proceed in THF, which we hypothesize is due to
inhibition of autoxidation by the presence of relatively weak C–H
bonds (vide infra).
With conditions in hand for the aerobic oxidation of PhI, we exam-
ined the O2-coupled synthesis of a family of hypervalent iodine
reagents that have been applied in synthetic chemistry (Table 2).
O
OH
– B
H3C
H
H3C
H3C
O
H3C
O
A
B
C
D
O
O
A
2
O
CH3
H3C
OH
H3C
O
OH
F
E
Aerobic oxidation is tolerant to a range of electron-donating and Figure 2 | Radical-chain mechanism for aldehyde autoxidation. Aldehyde
-withdrawing substituents on the aryl iodide (compounds 1), and autoxidation is among the oldest characterized aerobic oxidation reactions in
hydrolysis of the initially formed I(III) diacetates provides ready organic chemistry. Autoxidation of aldehydes to carboxylic acids proceeds
access to iodosyl benzene derivatives (2) in uniformly high yield. via initial hydrogen-atom abstraction (HAA) from an aldehyde A to generate
Substitution of the aromatic ring has been demonstrated to provide acyl radical B. Subsequent reaction between B and O2 generates acyl peroxy
a synthetic handle to tune both the activity and the aggregation state radical C. HAA from a second equivalent of A generates peracid D and
of aryl I(III) reagents35,36. Addition of TsOH to the oxidation of PhI chain carrier B. Conversion of peracid D to carboxylic acids is accomplished
affords Koser’s reagent (3)37, an acid-activated iodosylbenzene deriva- by a Baeyer–Villiger reaction via intermediate E. Here, we intercept reactive
tive, in 84% yield. Similarly, addition of carboxylic acids to the reaction oxidants generated during autoxidation (D and E) to access hypervalent
mixture directly affords the corresponding I(III) esters: oxidation in the iodine reagents. Coupling O2 reduction to the synthesis of hypervalent
presence of trifluoroacetic acid (TFA) and benzoic acid results in PhI iodine compounds provides a platform for oxidase chemistry.
2
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2873
Table 1 | Optimization of aerobic oxidation of iodobenzene.
ARTICLES
be coopted for the oxidation of aryl iodides. Consistent with this
hypothesis, the use of reaction solvents with relatively weak C–H
bonds (that is, THF) or the addition of 2,6-di-tert-butyl-4-
methylphenol (BHT), a common radical inhibitor, suppressed the
formation of hypervalent iodine products. To further probe the
mechanism of PhI oxidation, we followed the kinetics of PhI
R
O
O
I
O2, RCHO
I
Initiator, solvent
O
O
1
consumption and PhI(OAc)2 evolution by H NMR spectroscopy
R
in CDCl3 (Fig. 4; additional data are summarized in Supplementary
Figs 3 and 4). In the absence of CoCl2·6H2O, an induction period
is observed and evolution of PhI(OAc)2 displays sigmoidal growth
consistent with a radical chain process. In the presence of
CoCl2·6H2O, PhI(OAc)2 evolution still displays sigmoidal growth,
but the induction period for PhI oxidation to PhI(OAc)2 is
substantially shortened, which is consistent with more rapid
initiation of a radical chain process. Similar kinetic profiles were
measured for the oxidation of 4-iodotoluene (Supplementary Figs 5
and 6) and for the oxidation of PhI in AcOH-d4 (Supplementary
Figs 7 and 8). During these 1H NMR experiments, we did not
observe 1H NMR resonances of peracetic acid, but we did note
the initial evolution and subsequent disappearance of a quartet at
5.41 ppm, a singlet at 2.01 ppm and a doublet at 1.35 ppm, which
integrate in a 1:3:3 ratio (Supplementary Fig. 9). We attribute
RCHO
Solvent
Initiator
Yield (%)
1
PhCHO
DCE
DCE
DCE
DCE
DCE
DCE
DCE
CH3CN
AcOH
THF
None
None
None
None
0
2
6
42–91
48
75
99
73
98
0
2
3
4
5
6
7
8
9
10
i-PrCHO
n-PrCHO
CH3CHO
CH3CHO
CH3CHO
CH3CHO
CH3CHO
CH3CHO
CH3CHO
Cu(OAc)2·H2O
Mn(OAc)2·4H20
CoCl2·6H2O
CoCl2·6H20
CoCl2·6H20
CoCl2·6H20
Aerobic oxidation was optimized by examining the impact of experimental variables on the oxidation
of iodobenzene to iodobenzene diacetate. For optimization experiments, yields were determined by
1H NMR spectroscopy. DCE, 1,2-dichloroethane; AcOH, acetic acid; THF, tetrahydrofuran.
tosylation41 to afford oxygenated compound 12 in 74% yield by the these signals to Baeyer–Villiger intermediate E (Fig. 2)44. Consistent
action of standard autoxidation conditions with the addition of with this assignment, high-resolution mass spectrometry of the
para-toluene sulfonic acid (p-TSA) (Fig. 3b). Similarly, β-ketoester oxidation reaction reveals the presence of a signal at m/z = 143.0318
13 is readily tosylated to afford α-oxygenate 14 in 61% yield (M+Na+ for E) (Supplementary Fig. 10). Intermediate E is also
(Fig. 3c). Use of 20 mol% PhI in the α-tosylation of acetophenone observed when PhI oxidation is carried out in AcOH-d4.
led to the observation of 33% yield of compound 12, which provided Observation of E, which is the adduct of a molecule of aerobically
a proof-of-principle that PhI could be used as a catalyst for aerobic oxi- generated AcOOH and a molecule of CH3CHO, confirms that
dation chemistry. We hypothesize that the poor catalyst turnover aldehyde autoxidation is operative during aerobic oxidation of
observed in these reactions may be due to relatively slow α-oxygen- aryl iodides. Magnetization transfer experiments demonstrate that
ation of carbonyl substrates by aerobically generated I(III); if substrate compound E is in equilibrium with acetaldehyde and peracetic
functionalization is slow relative to aldehyde autoxidation, insufficient acid on the timescale of PhI oxidation (Supplementary Fig. 11).
I(I) will be generated to intercept reactive autoxidation intermediates. At this time, we cannot differentiate between aerobically generated
Application of aerobic oxidation of aryl iodides to oxidase
Table 2 | Application of aerobic oxidation chemistry to the
synthesis of a family of hypervalent iodine reagents.
catalysis. The ability to accomplish ligand exchange chemistry in
hypervalent iodine compounds allows the developed aerobic
oxidation of aryl iodides to be applied to substrate oxidation
chemistry that does not involve incorporation of oxygen in the
reaction products. For example, in the α-oxidation of β-ketoester
13, replacing p-TSA with tetrabutylammonium bromide ([TBA]Br)
results in aerobic bromination to afford compound 15 (57%
yield, see Supplementary page 14), not the α-oxygenation product
14 as demonstrated above. Unlike the oxygenation reactions
pictured in Fig. 3a–c, which require stoichiometric aryl iodide to
access synthetically useful oxidation yields, bromination could be
achieved with a catalytic amount of aryl iodide. With 20 mol%
1,2-diiodobenzene, bromination proceeds in 72% yield (Fig. 3d).
PhI is also a competent catalyst for bromination, but superior
yields are obtained with 1,2-diiodobenzene as catalyst.
We have extended aryl-iodide-catalysed aerobic oxidation to oxi-
dative dearomatization chemistry and C–H amination chemistry.
Using 20 mol% 1,2-diiodobenzene, Weinreb amide 16 (ref. 42)
undergoes aerobic dearomatization to afford lactam 17 in 77%
yield (Fig. 3e). Dehydrogenative N–H/C–H coupling to arylate
amines with unfunctionalized aromatics can also be accomplished
by the action of aryl iodide catalysis. With 10 mol% 1,2-diiodoben-
zene, amine 18 undergoes arylation with benzene43 to afford phe-
nylsulfonamide 19 in 78% yield. In each of the reactions pictured
in Fig. 3d–f, aerobic oxidation is accomplished with AcOH as the
only stoichiometric by-product.
RO
O2, CH3CHO
I
I
CoCl2·6H2O (1 mol%)
OR
R
R
AcOH, 23 ºC
AcO
HO
I
HO
I
I
OAc
OTs
O
R
O
1a (R = H), 92%
*
3, 84%
4, 96%*
1b (R = 4-OCH3), 80%
1c (R = 4-CH3), 84%
1d (R = 4-F), 91%
1e (R = 3-Br), 91%
1f (R = 4-CF3), 88%†
1g (R = 3,5-CH3), 81%
AcO
AcO
I
I
O
O
CH3
CF3
H3C
F3C
5, 63%
6, 95%
I
O
R
O
AcO
I
O
I
2a (R = H), 93%
2b (R = 4-OCH3), 91%
2c (R = 4-CH3), 87%
2d (R = 4-F), 89%
2e (R = 3-Br), 91%
2f (R = 4-CF3), 73%
2g (R = 3,5-CH3), 88%
O
O
I
S
t-Bu
AcO
O
7, 90%
8, 64%
Aerobic oxidation of aryl iodides provides access to a family of hypervalent iodine reagents that have
been demonstrated to be useful oxidants in synthetic chemistry. AcOH, acetic acid; OTs, tosylate.
*Reaction solvent in these oxidation reactions: 1,2-dichloroethane (DCE). †For this substrate,
dimerization affords (4-CF3C6H4I(OAc))2O, see Supplementary page 7.
Aerobic oxidation mechanism. Aldehyde-promoted aerobic oxidation
of aryl iodides was developed based on the hypothesis that strongly
oxidizing intermediates in aldehyde autoxidation chemistry could
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ARTICLES
O2, CH3CHO,
1,2-I2-C6H4 (20 mol%)
CoCl2·6H2O (1 mol%)
a
1. O2, CH3CHO, PhI
CoCl2·6H2O (1 mol%)
OAc
d
O
O
O
O
OAc
H3C
OEt
H3C
OEt
2. 9, BF3·OEt2
AcOH, Ac2O, 23 ºC
88% yield
[TBA]Br
CH3CN, H2O, 23 ºC
72% yield
F
F
H3C Br
CH3
9
10
13
15
O2, CH3CHO,
1,2-I2-C6H4 (20 mol%)
CoCl2·6H2O (1 mol%)
O2, CH3CHO, PhI
CoCl2·6H2O (1 mol%)
b
e
f
O
O
O
O
OCH3
OCH3
OTs
N
CH3
N
p-TSA·H2O, CH3CN,
60 ºC, 74% yield
DCE, 23 ºC
77% yield
H
O
H3CO
11
12
16
17
O2, CH3CHO,
1,2-I2-C6H4 (10 mol%)
CoCl2·6H2O (1 mol%);
c
Ts
OMe
O2, CH3CHO, PhI
CoCl2·6H2O (1 mol%)
O
O
O
O
N
H
OMe
Ts
+
N
H
H3C
OEt
H3C
OEt
p-TSA·H2O, CH3CN,
H2O, 60 ºC, 61% yield
TFA, DCE, HFIP,
23 ºC, 78% yield
H3C OTs
CH3
13
14
18
19
Figure 3 | Aerobic oxidation of PhI provides a broad platform to directly utilize O2 as the terminal oxidant in substrate oxidation reactions. a–c, Utilization
of PhI oxidation to oxygenate substrates is highlighted by 1,2-difunctionalization of olefins (a), α-oxygenation of acetophenone (b) and α-oxygenation of
β-keto esters (c). d–f, Ligand exchange chemistry at hypervalent iodine reagents and in situ aerobic oxidation support oxidase catalysis of
heterofunctionalization reactions, such as aerobic bromination of β-keto esters (d), oxidative dearomatization chemistry (e) and direct aerobic C–H amination
chemistry (f). The illustrated substrate oxidation reactions illustrate the utility of aryl iodide oxidation as a platform for oxidase catalysis by highlighting the
coupling of diverse modes of substrate oxidation to O2 reduction. AcOH, acetic acid; p-TSA, para-toluenesulfonic acid; [TBA]Br, tetrabutylammonium
bromide; DCE, 1,2-dichloroethane; TFA, trifluoroacetic acid; HFIP, 1,1,1,3,3,3-hexafluoroisopropanol.
AcO
I
I
OAc
O
O2
O
O
O
H3C OH
F
O
CH3
OH
OH
H3C
O
H3C
H
H3C
O
(CoCl2·6H2O)
A
E
A
D
5.0
4.0
3.0
2.0
1.0
0.0
a
5.0
4.0
3.0
2.0
1.0
0.0
b
1.0
1.0
0.8
0.6
0.4
0.2
0.0
0.8
0.6
0.4
0.2
0.0
0
2
4
6
8
0
2
4
6
8
10
Time (h)
Time (h)
Figure 4 | Aerobic oxidation of aryl iodides is accomplished by intercepting the oxidizing intermediates of aldehyde autoxidation chemistry.
a,b, Monitoring the kinetics of consumption of PhI (blue plus symbols) and evolution of PhI(OAc)2 (red crosses) by 1H NMR in the presence (a) or absence (b)
of Co2Cl2·6H2O, added as a radical initiator, indicates that Co(II) initiates autoxidation of PhI. At intermediate times during PhI oxidation, peroxo intermediate
E (black asterisks) is observed (by both 1H NMR and mass spectrometry), which confirms that autoxidation is operative during aryl iodide oxidation. We
cannot currently differentiate between D and E as the active oxidant for aryl iodides.
AcOOH or compound E, the adduct of AcOOH with CH3CHO, as Here, we redirect the reactive two-electron oxidants that are gener-
the active oxidant in PhI oxidation.
ated during aldehyde autoxidation to provide access to a family of
hypervalent iodine reagents. The synthesis strategy leverages the
intrinsic proclivity of O2 to participate in radical chain chemistry
Conclusions
Development of a broadly applicable platform for oxidase catalysis, (that is, autoxidation) to prepare selective two-electron oxidants
which utilizes O2 as the terminal oxidant without necessitating the for use in synthesis. The importance of generating hypervalent
incorporation of oxygen during substrate functionalization, would iodine-based oxidants, and not utilizing aldehyde autoxidation
provide new opportunities to utilize O2 as a sustainable oxidant in intermediates directly for substrate oxidation, is highlighted by the
chemical synthesis. Aldehyde autoxidation chemistry, in which an diversity of oxidative substrate functionalization chemistry that
aldehyde is converted to a carboxylic acid under the action of O2, can be coupled to O2 reduction using aryl iodides. We have demon-
is among the earliest examples of aerobic oxidation in organic strated that aryl-iodide-supported oxidase chemistry and catalysis
chemistry and proceeds via reactive peroxy radicals and peracids. can be leveraged for aerobic olefin functionalization, carbonyl
4
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2873
ARTICLES
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α-oxidation to introduce both oxygen and halogen functionality,
oxidative dearomatization reactions and aerobic C–H amination
chemistry. We anticipate that aryl-iodide-catalysed aerobic oxi-
dation chemistry will provide new opportunities and strategies to
directly utilize O2 in sustainable chemical synthesis.
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24. Chudasama, V., Fitzmaurice, R. J., Ahern, J. M. & Caddick, S. Dioxygen
mediated hydroacylation of vinyl sulfonates and sulfones on water. Chem.
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General method for the oxidation of iodoarenes. In a typical experiment, a 20 ml
scintillation vial was charged with glacial AcOH (2 ml), iodoarene (0.401 mmol) and
CoCl2·6H2O (0.004 mmol, 1 mol%) and was fitted with a rubber septum. The reaction
vessel was purged with O2 for 5 min before acetaldehyde (4.07 mmol, 10.2 equiv.) was
added in one portion. The reaction mixture was stirred under 1 atm O2, delivered by
inflated balloon at 23 °C for 5 h. The solvent was removed in vacuo and the residue was
dissolved in CH2Cl2. The organic layer was washed with distilled water and extracted
with CH2Cl2 (3 × 7 ml). The organic layer was dried over MgSO4 and solvent was
removed in vacuo to afford the corresponding iodobenzene diacetate. The isolated
compounds were characterized by 1H and 13C NMR spectroscopies.
Data availability. The characterization data and experimental protocol that are
described in this paper are available within the paper and its Supplementary
Information, or from the corresponding authors upon request.
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Received 24 June 2017; accepted 12 September 2017;
published online 16 October 2017
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Acknowledgements
The authors thank Texas A&M University and the Welch Foundation (A-1907) for
financial support.
Author contributions
A.M. and D.C.P. conceived of the project. A.M. and S.-M.H. carried out the experimental
work. A.M., S.-M.H. and D.C.P. analysed the data and wrote the manuscript.
Additional information
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Supplementary information and chemical compound information are available in the
online version of the paper. Reprints and permissions information is available online at
www.nature.com/reprints. Publisher’s note: Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations. Correspondence and
requests for materials should be addressed to D.C.P.
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des Benzaldehyds an der Luft [In German]. Ber. Dtsch Chem. Ges. 33,
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Competing financial interests
A provisional patent has been filed on the aerobic oxidation of aryl iodides.
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