The Role of Iodanyl Radicals as Critical Chain Carriers in Aerobic Hypervalent Iodine Chemistry

Article abstract of DOI:10.1016/j.chempr.2019.06.006

Selective O₂ utilization remains a substantial challenge in synthetic chemistry. Biological small-molecule oxidation reactions often utilize aerobically generated high-valent catalyst intermediates to effect substrate oxidation. Available synthetic methods for aerobic oxidation catalysis are largely limited to substrate functionalization chemistry by low-valent catalyst intermediates (i.e., aerobically generated Pd(II) intermediates). Motivated by the need for new chemical platforms for aerobic oxidation catalysis, we recently developed aerobic hypervalent iodine chemistry. Here, we report that in contrast to the canonical two-electron oxidation mechanisms for the oxidation of organoiodides, the developed aerobic hypervalent iodine chemistry proceeds via a radical chain mechanism initiated by the addition of aerobically generated acetoxy radicals to aryl iodides. Despite the radical chain mechanism, aerobic hypervalent iodine chemistry displays substrate tolerance similar to that observed with traditional terminal oxidants, such as peracids. We anticipate that these insights will enable new sustainable oxidation chemistry via hypervalent iodine intermediates. O₂ is routinely utilized in biological catalysis to generate high-valent catalyst intermediates that engage in substrate oxidation chemistry. Analogous synthetic chemistry via aerobically generated high-valent intermediates would enable new sustainable synthetic methods but is largely unknown because of the challenges in selective O₂ utilization. We have developed aerobic hypervalent iodine chemistry as a platform for coupling O₂ reduction with a diverse set of substrate functionalization mechanisms. Many of the synthetic applications of hypervalent iodine reagents rely on selective two-electron oxidation-reduction chemistry. Here, we report that one-electron oxidation reactions pathways via iodanyl radical intermediates are critical in aerobic hypervalent iodine chemistry. The new appreciation for the critical role that iodanyl radicals can play in the synthesis of hypervalent iodine compounds will provide new opportunities in sustainable oxidation catalysis. Aerobic hypervalent iodine chemistry provides a strategy for coupling the one-electron chemistry of O₂ with two-electron processes typical of organic synthesis. We show that in contrast to the canonical two-electron oxidation of aryl iodides, aerobic synthesis proceeds by a radical chain process initiated by the addition of aerobically generated acetoxy radicals to aryliodides to generate iodanyl radicals. Robustness analysis reveals that the developed aerobic oxidation chemistry displays substrate tolerance similar to that observed in peracid-based methods and thus holds promise as a sustainable synthetic method.

Full text of DOI:10.1016/j.chempr.2019.06.006

Article
The Role of Iodanyl Radicals as Critical Chain
Carriers in Aerobic Hypervalent Iodine
Chemistry
Sung-Min Hyun, Mingbin Yuan,
Asim Maity, Osvaldo Gutierrez,
David C. Powers
ogs@umd.edu (O.G.)
david.powers@chem.tamu.edu (D.C.P.)
HIGHLIGHTS
Aerobic hypervalent iodine
reagent synthesis via one-electron
radical mechanism
Common autoxidation
mechanism to main-group and
transition-metal complexes
The demonstration of iodanyl
radical during the oxidation of aryl
iodides
Functional-group tolerance
similar to that with oxidation by
peracids
Aerobic hypervalent iodine chemistry provides a strategy for coupling the one-
electron chemistry of O2 with two-electron processes typical of organic synthesis.
We show that in contrast to the canonical two-electron oxidation of aryl iodides,
aerobic synthesis proceeds by a radical chain process initiated by the addition of
aerobically generated acetoxy radicals to aryliodides to generate iodanyl radicals.
Robustness analysis reveals that the developed aerobic oxidation chemistry
displays substrate tolerance similar to that observed in peracid-based methods
and thus holds promise as a sustainable synthetic method.
Hyun et al., Chem 5, 1–17
September 12, 2019 ª 2019 Elsevier Inc.
https://doi.org/10.1016/j.chempr.2019.06.006

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Article
The Role of Iodanyl Radicals
as Critical Chain Carriers in Aerobic
Hypervalent Iodine Chemistry
1,3,
Sung-Min Hyun,1 Mingbin Yuan,2 Asim Maity,1 Osvaldo Gutierrez,2, and David C. Powers
*
*
SUMMARY
The Bigger Picture
O2 is routinely utilized in
Selective O2 utilization remains a substantial challenge in synthetic chemistry.
Biological small-molecule oxidation reactions often utilize aerobically gener-
ated high-valent catalyst intermediates to effect substrate oxidation. Available
synthetic methods for aerobic oxidation catalysis are largely limited to
substrate functionalization chemistry by low-valent catalyst intermediates
(i.e., aerobically generated Pd(II) intermediates). Motivated by the need for
new chemical platforms for aerobic oxidation catalysis, we recently developed
aerobic hypervalent iodine chemistry. Here, we report that in contrast to the ca-
nonical two-electron oxidation mechanisms for the oxidation of organoiodides,
the developed aerobic hypervalent iodine chemistry proceeds via a radical chain
mechanism initiated by the addition of aerobically generated acetoxy radicals
to aryl iodides. Despite the radical chain mechanism, aerobic hypervalent iodine
chemistry displays substrate tolerance similar to that observed with traditional
terminal oxidants, such as peracids. We anticipate that these insights will enable
new sustainable oxidation chemistry via hypervalent iodine intermediates.
biological catalysis to generate
high-valent catalyst intermediates
that engage in substrate oxidation
chemistry. Analogous synthetic
chemistry via aerobically
generated high-valent
intermediates would enable new
sustainable synthetic methods but
is largely unknown because of the
challenges in selective O2
utilization. We have developed
aerobic hypervalent iodine
chemistry as a platform for
coupling O2 reduction with a
diverse set of substrate
functionalization mechanisms.
Many of the synthetic applications
of hypervalent iodine reagents
rely on selective two-electron
oxidation-reduction chemistry.
Here, we report that one-electron
oxidation reactions pathways via
iodanyl radical intermediates are
critical in aerobic hypervalent
iodine chemistry. The new
INTRODUCTION
O2 is an attractive oxidant for use in synthetic chemistry because it is readily avail-
able, generates environmentally benign byproducts, and displays substantial reduc-
tion potential. Radical chain autoxidation—the spontaneous oxidation of organic
compounds upon exposure to O2—is a ubiquitous process in organic chemistry
that can affect most organic functional groups.1–4 Autoxidation chain reactions arise
because of spin conservative reactions of the triplet ground state of O2 (i.e., 3O2)
with singlet organic molecules (Figure 1A). On the commodity scale, autoxidation
of cumene and p-xylene produce phenol5 and terephthalic acid,6 respectively (Fig-
ure 1B). In fine-chemical synthesis, acyl radical intermediates generated during alde-
hyde autoxidation (Figure 2A) have been diverted toward olefin addition chemistry
(Figure 2B),7,8 alkyl radical intermediates generated by decarbonylation of acyl rad-
icals have been harnessed for alkylation of N-heterocycles (Figure 2C),9 and peroxy
radicals and peroxide intermediates have been diverted toward oxygen-atom trans-
fer (OAT) chemistry to olefins (i.e., Mukaiyama reaction)10–12 and to transition-metal
complexes (Figures 2D and 2E).13–15 Although these examples highlight the poten-
tial of autoxidation in specific synthetic applications, reliance on only those reactive
intermediates generated in autoxidation chemistry substantially limits the diversity
of substrate functionalization reactions that can be coupled to O2.
appreciation for the critical role
that iodanyl radicals can play in
the synthesis of hypervalent
iodine compounds will provide
new opportunities in sustainable
oxidation catalysis.
Motivated by the desire to couple diverse substrate oxidation mechanisms to the
reduction of O2, researchers have developed a wide variety of aerobic oxidation
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Figure 1. Radical Chain Autoxidation
(A) Autoxidation reactions proceed via peroxy radical and hydroperoxide intermediates.
(B) Autoxidation chemistry is utilized on the commodity scale to produce phenol, acetone, and
terephthalic acid.
methods. Among the most well developed is palladium (Pd) oxidase chemistry, in
which the diverse substrate functionalization mechanisms available to Pd(II) are
coupled to aerobic re-oxidation of Pd(0) intermediates.16–21 Pd oxidase catalysis has
been leveraged for a wide variety of substrate functionalization reactions: alcohol22–
24 and olefin oxidation, Aza-Wacker chemistry,25 arene oxidation,26,27 oxidative Heck
reactions,28–31 and allylic oxidation.32,33 From a mechanistic perspective, available
methods are limited to those that can be achieved by low-valent Pd catalysis (i.e.,
Pd(0)/Pd(II) cycles). General strategies that facilitate access to high-oxidation-state cat-
alytic cycles with O2 are largely unavailable.34–39
In the absence of aerobically generated two-electron oxidants capable of mediating
substrate functionalization chemistry via high-valent intermediates, an array of designer
synthetic oxidants have been developed. Hypervalent iodine compounds have
emerged as a particularly useful class of reagents that find application in mechanisti-
cally diverse oxidation reactions including a-oxidation of carbonyl compounds, alcohol
and amine dehydrogenations, oxidative dearomatization chemistry, olefin functionali-
zation, group transfer chemistry, and transition-metal catalysis.40–46 The utility of these
reagents derives from (1) the substantial reduction potential of many of these reagents,
(2) the often-observed two-electron oxidation-reduction chemistry,47–57 and (3) the
facility of ligand exchange reactions at hypervalent iodine centers. Drawbacks of hyper-
1Department of Chemistry, Texas A&M
University, College Station, TX 77843, USA
valent iodine reagents include the common requirement for (super)stoichiometric
loading of these reagents and the generation of substantial chemical waste during
both preparation and utilization of these species. If aerobic hypervalent iodine
chemistry were realized as a general platform, it would be complementary to existing
methodologies by providing entry to high-oxidation-state catalytic cycles with O2.
2Department of Chemistry and Biochemistry,
University of Maryland, College Park, MD 20742,
USA
3Lead Contact
*Correspondence: ogs@umd.edu (O.G.),
david.powers@chem.tamu.edu (D.C.P.)
In 2018, we accomplished the aerobic synthesis of hypervalent iodine reagents by
diverting reactive aldehyde-autoxidation intermediates and utilized the aerobically
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Figure 2. Aldehyde Autoxidation in Synthesis
(A) The manifold of reaction chemistry that is available during the autoxidation of acetaldehyde.
(B–E) Reactive intermediates in aldehyde autoxidation have been redirected to accomplish (B) olefin addition chemistry, (C) alkylation reactions, (D)
oxygen-atom transfer (OAT), and (E) transition-metal-catalyzed hydroxylation.
generated hypervalent iodine species as intermediates in a variety of synthetic
chemistries (Figure 3).58–60 This approach couples strongly oxidizing intermediates
generated during aldehyde autoxidation with disparate substrate oxidation mecha-
nisms. This strategy has provided a platform for coupling O2 reduction with the
broad classes of substrate functionalization chemistry that are available to hyperva-
lent iodine reagents, such as a-carbonyl oxidation, oxidative dearomative cycliza-
tion, C–H/N–H coupling, and alcohol dehydrogenation chemistry. Given the
frequency with which peracids are used in the synthesis of hypervalent iodine
reagents,61–65 our initial investigations were predicated on the hypothesis that
aerobically generated peracetic acid D could be diverted toward the oxidation of
PhI. Here, we report a detailed experimental and theoretical investigation of
aldehyde-promoted oxidation of aryl iodides. A combination of in situ spectroscopy,
kinetic studies, and computational investigations supports a mechanism in which
aldehyde-promoted aerobic oxidation of aryl iodides proceeds via one-electron
oxidation at iodine to generate iodanyl radicals, which subsequently generate the
observed I(III) products via a radical chain mechanism. The results of these studies
provide evidence for the critical role of single-electron chemistry and open-shell in-
termediates in hypervalent iodine chemistry and substantially enrich the mechanistic
landscape available for the synthesis of these important reagents.
RESULTS AND DISCUSSION
Figure 2A illustrates the manifold of reactions operative during the autoxidation of
acetaldehyde.66,67 Hydrogen-atom abstraction (HAA) from acetaldehyde A gener-
ates acyl radical B, which rapidly reacts with O2 to generate peroxy radical C.68
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Figure 3. Aerobic Hypervalent
Iodine Catalysis
Aerobically generated
hypervalent iodine
intermediates present a strategy
for accomplishing aerobic
oxidation catalysis via strongly
oxidizing intermediates.
HAA from a second equivalent of acetaldehyde affords radical chain carrier B and an
equivalent of peracetic acid D. Baeyer-Villiger reaction of D with A affords acetic acid
via the intermediacy of peroxide E. In addition, dimerization of peroxy radical C
generates 1O2 and 2.0 equiv of acetoxy radical G via the fragmentation of a transient
tetroxide intermediate (i.e., Russell termination; see Figure S1 for additional discus-
sion of this reaction step).69–73 Dimerization of acetoxy radicals G generates diacetyl
peroxide H.66 Methyl radical I can arise by decarboxylation of G or by decarbonyla-
tion of B.66,67 A number of the species illustrated in Figure 2A—oxygen-centered
radicals C and G, peroxides E and H, and peracetic acid—are potential oxidants
of aryl iodides during aldehyde-promoted aerobic oxidation.
Identification of Potential Oxidants
Previously, we observed initial formation and subsequent consumption of peroxide
E during acetaldehyde-promoted oxidation of iodobenzene (PhI) by in situ 1H NMR
spectroscopy.58 A 1H NMR magnetization transfer experiment demonstrated that E
equilibrates with acetaldehyde and peracetic acid rapidly relative to PhI oxidation.
To evaluate the presence of open-shell intermediates during the aerobic oxidation
of PhI, we carried out a series of electron paramagnetic resonance (EPR) measure-
ments by using N-tert-butyl-a-phenylnitrone (PBN, 1) as a radical spin trap (Fig-
ure 4).74 Figure 4A illustrates the X-band EPR spectrum obtained after the addition
of PBN to the reaction mixture of PhI, acetaldehyde, O2, and CoCl2. The spectrum
can be fit as the admixture of a triplet of doublets (aH = 2.14 G, aN = 14.06 G) and
a triplet (aN = 7.86 G). The triplet of doublets is attributed to PBN-trapped acetoxy
radical (2; Figure 4B),75,76 and the triplet is attributed to a radical arising from single-
electron oxidation of PBN (3, Figure 4C).77 The formation of PBN-trapped acetoxy
radical 2 was confirmed by electrospray ionization-mass spectrometry (ESI-MS) anal-
ysis (m/z = 258.1100, [M+Na]+; Figure S2). Addition of PBN to the acetaldehyde-
promoted oxidation of PhI in 1,2-dichloroethane (DCE) and CH2Cl2 also displayed
spectral features arising from compounds 2 and 3 (Figure S3). The presence of
open-shell intermediates was further implicated by analysis of the headspace of a re-
action in which PhI was oxidized under the dual action of acetaldehyde and O2,
which revealed that in addition to acetaldehyde, trace CO2 and CO were observed
(Figure S4). These observations implicate the generation of acyl radical intermedi-
ates during aldehyde autoxidation.
Evaluation of the Oxidation of PhI by Potential Closed-Shell Oxidants
We pursued the following experiments to evaluate the chemical competence of per-
acetic acid, Baeyer-Villiger peroxide E, diacetyl peroxide, and Co(OAc)3 as primary
oxidants in the aldehyde-promoted aerobic oxidation of aryl iodides.
Peracetic Acid
Peracetic acid D is often employed as the terminal oxidant in the synthesis of hyper-
valent iodine reagents. In our hands, treatment of PhI with a commercially obtained
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Figure 4. Spin-Trapped EPR Spectroscopy of Open-Shell Oxidants
(A) X-band EPR spectrum obtained after the addition of PBN (1) to the oxidation of PhI in AcOH;
experimental data (black trace) and fitting (red trace) are also shown. The obtained spectrum
displays features of both 2 and 3.
(B) Simulated spectrum of acetoxy radical adduct 2.
(C) Simulated spectrum of one-electron oxidation product 3.
32 wt % peracetic acid (5 equiv) in AcOH afforded PhI(OAc)2 in 92% yield, which
confirmed the chemical competence of peracetic acid as an oxidant of PhI.
Baeyer-Villiger Peroxides
Addition of a commercially available solution of peracetic acid to acetaldehyde re-
sulted in the evolution of peroxide E,78 along with 1-hydroperoxyethan-1-ol, the
adduct of H2O2, and acetaldehyde (Figure S5). Exposure of PhI to reaction mixtures
containing peroxide E resulted in no PhI(OAc)2 after 13 h (Figure S6), which indicates
that peroxide E is not a competent oxidant of PhI.
Diacetyl Peroxide
Diacetyl peroxide is potentially generated during acetaldehyde autoxidation by
dimerization of acetoxy radicals.66 Treatment of PhI with independently synthe-
sized79 diacetyl peroxide H in AcOH-d4 at 23ꢀC resulted in no reaction, as ascer-
tained by 1H NMR analysis for 17 h (Figures S7–S10). A potassium iodide (KI) test
confirmed the presence of peroxide after the reaction.
Co(OAc)3
To ensure consistent initiation of aldehyde autoxidation,80,81 we included Co(II) salts
in the optimized conditions for aldehyde-promoted PhI. In addition to functioning as
an autoxidation initiator, Co(III) species can oxidize peracids to generate peroxy rad-
icals (i.e., oxidation of D to generate C), and Co(II) species are readily oxidized to
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Figure 5. Hammett Analysis of Peracid and Aerobic Oxidation Conditions
Hammett plots of (A) the aldehyde-promoted aerobic oxidation of aryl iodides and (B) the peracetic acid oxidation of aryl iodides. Error bars indicate
the standard deviation of triplicate measurements.
Co(III) by peracids (i.e., D).82 One might also envision direct oxidation of PhI by
Co(III).82,83 The following lines of experimental evidence suggest that Co-based
additives are not intimately involved in the oxidation of PhI. (1) Co-based promoters
are not necessary for aldehyde-promoted aerobic oxidation of aryl iodide. Removal
of these additives from aerobic oxidation reactions results in variable initiation time,
but a high yield of PhI(OAc)2 can still be obtained.58 (2) Exposure of PhI to an AcOH
solution of Co(OAc)3,82 which is the product of aerobic oxidation of Co(II) in AcOH,
did not result in the observation of any PhI(OAc)2 (Figure S11). (3) Comparison of the
concentration-versus-time plots for aerobic oxidation with and without Co(II) (1 mol
% CoCl2$6H2O; Figure S12) revealed that although the length of time that is
required for initiation depends intimately on the presence of Co(II), once oxidation
commences, the presence of Co initiators does not affect the kinetics of oxidation.
Hammett Analysis
To probe the nature of the kinetically relevant oxidants responsible for aldehyde-
promoted aerobic oxidation of aryl iodides, we evaluated the impact of aryl iodide
substitution on the rate of aryl iodide oxidation for both aldehyde-promoted aerobic
oxidation and peracetic-acid-mediated protocols (Figure 5). Because of the pres-
ence of a kinetic induction period during aldehyde-promoted aerobic oxidation of
aryl iodides, initial rate data were obtained with a series of competition experiments
in which pairs of aryl iodides were exposed to aldehyde-promoted aerobic oxidation
conditions (Figure 5A; see Figures S13–S15 and Tables S1 and S2 for raw data).84
Each competition reaction was carried out in triplicate. The resulting data for alde-
hyde-promoted oxidation of aryl iodides are well correlated with s+ parameters
(r = –0.51, R2 = 0.98; Figure 5A) and less well correlated with s parameters (R2
=
0.93; Figure S16). In contrast, the Hammett plot pictured in Figure 5B, which displays
the initial rate data for peracetic acid oxidation of aryl iodides, is well correlated with
both s parameters (r = –2.10, R2 = 0.93; Figure 5B; see Figure S17 and Tables S3 and
6
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Table 1. Products from the Addition of PhI to Aldehyde Autoxidation Reactions in the Presence
of Cyclohexane
O
O2, CH3CHO
.
CoCl2 6H2O
Phl
AcO
O2, CH3CHO
l
OAc
.
CoCl2 6H2O
Entry
PhI Loading (Equiv)
Cyclohexanone Yield (%)
1
2
3
4
0.00
1.00
5.00
10.0
9.5
2.4
2.0
0.8
S4 for raw data) and is less well correlated with s+ parameters (R2 = 0.85;
Figure S18).85 The significantly different slopes of the Hammett plots pictured in
Figure 5 indicate that aldehyde-promoted aerobic oxidation and peracid-mediated
oxidation do not proceed via the same rate-determining transition state.
The sensitivity of aldehyde-promoted oxidation (r = –0.51) indicates the buildup of
positive charge during the rate-determining transition state of aldehyde-promoted
aerobic oxidation, but substantially less than was observed during peracid oxidation
(r = –2.10). The r-value for aldehyde-promoted oxidation is similar to r-values that
have been reported for the radical autoxidation of cumene derivatives (r = –0.41)86
and for the epoxidation of stilbene derivatives under aldehyde-autoxidation condi-
tions (r = –0.73)87 (a reaction proposed to proceed via initial addition of an aerobi-
cally generated acyl peroxy radical to the olefin). These results (1) demonstrate that
peracetic acid is not kinetically competent as the oxidant during aldehyde-pro-
moted aerobic oxidation and (2) suggest that open-shell species may serve as critical
oxidants during aldehyde-promoted aerobic oxidation.
Evaluation of the Oxidation of PhI by Potential Open-Shell Oxidants
On the basis of the observation of oxygen-centered radicals by spin-trapped EPR
and the results of Hammett analysis, we pursued a series of experiments to evaluate
the competence of these species as oxidants for PhI.
Kinetic Competition Experiments
Reactive oxidants generated during the autoxidation of aldehydes have previously
been demonstrated to be competent oxidants toward aliphatic C–H bonds.88,89 In
our study, exposure of a solution of cyclohexane and acetaldehyde to O2 afforded
cyclohexanone in 9.5% yield (Table 1, entry 1). Using a mixture of d12- and H12-cyclo-
hexane, we measured the kinetic isotope effect (KIE) for cyclohexane oxidation
under these conditions to be 4.8(4), which suggests that HAA from cyclohexane is
the rate-determining step in the generation of cyclohexanone. Using dispersion-cor-
rected DFT (UB3LYP-D3/def2-TZVPP-SMD(DCE)//UB3LYP/def2-TZVPP-SMD(DCE)),
we identified the barriers for HAA from cyclohexane by acetoxy radical G to be
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Scheme 1. Conversion of Iodosylbenzene to (Diacetoxyiodo)benzene
10.8 kcal/mol (computed kH/kD = 3.6) and by peroxy radical C to be 17.3 kcal/mol
(computed kH/kD = 6.1) (Figure S19). Previous measurements of the KIEs for HAA
by peroxy radicals have reported large values (kH/kD = 9–19).71,86,90 The observation
of acetoxy radicals by PBN-trapped EPR spectroscopy, in combination with the
measured KIE, suggests that cyclohexane oxidation most likely proceeds via initial
HAA from cyclohexane by acetoxy radical G.
To evaluate the kinetic competence of acetoxy radical G for oxidation of PhI, we
examined the aldehyde-promoted oxidation of hydrocarbon substrates in the pres-
ence of added PhI. We reasoned that if the reactive oxygen–centered radicals
responsible for C–H oxidation of cyclohexane (i.e., G) were also responsible for
PhI oxidation, PhI would be a competitive inhibitor of cyclohexane oxidation.
Consistent with this hypothesis, addition of an increasing amount of PhI to alde-
hyde-promoted cyclohexane oxidation reactions resulted in the suppression of
cyclohexanone evolution (Table 1, entries 2–4). Similarly, exposure of adamantane
to acetaldehyde autoxidation reaction mixtures resulted in 1-adamantanol in 47%
yield,91 which was reduced to 14% upon the addition of 1.0 equiv of PhI, and expo-
sure of ethylbenzene to acetaldehyde autoxidation reaction mixtures resulted in
acetophenone in 30% yield, which was reduced to 9% upon addition of PhI. The
yields for C–H oxidation and iodobenzene oxidation are anti-correlated: for
example, during oxidation of ethylbenzene, in the presence of 1.0 equiv of PhI, ace-
tophenone was generated in 9% yield and PhI(OAc)2 was generated in 53% yield; in
the presence of 5.0 equiv of PhI, acetophenone was generated in 5% yield, and
PhI(OAc)2 was generated in 100% yield (based on ethylbenzene). These data indi-
cate that PhI is a kinetic inhibitor of C–H oxidation and thus implicates open-shell
oxidants in the oxidation of PhI (Tables S5–S7).
Computational Results
In this section, we evaluate pathways that would generate either iodosylbenzene K92
or (diacetoxyiodo)benzene M because under the reaction conditions we examined
(i.e., in the presence of AcOH), iodosylbenzene was readily converted to (diacetox-
yiodo)benzene via the intermediacy of hydroxy iodinane L (Scheme 1).93 See Figures
S20–S28 for computational details.
Pathways via Initial Two-Electron Oxidation
We initiated our computational investigation by evaluating potential two-electron
OAT reactions from peracetic acid, peroxy radical C, and acetoxy radical G to afford
iodosylbenzene (Figure 6).94 The lowest-energy transition state located for oxygen-
ation of PhI by peracetic acid was TSDJ-FK (22.2 kcal/mol versus PhI and D), in which
OAT was activated by internal hydrogen bonding of the peracid proton to the
carbonyl group (Figure 6A). The located transition state is analogous to the butterfly
transition states invoked for olefin epoxidation with peracids.95 Potential ionic mech-
anisms via initial hydroxylation of PhI followed by recombination with acetate anions
were not found to be lower in energy (Figure S22). We also evaluated OAT from per-
oxy radical C and acetoxy radical G, reactions steps that have been suggested to be
8
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Figure 6. Analysis of Two-Electron Pathways
Evaluation of OAT from peracetic acid to PhI. Free energies (kcal/mol) were computed at the
UB3LYP-D3/def2-TZVPP-SMD(DCE)//UB3LYP/def2-TZVPP-SMD(DCE) level of theory.
operative in the autoxidation of phosphorous(III) compounds.96–102 Both processes
are substantially endergonic—OAT from C to generate iodosylbenzene K and ace-
toxy radical G is +12.1 kcal/mol, and OAT from G to generate iodosylbenzene K and
acyl radical B is +67.3 kcal/mol—and thus we will not consider these pathways
further (Figure S23).
Pathways via Initial One-Electron Oxidation
On the basis of Hammett analyses and PhI-mediated inhibition of C–H oxidation
chemistry, we examined one-electron oxidation pathways for the reaction of reactive
intermediates generated during aldehyde autoxidation (e.g., acetoxy radical G)
with PhI.103 Addition of acetoxy radical to form iodanyl radical N was uphill by
3.9 kcal/mol and was accessed via TSGJ-N, which was 8.9 kcal/mol above the
separated reactants (Figure 7). Iodanyl radical N displayed a bent geometry at the
ꢀ
˚
hypervalent iodine center (C–I–O: 97.6 ) and a long I–O bond (2.63 A; for compari-
son, I–O in M: 2.19 A [computed], 2.16 A [experimental]104). Iodanyl radical N resem-
bled intermediates proposed during alkylation reactions accomplished by photore-
dox catalysis.105,106 Evaluation of the spin density of N indicates substantial spin on
the iodine center with delocalization to the oxygen atoms of the acetate ligand (see
Table S8 for detailed analysis of the spin density of N). An I(II) compound resulting
from the addition of peroxy radical C to PhI could not be located as a stationary
point; all attempts resulted in evolution of iodosylbenzene with extrusion of the
acetoxy radical.
˚
˚
Reaction of I(II) intermediates (i.e., N) with peroxides present in solution would result
in radical chain propagation. On the basis of the relative facility of acetoxy versus
peroxy radical addition to PhI, we evaluated a variety of potential reaction pathways
for reactions of iodanyl radical N (Figure 8). Addition of peracetic acid to iodanyl
radical N to generate hydroxy iodinane L and acetoxy radical was downhill by
11.7 kcal/mol and proceeded via transition state TSDN-GL, which was calculated to
be 17.2 kcal/mol above the separated reactants. Reaction of iodanyl radical N
with either diacetyl peroxide H or peroxide E, which would generate I(III) products
and regenerate chain-carrying acetoxy radicals, was thermodynamically favored
and proceeded via transition states of similar, yet higher, energy (Figure S26).
Chain-propagating addition of peracetic acid to iodanyl radical N was found to be
the highest barrier along the computed pathway from PhI to PhI(OAc)2.107
Reaction of transiently generated iodanyl radicals with open-shell species in solution
would result in chain termination. We considered several potential termination path-
ways (Figure 9). Disproportionation of 2.0 equiv of iodanyl radical N to generate (diac-
etoxyiodo)benzene and iodobenzene was thermodynamically favored (–30.3 kcal/mol);
we were unable to locate a transition state for this process (Figure 9A). The addition of
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Chem (2019), https://doi.org/10.1016/j.chempr.2019.06.006
Figure 7. Analysis of Radical Chain Initiation
Computed pathways for initiation steps in which oxygen-centered radicals are added to PhI. Free
energies (kcal/mol) were computed at the UB3LYP-D3/def2-TZVPP-SMD(DCE)//UB3LYP/def2-
TZVPP-SMD(DCE) level of theory.
acetoxy radical G to iodanyl radical N proceeded without barrier (Figure 9B), as
determined by a scan about the O–I bond, leading to (diacetoxyiodo)benzene
(–26.4 kcal/mol). In addition to productive termination steps leading to the production
of PhI(OAc)2, unproductive termination, such as loss of acetoxy radical followed by
radical coupling to generate diacetyl peroxide, was also downhill (Figure 9C).
Summary of Mechanistic Data
Figure 10 summarizes the radical chain process that is consistent with the available
experimental and computational results. Russell termination of 2.0 equiv of peroxy
radical C generated 1O2 and 2.0 equiv of acetoxy radical G. Addition of acetoxy
radical G to PhI generated iodanyl radical N. Reaction of N with peracetic acid
generated hydroxy iodinane L, which reacted spontaneously with AcOH to afford
the observed PhI(OAc)2, and regenerated acetoxy radical G. Radical chain termina-
tion was accomplished either by combination of iodanyl radical N with acetoxy
radical G or by disproportionation of iodanyl radical N. In this chain reaction, both
iodanyl radical N and acetoxy radical G were chain carriers. The oxidation mecha-
nism that emerged from these studies shares common features with autoxidation
reactions of some main-group species and transition-metal complexes, which—
unlike simple organics—can access expanded valences. For example, the radical
autoxidation of phosphorous(III) derivatives to generate phosphorous(V) oxides
has been extensively studied (Figure 10B).96–102 On the basis of both kinetic data
and EPR spectroscopy, four-coordinate phosphanyl radicals, generated by the
addition of peroxy and alkoxy radicals to P(III) derivatives, have been implicated
as autoxidation intermediates. Similarly, during the aerobic oxidation of dimethyl
Pd(II) complexes, transient peroxo Pd(III) intermediates generated by the addition
of oxygen-centered radicals have been implicated (Figure 10C).108
Figure 8. Analysis of Radical Chain Propagation
Computed pathways for radical chain propagation by reaction of iodanyl radical N with peracetic
acid D. Free energies (kcal/mol) were computed at the UB3LYP-D3/def2-TZVPP-SMD(DCE)//
UB3LYP/def2-TZVPP-SMD(DCE) level of theory.
10
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Chem (2019), https://doi.org/10.1016/j.chempr.2019.06.006
Figure 9. Analysis of Radical Chain Termination
Reaction pathways for (A) disproportionation of 2.0 equiv of iodanyl radical N, (B) addition of
acetoxy radical G to iodanyl radical N, and (C) loss of diacyl peroxide H from 2.0 equiv of iodanyl
radical N. Free energies (kcal/mol) were computed at the UB3LYP-D3/def2-TZVPP-SMD(DCE)//
UB3LYP/def2-TZVPP-SMD(DCE) level of theory.
Analysis of the free-energy surface for two-electron oxidation of PhI by peracetic
acid versus the radical chain mechanism advanced for aldehyde-promoted aerobic
oxidation rationalizes the observation that although peracetic acid is a chemically
competent oxidant for PhI, it is not kinetically competent during aldehyde-pro-
moted aerobic oxidation. Addition of acetoxy radical to PhI proceeded with a barrier
of 8.9 kcal/mol. The barrier to oxidation of PhI by peracetic acid was computed to be
22.2 kcal/mol, whereas the highest barrier calculated along the radical chain mech-
anism depicted in Figure 10 was oxidation of iodanyl radical N by peracetic acid at
21.1 kcal/mol. These relative barrier heights are consistent with a Curtin-Hammett
scenario, in which rapid reversible addition of acetoxy radical to PhI proceeds to
generate N, and selectivity for one- and two-electron oxidation is governed by the
relative barrier heights for reaction of peracetic acid with N and PhI, respectively.
Impact on Synthetic Chemistry
Interest in understanding the mechanism(s) relevant to aerobic hypervalent iodine
chemistry is in part motivated by the desire to enable aerobic oxidation catalysis
via hypervalent iodine intermediates. A serious challenge to achieving hypervalent
iodine catalysis is the relative rates of iodine-centered oxidation and direct substrate
oxidation by the terminal oxidant. Recently, substantial progress has been made
toward realizing hypervalent iodine catalysis using m-CPBA and other peracids as
terminal oxidants. To evaluate the functional-group tolerance of the radical chain
aerobic oxidation of PhI, we carried out robustness analyses109 for PhI oxidation
by our aerobic protocol and for m-CPBA oxidation (Figure 11). In this experiment,
small molecules featuring a variety of functional groups were added to a reaction,
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Chem (2019), https://doi.org/10.1016/j.chempr.2019.06.006
Figure 10. Valence Expansion and Open-Shell Intermediates during Autoxidation Chain Reactions
(A) Summary of the reaction steps involved in aldehyde-promoted aerobic oxidation of aryl iodides.
(B and C) Valence expansion during radical chain autoxidation has also been implicated during (B) the autoxidation of P(III) compounds and (C) the
autoxidation of late-metal complexes.
and both the impact on the reaction yield and the amount of recovered additive
were recorded. The results of these experiments revealed that despite the radical
chain mechanism, the functional-group tolerance of the two conditions is remarkably
similar. Challenges to both sets of conditions include electron-rich aromatic
substrates (i.e., phenol and aniline) and C–C multiply bonded substrates. Similar
analysis of the aryliodide-catalyzed cross-coupling of benzene with N-methoxy-4-
methylbenzenesulfonamide is detailed in Figure S29.
Conclusions
Development of new strategies for coupling O2 reduction with oxidative substrate
functionalization chemistry is required for realizing sustainable synthetic chemistry.
In furtherance of this goal, we developed new strategies for accessing hypervalent
iodine compounds from O2 by intercepting reactive oxidants generated during
aldehyde-autoxidation chemistry. Here, we utilized experiment and theory to
demonstrate that hypervalent iodine reagents are accessed by a radical chain reac-
tion initiated by aerobically generated acetoxy radicals. Aerobically generated ace-
toxy radicals and the iodanyl radicals resulting from their addition to aryl iodides are
critical chain carriers during aerobic oxidation. This report represents the first
demonstration of the important role of I(II) species during the oxidation of aryl io-
dides. These observations are striking given that application of hypervalent iodine
reagents in synthesis is largely predicated on the well-behaved two-electron oxida-
tion-reduction chemistry characteristic of these species.
12
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Chem (2019), https://doi.org/10.1016/j.chempr.2019.06.006
Figure 11. Robustness Analysis for Aerobic Oxidation of Aryl Iodides
Robustness analysis for oxidation of PhI in the presence of a variety of small-molecule additives (a–q). The functional-group tolerance for aerobic
oxidation (black) is similar to that of m-CPBA oxidation (red).
A continuing challenge for the development of sustainable oxidation chemistry is the
need to identify chemical strategies that provide access to strong chemical oxidants,
such as hypervalent iodine compounds, under sufficiently mild conditions to be
compatible with broad families of substrates. Robustness analysis reveals that the
developed aerobic oxidation chemistry displays substrate tolerance similar to that
of more commonly employed peracid-based methods, but oxidatively labile sub-
strates, such as olefins, remain a challenge. We anticipate that the demonstration
of the critical role of one-electron processes and iodanyl radical intermediates in
the preparation of hypervalent iodine reagents will provide the mechanistic basis
for the development of strategies to achieve sustainable substrate oxidation under
mild reaction conditions.
EXPERIMENTAL PROCEDURES
Full experimental procedures are provided in the Supplemental Information.
SUPPLEMENTAL INFORMATION
Supplemental Information can be found online at https://doi.org/10.1016/j.chempr.
2019.06.006.
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Chem (2019), https://doi.org/10.1016/j.chempr.2019.06.006
ACKNOWLEDGMENTS
The authors thank Texas A&M University; the University of Maryland, College Park
(UMD); the Welch Foundation (grant A-1907 to D.C.P.); and the National Science
Foundation (CAREER 1751568 to O.G. and CAREER 1848135) for financial support.
We also thank UMD Deepthought2, the Maryland Advanced Research Computing
Center BlueCrab High Performance Computing Cluster, and the Extreme Science
and Engineering Discovery Environment (CHE160082 and CHE160053) for compu-
tational resources and Siyoung Sung for assistance with GC measurements.
AUTHOR CONTRIBUTIONS
O.G. and D.C.P. conceived the study. S.-M.H. and A.M. carried out experimental
work, and M.Y. carried out computational studies. All authors contributed to inter-
preting the data and writing the manuscript.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: February 21, 2019
Revised: May 14, 2019
Accepted: June 12, 2019
Published: July 3, 2019
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16
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Please cite this article in press as: Hyun et al., The Role of Iodanyl Radicals as Critical Chain Carriers in Aerobic Hypervalent Iodine Chemistry,
Chem (2019), https://doi.org/10.1016/j.chempr.2019.06.006
PBN to the oxidation of PhI with peracetic
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by open-shell oxidants.
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