Mechanism of Hydrocarbon Functionalization by an Iodate/Chloride System: The Role of Ester Protection

Article abstract of DOI:10.1021/acscatal.7b04397

Mixtures of chloride and iodate salts for light alkane oxidation achieve >20% yield of methyl trifluoroacetate (TFA) from methane with >85% selectivity. The mechanism of this C-H oxygenation has been probed by examining adamantane as a model substrate. These recent results lend support to the involvement of free radicals. Comparative studies between radical chlorination and iodate/chloride functionalization of adamantane afford statistically identical 3°:2° selectivities (～5.2:1) and kinetic isotope effects for C-H/C-D functionalization (k_H/k_D = 1.6(3), 1.52(3)). Alkane functionalization by iodate/chloride in HTFA is proposed to occur through H-atom abstraction by free radical species including Cl^? to give alkyl radicals. Iodine, which forms by in situ reduction of iodate, traps alkyl radicals as alkyl iodides that are subsequently converted to alkyl esters in HTFA solvent. Importantly, the alkyl ester products (RTFA) are quite stable to further oxidation under the oxidizing conditions due to the protecting nature of the ester moiety.

Full text of DOI:10.1021/acscatal.7b04397

Research Article
pubs.acs.org/acscatalysis
Cite This: ACS Catal. 2018, 8, 3138−3149
Mechanism of Hydrocarbon Functionalization by an Iodate/Chloride
System: The Role of Ester Protection
Nichole A. Schwartz,†,∥ Nicholas C. Boaz,‡,∥,⊥ Steven E. Kalman,†,# Thompson Zhuang,‡
Jonathan M. Goldberg,‡ Ross Fu,§ Robert J. Nielsen,§ William A. Goddard, III,§ John T. Groves,*,‡
and T. Brent Gunnoe*,†
†Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904, United States
‡Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States
§Materials and Process Simulation Center (139-74), California Institute of Technology, Pasadena, California 91125, United States
S
* Supporting Information
ABSTRACT: Mixtures of chloride and iodate salts for light alkane oxidation achieve >20%
yield of methyl trifluoroacetate (TFA) from methane with >85% selectivity. The mechanism of
this C−H oxygenation has been probed by examining adamantane as a model substrate. These
recent results lend support to the involvement of free radicals. Comparative studies between
radical chlorination and iodate/chloride functionalization of adamantane afford statistically
identical 3°:2° selectivities (∼5.2:1) and kinetic isotope effects for C−H/C−D
functionalization (kH/kD = 1.6(3), 1.52(3)). Alkane functionalization by iodate/chloride in
HTFA is proposed to occur through H-atom abstraction by free radical species including Cl• to give alkyl radicals. Iodine, which
forms by in situ reduction of iodate, traps alkyl radicals as alkyl iodides that are subsequently converted to alkyl esters in HTFA
solvent. Importantly, the alkyl ester products (RTFA) are quite stable to further oxidation under the oxidizing conditions due to
the protecting nature of the ester moiety.
KEYWORDS: methane, ethane, chloride, partial oxidation, functionalization, radical, iodate
Free radical chain reactions such as chlorination and
bromination offer a strategy to break the strong C−H bonds
of alkanes.12 For example, methane functionalization can be
accomplished using catalytic oxychlorination, whereby alkanes
are chlorinated using mixtures of HCl and O2 at high
temperature with a heterogeneous catalyst (eq 1).23−39
However, overoxidation is a chronic issue for oxychlorination
reactions because of the decreased C−H bond dissociation
enthalpy (BDE) of CH3Cl (101 kcal/mol)40 versus CH4 (104
kcal/mol).41 Thus, as the oxidized product is often more
reactive than the parent hydrocarbon, the production of
polyhalogenated species is a significant problem.42,43 In order
to achieve high selectivity, alkane conversion is generally
limited to < 10%.44 This issue is also problematic for ethane
and propane.45
INTRODUCTION
■
The components of natural gas are increasing sources of energy
and chemical feedstocks as a result of new technologies for
economical shale gas extraction.1−4 Current methods to
convert light alkanes to more valuable compounds (e.g.,
methane to methanol, ethane to ethylene, and propane to
propylene) require forcing conditions and are energy
intense.5−9 Accordingly, new processes, homogeneous or
heterogeneous, for the direct conversion of light hydrocarbons
into higher value functionalized compounds have been of
interest.7,10
The mono-oxidation of a C−H bond of methane using 1/2
O2 to generate methanol is an exothermic reaction. However,
the strong nonpolar bond between carbon and hydrogen
presents challenges. For example, the weaker C−H bonds of
methanol (96 kcal/mol versus 104 kcal/mol for methane) often
lead to overoxidation.11−15 To circumvent this problem, current
methods for methanol production from methane generally rely
on an indirect process. Methane is reformed with steam to yield
a mixture of CO and H2 (known as synthesis gas or syngas),
which can be transformed in a second step into methanol.7,16
The generation of syngas requires high temperatures and
pressures, which necessitates substantial capital investment as
well as the benefit of “economy of scale”.7,14,17,18 Thus, non-
syngas processes that directly and selectively convert the C−H
bonds of light alkanes to C−X (X = halide or heteroatom
functionality) bonds have been of high interest.12,19−22
catalyst
CH4 + HX + 0.5O2 ⎯⎯⎯⎯⎯⎯→ CH3X + H2O
(1)
heat
In another functionalization strategy, molecular metal
complexes and elemental iodine have been used to initiate
electrophilic functionalization of C−H bonds in oleum.46−53
While promising, many of these transformations are limited by
the need for superacidic reaction media, which renders product
isolation difficult.54 Recently, high-valent main-group com-
Received: December 20, 2017
Revised: February 19, 2018
© XXXX American Chemical Society
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pounds (e.g., TlIII and PbIV) have been shown to stoichio-
metrically functionalize the C−H bonds of alkanes in
nonsuperacidic solvent by a proposed electrophilic process.55
Additionally, a perfluoroaryl iodine(III) complex capable of
activating and functionalizing the C−H bonds of methane and
ethane selectively in HTFA (TFA = trifluoroacetate) has been
reported.56
We recently reported the partial oxidation of light alkanes
using combinations of iodate or periodate salts and chloride in
HTFA to generate alkyl esters (RTFA), a process that we label
hypervalent iodine/chloride alkane oxidation (HIAO).57,58
Methane, ethane, and propane are functionalized to the
corresponding ester with yields >20%, based on alkane, with
>80% selectivity. The reactions occur in nonsuperacidic media
and are tolerant of oxygen and water. Since oxygen, a radical
trap,59 does not inhibit alkane functionalization, it was initially
proposed that a non-free-radical pathway is highly possible. The
presence of chloride is essential, indicating that it may be
necessary to generate the active species for C−H bond
breaking. Similar activity was not obtained with I2, suggesting
that HIAO is not merely due to the in situ generation of I2,
which would then lead to a catalytically active species.57
We report herein an experimental mechanistic study of
hydrocarbon oxidation by the chloride/iodate process (Scheme
1). The experimental results lead us to conclude that the HIAO
radicals, the tolerance of the iodine oxide/chloride system to
aerobic conditions initially led us to suspect that the reaction
mechanism does not involve alkyl radicals as reaction
intermediates.57,58,60 Thus, on the basis of preliminary data,
we speculated that there was a reaction pathway that did not
involve free-radical-based C−H abstraction.
To aid in the mechanistic study of the HIAO process,
adamantane was used. Adamantane contains a mixture of
secondary and tertiary C−H bonds, which allows for the
probing of functionalization selectivity. As shown in Scheme 2,
Scheme 2. Oxidation of Adamantane Using Potassium
Chloride and Ammonium Iodate
adamantane is oxidized cleanly by iodate/chloride to the
tertiary trifluoroacetate ester using neat trifluoroacetic acid as a
solvent. Similar to observations with light alkanes, in the
absence of KCl, only trace amounts of product are formed
(<1%). During the reaction, molecular iodine is produced,
indicating the reduction of the iodate anion under the reaction
conditions (see Figure S1 in the Supporting Information).
Quantification by UV−vis spectroscopy indicates that 0.152(8)
mmol of I2 is produced after 1 h at 100 °C, 30% of the
theoretical maximum (Scheme 2). The stoichiometry and high
yield of 1-adamantyl trifluoroacetate suggest that the average
oxidation state of iodine at the end of the reaction should be
I(III); however, I(III) species such as iodites are known to
disproportionate.61,62 For this reaction, we have not attempted
to achieve mass balance, but we assume that unaccounted-for
iodine is likely unreacted iodate and perhaps some iodine(III)
species.
We found that 2-adamantyl trifluoroacetate quickly rear-
ranges in trifluoroacetic acid to the tertiary acetate compound,
thus obscuring any mechanistic insight gained from the
selectivity of the functionalization step. For example, heating
2-adamantyl trifluoroacetate in HTFA for 15 min resulted in
quantitative conversion to 1-adamantyl trifluoroacetate
(Scheme 3). The analogous rearrangement was not observed
when acetic acid was used as a solvent, where both secondary
and tertiary oxidation was observed (see below).
a
Scheme 1. Overview of the HIAO Process
a
RH = methane, ethane, propane, adamantane, etc.; X = OAc, TFA.
occurs by a radical-based pathway with its unique selectivity
resulting from the protecting effect of the ester moiety of the
product. Importantly, under the HIAO reaction conditions, we
conclude that the ester functionality protects the functionalized
alkanes (e.g., MeTFA and EtTFA) against overoxidation. This
is a surprising result, given the weaker C−H bonds of MeTFA
and EtTFA (versus methane and ethane, respectively) and the
evidence that the HIAO process involves free-radical-based
homolytic C−H bond breaking.
RESULTS AND DISCUSSION
■
Simple combinations of iodine oxides (in oxidation states III, V,
and VII) with a catalytic amount of chloride in HTFA
selectively oxidize light alkanes (methane, ethane, and propane)
to alkyl esters (trifluoroacetate) and alkyl chlorides.57,58 Our
initial reports showed that this process is effective with a variety
of hypervalent iodine oxides, including iodates, periodates,
I(TFA)3, and (IO)2S2O7, but catalytic amounts of chloride are
required for substantial yields of MeTFA. For example, with
iodate in the absence of KCl <1% yield of MeTFA was
observed, whereas with substoichiometric amounts (in
comparison to iodate) of chloride, yields >20% based on
methane were obtained.57 Similarly, with I(TFA)3 the yields of
MeTFA were 7% and 43%, with respect to I(TFA)3, in the
absence and presence of chloride. Additionally, the ability of the
reaction to tolerate nonsuperacidic solvent conditions, even
water, indicated that the mechanism of the HIAO process likely
differs from that of the iodine/oleum reaction for C−H
functionalization.49 Due to the ability of dioxygen to trap alkyl
Scheme 3. Heating 2° Adamantyl Ester Derivatives in Acid,
Generating the 3° Product for the Trifluoroacetate but Not
for Acetate
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The combination of a chloride salt and an iodate salt in
trifluoroacetic acid immediately yields a golden yellow solution
with white and yellow solids (Figure S4). Absorbances in the
UV−vis spectrum of this mixture indicate that it contains
chlorine (∼330 nm) and ICl and/or ICl3 (∼460 nm) (Figure
1). Because of the overlapping peaks in the UV−vis spectrum,
we are not able to differentiate between formation of ICl versus
ICl3.
Scheme 4. Oxidation of Adamantane Using Potassium
Chloride and Ammonium Iodate in Glacial Acetic Acid
(Black) and Radical Chlorination of Adamantane Using N-
Chlorosuccinimide (NCS) in Glacial Acetic Acid (Blue)
a
a
Data are from three separate experiments with 3°:2° reported as an
average with standard deviations shown for the ratios of 3°:2°
selectivity.
Scheme 5. (A) Intermolecular Deuterium KIE for the
Chloride/Iodate Catalytic Oxidation of Adamantane in
Acetic Acid and (B) Intermolecular Deuterium KIE for
a
Radical Chlorination of Methane of Adamantane
Figure 1. UV−vis spectra resulting from the yellow mixture of
potassium chloride and potassium iodate in HTFA (top, black), pure
ICl (bottom, red), and pure ICl3 (middle, blue). Conditions for the
black spectrum: 0.15 mmol of KCl, 1.0 mmol of KIO3, and
trifluoroacetic acid at room temperature. The peak for Cl2 was
determined experimentally by preparing an authentic standard in
HTFA.
As chlorine formation is evident from the UV−vis spectrum
of the iodate/chloride mixture in HTFA, the possibility of a
chlorine-radical-based functionalization pathway was probed
further. To examine whether chlorine radicals are possibly
involved in the HIAO process for adamantane functionaliza-
tion, the selectivity of the iodate/chloride reaction with
adamantane was compared to the selectivity of a radical
chlorination. In order to avoid the rearrangement observed in
HTFA, we performed experiments in acetic acid (HOAc). As
shown in Scheme 4, both the HIAO process and the
functionalization promoted by N-chlorosuccinimide (NCS),
which has been shown to yield chlorine radicals in the presence
of a radical initiator such as benzoyl peroxide,63 yield similar
tertiary to secondary selectivity: ∼5.2:1 on a per-hydrogen
basis. Previous reports indicated that radical chlorination of
adamantane in benzene using NCS or Cl2 proceeded with
tertiary to secondary selectivity similar to our results in HOAc
on a per-hydrogen basis: 4.9:1 and 4.7:1, respectively.64,65 In
each case, only monofunctionalized products were observed.
Additionally, as shown in Scheme 5, when a 1:1 mixture of
perprotio- and perdeuteroadamantane are used, nearly identical
kinetic isotope effects are observed for the HIAO process and
radical chlorination using NCS and benzoyl peroxide. The
reaction of adamantane and adamantane-d16 with iodate/
chloride in acetic acid reveals a kH/kD value of 1.52(3), which is
statistically identical with the kH/kD value, 1.6(3), for the
reaction using NCS. These results are consistent with the
HIAO process for adamantane oxidation likely involving
a
NCS = N-chlorosuccinimide.
chlorine radicals. We note that the use of N-chlorosuccinimide
as an unambiguous source of chlorine atoms has been
contested.66 While the role of the succinimidyl versus chlorine
radical has not been resolutely elucidated, N-chlorosuccinimide
was utilized in this selectivity study to provide a reference for
radical-based functionalization that results in chlorination.
N-Hydroxyphthalimide (NHPI), a well-studied reagent for
hydrogen atom abstraction,67 was tested as a substitute for
chloride in order to determine if the chloride in the HIAO
process ultimately acts as a hydrogen atom abstraction agent. In
acetic acid at 180 °C, adamantane was converted to the
functionalized product in 86% yield with NHPI and NH4IO3
(Scheme 6). Thus, chloride is potentially acting as a precursor
for a hydrogen atom abstraction reagent. The NHPI-mediated
functionalization of adamantane is likely more selective than
that with iodate/chloride due to the lower reactivity of the
phthalimide N-oxyl (PINO) radical in comparison to chlorine
radical,68−70 as the BDE of the O−H bond of NHPI is 14 kcal/
mol weaker than that of the H−Cl bond.45
The previously observed tolerance of the HIAO system to
dioxygen could indicate a nonradical reaction pathway, as the
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propaneperoxoate, an ethyl radical precursor,78 is heated in
acetic acid in the presence of stoichiometric iodine, ethyl iodide
is produced as the main product. With these results in hand, we
probed for the formation of ethyl iodide in the iodate/chloride
functionalization of ethane in acetic acid. In fact, heating (180
°C) a mixture of ethane, iodate, and chloride in acetic acid and
analyzing the reaction mixture by 1H NMR spectroscopy
reveals the formation of ethyl iodide (Scheme 8). This result is
Scheme 6. Functionalization of Adamantane Using a Mixture
of N-Hydroxyphthalimide (NHPI) and Ammonium Iodate
in Acetic Acid
Scheme 8. Functionalization of Ethane in Acetic Acid Using
Iodate/Chloride Yielding a Mixture of Ethyl Iodide, Ethyl
Chloride, Ethyl Acetate, and Methyl Acetate
trapping of methyl radicals by dioxygen occurs at nearly
diffusion-controlled rates.60 Thus, if alkyl free-radical inter-
mediates were formed, it was anticipated that alkyl radicals
would be rapidly trapped by dioxygen and prevent the
formation of alkyl esters.60 However, the rate of reaction
between alkyl radicals and molecular iodine, which is produced
under reaction conditions for the iodate/chloride functionaliza-
tion process, is approximately half as rapid as trapping by
dioxygen (2.5 × 109 L mol−1 s−1 for I2 versus 4.9 × 109 L mol−1
s−1 for O2).60,71,72 This indicates that, if iodine is present in
significant concentration, it could intercept a putative alkyl
radical prior to a reaction with dioxygen. Because MeI reacts
rapidly with NH4IO3 in HTFA to form MeTFA in nearly
quantitative yield,57 the formation of MeI as an intermediate is
unlikely to be detected. Under oxidizing conditions, alkyl
iodides have been reported to convert to alcohols and
acetates.73−77
a
a
See text and Scheme 14 regarding MeOAc production.
consistent with the formation of an ethyl radical, which is
trapped by molecular iodine formed in situ. Thus, the
formation of methyl iodide from methyl radicals during
methane functionalization in HTFA is also viable, but rapid
conversion of MeI to MeTFA would prevent detection.
To determine the relative stabilities of RI and RTFA (R =
Me, Et) under the HIAO conditions, each was tested under a
standard set of conditions (Schemes 9 and 10). Both alkyl
As a test for possible formation of alkyl iodide intermediates,
we probed two aspects: (1) if ethyl iodide converts to ethyl
acetate in acetic acid quickly under reactions conditions and (2)
if ethyl radical can be trapped by iodine under reaction
conditions. As shown in Scheme 7 and Figure 2, when tert-butyl
Scheme 9. MeI Conversion to MeTFA and MeCl under
Functionalization Conditions
Scheme 7. Heating tert-Butyl Propaneperoxoate in the
a
Presence of Iodine Yields Ethyl Iodide
Scheme 10. EtI Conversion to EtTFA, EtCl, and
Difunctionalized Ester Product under Functionalization
Conditions
a
Ethyl iodide yield is reported as the average and standard deviation of
four trials.
iodides, MeI and EtI, are completely consumed under these
conditions after 20 min. MeI is converted to MeTFA and MeCl
(Scheme 9). While EtI is observed in HOAc (see Scheme 8),
EtI is consumed quickly to form EtTFA, EtCl, and 1,2-
bis(trifluoroacetyl)ethane in the stronger acid, HTFA. Mean-
while, the ester-protected species, MeTFA and EtTFA, are
moderately stable under these HIAO reaction conditions with
90% and 55%, respectively, remaining after heating at 180 °C
for 20 min. The trifluoroacetate moiety prevents overoxidation
(Figures 3 and 4), to a higher degree for MeTFA than for
EtTFA.
In order to compare the rate of functionalization of the light
alkanes to form the RTFA products to the rate of RTFA
consumption, the conversion of methane and ethane to
MeTFA and EtTFA and the consumption of MeTFA and
EtTFA were studied at 140 °C (Figures 3 and 4). The products
of MeTFA and EtTFA conversion were not characterized.
Figure 2. 1H NMR spectrum resulting from heating tert-butyl
propaneperoxoate in the presence of iodine. Conditions: 0.1 mmol
of tert-butyl propaneperoxoate, 0.05 mmol of iodine, 1 mL of acetic
acid-d4 at 180 °C for 1 h. Cyclopentane (0.05 mmol) was added as an
internal standard.
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Figure 3. Methane functionalization and MeTFA decay in the presence of KCl, NH4IO3, and HTFA at 140 °C as a function of time.
Figure 4. Ethane functionalization (left) and EtTFA decay (right) in the presence of KCl, NH4IO3, and HTFA at 140 °C as a function of time.
Because the methane functionalization reaction to yield
MeTFA is complete within 1 h at 180 °C, the lower
temperature (140 °C) was used such that methane
functionalization could be examined over a longer period of
time to provide a better comparison to the rate of MeTFA
decay. MeTFA is very stable under the reaction conditions,
with 85% remaining after 16 h at 140 °C. However, this places
an upper limit on loss of MeTFA due to chemical oxidation, as
some MeTFA is lost due to its high volatility. Under the HIAO
reaction conditions, EtTFA is less stable than MeTFA, with
41% of the added EtTFA remaining after 8 h at 140 °C.
Although the rates of decay and functionalization cannot be
rigorously compared directly due to the unknown concen-
tration of alkane in solution during the reaction, the relative
rates of decay and functionalization under the reaction
conditions used can be determined from the slopes of plots
of MeTFA decay and production over time. While the plot of
MeX (X = Cl, TFA) production versus time is linear for the
reaction with methane (R2 = 0.96, Figure 3 and Figure S14),
the plot of EtX production versus time is not. To compare the
rates of functionalization and decay, the rate of RX production
was determined using the first data point, and linear fits of the
RTFA decay data were used (Figure S15). Accordingly, the
ratios of RX production versus decay are 11 and 9 for R = Me,
Et, respectively.
peroxide (Scheme 11, without added iodine), MeTFA is not
produced. However, upon addition of small amounts of I2
Scheme 11. Radical Chlorination of Methane in the Presence
of Added Iodine (See Figure 5) Producing MeTFA and
a
MeCl
a
Note that MeCl formation was not quantified due to partial overlap
1
with the H NMR resonance from succinimide, which is generated
from N-chlorosuccinimide (NCS).
(Scheme 11 and Figure 5), MeTFA is generated. A decrease in
MeTFA yield is observed with ≥ 0.34 mmol of iodine.
Free-radical-based functionalization of methane generally
operates with poor selectivity, as the products contain weaker
bonds in comparison to those in methane, which leads to
undesired overoxidation. While the HIAO process exhibits high
selectivity, it may occur by a radical pathway as a result of the
protecting effect of the TFA ester moiety. Under typical radical
chlorination conditions using N-chlorosuccinimide and benzoyl
Figure 5. MeTFA production as a function of added iodine to radical
chlorination functionalization of methane in HTFA.
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Although we are unsure of the cause of this decrease in MeTFA
yield, it is possible that I2 traps radical intermediates that are
important for the methane functionalization chemistry. Because
MeCl does not rapidly convert to MeTFA under the reaction
conditions, this demonstrates that iodine is an efficient radical
trap that produces MeI, which is quickly converted to MeTFA.
The effect of adding I2 to the HIAO methane functionalization
reaction was also investigated for comparison. As shown in
Figure 6, the addition of ≥ 0.3 mmol of iodine similarly inhibits
While previous findings indicated that the reaction of iodate/
chloride with methane in acetic acid produces MeOAc,57 recent
results show that the MeOAc formed under these conditions is
the result of reaction with acetic acid and not methane
functionalization. Pressurizing a mixture of KCl and NH4IO3 in
HOAc with argon, rather than methane, gave MeOAc yields
statistically identical with those for reactions with methane
(Scheme 14). Furthermore, GC-MS analysis of a reaction with
perprotiomethane in acetic acid-d4 indicated that the fully
deuterated product CD3CO2CD3 accounts for > 90% of
MeOAc production, while the product that would arise from
methane functionalization, CD3CO2CH3, accounts for < 2%.
Consistent with these observations, UV−vis analysis indicates
that Cl2 and ICl/ICl3, which have been proposed as the reactive
intermediate species, are not produced in HOAc (Figure 7,
overlaid with data in HTFA for comparison).
The experimental results reported herein are consistent with
recent computational efforts that indicate that the HIAO
system might proceed through a pathway that involves free
radical intermediates.79 The computational modeling predicts
−
−
that transient intermediates IO2Cl2 and IOCl4 are formed,
which can lead to the formation of IO2 and Cl• radicals
•
(Scheme 15). Both IO2 or Cl• are capable of abstracting a
•
hydrogen atom from methane, and the methyl radicals are
predicted to react with iodine to give MeI, which is converted
to MeTFA and protected from overoxidation.
Figure 6. Functionalization of methane with KCl (0.67 mmol) and
NH4IO3 (7.7 mmol) in HTFA at 180 °C for 1 h with added I2. The
plot shows the yield of MeX after 1 h of reaction as a function of added
I2.
The reduction of iodate should produce water during the
hydrocarbon functionalization process. In order to probe for
the production of water experimentally, the change in the
1
chemical shift of the HTFA H NMR resonance was analyzed
methane functionalization. To determine the stability of
MeTFA under radical chlorination conditions, MeTFA was
heated at 180 °C in the presence of N-chlorosuccinimide and
benzoyl peroxide (Scheme 12). In agreement with the study of
MeTFA stability under HIAO conditions, MeTFA is relatively
stable under chlorination conditions, with about 83% remaining
after 1 h at 180 °C.
for a series of DTFA/H2O mixtures using methylene chloride
as the internal standard. As the water concentration increases,
the resonance due to HTFA shifts upfield (Figure S20). The
methane functionalization reaction was then performed in
DTFA. Following the functionalization reaction, methylene
chloride was added as an internal standard, and the reactions
1
were analyzed by H NMR spectroscopy. In each of the three
trials, the resonance was observed from δ 10.32 to 10.33 ppm,
corresponding to a solution with approximately 1.6 mmol of
H2O. This corresponds to an ∼28% yield of H2O based on the
starting amount of iodate (note that 100% yield of H2O is
achieved through formation of 3 equiv of H2O per equivalent of
iodate).
Scheme 12. Stability of MeTFA under Radical Chlorination
Conditions in HTFA
a
These data indicate that HIAO likely occurs by a pathway
that involves free radicals. Scheme 16 shows a simplified
reaction scheme based on our combined computational and
experimental studies. While this does not include all
intermediates or reactions predicted to be present or occurring
in situ, it is useful as an overall representation of the proposed
key intermediates and transformations for HIAO. We propose
that chloride is oxidized to chlorine, which is homolytically
cleaved to give chlorine radicals that can abstract a hydrogen
atom from an alkane to give alkyl radical and HCl. In addition,
C−H bond breaking by IO2• is possible. The alkyl radical reacts
with iodine, formed in situ, to give alkyl iodide, which converts
to protected alkyl esters in HTFA. The HIAO process differs
from traditional chlorination processes in that the chloride is
catalytic for the HIAO process rather than stoichiometric.
Unlike traditional radical-based alkane functionalization,
HIAO exhibits good selectivity at reasonable conversions for
the monofunctionalized product. This is demonstrated by the
stability of RTFA (R = Me, Et) under the reaction conditions
(Figures 3 and 4). Despite the C−H bond energy of MeTFA
a
NCS = N-chlorosuccinimide.
To further compare the HIAO process for light alkane
functionalization to free-radical-based chlorination, propane
was used to probe the selectivity for 2° versus 1° functionalized
products. Propane oxidation was performed with either KCl/
NH4IO3 or NCS/benzoyl peroxide in HTFA at 120 °C for 30
min (Scheme 13). Low temperature, short reaction time, and
subsequently, low conversions were used in order to minimize
the generation of difunctionalized products so that the
selectivity of the monofunctionalization process could be
probed. The selectivity for internal versus terminal functional-
ization of propane differs between the two processes, with a
2°:1° ratio of 17.0(8):1 for KCl/NH4IO3 and 5.6(6):1 for
NCS/benzoyl peroxide on a per-hydrogen basis (Scheme 13).
Difunctionalized products were produced in minor amounts
under these conditions and are not used in the calculation of
the 2°:1° selectivity.
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Scheme 13. Product Yields with Respect to Propane for the Reaction of KCl/NH4IO3 or N-Chlorosuccinimide (NCS) and
a
Benzoyl Peroxide in HTFA at 120 °C
a
Approximate yields are shown with respect to propane (∼9 mmol). Difunctionalized products were not used in the calculation of 2°:1° selectivity.
ment of the study is that this free-radical-based C−H bond
functionalization method protects the mono-oxidized product from
overoxidation.
Scheme 14. Reaction of Methane or Argon with KCl/
NH4IO3 Gives Equivalent Amounts of MeOAc
Such a protecting effect might find application in other
strategies for hydrocarbon oxidation. Importantly, the reactivity
is not merely a facet of the C−H bond energy. The reaction
rate varies inversely with C−H bond energy, as the weaker
internal C−H bond of propane appears to react more rapidly
than the stronger terminal C−H bond.57 Rather, the influence
of the ester functionality appears to be more nuanced than just
reducing the C−H bond energy. We interpret the effect of TFA
as a protecting group to overoxidation to possibly be a
manifestation of the polar effect, as discussed originally by
Walling et al.80 Thus, while for the HIAO process the
explanation of this effect is not yet entirely clear, the TFA
group could serve to reduce the polarity of the transition state
(compare the expected polarity of TFA-C(H)2···H···Cl vs that
of H3C···H···Cl), which can result in an increase in the
activation barrier relative to the more polar transition state for
H atom abstraction from the alkane.81 Recent treatments using
DFT have shown dramatic effects (∼10 kcal/mol) of strongly
electron withdrawing substituents on energy barriers for C−H
hydrogen abstraction by chlorine atoms.82 Thus, the protecting
effect that we have observed might be extended to other
conditions, suggesting the potential for broad impact for
radical-based alkane functionalization processes.
Figure 7. UV−vis spectra of mixtures of KCl (0.10 mmol) and
NH4IO3 (1 mmol) in 3 mL of HTFA or HOAc.
Scheme 15. Likely Intermediates Determined from
Computational Modeling (in Blue) Reacting with Iodine
Radical To Give Cl− and Two Species That Are Predicted to
Activate Methane C−H Bonds under the HIAO Reaction
Conditions (in Red)
SUMMARY AND CONCLUSIONS
■
Our new experimental results are consistent with the oxidation
of hydrocarbons using mixtures of chloride and iodate
proceeding through a pathway that involves the generation of
Scheme 16. General Overview Depicting the Catalytic
•
a
free radicals, chlorine, and IO2 , which are likely responsible for
Nature of Chloride in the HIAO Process
homolytic C−H bond cleavage. The oxidation of adamantane
by KCl/NH4IO3 in acetic acid shows both product selectivity
and C−H/C−D deuterium KIEs similar to those of radical
chlorination under similar reaction conditions. Additionally, the
reaction of alkyl radicals with molecular iodine, generated in
situ under the HIAO reaction conditions, is likely facile even
under aerobic conditions, suggesting that the presence of
oxygen does not influence the reaction. The high selectivity of
the HIAO process for the mono-oxidized product is particularly
notable, given its likely operation through a free-radical-based
pathway. The protection of the mono-oxidized alkyl ester from
further oxidation is crucial in order to obtain both high
selectivity and high yields on the basis of the starting light
alkane.
a
Possible hydrogen atom abstraction from RH by IO2 radical has been
omitted for clarity, but according to computational modeling the IO2
radical is a possible intermediate.
being 2.3 kcal/mol lower than that of methane,79 MeTFA
consumption is relatively slow. The most fundamental advance-
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reaction mixture was cooled to room temperature and was
subsequently added to a solution of dodecane (1 mmol) in
chloroform (5 mL). This mixture was then extracted twice with
10 mL of water, and the organic washings were dried over
MgSO4. The mixture was then analyzed via GC-MS, and the
yields of adamantyls were determined relative to dodecane, the
added internal standard. Each reaction condition was repeated a
minimum of three times with the average of all reactions
reported.
EXPERIMENTAL SECTION
■
Caution! Many of the reagents and conditions described herein
are potentially hazardous.83 Appropriate safety procedures
should be consulted prior to handling concentrated acids,
strong oxidants, and mixtures of hydrocarbon substrates and
oxygen.
Materials. Unless indicated otherwise, all reactions were
carried out under ambient atmosphere. Adamantane, potassium
chloride, ammonium iodate, tert-butyl hydroperoxide, iodine,
trifluoroacetic acid, glacial acetic acid, propionic acid, trifluoro-
acetic anhydride, methyl trifluoroacetate, ethyl trifluoroacetate,
ethyl iodide, methyl iodide, cyclopentane, chloroform, dichloro-
methane, dodecane, trifluoroacetic acid-d, acetic acid-d4,
benzene-d6 and benzoyl peroxide were purchased from
commercial sources and used without further purification. N-
Chlorosuccinimide was purchased commercially and recrystal-
lized from glacial acetic acid prior to use. Methane, ethane,
propane, and argon were purchased from GTS-Welco and used
as received. Authentic standards of adamantyl ester products
were prepared by published literature methods from the
commercially available alcohols.84 GC-MS analysis was
performed using an Agilent Technologies 7890A gas chromato-
graph equipped with a fused silica column and electron impact
mass analyzer or using a Shimadzu GCMS-QP2010 Plus system
with a 30 m × 0.25 mm SHRXI-5MS column with 0.25 μm
thickness using electron impact ionization. NMR analysis was
performed using a Bruker 300 Avance, Avance III 800, Avance
III 600, or Avance DRX-600 or a Varian Inova 500
spectrometer. NMR data of reaction mixtures from methane
and ethane functionalization reactions were obtained using neat
HTFA or HOAc with a capillary of C6D6 as an internal lock
reference. Chemical shifts for 1H NMR are reported relative to
the internal standards of HOAc (δ 2.04), nitromethane (δ 4.18)
or dichloromethane (δ 5.03). UV−vis spectra were collected on
a Carey Varian Bio 300 UV−vis spectrophotometer.
Oxidation of Adamantane Using Ammonium Iodate
and Potassium Chloride in Acid. In a typical reaction, an 8
mL microwave vial equipped with a stir bar was charged with
ammonium iodate (1 mmol), adamantane (1 mmol), and
potassium chloride (0.15 mmol). Neat acid (4 mL) was then
added to the solution and the vial sealed with a crimp cap. The
vials were then heated in an oil bath at 180 °C for 1 h with
vigorous stirring (1150 rpm). After 1 h, the reaction mixture
was cooled to room temperature and was subsequently added
to a solution of dodecane (1 mmol) in chloroform (5 mL).
This mixture was then extracted twice with 10 mL of water, and
the organic washings were dried over MgSO4. The mixture was
then analyzed via GC-MS, and the yields of adamantyls were
determined relative to dodecane, the added internal standard.
Each reaction condition was repeated a minimum of three
times with the average of all reactions reported.
Synthesis of tert-Butyl Peroxypropionate. The title
compound was synthesized by adapting the method described
by Yur’ev and co-workers.86 A 100 mL round-bottom flask
equipped with a stir bar was charged with CDCl3 (5 mL) and
propionic acid (5 mmol). The mixture was cooled to 0 °C, and
pyridine (5 mmol) was added dropwise to the vigorously
stirred solution. The solution was then stirred at 0 °C for 15
min. Then, tert-butyl hydroperoxide (3 mmol) and pyridine (5
mmol) were added dropwise to the stirred solution in
sequence. The solution was stirred for 45 min and then slowly
warmed to room temperature. The solution was then washed
with saturated aqueous sodium bicarbonate (3 × 5 mL) and 1
M HCl (2 × 5 mL), and the organic washings were dried over
MgSO4. The solution was then concentrated in vacuo (behind a
1
blast shield) to yield the title compound. H NMR (CDCl3,
3
300 MHz, δ): 2.27 (q, CH3CH2CO3C(CH3)3, JHH = 8 Hz,
2H), 1.25 (s, CH3CH2CO3C(CH3)3, 9H), 1.13 (t,
3
CH3CH2CO3C(CH3)3, JHH = 8 Hz, 3H). 13C NMR (CDCl3,
125 MHz, δ): 172.1 (CH3CH2CO3C(CH3))3, 83.6
(CH3CH2CO3C(CH3))3, 26.4 (CH3CH2CO3C(CH3)3, 25.0
(CH3CH2CO3C(CH3))3, 9.5 (CH3CH2CO3C(CH3))3.
Pyrolysis of tert-Butyl Peroxypropionate in the
Presence of Iodine. A J. Young NMR tube was charged
with tert-butyl peroxypropionate (0.1 mmol), iodine (0.05
mmol), cyclopentane (0.05 mmol as internal standard), and
acetic acid-d4 (1 mL). The NMR tube was sealed and heated in
an oil bath at 180 °C for 1 h. The mixture was cooled to room
1
temperature and analyzed by H NMR spectroscopy. Ethyl
iodide production was quantified relative to the integration of
the cyclopentane internal standard, and the presence of ethyl
iodide was confirmed by spiking the reaction with an authentic
standard of ethyl iodide. This reaction was repeated four times,
and the yield was reported as an average of the four trials.
Intermolecular KIE Determination for the Functional-
ization of Adamantane by N-Chlorosuccinimide/Benzo-
yl Peroxide and KCl/NH4IO3. Intermolecular KIEs for
functionalized adamantyl products were determined by
performing the reactions in the presence of a 1:1 stoichiometric
ratio of perprotioadamantane (0.5 mmol) and perdeuterioada-
mantane (0.5 mmol). Only 20 mol % of oxidant relative to the
total molar amount of substrate was added to make sure that
conversion was kept below 20%. The intermolecular deuterium
KIE was then obtained by determining the ratio of protio
product to deuterio product using GC-MS. The reported KIE
ratio is the average of at least three individual experiments.
Oxidation of Ethane with the Iodate/Chloride System
in Acetic Acid. In air, a custom-built stainless steel pressure
reactor with a Teflon liner57,58 was charged with NH4IO3 (7.7
mmol), KCl (0.67 mmol), HOAc/Ac2O (8.0 mL, 19:1 v/v),
and a stir bar. The reactor was sealed, purged with Ar, and
subsequently pressurized to 300 psi with ethane. After the
mixture was stirred (800 rpm) at 180 °C for 1 h, the reactor
was cooled to room temperature. The reactor was carefully
Chlorination of Adamantane with N-Chlorosuccini-
mide. Chlorination of adamantane was carried out according
to a literature procedure.85 An 8 mL microwave vial equipped
with a stir bar was charged with adamantane (1 mmol), N-
chlorosuccinimide (1 mmol), and benzoyl peroxide (0.01
mmol, to act as a radical initiator) and sealed with a crimp cap
equipped with a Teflon septum. The vial was then flushed with
argon for 20 min. Glacial acetic acid (4 mL), which had been
degassed by refluxing under Ar(g) for 1 h, was then added via
syringe. The sealed vial was then heated to 180 °C for 1 h in an
oil bath with vigorous stirring (1150 rpm). After 1 h, the
1
vented, and an aliquot was removed and centrifuged for H
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NMR analysis. Using a standard of methylene chloride, 0.31(3)
mmol of EtOAc, 0.27(1) mmol EtCl, 0.06(1) mmol EtI and
0.46(9) mmol MeOAc were detected. This procedure was
performed in triplicate.
to determine the mole percent of added water on the basis of
the chemical shift of the TFA resonance. To determine the
amount of water that was produced, the total volume of the
mixture following the reaction was measured and used to
calculate an amount using the mole percent obtained from the
calibration curve.
Oxidation of Methane with N-Chlorosuccinimide and
Benzoyl Peroxide with or without Added Iodine. A
custom-built stainless steel pressure reactor57,58 was charged
with N-chlorosuccinimide (3.5 mmol), benzoyl peroxide (0.035
mmol), HTFA (8.0 mL), iodine (0.0335, 0.067, 0.335, or 0.67
mmol, if added), and a stir bar in the glovebox. HTFA was
heated to reflux for 1 h under N2 prior to being added to the
reactor. The reactor was sealed and pressurized with 500 psi of
argon. After the mixture was stirred (800 rpm) at 180 °C for 1
h, the reactor was cooled to room temperature. The reactor was
carefully vented, and acetic acid was added as an internal
standard. The reaction mixture was stirred, and an aliquot was
removed and centrifuged for 1H NMR analysis. This procedure
was performed in triplicate.
Consumption of Functionalized Products (RI and
RTFA) under HIAO Conditions. A custom-built stainless
steel pressure reactor with a Teflon liner57,58 was charged with
RI or RTFA (1 mmol, R = Me, Et), NH4IO3 (7.7 mmol), KCl
(0.67 mmol), HTFA (8.0 mL), and a stir bar. The reactor was
sealed and pressurized with 100 psi of Ar. After the mixture was
stirred (800 rpm) at 180 °C for 20 min, the reactor was cooled
to room temperature. The reactor was carefully vented, and
nitromethane was added as an internal standard. The reaction
mixture was stirred, and an aliquot was removed and
centrifuged for 1H NMR analysis. This procedure was
performed in triplicate.
Oxidation of Propane with KCl/NH4IO3. In air, a custom-
built stainless steel pressure reactor with a Teflon liner57,58 was
charged with NH4IO3 (7.7 mmol), KCl (0.67 mmol), HTFA
(8.0 mL), and a stir bar. The reactor was sealed and pressurized
with 100 psi of propane. After the mixture was stirred (800
rpm) at 120 °C for 30 min, the reactor was cooled to room
temperature. The reactor was carefully vented, and acetic acid
was added as an internal standard. The reaction mixture was
Consumption of MeTFA under Radical Chlorination
Conditions. A custom-built stainless steel pressure reactor57,58
was charged with N-chlorosuccinimide (3.5 mmol), benzoyl
peroxide (0.035 mmol), HTFA (8.0 mL), and a stir bar in the
glovebox. HTFA was heated to reflux for 1 h under N2 prior to
being placed in the reactor. The reactor was sealed and
pressurized with 500 psi of argon. After the mixture was stirred
(800 rpm) at 180 °C for 1 h, the reactor was cooled to room
temperature. The reactor was carefully vented, and acetic acid
was added as an internal standard. The reaction mixture was
1
stirred, and an aliquot was removed and centrifuged for H
NMR analysis. This procedure was performed in triplicate.
Oxidation of Propane with N-Chlorosuccinimide and
Benzoyl Peroxide. A custom-built stainless steel pressure
reactor with a Teflon liner57,58 was charged with N-
chlorosuccinimide (7 mmol), benzoyl peroxide (0.07 mmol),
HTFA (8.0 mL), and a stir bar in the glovebox. HTFA was
heated to reflux for 1 h under N2 prior to being added to the
reactor. The reactor was sealed and pressurized with 100 psi of
propane. After the mixture was stirred (800 rpm) at 120 °C for
30 min, the reactor was cooled to room temperature. The
reactor was carefully vented, and acetic acid was added as an
internal standard. The reaction mixture was stirred, and an
1
stirred, and an aliquot was removed and centrifuged for H
NMR analysis. This procedure was performed in triplicate.
Conversion of Adamantyl Esters in Acid. A custom-built
stainless steel pressure reactor57,58 was charged with the
secondary adamantyl ester (trifluoroacetate or acetate) and 4
mL of the corresponding acid (HTFA or glacial HOAc). The
reactor was sealed and pressurized with 100 psi of argon. After
the mixture was stirred (800 rpm) at 180 °C for 15 min, the
reactor was cooled to room temperature. The reactor was
carefully vented, and nitromethane was added as an internal
standard. The reaction mixture was stirred, and 5 mL of DCM
was added. The reaction mixture was then washed with water
(2 × 10 mL), and the organic washings were dried over
MgSO4. The mixture was then analyzed via GC-MS. Each
reaction condition was performed three times.
1
aliquot was removed and centrifuged for H NMR analysis.
This procedure was performed in triplicate.
Calibration Curve for Quantification of Water
Production. A series of DTFA (99.5% D)/H2O mixtures
were made by serially diluting a 50 mol% H2O and DTFA
solution (Figure S20). Each was placed in an NMR tube with a
C6D6 capillary, and dry dichloromethane was added as an
internal standard, referenced to δ 5.03 ppm. These were
1
analyzed by H NMR spectroscopy using the C6D6 capillaries
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.7b04397.
as internal lock references. The shifts of the TFA resonances
varied as a function of the water concentration. A control with
neat DTFA was also analyzed and referenced to dichloro-
methane. This calibration curve was used to determine the
amount of water that was produced from methane function-
alization by HIAO in DTFA.
Methane Functionalization Reaction in DTFA. A scaled-
down methane functionalization reaction (100 psi of CH4, 0.17
mmol of KCl, 1.9 mmol of NH4IO3, 2 mL of DTFA) was run in
triplicate using DTFA from the same ampule. The reactors
were heated at 180 °C for 1 h and the mixtures stirred at 800
rpm. Dichloromethane was added as an internal standard after
the reaction. The reaction mixtures were analyzed as in
previously mentioned light alkane functionalization reactions,
using a C6D6 capillary as an internal lock reference. The
volumes of the reaction mixtures following the reaction were
also measured. The calibration curve discussed above was used
■
S
1
UV/vis spectra, representative GC traces and H NMR
spectra, standard curves for the determination of water
and iodine concentrations, and GC-MS fragmentation
data (PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail for J.T.G.: jtgroves@princeton.edu.
*E-mail for T.B.G.: tbg7h@virginia.edu.
■
ORCID
Robert J. Nielsen: 0000-0002-7962-0186
William A. Goddard III: 0000-0003-0097-5716
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John T. Groves: 0000-0002-9944-5899
T. Brent Gunnoe: 0000-0001-5714-3887
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Present Addresses
⊥Department of Chemistry, North Central College, Naperville,
IL 60540, United States.
#Chemistry Program, School of Natural Sciences and
Mathematics, Stockton University, Galloway, NJ 08205, United
States.
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Author Contributions
∥N.A.S. and N.C.B. contributed equally.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(22) Goldberg, K. I.; Goldman, A. S. Large-Scale Selective
This work was supported by the U.S. Department of Energy
(USDOE), Office of Energy Efficiency and Renewable Energy
(EERE), Advanced Manufacturing Office Next Generation
R&D Projects, under contract no. DE-AC07-05ID14517.
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