Tunneling Controls the Reaction Pathway in the Deformylation of Aldehydes by a Nonheme Iron(III)-Hydroperoxo Complex: Hydrogen Atom Abstraction versus Nucleophilic Addition

Article abstract of DOI:10.1021/jacs.9b02272

Mononuclear nonheme iron(III)-hydroperoxo intermediates play key roles in biological oxidation reactions. In the present study, we report the highly intriguing reactivity of a nonheme iron(III)-hydroperoxo complex, [(TMC)Fe^III(OOH)]²⁺ (1), in the deformylation of aldehydes, such as 2-phenylpropionaldehyde (2-PPA) and its derivatives; that is, the reaction pathway of the aldehyde deformylation by 1 varies depending on reaction conditions, such as temperature and substrate. At temperature above 248 K, the aldehyde deformylation occurs predominantly via a nucleophilic addition (NA) pathway. However, as the reaction temperature is lowered, the reaction pathway changes to a hydrogen atom transfer (HAT) pathway. Interestingly, the reaction rate becomes independent of temperature below 233 K with a huge kinetic isotope effect (KIE) value of 93 at 203 K, suggesting that the HAT reaction results from tunneling. In contrast, reactions with a deuterated 2-PPA at the α-position and 2-methyl-2-phenylpropionaldehyde proceed exclusively via a NA pathway irrespective of the reaction temperature. We conclude that the bifurcation pathways between NA and HAT result from the tunneling effect in the HAT reaction by 1. To the best of our knowledge, this study reports the first example showing that tunneling plays a significant role in the activation of substrate C-H bonds by a mononuclear nonheme iron(III)-hydroperoxo complex.

Full text of DOI:10.1021/jacs.9b02272

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Communication
Tunneling Controls the Reaction Pathway in the Deformylation
of Aldehydes by a Nonheme Iron(III)-Hydroperoxo Complex:
Hydrogen Atom Abstraction versus Nucleophilic Addition
Seong Hee Bae, Xiao-Xi Li, Mi Sook Seo, Yong-Min Lee, Shunichi Fukuzumi, and Wonwoo Nam
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 29 Apr 2019
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Tunneling Controls the Reaction Pathway in the Deformylation of
Aldehydes by a Nonheme Iron(III)-Hydroperoxo Complex: Hydro-
gen Atom Abstraction versus Nucleophilic Addition
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Seong Hee Bae,† Xiao-Xi Li,† Mi Sook Seo,† Yong-Min Lee,† Shunichi Fukuzumi,*,†,‡ and
Wonwoo Nam*,†,§
†
Department of Chemistry and Nano Science, Ewha Womans University, Seoul 03760, Korea
‡
Faculty of Science and Engineering, Meijo University, SENTAN, Japan Science and Technology Agency (JST), Nagoya, Aichi
468-8502, Japan
§
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Suzhou Research Institute of LICP, Lanzhou Institute of Chem-
ical Physics (LICP), Chinese Academy of Sciences, Lanzhou 730000, China
Supporting Information Placeholder
ABSTRACT: Mononuclear nonheme iron(III)-hydroperoxo
intermediates play key roles in biological oxidation reactions.
In the present study, we report a highly intriguing reactivity of
Scheme 1. Reaction Pathways, HAT vs NA, and Sub-
strates Used in the Mechanistic Study of Aldehyde De-
formylation by an Iron(III)-Hydroperoxo Intermediate
a
nonheme
III
iron(III)-hydroperoxo
complex,
2+
[(TMC)Fe (OOH)] (1), in the deformylation of aldehydes,
such as 2-phenylpropionaldehyde (2-PPA) and its derivatives;
that is, the reaction pathway of the aldehyde deformylation by
1 varies depending on reaction conditions, such as tempera-
ture and substrate. At temperature above 248 K, the aldehyde
deformylation occurs predominantly via a nucleophilic addi-
tion (NA) pathway. However, as the reaction temperature is
lowered, the reaction pathway changes to a hydrogen atom
transfer (HAT) pathway. Interestingly, the reaction rate be-
comes independent of temperature below 233 K with a huge
kinetic isotope effect (KIE) value of 93 at 203 K, suggesting
that the HAT reaction results from tunneling. In contrast,
reactions with a deuterated 2-PPA at the α-position and 2-
methyl-2-phenylpropionaldehyde proceed exclusively via a NA
pathway irrespective of the reaction temperature. We conclude
that the bifurcation pathways between NA and HAT result
from the tunneling effect in the HAT reaction by 1. To the
best of our knowledge, this study reports the first example
showing that tunneling plays a significant role in the activation
of substrate C-H bonds by a mononuclear nonheme iron(III)-
hydroperoxo complex.
hydroperoxide intermediates are less clearly understood and
remain to be elusive.
Very recently, Kumar, Sastri, de Visser, and their co-
workers reported an interesting observation that a manga-
nese(III)-peroxo complex reacts with 2-phenylpropionaldehyde
(2-PPA) through a HAT pathway instead of the commonly
proposed nucleophilic addition (NA) pathway in the de-
7
formylation of aldehydes by metal-peroxo species. Evidence
proposing the HAT mechanism in the deformylation of 2-PPA
by the Mn(III)-peroxo complex was the kinetic isotope effect
(KIE) value of ~5.4 when 2-PPA and a deuterated 2-PPA at
the α-position (α-[D1]-2-PPA) were used as substrates. In addi-
tion, 2-methyl-2-phenylpropionaldehyde (2-Me-2-PPA) did
not react with the Mn(III)-peroxo complex. Thus, 2-PPA and
its derivatives were shown to be excellent substrate probes that
can be used in distinguishing the HAT vs NA pathways in
oxidation reactions by metal-oxygen intermediates (Scheme 1).
In the present study, we have investigated the reactions of a
mononuclear nonheme iron(III)-hydroperoxo complex,
Oxygen-containing iron species, such as iron(III)-superoxo,
iron(III)-peroxo, iron(III)-hydroperoxo, and iron(IV)-oxo, are
key intermediates in the activation of dioxygen by mononucle-
1,2
ar nonheme iron enzymes and their model compounds.
Among the iron-oxygen species, nonheme iron(III)-
hydroperoxo intermediates have shown an interesting ampho-
3,4
teric reactivity in electrophilic and nucleophilic reactions,
compared to the nucleophilic reactivity of iron(III)-peroxo
5
species and the electrophilic reactivity of iron(IV)-oxo spe-
2
cies. Other metal-hydroperoxo complexes have also shown
III
2+
[(TMC)Fe (OOH)]
(1, TMC = 1,4,8,11-tetramethyl-
reactivities as electrophiles in hydrogen atom transfer (HAT)
and oxygen atom transfer (OAT) reactions and as nucleophiles
3a
1,4,8,11-tetraazacyclotetradecane), with 2-PPA and its deriv-
atives to address the following fundamental questions: (1) Are
the HAT and NA pathways competing to each other in the
6
in aldehyde deformylation reactions. However, chemical
properties and reactivities of the nonheme metal-
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Table 1. Rate Constants, k2(H) and k2(D), Determined in the Reac-
1
2
3
4
5
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tions of 1 with 2-PPA and α-[D1]-2-PPA at Various Temperaturesa
k2(H) and k2(D), M–1 s–1
temp.
(K)
entry
k2(H)/k2(D)
2-PPA
α-[D1]-2-PPA
1
2
3
4
5
263
268
253
248
243
3.0
1.7
1.0
3.0
1.7
1.0
1.0
1.0
1.0
1.0
1.1
7.3 × 10–1
4.3 × 10–1
2.9 × 10–1
1.9 × 10–1
1.7 × 10–1
1.6 × 10–1
1.6 × 10–1
1.5 × 10–1
1.4 × 10–1
1.4 × 10–1
7.3 × 10–1
4.0 × 10–1
2.3 × 10–1
1.1 × 10–1
6.1 × 10–2
3.4 × 10–2
1.8 × 10–2
8.0 × 10–3
3.8 × 10–3
1.5 × 10–3
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238
233
228
223.
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203
1.3
1.7
2.8
4.7
8.9
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93
aSee experimental conditions in SI, Experimental Section.
Figure 1. (a) UV-vis spectral changes observed in the reaction of 1
(0.50 mM) and 2-PPA (5.0 mM) in acetone/trifluoroethanol (v/v =
3:1) at 253 K. Insets show the time profiles for the decay of 1 in the
reactions of 1 (0.50 mM) with 2-PPA (5.0 mM; blue circles) and α-
[D1]-2-PPA (5.0 mM; red circles) at 253 K (left panel) and 1 (0.50
mM) with 2-PPA (20 mM; blue circle) and α-[D1]-2-PPA (200 mM;
red circle) at 203 K (right panel). (b) Plots of pseudo-first-order rate
constants (kobs) vs concentrations of 2-PPA (blue circles) and α-[D1]-2-
PPA (red circles) in the reactions of 1 with 2-PPA and α-[D1]-2-PPA
at 203 K.
deformylation of aldehydes by 1 (i.e., HAT vs NA in Scheme
1)? (2) If yes, what are the reaction conditions that modulate
the reaction pathways? (3) Then, why (and how) are the reac-
tion pathways changed depending on the reaction conditions?
We now report that the reaction pathway in the deformylation
of aldehydes by 1 varies depending on the reaction conditions,
such as temperature and substrate, and tunneling is an im-
portant factor that triggers the HAT reaction at low tempera-
ture. To the best of our knowledge, the present study reports
the first example of tunneling effect that plays a significant role
in the activation of substrate C-H bonds by a nonheme
iron(III)-hydroperoxo complex.
Figure 2. Eyring plots of ln(k2/T) vs T–1 for the deformylation reac-
tions of 2-PPA (blue circles) and α-[D1]-2-PPA (red circles) by 1.
–1 –1
the same (i.e., 1.0 M
s at 253 K) (Table 1, entry 3; Figure
S3b). In addition, product analysis of the 2-PPA and α-[D1]-2-
PPA reaction solutions revealed the formation of acetophe-
none as the product (85(4)% yield).
We also performed the reactions of 1 with 2-PPA and α-
[D1]-2-PPA in the temperature range from 203 to 263 K; the
k2(H) and k2(D) values were determined from the slopes of the
linear plots of the pseudo-first-order rate constants vs concen-
trations of 2-PPA and α-[D1]-2-PPA (Table 1; Figure S3).
First, the k2(H) and k2(D) values determined at temperatures
above 248 K were the same, giving the k2(H)/k2(D) ratio of 1.0
(Table 1, entries 1 – 4). Interestingly, as the reaction tempera-
ture was lowered, the k2(D) values became smaller than the
k2(H) values, giving the k2(H)/k2(D) ratio of >1, and a large
k2(H)/k2(D) ratio of 93 was obtained at 203 K (Table 1, entry
13; Figure 1b).
The iron(III)-hydroperoxo complex, 1, was prepared and
3a
characterized according to the published methods. Addition
of 2-PPA to 1 in acetone/trifluoroethanol (v/v = 3:1) at 253 K
under an Ar atmosphere resulted in the decay of 1 with the
IV
2+
concurrent formation of [(TMC)Fe (O)] (Figure 1a). The
IV
2+
[(TMC)Fe (O)] product was characterized using electron
paramagnetic resonance (EPR) spectroscopy and cold-spray
ionization mass spectrometer (CSI-MS) (Supporting Infor-
mation (SI), Figure S1); the yield of [(TMC)Fe (O)] was
~100% based on the absorbance at 820 nm (ε = 400 M cm
for 1). Similarly, 1 reacted with α-[D1]-2-PPA under the iden-
tical conditions, showing that the reaction rate and spectral
changes were the same as those of the reaction of 1 with 2-
PPA (see Figure 1a, inset (left panel); Figure S2); the second-
order rate constants, k2(H) and k2(D), for the reactions of 1 with
2-PPA and α-[D1]-2-PPA, respectively, were determined to be
IV
2+
–1
–1
Further, as the Eyring plots are shown in Figure 2, a linear
correlation of ln(k2(D)/T) vs T–1 was observed in the reaction of
1 and α-[D1]-2-PPA in the whole temperature range (Figure 2,
red circles), affording an activation enthalpy (ΔH‡) of 13 kcal
8
–1
–1
–1
mol and an activation entropy (ΔS‡) of –8.5 cal mol K .
Interestingly, in the reaction of 1 and 2-PPA, a linear correla-
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Scheme 3. Proposed Mechanisms for the Reactions of 1
with 2-PPA and α-[D1]-2-PPA
Scheme 2. Reactions of 1 with 2-PPA and α-[D1]-2-PPA
Carried Out in the Presence of 18O2 and CCl3Br
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tion of ln(k2(H)/T) vs T–1 was observed at temperatures above
248 K (Figure 2, blue circles) but curved from 248 K to 233 K.
At temperatures below 233 K, the reaction rates, k2(H), were
temperature-independent (Figure 2, blue line). It is noted that
the temperature insensitivity of the reaction rate with a large
k2(H)/k2(D) ratio is the indication of the involvement of tunnel-
larly, when the reactions of 1 with 2-PPA and α-[D1]-2-PPA
were carried out in the presence of CCl3Br at 213 and 253 K,
we observed the formation of a brominated 2-PPA product
only in the reaction of 1 and 2-PPA at 213 K (Scheme 2B;
Figures S7 and S8). Other reactions, such as the reaction of 1
and 2-PPA at 253 K and the reactions of 1 and α-[D1]-2-PPA
at 213 and 253 K, did not yield the brominated 2-PPA prod-
uct but acetophenone as the product (Scheme 2B; Figures S7a
9-11
ing (vide infra).
Another substrate probe that we used in this mechanistic
study was 2-methyl-2-phenylpropionaldehyde (2-Me-2-PPA)
(see the structure in Scheme 1); Kumar, Sastri, de Visser, and
their co-workers reported that their Mn(III)-peroxo complex
did not react with 2-Me-2-PPA, since the Mn(III)-peroxo re-
7
acted with aldehyde solely via a HAT pathway. In our study,
18
and S9). Based on the results of the O2 and CCl3Br experi-
ments, we propose that a carbon radical species was generated
however, a linear correlation of ln(k2/T) vs T–1 was observed in
the reaction of 1 and 2-Me-2-PPA (Figure S4 and Table S1);
the low reactivity of 2-Me-2-PPA, compared to that of α-[D1]-
2-PPA, is probably due to a steric effect and/or an electronic
from a H-atom abstraction of 2-PPA by 1 at 213 K (see
13
Scheme 3A). In other reactions, such as the reaction of 1 and
2-PPA at 253 K and the reactions of 1 and α-[D1]-2-PPA at
213 and 253 K, such a carbon radical species was not generat-
ed (see Scheme 3B). We therefore conclude that the reaction of
1 and 2-PPA at 213 K occurs via a HAT pathway (Scheme
3A), whereas the reaction of 1 and 2-PPA at 253 K and the
reactions of 1 and α-[D1]-2-PPA at 253 and 213 K occur via a
NA pathway (Scheme 3B).
o
effect of substrates in nucleophilic reactions (e.g., 2 -CHO for
o
α-[D1]-2-PPA vs 3 -CHO for 2-Me-2-PPA).
The results presented above are interpreted as follows: (1)
In the reactions of 1 with α-[D1]-2-PPA and 2-Me-2-PPA, the
deformylation occurs solely via a NA pathway irrespective of
reaction temperature. (2) In the reaction of 1 and 2-PPA, a NA
pathway is dominant at the temperatures above 248 K, but a
HAT pathway is being involved at the temperature below 243
K and becomes dominant at lower temperatures, affording
large k2(H)/k2(D) values (e.g., k2(H)/k2(D) of 93 at 203 K) (Ta-
ble 1; Figure 1b). Thus, based on the observations of a large
k2(H)/k2(D) ratio and the temperature insensitivity of the reac-
tion rate at low temperatures, we propose that the reaction of
1 and 2-PPA occurs via a H-atom abstraction and tunneling
In conclusion, we have demonstrated that the reaction
pathway in the deformylation of 2-PPA by a nonheme ion(III)-
hydroperoxo complex (1) changes depending on reaction con-
ditions, such as reaction temperature and substrate; (1) a HAT
pathway in the reaction of 1 and 2-PPA at temperatures below
233 K and (2) a NA pathway in the reaction of 1 and 2-PPA at
temperature above 248 K and in the reactions of 1 and 2-PPA
derivatives (e.g., α-[D1]-2-PPA and 2-Me-2-PPA) irrespective
of reaction temperature. More importantly, we have shown
that tunneling plays a significant role in the HAT reaction.
Thus, this study has provided valuable insights into controlling
the reaction pathway by tunneling effect as the third reactivity
paradigm in addition to the thermodynamic and kinetic con-
12
plays a pivotal role in overriding the NA pathway.
We then carried out the reactions of 1 with 2-PPA and α-
18
[D1]-2-PPA in the presence of O2 at 253 K and found that
18
no O was incorporated into the acetophenone product (Fig-
IV
2+
ure S5b) (Scheme 2A); the [(TMC)Fe (O)] product did not
18
contain O either (Figure S6a). Interestingly, when the reac-
tion of 1 and 2-PPA was carried out in the presence of O2 at
213 K, a significant amount of O was found in the acetophe-
none product with the formation of [(TMC)Fe ( O)]
(Scheme 2A; Figures S5d and S6b). However, no O-
incorporation into the acetophenone product was observed in
the reaction of 1 and α-[D1]-2-PPA at 213 and 253 K. Simi-
14
trol. In future study, we will attempt to elucidate the funda-
18
mental aspects of the tunneling effect on the C-H bond activa-
tion of hydrocarbons by nonheme iron-hydroperoxo interme-
diates as well as the detailed mechanisms of the HAT and NA
pathways in the deformylation reaction by the nonheme
iron(III)-hydroperoxo complex, 1.
18
IV 16
2+
18
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(5) Cho, J.; Sarangi, R.; Nam, W. Mononuclear Metal–O2 Complexes
ASSOCIATED CONTENT
Bearing Macrocyclic N-Tetramethylated Cyclam Ligands. Acc. Chem.
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1
2
3
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Supporting Information.
Experimental details, Table S1, and Figures S1 – S9. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(6) (a) Sankaralingam, M.; Lee, Y.-M.; Jeon, S. H.; Seo, M. S.; Cho, K.-
B.; Nam, W. A Mononuclear Manganese(III)–Hydroperoxo Com-
plex: Synthesis by Activating Dioxygen and Reactivity in Electro-
philic and Nuclerophilic Reactions. Chem. Commun. 2018, 54, 1209.
(b) Shin, B.; Sutherlin, K. D.; Ohta, T.; Ogura, T.; Solomon, E. I.;
Cho, J. Reactivity of a Cobalt(III)−Hydroperoxo Complex in Elec-
trophilic Reactions. Inorg. Chem. 2016, 55, 12391. (c) Wang, C.-C.;
Chang, H.-C.; Lai, Y.-C.; Fang, H.; Li, C.-C.; Hsu, H.-K.; Li, Z.-Y.;
Lin, T.-S.; Kuo, T.-S.; Neese, F.; Ye, S.; Chiang, Y.-W.; Tsai, M.-L.;
Liaw, W.-F.; Lee, W.-Z. A Structurally Characterized Nonheme Co-
balt–Hydroperoxo Complex Derived from Its Superoxo Intermedi-
ate via Hydrogen Atom Abstraction. J. Am. Chem. Soc. 2016, 138,
14186. (d) Tcho, W.-Y.; Wang, B.; Lee, Y.-M.; Cho, K.-B.; Shearer,
J.; Nam, W. A Mononuclear Nonheme Cobalt(III)–Hydroperoxide
Complex with an Amphoteric Reactivity in Electrophilic and Nucle-
ophilic Oxidative Reactions. Dalton Trans. 2016, 45, 14511. (e) Kim,
S.; Ginsbach, J. W.; Lee, J. Y.; Peterson, R. L.; Liu, J. J.; Siegler, M.
A.; Sarjeant, A. A.; Solomon, E. I.; Karlin, K. D. Amine Oxidative
N-Dealkylation via Cupric Hydroperoxide Cu-OOH Homolytic
Cleavage Followed by Site-Specific Fenton Chemistry. J. Am. Chem.
Soc. 2015, 137, 2867. (f) So, H.; Park, Y. J.; Cho, K.-B.; Lee, Y.-M.;
Seo, M. S.; Cho, J.; Sarangi, R.; Nam, W. Spectroscopic Characteri-
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AUTHOR INFORMATION
Corresponding Author
wwnam@ewha.ac.kr
fukuzumi@chem.eng.osaka-u.ac.jp
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by the NRF of Korea through CRI
(NRF-2012R1A3A2048842 to W.N) and Basic Science Re-
search Program (2017R1D1A1B03029982 to Y.M.L. and
2017R1D1A1B03032615 to S.F.) and the Grants-in-Aid (no.
16H02268 to S.F.) from MEXT.
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tuitive H-Abstraction Reactivity of Nonheme Fe(IV)O Oxidants with
Alkanes? J. Am. Chem. Soc. 2015, 137, 722.
ture independent rate constant due to complete tunneling that
changes the selectivity and reactivity ordering as shown in Figure 2 is
the first time to be demonstrated in this paper.
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(12) The change of reaction pathway depending on reaction temperature
due to tunneling9-11 has been reported recently in the oxidation of cy-
clohexene by an iron(IV)-oxo porphyrin π-cation radical species:
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Fukuzumi, S.; Nam, W. Tunneling Effect That Changes the Reac-
tion Pathway from Epoxidation to Hydroxylation in the Oxidation of
Cyclohexene by a Compound I Model of Cytochrome P450. J. Phys.
Chem. Lett. 2017, 8, 1557. It should be noted, however, that tempera-
(13) Huang, X.; Groves, J. T. Beyond Ferryl-Mediated Hydroxylation: 40
Years of the Rebound Mechanism and C–H Activation. J. Biol. Inorg.
Chem. 2017, 22, 185.
(14) Schreiner, P. R. Tunneling Control of Chemical Reactions: The
Third Reactivity Paradigm. J. Am. Chem. Soc. 2017, 139, 15276.
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