Keto-Enol Tautomerization Triggers an Electrophilic Aldehyde Deformylation Reaction by a Nonheme Manganese(III)-Peroxo Complex

Article abstract of DOI:10.1021/jacs.7b10033

Oxygen atom transfer by high-valent enzymatic intermediates remains an enigma in chemical catalysis. In particular, manganese is an important first-row metal involved in key biochemical processes, including the biosynthesis of molecular oxygen (through the photosystem II complex) and biodegradation of toxic superoxide to hydrogen peroxide by superoxide dismutase. Biomimetic models of these biological systems have been developed to gain understanding on the structure and properties of short-lived intermediates but also with the aim to create environmentally benign oxidants. In this work, we report a combined spectroscopy, kinetics and computational study on aldehyde deformylation by two side-on manganese(III)-peroxo complexes with bispidine ligands. Both manganese(III)-peroxo complexes are characterized by UV-vis and mass spectrometry techniques, and their reactivity patterns with aldehydes was investigated. We find a novel mechanism for the reaction that is initiated by a hydrogen atom abstraction reaction, which enables a keto-enol tautomerization in the substrate. This is an essential step in the mechanism that makes an electrophilic attack on the olefin bond possible as the attack on the aldehyde carbonyl is too high in energy. Kinetics studies determine a large kinetic isotope effect for the replacement of the transferring hydrogen atom by deuterium, while replacing the transferring hydrogen atom by a methyl group makes the substrate inactive and hence confirm the hypothesized mechanism. Our new mechanism is confirmed with density functional theory modeling on the full mechanism and rationalized through valence bond and thermochemical cycles. Our unprecedented new mechanism may have relevance to biological and biomimetic chemistry processes in general and gives insight into the reactivity patterns of metal-peroxo and metal-hydroperoxo intermediates in general.

Full text of DOI:10.1021/jacs.7b10033

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Article
Keto-enol tautomerization triggers an electrophilic aldehyde
deformylation reaction by a nonheme manganese(III)-peroxo complex
Fabián G. Cantú Reinhard, PRASENJIT BARMAN, Gourab Mukherjee, Jitendra
Kumar, Deep Kumar, Devesh Kumar, chivukula V. sastri, and Sam P. de Visser
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b10033 • Publication Date (Web): 17 Nov 2017
Downloaded from http://pubs.acs.org on November 17, 2017
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Keto-enol tautomerization triggers an electrophilic aldehyde de-
formylation reaction by a nonheme manganese(III)-peroxo complex.
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‡


§
Fabián G. Cantú Reinhard, Prasenjit Barman, Gourab Mukherjee, Jitendra Kumar, Deep Ku-
§
§
,
,‡
mar, Devesh Kumar, Chivukula V. Sastri* and Sam P. de Visser*
‡
The Manchester Institute of Biotechnology and School of Chemical Engineering and Analytical Science, The Universi-
ty of Manchester, 131 Princess Street, Manchester M1 7DN, United Kingdom

Department of Chemistry, Indian Institute of Technology Guwahati 781039, Assam, India
§
Department of Applied Physics, School of Physical Sciences, Babasaheb Bhimrao Ambedkar University, Lucknow
2
26025, UP, India
ABSTRACT: Oxygen atom transfer by high-valent enzymatic intermediates remains an enigma in chemical catalysis. In par-
ticular, manganese is an important first-row metal involved in key biochemical processes including the biosynthesis of mo-
lecular oxygen (through the photosystem II complex) and biodegradation of toxic superoxide to hydrogen peroxide by su-
peroxide dismutase. Biomimetic models of these biological systems have been developed to gain understanding on the
structure and properties of short-lived intermediates but also with the aim to create environmentally benign oxidants. In
this work, we report a combined spectroscopy, mass spectrometry, kinetics and computational study on aldehyde de-
formylation by two side-on manganese(III)-peroxo complexes with bispidine ligands. Both manganese(III)-peroxo com-
plexes are characterized by UV-Vis and mass spectrometry techniques and their reactivity patterns with aldehydes was in-
vestigated. We find a novel mechanism for the reaction that is initiated by a hydrogen atom abstraction reaction, which en-
ables a keto-enol tautomerization in the substrate. This is an essential step in the mechanism that makes an electrophilic
attack on the olefin bond possible as the attack on the aldehyde carbonyl is too high in energy. Kinetics studies determine a
large kinetic isotope effect for the replacement of the transferring hydrogen atom by deuterium, while replacing the trans-
ferring hydrogen atom by a methyl group makes the substrate inactive and hence confirm the hypothesized mechanism. Our
new mechanism is confirmed with density functional theory modelling on the full mechanism and rationalized through va-
lence bond and thermochemical cycles. Our unprecedented new mechanism may have relevance to biological and biomi-
metic chemistry processes in general and gives insight in metal-peroxo and metal-hydroperoxo intermediates in general.
4
Introduction.
cluster. This cluster binds water molecules and reacts
them to one molecule of molecular oxygen with the release
of four protons.
Metalloenzymes are powerful oxidants in nature that
catalyze important reactions for Biosystems. Most of these
1
metalloenzymes utilize iron as their central co-factor, due
to its high natural abundance. Another transition metal in
relatively large abundance in the Earth Crust is manganese
and, as such, Nature has found key uses of it in various
In biomimetic chemistry, synthetic manganese contain-
ing models of SOD and PSII have been created and studied
for their chemical properties and reactivity.
5
2
biological transformations. Thus, manganese complexes
are strong oxidizers and consequently, the active site of
3
superoxide dismutase (SOD) contains a central Mn atom.
SOD is involved in the biodegradation of superoxide radi-
cals and converts them on a manganese center to hydrogen
peroxide. Often SOD enzymes are anchored to a catalase
enzyme that react and detoxify hydrogen peroxide. Anoth-
er biological system with manganese coordination is the
Photosystem II (PSII) active cluster, which contains four
manganese atoms held together with bridging oxygen at-
2
+
oms and a dangling Ca ion in a cubane-type Mn
4
5
O Ca
1
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Figure 1. Manganese(III)-peroxo complexes investigated in this work.
In several of these studies a manganese-peroxo was in-
vestigated and the spectroscopic features of the complexes
was established with UV-Vis, resonance Raman, infrared
absorption, and electron paramagnetic resonance (EPR)
of those points upwards and the other two are aligned
with the xy-plane. Our combined experimental and compu-
tational study gives evidence of a novel reaction mecha-
nism starting with a rate determining hydrogen atom ab-
straction reaction and followed by a reshuttle of the hy-
drogen atom through a keto-enol tautomerization to set up
a low energy nucleophilic attack of peroxo on an olefin
bond of the substrate. Alternative reaction mechanisms
were tested and ruled out. Our observations are confirmed
with computational modelling that rationalized the reac-
tion mechanism with valence bond and thermochemical
cycles.
6
,7
spectroscopy. Furthermore, the reactivity of manganese-
peroxo with respect to substrates was investigated and
efficient conversion to aldehydes into deformylation prod-
8
ucts was obtained. However, the exact details of the
mechanism remain a mystery. Therefore, manganese(III)-
peroxo shows interesting reactivity patterns with sub-
strates that are still poorly understood.
Recently, our groups have shown that bispidine ligated
manganese(III)-peroxo reacts with aldehydes through a
rate determining hydrogen atom abstraction reaction as
evidenced from a large kinetic isotope effect (KIE) for the
Methods.
Experimental procedures. Our procedures are similar
9
replacement of the -hydrogen atom by deuterium. Radi-
to previous studies of our groups and will be summarized
cal trapping experiments and density functional theory
calculations further confirmed the rate determining hy-
drogen atom abstraction and rationalized that this is origi-
nating from a more feasible electron transfer from peroxo
to Mn as compared to substrate carbonyl. The question,
therefore, is how the ligand system of the metal influences
the bifurcation pathways between hydrogen atom abstrac-
tion, i.e. the electrophilic pathway, versus nucleophilic
pathways.
1
0
briefly here. All reagents were obtained from Aldrich
Chemical Co., and obtained at the best available purity and
used without further purification unless otherwise indicat-
ed. Solvents were dried according to published procedures
and distilled under argon prior to use. The piperidone
backbone of the ligands L and L were prepared according
1
1
1
2
12
to a literature protocol, and used to generate the
II
1
II
2
[
Mn (L )](ClO
4
)
2
and [Mn (L )](ClO
4
)
2
complexes. Subse-
quently, the manganese(III)-peroxo complexes were pre-
To test the ligand effect on the bifurcation pathways we
followed our study up with a detailed study on two func-
tionally isomeric pentadentate manganese(III)-peroxo
complexes resulting in different orientations of two pyri-
II
pared by reacting their corresponding Mn systems with
10 equiv. of H and 2.5 equiv. triethylamine (TEA) in
acetonitrile (2 mL) at 15°C.
-Methyl-2-phenylpropionaldehyde (2-Me-PPA) was
synthesized in our laboratory according to a literature
procedure, while -[D
[D ]-PPA, 90%, D enriched) was purchased from RVL
Scientific & Engineering Pvt. Ltd. (Lucknow, India) and the
purity of the compound was confirmed by NMR. All NMR
spectra were recorded in CDCl .
2
O
2
2
3
dine groups with respect to N nitrogen of the bispidine
back-bone. In particular, we synthesized manganese(III)-
peroxo complexes with bispidine ligand systems (see Fig-
13
1
]-2-phenylpropionaldehyde (-
III
1
+
III
2
+
1
ure 1), namely [Mn (O
2
)(L )] (1) and [Mn (O )(L )] (2)
2
1
with
L
=
dimethyl-2,4-di(2-pyridyl)3-(pyridin-2-
ylmethyl)-7-benzyl-3,7-diaza-bicyclo[3.3.1] nonan-9-one-
2
3
1
,5-dicarboxylate) and L = dimethyl 2,4-di(2-pyridyl)-3-
benzyl-7-(pyridin-2-ylmethyl)-3,7-diazabicyclo[3.3.1]
1
nonan-9-one-1,5-dicarboxylate). Thus ligand L has three
Syntheses and characterization. Bispidine ligands
pyridine groups pointing upwards, i.e. along the molecular
(
0.17 mmol) were dissolved in acetonitrile and mixed with
z-axis with the ortho-C–H groups in hydrogen bonding
II
Mn (ClO
4
)
2
•2CH
3
CN salt (0.22 mmol in CH CN) under inert
3
2
distance to the sixth ligand, whereas in ligand L only one
conditions. The pale yellow solution was refluxed over-
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the correct transition. To improve the energetics, single
night and filtered through a 0.2 micron syringe filter and
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layered with ether to obtain a white crystal suitable for X-
ray diffraction. The cif file of the complexes is deposited at
the Cambridge Crystallographic Data Centre (CCDC) with
the following deposition numbers CCDC 1022749 and
point calculations using an LACV3P+ basis set with core
potential on Mn and 6-311+G* on the rest of the atoms was
performed: Basis set BS2. Previously, we showed that little
changes in structure and energetics are obtained for
UB3LYP/BS1 versus UB3LYP/BS2 geometry optimiza-
1
022750. Caution! Metal perchlorate salts are potentially
1
9
explosive and should be handled with excessive care.
tions. Furthermore, the spin state ordering and relative
energies of related manganese complexes were tested us-
2
0
ing a range of alternative DFT and ab initio methods.
Instrumentation. NMR ( H and 13C) spectra were rec-
orded with a Bruker 600/150 MHz spectrometer. UV-Vis
spectra and kinetic measurements were performed with a
Hewlett Packard 8453 spectrophotometer equipped with
either a constant temperature circulating water bath or a
liquid nitrogen cryostat (Unisoku) with a temperature con-
troller. High Resolution electrospray ionization mass spec-
1
Based on the fact that manganese(III)-peroxo has a high-
spin state ground state, we selected B3LYP as computa-
tional method and the results reproduce the experimental
trends well.
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Kinetic isotope effects (KIE) were evaluated computa-
tionally by reevaluating the free energy and vibrational
frequencies of the structures, whereby one or more hydro-
III
1
+
III
2
+
tra (ESI-MS) of [Mn (O
2
)(L )] and [Mn (O )(L )] were
2
21
gen atom is replaced by deuterium. The Eyring kinetic
recorded on a Waters (Micromass MS Technologies) Q-TOF
Premier mass spectrometer by infusing pre-cooled sam-
isotope effect (KIEEyring) is determined from the change in
‡
–
1
free energy of activation (G ) between the system with
ples directly into the source at 15 μL min using a syringe
pump. The spray voltage was set at 2 kV and the capillary
temperature at 80°C.
hydrogen and deuterium atoms, Eq 1, with R representing
the gas constant and T the temperature (298K).
KIEEyring = exp {(G‡
– G‡
)/RT}
(1)
Reactivity Studies. The chemical reactions were moni-
tored in a 10 mm path length cuvette by measuring the UV-
Vis spectral changes of the reaction solutions as a function
of time. The rate constants were determined by fitting the
changes in absorbance of the intermediates under study.
The rate constants were averaged from three individual
experiments, and resulted in a standard deviation of less
than 10% of the given values.
D
H
In addition, we estimated the Wigner kinetic isotope ef-
fect (KIEWigner), which corrects KIEEyring with tunneling cor-
rections Q
t
for the hydrogen and deuterium reactions
through Eq 2 and 3. These equations contain Planck’s con-
stant (h), Boltzmann’s constant (k
B
) and the imaginary
frequency in the transition state ().
Product Analysis. Product analysis was performed on a
WATERS ACQUITY UPLC equipped with a variable wave-
length UV-200 detector. Products were separated on a Wa-
ters Symmetry C18 reverse phase column (4.6  250 mm),
and detection was made at 215 and 254 nm and product
yields were determined by comparison with standard
curves of known authentic samples. All experiments were
done at least in triplicate.
Computational procedures. Density functional theory
(
DFT) calculations were performed on the catalytic reac-
tion mechanism of deformylation of 2-
phenylpropionaldehyde (2-PPA) by [Mn (O )(L )] and
)(L )] following previously tested and bench-
III
1
+
2
III
2
+
[Mn (O
2
1
4
marked procedures. We took initial structures from our
9
previous study, but reoptimized all geometries in Gaussi-
an-09 with a full solvent model as mimicked by a the polar-
ized continuum model (PCM) with a dielectric constant of
3
7.5 mimicking acetonitrile.15,16 These geometry optimiza-
tions utilized the unrestricted B3LYP hybrid density func-
tional method in combination with an LACVP basis set with
core potential on Mn and 6-31G* on the rest of the atoms
1
7,18
(
basis set BS1).
The nature of the stationary points was
confirmed through a frequency calculation also under solu-
tion conditions calculated with the PCM model. All local
minima had real frequencies only, while the transition
states were characterized by a single imaginary mode for
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Page 4 of 14
KIEWigner = KIEEyring  Qt,H/Qt,D
(2)
(3)
the xy-plane and will not interact with the approaching
substrate.
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2
Q
t
= 1 + (h/k
B
T) /24
Results.
In this work we describe the synthesis, characterization
and reactivity patterns of two novel side-on manga-
nese(III)-peroxo complexes with a pentadentate bispidine
III
1
+
III
2
+
N5 ligand, i.e. [Mn (O
2
)(L )] (1) and [Mn (O )(L )] (2),
2
Figure 1. These two ligand systems have their equatorial
pyridine groups either axial or equatorial to the manga-
nese(III)-peroxo group and, hence interact differently with
an approaching substrate. The weak intermolecular inter-
actions separating the two complexes may incur functional
differences due to the way substrate can approach to the
catalytic center and/or the stability of the reactant com-
plex. Therefore, these models may give insight into the
properties and functions of enzymatic catalysts where
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substrate approach is often tightly controlled.
II
2
]2+
Upon addition of 10 equiv. of H
2
O
2
to [Mn (L )(ClO
4 2
)
in the presence of 2.5 equiv. of TEA a brown intermediate
is formed with distinctive absorption features, Figure S2.
The ESI mass spectra of 1 and 2 exhibit prominent peaks
with m/z 678 and an isotope pattern that identify them as
III
1
+
III
2
+
16
[
Mn (O
2
)(L )] and [Mn (O
2
)(L )] . When H
2
O was re-
2
1
8
placed by H
2
O
2
in the reaction mixture, the mass of the
parent ion increased with four units indicative of a dioxy-
gen-bound complex. We attempted to resolve the reso-
nance Raman spectrum of 1 and 2, but due to degradation
of the manganese complexes caused by scattering all our
efforts failed.
Subsequently, we investigated the deformylation behav-
ior of compounds 1 and 2 in a reaction with 2-
phenylpropionaldehyde (2-PPA). This was done by moni-
toring the change in UV-Vis absorption spectra as a func-
tion of time after the addition of substrate. In particular,
the aldehyde deformylation reaction and the mechanism of
substrate activation by side-on manganese(III)-peroxo was
III
1
+
investigated from the reactivity of [Mn (O
2
)(L )] and
III
2
+
Figure 2. Kinetics of the reaction of 2 with 2-PPA. (a) UV-Vis
spectral changes of 2 (2 mM) upon addition of 2-PPA (120
mM) in the presence of TEA (5 mM) and hydrogen peroxide
[Mn (O
2
)(L )] with 2-PPA under the same experimental
reaction conditions (Figure 2). Addition of 2-PPA to 2 in
acetonitrile at 15°C led to immediate decay of the interme-
diate and the formation of acetophenone product as identi-
fied by NMR. The pseudo first-order rate constant for the
decay of 2 increased linearly with increasing concentration
of 2-PPA, and enabled us to measure the second-order rate
(
20 mM) in CH CN at 15°C. The inset shows the time course of
3
the absorbance at 450 nm. (b) Plot of kobs against the concen-
tration of 2-PPA and the derived second-order rate constant
for the reaction of 2 mM 1 and 2 with 2-PPA at various con-
centrations in CH
are given]. (c) Plot of kobs against the concentration of -[D
PPA (~90%, D enriched, ■) with 2 in CH CN at 15°C.
3
CN at 15°C [data for 2 (red •) and 1 (blue •)
–
1
–1 –1
constant: k
2
= 1.42 × 10 M s . For comparison, the sec-
1
]-
III
1
+
ond-order rate constant for the reaction of [Mn (O
2
)(L )]
s . Therefore, it appears
)(L )] reacts with 2-PPA about five times
–
2
–1 –1 9
3
with 2-PPA was 2.74 × 10
M
III
2
+
that [Mn (O
2
To understand the details of the rate determining step
1
faster than the isomeric oxidant with ligand L . These re-
sults were in fact in opposite trend to those obtained in the
reactivity of the corresponding manganese(IV)-oxo com-
III
1
+
III
2
+
for the reaction of [Mn (O
-PPA, we decided to investigate the kinetic isotope effect
KIE) for replacing the -hydrogen atom with deuterium
2
)(L )] and [Mn (O
2
)(L )] with
2
(
(
IV
1
2+
IV
2
2+ 12d
plexes [Mn (O)(L )] and [Mn (O)(L )] .
A possible
Figure 2c). Thus, upon addition of -[D ]-PPA (90%, D-
enriched) to 2 in acetonitrile at 15°C the absorption of the
1
reason for the change in rate constant ordering is the
shape of the ligand system, whereby the L ligand (see Fig-
1
intermediates shows decay from which we determined a
ure 1) has protons pointing upwards toward the peroxo
–2
–1 –1
second-order rate constant of k
2
= 2.67  10
M
s .
2
group, whereas in the L ligand the pyridine moieties are in
Hence, the reaction between 2 and 2-PPA proceeds with a
KIE = 5.3 and it can be concluded that the reaction has a
4
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rate determining hydrogen atom abstraction step. A com-
parable KIE value of 5.4 was determined for the reactivity
tion mechanism of manganese(III)-peroxo with aldehydes
1
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3
4
5
6
7
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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proceeds through a radical intermediate species.
tion of 2-PPA to intermediate 2 in the presence of excess
CBrCl or CBr in acetonitrile at 15°C, leads to the for-
9,23
Addi-
9
difference of 1 with 2-PPA/-[D ]-PPA. Consequently,
1
III
1
+
III
2
+
both [Mn (O
2
)(L )] and [Mn (O
2
)(L )] react with 2-PPA
3
4
through a rate determining hydrogen atom abstraction and
a KIE that deviates from unity and most likely their reac-
tion mechanisms will be similar.
mation of -brominated product of the 2-PPA exclusively,
Scheme 2, which was confirmed by NMR analysis (see
Supporting Information, Figure S4). Consequently, our
radical trapping experiment confirms a radical mechanism
that most likely starts with hydrogen atom abstraction
from the -position of 2-PPA.
To further ascertain that hydrogen atom abstraction
from the -position is key to the reaction mechanism, we
used a mechanistic probe, namely 2-methyl-2-phenyl pro-
pionaldehyde (2-Me-PPA), Scheme 1. Lack of reactivity
with this probe would confirm that the rate determining
step is indeed -hydrogen atom abstraction and no nucle-
ophilic pathway is possible. When we add 2-Me-PPA to 2 at
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
5°C, however, no reaction products are observed and only
II
2
2+
natural decay profiles back to [Mn (L )] are seen due to
the short lifetime of the parent complex in solution (t1/2
5 min). After analyzing the reaction solution with ESI-MS

4
III
2
+
Scheme 2. Reaction of [Mn (O
2
)(L )] with radical
we do not find any evidence of deformylated products.
Consequently, the reactivity study with 2-Me-PPA as a
mechanistic probe confirms that the reaction of 2 with 2-
PPA does not proceed through a rate determining nucleo-
philic attack on the carbonyl group but is initiated by acti-
vation of the -hydrogen atom instead.
trapping substrates.
In conclusion, experimental kinetics studies find that al-
dehyde deformylation starts with a rate determining hy-
drogen atom abstraction from the -position of 2-PPA
leading to a radical intermediate. On the other hand, no
III
2
+
reactivity is observed between [Mn (O )(L )] and sub-
2
strates with weak C–H bonds such as cyclohexadiene. To
understand the reaction mechanisms and explain the reac-
tivity patterns of side-on manganese(III)-peroxo with sub-
strates, a computational study was performed.
Computational modelling. To explain the experimen-
tally obtained results on the reactivity of side-on manga-
nese(III)-peroxo with aldehydes, we embarked on a densi-
ty functional theory study on the possible reaction mecha-
nisms leading to aldehyde deformylation by these com-
plexes. Although we tested many possible mechanisms and
spin states (vide infra), our lowest energy pathway leading
to the first oxygen atom transfer is on a quintet spin state,
Figure 3. The reaction starts with a hydrogen atom ab-
straction via transition state TSHAT1 and forms a manga-
III
2
+
Scheme 1. Reaction of [Mn (O )(L )] with substrates.
2
To test whether the manganese(III)-peroxo can react ef-
ficiently through hydrogen atom abstraction, we decided
to test alternative substrates with weak C–H bonds. Addi-
tion of 1,4-cyclohexadiene to either 1 or 2 did not lead to
decay of the spectroscopic features of the manganese(III)-
nese(II)-hydroperoxo with a radical intermediate I .
1
III
1
+
peroxo structures, Scheme 1, hence [Mn (O
2
)(L )] and
III
2
+
[Mn (O
2
)(L )] are unable to react via desaturation path-
ways. This is surprising as the deformylation reaction de-
scribed above appears to have a rate determining hydro-
III
2
+
gen atom abstraction step from 2-PPA to [Mn (O )(L )] .
2
Moreover, the mechanistic probes ruled out the more
commonly seen nucleophilic attack on the carbonyl group.
Computational modelling, vide infra, established the rea-
sons behind the lack of reactivity towards cyclohexadiene
as resulting from an energetically high second hydrogen
atom abstraction.
Finally, a radical trapping experiment with bromotri-
chloromethane was performed to establish that the reac-
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
5TS1
5TS2
OH: 1.029
OH: 1.503
OO: 1.427
CO: 1.384
OO: 1.841
5TS
1.995
CH: 1.448
OH: 1.163
OO: 1.372
HAT2
i616 cm1
OH: 1.327
OH: 1.106
OO: 1.375
i1466 cm1
i1722 cm
1
i735 cm
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5TSHAT1
III
2
+
Figure 3. Potential energy profile (UB3LYP/BS2//UB3LYP/BS1+ZPE) for oxygen atom transfer from [Mn (O
energies in kcal mol . Transition state structures give distances in angstroms and the imaginary frequency in cm .
2
)(L )] to 2-PPA with
–
1
–1
–
1
In the quintet spin state the barrier is 19.2 kcal mol
drogen atom by deuterium should give a major change in
the value of the free energy of activation, and, hence, a
large kinetic isotope effect, as indeed observed experi-
mentally and reported above in Figure 2. Moreover, the
transition states are late with long C–H and short O–H dis-
tances for TSHAT1 (1.448 and 1.163 Å, respectively), while
the transferring hydrogen atom in TSHAT2 is closer to the
donor hydroperoxo group (1.106 Å) than the accepting
alcohol oxygen atom (1.327 Å).
–1
and the reaction is endothermic by 7.0 kcal mol .
26
Rather than radical rebound, however, as is common in
2
4
typical hydrogen atom abstraction reactions, actually the
hydrogen atom is bounced back to substrate to give the
enol form of substrate and manganese(III)-peroxo via a
subsequent barrier TSHAT2 of 4.5 kcal mol . The enol form
of the reactant ( Reenol) is slightly lesser stable than the
keto form (by 5.4 kcal mol ). Once the reactant is in the
enol-form, the manganese(III)-peroxo part of the reactant
complex attacks the substrate olefin bond via a nucleo-
5
5
–1
5
–
1
In the enol-form, a nucleophilic attack takes place of the
manganese(III)-peroxo group on the double bond through
a C–O bond formation via TS1. This transition state has a
5
–1
5
philic transition state TS1 of 20.4 kcal mol to form the
5
5
–1
radical intermediate I
2
. Energetically, I
2
is close in energy
and Reenol and will react via an O–O cleavage barrier
TS2) to form a manganese(III)-oxo complex and an epox-
) in a highly exothermic process. As such, the com-
putational studies implicate that probably the first steps in
the reaction mechanism will be reversible, but the step
will be irreversible. We also tested the triplet
spin pathway, but found it at least 20 kcal mol higher in
energy along the full profile (see Supporting Information).
relatively large imaginary frequency of i735 cm due to
5
5
to I
1
the simultaneous C–O bond formation and proton transfer
from enol to peroxo. Thus, the peroxo bond weakens to
1.427 Å and a C–O interaction of 1.995 Å is formed.
5
(
5
ide ( I
3
5
5
from I
2
to I
3
–1
5
5
Geometrically, TSHAT1 and TSHAT2 have features typical
of hydrogen atom abstraction barriers seen before for the
reaction of heme and nonheme iron(IV)-oxo with aliphatic
substrates. Both barriers have a large imaginary frequen-
cy, which implies that substitution of the transferring hy-
25
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1
2
3
4
5
6
7
8
9
1
.794
2.130
i139 cm
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5TS5
5
Figure 4. Potential energy profile (UB3LYP/BS2//UB3LYP/BS1+ZPE) for oxygen atom transfer from I
3
leading to products with
–
1
–1
energies in kcal mol . Transition state structure gives distances in angstroms and the imaginary frequency in cm .
1.526
1.990
1.739
2.055
i480 cm
1
i803 cm1
5TS
5TS
nucl
reb
Figure 5. Alternative nucleophilic transition states along the pathway of aldehyde deformylation by side-on manganese(III)-
peroxo as calculated at UB3LYP/BS2//UB3LYP/BS1+ZPE level of theory. Energies are in kcal mol . Transition state structures
–1
–1
give distances in angstroms and the imaginary frequency in cm .
After the transition state the system relaxes to a local
minimum that has a single bond for the C–O interaction
and a radical on the neighboring carbon atom. In addition,
the dioxygen moiety moves from a side-on to an end-on
a low-energy manganese(III)-oxo species. The imaginary
mode in the transition state indeed reflects the O–O bond
cleavage on the one hand and the epoxide ring-closure on
the other hand.
5
conformation. The dioxygen bond cleaves in TS2 at an
The next stage in the mechanism from epoxide to final
deformylation products is given in Figure 4. Thus, the man-
ganese(III)-oxo group abstracts a hydrogen atom in
–
1
energetic cost of 19.8 kcal mol . In this step simultaneous
to the O–O bond breaking an epoxide ring is formed to give
5
I
3
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from the alcohol position of substrate, which breaks the
ceptor groups through long interactions of 1.990 and 1.739
Å.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
epoxide ring to form a complex between manganese(II)-
5
hydroxo and a radical ( I
4
). This step has an almost barri-
Additionally, various other pathways were tested (see
5
5
erless reaction pathway via TS3 and hence the TS3 struc-
Supporting Information) including rebound of the OH
group to the aldehyde carbon atom. However, this OH re-
bound pathway formed a biradical species that is very high
ture could not be properly characterized. An estimate from
–
1
the geometry scan predicts it to be less than 1 kcal mol in
5
energy above the value of I
4
. The subsequent OH rebound
–1
in energy (>50 kcal mol ). Also, OOH transfer from the
leads to simultaneous epoxide ring-opening, C–C bond
5
manganese(II)-hydroperoxo intermediate ( I
1
) to the radi-
cleavage and the formation of formic acid and
5
–1
cal gave a barrier ( TS’reb) of well over 25 kcal mol in en-
ergy. Unfortunately, no subsequent pathways leading to
aldehyde deformylation products could be identified, and
therefore the mechanism was ruled out.
5
methylphenylketone products via transition state TS4.
–
1
The imaginary frequency of i139 cm indeed reflects the
C–C bond breaking and the dissociation of methylphenyl-
ketone from the complex. At the same time the OH re-
bound to the HCO leaving group gives formic acid as the
second product. The overall reaction mechanism has two
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Finally, a mechanism was considered for nucleophilic at-
tack of manganese(III)-peroxo on the secondary carbon
atom of the enol form of 2-PPA. The intermediate formed
highly exothermic reaction steps, namely the formation of
–
1
through this pathway is high in energy (>40 kcal mol
5
the manganese(III)-oxo species ( I
3
) and the final reaction
5
with respect to Reald) and consequently the pathway is
step leading to methylphenylketone and formic acid prod-
ucts. These two steps will be irreversible, although other
reactions steps may be reversible.
ruled out as a viable reaction mechanism.
In conclusion, the lowest energy reaction mechanism for
aldehyde deformylation by manganese(III)-peroxo com-
plexes we have identified starts with hydrogen atom ab-
straction from the -position followed by a reshuttle,
whereby the aldehyde is converted into an enol that can
efficiently react via nucleophilic addition with the side-on
manganese(III)-peroxo.
In summary, the lowest energy pathway for aldehyde de-
formylation by side-on manganese(III)-peroxide of 2-PPA
is -hydrogen atom abstraction followed by reshuttle and
tautomerization to form the enol form and nucleophilic
attack on the olefin bond. Oxygen atom transfer then gives
epoxide that through a low-barrier hydrogen atom transfer
gives formic acid and methylphenylketone products.
Discussion.
To understand the unusual mechanism found for alde-
hyde deformylation by manganese(III)-peroxo complexes,
we analyzed the structure and electronic configuration of
all species in detail and set up valence bond and thermo-
chemical cycles to explain the mechanism and rationalize
the observed reactivities.
Alternative mechanisms. Several alternative pathways
for aldehyde deformylation by side-on manganese(III)-
peroxo complexes were considered, as shown in Figure 5.
Firstly, a direct nucleophilic attack on the carbonyl group
of 2-PPA was considered by side-on manganese(III)-
peroxo. The nucleophilic pathway proceeds via a transition
5
state TSnucl to form the nucleophilic addition intermediate
5
I
nucl (Figure 5). Similarly to the results reported previous-
Thermochemical modelling. Let us first try to predict
the hydrogen atom abstraction barriers for the keto and
enol form of 2-PPA by side-on manganese(III)-peroxo
complexes. The driving force for the hydrogen atom ab-
straction, can be written as the difference in energy be-
tween the C–H/O–H bond that is broken and the O–H bond
formed of the manganese(II)-hydroperoxo, which in gen-
eral terms using substrate SubH is given in Eq 4.
9
‡
ly, this is a high-energy pathway with a barrier of E +ZPE
–
1
=
27.7 kcal mol . The transition state has an imaginary
–1
frequency of i480 cm , which reflects the C–O bond for-
mation between peroxo and carbonyl moieties and simul-
taneously the peroxo moves from side-on to end-on. Clear-
ly, the direct nucleophilic addition from side-on peroxo is
well higher in energy than the hydrogen atom abstraction
–
1
reported above in Figure 4 by at least 8.5 kcal mol and
hence will not be competitive.
III
2
+
II
2
+
•
[
Mn (O
2
)(L )] + SubH  [Mn OOH(L )] + Sub
We also investigated mechanisms starting from the
5
(4)
manganese(III)-hydroperoxo intermediate I and, in par-
1
ticular, looked at OH rebound to form manganese(III)-oxo
5
and 2-hydroxo-2-phenyl-propionaldehyde ( I
6
). Although,
The overall reaction (Eq 4) has an energy corresponding
to the driving force Erp and can be written as the differ-
ence between two bond dissociation free energies (BDFEs)
of the bonds that are formed and broken as defined in Eq 5
– 7. Thus, the BDFE values for the substrate C–H bond of
the aldehyde from of 2-PPA and the O–H bond of the enol
form of 2-PPA are defined as through Eq 5 as BDFECH(2-
PPA) and BDFEOH(2-PPA). Values were calculated from a
full geometry optimization of 2-PPA and 2-PPA with the
5
I is considerably more stable than the epoxide interme-
6
5
diate I
3
reported above. Actually, its formation barrier is
considerably higher in energy. Therefore, despite the fact
5
5
that I
6
is a more stable intermediate than I the preferred
3
reaction intermediate leading to aldehyde deformylation
5
5
will pass I . The OH rebound transition state ( TSreb) has
3
typical features seen before for OH transfer from iron(III)-
27
hydroperoxo complexes, with simultaneous O–O cleav-
age and C–O bond formation in a concerted reaction step.
The OH group is located midway between donor and ac-
•
transferring hydrogen atom removed (Sub ) and the free
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Scheme 3. Reactivity channels of [Mn (OOH)(L )]
II
2
+
energy difference obtained from Eq 5. Subsequently, we
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
calculated the BDFEOH value of the manganese(II)-
hydroperoxo species from its free energy difference with
the manganese(III)-peroxo and a hydrogen atom (Eq 6) as
defined as BDFEOH(Ox).
through hydrogen atom abstraction (top) or O–O bond
cleavage (bottom).
To compare the BDFECH of 2-PPA with typical substrates
used in hydrogen atom transfer reactions, we calculated
the BDFECH of 1,4-cyclohexadiene. Interestingly, the
•
•
SubH  Sub + H + BDFEAH
(5)
–1
BDFECH of 1,4-cyclohexadiene is 61.9 kcal mol , which is
II
2
+
III
2
+
•
midway in between the values for breaking the C‒H bond
of the keto-form of 2-PPA and the O‒H bond of the enol
form. Therefore, theory would expect the first aliphatic
hydrogen atom abstraction of 1,4-cyclohexadiene by side-
on manganese(III)-peroxo to proceed with similar rate
constants as 2-PPA. However, no benzene products are
obtained, which probably means that the subsequent reac-
tion step between manganese(II)-hydroperoxo and the
[
Mn OOH(L )]  [Mn (O
2
)(L )] + H + BDFEOH
(
6)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Grp = BDFEAH(SubH) – BDFEOH(Ox)
(7)
Therefore, the driving force for the hydrogen atom ab-
straction from substrate (Grp), be it in the keto or enol
III
2
+
C
6
7
H radical does not lead to products and a further hydro-
form, by [Mn (O
2
)(L )] can be written in terms of BDFE of
gen atom abstraction is hampered. As side-on manga-
nese(III)-peroxo can abstract a hydrogen atom from 2-PPA
this implies that the cyclohexadiene reaction is prevented
due to an energetically unfavorable second hydrogen atom
abstraction performed by the manganese(II)-hydroperoxo
species. Thus, side-on manganese(III)-peroxo will not react
with aliphatic C‒H bonds through substrate hydroxylation.
donor and acceptor groups, Eq 7. We calculate BDFE val-
–
1
ues of 66.1 and 55.9 kcal mol for hydrogen atom abstrac-
tion from the keto and enol form of 2-PPA, respective-ly. In
agreement with the potential energy landscape in Figure 4
above, these BDFECH values implicate that it is easier to
abstract a hydrogen atom from the enol-form of substrate
than from the -position of the aldehyde.
–
1
To test this hypothesis, we calculated the hydrogen atom
Furthermore, BDFEOH values of 56.6 and 61.1 kcal mol
II
2
+
II
1
+
II
2
+
abstraction energy by [Mn OOH(L )] at either the distal or
proximal oxygen atom, Scheme 3. In particular, we calcu-
lated the diabatic hydrogen atom abstraction energy by the
manganese(II)-hydroperoxo species as a full geometry
were obtained for [Mn OOH(L )] and [Mn OOH(L )] , re-
spectively. Consequently, the driving forces for hydro-gen
)(L )] from 2-PPA in its keto
form is G = 5.0 kcal mol , which is in excellent agreement
with the reaction free energy from Reald to I of 6.2 kcal
III
2
+
atom abstraction of [Mn (O
2
–
1
I
2
+
5
5
optimization
[
of
either
Mn (O(H)OH)(L )] led to dissociation of both complexes.
Proximal donation of a hydrogen atom has a driving force
[Mn (OOH
2
)(L )]
or
1
I
2
+
–
1
mol (Table S3, Supporting Information). Similarly, the
driving force from hydrogen atom abstraction of the enol
–
1
of only 5.2 kcal mol , whereas proximal donation gives an
endothermic BDFE value. Consequently, despite the fact
that manganese(III)-peroxo is able to abstract hydrogen
atoms from weak aliphatic C‒H bonds, the resulting man-
ganese(II)-hydroperoxo is inactive and thermodynamically
unable to react further to give either alcohols or a dehy-
drogenation of substrate.
III
2
+
–1
form of 2-PPA by [Mn (O )(L )] of G = –5.2 kcal mol
2
5
5
matches the free energy difference between Reenol and I
1
reasonably well.
To find out, whether the manganese(II)-hydroperoxo
has other catalytic abilities, we calculated its homolytic
and heterolytic O‒O bond cleavage free energies, see bot-
tom part of Scheme 3. Similar to that seen for nonheme
2
8
iron(III)-hydroperoxo complexes, also here the heterolyt-
–
1
ic cleav-age is high in free energy (>30 kcal mol ) and can
be ruled out. Homolytic cleavage is endothermic by 11.2
–1
kcal mol and, therefore, although a slow process, may be
feasible. As such, the only probably reaction pathway for
manganese(II)-hydroperoxo is homolytic cleavage of the
O‒O bond but will only be possible if the bond that is sub-
sequently formed is strong enough to balance the energetic
cost of the O–O bond breaking mechanism.
Valence bond rationalization of the mechanism. Fig-
ure 6 gives the electronic delineation of the properties a
rate determining reaction barrier should possess and how
9
,21,29
this links to the properties of reactants and products.
Thus, as an example we consider the hydrogen atom ab-
straction reaction from a reactant complex (Re) via a tran-
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Page 10 of 14
sition state (TSHAT) leading to a radical intermediate (IHAT).
stants.31 In addition, we predicted regioselectivity ratios of
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
We now envisage the local minima to reside in a parabolic
function (y, representing the potential energy) along the
reaction coordinate axis (x) for the hydrogen atom ab-
straction with the reactants in the origin (x = 0) and the
radical intermediate at the value x = 1. Mathematically, the
potential energy functions for the reactant and inter-
mediate states can then be described as shown in Eq 8 and
aliphatic hydroxylation versus decarboxylation reactions
in cytochrome P450 peroxygenase enzymes using VB
3
2
models.
Subsequently, we attempted to estimate the Franck-
Condon energies (EFC,Re) from electronic changes along the
reaction mechanism for hydrogen atom abstraction (HAT)
and nucleophilic addition (NA). Figure 7 displays the elec-
tronic changes during the hydrogen atom abstraction step
9
with a, b, c, and d some constants that determine the
shape and curvature of the two parabolic functions.
5
III
2
+
between [Mn (O )(L )] and substrate. Obviously, the
2
hydrogen atom abstraction implies the breaking of a sub-
strate C–H (or O–H in the case of the enol structure) bond
orbital of the substrate (CH) that splits into two atomic
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Re = ax2
y
y
(8)
(9)
2
I
= bx + cx + d
orbitals (2p
C
and 1s each with one electron). Therefore,
H
the value of EFC,Re will contain the energy to break the CH
bond, E(C–H).
It has been shown through valence bond modelling that
the transition state connecting two local minima is located
nearby the curve crossing of the VB curves of the reactant
30
and product wave functions. If we assume the crossing
happens in x = ½ then we can derive a function for the
crossing point of the two curves as a function of two varia-
bles, namely the difference in energy between the two
functions in x = 0, i.e. the Franck-Condon energy in the re-
actants (EFC,Re), and the driving force for the hydrogen at-
om abstraction reaction (Erp), Eq 10.
Ecross = ¼ EFC,Re + ¾ Erp
(10)
Figure 6. Definition of a reaction barrier and its connection to
the vertical excitation energy in the reactants (EFC,R) and the
driving force for the reaction (Erp).
Further, it has been shown that the curve crossing ener-
gy is a fraction B (the resonance energy) above the actual
30
transition state, so that the height of the reaction barrier
can be estimated from the Franck-Condon energy between
the two states in the reactants, the driving force and the
resonance energy. Previously, we used this procedure suc-
cessfully to predict trends in aromatic hydroxylation reac-
tions by iron(IV)-oxo porphyrin cation radical models and
benchmarked the results against experimental rate con-
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0
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9
0
Figure 7. Electronic changes during the hydrogen atom abstraction from substrate by quintet spin side-on manganese(III)-peroxo.
Dots represent electrons and lines between dots a bond orbital.
Figure 8. Electronic changes during the nucleophilic addition from substrate by quintet spin side-on manganese(III)-peroxo. Dots
represent electrons and lines between dots a bond orbital.
–
1
In addition, the peroxo double bond (OO,xy/*OO,xy
)
complex (78.2 kcal mol ), whereas Eexc,Mn was taken as the
breaks with energy E/*OO,xy and the four electrons are re-
distributed over the manganese-peroxo system: Two of
those will pair up with the 3dxz on manganese to form a
energy difference between the *OO,xy and *yz orbitals with
-spin. These values gave us a prediction of EFC,Re,HAT
,
whereas the energy difference of the BDECH of the sub-
2
1
6
2
+
three-electron MnO bond (MnO,xz *MnO,xz ), the third elec-
tron stays as a 2p on oxygen and will pair up with 1s to
strate and the BDEOH of [MnOOH(L )] gave Erp = 8.0 kcal
–1
H
mol . Based on Eq 10 and 11 we estimated the hydrogen
atom abstraction barrier from the keto position as E VB,HAT
= 18.5 kcal mol . For comparison, using transition state
theory, the experimental second-order rate constant of k
‡
form the O–H orbital (O2–H), while the fourth electron is
promoted into the virtual 3dyz orbital on manganese
(Eexc,Mn). Consequently, the Franck-Condon energy should
correlate with the breaking of the MnO,xz orbitals, the for-
mation of the O–H orbital, the breaking of the C–H orbital
and the electron transfer from peroxo to manganese, Eq
–1
2
=
–
1
–1
0.142 M
s
corresponds to a free energy of activation of
‡
–1
G 2,exp = 18.9 kcal mol at 15C. Therefore, our DFT model
predicts the hydrogen atom abstraction barrier perfectly
and explains the contributions from orbital/bond breaking
and forming processes.
1
1.
Finally, we analyze the VB electronic configuration
changes for the nucleophilic reaction of manganese(III)-
peroxo with aldehyde in Figure 8. Similarly to the hydro-
gen atom abstraction step, the OO,xy/*OO,xy orbital couple
is rehybridized and converted back into atomic orbitals,
whereby again two of those electrons will form a new
E
FC,Re,HAT = E(C–H) + E/*OO,xy + Eexc,Mn
(11)
The E(C–H) was determined from the adiabatic values us-
–
1
ing Eq 5 above as 82.6 kcal mol . The E/*OO,xy energy was
determined from the orbital energy difference of the -
type OO,xy and *OO,xy orbitals in the quintet spin reactant
2
1
three-electron bond along the Mn–O axis (MnO,xz *MnO,xz ).
1
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The remaining two electrons originating from the
OO,xy/*OO,xy orbitals are donated into the new -bond for
the C–O interaction. This results in the breaking of the -
bond of the carbonyl (in the keto-form) or olefin (in the
enol-form) bond of the substrate.
Author Contributions
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
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3
3
3
3
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4
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4
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5
5
5
5
5
5
5
5
6

The manuscript was written through contributions of all au-
thors. All authors have given approval to the final version of
the manuscript.
To estimate the VB barrier for the nucleophilic attack,
we again took the energy to break the OO,xy/*OO,xy orbitals
(E/*oo,xy) as well as the energy to break the double bond
(E,Sub), Eq 12. The energy E,Sub for the keto and enol forms
of the substrate was determined from the singlet-triplet
ACKNOWLEDGMENT
FGCR thanks the Conacyt (Mexico) for a studentship. DK &
SPdV thank the University of Manchester for a Targeting GCRF
Applications in Industrial Biotechnology: Enhancing Interna-
tional Collaborations award. Research support was provided
by the Department of Science and Technology (SERB), India
(EMR/2014/000279) to CVS. DK and JK acknowledge finan-
–
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
energy gap in the isolated forms as 83.1 and 77.5 kcal mol
1
,
respectively. That way, we predict a nucleophilic barrier
–
1
cial
support
from
DBT,
New
Delhi
height of 24.8 kcal mol for direct attack of aldehyde on
side-on manganese(III)-peroxo. This value is in good quan-
titative agreement with the DFT barrier reported above
and explains the electrostatic interactions relevant for the
barrier height. It also shows that it will be easier for the
enol form to react through nucleophilic addition then the
keto form as the singlet-triplet energy gap in the double
bond is much higher.
(
BT/PR14510/BID/07/334/2010).
ABBREVIATIONS
SOD, superoxide dismutase; PSII, Photosystem II; DFT, density
functional theory; KIE, kinetic isotope effect; PPA, phe-
nylpropionaldehyde; TEA, triethylamine; ESI-MS, elec-
trospray ionization – mass spectrometry; PCM, polarized con-
tinuum model; VB, valence bond; CHD, cyclohexadiene.
EFC,Re,NA = E,Sub + E/*OO,xy
(12)
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