Deformylation Reaction by a Nonheme Manganese(III)–Peroxo Complex via Initial Hydrogen-Atom Abstraction

Article abstract of DOI:10.1002/anie.201604412

Metal–peroxo intermediates are key species in the catalytic cycles of nonheme metalloenzymes, but their chemical properties and reactivity patterns are still poorly understood. The synthesis and characterization of a manganese(III)–peroxo complex with a pentadentate bispidine ligand system and its reactivity with aldehydes was studied. Manganese(III)–peroxo can react through hydrogen-atom abstraction reactions instead of the commonly proposed nucleophilic addition reaction. Evidence of the mechanism comes from experiments which identify a primary kinetic isotope effect of 5.4 for the deformylation reaction. Computational modeling supports the established mechanism and identifies the origin of the reactivity preference of hydrogen-atom abstraction over nucleophilic addition.

Full text of DOI:10.1002/anie.201604412

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International Edition: DOI: 10.1002/anie.201604412
German Edition: DOI: 10.1002/ange.201604412
Biomimetic Models Very Important Paper
Deformylation Reaction by a Nonheme Manganese(III)–Peroxo
Complex via Initial Hydrogen-Atom Abstraction
Prasenjit Barman, Pranav Upadhyay, Abayomi S. Faponle, Jitendra Kumar,
Sayanta Sekhar Nag, Devesh Kumar,* Chivukula V. Sastri,* and Sam P. de Visser*
Abstract: Metal–peroxo intermediates are key species in the
catalytic cycles of nonheme metalloenzymes, but their chemical
properties and reactivity patterns are still poorly understood.
The synthesis and characterization of a manganese(III)–
peroxo complex with a pentadentate bispidine ligand system
and its reactivity with aldehydes was studied. Manganese(III)–
peroxo can react through hydrogen-atom abstraction reactions
instead of the commonly proposed nucleophilic addition
reaction. Evidence of the mechanism comes from experiments
which identify a primary kinetic isotope effect of 5.4 for the
deformylation reaction. Computational modeling supports the
established mechanism and identifies the origin of the reactivity
preference of hydrogen-atom abstraction over nucleophilic
addition.
been developed that have a ligand architecture suitable for
studies in solution but have a coordination sphere that
resembles enzyme analogues and consequently may give
insight into the chemical and spectroscopic properties of
enzymatic intermediates and their reactivity patterns.[4]
In the past few years, several biomimetic metal–peroxo
adducts of iron and manganese have been prepared and
characterized with UV/Vis, electronic absorption, electron
paramagnetic resonance (EPR), and X-ray absorption spec-
troscopy techniques.[5,6] Furthermore, reactivity patterns with
model substrates were studied, which showed that these
metal–peroxo species mainly react through nucleophilic
addition reactions.[7,8] Recently, a nonheme manganese(III)–
peroxo complex with cyclam-type ligand was spectroscopi-
cally characterized with electronic absorption, EPR, and X-
ray absorption techniques. Moreover, the complex was shown
to react with manganese(II) chloride to form manganese-
(IV)–oxo and manganese(III)–hydroxo complexes.[9]
Synthetic metal–peroxo complexes are known to react
with aldehydes efficiently in a proposed nucleophilic reaction
mechanism. However, an alternative mechanism, not consid-
ered previously, concerns a rate determining hydrogen-atom
abstraction from the a-position prior to oxygen-atom transfer.
Recent work on metal–bispidine ligand systems showed that
these complexes react efficiently with substrates through
hydrogen-atom abstraction, owing to their rigid ligand frame-
work, and reaction rates could be monitored effectively over
a broad temperature and concentration range.[10] Therefore,
we decided to investigate the relative reactivity of the
[MnIII(L1)(O2)]+ complex (Scheme 1) with aldehydes and
study the possible nucleophilic addition versus hydrogen-
atom abstraction mechanisms. In particular, we report the
synthesis and characterization of a novel side-on manganese-
(III)–peroxo complex with a pentadentate bispidine N5
ligand, [MnIII(L1)(O2)]+ (1),[11] Scheme 1, and study its
reactivity patterns with 2-phenylpropionaldehyde (2-PPA)
and its a-deuterated form.
T
he chemistry of metal–dioxygen intermediates has
attracted interest in the field of biological as well as
bioinorganic chemistry communities for many decades.
These complexes are key intermediates in the catalytic
cycles of metalloenzymes that activate and utilize molecular
oxygen for vital biological processes in the human body,
including the metabolism of drugs and the biosynthesis of
hormones.[1] Although many metalloenzymes use iron as the
central cofactor, several actually use manganese instead.
Biologically active manganese ions are included, for instance,
in the oxygen-evolving complex of photosystem II,[2] but also
in superoxide dismutase that catalyzes the detoxification of
superoxide and hydrogen peroxide to water.[3] The manga-
nese–peroxo intermediate has been postulated as an impor-
tant intermediate in these catalytic cycles; however, as it is
short-lived, there currently is no experimental evidence
available. Therefore, synthetic biomimetic models have
[*] P. Barman, S. S. Nag, Dr. C. V. Sastri
Department of Chemistry, Indian Institute of Technology Guwahati
Assam, 781039 (India)
E-mail: sastricv@iitg.ernet.in
The starting manganese(II) complex, [MnII(L1)(ClO4)2]2+
(2), was synthesized by reacting MnII(ClO4)2·2CH3CN with
the pentadentate bispidine ligand (L1) in CH3CN under an
argon atmosphere, in analogy to previously reported proce-
dures.[12] Addition of 10 equivalents of H2O2 to a colorless
solution containing [MnII(L1)(ClO4)2]2+ (2; 2 mm) and trie-
thylamine (TEA; 2.5 equivalents) in an acetonitrile solution
at 158C afforded a blue intermediate (1) with an absorption
band at 605 nm (e = 270 Lmolꢀ1 cmꢀ1; with a half-life of about
60 minutes (Figure 1a; see the Supporting Information for
experimental details). The blue intermediate is characterized
with various spectroscopic techniques including UV/Vis, high-
P. Upadhyay, J. Kumar, Dr. D. Kumar
Department of Applied Physics, School of Physical Sciences
Babasaheb Bhimrao Ambedkar University
Lucknow, 226025 (India)
E-mail: dkclcre@yahoo.com
A. S. Faponle, Dr. S. P. de Visser
Manchester Institute of Biotechnology and School of Chemical
Engineering and Analytical Science, The University of Manchester
131 Princess Street, Manchester M1 7DN (UK)
E-mail: sam.devisser@manchester.ac.uk
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under
http://dx.doi.org/10.1002/anie.201604412.
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Figure 2. Kinetics of the reaction of 1 with 2-PPA: a) UV/Vis spectral
changes of 1 (2 mm) upon addition of 2-PPA (160 mm) in the presence
of TEA (5 mm) and hydrogen peroxide (20 mm) in CH3CN at 158C.
Inset: time course of the absorbance at 605 nm. b) Plot of kobs against
the concentration of 2-PPA and a-[D1]-PPA (ca. 90%, D-enriched) and
the derived second-order rate constant for the reaction of 2 mm 1 with
*
Scheme 1. Reactant complex [MnIII(L1)(O2)]+ and the possible reactivity
patterns with 2-PPA substrate.
substrate at various concentrations in CH3CN at 158C for 2-PPA (
,
*
blue) and a-[D1]-PPA ( , red).
corresponds to [MnIII(L1)(O2)]+ (Figure 1b). These spectra
are similar to those found by Jackson et al. on an analogous
manganese(III)–peroxo complex.[9]
The nucleophilic and electrophilic character of 1 was then
investigated in a reaction with 2-PPA as a substrate. Previous
work showed that manganese(III)–peroxo complexes react
with aldehydes to give the corresponding deformylated
products by attacking the carbonyl group in a nucleophilic
reaction.[6c,d] Upon addition of 2-PPA to 1 in CH3CN at 158C,
the intermediate decayed immediately and led to acetophe-
none as product (Figure 2a). The pseudo first-order rate
constant of the decay of 1 increased linearly with increasing 2-
PPA concentration, thus giving a second-order rate constant
of 2.74 ꢀ 10ꢀ2 Lmolꢀ1 sꢀ1.
To establish whether the mechanism proceeds through
a nucleophilic attack on the carbonyl group we used 2-methyl-
2-phenylpropionaldehyde (2-Me-2-PPA) as a mechanistic
probe. Upon addition of 2-Me-2-PPA to 1 at 158C, the
intermediate decays at the rate of its natural decay. However,
when the reaction solutions were analyzed with ESI-MS no
deformylated products were observed. These results demon-
strate that the manganese(III)–peroxo does not react with 2-
PPA through a nucleophilic attack on the carbonyl group. As
such, the work contradicts previous studies on the reactivity
of nonheme and heme metal–peroxo complexes with alde-
hydes, that all reported a nucleophilic mechanism.[5b,6a,13]
To find out whether an alternative pathway was possible
starting with an initial hydrogen-atom abstraction, we decided
to investigate the reaction with a-[D1]-PPA. Thus, upon
Figure 1. a) UV/Vis spectra of formation of 1 (2 mm) upon addition of
[Mn(L1)]2+ (2; green line) in the presence of TEA (5 mm) and H2O2
(20 mm) in CH3CN at 158C. Inset: the time trace for the formation the
1. b) ESI-MS spectrum of 1. Inset: the observed isotope distribution
patterns for [Mn(L1)(O2)]+.
resolution electrospray ionization-mass spectrometry (ESI-
MS), and DFT. The ESI mass spectra of 1 exhibit a prominent
ion peak with m/z 678.31, its isotopic distribution pattern
2
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addition of a-[D1]-PPA (ca. 90%, D-enriched) to 1 in CH3CN
ing Information, Figures S15 and S18. Herein, we will focus
at 158C we determined a second-order rate constant of 5.05 ꢀ
10ꢀ3 Lmolꢀ1 sꢀ1 (Figure 2b). Therefore, our kinetics studies
establish the manganese(III)–peroxo complex to react with 2-
PPA via a rate determining hydrogen-atom abstraction
reaction from the a-position with a kinetic isotope effect
(KIE) of 5.4.
To find further evidence of this novel reaction mechanism,
we performed a radical trapping experiment with bromotri-
chloromethane using procedures reported previously.[14]
Addition of 2-PPA to intermediate 1 in the presence of
excess CCl3Br (or CBr4) in CH3CN at 158C, leads to the
formation of a-brominated product of the 2-PPA exclusively,
which was confirmed by NMR analysis (Supporting Informa-
tion). Consequently, our kinetics and reactivity studies clearly
reveal a novel reaction mechanism between manganese(III)–
peroxo complexes with aldehydes starting from an a-hydro-
gen-atom abstraction step.
To gain further insight into the rate determining step for
the reaction of manganese(III)–peroxo with aldehydes, we
decided to follow the experimental work up with a set of
density functional theory calculations using previously
reported procedures.[15] Two pathways were investigated,
namely 1) hydrogen-atom abstraction by 1 from the a-
position of 2-PPA; and 2) nucleophilic attack of the peroxo
group on the carbonyl moiety of 2-PPA. The optimized
geometries of the hydrogen-atom abstraction (5TSHA) and
nucleophilic transition state (5TSNA) are given in the Support-
on the analysis of the results and the understanding as to why
the hydrogen-atom abstraction pathway is favorable. The
hydrogen-atom abstraction barrier is relatively central with
ꢀ
ꢀ
close values of the C H and H O distances and as expected
ꢀ ꢀ
happens with a large imaginary frequency for the C H O
stretch typical for hydrogen-atom abstraction reactions.[16] In
agreement with experimental observation the lowest barrier
is 5TSHA (DE + ZPE° = 23.9 kcalmolꢀ1). By contrast, the
nucleophilic transition state (5TSNA) is well higher in energy
(DE + ZPE° = 28.7 kcalmolꢀ1).
To understand the mechanistic preference of hydrogen-
atom abstraction over nucleophilic addition, we devised
a novel two-parabola curve crossing diagram to explain the
reaction mechanism, which shows analogy to the valence
bond curve crossing diagrams of Shaik.[17] Figure 3 shows
details of the two-parabola curve crossing model. Thus, we
consider the reaction along the reaction coordinate (x) that
starts in the reactants (at x = 0) that is connected to another
local minimum at x = 1 via a reaction barrier. We assume that
the potential energy curve (y) can be described with
a parabola with function yR = ax2 for the reactant complex
and yP = bx2 + cx + d for the products. If we assume that the
transition state for the reaction happens at a reaction
coordinate x = 1= then these two curves will cross at x = 1=
2
2
and using the values for yP(0), yP(1= ), yP(1), and yP’(1), we can
2
derive an equation for the curve crossing energy (DEcross) as
a function of the Franck-Condon energy in the reactants
Figure 3. Two-parabola curve-crossing rationalization of the hydrogen-atom abstraction pathway in the reaction of 1 with 2-PPA. Bond orbital
changes along the pathways highlighted. Dots represent electrons, and a line between two dots is a bond occupied by two electrons. Straight
arrows indicate spin orbitals. Also shown is the VB representation of the alternative nucleophilic intermediate PNA
.
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=
(EFC,R) and the driving force for the reaction (DErp),
C O p-bond move to the carbonyl oxygen atom. The
Equation (1), as defined in Figure 3.
resonance energy for the nucleophilic pathway is one-half of
ꢀ
ꢀ
the sum of the C O and Mn O bonds that are formed, while
a value of EPPA,p=184.7 kcalmolꢀ1 was estimated. Based on
first principles, we estimate the nucleophilic barrier to be
DE°VB,NA = 44.9 kcalmolꢀ1.
3
DEcross ¼ 1= EFC,R þ = DErp
ð1Þ
4
4
As shown previously using valence-bond curve-crossing
diagrams,[17] the actual transition state is below the curve
crossing energy by an amount B (the resonance energy), so
that we can predict the value of the transition state based on
estimates for EFC,R, DErp, and B with Equation (2).
The VB modeling, therefore, predicts that the side-on
manganese–peroxo will react with 2-PPA through preferen-
tial a-hydrogen-atom abstraction rather than via nucleophilic
addition. This is possible thanks to its small redox potential
that enables efficient electron transfer from peroxo to
manganese, which is a lower energy pathway than transferring
DE°
¼ DEcrossꢀB
ð2Þ
VB,HAT
an electron from peroxo to substrate carbonyl. Furthermore,
ꢀ1
We then analyzed the bond breaking and orbital changes
between reactants, transition states and intermediates for the
rate determining reaction step to predict the Franck–Condon
energy between R and R* and give details in Figure 3 in
a valence bond format. These VB schemes were used
previously to predict reactivities and rationalize reactivity
trends.[18,19] Thus, the hydrogen-atom abstraction is accom-
plished through the breaking of the sCH bond of the substrate
leading to atomic 2pC and 1sH orbitals, which energetically is
ꢀ
the C H bond strength of the substrate is only 80.3 kcalmol
and despite the fact that the side-on peroxo will give a weaker
ꢀ
ꢀ
O H bond, actually a strong Mn O three-electron bond is
formed, which gives the reaction to large driving force. By
5
5
ꢀ
contrast, the nucleophilic pathway gains a rather weak C O
bond probably due to stereochemical repulsions of the ligand
substituents interfering with the bond formation, so that this
process overall will cost more energy. Therefore, the side-on
manganese–peroxo with bispidine ligand system will prefer-
entially react via hydrogen-atom abstraction rather than
nucleophilic addition with aldehydes through its availability
of low-energy metal 3d orbitals that can pick up an electron
from the peroxo group. Further research will need to be done
on synthetic and enzymatic manganese and iron–peroxo
complexes, such as the aldehyde deformylating dioxyge-
nases,[20] to find out whether this is a general mechanism.
ꢀ
equal to the bond dissociation energy of the C H bond
2
(BDECH). On the oxidant side of the reaction the pOO,xy
2
p*OO,xy pair of orbitals revert back to atomic orbitals and
will cost an energy EO=O. This will generate two doubly
occupied 2p atomic orbitals, one on each oxygen atom. One of
those 2p electrons on the terminal oxygen atom will form
a bond with the incoming hydrogen atom, while the other
electron is transferred to the 3dyz orbital on Mn. Finally, the
other 2p orbital on oxygen atom O1 will form a three-electron
bond with the 3dxz orbital on manganese and form the pMnO,xz
and p*MnO,xz pair of orbitals. The Franck–Condon energy,
Acknowledgements
therefore, can be described as the sum of BDECH, EO O, and
=
Research support was provided by the Department of Science
and Technology (SERB), India (EMR/2014/000279) to C.V.S.
The National Service of Computational Chemistry Software
(NSCCS) is acknowledged for CPU time to S.d.V. A.S.F.
thanks the Tertiary Education Trust Fund Nigeria for
a studentship. D.K. is the Ramanujan Fellow of the Depart-
ment of Science and Technology, New Delhi (India).
EET. We calculate a BDECH value for the a-position of 2-PPA
of 80.3 kcalmolꢀ1, while the energy difference between the
pOO,xy and p*OO,xy was found to be 129.1 kcalmolꢀ1 in the side-
on manganese(III)–peroxo complex. Finally, the excitation
energy from p*OO,xy to 3dyz was estimated to be 96.6 kcal
molꢀ1. The resonance energy, as before,[17] was taken as one
half of the weakest bonds that are either broken or formed,
ꢀ
ꢀ
which in this case is the sum of the O H and Mn O bond. As
such, we estimate a hydrogen-atom abstraction barrier of
24.5 kcalmolꢀ1, which is in excellent agreement with the DFT
barrier reported above.
Keywords: biomimetic models · density functional theory ·
enzyme models · hydrogen-atom abstraction ·
reaction mechanisms
Subsequently, we investigated the bond breaking and
electron rearrangements for the nucleophilic addition reac-
tion of which we show the VB representation of the product
configuration in Figure 3. The reaction is initiated with the
breaking of the carbonyl p-bond (EPPA,p) as well as the
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4
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lich, Angew. Chem. Int. Ed. 2010, 49, 2622 – 2625; Angew. Chem.
2010, 122, 2679 – 2682.
[20] L. J. Rajakovich, H. Nørgard, D. M. Warui, W.-C. Chang, N. Li,
S. J. Booker, C. Krebs, J. M. Bollinger, Jr., M.-E. Pandelia, J.
Am. Chem. Soc. 2015, 137, 11695 – 11709.
[11] L1 = dimethyl-2,4-di(2-pyridyl)3-(pyridin-2-ylmethyl)-7-benzyl-
3,7-diaza-bicyclo[3.3.1] nonan-9-one-1,5-dicarboxylate.
[12] P. Barman, A. K. Vardhaman, B. Martin, S. J. Wçrner, C. V.
Sastri, P. Comba, Angew. Chem. Int. Ed. 2015, 54, 2095 – 2099;
Angew. Chem. 2015, 127, 2123 – 2127.
Received: May 6, 2016
Revised: June 3, 2016
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Biomimetic Models
Grab the hydrogen first: A combined
spectroscopic, kinetic, and computa-
tional modeling study gives first evidence
of a rate-determining hydrogen-atom
abstraction reaction for aldehyde defor-
mation reactions by nonheme
P. Barman, P. Upadhyay, A. S. Faponle,
J. Kumar, S. S. Nag, D. Kumar,*
C. V. Sastri,*
S. P. de Visser*
&&&& — &&&&
manganese(III)–peroxo complexes (see
picture: Mn brown, C gray, O red, N blue,
H white).
Deformylation Reaction by a Nonheme
Manganese(III)–Peroxo Complex via
Initial Hydrogen-Atom Abstraction
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!