Hydrogen by Deuterium Substitution in an Aldehyde Tunes the Regioselectivity by a Nonheme Manganese(III)–Peroxo Complex

Article abstract of DOI:10.1002/anie.201905416

Mononuclear nonheme Mn^III-peroxo complexes are important intermediates in biology, and take part in oxygen activation by photosystem II. Herein, we present work on two isomeric biomimetic side-on Mn^III-peroxo intermediates with bispidine ligand system and reactivity patterns with aldehydes. The complexes are characterized with UV/Vis and mass spectrometric techniques and reaction rates with cyclohexane carboxaldehyde (CCA) are measured. The reaction gives an unusual regioselectivity switch from aliphatic to aldehyde hydrogen atom abstraction upon deuteration of the substrate, leading to the corresponding carboxylic acid product for the latter, while the former gives a deformylation reaction. Mechanistic details are established from kinetic isotope effect studies and density functional theory calculations. Thus, replacement of C?H by C?D raises the hydrogen atom abstraction barriers and enables a regioselectivity switch to a competitive pathway that is slightly higher in energy.

Full text of DOI:10.1002/anie.201905416

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Accepted Article
Title: Hydrogen by Deuterium Substitution in an Aldehyde Tunes the
Regioselectivity by a Nonheme Manganese(III)-Peroxo Complex.
Authors: Prasenjit Barman, Fabian Cantu Reinhard, Umesh Kumar
Bagha, Devesh Kumar, Chivukula Sastri, and Samuel de
Visser
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201905416
Angew. Chem. 10.1002/ange.201905416
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Angewandte Chemie International Edition
10.1002/anie.201905416
COMMUNICATION
Hydrogen by Deuterium Substitution in an Aldehyde Tunes the
Regioselectivity by a Nonheme Manganese(III)-Peroxo Complex**
[
a]
[b]
[a]
[c]
Prasenjit Barman, Fabián G. Cantú Reinhard, Umesh Kumar Bagha, Devesh Kumar, Chivukula
[
a]
[b]
V. Sastri* and Sam P. de Visser*
Abstract: Mononuclear nonheme Mn(III)-peroxo complexes are
important intermediates in biology, and for instance take part in the
oxygen activation by Photosystem II. Herein, we present work on
two novel isomeric biomimetic side-on Mn(III)-peroxo intermediates
with bispidine ligand system and reactivity patterns with aldehydes.
The complexes are characterized with UV-Visible and mass
spectrometric techniques and reaction rates with cyclohexane
carboxaldehyde (CCA) have been measured. The reaction gives an
unusual regioselectivity switch from aliphatic to aldehyde hydrogen
atom abstraction upon deuteration of the substrate leading to the
corresponding carboxylic acid product for the latter, while the former
gives a deformylation reaction. Mechanistic details are established
from kinetic isotope effect studies alongside density functional theory
calculations. Thus, replacement of C–H by C–D raises the hydrogen
atom abstraction barriers and enables a regioselectivity switch to a
competitive pathway that is slightly higher in energy.
of these enzymes include either a manganese-oxo, manganese-
superoxo or manganese-peroxo structure as active intermediate
in their catalytic cycle; however, these structures are short-lived
and few have been characterized experimentally. As
a
consequence, biomimetic models have been created of
manganese(III)-peroxo complexes that have ligand features of
[
4]
the enzymatic structures but lack the protein surrounding.
A number of biomimetic manganese(III)-peroxo complexes have
been synthesized and characterized with spectroscopic
[
5]
methods. In addition, for some of those the reactivity against
[6]
substrates was tested.
Thus, in general side-on
manganese(III)-peroxo reacts via nucleophilic pathways, for
[
7]
instance, through deformylation of aldehydes. Several of these
metal-peroxo complexes have shown unusual reactivity patterns,
whereby, for instance, aldehydes were converted into alkanes in
[
8]
the presence of a switchable H-atom donor. Recent work of
our groups implicated aldehyde deformylation of 2-
phenylpropionaldehyde (2-PPA) to start with an initial and rate
determining hydrogen atom abstraction followed by keto-enol
In general, dioxygen in nature is mostly inert and will not react
with substrates directly. In order to activate oxygen to its more
reactive form, enzymes bind dioxygen on a transition metal
center and through the use of either protons/electrons or a co-
substrate convert it into an high-valent metal-oxo, metal-peroxo,
tautomerization and a deformylation reaction and confirmed the
[9]
electrophilic nature of these oxidants.
Clearly, side-on
manganese(III)-peroxo complexes show a versatile reactivity
pattern with a variety of substrates that is poorly understood,
which encouraged us to look deeper into their reactivity with
substrates.
[
1]
metal-hydroperoxo or metal-superoxo species.
These
intermediates are responsible for the biological transformations
[
2]
of substrates in enzymes. As the active oxygen species in
enzymes are short-lived and highly reactive they are difficult to
study experimentally. Manganese ions are present in the active
site structure of numerous enzymes that utilize molecular
oxygen, and are involved in harmful superoxide detoxification,
[
3]
decomposition of hydrogen peroxide, and water splitting. Most
[
a]
Dr. P. Barman, Mr. U.K. Bagha, Dr. C.V. Sastri
Department of Chemistry
Indian Institute of Technology Guwahati
Guwahati (Assam), India, 781039
sastricv@iitg.ernet.in
Figure 1. Oxidants investigated in this work. DFT optimised structures of
[Mn (O )(L )] (left, X = N, Y = C), and [Mn (O )(L )] (right, X = C, Y = N).
2 2
III
1
III
2
In this work, we report the synthesis and characterization of two
side-on manganese(III)-peroxo complexes (Figure 1) with a
pentadentate N5 bispidine ligand backbone, namely
[b]
Dr F.G. Cantú Reinhard, 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
III
1
+
III
2
+
1
[
2 2
Mn (O )(L )] (1) and [Mn (O )(L )] (2) with L = dimethyl-2,4-
7DN, United Kingdom
di(2-pyridyl)3-(pyridin-2-ylmethyl)-7-benzyl-3,7-diaza-
sam.devisser@manchester.ac.uk
2
bicyclo[3.3.1] nonan-9-one-1,5-dicarboxylate) and L = dimethyl
[
c]
Dr. D. Kumar
2,4-di(2-pyridyl)-3-benzyl-7-(pyridin-2-ylmethyl)-3,7-
Department of Applied Physics
School of Physical Sciences
Babasaheb Bhimrao Ambedkar University
Lucknow, India, 226025
[9-11]
diazabicyclo[3.3.1]
nonan-9-one-1,5-dicarboxylate).
Treatment of a colorless solution of the manganese(II) precursor
with 10 equivalents of and triethylamine (TEA; 2.5
equivalents) in CH CN at 15 ºC results in the formation of a blue
2 2
H O
dkclcre@yahoo.com
3
[
10]
and brown intermediate for 1 and 2, respectively. The identity
of complexes 1 and 2 was confirmed from ultraviolet–visible
absorption spectroscopy (UV-Vis) and electrospray ionization-
[
**]
Research support was provided by the Department of Science and
Technology (SERB), India (EMR/2014/000279) to CVS. SdV and
CVS thank the British Council for a UK-India Research Initiative
grant (DST/INT/UK/P-151/2017). FC thanks the Conacyt Mexico for
[9,10]
mass spectrometry (ESI-MS) studies.
Few metal-peroxo
a
studentship. DK acknowledges financial support from the
Department of Biontechnology, New Delhi
BT/PR14510/BID/07/334/2010)
oxidants have been reported that react via hydrogen atom
abstraction reactions, therefore, we decided to extend our work
to other substrates to evaluate the factors responsible for such
(
Supporting information for this article is given via a link at the end of
the document.
1
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Angewandte Chemie International Edition
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COMMUNICATION
unique reaction pathways. As such we investigated the reactivity
of complexes 1 and 2 with cyclohexane carboxaldehyde (CCA)
as it is a classical substrate used in several reactivity studies by
manganese(III)-peroxo complexes and generally gives
-[D
1
]-CCA with 1 were 50 times faster when compared with
parent CCA and implicated an effective KIE = 0.02. The product
analysis by NMR revealed that the product for the reaction of -
[D ]-CCA with 1 was cyclohexane carboxylic acid (Scheme 1)
1
rather than the expected cyclohexanone. This clearly indicates a
regioselectivity switch for hydrogen atom abstraction from the -
position of substrate to the aldehyde hydrogen atom instead.
The observed second-order rate constants for the reaction of -
1
[D ]-CCA with 1 and 2 were 3.37 M s and 1.16 M s ,
respectively. These observed trends are in contrast to those
[
7d,12]
cyclohexanone as product.
Upon addition of 40 equiv. of CCA to 1 in CH
3
CN at 15 ºC, the
intermediate decayed immediately and led to cyclohexanone as
product (Figure 2). The pseudo-first-order rate constant of the
decay of 1 increased linearly with increasing CCA concentration,
thus enabling us to determine the second-order rate constant of
–
1
–1
–1 –1
–
1 –1
the reaction: k
2
= 0.064 M s (Figure 2b). By contrast, the
obtained for the reaction of 1 and 2 with 2-PPA. As far as we
second-order rate constant for the oxidation of CCA by 2 gave a
1
know, our observation of the oxidation of -[D ]-CCA to its
–1 –1
rate constant of k
2
= 0.291 M s . The rate changes between 1
corresponding acid is the first experimental evidence of a
Mn(III)-peroxo intermediate that reacts via an electrophilic
oxidation reaction. The observed oxidation rates of 1 and 2
and 2 are similar to those reported previously for the oxidation of
[
9]
2-PPA.
IV
1
2+
follow a similar trend as shown previously for [Mn (O)(L )]
IV
2 2+ [10]
versus [Mn (O)(L )] .
This unique regioselectivity switch
observed here may be the result of two competing pathways that
are close in energy and whereby deuteration reverses the
ordering of the transition states and hence the product
distributions as seen, for instance, in the hydroxylation of
ethylbenzene versus ethylbenzene-[D10
]
with iron(IV)-oxo
[
13]
complexes.
Scheme 1. Products obtained for the reaction of 1 and 2 with substrates.
In order to substantiate our hypothesis further, we synthesized
1
(
,2-di-deuterio-cyclohexane carboxaldehyde(~90%, D enriched)
1,2-[D ]-CCA). Upon addition of 40 equiv. of 1,2-[D ]-CCA to 1
CN at 15°C, the corresponding intermediate readily
2
2
in CH
3
decays and enabled us to follow the reaction spectroscopically.
–
2
–1
–1
A second-order rate constant of 4.8  10
M
s
with an
effective KIE of 70 were determined.
To gain insight into the regioselectivity switch and the nature of
the oxidant and reactivity patterns, we decided to complement
our work with a density functional theory study. Although several
density functional theory methods were tested, see Supporting
Information, we will focus on the B3LYP and B3LYP-D3 results
in the main text only. In general, all methods predict the same
trends and give analogous optimized structures. We then
calculated a reactant complex (Re) of CCA with 1. The geometry
and electronic configuration of the manganese-peroxo complex
changed little upon complexation with CCA. Thereafter, two
hydrogen atom abstraction pathways were investigated, namely
Figure 2. Kinetic studies for the reaction of 1 and 2 with CCA: a) UV-Vis
spectral changes of 1 (2 mM) upon addition of CCA (120 mM) in the presence
of TEA (5 mM) and hydrogen peroxide (20 mM) in CH CN at 15°C. Inset
3
shows the time course of the absorbance at 605 nm. b) Plot of kobs against the
concentration of CCA: second-order rate constant for the reaction of 2 mM 1
(
blue ) and 2 (red ) with various substrate concentrations in CH
c) Plot of kobs against the concentration of -[D ]-CCA (~90%, D enriched) with
mM 1 and 2 in CH CN at 15°C [data for 1 (blue ) and 2 (red ) are given.
3
CN at 15°C.
1
2
3
As previous work reported a rate-determining hydrogen atom
abstraction reaction, we decided to synthesize -[D ]-CCA and
repeat the kinetics experiments with 1 and 2 (Figure 2c).
Surprisingly, upon addition of 40 equiv. of -[D ]-CCA to 1 at
5°C, an enhanced reaction rate as compared to CCA was
observed. The second-order rate constants for the reactivity of
5
1
via transition state TSHA,ald for hydrogen atom abstraction from
5
the aldehyde C–H bond and via transition state TSHA, for

1
hydrogen atom abstraction from the C -H bond of CCA.
1
2
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COMMUNICATION
DG‡
DG‡

ald
DGWertz / DGvibr
DGWertz / DGvibr
rCH: 1.425 {1.406}
rOH: 1.147 {1.173}
rCH: 1.422 {1.447}
rOH: 1.161 {1.155}
1
1
7.8 / 18.6
9.6 / 19.5
18.9 / 18.1
18.6 / 18.0
19.7 / 18.5
rMnO: 1.971 {2.003}
rOO: 1.410 {1.427}
rMnO: 1.995 {2.018}
rOO: 1.439 {1.445}
17.5 / 18.0
5TSHA,
5TSHA,ald

Figure 3. Hydrogen atom abstraction transition states optimized at UB3LYP/BS1 {UB3LYP-D3/BS2} from aldehyde group (left) and C –H bond (right) with bond
lengths in angstroms. The Table gives corrected (Wertz/vibrational) free energies of activation calculated at UB3LYP/BS2//UB3LYP/BS1 level of theory for the two
–1
pathways for hydrogen atom subtraction by 1 from CCA, 1-[D
1
]-CCA and 2-[D
1
]-CCA with values in kcal mol
.
In both cases an end-on manganese-hydroperoxo with
a
the Table in Figure 3. As can be seen from Figure 3, the two
barriers ( TSHA,ald and TSHA,) are within 1 kcal mol from each
other and dependent on the model and calculation procedure
5
5
–1
substrate radical is formed (IHA,ald and IHA,) after hydrogen atom
abstraction. The two hydrogen atom abstraction transition states
are shown in Figure 3 and give the typical features seen
(see Supporting Information for
different methods and basis sets) either TSHA, or TSHA,ald is
a detailed comparison of
[
9]
5
5
5
before. Thus, TSHA,Ald is late with a long C–H distance of 1.425
1.406} Å and a short O–H distance of 1.147 {1.173} Å and with
{
lower in energy. Within transition state theory, the experimental
2
1 1
the hydroperoxo group in end-on configuration as calculated at
the B3LYP/BS1 {B3LYP-D3/BS2} level of theory. As such there
is little effect of changing the basis set on the optimized
geometries of the transition state structures. Although the
optimized geometries have end-on features, actually an intrinsic
reaction coordinate scan (Supporting Information, Figure S23),
shows the structure to connect to the side-on Mn(III)-peroxo
reactant, but upon approach of substrate to oxidant it reorients
rate constant of 6.4  10 M s would correspond to a free
1
energy of activation of 18.4 kcal mol . Therefore, our computed
barriers with vibrational corrections included are in excellent
agreement with the experimental values and also predict the
correct regioselectivity.
With vibrational corrections applied, the lowest free energy of
5
‡
–1
activation is via TSHA, with a DG ,vibr = 18.1 kcal mol , while
‡
the aldehyde hydrogen atom abstraction is DG ald,vibr = 18.6 kcal
mol . As such, the calculations reproduce the experimental
–
1
from side-on to end-on Mn(III)-peroxo without an isomerization
5
barrier. The aliphatic hydrogen atom abstraction barrier ( TSHA,
)
product distributions and predict regioselective hydrogen atom

also is late with similar C–H and O–H distances with respect to
abstraction of the C –H bond. Although the Wertz-corrected free
5
TSHA,ald with distances of 1.422 {1.447} and 1.161 {1.155} Å as
energies point to a reversed regioselectivity, actually upon

calculated at the B3LYP/BS1 {B3LYP-D3/BS2} level of theory,
respectively. In general, late hydrogen atom abstraction
transition states correspond to energetically high barriers,
which indeed is seen for this process and matches the
experimental reaction rates well.
deuteration of the C –H group both models predict a rise of
5
1
5
TSHA, by about 1 kcal mol , while the TSHA,ald barrier drops
[
14]

slightly. As a consequence, singly deuteration of the C –H group
results in a regioselectivity switch from C H hydrogen atom

abstraction to aldehyde hydrogen atom abstraction. On the other
Free energies of activation for the two reaction pathways were
calculated from the Gaussian frequencies using thermal, solvent
and entropic corrections to the enthalpy. As gas-phase
calculated entropies tend to be overestimated with respect to
hand, deuteration of the aldehyde position of substrate raises
5
5
the TSHA,ald barriers, but keeps the TSHA, barriers more or less
the same. The computational trends, therefore, are in agreement
with experimental observation and implicate a regioselectivity
[
15]
experiment, we applied two entropic correction models. Firstly, switch upon deuteration of the -position of CCA substrate. As
[
15]
we used the Wertz correction (model 1) that scales the
reasoned before,
a HAT reaction has a large zero-point
‡
molecular entropy of each compound (DGWertz ). Secondly, the
energy due to the loss of one C–H vibration in the complex. In
–
1
lowest entropy contributions for low vibrational frequencies (<50
general, HAT barriers increase in energy by a few kcal mol
upon deuteration of the transferring hydrogen atom.
–1
‡
[16]
cm ) were ignored from the free energies in model 2 (DGvibr ).
These two different free energies of activation for hydrogen atom
abstraction from the - and aldehyde C–H positions are given in
Thus,
with two competing barriers very close in energy, substrate
3
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Angewandte Chemie International Edition
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COMMUNICATION
deuteration raises the lowest barrier in energy and leads to a
regioselectivity switch.
Valentine, E. I. Solomon, W. Nam, Nature 2011, 478, 502–505; f) D. F.
Leto, S. Chattopadhyaay, V. W. Day, T. A. Jackson, Dalton Trans. 2013,
42, 13014–13025; g) D. Brazzolotto, F. G. Cantú Reinhard, J. Smith-
As shown before, hydrogen atom abstraction reactions often
have barriers that correlate with the strength of the C–H bond
Jones, M. Retegan, L. Amidani, A. S. Faponle, K. Ray, C. Philouze, S.
P. de Visser, M. Gennari, C. Duboc, Angew. Chem. Int. Ed. 2017, 56,
[
17]
that is broken in the process. Therefore, we calculated the C–
8211–8215.

H bond dissociation energy (BDE) of the C –H and Caldehyde–H
[
6]
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bonds from the energy of the substrate with respect to an
isolated hydrogen atom and the substrate radical and find values
–
1
of DG = 72.1 and 79.5 kcal mol . Based on these values, the
reaction should give dominant hydrogen atom abstraction from

the C –H bond as seen for the natural substrate. The reason the
5
5
–1
TSHA, and TSHA,ald barriers are within 1 kcal mol probably is
[
a) R. B. VanAtta, C. E. Strouse, L. K. Hanson, J. S. Valentine, J. Am.
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1
due to electrostatic repulsions between the L ligand protons and
those from the approaching substrate that are stronger in TSHA,
than in TSHA,ald, where the cyclohexane ring is further away from
5
5
the ligand structure.
In summary, a Mn(III)–peroxo complex bearing a pentadentate
bispidine backbone was synthesized and characterized with
various spectroscopic techniques and studied with DFT. We
demonstrate here for the first time that the Mn(III)–peroxo
complex is capable of performing electrophilic oxidation of
substrates through the hydrogen atom abstraction from the C–H
bond of an aldehyde to gives the corresponding acid as a
product.
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[
11]
L
= dimethyl-2,4-di(2-pyridyl)3-(pyridin-2-ylmethyl)-7-benzyl-3,7-diaza-
2
bicyclo[3.3.1] nonan-9-one-1,5-dicarboxylate and L = dimethyl 2,4-di(2-
pyridyl)-3-benzyl-7-(pyridin-2-ylmethyl)-3,7-diazabicyclo[3.3.1] nonan-9-
one-1,5-dicarboxylate).
Experimental Section
Experimental Details see Supporting Information.
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A. S. Borovik, J. Am. Chem. Soc. 2008, 130, 8888–8889.
Keywords: Nonheme • Biomimetic models • Kinetic isotope
effects • Oxidation Reaction • Hydrogen atom abstraction •
Density functional theory
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Angewandte Chemie International Edition
10.1002/anie.201905416
COMMUNICATION
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COMMUNICATION
A combined experimental and
computational study gives the first
evidence of electrophilic reactivity of a
side-on manganese(III)-peroxo
complex. Furthermore, isotopic
substitution of substrate changes the
regioselectivity of the reaction and the
product distributions.
Prasenjit Barman, Fabián G. Cantú
Reinhard, Umesh Kumar Bagha,
Devesh Kumar, Chivukula V. Sastri* and
Sam P. de Visser*
Page No. – Page No.
Hydrogen by Deuterium Substitution
in an Aldehyde Tunes the
Regioselectivity by a Nonheme
Manganese(III)-Peroxo Complex
5
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