Nickel(II) complexes of a 3N ligand as a model for diketone cleaving unusual nickel(II)-dioxygenase enzymes

Article abstract of DOI:10.1039/c7dt04739h

Diketone substrate bound nickel(ii) complexes of 2,6-bis(1-methylbenzimidazolyl)pyridine have been synthesized and characterized as relevant active site models for unusual diketone cleaving Ni(ii)-dependent enzymes Ni-ARD and DKDO. The average Ni-N_py/benzim bond distances (2.050-2.107 ?) of model complexes are almost identical to the Ni-N_His bond distances of Ni^II-ARD (2.02-2.19 ?). The reaction of these adducts with dioxygen exhibited C-C cleavage with the rate of k_O2, 5.24-73.71 × 10^-3 M^-1 s^-1. The phenyl substituted adduct regioselectively elicits 52% of benzoic acid as the major product.

Full text of DOI:10.1039/c7dt04739h

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Nickel(II) complexes of 3N ligand as a model for diketone cleaving
unusual nickel(II)-dioxygenases enzymes
Ramamoorthy Ramasubramanian,a Karunanithi Anandababu,a Mukesh Kumar,b and
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Ramasamy Mayilmurugana*
www.rsc.org/
Dedicated to Professor Dr. Peter Comba on the occasion of 65th birthday
98, His-140), one glutamate (Glu-102) amino acid residues and two
water molecules in an octahedral geometry. Thus, ARD is the only
The diketone substrate bound nickel(II) complexes of 2,6-bis(1-
methylbenzimidazolyl)pyridine have been synthesized and
characterized as relevant active site models for unusual diketone known example of Ni-(II)-dependent dioxygenase in literature.9
cleaving Ni(II)-dependent enzymes Ni-ARD and DKDO. The average
Ni-Npy/benzim bond distances (2.050 - 2.107 Å) of model complexes
are almost identical to the Ni-NHis bond distances of NiII-ARD (2.02
- 2.19 Å). The reaction of these adducts with dioxygen exhibited
C-C cleavage with the rate of kO2, 5.24 - 73.71 × 10-3 M-1 s-1. The
phenyl substituted adduct regioselectively elicits 52% of benzoic
acid as the major product.
Another enzyme DKDO presents in Acinetobacter johnsonii and
adopted an unusual high spin FeII-tris-histidine motif to break Csp3
-
Csp3 bond using dioxygen (Scheme 1).10 The scheme 1 illustrates the
fundamental difference in the active sites and the choice of
substrate and their subsequent regioselective C-C bond cleavage
using dioxygen.9,10 Though FeII and NiII ARD uses the same scaffold
of amino acid residues (3His-1Glu) and substrate, the FeII-ARD
facilitates the regioselective breaking of C(1)-C(2) and NiII-ARD
affords oxidative cleavage of C(1)-C(2) and C(2)-C(3) bonds of
acireductone substrate using dioxygen.3,10,11
Metalloenzyme plays a crucial role in dioxygen activation for
enzymatic reaction in various living organisms.1 Especially, a class of
non-heme iron enzymes like catechol dioxygenases are capable of
cleaving aromatic C-C bonds by incorporating both the atoms of
dioxygen. The enzymology and biomimetic chemistry of these
enzymes have been studied extensively earlier.2 However,
investigation of oxidative cleavage of the aliphatic C-C bond by non-
heme enzymes have not been well explored and several scientific
questions are unaddressed until today.3 These enzymes include
R2
2
R1
O-
3
1
O
R3
O2
NHis
NHis
NHis
H
NHis
NHis
2O
H
NHis
NHis
2O
(DKDO),4
2,4’
dihydroxyaceto-
H
NHis
NHis
2O
FeII
diketone
dioxygenase
NiII
FeII
H
2O
phenonedioxygenase,5 hydroxyethylphosphonate-dioxygenase6 and
acireductone dioxygenases (ARD)7 which are the subject of
continuous interest. Of them, DKDO and ARD use diketonate type
of substrates and coordinated to FeII/NiII centre. They cleave
aliphatic Csp3-Csp3 bond regioselectively by incorporating dioxygen
effectively. The ARD is found in a variety of species, including
human where it involves in methionine salvage pathway.8 It utilizes
both FeII and NiII centres coordinated to three histidines (His-96, His-
H
2O
H2O
OGlu
OGlu
OH2
Ni-ARD
Fe-ARD
Fe-DKDO
O
O
O
+
CO
O-
O
O
+
R3 O-
R3
O-
/R1
+
R1
R3 O-
R1
O
O
=
=
=
R1
R2
R3
SMe
(CH2)2
OH
H
=
H
R
R2
Me
1,R3
=
=
=
R1
R2
R3
SMe
(CH2)2
OH
H
=
-C2 and -C
C2 3 cleavage
C1
-C
C1 2 cleavage
Scheme 1. Active site structures of diketone cleaving enzymes and mode of
C-C bond cleavage using dioxygen.
aBioinorganic Chemistry Laboratory/Physical Chemistry, School of Chemistry,
Madurai Kamaraj University, Madurai 625021, Tamilnadu, India.
E- mail: mayilmurugan.chem@mkuniversity.org, ramamayil@gmail.com
Biomimetic complexes would provide a better understanding of
mechanistic insights as well as help to design a robust catalyst
inspired by nature. In fact, only a few models have been reported
for FeII and NiII-ARD and DKDO to date. Berreau and co-workers
studied biomimetic models of ARDs, and most of them use
bRadiation Biology and Health Sciences Division, Bhabha Atomic Research Centre,
Mumbai, Maharashtra- 400 085, India.
Electronic Supplementary Information (ESI) available: synthesis and
characterization of complexes, crystallographic and kinetics data are available as
supplementary information. See DOI: 10.1039/x0xx00000xAddress here.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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derivatives of tris(2-pyridylmethyl)amine ligand systems, which
preferred distorted octahedral geometry.12 Similarly, Nunes and co-
workers have shown unpredictably slow reaction of NiII-acac
complex of ethylenediamine over 18 days or 3.5 h 90 °C under air in
water as a preliminary report without any detailed investigations.13
Recently, Limberg and co-workers14 and Fiedler and co-workers15
have reported iron(II) complexes of modified anionic tris-pyrazole
borate, tris(2-phenylimidazol-4-yl)phosphine and its derivatives as
successful models for DKDO. Hence, we envisioned to develop a
bio-inspired model system that exhibits similar chemical
environment to the active geometry of enzymes and their
functions. Thus, we have synthesized differently substituted acacX
(acetyl acetone; X = Me, t-Bu, Ph) adducts of mononuclear NiII-
complex of 2,6-bis(1-methyl-benzimidazolyl)-pyridine16 as relevant
active site mimics for Ni-ARD and NiII-substituted model for DKDO.
The present model complex–adducts are not only duplicating the
function of NiII-ARD but also elegantly act as structural and
functional models for NiII-substituted DKDO. The reaction of these
adducts with dioxygen produces the aliphatic C-C bond breakage
under a mild condition, which is modified by an electronic variation
on the substrate.
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DOI: 10.1039/C7DT04739H
Figure 1. Electronic spectra (1 × 10-4 M); inset: FT-IR spectra and cyclic
voltammetry of 1 - 3 (1 × 10-3 M). TBAP (0. 1 M) was used as supporting
electrolyte. Scan rate: 100 mV s-1.
On recrystallization of complexes in CH3CN, only 2 and 3 were
afforded the single crystals suitable for X-ray diffraction analysis.
The molecular structures of 2 and 3 adopt distorted-octahedral
coordination geometry around NiII-centre via bi-and tri-dentate
coordination of the corresponding β-diketonate and ligand
respectively and a solvent molecule (Figure 2). The Ni-Npy distances
[2, 2.068(3); 3, 2.050(3) Å) are slightly shorter than Ni-Nbenzim bonds
[2.088(3) - 2.107(3) Å]. One of the Ni-Oacac bond distances in 3
[2.057(3) Å] is slightly longer than that of 2 [2.009(2) Å] but other
Ni-Oacac bond distances are almost identical to each other (∼ 2.0 Å).
The solvent molecules CH3CN and H2O are coordinated at longer
bond distances [Ni-N, 2.131(3) and Ni-O, 2.057(3) Å] (Table S1, S2).
This indicates that labile nature and possibly replaced by substrate
bound dioxygen species during catalysis in solution. The Ni-Npy/benzim
bond distances in 2 and 3 are almost identical to the Ni-NHis bond
distances (2.02 - 2.19Å) of NiII-ARD.3, 8, 10
R
R
N
R
N
N
N
N
NiII
N
O
O
N
N
N
N
Et N
CH3CN,
3
O
Sol
+
O
NiClO .6H O
NiCl2
(or)
4
2
R
=
R
Me, t-But, Ph
[Ni(L)(acacMe)(CH3CN)]ClO4
[Ni(L)(acact-but)(CH3CN)]ClO4
[Ni(L)(acacPh)(H2O)]Cl
1
2
N3
N3
3
N1
O3
N6
Ni
N4
N1
N4
Scheme 2. Synthesis of nickel(II) complex-substrate adducts.
Ni
O2
O1
O1
NiII-complexes
O2
The
model
enzyme-substrate
[Ni(L)(acacMe)(H2O)]ClO4 (1), [Ni(L)(acact-Bu)(CH3CN)]ClO4 (2) and
[Ni(L)(acacPh)(H2O)]Cl (3) were synthesised by the reaction of
Ni(ClO4)2 or NiCl2 with ligand and their corresponding acac-substrate
in presence of one equivalent Et3N in CH3CN. The complexes were Figure 2. The molecular structures of 2 (left) and 3 (right). Pov-ray figures
drawn from 50% probability factor of thermal ellipsoids. Hydrogen atoms,
counterions are omitted for clarity.
isolated as orange-brown solid with good yields of 71 - 75%. The
formation of complexes were confirmed by HR-MS in CH3CN 1: m/z,
573.2533 for [Ni(L)acacMeCH3CN]+·2H2O; 2: m/z, 581.2271 for
[Ni(L)(acact-Bu)]+ and 3: m/z, 679.3042 for [Ni(L)(acacPhCl)]+Na
(Figure S1-S3) and further supported by elemental analysis. The
absorption spectra of 1 - 3 exhibit acac-to-NiII LMCT transitions at
371, 375 and 377 nm respectively, (Figure 1, Table S3). Also, the π-
π* transitions around 355 - 360 nm were noted for all the
complexes. Very similar transitions were observed for DKDO and
their relevant model compounds.12-15 All the complexes have shown
almost identical Ni-Oacac IR stretching frequency around 1600 cm-1
and 1565 cm-1 (Figure 1). Almost a similar quasi-reversible Ni2+/3+
redox couples were exhibited around 0.873 and 0.84 V for 1 and 2
respectively. However, on introducing a more electron releasing
phenyl groups on acac substrate as in 3 results lowering of the
Ni2+/3+ redox potential to 0.771 V (Table 1). This indicates the
decrease in the Lewis acidity of NiII-center in 3 and thus largely
affects the rate of the dioxygenase reaction (cf. below).
The pH of complexes was measured as 1, 5.47; 2, 5.73 and 3,
5.96 in 10% H2O and acetonitrile solution. At this pH range, no
dioxygenations were facilatated. Then, the addition of one
equivalent of Et3N (pka, 11.01) raised pH of solutions to 7.12, 7.26
and 7.41 respectively for 1 - 3, which accelerate dioxygenations.
The dioxygenation reactions of 1 - 3 have been investigated by
monitoring decay of acac → NiII LMCT band around 371 - 377 nm
using one equivalent of Et3N in acetonitrile (Figure 3, S4 – S15;
Table 1) under pseudo-first order reaction condition due to excess
of dioxygen. The decay of LMCT band indicates that breaking of the
aliphatic Csp3-Csp3 bond of the substrate. The complex 1 exhibited
the rate of the reaction kobs, 57.56 × 10-5 s-1. The complex 2 shows a
decrease in the rate of the reaction (kobs, 34.62 × 10-5 s-1) and it is
further decreased significantly for 3 (kobs, 4.25 × 10-5 s-1) than 1 due
to increasing bulkiness as t-Bu and -Ph substituents in substrate.
2 | J. Name., 2012, 00, 1-3
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This is clearly revealing that the steric crowding on acac substrate (Figure S20 - S21). Nevertheless, benzoic acid as a majVoierwpArrotidcluecOtnflioner
DOI: 10.1039/C7DT04739H
influences the rates of dioxygenation reactions considerably. The 3 has been identified by GC-MS. No dioxygen reaction was noticed
kO2 (= kobs/[O2]) values were calculated by including dissolved
oxygen concentration in acetonitrile, 8.1 × 10-3 M-1.17 Almost similar
reactivity but decreased in rates were observed for dioxygenation
of 1 using piperidine (kobs, 55.16 × 10-5 s-1) and pyridine (kobs, 37.84×
10-5 s-1) (Figure S8, S9). This is may be due to the fact of higher and
lower pka values of piperidine (pka, 11) and pyridine (pka, 5.2) and
also N- coordinating bases possibly ligate to nickel(II) center so that
hinders the dioxygenation reaction.
without using Et3N, which is possibly needed to maintain pH ≈ 7.0
to stabilize enol tautomer during dioxygen reaction as similar to
native DKDO enzyme.9,10 In a separate experiment, complex 3 was
reacted with dioxygen in presence of Et3N in CH3CN stirred for 18
hours and products were analyzed and quantified by GC-MS and 1H-
NMR. The GC-MS analysis revealed 52% of benzoic acid, a trace of
benzil which is formed via Lewis acid-promoted migration of
trione12 and unidentified side products (Scheme 3). The CO2 is also
generated during the reaction and trapped as CaCO3 by purging a
headspace gas evolved into a saturated solution of Ca(OH)2, which is
confirmed by νst at 1394 cm-1 for CO32- in IR spectra (Figure S17). On
other hand, the purging of a headspace gas evolved into one
equivalent of aqueous PdCl2 solution resulted in no precipitation of
Pd(0)12 and clearly indicates that absence of CO evolution during the
dioxygenation reaction. The dioxygenation reaction of 3 with an
excess of water (50%) in acetonitrile afforded 40% of benzoic acid
as a major cleavage product, which is similar to those of obtained in
10% of water medium.
O
O
O
O
O
,
O
N
N
N
Et N
O
N
O22, Et33N
-
+
N
+
N
+
CO
CO22
O-
O
+
Ph
Ph
II
N
Ph
Ph
Ph
Ph
N
NiII
CH CN
CH33CN
N
N
Ni
O
O
H
H22O
O
52%
52%
Figure 3. The oxygenation kinetics for the reaction of 2 (6 × 10-4 M) with
saturated dioxygen in acetonitrile at 25 ˚C. (Inset) Time Vs Absorbance at
373 nm.
O
O
Ph
Ph
Ph
Ph
Scheme 3. The reaction of 3 with dioxygen in CH3CN at 25 ˚C.
The kO2 values are in the range of 5.24 - 73.71 × 10-3 M-1 s-1 for 1
- 3 and it follows the order of 1 > 2 > 3 (Table 1). Similarly, the half-
life period of complex-substrate adducts was calculated by using t1/2
= 0.693/kobs and values are in the range of 0.34 - 4.58 h (Table 1).
This trend reveals that on increasing bulkiness of substrates from
methyl to phenyl considerably affects dioxygenation reactions.
Further, this trend is following very similar tendency of the Ni2+/3+
redox potential of complexes, 1 > 2 > 3. This is indicating that higher
Ni2+/3+redox potential results in enhancement of dioxygenation
reactions. Thus, the dioxygen activation capability of complexes not
only affected by steric factor but also tuned by redox potentials.
Interestingly, 10% of water was included in the reaction medium to
mimic aqueous reaction condition as in natural enzymes. A very
similar kinetic change was observed with the almost identical rate
of dioxygenation reactions (kO2, 4.9 - 67.06 × 10-3 M-1 s-1) for 1 – 3
and 41% of benzoic acid were formed as a major product for 3.
However, the rate of dioxygenation reactions is relatively slow as
compared to previously reported analogues diketone substrate,
where electronegative chloro/hydroxy substitutions at active
methylene group accelerated the reactions.12 The cleavage
products of 1 and 2 were not identified by routine workups as they
form inseparable products. But the reaction mixture of 1 shows ESI-
MS clusters corresponds to [NiII(L)(CH3COO)H2O] and
[NiII(L)(CH3CN)2]+Na in 3 hours. However, ESI-MS analysis after 16
hours exhibited formation only bis-complex [Ni(L2).H2O]. On other
hand, the reaction mixture of 2 displayed ESI-MS spectra
corresponds to bis-complex formation even at shorter reaction time
Further to verify the sources of oxygen the 18O2 labeling studies
have been performed for 3 and found to be the incorporation of at
least one labeled oxygen atom into benzoic acid (43%) (Figure S17).
The lower percentage of 18O incorporation into benzoic acid arises
possibly due to exchange of 18O with H2O in CH3CN and during
aqueous workup using HCl as previously observed.18 Similarly, when
the reaction using an excess of H218O is carried out in presence
dioxygen has shown only 3.83% of labeled benzoic acid (Figure S18).
The reaction of 3 without dioxygen in presence of excess of H218O
and H216O exhibited no cleavage product and recovered only the
substrate acacPh.
Table 1. Kinetic dataa and product analysisb for oxidative cleavage
of 1 - 3 in CH3CN
Complex E1/2 (V)
kobs
t1/2
(h)
kO2
Yieldb
(×10-5 s-1)
(×10-3 M-1 s-1)
1
2
3
0.873
57.56 ± 0.01
54.32 ± 0.03c
34.62 ± 0.02
32.25 ± 0.02c
4.25 ± 0.01
0.34
0.56
4.58
73.71 ± 0.01
67.06 ± 0.06c
42.74 ± 0.07
39.81 ± 0.03c
5.24 ± 0.02
ND
-
ND
0.84
ND
-
ND
0.771
-
52%
41%c
3.97 ± 0.03c
4.90 ± 0.04c
akO2 = kobs/[O2]. [O2] in CH3CN, 8.1 × 10-3 M; t1/2= 0.693/ kobs; bIsolated yields;
ND – not detected; c10% of H2O is used.
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These results unambiguously suggesting that C-C bond breakage 1. (a) Z. Chen and G. Yin, Chem. Soc. Rev., 2015, 44, 1V0ie8w3–Ar1ti1cl0e0O;nl(ibne)
M. Sono, M. P. Roach, E. D. Coulter and J. H. Dawson, Chem. Rev.,
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3317–3337.
DOI: 10.1039/C7DT04739H
of 1,3-diketone substrate proceeds via incorporation of dioxygen
mediated by NiII-center and not operating via a hydrolytic type of
reactions. In addition, the reaction of 3 with dioxygen was carried
out in the presence of radical scavenger 1,1,5,5-
tetramethylpentamethylene nitroxide (TEMPO), afforded 49% of
benzoic acid as a major product. This yield is almost similar to that
of obtained without TEMPO. This observation suggesting that the
radical process might not be involved in the present dioxygenation
reaction. We attributed that rate of the reactions is influenced by
steric nature offered by substituents on acac substrate and redox
properties. The mechanism of C-C bond breakage possibly proceeds
through a 5-coordinate transition state as a key intermediate
formed by activation of the substrate as proposed in both DKDO as
well ARDs enzyme catalysis.9,10,19 Further, the Ni(II) centre is only
facilitating to delocalize the electron density to appreciate reaction
via substrate activation by molecular dioxygen (scheme 4). The
time-dependent cyclic voltammograms of 1 - 3 in presences of
dioxygen showed no concomitant changes in Ni2+/3+ redox potential
even after 3 hours (Figure S16).
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N
NiII
N
N N
NiII
N
N
NiII
N
N
N
N
O
N
O
B- H+
N
O
-
O2
NiII
X
,
X
O-
O-
-
O
O
8. (a) T. C. Pochapsky, S. S. Pochapsky, T. Ju, H. Mo, F. Al-Mjeni and
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M. Dang, R. B. Goldsmith, M. J. Maroney and T. C. Pochapsky,
Biochemistry, 2008, 47, 2428–2438.
X
O
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
O
O
H
H
H
O
O
=
X-
B
CH CN
3
2O,
-
Base
9. (a) M. J.Maroney and S. Ciurli, Chem. Rev., 2014, 114, 4206–
4228; (b) A. R. Deshpande, K. Wagenpfeil, T. C. Pochapsky, G. A.
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Berreau, Inorg. Chem., 2008, 47, 10832–10840.
N
NiII
N
N
N
O
N
O
O
N
Path 1
NiII
O-
O-
Ph
O
O
O
H
Ph
C-C
Cleavage
O2
-C
Ph
-Ph
Ph
Ph
H
O2
O
O
O
O
OH-
H+
Path 2
N
N
NiII
N
N
NiII
N
N
N
N
O
N
NiII
B-
Ph
O
O
H-
-
Ph
O
O
O
O
O
-C
O
O
Ph
Ph
Ph
Ph
Ph
Ph
Benzil
Benzoyl
migration
H
O
O
O
H
O
H
Trione
H-
Migration
Scheme 4. Proposed pathway for the reaction of 3 with dioxygen.
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In summary, we synthesized Ni(II)-complexes as biomimetic
models for active site-adducts for Ni-ARD and Ni-substituted DKDO
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cleavage of the aliphatic C-C bond using dioxygen via substrate
activation mechanism without changing the oxidation state of
nickel(II) as similar to the wild-type Ni-ARD enzyme.
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ACKNOWLEDGEMENT
We acknowledge Science and Engineering Research Board (SERB),
New Delhi, Board of Research in Nuclear Sciences (BRNS), Mumbai
and Department of Biotechnology (DBT), New Delhi for funding.
Notes and references
19. S. Hoof, M. Sallmann, C. Herwig, B. Braun-Cula and C. Limberg,
Dalton Trans., 2017, 46, 16792–16795.
4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C7DT04739H
Table of Contents Graphic and Synopsis
Nickel(II) complexes of 3N ligand as a model for diketone cleaving
unusual nickel(II)-dioxygenases enzymes
Ramamoorthy Ramasubramanian,a Karunanithi Anandababu,a Mukesh Kumar,b and
Ramasamy Mayilmurugana*
The diketone substrate bound nickel(II) complexes of 2,6-bis(1-methylbenzimida-
zolyl)pyridine have been synthesized and characterized as a relevant active site mimics for
unusual diketone cleaving Ni(II)-dependent enzymes (Ni-ARD, DKDO). The reaction of adducts
with O2 exhibited C-C cleavage and phenyl substituted adducts regioselectively afforded benzoic
acid major products.
1