Oxygen mediated highly efficient cobalt(ii) porphyrin-catalyzed reduction of functional chromones: experimental and computational studies

Article abstract of DOI:10.1039/C9NJ00266A

The highly efficient oxygen mediated reduction of functional chromones with sodium borohydride (NaBH₄) catalyzed by cobalt(ii) porphyrins afforded biologically active chroman-4-ols as the reduction products in 80-98% yields. Oxygen assists in the formation of hydridocobalt(iii) porphyrin as a key intermediate, which releases hydride rapidly to reduce the chromones. Additionally, the correlation between quantum calculation results of the catalysts' conversions, yields, times and logarithms of the rate constants for the oxygen assisted reduction reaction was studied. The mechanism of the reaction was also justified by establishing a quantitative relationship between the rate constant, the α-HOMO orbital of the catalytic complex and the stabilization energy of the complex with oxygen.

Full text of DOI:10.1039/C9NJ00266A

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Oxygen mediated highly efficient cobalt(II) porphyrin-catalyzed reduction of functiVoienwaArlticle Online
chromones: Experimental and Computational studies
DOI: 10.1039/C9NJ00266A
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Poonama,b,*, Pratibha Kumaric, Maria Grishinab, Vladimir Potemkinb, Abhishek Vermad,
Brijesh Rathib,d
aDepartment of Chemistry, Miranda House, University of Delhi, Delhi-110007, India
bSouth Ural State University, Laboratory of Computational Modeling of Drugs, 454080, Russia
cDepartment of Chemistry, Deshbandhu College, University of Delhi, Delhi-110007, India
dLaboratory for Translational Chemistry and Drug Discovery, Department of Chemistry,
Hansraj College, University of Delhi, Delhi-110007, India
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Abstract:
Highly efficient oxygen mediated reduction of the functional chromones with sodium
borohydride (NaBH4) catalyzed by cobalt (II) porphyrins afforded the biologically active
chroman-4-ols as reduced product in 80–98% yields. Oxygen assists in the formation of
hydridocobalt(III) porphyrin as a key intermediate, which releases hydride rapidly to reduce
chromones. Additionally, a correlation between the quantum calculations of catalysts with
conversions, yields, time and logarithms of the rate constants for the oxygen assisted reduction
reaction was studied. The mechanism of the reaction was also justified by quantitative
relationship between the rate constant, α-HOMO orbital of the catalytic complex and the
stabilization energy of the complex with oxygen.
Keywords:
Chromones,
Reduction,
Porphyrins,
Sodium
borohydride,
Hydridocobalt(III)porphyrin, Quantum Calculations
Correspondence
Dr. Poonam
Email: poonam.chemistry@mirandahouse.ac.in
Fax: +91-11-27667437

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Introduction
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Chromones are significant member of the flavonoid family that contributes for pigmentation
in fruits, vegetables, flowers and also flavors in the food materials. Chromones, an important
class of heterocyclic compounds contains two chromophoric units i.e. C=C and C=O, are the
essential component of various natural products and medicinal agents.1 Chromones actively
participate in several plant cycles, including growth regulation, indole acetic acid oxidation
and dormancy inhibition as well as exhibit cytokinin-type behavior and stimulating oxygen
uptake in plant tissue.2 Chromone analogs are abundant in nature and exhibit a variety of
biological activity viz. anti-bacterial,3 anti-oxidant,4 immunostimulators,5 anti-ulcers,6 anti-
inflammatory,7, 13 anti-cancer,8 anti-HIV,9 biocidal,10 wound healing,11 anti-fungal,12 immune-
stimulatory13 and anti- Alzheimer.14
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The reduced analogs of chromones possessing hydroxyl group are known to exhibit various
biological activities with outstanding pharmacological profile.15 In general, when a chromone
(1) is subjected to reduction, various bioactive compounds are obtained such as chroman-4-
ones, chroman-4-ols, chromenes, chromans and chromenols. Recently, Transition-metal-
catalyzed asymmetric hydrogenation of chromones was also explored to give chiral reduced
products.16 As such, a number of reducing agents like DIBAL-H,17 complex hydrides,18
Lithium aluminium hydride,19 NaBH4/Lewis acid,20 NaBH4/excimer laser21 and nickel boride22
have been employed to achieve the reduction of chromones.23 However, these methods suffer
from several drawbacks such as harsh reaction conditions, slower reaction rates, formation of
mixture of products, low yield of products, consumption of catalyst and tedious work up
procedures.
Several catalytic systems based on metalloporphyrins (MTPPs) and metallophthalocyanines
(MPc) have been developed for various oxidative and reductive chemical transformations.24
The excellent electrocatalytic properties, stability of porphyrins25 and their ability to coordinate
to the large number of metal ions26 advocated them as the promising catalysts. The exceptional
catalytic properties of MTPP are due to the diversity of the central metal ions as well as the
substituent groups on the macrocycle. Additionally, the easy recovery and reusability of MTPP
catalysts position them as an attractive alternative to the existing catalytic method for the
efficient reduction reactions. In continuation of our work to highlight and elaborate the role of
MTPPs as reduction-promoting catalyst. Herein, we report an efficient, and rapid reduction of
substituted chromones (1a–1e) using NaBH4 in the presence of a series of MTPP (3a–3f), under

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oxygen at room temperature. Oxygen mediated reduction of the functional chromones VwiewitAhrticle Online
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sodium borohydride (NaBH4) catalyzed by cobalt (II) porphyrins gave chroman-4-ols as
reduced product in 82–99% yields. Oxygen assists in the formation of hydridocobalt(III)
porphyrin as a key intermediate, which releases hydride rapidly to reduce chromones. In
addition, a correlation between the conversions, yields, logarithms of the rate constants and the
times of 98% conversion with the energy of the highest occupied α molecular orbitals (α-
HOMOc) of catalysts was studied by the quantum calculations of the catalyst. We have also
studied the significant spectroscopic properties, computational studies and modeling approach
to explain the mechanism of the reaction.
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Results and Discussion
As a part of our ongoing interest to optimize and extend the scope of MTPP as reduction-
promoting catalysts, we have developed an efficient, and rapid reduction of functionalized
chromones (1a–1e) using NaBH4 in the presence of a series of MTPPs (3a–3f), under oxygen
at room temperature (Scheme 1). The reactions were optimized in the presence of several
MTPP catalysts to achieve selectivity and higher yields of the reduced products, chroman-4-
ol.
O
R1
O
R1
MTPP, O2
NaBH4, MeOH
R2
R2
1a- 1e
O
2a-2e
OH
1a, 2a R1= C6H5, R2= H
1b, 2b R1= H, R2= H
R1
1c, 2c R1= H, R2= C6H5
1d, 2d R1= 4'- CH3C6H5, R2= H
1e, 2e R1= 4'- ClC6H5, R2= H
3a R1= -C6H5, M= Co(II)
N
N
N
N
3b R1= -C6H4-4-CH3,M= Co(II)
3c R1= -C6H4-4-OCH3,M= Co(II)
3d R1= -C6H4-4-NO2,M= Co(II)
3e R1= -C6H5, M= Ni(II)
M
R1
R1
3f R1= -C6H5, M= Fe(III)
MTPP (3a-3f )
R1
Scheme 1. Reduction of chromones 1-2
The reduction of chromone (1a) with NaBH4 in the absence of MTPP (3a–3g) did not yield
chroman-4-ols, even after 24 h (Table 1, entry 1-2). The same reaction in the presence of
cobalt(II) porphyrin (3a) gave chroman-4-ol (2a) in 97% yield under oxygen atmosphere in 10
min, however, this reaction affords chroman-4-ol (2a) in only 65 % after 2 hr in absence of
oxygen (Table 1, entry 3-4). The remarkable effect of oxygen on reduction reaction encouraged
us to study this reaction in detail. The reaction conditions were optimized by varying molar

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ratio of reactant, catalyst and sodium borohydride in the reduction of 1a (Table 1). A noticeable
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decrease in the yield of 2a was observed on reducing the amount of the catalyst (Table 1, entry
5-6). The efficiency of the reductive system improves on increasing the molar ratio of 1a:
NaBH4 from 10: 10 to 10: 30 (Table 1, entry 7-9, 4).
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Table 1. Reduction of 1a to 2a with NaBH4 catalyzed by 3a in methanol under different
reaction conditions
Entry System
Substrate:
Catalyst:
NaBH4
Time
Conv. Yield
k, c-1
t98,
(%)a
of 2a
(%)b
0
min.
1. 1a/3a/NaBH4
1 : 0 : 10
24 h
24 h
2 h
0
-
-
2. 1a/3a/NaBH4/O2
3. 1a/3a/NaBH4
1 : 0 : 10
10 : 1 : 30
10 : 1 : 30
50 : 1 : 250
100 : 1 :500
10 : 1 : 10
10 : 1 : 20
0
0
-
-
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65
0.000154
0.006520
0.002953
0.002379
0.002310
0.001657
0.002601
423
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28
39
25
4. 1a/3a/NaBH4/O2
5. 1a/3a/NaBH4/O2
6. 1a/3a/NaBH4/O2
7. 1a/3a/NaBH4/O2
8. 1a/3a/NaBH4/O2
9. 1a/3a/NaBH4/O2
10 min 98
10 min 83
10 min 76
97
80
70
5 min
50
46c
10 min 63
62
10 : 1 : 25
10 min 79
81
b
c
aBased on substrate 1a. Isolated yields. 2-Phenyl-chroman-4-one[24a] was isolated in 14%
yield.
2-Phenyl-Chroman-4-one was also isolated in 14% yield when the reaction was performed with
equimolar amount of NaBH4 with respect to 1a, indicating the step-wise reduction pathway of
chromones by the present catalytic system. It was observed that the nature of substituents
attached to phenyl ring of Co(II) porphyrin have an impact on the reduction of chromones
(Table 2, entries 1–4). Co(II) porphyrin bearing electron donating group exhibits better
catalytic activity than that of bearing electron withdrawing group, as electron donating group
attached to Co(II) porphyrin ring increases the oxygen binding rate to Co(II) porphyrin, in
comparison to electron withdrawing group which decreases the affinity of Co(II) porphyrin
towards oxygen.27 The reduction was also investigated by employing different MTPPs (3a–3f)
and metal salts (Table 2, entries 1–9). The use of Ni(II) or Fe(III) porphyrin as catalyst yielded
the product 2a in lesser amount than that of using Co(II) porphyrin. This could be attributed to
the more stabilization of reaction intermediate by central cobalt ion than other metal ions (Table
2, entries 5 and 6). Literature studies showed that cobalt-hydride (Co– H) species is mainly

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responsible for the catalytic efficacy of cobalt complexes during the catalytic reduction
reaction. Various examples with porphyrinoid cobalt complexes28 and cobalt hydrides with
non-porphyrinoid ligands have been investigated.29
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Table 2. Reduction of 1 to 2 with NaBH4 in methanol under oxygen using different catalystsa
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Entry Substrate Catalyst Product Time Conv.
(min) (%)b
Yield
of 2
(%)c
97
k, c-1
t98,
min.
1.
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
3a
3b
2a
2a24a
2a
10
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10
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10
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10
98
92
98
98
82
74
58
48
41
98
98
0.006520
0.004210
0.006520
0.002122
0.002858
0.002245
0.001446
0.001090
0.000879
0.006520
10
15
10
31
23
29
45
60
74
10
10
2.
91
96
69
80
71
52
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38
97d
3.
3c
4.
3d
2a
5.
3e
2a
6.
3f
2a
7.
CoCl2
NiCl2
FeCl3
3a
2a
8.
2a
9.
2a
10.
11.
2b
2c24b
3a
96 (cis 0.006520
65%,
trans
31%)
12.
13.
1d
1e
3a
3a
2d24a
2e24a
10
10
99
98
98
96
0.007675
0.006520
8
10
aReaction conditions - substrate : catalyst : NaBH4 = 10 : 1 : 30. Based on substrate 1a.
cIsolated yields. d The yield of 2b was 94 %, 88% and 85% after 1st, 2nd and 3rd run, respectively
when recovered catalyst 3a was used as catalyst.
b
The reduction of 1a to 2a was not very effectual when CoCl2, NiCl2 and FeCl3 metal salts were
used as catalysts in place of metalloporphyrin (Table 2, entries 7–9). Moreover, the metal salt
catalysts decomposed after the reductions and turn into black which could not be reused for
further reduction reactions. On the other hand, Co(II) porphyrin catalysts can be isolated and
recovered easily from the reaction mixture by filtration (little fraction of MTPPs was also
isolated during column chromatographic separation of product from the reaction mixture). The

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in its activity (Table 2, entry 10).
The reduction of substituted chromones 1b-1e was also achieved very well by the present
reductive system (Table 2, entry 10-13), however no major changes in the yield of the product
2b-2e were observed.
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In order to understand the reduction pathway of chromones and the role of reducing agent
(NaBH4) and solvent (MeOH), two significant reactions were performed as shown in Scheme
2. Co(II) porphyrin (3a) catalyzed reaction of 7,8-benzoflavone was carried out using NaBD4
in methanol (CH3OH) and with NaBH4 in CD3OD under oxygen at room temperature (Scheme
2). The results were noticeable, the formation of products 424a and 524a evidently specify that
hydrogen at C-2 and C-4 comes from sodium borohydride and the source of hydrogen at C-3
and C-4(OH) is methanol solvent.
To understand the reaction mechanism clearly, the UV-vis spectral studies of 3b with the
addition of NaBH4 in methanol were carried out under oxygen atmosphere (Fig. 5, supporting
information). The UV-vis spectrum of 3b in methanol under oxygen atmosphere exhibits Soret
band at 430 nm and Q band at 544 nm. These peaks may be ascribed to the generation of
CoTPP-O2 complex by the interaction or oxidation of CoTPP with oxygen in the solution. On
addition of NaBH4 to the solution of 3b initially causes a decrease in the intensity of Soret band
and Q band and gradually the peaks become broad at 420 nm and 535 nm with blue shift.
H
D
O
Ph
H
O
O
Ph
H
O
Ph
H
NaBH4, O2
NaBD4, O2
Co(II)TPP
MeOD
Co(II)TPP
MeOH
D
H
H
DO
D
HO
5
4
7,8-benzoflavone
Scheme 2. Reduction of 7,8-benzoflavone using NaBD4 in MeOH or NaBH4 in MeOD
catalyzed by Co(II)TPP under oxygen.
Steadily, new peaks with growing intensity appear at 410 nm and 525 nm, which could be
attributed to the generation of hydridocobalt(III)porphyrin intermediate. This is in accordance
with the reported UV-vis spectrum of hydridocobalt(III)pthalocyanine species.24
In addition, the formation of hydridocobalt(III)porphyrin, as an intermediate was investigated
1
by carrying out H NMR titrations using Co(II) porphyrin (3b) and NaBH4 in MeOD as a
solvent under oxygen atmosphere. A substantial up-field shift observed for γ-CH3 group
present in the aromatic ring in 3b from δ2.8 to δ2.4 on addition of 1:2 ratio of NaBH4, which
may be ascribed to the shielding effect caused after the formation of

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hydridocobalt(III)porphyrin intermediate (Fig. 1-3, supporting information). OnDOadI: d10i.t1i0o39n/Co9NfJ00266A
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NaBH4 disappearance of aromatic protons and β-pyrrolic protons from their respective
1
positions [peaks in H NMR of 3b: δ 8.21(d) J=9.6 Hz Hα (aromatic), δ8.23(d) J=9.6 Hz
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Hα’(aromatic), δ8.23(d) J=6.4Hz Hβ (aromatic), δ8.23(d) J=6.4 Hβ’ (aromatic), β-pyrrolic
protons δ9.3(s)] were also observed (Fig. 3, supporting information).
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As per results, the use of oxygen has marked effect and outstanding contribution on the
acceleration of reduction reaction using cobalt(II) porphyrins. It makes reaction superfast with
complete conversion of substrate and regeneration of catalyst. It is believed that the reduction
of 1 proceed initially via the formation of O2-Co(II)porphyrin complex 6 (Scheme 3). It has
been known that transition metal porphyrins weakly interacts with oxygen and act as a
promising molecular catalysts for redox reactions.30 In presence of sodium borohydride
(NaBH4), the weak interactions between O2 and Co(II)porphyrin complex 6, cleaved to
generate hydridocobalt(III)porphyrin species 7.31
Co(II)TPP
O
R1
R2
3
O2
O2
H
HO
MeOH
2
O2 Co(II)TPP
O2
6
H
H
O
O
R1
R2
BH4
O2
MeOH
B(OMe)3
BH3
3H2
Chroman-4-one
H Co(III)TPP
MeOH
7
O
R1
R2
1
O
Scheme 3. Proposed mechanism for the reduction of substituted Chromones (1)
Unfortunately, the corresponding hydride species is not isolatable in cobalt porphyrins. Similar
type of formation of hydridocobalt(III)porphyranoid species using reducing agents are reported
in literature.32 Oxygen Assist in the homolytic cleavage of H-Co(III)TPP 7 and the release of
Hydrogen radical and regeneration of 6. Therefore, stepwise reduction of α,β-conjugated
carbonyl system present in chromones takes place through radical mechanism by

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hydridocobalt(III)porphyrin intermediate to give chroman-4-one and 2, respectively. This
addition is in accordance with the catalysis by cobalt complexes33 and the structurally related
MTPPs.28, 34 The proposed mechanism justifies the formation of chroman-4-one as transient
product and the presence of deuterium in 4 and 5 at specific carbons (Scheme 2) in the reduction
process.
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Additionally, the rate constants of the reactions were calculated. It was assumed that all the
reactions are of the first order with respect to chromone, since in the majority of cases, the
concentration of sodium borohydride is significantly higher. In this case, the rate equation is
the following;
dC
= −kC
dt
where C is the concentration of chromone, mole/l; t - time, s; k is the rate constant, s-1.
Transforming the equation, we get
dC
= −kdt
C
Integration of this differential equation from the initial concentration C0 to the concentration
of unreacted chromone C0 – Cdc (Cdc is the concentration of the reacted substance) and within
the time (t) to reach C0 – Cdc leads to the following
1
k = ln
t
C0
C0 −Cdc
Dividing the numerator and denominator by C0 and multiplying by 100 we get








1
100
k = ln
Cdc
C0
t
100 −100




Cdc
C0
Knowing that
is the transformation (Conv.), we write the final formula for calculating
100
the rate constant,
1
k = ln
t
100


(1)




100−Conv.
The calculated rate constants are presented in Tables 1, 2.
Knowing the rate constants of the processes, it is also easy to calculate the 98% conversion
times (the most typical conversion for the best catalyst 3a under the best conditions) t98 using
the formula obtained by transforming equation (1)

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1
t98 = ln
k
100
1


= ln 50
( )




100−98
k
The calculated 98% conversion times are also presented in Tables 1, 2.
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The quantum calculations of catalysts show that the conversions, yields, logarithms of the rate
constants and the times of 98% conversion correlate well with the energy of the highest
occupied α molecular orbitals (α-HOMOc) of catalysts. The correlation coefficients are R =
0.882, 0.877, 0.837 and 0.856, respectively. The relationships, using the examples of
conversion and logarithm of the rate constant, are shown in Fig. 5 ESI. Values α-HOMOc are
presented in Table 3. The correlation coefficients with the rate constants calculated by the
kinetic equations for 1.5 and 2 orders are significantly lower and do not exceed 0.75.
Usually, the HOMO energy determines the oxidation capacity of the compound (the higher the
HOMO energy of the orbitals, the easier the oxidation of the compound occurs). In this process,
BH4−
not the catalyst but the anion
is oxidized due to which the reduction of chromones to
chroman-4-ol occurs, therefore it was assumed that the reduction of chromones is determined
by complexes with catalysts. In this case, the catalysts induce the energy of its HOMO to the
reducing agent (
− ), enhance its reducing activity and, in fact, substantially determine the
BH4
reduction process of chromones.
Indeed, the modeling of “catalysts – anion” complexes within the MOPS algorithm with
subsequent geometry optimization (refinement) of the complexes within the unrestricted DFT
B3LYP 6-311G (d, p) show that the α-HOMO energy of the complexes (α-HOMOcx) correlate
much better with the conversions, yields, logarithms of the rate constants and times of 98%
conversions (R = 0.891, 0.881, 0.921 and 0.874, respectively). The relationships, using the
examples of conversion and logarithm of the rate constant, are shown in Fig. 6 ESI. The α-
HOMOcx values are presented in Table 3. In addition, the α-HOMO energy in the complexes
significantly increases respectively to both the energy of individual α-HOMOc catalysts (on
−
average by 0.100 a.u.) and to HOMO energy of
(its HOMO energy is -0.0807 a.u.), up to
BH4
positive values. Thus, it confirms above-mentioned hypothesis that the catalysts induce the
energy of its HOMO orbitals to the reducing agent (
− ) and significantly enhance its
BH4
reducing activity. Thus, it can be assumed that the reduction process of chromones is
determined by oxidation NaBH4 or its electron excitation, i.e. transition of electron from the α-
HOMO level to some energy level E0. In this case, the activation energy of the process should
be equal to the difference between E0 and α-HOMO. Therefore, the increase of HOMO energy

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under the influence of catalysts provides a decrease of the activation energy and an increaVsieewiAnrticle Online
the rate constant quite agrees with the theory of homogeneous catalysis.35
DOI: 10.1039/C9NJ00266A
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It should be noted that, if we assume 1.5 or 2 reaction order and calculate the corresponding
rate constants, then their correlation coefficients with α-HOMOcx are only 0.729 and 0.756,
respectively, which indicates the correct initial assumption of the reaction order. A typical
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BH4−
BH4−
structure of
– MTPP complex is presented in Fig.1. The structures of the
– MTPP
3a-c complexes are very similar. The distances from the metal to the two nearest hydrogens in
them and from the metal to the boron are in a narrow range of 1.647 ± 0.002 Å and 2.022 ±
BH4−
0.042 Å, correspondingly. The structure of complex
– MTPP 3f slightly differs from
other MTPPs due to the presence of the counterion Cl- in this catalyst. The structures of
complexes with salt-based catalysts are characterized by a somewhat wide variety. Contact
distances M ... H are in the range 1.626 ± 0.015 Å and M ... B in the range 1.837 ± 0.067 Å. It
should be noted that for salts these distances are shorter than for MTPPs.
Concerning the influence of oxygen on the processes, the simulation of catalyst complexes
BH4−
(Cat) with oxygen and
was performed using the MOPS algorithm with subsequent
geometry optimization (refinement) within unrestricted DFT B3LYP 6-311G (d, p). The
complex formation energy is calculated as the difference between the total energy of the
products and the total energies of the starting substances of the processes
−
BH4
−
O ‧Cat +
2
O ‧Cat‧
BH4
2
The formation energies are presented in Table 3.
Table 3. The energy characteristics of the catalysts and their complexes (reagents and catalysts
correspond to the Entries in Table 2; reaction conditions – substrate: catalyst : NaBH4 = 10 : 1
: 30. Time 10 min.)
Entry α-HOMOc, a.u. α-HOMOcx, a.u. Ek, a.u. ΔE, kJ/mole
1.
2.
3.
4.
5.
-0.0446
-0.0430
-0.0358
-0.0641
-0.0573
0.1140
-0.0157
0.0517
-0.0461
-0.0064
-454.3
-454.3
-455.1
-454.0
-454.3
4.50
2.60
3.59
2.15
2.73

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6.
-0.0591
-0.1721
-0.1831
-0.1256
-0.0446
-0.0446
0.0129
-0.0062
-0.1169
-0.103
0.2
-0.4
1.37DOI: 10.1039/C9NJ00266A
7.
1.09
-0.53
-0.33
4.50
8.
0.0
9.
-0.1
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10.
11.
0.1140
0.1140
-454.3
-454.3
4.50
12.
13.
-0.0446
-0.0446
0.1140
0.1140
-454.3
-454.3
4.50
4.50
BH4−
It should be noted a very profitable process of complexation of MTPPs with
and O2,
yielding in a decrease in energy by 454.0 – 454.3 a.u., while for the inorganic catalysts this
process practically does not lead to a change in energy. Thus, oxygen stabilizes the catalytic
BH4−
MTPPs(3a-e)-O2 complexes are very similar. The typical structure of the complexes are shown
in Fig. 2 in example -MTPP(3a)-O2. Modeled structures of MTPPs complexes with
complexes of porphyrins, which yields in better synthesis results. The structures of
-
BH4−
oxygen do not contradict the structural data described in article.36
a)
b)
c)
BH4−
Fig.1. The structure
– MTPP 3a complex. View along a) first, b) the second and c) the
third inertial axes
It should be noted the change in orientation of
BH4−
relatively to that without oxygen (Fig.1). The distance M…H 1.6550 ± 0.0046 Å, M...B 3.244
in complexes with oxygen (Fig.1)

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± 0.066 Å, M...O 1.896 ± 0.066 Å and angles M…O=O 103.83 ± 0.22o in complexes aVrieewiAnrticle Online
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very narrow range. MTPP 3f differs from other due to the presence of a counterion. The
complexes CoCl2, NiCl2, and FeCl3 differ each other very significantly due to the presence of
an additional counterion in FeCl3 compared to others, and an even number of electrons
distinguishing NiCl2 from others. Only the M…O distances are similar for the complexes of
the salts in range 1.845 ± 0.030 Å, which is slightly shorter than that for MTPPs. The angles
differ seriously from MTPPs and vary from 67o to 83o.
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a)
b)
c)
Fig. 2. The structure of MTPP 3a complexes with oxygen and
− ,View along a)
BH4
first; b) the second and c) the third inertial axis
Indeed, according to theories of homogeneous catalysis,35 catalysts generally react with one or
more reactants to form intermediates that subsequently give the final reaction product, in the
process regenerating the catalyst. Catalysts work by providing an (alternative) mechanism
involving a different transition state and lower activation energy. Consequently, more
molecular collisions have the energy needed to reach the transition state. Hence, catalysts can
enable reactions that would otherwise be blocked or slowed by a kinetic barrier. Thus, a
catalytic process often involves two or more stages.
Thus, assuming that the first stage is the formation of a catalytic complex and its energy is
proportional to Ek, then the rate constant of this stage (k1) can be determined, according to the
Arrhenius equation, as
k = A exp(−aE / RT)
,
1
1
k
(A1 is the pre-exponent of the first stage; a is a coefficient; R is the universal gas constant; T is
the absolute temperature) and the second stage is the reduction of chromone, i.e. the electron

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transfer of from. Assuming that the activation energy is proportional to the difference between
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E0 and α-HOMOcx, then the rate constant (k2) of this process
k = A exp(−b E −α-HOMO / RT)
(
)
2
2
o
cx
where A2 is the pre-exponent of the first stage; b is a coefficient.
Then, the rate constant k of the whole two-stage process is
k = A A exp(−aE / RT)exp(−b E −α-HOMO / RT)
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(
)
1
1
2
k
0
cx
or
k = Aexp(−aE / RT −b E −α-HOMO / RT)
(
)
k
0
cx
where A = A1A2 is the pre-exponent of the whole two-stage process.
In this case, the activation energy of the whole two-stage process is equal to
.
k
aE / RT +b E −α-HOMO
(
)
k
0
After logarithmization of the equation and opening the brackets, we get
ln k = ln A−bE0 / RT −aEk / RT +bα-HOMOcx / RT
ln A−bE / RT
and denoting a0 =
, a1 = −a / RT и a2 = b / RT , we get the following two-factor
0
regression equation
ln k = a0 + a1Ek +a2α-HOMOcx
The performed regression analysis showed that the coefficients a0 = –6.31; a1 = –
0.00146; a2 = 5.92.
The correlation coefficient of the calculated (lnk(calc.)) and experimental ln k for this equation
is 0.973, the standard deviation of (lnk(calc.)) and ln k is 0.19. The relationship between the
calculated and experimental values is presented in Fig.3.
This equation has a good physical meaning but it does not make it possible to determine the
actual activation energy and the pre-exponent due to the fact that a0 coefficient includes two
unknown values lnA and E0 at once. Their determination these values requires experiments at
several temperatures. According to the Slater’s theory of unimolar reactions,37 the value of the
pre-exponential factor should be equal to the frequency of the bond breaking in process. In this
case the pre-exponent should be 71.95‧1012 s-1, then it is easy to define E0 as
2
2
E = (ln A−a )RT / b = (ln A−a )R T / a = 34.5kJ / mole
. However, Slater's theory is
0
0
0
2
suitable for cases where the limitative stage is the chemical bond breakage. But in our case, the
limitative stage it is electron excitation or electron transfer. However, it is possible to calculate
the decrease in activation energy (ΔE) under the influence of catalyst and oxygen as bα-

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BH4−
HOMOcx – aEk + 0.0804b (–0.0804 is α-HOMOcx of
). These values are presented in
DOI: 10.1039/C9NJ00266A
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Table 3. In addition, the proposed approach and the resulting equation give the possibility of
planning new synthetic strategies and developing new catalytic systems.
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Fig.3. Calculated and experimental logarithms of rate constants
Conclusions
Hence, Co(II)porphyrin in presence of oxygen proved to be effective catalytic system
as the quantum calculations of catalysts showed that the conversions, yields, logarithms of the
rate constants and the times of 98% conversion correlate well with the energy of the highest
occupied α molecular orbitals (α-HOMOc) of catalysts. Consequently, the catalysts induces the
energy of its HOMO orbitals to the reducing agent (
− ) and significantly enhance its
BH4
reducing activity. This reduction pathway result in the formation of hydridocobalt(III)
porphyrin as a key intermediate. This intermediate further catalyzes the reduction of
functionalized chromones to biologically active chroman-4-ols through hydrogen radical
transfer mechanism. The role of oxygen is to stabilize catalytic complexes of porphyrin and
accelerate the generation of an important intermediate i.e. hydridocobalt(III) porphyrin, in
presence of sodium borohydride and later, to assist the release of Hydrogen radical from
hydridocobalt(III) porphyrin. Further, the features of the mechanism of catalytic reduction of
chromones are considered, the role of the catalyst and oxygen in this process is justified. The
influence of the orbital characteristics of the catalytic complex and its stabilization by oxygen
on the activation energy and process rate constant is shown. A quantitative relationship
between the rate constant and the α-HOMO orbital of the catalytic complex and the

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stabilization energy of the complex with oxygen is proposed. The proposed approach to
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modeling catalytic complexes in conjunction with a quantitative model makes it possible to
plan new synthetic strategies and develop new catalytic systems. Moreover, this approach can
be used for study of the natural metalloporphyrin-containing enzymes, for example,
hemoglobin, myoglobin, peroxidases, cytochromes, lipo- and cyclooxygenases.
The additional advantages of the present catalytic system include simplicity, an easy work-up
procedure, very less reaction time, excellent product yields, reusability of the catalyst and mild
reaction conditions.
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Experimental Section
All the melting points are corrected and were determined on a Thomas Hoover Unimelt
capillary melting point apparatus. The IR spectra were recorded on a Perkin Elmer 1710 FTIR
spectrometer and the νmax are expressed in cm-1. The electronic spectra were recorded on a
Perkin Elmer Lambda-35 UV/Vis spectrophotometer and the λmax are expressed in
nanometres. The 1H NMR, 13C NMR, spectra were recorded on Bruker Avance-300 and Bruker
Avance-400 spectrometers using TMS as the internal standard (chemical shifts in ppm). The
TOF LC/MS spectra were recorded on a Hybrid Quadruple-TOF LC/MS mass spectrometer
1011273/A using ion spray. ESI-MS spectra were recorded on Micromass LCT KC 455 using
electrospray positive ion mass spectra. The substituted chromones (1a–1e) were prepared
according to the literature methods.24b Metalloporphyrins (3a-3f) were prepared according to
the literature method.38 The formation of compound 2b was confirmed by melting point
determination.
Procedure for the reduction of 2-Phenyl-chromen-4-one (1a) with sodium borohydride
(NaBH4) catalyzed by MTPP (3a) under oxygen: To the solution of substrate (1a
)
(100mg, 0.450mmol) in dry methanol (25 ml), MTPP (3a) (30.22mg, 0.045mmol) was
added. The solution was stirred at room temperature under oxygen and NaBH4 (51.3mg,
1.35mmol) was added in portions. The progress of the reaction was checked by TLC. The
reaction mixture was filtered to remove the catalyst (3a) (28.67mg) and the filtrate was
concentrated under reduced pressure. The resulting solid was chromatographed over silica
gel (60–120 mesh) and the product was separated by column chromatography using ethyl
acetate/petroleum ether (varying from 1:99 to 10:90, v/v) as eluents. The product was
recrystallized with chloroform/petroleum (1:1, v/v). The recovered catalyst was washed
with methanol and reused to catalyze further reduction reactions.

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2-Phenyl-chroman-4-ol (2a)
24a Yield: 97mg; mp 146oC (lit mp 148oC). IR (KBr): 3V3ie0w3Ar,ticle Online
DOI: 10.1039/C9NJ00266A
2959, 2918, 1580, 1484, 1454, 1343, 1228, 1065, 1038, 905, 758, 703 cm–1. 1H NMR (400
MHz, CDCl3): δ = 1.92 (d, J = 8.4 Hz, 1H, OH), 2.12 (ddd, J = 13.2, 11.6, 10.8 Hz, 1H,
Ha-3), 2.49 (ddd, J = 13.2, 6.4, 2.0 Hz, 1H, He-3), 5.08 (m, 1H, H-4), 5.16 (m, 1H, H-2),
6.89 (dd, J = 8.2, 0.8 Hz, 1H, H-8), 6.98 (dt, J = 7.4, 1.2 Hz, 1H, H-6), 7.20 (m, 1H, H-7),
7.32-7.45 (m, 5H, H-2’- 6’), 7.51 (d, J = 7.6 Hz, 1H, H-5). 13C NMR (75 MHz, CDCl3): δ
= 40.03 (C-3), 65.80 (C-4), 76.82 (C-2), 116.72 (C-8), 120.96 (C-6), 125.70 (C-4a), 126.06
(C-5), 126.95 (C-2’, 6’), 128.21 (C4’), 128.65 (C-3’, 5’), 129.17 (C-7), 140.47 (C-1’),
154.45 (C-8a). MS (LC-MS): m/z calcd for C15H14O2H: 226; found: 227 [M + H+]. UV-
vis (CHCl3): λmax (log ε) = 242 (3.19), 278 (3.31), 285(3.29) nm. Anal. Calc for C15H14O2:
C, 79.62; H, 6.24. Found: C, 79.52; H, 6.32. [Refer Fig. 6, supporting information]
Procedure for the reduction of Chromen-4-one (1b) with sodium borohydride (NaBH4)
catalyzed by MTPP (3a) under oxygen: To the solution of substrate (1b) (100mg,
0.684mmol) in dry methanol (25 ml), MTPP (3a) (45.94mg, 0.068mmol) was added. The
solution was stirred at room temperature under oxygen and NaBH4 (77.62mg, 2.05mmol)
was added in portions. The progress of the reaction was checked by TLC. The reaction
mixture was filtered to remove the catalyst (3a) (43.95mg) and the filtrate was
concentrated under reduced pressure. The resulting solid was chromatographed over silica
gel (60–120 mesh) and the product was separated by column chromatography using ethyl
acetate/petroleum ether (varying from 1:99 to 10:90, v/v) as eluents. The products were
crystallized with chloroform/petroleum (1:1, v/v).
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Chroman-4-ol
Procedure for the reduction of 2-Phenyl-chromen-4-one (1c) with sodium borohydride
(NaBH4) catalyzed by MTPP (3a) under oxygen: To the solution of substrate (1c
(
2b) Yield: 97mg; mp 42o C (lit mp 42-44oC).
)
(100mg, 0.450mmol) in dry methanol (25 ml), MTPP (3a) (30.22mg, 0.045mmol) was
added. The solution was stirred at room temperature under oxygen and NaBH4 (51.3mg,
1.35mmol) was added in portions. The progress of the reaction was checked by TLC. The
reaction mixture was filtered to remove the catalyst (3a) (28.68mg) and the filtrate was
concentrated under reduced pressure. The resulting solid was chromatographed over silica
gel (60–120 mesh) and the products were separated by column chromatography using ethyl
acetate/petroleum ether (varying from 1:99 to 10:90, v/v) as eluents. The products were
crystallized with chloroform/petroleum (1:1, v/v).
Cis-3-Phenyl-chroman-4-ol (2c)24b Yield: 65mg; Mp 76 oC (lit. 75 oC); 1H NMR (400 MHz,
CDCl3) 3.35 (1H, dt, J = 11.7, 2.9 Hz, H-3), 4.30 (1H, ddd, J = 10.5, 2.9, 1.1 Hz, H-2a), 4.58

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(1H, dd, J = 11.7, 10.5 Hz, H-2b), 4.75 (1H, br s, H-4), 6.88–6.96 (2H, m, H-5DaOnI:d10.610)3,9a/Cn9dNJ00266A
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7.21–7.37 (7H, m, Ar H); C NMR (100 MHz, CDCl3): δ = 44.2, 64.1, 67.2, 116.9, 120.6,
123.5, 127.5, 128.4, 128.9, 129.9, 130.6, 137.7 and 154.2; MS (LC-MS) m/z calcd for
C15H14O2: 226.0; found: 227.0 [M + H+]. [Refer Fig. 6, supporting information]
Trans-3-Phenyl-chroman-4-ol (2c)24b Yield: 31mg; Mp 97 oC (lit. 98 oC); 1H NMR (400
MHz, CDCl3) 3.19 (1H, td, J = 8.3, 7.3, 3.9 Hz, H-3), 4.27 (1H, dd, J = 11.2, 8.3 Hz, H-
2a), 4.38 (1H, dd, J = 11.2, 3.9 Hz, H-2b), 4.99 (1H, m, H-4), 6.87–6.99 (2H, m, H-5 and
6), and 7.20–7.52 (7H, m, Ar H,); 13C NMR (75 MHz, CDCl3): δ = 47.2, 68.1, 69.4, 116.6,
120.9, 124.7, 127.6, 128.0, 128.2, 129.1, 129.3, 138.6 and 154.2; MS (LC-MS) m/z calcd
for C15H14O2: 226.0; found: 227.0 [M + H+]. [Refer Fig. 6, supporting information]
Procedure for the reduction of 2-(4’-methyl-phenyl)-chromen-4-one (1d) with sodium
borohydride (NaBH4) catalyzed by MTPP (3a) under oxygen: To the solution of substrate
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(
1d) (100mg, 0.423mmol) in dry methanol (25 ml), MTPP (3a) (28.42mg, 0.042mmol)
was added. The solution was stirred at room temperature under oxygen and NaBH4
(48.0mg, 1.26mmol) was added in portions. The progress of the reaction was checked by
TLC. The reaction mixture was filtered to remove the catalyst (3a) (27.07mg) and the
filtrate was concentrated under reduced pressure. The resulting solid was chromatographed
over silica gel (60–120 mesh) and the product was separated by column chromatography
using ethyl acetate/petroleum ether (varying from 1:99 to 10:90, v/v) as eluents. The
products were crystallized with chloroform/petroleum (1:1, v/v).
24a
2-(4’-methyl-phenyl)-chroman-4-ol
(
2d
)
Yield: 98mg; mp 108-109o C (lit mp 109-
110o C). IR (film): 3366, 2921, 1625, 1581, 1518, 1485, 1458, 1270, 1231, 1068, 1040,
906, 812, 757 cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.01 (d, J = 8.0 Hz, 1H, OH), 2.11
(ddd, J = 13.0, 11.6, 10.8 Hz, 1H, Ha-3), 2.36 (s, 3H, CH3), 2.45 (ddd, J = 13.0, 6.2, 2 Hz,
1H, He-3), 5.04 (m, 1H, H-4), 5.11 (dd, J – 11.6, 2.0 Hz, 1H, H-2), 6.66 (dd, J = 8.2, 1.0
Hz, 1H, H-8), 6.96 (dt, J = 7.4, 1.2 Hz, 1H, H-6), 7.17 (m, 3H, H-7, H3’, 5’), 7.31 (m, 2H,
13
H-2’-6’), 7.51 (d, J = 7.8 Hz, 1H, H-5). C NMR (100 MHz, CDCl3): δ = 21.22 (CH3),
39.90 (C-3), 65.85 (C-4), 76.77 (C-2), 116.76 (C-8), 120.92 (C-6), 125.76 (C-5), 126.13
(C-2’, 6’), 127.01 (C-4a), 127.01 (C-7), 129.35 (C-3’, 5’), 137.50 (C-4’), 138.06 (C-1’),
+
154.57 (C-8a). MS (LC-MS): m/z calcd for C16H16O2: 240; found: 240 [M ]. UV-vis
(CHCl3): λmax (log ε) = 241 (4.02), 261 (3.85), 279 (4.06), 286 (4.12), 299 nm (3.89). Anal.
Calc for C16H16O2: C, 79.97; H, 6.71. Found: C, 80.14; H, 6.88. [Refer Fig. 6, supporting
information]

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Procedure for the reduction of 2-(4’-chloro-phenyl)-chromen-4-one (1e) with sodium
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borohydride (NaBH4) catalyzed by MTPP (3a) under oxygen: To the solution of substrate
1e) (100mg, 0.389mmol) in dry methanol (25 ml), MTPP (3a) (26.12mg, 0.038mmol)
(
8
9
was added. The solution was stirred at room temperature under oxygen and NaBH4
(44.14mg, 1.16mmol) was added in portions. The progress of the reaction was checked by
TLC. The reaction mixture was filtered to remove the catalyst (3a) (25.16mg) and the
filtrate was concentrated under reduced pressure. The resulting solid was chromatographed
over silica gel (60–120 mesh) and the product was separated by column chromatography
using ethyl acetate/petroleum ether (varying from 1:99 to 10:90, v/v) as eluents. The
products were crystallized with chloroform/petroleum (1:1, v/v).
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2-(4’-chloro-phenyl)-chroman-4-ol (2e)
24a Yield: 96mg; mp 160-161o C (lit mp 160-161o
C). IR (KBr): 3382, 2924, 1581, 1485, 1459, 1303, 1270, 1227, 1065, 1039, 1012, 904,
864, 820, 755 cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.75 (d, J = 8.6 Hz, 1H, OH), 2.10
(m, 1H, Ha-3), 2.50 (ddd, J = 13.1, 6.1, 1.6 Hz, 1H, He3), 5.10 (m, 1H, H-4), 5.16 (dd, J=
11.7, 1.6 Hz, 1H, H-2), 6.88 (d, J = 8.2 Hz, 1H, H-8), 7.00 (m, 1H, H-7), 7.22 (m, 1H, H-
6), 7.38 (m, 4H, H-2’-6’), 7.52 (d, J = 7.6 Hz, 1H, H5). 13C NMR (100 MHz, CDCl3): δ =
40.05 (C-3), 65.68 (C-4), 76.85 (C-2), 116.71 (C8), 121.18 (C-6), 125.61 (C-4a), 126.96
(C-5), 127.46 (C-2’, 6’), 128.84 (C-3’, 5’), 129.27 (C-7), 133.94 (C-4’), 139.04 (C-1’),
+
154.23 (C-8a). MS (LC-MS): m/z calcd for C15H13ClO2: 260.71; found: 261 [M ]. UV-
vis (CHCl3): λmax (log ε) = 239 (3.25), 277 (3.33), 285 nm (3.29). Anal. Calc for
C15H13ClO2: C, 69.10; H, 5.03. Found: C, 69.43; H, 5.12. [Refer Fig. 6, supporting
information]
Reduction of 2-Phenyl-chromen-4-one (1a) with equimolar amount of NaBH4 catalyzed by
cobalt(II) porphyrin (3a) in methanol
To a mixture 2-Phenyl-chromen-4-one (1a) (100mg, 0.450mmol) and (3a) (30.22mg,
0.045mmol), NaBH4 (17.02mg, 0.450mmol) was added in methanol under oxygen atmosphere.
The reaction mixture was stirred at room temperature for 5 min. After removing the catalyst 3a
(28.56mg) by filtration, the filtrate was concentrated under reduced pressure. The reduced
product 2-Phenyl-chroman-4-one (14mg, 14 % yield) and 2a (46mg, 46 % yield) were
separated by preparative TLC (solvent system: ethyl acetate/ hexane 5: 95, v/v).
o
2-Phenyl-chroman-4-one24a Yield: 14mg; mp 76-77 C (lit mp 76-77oC). IR (KBr): 3038,
2897, 1689, 1606, 1461, 1303, 1227, 1148, 1114, 1066, 985, 907, 766, 700 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 2.88 (dd, J = 16.9, 3 Hz, 1H, He-3), 3.08 (dd, J = 16.9, 13.2 Hz, 1H,

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Ha-3), 5.48 (dd, J = 13.2, 2.4 Hz, 1H, CH), 7.03-7.07 (m, 2H, Ar H), 7.38-7.53 (m, 6H, AVrieHw A)r,ticle Online
DOI: 10.1039/C9NJ00266A
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7.94 (d, J = 8.1 Hz, 1H, ArH).
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Computational Methods
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Geometry optimization and calculation of the electronic, charge, and energy characteristics of
all individual molecules were carried out at the unrestricted DFT B3LYP 6-311G(d, p) level of
theory.
To simulate catalytic complexes, preliminarily the MOPS algorithm was used,39-56 which
search for the optimal geometry of a complex along all modes of translational, vibrational, and
rotational movement in the combined force field MM3/MERA with a continual account the
solvent influence according to the MERA model.39 The applicability of this approach for
studying organic, inorganic and combined systems was previously shown elsewhere.40-57 The
MOPS algorithm was used for the modeling of oxyhydrate gels formation,54 for the modeling
of crystal structures of triosmium clusters,41,42,45,47,51,52,56 for the study of organic molecules
complexation during chemical reactions,39,43,45,48,50,55 for the modeling of proteins affinity for
the modeling of crystal structures and interaction energies of gas hydrates.49 ,54 The calculated
energies, thermodynamic characteristics (such as enthalpies, entropies, Gibbs free energies);
modeled structures of complexes, crystals and clusters; predicted yields, rates, regio- and
stereospecificity of reactions were in a good agreement with the experimental ones that shown
enough in the above listed publications. Further, the geometry optimization (refinement) and
the subsequent calculation of the electronic, charge, and energy characteristics of the
complexes were carried out using unrestricted DFT B3LYP 6-311G(d, p).
Conflict of interest
The authors declare no conflict of interest.
Acknowledgments
This work is financially supported by UGC-BSR Research Start-Up Grant [F.30-375/2017
(BSR)], by Act 211 Government of the Russian Federation, contract 02.A03.21.0011 and by
Ministry of Education and Science of Russia (grants 4.8298.2017/8.9, 4.7279.2017/8.9). We
are also thankful to the University of Delhi and Laboratory of Computational Modeling of
Drugs, South Ural State University for providing assistance. BR is highly grateful to Defence
Research & Development Organization, Ministry of Defence, Government of India for
financial assistance (ERIP/ER/1503205/M/01/1641).

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Note: Supporting information of this article is available.
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