Coordination Chemistry Reviews 309 (2016) 68–83

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Coordination Chemistry Reviews

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Review

Redox chemistry of cobalamin and its derivatives

I.A. Dereven’kov a,∗ , D.S. Salnikov a , R. Silaghi-Dumitrescu b , S.V. Makarov a , O.I. Koifman a
a
Institute of Macroheterocyclic Compounds, Ivanovo State University of Chemistry and Technology, Sheremetevskiy str. 7,
Ivanovo 153000 Russian Federation
b
Department of Chemistry, Babes-Bolyai University, Arany Janos 11, Cluj-Napoca RO-400024 Romania

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
2. Dependence of the coordination properties of cobalamins and their derivatives on the oxidation state of the cobalt ion . . . . . . . . . . . . . . . . . . . . . . . . . . 69
3. Mechanisms for the reduction reactions of the Co(III) forms of cobalamins and their derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
4. Mechanisms of reduction reactions for Co(II) forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
5. Mechanisms of oxidation of the Co(II) forms of cobalamins and their derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
6. Oxidation mechanisms for Co(I) cobalamins and their derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

a r t i c l e i n f o a b s t r a c t

Article history: A comprehensive review on redox reactions of Co(III), Co(II) and Co(I) forms of cobalamins (vitamin B12)
Received 8 September 2015 and their derivatives (cobinamide, cobyrinates) is presented. An influence of coordination environment
Received in revised form 31 October 2015 of cobalt ion on reactivity of corresponding species is discussed. Mechanisms of reduction of Co(III) and
Accepted 1 November 2015
Co(II) species as well as oxidation of Co(II) and Co(I) complexes are given in terms of their in vivo and
Available online 14 November 2015
catalytic implications.
© 2015 Elsevier B.V. All rights reserved.
Keywords:
Cobalamin
Vitamin B12
Free radicals
Reduction
Oxidation
Reaction mechanisms

1. Introduction studies. Several general reviews are available [1–3], as well as work
summarizing interim results in relatively narrow areas: chemical
Cobalamins (Cbls; Fig. 1) are the most common in vivo cobalt modification of the structure of cobalamin [4] and their peptide
compounds, as well as the most complex vitamins in their struc- derivatives [5], Cbl-dependent enzymes [6], transport and pro-
ture – and have hence been the subject of various and extended cessing cobalamins in vivo [7–9], activation of Co C bonds in
adenosylcobalamin-dependent enzymes [10], catalytic reactions
involving Cbls [11], corrin-based antivitamins [12,13], medical
applications of cobalamin derivatives [14] and others. Neverthe-
Abbreviations: Cbl, cobalamin; Cbi, cobinamide; Ado, 5 -deoxyadenosyl;
less, there have been no reviews dedicated to the redox reactions
ATP, adenosine triphosphate; bpy, 2,2 -bipyridine; CASPT2, complete active
space perturbation theory; CASSCF, complete active space self-consistent field; of the cobalamins.
CoA, coenzyme A; DDT, 1,1-bis(4-chlorophenyl)-2,2,2-trichloroethane; DMBI, 5,6- Cobalamin transport in mammals [7–9], its ligation changes
dimethylbenzimidazole; DMF, dimethyl formamide; DMSO, dimethyl sulfoxide; [7–9], the synthesis of coenzyme forms [6,9] and, in fact, Cbl-
DFT, density functional theory; GSH, l-glutathione; HMS, hydroxymethanesulfinate; dependent enzymatic processes [6,10] all include as a main event
LMCT, ligand to metal charge transfer; LUMO, lowest unoccupied molecular orbital;
MOF, metal-organic frameworks; NHE, normal hydrogen electrode.
oxidation or reduction of the cobalt ion. Under physiological con-
∗ Corresponding author. Tel.: +7 4932 327357; fax: +7 4932 417995. ditions, Co(III), Co(II), and Co(I) forms of cobalamins are known.
E-mail address: derevenkov@gmail.com (I.A. Dereven’kov). Cbl(I) is the necessary form for the synthesis or organo-cobalamins

http://dx.doi.org/10.1016/j.ccr.2015.11.001
0010-8545/© 2015 Elsevier B.V. All rights reserved.
 I.A. Dereven’kov et al. / Coordination Chemistry Reviews 309 (2016) 68–83 69

Fig. 1. Structures of cobalamin (A), cobinamide (B), cobyrinic acid (C) and heptamethyl cobyrinate (cobester) (D).

(Co(III)-complexes) involved in the transfer of a methyl moiety
(methylcobalamin, MeCbl) and isomerization of various substrates
(adenosylcobalamin, AdoCbl). Deactivation of Cbl(I) leads to the
formation of Cbl(II), which is also formed by homolysis Co C bond
in AdoCbl-dependent enzymes.
Catalytic conversion of various organic substrates is also pos-
sible using cobalamin derivatives (e.g., cobyrinates, cobesters,
cobinamides (Cbi); Fig. 1) [11,15,16]. In such cases again, the key
steps involve redox transitions between the Co(III), Co(II) and Co(I)
forms of these complexes. The mechanisms of these reactions are
quite diverse, but this is not sufficiently reflected in the currently
available reviews. This article summarizes the redox chemistry
of cobalamins and their derivatives, including the reduction pro-
cesses on Co(III) and Co(II) forms, as well as oxidation of Co(I) and
Co(II).
2. Dependence of the coordination properties of
cobalamins and their derivatives on the oxidation state of
the cobalt ion
Cobalamin redox reactivity is strongly dependent on the coordi-
nation state of the cobalt ion. Coordination properties directly affect
both the redox potential of the Co(III)/Co(II) and Co(II)/Co(I) pairs,
and the availability of coordination sites necessary for engaging
into a complex with the reducing agent.
Cbls(III) (Fig. 1) are complexes where the corrin nitrogen atoms
occupy the four equatorial coordination sites, while the fifth coor-
dination site at the bottom (␣) axial position is either occupied by a
nitrogen atom of the 5,6-dimethylbenzimidazole (DMBI) unit of the
nucleotide chain (in the base-on form of cobalamin) or by an oxy-
gen atom of a water molecule (in the base-off form of cobalamin, or
70 I.A. Dereven’kov et al. / Coordination Chemistry Reviews 309 (2016) 68–83
Fig. 2. Coordination states of Co(III), Co(II) and Co(I)-corrins.
Source: Adapted from Ref. [3].
in incomplete corrinoids). The sixth coordination site (␤-position)
is available for coordination of various exogenous groups (X = H2 O,
CN− , CH3 − and others).
It is believed that Co(III) corrinoids are mostly hexacoordinated,
while the Co(II) form tends to be pentacoordinated, and Co(I) –
tetracoordinated (Fig. 2) [3].
It is important to mention that there are a number of exceptions
to this rule. For example, an axial ligand with a strong trans-
influence will lead to pentacoordinated Co(III)–corrin complexes.
Thus, the pressure dependence of UV–Vis spectra of MeCbl and
vinyl–cobinamide (vinyl–Cbi(III)) (where the methyl and vinyl lig-
ands have strong electron-donating properties) can be explained by
the equilibria hexacoordinated base-on MeCbl ↔ pentacoordinated
base-off MeCbl, and hexacoordinated vinyl–Cbi(III)–H2 O ↔ pen-
tacoordinated vinyl–Cbi(III), which are displaced toward the
hexacoordinated state with increasing pressure [17]. Similarly,
nitroxylcobalamin (Cbl(III)–NO− ) in neutral and alkaline aqueous
solutions features significant amounts of the deprotonated base-off
form, as demonstrated by 13 C and 31 P NMR [18]. Since the nitroxyl
anion exhibits a strong trans-influence [18], it can be assumed that
the base-off form is indeed pentacoordinated.
For Cbl(II) there are also a few exceptions known from the
classic pentacoordinated state [19–21]. In the early stages of the
reaction between Cbl(II) and dithionite (S2 O4 2− ), a loss of the
EPR signal of the starting Co(II) is observed; the resulting state
is very stable in the absence of oxygen, and is oxidized by O2 to
Cbl(III)–SO3 2− . The most adequate representation of this complex
would be Co(II)–SO2 •− , where the unpaired electrons of Co(II) and
SO2 •− are coupled to each other. This complex has a pKa = 4.8 at
25 ◦ C, corresponding to a base-on ↔ base-off transitions and imply-
ing that at least under certain conditions Co(II) is hexacoordinated
Co(II) [22].
A hexacoordinated complex of cobalamin(II) is also obtained
with SCN− . Thus, Cbl(II) is capable of binding thiocyanate in an
alkaline medium (K = 3.6 ± 0.3 M−1 at 25 ◦ C, I = 1 M). The UV–Vis
spectrum of the resulting complex is markedly different from that
of thiocyanato-cobinamide(II), which speaks of their structural
differences (while, as expected, the UV–Vis spectra of the base-off
complexes Cbl and Cbi are very similar to each other). Significant
changes were also observed in the structure of Cbl(II) EPR signal
upon addition of thiocyanate. The Cbl(II)–SCN− complex displays
a typical acid–base equilibrium with pKa = 3.4 a 25 ◦ C, in which
only a protonation of bound DMBI can occur, since thiocyanate is
protonated in strongly acidic medium. These facts indicate the for-
mation of a hexacoordinated complex with a significantly labilized
Fig. 3. Hydrogen bonding of cobalamin(I).
Source: Adapted from Refs. [28,30,31].
Co(II)–Nax (DMBI) bond compared to the original Cbl(II)base-on .
DFT calculations do not exclude the possibility of the formation of
hexacoordinated complexes of Cbl(II) with SCN− , where one of the
axial bonds is considerably weakened. Ligation of thiocyanate in
this case was predicted by DFT data to occur more preferably via
the nitrogen atom than via the sulfur atom, as also observed for
Co(III)-complexes of cobalamin and cobinamide [23].
There are also known examples of tetracoordinated Cbl(II).
Spectroscopic and X-ray data on the binding of cobalamin(II) to
ATP:cobalamin adenosyltransferase, the enzyme that synthesizes
AdoCbl in vivo, supports Co(II) state with very weak axial interac-
tions [24–26].
Despite the fact that Cbl(I) is considered to be tetracoordinatied
based on spectral data [21,27], the absence of crystallographic data
does not allow to consider this point of view unique. DFT calcula-
tions predict a possibility of the formation of one or two hydrogen
bonds between Co(I) and H-donor (H2 O [28–30], protonated imi-
dazole [28], aminoacids such as tyrosine [31]; Fig. 3).
3. Mechanisms for the reduction reactions of the Co(III)
forms of cobalamins and their derivatives
Conversion of aqua-Co(III)-corrinoids to Co(II) complexes occurs
relatively easily. On one hand, this is due to the sufficiently high
potential of the Co(III)/Co(II)-couples. On the other hand, the high
mobility of water ligand facilitates its substitution by the reducing
agent. The redox potentials of the H2 OCbl(III)base-on /Cbl(II)base-on
and (H2 O)2 Cbi(III)/Cbi(II) pairs are +0.20 and +0.51 V at 22 ◦ C
(relative to the normal hydrogen electrode, NHE) [32], which is
higher than those of the potential biological partners in reduction
reactions.
Redox potential of Cbl(III) is strongly dependent on pH: a value
of +0.20 V (22◦ C, NHE), remains independent only in the region
 I.A. Dereven’kov et al. / Coordination Chemistry Reviews 309 (2016) 68–83
Scheme 1. A common mechanism of reduction of aquacobalamin.
Source: Adapted from Ref. [22].
between pH 2.9 and 7.8 and moves to more negative values above
pH 7.8 and more positive values below pH 2.9 [32]. Latter can be
explained by acid-base transformations of axial ligand depending
on basicity of medium: at pH >7.8 aqua ligand is deprotonated to
hydroxide (reaction (1)), at pH <2.9 DMBI attaches proton giving
Cbl(II) and Cbl(III) base-off-species (Fig. 2).
Several suitable reducing agents for the aqua-forms of Cbl(III)
and Cbi(III) to the corresponding Co(II)-complexes are known –
including ascorbic acid [33], monosaccharides [34,35], sodium
borohydride[36], sodium formate [37], and thiols [38].
Ascorbic acid is an effective reductant of aquacobalamin, with
a rate of 24 M−1 s−1 at pH 7.0; 25 ◦ C [33]. However, the oxidation
product of ascorbate, dehydroascorbic acid, is sufficiently stable
in neutral and acidic solution and has oxidizing properties, which
may negatively influence the course of experiments on the reac-
tivity of Co(II)-corrinoids. Under certain conditions, destruction of
the macrocycle was also reported [33,39]. Notably, this destruction
refers primarily to experiments conducted under aerobic condi-
tions, where the inevitably produced hydrogen peroxide is, as most
reactive oxygen species, likely to destroy corrin [33].
Reduction of aquacobalamin by formate [37] depends on the
acid–base properties of two reagents: there was a decrease in rate
at pH <5 in due to formate protonation (pKa = 3.53 [37]) and at pH >7
due to Cbl(III)–OH2 deprotonation to Cbl(III)–OH− (pKa = 7.75 [40]).
The hydroxide ligand is inert to substitution, so that the reduction
of Cbl(III)–OH− requires preliminary protonation (Scheme 1). It is
also expected that the reduction of Cbl(III)–OH2 by formate involves
hydride transfer, yielding Cbl(I), which rapidly comproportionates
with Cbl(III)–OH2 by reaction (1) [41]. However, direct evidence
for the formation Cbl(I) system is not available. Formate has a
significant drawback for synthesis of Cbl(II): in order to achieve
optimal rate of reduction, relatively high concentrations of formate
are needed (>10 mM).
Cbl(I) + Cbl(III)–OH2 → 2Cbl(II) + H2 O.
Cbl(III)–OH2 is reducible with glucose in alkaline medium [34].
The reaction proceeds at a low rate and yields Cbl(II). The active
form of the reducing agent is the glucose anion, only available
under strongly alkaline medium – where, however, the concentra-
tion of the active form of cobalamin is very low, which explains the
very low rates of the process. Reduction of dihydroxycobinamide
[35] under these conditions proceeds at a higher rate and com-
prises two successive stages: Co(III) → Co(II) and Co(II) → Co(I). The
higher rate of the first stage is due to the greater availability of the
aquahydroxo form (pKa for transition to dihydroxo: 10.3 at 25 ◦ C).
In a strongly alkaline media the mechanism of the first reduction
step is also changed: while at pH 11 reduction by excess glucose or
fructose is described by an exponential equation, the shape of the
kinetic curve becomes typical for an autocatalytic reaction at pH 13.
Apparently, the one-electron oxidized versions of the monosaccha-
rides, which, probably, are more efficient reducing agents for Co(III),
are more stable in such strongly alkaline media and can accumu-
late to amounts which allow them to play an important part in the
reduction of the cobalt.
Reduction by monosaccharides is a convenient method of
obtaining reduced forms of cobalamin derivatives [42], since
71
monosaccharides possess reductive activity only at strongly alka-
line pH – so that pH value of 12–13 are preferred for the actual
reduction of the cobalt, after which the reactivity of the product
may be explored at ease using lower pH values, where the excess
monosaccharides are redox-inactive enough to avoid interferences.
However, the most convenient route to Co(II) as well as to Co(I)
is reduction with sodium borohydride [36]. Depending on the con-
centration of the reducing agent, the reaction may be stopped
at Co(II) or continued on to Co(I). The excess reducing agent can
be quenched either by performing the reduction in weakly acidic
media (e.g., pH 4–5, where within about 1 h the remaining NaBH4
decomposes generating H2 and borate derivatives), or by adding
acetone after completion of the desired reduction reaction.
Aqua Cbl(III) and Cbi(III) react with thiols via rather complicated
mechanisms, with various products depending on the nature of the
starting reactants. With Cbl(III)–OH2 , glutathione (GSH) [40,43], N-
acetylcysteine [44], homocysteine [44], ␥-glutamylcysteine [45],
or captopril [46] yield reasonably stable Cbl(III)–SR− complexes,
whose structure was established by X-ray diffraction. These thi-
olate complexes are stable in neutral, weakly acidic and weakly
alkaline solutions. In a strongly acidic medium a slow hydrolysis
to the original RSH and Cbl(III)–OH2 is observed [47]. At neutral
pH, the UV–Vis spectra of these complexes vary little even after
several hours in the presence of a large excess of the corresponding
thiol. In alkaline media, reduction yields Cbl(II) and the correspond-
ing disulfide, and requires a minimum of two equivalents of thiol
[48]. EPR data suggest that it is possible to capture thiyl radical by
Co(II)-complexes [48].
Thiolatocobalamins exhibit so-called “atypical” UV–Vis spectra,
similarly to organo-Cbls(III), sulfito-Cbl(III) [49], phenolato-Cbl(III)
[50], and some other species, which are distinct from “typical”
spectra of Cbl(III)–OH2 , Cbl(III)–CN− and others. A major difference
between these groups is in position of ␥-band, which is typically
located at 350 nm, but red-shifted and weakly structured in “atyp-
(1)
ical” spectra. DFT computations performed on Cbl(III)–SG− models
[51], [52] reveal similarity between Co(III) S and Co(III) C bonds,
i.e., GS− and CH3 − groups strongly decrease effective charge on Co
ion via ␴-donation and substantially shifts energy of 3d-orbitals to
more positive values. High energy of 3d-orbitals enables their mix-
ing with corrin ␲-orbitals increasing number of electron transitions
in ␥-region with similar energies and explains appearance of “atyp-
ical” spectra [51]. In Cbl(III)–OH2 or Cbl(III)–CN− , a sharp ␥-band of
UV–Vis spectrum is generally contributed by ␲ → ␲* corrin-based
transitions, since their energy exceeds that of Co 3d → ␲* corrin-
based excitations.
Reduction of Cbl(III)–OH2 by l-cysteine occurs more easily than
with the above thiols [38], and is possible even in a weakly acidic
medium. Likewise facile is reduction of Cbl(III)–OH2 by dithiotreitol
(DTT) [48].
The interaction of Cbl(III)–OH2 [53] and (H2 O)2 Cbi(III) [54] with
hydrogen sulfide is a special case, with distinctly more complex
mechanisms than in the case of the thiols discussed above. In
acidic and neutral media under anaerobic conditions, aquacobal-
amin reacts with hydrogen sulfide in three steps (Scheme 2) [53].
The first stage entails rapid substitution of water by hydrogen
sulfide, which proceeds at a higher rate than the formation of
72 I.A. Dereven’kov et al. / Coordination Chemistry Reviews 309 (2016) 68–83
Scheme 2. A mechanism of reaction between aquacobalamin and hydrogen sulfide.
Source: Adapted from Ref. [53].
thiolate complexes under the same conditions. For example, the
second-order rate constant with hydrogen sulfide at pH 4.5, 25 ◦ C is
(66 ± 1) M−1 s−1 , as opposed to (18.1 ± 0.1) M−1 s−1 for glutathione
(at pH 5.0, 25 ◦ C). The reaction of aquacobalamin with hydrogen sul-
fide entails both molecular H2 S and the deprotonated form, HS− –
with rate constants of (58 ± 3) and (527 ± 89) M−1 s−1 , respectively,
which is consistent with the higher nucleophilicity of the HS− form.
For glutathione, the rates of reaction with three forms – protonated
at the thiol, deprotonated at the thiol and protonated at the amino
group, and deprotonated at the thiol as well as at the amino group,
are 18.5, (28 ± 10) and (163 ± 8) M−1 s−1 , respectively [40]. Com-
parison of the rate constants for the individual steps shows higher
reactivity for H2 S and HS− compared to GSH and GS− .
During the next two steps of the cobalamin-sulfide the changes
in the UV–Vis spectrum are suggestive of cobalt reduction, but
the spectrum of the final product is clearly different from Cbl(II).
It is suggested that during these stages electron transfer occurs
from hydrogen sulfide to Co(III), with the resulting sulfide radi-
cal remaining within the inner coordination sphere of the resulting
Co(II). Since the sulfide radical reacts at high rates with the remain-
ing hydrogen sulfide (reactions (2) and (3)) [55], it is assumed that
during the last stage of the Cbl–sulfide interaction a reversible
interaction of the bound sulfide radical bound with a second
molecule of hydrogen sulfide occurs, which can lead to a shift in
the equilibrium toward pentacoordinated Cbl(II).
HS− + S•− ↔ HSS•2− . (2)
HS −
+ HS• ↔ HSSH•− . (3)
Interaction of diaqua-cobinamide with hydrogen sulfide [54]
occurs much faster than the reaction involving Cbl(III)–OH2 . More-
over, both axial water molecules may be replaced by hydrogen
sulfide. Substitution of the first H2 O occurs at a high rate constant
– at pH 4.5, 25 ◦ C it is (2112 ± 171) M−1 s−1 , and at pH 9.6, 25 ◦ C it is
(11,051 ± 615) M−1 s−1 , which is more than an order of magnitude
greater than for the corresponding reactions of Cbl(III)–OH2 . Inter-
action of the monohydrosulfide complex with a second molecule
of H2 S occurs at a lower rate (rate constant 81.7 M−1 s−1 at pH 9.5,
25 ◦ C), which may be explained by the fact that at this pH a signifi-
cant fraction of the complex is in the (HS− )(HO− )Cbi(III) form, inert
to substitution.
In two subsequent stages electron transfer occurs from sulfide
ion to Co(III), resulting in the formation Cbi(II)–S•− , and then react-
ing the latter with a second molecule of hydrogen sulfide, as in the
case of Cbl(III)–OH2 . Electron transfer is more facile with complexes
containing one molecule of hydrogen sulfide. Probably, addition of
the second H2 S molecule to the complex increases the nucleophilic-
ity of the system, which leads to more negative redox potentials.
It is important to underline that the reaction of hydrogen sul-
fide with cobalamin and cobinamide under anaerobic conditions
does not lead to modifications of the macrocycle, as indicated by
subsequent conversion to known complexes (for example, methyl
or dicyano derivatives). However, if this reaction is carried out in the
presence of oxygen, modified corrin complexes are observed [53].
Interestingly, interaction of diaquacobinamide with hydrogen
sulfide in alkaline medium in an equimolar ratio leads to the for-
mation of a relatively stable complex, the UV–Vis spectrum of
which resembles Cbi(II) with the notable addition of a relatively
intense absorption band at 778 nm, which is extremely rarely seen
in corrin systems [54]. It is assumed that the long-wavelength
absorption bands in the complexes correspond to corrinoid ligand-
to-metal charge transfers (LMCT). These absorption bands have
been observed in complexes of cobalamin with I− , Br− , Cl− and
thiourea [56]. A 634-nm band also arises in a cobyrinate complex
with pentafluorophenylthiolate. Probably the strong polarization
of the Co(III) S bond affects energy of Co 3dz2 orbital and decrease
energy of corrin ␲ → Co 3dz2 transition corresponding to red region
of UV–Vis spectrum [57]. Apparently, the Cbi(II)–S•− complex also
displays notable charge transfer between the metal and the axial
ligand.
Understanding the interaction of Cbl(III) and Cbi(III) with H2 S is
also relevant for the use of these metal complexes as antidotes of
hydrogen sulfide. Hydrogen sulfide is a potent toxin originated from
a number of natural and industrial sources inhibiting cytochrome
c oxidase in human body. Several recent studies report that high
doses of Cbl(III)–OH2 can decrease a mortality associated with
H2 S exposure [58–60]. Since oxidation of H2 S in vivo occurs in
time-scale of several minutes, administration of aquacobalamin
in poisoned victims should be carried out immediately (1–4 min
after contact with H2 S) [60]. Furthermore, some forms of Cbi(III)
(viz., aquahydroxo-, sulfito- and dinitro-species of Cbi(III)) are also
effective antidotes for hydrogen sulfide with efficacy exceeding
that of aquacobalamin [61]. Moreover, Cbi(III)-species are more
advantageous than Cbl(III)–OH2 due to the higher water solubility
of the former [61]. Probable mechanisms of action of Cbl(III) and
Cbi(III) complexes as antidotes includes binding of H2 S to Co(III)
[62], oxidation of H2 S by Co(III) [63] and others [60]. According
to our data, both coordination and oxidation pathways occur in
H2 S/Co(III)-reaction, i.e., Co(III)-complexes readily bind one [53]
or two H2 S molecules [54] followed by slower reduction of Co(III)
to Co(II) [53,54]. Nevertheless, these studies [53,54] were per-
formed under anaerobic conditions and an influence of oxygen on
H2 S/Co(III)-system remain unassessed. On the other hand, refer-
ence [64] questions the detoxifying properties of the corrinoids
due to binding of free hydrogen sulfide, since most of the hydro-
gen sulfide within the blood stream would rapidly be subjected
to oxidation by plasma proteins [63]. Probably, further considera-
tion of the interaction between corrinoids and persulfides and thiyl
radicals would allow elucidation of these mechanisms of action of
cobalamin and cobinamide.
Complexes of cobalamin [65] and heptamethylcobyrinate [57]
with pentafluoriphenylthiolate display stabilities intermediate
between those of complexes with biological thiols and hydrogen
sulfide, respectively. The cobalamin–pentafluorophenylthiolate
complex is stable at −15 ◦ C in methanol; at room temperature,
however, Cbl(II) and the corresponding disulfide are formed [65].
Synthesis of cobirinate complexes with pentafluorophenylthiolate
at room temperature is possible, but photolysis or thermolysis of
the complex is also observed [57].
The reactions of aquacobalamin with the stronger sulfur-
containing reducing agents dithionite (S2 O4 2− ) [22], sulfoxylate
(SO2 2− ) [66], and hydroxymethanesulfinate (HOCH2 SO2 − ) have
also been described [67]. As noted above, the reaction between
Cbl(III)–OH2 and S2 O4 2− leads to the hexacoordinated Cbl(II)
complex with the radical SO2 •− . This complex is also formed
during the reaction Cbl(III)–OH2 with sulfoxylate [66] (SO2 H− ,
obtained by decomposition of thiourea dioxide in an alkaline
 I.A. Dereven’kov et al. / Coordination Chemistry Reviews 309 (2016) 68–83
medium under anaerobic conditions [68]), as well as with hydrox-
ymethanesulfinate [67]. The final product in the reduction with
hydroxymethanesulfinate in strongly alkaline medium is Cbl(I).
With dithionite, the reducing agent is the SO2 •− radical, formed
in reaction (4) from S2 O4 2− [69].
S2 O4 2− ↔ 2SO2 •− .
Reduction of cobalamin derivatives containing strongly bound
ligands at the ␤-position (e.g., CN− , CH3 − , Ado− and others),
is much slower than for the aquacomplexes. Electrochemical
reduction of cyanocobalamin is observed at −0.76 V (vs. NHE,
in DMSO/propanol), which corresponds to an irreversible two-
electron process, i.e., the reaction product is Cbl(I) [70]. Reduction
of organocobalamins occurs at even lower values of potentials. For
example, the irreversible reduction of MeCbl occurs at −1.20 V (vs.
NHE, 20 ◦ C), while AdoCbl is reduced at −1.04 V (in DMF/methanol)
[71]. DFT calculations have correlated such redox potential obser-
vations for alkylcobalamins with the energy of the LUMO [72].
The kinetics of the reaction between Cbl(III)–CN− and dithionite
or hydroxymethanesulfinate were also analyzed [73]. With S2 O4 2−
the reaction rate is pH-independent, while in the case of hydrox-
ymethanesulfinate the rate increases with the pH. Concentration
dependences have a non-linear shape and reach a plateau at high
concentrations of the reducing agent. Interestingly, the rate con-
stants at the plateau phase for S2 O4 2− and HOCH2 SO2 − are identical
to each other (0.03 s−1 at 25 ◦ C). It is important to emphasize
that this value is close to the dissociation rate constant for DMBI
Cbl(III)–CN− (0.042 s−1 at 25 ◦ C) [74]. Additionally, the activation
parameters are also identical for the reduction reaction and for
DMBI elimination. This indicates that the rate-determining step
of the process is the dissociation DMBI, followed by rapid com-
plexation by the reducing agent, and electron transfer (Scheme 3).
Cyanide binds weakly to the Co(II) corrins and, therefore, leaves the
complex [70]. The reaction product in this case is Cbl(II)–SO2 •− , as
in the case of the aqua complexes.
Despite the very low value of the reduction potential of
Cbl(III)–CN− and the extremely low rate of its interaction with
reducing agents, in living organisms, there are effective ways to
transform this complex to coenzyme forms. One of the stages of
this process is reduction to Cbl(II). In mammals, decyanation of
Cbl(III)–CN− is accomplished the CblC trafficking protein, which
uses as the electron source methionine synthase reductase [75], or
glutathione [76]. Binding of cyanocobalamin to the CblC protein
leads to a base-off form [77,78], which is expected to facilitates the
decyanation [77,78] in ways reminiscent of the above-discussed
reduction of Cbl(III)–CN− by sulfur-based reductants [73].
There are several routes for chemical reduction of alkylkobal-
amins [79]. For example, carbon monoxide, sodium dithionite
and sodium stannite reduce methylcobalamin in strongly alkaline
media. The reaction proceeds at a low rate, but the removal of DMBI
leads to a further increase in the reaction rate, of about 10-fold;
indeed, the base-off forms of organocobalamins have a higher redox
potential than base-on ones [80].
The interaction of alkylcorrinoids with thiols [81,82] pro-
ceeds at low rates, yielding cobalamin(II) and the corresponding
thioether. The mechanism involves attack of thiolate on the Co C
Scheme 3. A mechanism of reduction of cyanocobalamin.
Source: Adapted from Ref. [73].
73
bond, leading to the formation Cbl(I) species which is not directly
detected in the system, arguably due to its high reactivity – so high
that even protons may oxidize it to Cbl(II).
In the case of base-off complexes, ESI–MS data have confirmed
the formation of the six-coordinate thiolate complex preceding
deligation [83]. However, it is unlikely that the incoming trans-
(4)
thiolate has a significant influence on the activation of the Co C
bond, since the strength of the latter is practically independent
on the presence of ligands in the ␣-position [84,85]. Pyridine and
Zn2+ do affect the reaction rates, presumably by facilitating thiol
deprotonation [83].
Systems such as the CblC-trafficking protein illustrate deligation
reactions of alkylcobalamins in biological systems. In this case, a
transition to the base-off form occurs upon binding to the protein
[86,87]. This particular reaction requires GSH, which is eventually
converted into the corresponding thioether. It is assumed that the
mechanism involves a nucleophilic substitution of the alkyl moiety
by the thiolate, which leads to the formation of Cbl(I). While the
CblC catalytic processes is more than 10,000 times faster than the
uncatalyzed one, the reason for such a significant catalytic effect is
not clear [87].
An interesting result was obtained in the study of the inter-
action between AdoCbl bound to the Caenorhabditis elegans CblC
protein, and GSH [88]: Cbl(I) is formed at a relatively high rate, in
contrast with the fact that free AdoCbl reacts only very slowly with
GSH. Moreover, excess glutathione significantly contributed to the
stabilization of the Cbl(I) form in the presence of oxygen. Proba-
bly, further structural studies of the CblC/Cbl complex may help
understand the cause of this efficient activation of cobalamin by an
otherwise relatively weak reducing agent – glutathione.
Synthetic derivatives of cobalamin are known (so-called “Antivi-
tamins B12 ”), which can minimize deligation at the Co within
the CblC-protein. Such complexes include 4-ethylphenylcobalamin
(with a Co C(phenyl) bond) [89], and phenylethynylcobalamin
(with the acetylenic moiety bound at Co) [90]. Impaired deligation
in vivo implies increased resistance toward transformation toward
the coenzyme form, so that the enzymes binding these “antivita-
mins” are deprived of their catalytic function. This is important, for
example, for the development of drugs that suppress cancer cells,
as these require large amounts of cobalamin for their growth. In
addition, inhibition of Cbl-dependent enzymes in vivo may be rele-
vant for a set of degenerative brain and nerve diseases, attributable
to a lack of vitamin B12 .
Thus, two types of mechanisms have been discussed for reduc-
tion of alkylcobalamins (Scheme 4). One type of mechanism
involves the outer-sphere reaction of the reducing agent with a
base-off form of the alkylcobalamin, yielding (according to quan-
tum chemical calculations) a corrin anion radical [91]. The reduced
form of the complex displays a dramatically increased rate of cleav-
age of the Co C bonds (∼1015 times), leading to Co(I) and the alkyl
radical of [92] or, in the presence of acids, Co(II) and the respective
hydrocarbon [93]. Indeed, alkyl radicals were demonstrated using
spin trapping during electrochemical reduction of organocobal-
amins in DMF [94,95]. Decomposition of the reduced alkyl complex
may be facilitated by the transition to a base-off state [91]. In the
second type of reduction mechanism, the reductants are thiols,
74 I.A. Dereven’kov et al. / Coordination Chemistry Reviews 309 (2016) 68–83

Scheme 4. Mechanisms of reduction of alkylcobalamins

Source: Adapted from Refs. [91–97].

and they directly attack the Co C bond. The transition state in this Table 1
Thermodynamic and kinetic parameters of Cbl(II) ↔ Cbl(I) transformations at 22 ◦ C
case (RS-Me-Cbl) can be described either as closed-shell [96] or as
(adapted from [100]).
open-shell biradical in which one of the electrons has moved from
thiolate onto the corrin [91,97]. Reaction Value

pKa
4. Mechanisms of reduction reactions for Co(II) forms
(5) 2.9
Reduction of Cbl(II) to Cbl(I) proceeds much more compli-
cated than reduction of Cbl(III) to Cbl(II). The potential for the
Cbl(II)base-on /Cbl(I) transition is −0.61 V (vs. NHE, 22 ◦ C), while
under similar conditions the potential for the Cbl(II)base-off /Cbl(I) (6) 4.9a
pair is −0.50 V [32]. These values are significantly lower than the
potential of the biological reducing agent – generally considered
to be the flavin enzyme, methionine synthase reductase [98], for
which the potential of the semiquinone/hydroquinone is −0.28 V
(7) 1.0
(pH 7.0, 25 ◦ C) [99]. Values of pKa , standard potentials and rate
constants related to Cbl(II)/Cbl(I) species (reactions (5)–(11)) are
summarized in Table 1. Standard potentials (NHE), V
The set of reductants able to afford Co(I) corrinoids is rela-
tively small, including Zn [27], Ti(III) [101], NaBH4 [36], SO2 2−
−0.496
and HOCH2 SO2 − (both in alkaline media) [66,67], monosaccharides (8)

[35] and thiols [102,103] (the latter two only for Cbi(II) in alkaline
media).
The kinetics of the reaction between Cbi(II) and monosaccha-
rides [35] (notably, Cbl(II) is inert in such reactions) displays (9) −0.498
nonlinear concentration dependences which can be linearized in
inverse coordinates, and the reaction order for the hydroxide ion is
two. The mechanism of the reaction includes rapid reversible coor-
dination of the ionized form of the monosaccharide at the Co(II) (10) −0.607
center, leading to the formation of a pentacoordinated complex
(reactions (12) and (13)), and then the interaction of this complex Rate constants, s−1
with OH− with the subsequent transfer of the electron to Co(II)
(reaction (14)). Probably, the coordination of the reducing agent is (11) 105 (on-reaction)
not possible on Cbl(II), due to the trans DMBI. Reduction of Cbi(II) 1.6 × 103 (off-reaction)
proceeds well with thiols under basic conditions or in the presence a
pKa = 5.56 at 25 ◦ C [36].
of base in methanol, which is not observed for Cbl(II) [102].
GlcH ↔ Glc− + H+ . (12)
− − Interaction of Co(II)-corrinoids with stronger reducing agents
H2 O–Cbi(II) + Glc ↔ Glc–Cbi(II) + H2 O. (13)
(sulfoxylate, hydroxymethanesulfinate) proceeds well under strin-
gent conditions (strongly alkaline medium, an excess of reducing
− agent). The reduction of Co(II)–SO2 •− complexes of cobalamin and
Glc–Cbi(II) + OH−
cobinamide by sulfoxylate occurs with approximately equal rates:
→ Cbi(I) + products of oxidation of monosaccharide. (14) the rate constant for the reaction with Cbl(II)–SO2 •− is (2.83 ± 0.11)
 I.A. Dereven’kov et al. / Coordination Chemistry Reviews 309 (2016) 68–83
Scheme 5. A mechanism of reduction of Co(II)-corrins by sulfoxylate (SO2 2− ).
Source: Adapted from Ref. [67].
M−1 s−1 vs. (2.18 ± 0.07) M−1 s−1 for Cbi(II)–SO2 •− at pH 13.0, 25 ◦ C
[67]. The pH dependence of the process is described by an S-
shaped curve with a pKa = 13.47 ± 0.07 at 25 ◦ C [67], consistent with
deprotonation of the anion SO2 H− [104] and implying that the
reducing agent for Co(II) is SO2 2− . In cases where a separate pre-
liminary reduction to Co(II) is achieved using ascorbate (to avoid
accumulation of the SO2 •− radical anion) allows for more facile
subsequent reduction to Co(I). This confirms that a Co(II)-anion-
radical complex is not a prerequisite for reduction of Co(II) by SO2 2−
(Scheme 5).
The addition of dithionite impairs conversion of Co(II) to Co(I),
and at [S2 O4 2− ] > 0.05 M Co(I) is no longer obtained, which indi-
cates the occurrence of the reverse reaction, oxidation of Co(I) by
dithionite. Indeed, addition of dithionite to Co(I) corrins leads to
their oxidation to Co(II)–SO2 •− [66].
For the reaction of Co(II) complexes with hydroxymethanesul-
finate (HMS), the dependence of the observed rate constant on
the concentration of HMS is linear only in the inverse coordi-
nates (1/kapp. vs. 1/[HMS]), which is typical of a reaction occurring
through rapid reversible complex formation and subsequent decay.
The observed reaction rate constant increases linearly with [OH− ],
indicating that hydroxide participates in the process. Thus, the for-
mation of Co(I) entails reactions (15) and (16) [67].
Co(II)–SO2 •− + HOCH2 SO2 − ↔ − HOCH2 SO2 –Co(II) + SO2 •− . (15)
− bond lengths would be ∼2.25 Å, depending primarily on the type
HOCH2 SO2 –Co(II) + OH−
→ Co(I) + products of oxidation of HMS. (16)
Kinetics data suggest a dependence of the reduction mecha-
nisms of Co(II) cobalamins and cobinamides on the nature of the
reducing agent. Thus, reduction of Cbl(II) and Cbi(II) with sulfoxy-
late or sodium hydroxymethanesulfinate (strong electron donors)
proceeds with comparable rates, while reduction of the same metal
complexes by monosaccharides (weaker electron donors) proceeds
differently.
Co(I) corrinoids may be prepared photochemically by irra-
diation in solution at appropriate wavelengths. For example,
without added photosensitizer the Co(I) heptametilcobyrinate
can be obtained by irradiation of a methanolic solution or
a solution in an ionic liquid (N-methyl-N-propylpyrrolidinium
bis-(trifluoromethanesulfonyl) amide) in the presence of tri-
ethanolamine, with 365-nm light [105]. In the ionic liquid the
reaction is ∼10 times faster. Two mechanisms have been proposed
for this process. In the first case, corrin photoexcitation leads to
electron transfer from the macrocycle to metal, thereby forming a
corrin radical cation. In the second case, a transient complex may be
formed between the photoexcited corrinoids and triethanolamine,
allowing electron transfer to the cobalt (Scheme 6).
75
Photosensitizers can facilitate the formation of Co(I)-corrinoids
(Scheme 6). It is reported that in the presence of [Ru(II)(bpy)3 ]Cl2 ,
the Co(I) form of heptamethylcobyrinate can be obtained by
irradiation with visible light (wavelength not specified) [106]. Pho-
tosynthesis of styrene-based polymers with covalently attached
dicyanohexamethylcobyrinate and Ru(bpy)3 , using light at 
≥420 nm, has been reported to also enatil Co(I) formation
[107]. Simultaneous immobilization of heptamethylcobyrinate and
Ru(bpy)3 in MOF (metal-organic frameworks) also allows Co(I)
formation when irradiated with visible light ( ≥ 420 nm) [108].
Alternative photosensitizers in this reaction may also be the less
expensive dyes Rose Bengal [109] and Rhodamine B [110] – using
 ≥ 440 nm.
Co(II)-corrinoids may also be photoreduced using TiO2
[111,112]. Cyanocobyrinic acid applied to a TiO2 surface is reduced
to Co(I) upon UV irradiation ( = 365 nm) [112].
As shown above, the reduction of cobalamin(II) complexes is a
relatively challenging reaction; nevertheless, living organisms have
developed catalytic mechanisms to implement this process. One
such pathway entails conversion of the Cbl(II) to the tetracoordi-
nated form upon binding to the enzyme active site – as it is indeed
expected that the removal of nucleophiles from the coordination
sphere will reduce the potential of the Co(II)/Co(I) couple [27]. Such
a complex was detected as part of the ATP: cobalamin adenosyl-
transferase [24–26,113]. An alternative route for the reduction of
cobalamin(II) is based on the hypothesis of the formation of Co(I)
– H–X hydrogen bonds [28–31]. The DFT-calculated value of such
of substrate [28]. Calculations show that the transition from the
pentacoordinated Cbl(II)base-off to pseudo-pentacoordinated Cbl(I)
– H–X is thermodynamically more favorable than the transition to a
simple tetracoordinated Cbl(I), and the process is even further facil-
itated if two hydrogen bonds are involved instead of one [28,29].
To date, it has not been possible to obtain crystallographic informa-
tion on Cbl(I), presumably due to its unusually high reactivity. In
favor of this hypothesis is the fact that hydrogen bonding to simpler
(non-corrinoid) Co(I) centers is known experimentally [114].
Activation of the corrinoid-[Fe–S] protein, which carries out the
transfer of a methyl group from methyltetrahydrofolate to acetyl-
CoA, is also instructive in these respects. Binding of the activator (an
iron-sulfur protein itself) is essential for electron transfer from the
[2Fe2S] cluster to the Co(II)-corrinoid in the presence of ATP. This
binding leads to significant structural changes, which are supported
by resonance Raman [115] and EPR spectroscopy [115,116] as well
as by crystallographic data [116]. Thus, a water molecule (∼2.5 Å
Co(II) – O bond length [117]) at the Cbl ␤-position is replaced
(upon binding of the activator protein) by a serine HO side-
chain with a Co(II) – H contact at 2.5 Å [115]. The reason for this
replacement is unclear (the authors of [116] suggest that this sub-
stitution contributes to the displacement of the redox potential of
the Co(II)/Co(I) couple in the negative direction, i.e., stabilizes the
Co(II) state).
76 I.A. Dereven’kov et al. / Coordination Chemistry Reviews 309 (2016) 68–83
Scheme 6. Possible mechanisms of UV–Vis light driven Cbx(II) reduction without (A) or with (B) photosensitizer added in system.
Source: Adapted from Refs. [105,110].
5. Mechanisms of oxidation of the Co(II) forms of
cobalamins and their derivatives
Despite its relatively high redox potential, Cbl(II) is a fairly
strong reducing agent of free radicals. This is explained primarily by
the presence of an unpaired electron in the metal 3dz2 orbital, per-
pendicular to the plane of the macrocycle. Contact with an unpaired
electron of the oxidant hardly affects macrocycle and minimizes
destruction of the complex during the reaction [118].
Co(II)-corrinoids react with oxygen through a fast reversible
oxygen binding step, eventually yielding the Co(III) state (reaction
(17)). Evidence for a transient Co(III)–O2 •− adduct has come form
EPR [119–122], quantum chemical calculations [123], and crystal-
lography [124].
Co(II) + O2 ↔ Co(III)–O2 •− →→ Co(III)–solv. + H2 O2 + O2 .
solv. = H2 O, MeOH, etc.
Cbl(II) reacts very rapidly with superoxide [125,126], yield-
ing Cbl(III) without modification of the corrin (reaction (18)).
The rate constant (measured with a steady-state flux of
superoxide from the xanthine oxidase/acetaldehyde system) is
(6.8 ± 0.8) × 108 M−1 s−1 at pH 7.4, 25 ◦ C, which is comparable to
the rate constant for superoxide dismutation (2 × 109 M−1 s−1 in
the presence of Cu, Zn – superoxide dismutase) [125]. Similar rates
((3.78 ± 0.07) × 108 M−1 s−1 ) were observed when superoxide was
obtained by radiolysis. Co(III) corrinoids do not react with super-
oxide [126].
Cbl(II) + O2 •− + 2H3 O+ → Cbl(III)–OH2 + H2 O2 + H2 O.
The reaction between Cbl(II) and H2 O2 occurs at a slower rate
[125]. The H2 O2 is able to destroy the corrin [33]; this happens
in systems containing both reductants (e.g., ascorbic acid [33,39],
thiols [127], polyphenolic compound [127]) and molecular oxy-
gen. Under such conditions, Co(III) ↔ Co(II) redox cycling leads to
considerable amounts of H2 O2 as side-products. Then, according
to reaction (19), hydroxyl radicals may cause degradation of the
cobalamin. This phenomenon occurs in foods fortified with vita-
min B12 and containing a significant amount of reducing agents
such as polyphenols [127].
Cbl(II) + H2 O2 → Cbl(III)–OH− + OH• .
Probably the most thoroughly investigated reaction of Cbl(II)
is the one with NO. This reaction can take place in vivo, as NO
was shown to be able to inhibit Cbl-dependent enzymatic pro-
cesses [128,129] and Cbls influence NO-related events [130–132].
NO binding to cobalamin proceeds at a high rate (the rate constants
at pH 1.0 and 7.4, 25 ◦ C, are 5.0 and 7.4 × 108 M−1 s−1 , respectively)
and is reversible (the dissociation rate constants at pH 3.6 and 7.4,
25 ◦ C are 1.7 and 5.6 s−1 , respectively) [133]. The resulting complex
is EPR-silent [133], its resonance Raman spectrum shows band at
514 cm−1 assigned to a bent Co(III)–NO− bond [134]. Nitrogen(II)
within a nitroxyl NO− ligand was confirmed later by 15 N NMR [133]
and X-ray analysis [135,136]. DFT calculations show, however, that
a more precise description of the structure of the complex would
be a hybrid between the Cbl(III)–NO− and Cbl(II)–NO resonance
structures [137].
(17) The activation parameters of the direct reaction at
pH 7.4 are: H =/ = 24.5 kJ mol−1 , S =/ = +7 J K−1 mol−1 ,
V =/ = +5.4 cm3 mol−1 . Since the small positive values of entropy
and volume activation are characteristic of a dissociative inter-
change (Id ) mechanism, the authors proposed a scheme for the
reaction with a rapid reversible formation of a hexacoordinated
aqua-cobalamin(II) intermediate, and the subsequent replacement
of bound water molecule by NO (Scheme 7) [133].
The rate of the forward reaction between Cbi(II) and NO is
comparable to that of Cbl(II) (2.4 ± 108 M−1 s−1 at pH 7.4, 25 ◦ C),
but the rate of reverse process is significantly lower (0.019 s−1 at
pH 7.4, 25 ◦ C) [138]. The higher affinity of Cbi(II) to NO, and the
absence of a base in the ␣-position, lead to a significant differ-
(18) ence in the properties of the Cbl(II) and Cbi(II) nitrosyl complexes:
nitrosylcobinamide is relatively stable in the presence of oxygen
[139], whereas nitrosylcobalamin rapidly oxidized to a mixture of
nitro and aquacobalamin [140]. In this context, Cbi(II)–NO has been
Scheme 7. A mechanism of nitric oxide binding by Cbl(II).
(19) Source: Adapted from Ref. [133].
 I.A. Dereven’kov et al. / Coordination Chemistry Reviews 309 (2016) 68–83 77

proposed as hypotensive agent [139] as well as wound healing instead reacts with NO (reaction (21)), so that the final products
accelerator [141]. In addition, cobinamide can act as an effective are Cbl(III)–NO− and Cbl(III)–OH2 .
NO trap in the body, with potential use for controlling the concen-
tration of this important signaling molecule [142]. HNO2 ↔ NO2 − + H+ . (27)
There are several routes toward Cbl(III)–NO− . For instance, 2HNO2 ↔ NO+ + NO2 − + H2 O. (28)
Cbl(III)–SG− reacts very rapidly with NO (2.8 × 103 M−1 s−1 at pH
7.0), yielding Cbl(III)–NO− via a mechanism proposed to involve NO+ + Cbl(II) → Cbl(III) + NO. (29)
formation of Cbl(II)–ONSG intermediate further decomposing to
Cbl(II) reacts rapidly with sodium nitroprusside
Cbl(III)–NO− and thyil radical [143]. The subsequently-derived
(Na2 [Fe(CN)5 NO]). In the initial step, there is a rapid reversible
activation parameters (H =/ = 41 kJ mol−1 , S =/ = –42 J K−1 mol−1 ,
complex formation between [Fe(II)(CN)5 NO]2− and Cbl(II) (reac-
V =/ = –9.6 cm3 mol−1 ) are characteristic for an associative mech-
tion (30)), which after intramolecular electron transfer becomes
anism [144] and support a transient formation of Cbl(II)–ONSG.
Cbl(III)–[Fe(I)(CN)4 NO]2− and CN− (reaction (31)). The latter is
Alternatively proposed mechanism for the reaction [144] involves
then able to substitute the [Fe(I)(CN)4 NO]2− fragment on Co(III)
two NO-molecules and proceeds via reversible formation of an
(reaction (32)). Nitroprusside is also capable of substituting the
intermediate complex of Cbl(III)–SG− with NO (as a rate determin-
[Fe(I)(CN)4 NO]2− fragment (reaction (33)) [149].
ing step), followed by fast decay to Cbl(II) and nitrosothiol (reaction
(20)). The excess NO shifts the equilibrium toward the products Cbl(II) + [Fe(II)(CN)5 NO]2− ↔ Cbl(II)–[Fe(II)(CN)5 NO]2− . (30)
(reaction (21)) [144]. Nevertheless, reaction stoichiometry was not
determined providing no preference for any proposed pathways.

Cbl(III)–SG− + NO ↔ Cbl(II)–ONSG ↔ Cbl(II) + GSNO. (20) Cbl(II)–[Fe(II)(CN)5 NO]2− ↔ Cbl(III)–[Fe(I)(CN)4 NO]2− + CN− .

(31)
Cbl(II) + NO ↔ Cbl(III)–NO− . (21)

Nitroxylcobalamin is formed during the reaction of aquacobal-

amin with R2 N–NONO derivatives (1-(N,N-dialkylamino)diazen-1-
ium-1,2-diolates). The mechanism of the reaction involves rapid Cbl(III)–[Fe(I)(CN)4 NO]2− + CN−
reversible coordination of R2 N–NONO to Co(III) and the subsequent
↔ Cbl(III)–CN− + [Fe(I)(CN)4 NO]2− . (32)
slow decay of the complex to Cbl(III)–NO− and the corresponding
nitrosamine (reaction (22)) [145].

Cbl(III)–OH2 + R 2 N–NONO ↔ R 2 N–NONO–Cbl(III) + H2 O

Cbl(III)–[Fe(I)(CN)4 NO]2− + [Fe(II)(CN)5 NO]2−
→ Cbl(III)–NO− + R 2 N–NO. (22)
↔ Cbl(III)–[Fe(II)(CN)5 NO]2− + [Fe(I)(CN)4 NO]2− . (33)

The authors of [146] believe that Cbl(III)–NO− is formed dur-

ing the reaction of Cbl(III)–OH2 with Angelli’s salt (Na2 N2 O3 ). The
reaction mechanism includes two parallel routes: direct interac-
tion of Cbl(III)–OH2 with the decay product of Angelli’s salt (HNO,
reactions (23) and (24), noting that the side product NO2 − may
slow down reaction (24)), and a rapid reversible complex for-
mation between Cbl(III) and HN2 O3 − with subsequent decay to
Cbl(III)–NO− and NO2 − (reaction (25)).
− −
HN2 O3 → HNO + NO2 .
−
HNO + Cbl(III)–OH2 → Cbl(III)–NO + H2 O + H . +
Cbl(II) reacts very rapidly with nitrogen dioxide (NO2 • ) (rate
constant at pH 7.4, 25 ◦ C: 3.5 ± 108 M−1 s−1 ). The product (reaction
(34)) is nitrocobalamin, which does not further interact with NO2 •
[150].
Cbl(II) + NO2 • → Cbl(III)–NO2 − . (34)
Cbl(II) efficiently reacts with peroxynitrous acid (ONOOH): the
rate constant at 25 ◦ C is 1.6 × 106 M−1 s−1 . During the one-electron
(23)
reduction ONOOH forms NO2 • (reaction (35)), which is then further
(24) reduced to NO2 − (reaction (34)) [151].

Cbl(II) + ONOOH → Cbl(III)–OH− + NO2 • . (35)

Cbl(II) reacts with nitroxyl (HNO/NO− )

Cbl(III)–OH2 + HN2 O3 − ↔ Cbl(III)–HN2 O3 − + H2 O
→ Cbl(III)–NO− + NO2 − .
Generation of Cbl(III)–NO− and Cbi(II)–NO may also occur by
reductive nitrosylation of Cbl(III) with a mixture of NO and NO2 −
at pH <4. The process is reversible and can be represented as
the macroscopic equilibrium (reaction (26)) (K = 0.6 ± 0.2 at 25 ◦ C)
[147]:
yielding Cbl(III)–NO−
and N2 as final products. Reaction stoichiometry was found to
(25) be [Cbl(II)]0 : [HNO]0 = 1: 2 and authors suggested the following
mechanism (reactions (21), (36) and (37)) [152]. In this scheme,
generation of Cbl(I) by reaction (36) seems to be disadvantageous,
since Cbl(I) is very reactive toward NO formed (see below). DFT
and CASSCF calculations predict an existence a Cbl(II)–HNO adduct
[123], which can be the first intermediate in this mechanism.
Cbl(II) + HNO → Cbl(I) + NO + H+ . (36)

Cbl(III)–NO2 − + 2NO + H2 O ↔ Cbl(III)–NO− + 2HNO2 . (26) 2Cbl(I) + 2HNO + 2H+ → Cbl(I) + N2 + H2 O. (37)

Also very fast is the reaction between Cbl(II) and the carbonate
Cbl(II) reacts with nitrite under acidic conditions (reactions
radical (CO3 •− ). It consists of three successive stages. During the
(27)–(29)). The rate-determining step is nitrosonium ion (NO+ )
first stage (rate constant at pH 9.0: 2.0 × 109 M−1 s−1 ; reaction (38))
formation from with nitrous acid (28). The subsequent reaction
Cbl(II) is oxidized to hydroxocobalamin, while the subsequent two
between Cbl(II) and NO+ (reaction (29)) occurs at a higher rate
stages entail modifications of the corrin ring [153].
and leads to the formation of Cbl(III) and NO, which do not further
react with each other [148]. The remaining Cbl(II) in the system Cbl(II) + CO3 •− + H2 O → Cbl(III)–OH− + HCO3 − . (38)
78 I.A. Dereven’kov et al. / Coordination Chemistry Reviews 309 (2016) 68–83
Based on the above data it can be concluded that Co(II)-
corrinoids effectively react with many species responsible for
oxidative as well as nitrosative stress. Not surprisingly then, in vitro
experiments have shown that cobalamins have antioxidant prop-
erties [154].
One feature of the Co(II)-corrinoids is their ability to methylate
with methyl iodide [102,103], and in some cases, methyl tosylate
[102] in the presence of thiols. It is important to stress that there is
no direct reaction between Cbl(II) and the methylating agent. Two
mechanisms were proposed for these processes, depending on the
pH, the type of the metal complex, thiol and methylating agent.
The first is due to the ability of thiols to reduce of Co(II) base-off
corrinoids in alkaline media to Co(I) (reaction (39)), which readily
accepts a methyl group (reaction (40)). The second route is observed
in acidic environments, reduction of Co(II) is impossible at low con-
centrations of thiolate; here, the reaction is assumed to involve a
Co(II)–RSH complex (reaction (41)), which then reacts with MeI
forming a so-called ‘Pratt complex’ [RSH–Co(II)–MeI], which fur-
ther transforms into Me–Co(III) (reaction (42)) [102,103].
2Co(II) + 2RSH ↔ 2Co(I) + RSSR + 2H+ . (39)
Co(I) + MeI →→ Me–Co(III) + I− . (40)
Co(II) + RSH ↔ RSH–Co(II). (41)
RSH–Co(II) + MeI ↔ RSH–Co(II)–MeI
→ Me–Co(III) + ½RSSR + I− . (42)
While Cbl(II) does not directly react with dehydroascorbic acid
(DHA), the addition of GSH [155], cysteine [156], N-acetylcysteine
[156] or SCN− [155] leads to oxidative formation of RS− –Cbl(III)
complexes, and two-electron reduction of DHA to ascorbic acid.
Importantly, this reaction does not proceed in the presence of other
amino acids (those that do not contain sulfur, and even methionine
[156]), while in the presence of S-methylglutathione the process
proceeds with a very low rate [155]. Detailed kinetic data are avail-
able for this reaction in acidic and neutral media, where the rate
increases with pH, and with [RSH]. The mechanism involves rapid
reversible coordination of the thiol to Co(II); interaction of this com-
plex with DHA leads to RS− –Co(III) and ascorbyl radical – which
dismutates to dehydroascorbic and ascorbic acid (Scheme 8) [156].
The formation of Cbl(II) complex with SCN− was confirmed exper-
imentally by EPR and UV–Vis spectroscopy, as well as by quantum
chemical calculations [23], while the GSH–Cbl(II) complex was
confirmed by cryo-MS [155] and EPR [157], which is, probably, pen-
tacoordinated [157]. Further quantum chemical calculations can
provide more precise insight in structure of Co(II)-complexes with
thiols relevant to this reaction. Such complexation lowers the redox
Scheme 8. A mechanism of thiolate-assisted reduction of DHA by Cbl(II).
Source: Adapted from Ref. [156].
potential of the Co(III)/Co(II) couples, i.e. increases the reducing
properties of cobalamin(II) [155] as yet another illustration of the
manner whereby the coordination environment of the ion Co(II)
directly modulates its redox properties. Perhaps further study of
redox reactions involving other Co(II)-corrinoids may allow more
insight, as their formation occurs much more easily than that of
Cbl(II) complexes [158].
Cbl(II) reacts with inorganic Co(III) complexes (chloride, bro-
mide, iodide, azide, thiocyanate, or pyrazine derivatives of
Co(III)(NH3 )5 and Co(III)(bpy)3 ). The reaction products are aqua-
cobalamin and the Co(II) salt. The electron transfer occurs in
inner-sphere manner with Co(III)(NH3 )5 , while for Co(III)(bpy)3 it
is outer-sphere [159].
6. Oxidation mechanisms for Co(I) cobalamins and their
derivatives
Cbl(I) is a very strong natural nucleophile (“supernucleophile”)
and a strong reductant. On the Pearson scale it displays a nucle-
ophilicity of 14.4 [160,161], which is much higher than of other
biological centers. According to CASPT2 [162] and CASSCF [163]
calculations, the Cbl(I) ground state entails a mixture of Co(I) (d8 )
and Co(II)-(d7 )-corrin radical configurations, with a significant pre-
dominance of the former. The reason for the high reactivity of Cbl(I)
can be a significant destabilization of the 3dz2 orbital and its conve-
nient orientation for contact with an oxidizing agent [27], as well as
the presence of the biradical component in the ground-state wave
function [163].
One of the most prominent reactions of Co(I) complexes is the
one with protons – and Co(I)-corrinoids are not exception: they
are poorly stable in aqueous solutions, eventually yielding Cbl(II)
and H2 in an process displaying oscillatory kinetics. Oscillations are
observed in the pH range 2–12; their period depends on the tem-
perature, and they disappear under the action of light. However,
their origin is unclear and no reaction intermediates were observed
experimentally [164].
Cbl(I) is much more stable in acidic environments than other
Co(I) complexes, and displays a protonation pKa of ∼1 (reaction
(7)) [165], much smaller than for other Co(I) complexes [166].
Hydrogen-generating photocatalytic systems based on corri-
noids have been proposed [112,166]. The yield of hydrogen by
irradiating a neutral Cbi aqueous solution in the presence of tri-
ethanolamine or eosin Y, was lower than using cobaloxime as
catalyst [166]. Significantly higher yields of hydrogen were afforded
by cyanoaquacobyrinate immobilized on TiO2 . In the latter case,
addition of spin-trapping compounds affects the hydrogen yield,
which suggests involvement of H-radicals in the process [112].
The proposed mechanism for the interaction of Cbl(I) with
protons [112] involves, as a key step, the formation of hydridocobal-
 I.A. Dereven’kov et al. / Coordination Chemistry Reviews 309 (2016) 68–83 79

amin(III) (reaction (43)), which then dismutates, or reacts with Cbl(III)–H− + N2 O → Cbl(III)–OH− + N2 . (57)
protons (directly or after prior reduction to Co(II)-hydride), yielding
Reduction of hydroxylamine occurs at relatively low rate [175].
molecular hydrogen (reactions (44)–(47)). Hydridocobalamin was
The active form of the oxidant in this case is NH3 OH+ , probably
also assumed as a reagent reduction of double bonds [112].
according to reaction (58). Methylation of the nitrogen atom of
Co(I) + H+ → Co(III)–H− . (43) hydroxylamine increases the rate of reaction.
−
2Co(III)–H → 2Co(II) + H2 . (44) NH3 OH+ + Cbl(I) → NH3 + Cbl(III)–OH− . (58)
− + •−
Co(III)–H + H → Co(III) + H2 . (45) Sulfite reacts with Cbl(I) to yield a Cbl(II)–SO2 complex, in
− −
a process where HSO3 − , S2 O5 2− and SO2 ·H2 O may act as oxi-
Co(III)–H + ē → Co(II)–H . (46) dants (reactions (59)–(61)), wherein the reactivity of the substrates
− +
Co(II)–H + H → Co(II) + H2 . (47) decreases in the series: SO2 ·H2 O > S2 O5 2− > HSO3 − . Very rapid is
also the reaction of Cbl(I) with thiosulfate. In this case, the oxidant
Cbl(I) also reacts with nitrogen oxides and oxyanions, such as is probably HS2 O3 − (reaction (62)), which is ultimately converted
NO3 − , ONOO− , NO2 − , NO, N2 O, NH2 OH. The reaction with nitrate to HS− and SO3 2− (reaction (63)) [176].
[167,168] in acidic medium has NH4 + as final product [168]; the
active form reacting with Cbl(I) is HNO3 (reaction (48)) [168]. Cbl(I) Cbl(I) + HSO3 − → Cbl(II)–SO2 •− + OH− . (59)
reacts with HNO2 , eventually leading to the formation of NH2 OH in Cbl(I) + SO2 ·H2 O → Cbl(II)–SO2 •− + H2 O. (60)
slightly alkaline media (reactions (49) and (50)) [168]. It is likely
Cbl(I) + S2 O5 2−
→ Cbl(II)–SO2 •− + SO3 2−
. (61)
that nitrite is an intermediate product of nitrate reduction, and
variations in the composition of the final reaction products may be
explained by the pH dependence of the reactivity of hydroxylamine
(see below). Cbl(I) + HS2 O3 − → Cbl(II) + HS• (or SO3 •− ) + SO3 2− (or HS− ).

Cbl(I) + HNO3 → Cbl(III)–OH− + NO2 − . (48) (62)

+ −
Cbl(I) + HNO2 + H → Cbl(III)–OH + HNO. (49)
+ −
Cbl(I) + HNO + H + H2 O → Cbl(III)–OH + NH2 OH. (50) Cbl(I) + HS• (or SO3 •− ) → Cbl(II) + HS− (or SO3 2− ). (63)

Cbl(I) reacts very rapidly with peroxynitrite [169] (in its ONOO− The reaction of Cbl(I) with dithionite is the only known example
as well as ONOOH forms), with N2 reported as product. It is not of chemical reduction of this compound. In this process Cbl(I) reacts
clear what is the difference in the mechanisms of the reduction with dithionite itself, S2 O4 2− , as well as with its monomerization
of the two isomers (nitrate and peroxynitrite), leading to different product, SO2 •− . Since sulfoxylate is formed during the reaction, and
final products, but one can assume that a key role is played by the it can act as reducing agent for Cbl(II), the following macroscopic
activation of ON OOH bond, which leads to the formation of NO – equilibria can be proposed (reactions (64) and (65)) [176].
an intermediate not common in the reduction of HNO3 . Cbl(I) + SO2 •− ↔ Cbl(II) + SO2 2− . (64)
Cbl(I) reacts rapidly with NO in solution, yielding to N2 O and
Cbl(I) + S2 O4 2−
↔ Cbl(II)–SO2 •− + SO2 2−
. (65)
N2 [170]. On the other hand, electrochemical reduction of NO on a
glassy carbon electrode modified with cyanocobalamin, leads to Cbl(I) is capable of reducing disulfides to thiols. Possibly, dur-
NH3 and NH2 OH [171]. Under such conditions, cyanocobalamin ing the rate-determining step (reaction (66)), a mixture of thiol
is reduced to Cbl(I). Probably, HNO is produced in the course of and thiyl radical is formed–with the latter affording a more rapid
the one-electron reduction of NO (reaction (52)), followed by rapid subsequent reaction with Cbl(I) (reaction (67)) [177].
dimerization and decomposition to N2 O (reaction (52)).
Cbl(I) + RSSR → Cbl(II) + RS− + RS• . (66)
Cbl(I) + NO + H+ → Cbl(II) + HNO. (51)
Cbl(I) + RS• → Cbl(II) + RS− . (67)
2HNO ↔ H2 N2 O2 → N2 O + H2 O. (52)
Cbl(I) also reduces various transition metal ions. Thus, it reduces
Cbl(I) is capable to reduce HNO [152]. In this case, neither V(IV) (vanadyl) and Mo(VI) (molybdate) to V(II) and Mo(III), respec-
NH4 + nor NH2 OH are reaction products, which implies reduction of tively (reactions (68)–(71)), and this reaction is autocatalytic, which
HNO to N2 . Authors suggested the following mechanism (reactions is explained by the higher oxidizing properties of V(III) and Mo(V),
(53) and (54)) involving transient formation of iminoxyl radical formed in the initial one-electron reduction [178].
(H2 NO• ). Therefore, reactions (51)–(54) can explain the formation
of N2 O and N2 as final products of reaction between Cbl(I) and NO. Cbl(I) + V(IV) → Cbl(II) + V(III). (68)
+
Cbl(I) + HNO + H → Cbl(II) + H2 NO• . (53) Cbl(I) + V(III) → Cbl(II) + V(II). (69)

2H2 NO• → N2 + 2H2 O. (54) Cbl(I) + Mo(VI) → Cbl(II) + Mo(V). (70)

It is also possible to explain a number of products of reactions
between Cbl(I) and nitrogen oxy-derivatives by the reason in the
difference in the coordination mode of NO-motif (nitro vs. nitrito),
as in the case of other tetrapyrrole complexes [172,173].
N2 O is reduced by Cbl(I) to N2 [41,174]. Two routes are proposed
for this reaction, depending on the species acting as actual reduc-
tant: Cbl(I) directly (reactions (55) and (56)) or hydridocobalamin
(reaction (57)) [41].
Cbl(I) + N2 O → Cbl(II) + N2 O− .
− + −
Cbl(I) + N2 O + H → Cbl(II) + N2 + OH .
Cbl(I) + Mo(V) → Cbl(II) + Mo(IV). (71)
It is known that Cbl(I) exhibits high reactivity toward various
organic compounds: methyl group donors [179–190], epox-
ides [191–193], halides [194–202], and unsaturated compounds
[193,203].
Interaction of Cbl(I) with CH3 -donors is a key step in the
catalytic cycle of the transfer of a methyl group in living organ-
isms. Such donors may be methyltetrahydrofolate [101,179],
(55) methylamines [180–182], methyl sulfides [183], methoxides [184],
methyl phosphates [185]. Notably, the direct interaction of Cbl(I)
(56) with CH3 -donors takes place at very low rates [186], and it remains
80 I.A. Dereven’kov et al. / Coordination Chemistry Reviews 309 (2016) 68–83
Scheme 9. A mechanism of Cbl(I)-assisted dehalogenation of DDT.
Source: Adapted from Refs. [94,200].
unclear how enzymes achieve acceleration of this reaction. Tra-
ditionally, the process is assumed to entail an SN2 -mechanism
of nucleophilic substitution, but one cannot exclude an alterna-
tive mechanism involving electron transfer, where the reaction
proceeds via a Co(II) – pterin–radical complex, and a subsequent
transfer of the methyl group [187–190].
Epoxides (oxiranes) are toxic metabolites produced, among oth-
ers, by cytochrome P450 enzymes acting on compounds containing
double bonds (acrylamide, 1,3-butadiene and others). With Cbl(I),
epoxides form a stable complex via a Co C bond. Such processes
have been employed in proposed efficient methods for the deter-
mination of epoxides in vivo [191–193].
Cbl(I) effects dehalogenation reactions of organic compounds,
and has as such been proposed to be involved in forms of anaerobic
respiration, where the final electron acceptor is a halogenated
compound (“halorespiration”). Such dehalogenations are also
of ecological interest, considering the halogenated nature of
many organic environmental pollutants (e.g., DDT, polychlorethy-
lene). Although for polychlorethylene the reaction is reported
in several instances [194–198], there is no clear understand-
ing of the reaction mechanism. Most recently [198,204] it has
been proposed that the interaction of tetrachlorethylene or
trichlorethylene with Cbl(I) leads to the formation of solvent-
caged [Cbl (II)–vinyl• ] radical pairs, which can then either lead
to an organocobalamin, or the vinyl radical may be liberated
into the solvent. A variety of methods have been developed
for the dehalogenation of 1,1-bis(4-chlorophenyl)-2,2,2-
trichloroethane (DDT) [94,105,106,108–110,199,200]. In DMF,
the main products are 1,1-bis(4-chlorophenyl)-2,2-dichloroethane
(DDD), 1,1-bis(4-chlorophenyl)-2,2-dichloroethylene (DDE),
1-chloro-2,2-bis(4-chlorophenyl)ethylene (DDMU) and 1,1,4,4-
tetrakis(4-chlorophenyl)-2,3-dichloro-2-butene (TTDB) [94],
while in ionic liquids 1,19-(ethylidene)-bis(4-chlorobenzene)
(DDO), 1,19-(ethenylidene)-bis(4-chlorobenzene) (DDNU) and
1,19-(2-chloroethylidene)-bis(4-chlorobenzene) (DDMS) are
reported [200]. The proposed mechanism involves nucleophilic
substitution of the first chlorine atom in DDT by cobalamin(I),
yielding an organocobalamin. Subsequent cleavage of the Co C
bond by light or electrolysis yields an organic radical, which when
liberated into the solvent is converted into the above range of
products (Scheme 9) [94]. Also studied has been the reaction
between Cbl(I) and sucralose (Suc), an artificial sweetener con-
taining three chlorine atoms. An initial substitution of one of the
three chlorine atoms leads to the corresponding organocobalamin
(Cbl–Suc), which may also possibly occur in vivo [201]. This com-
plex can collapse under the influence of light, acids, or electrolysis
[202].
The dehalogenation processes of chlorlorethylene in vivo and
in vitro are generally similar to each other [205], with differences
discussed below. During the first stage of the catalytic cycle of
the reductive dehalogenase enzyme, outer-sphere electron transfer
occurs from Co(I) to the substrate (over a distance of ∼5.8 Å [206]),
which leads to the formation of a halogen ion and an organic rad-
ical [206,207]. A direct interaction of the Co(II) with the radical
is in principle possible, leading to an organocobalamin (and more
so if the reaction occurs with free Cbl(I) instead of the enzyme).
 I.A. Dereven’kov et al. / Coordination Chemistry Reviews 309 (2016) 68–83 81

Acknowledgements

This work was supported by Russian Scientific Foundation,

agreement No. 14-23-00204, Council on Grants of the President
of the Russian Federation for state support of young Russian
researchers (project number MK-3661.2015.3), and the Romanian
Ministry of Education and Research (PCE 418/2012).

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