Vitamin B12 Catalysis: Probing the Structure/Efficacy Relationship

Article abstract of DOI:10.1002/chem.201606059

Vitamin B₁₂ is a cofactor for many enzymes, but it also functions as a catalyst in C?C bond-forming reactions. Herein, the impact of corrin structural modifications on their catalytic efficacy was examined. Derivatives with various substituents at c-, d-, and meso-positions were synthesised by using traditional and new microwave methodologies, and then tested in the model reaction of 1,1-diphenylethylene with ethyl diazoacetate. To complement the experimental data, cyclic voltammetry and DFT calculations were performed. Mainly alterations at the c- or d-positions influence both the reaction yield and selectivity.

Full text of DOI:10.1002/chem.201606059

A Journal of
Accepted Article
Title: Vitamin B12 catalysis - probing the structure/efficacy relationship
Authors: Maksymilian Karczewski, Michał Ociepa, Katarzyna Pluta,
Keith óProinsias, and Dorota Gryko
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201606059
Link to VoR: http://dx.doi.org/10.1002/chem.201606059
Supported by

Chemistry - A European Journal
10.1002/chem.201606059
FULL PAPER
Vitamin B catalysis - probing the structure/efficacy relationship
1
2
[
a]
[a]
[a]
[a]
[a]
Maksymilian Karczewski, Michał Ociepa, Katarzyna Pluta, Keith ó Proinsias, * Dorota Gryko *
Abstract: Vitamin B12 is a cofactor for many enzymes but it also
functions as a catalyst in C-C bond forming reactions. In the present
study, the impact of corrin structural modifications on their catalytic
and Knapton’s DFT calculations unveiled the effect of meso-
substituents on the electron density on the central cobalt ion.
The introduction of a chlorine atom at the meso-position causes
1
1-13
efficacy was examined. Derivatives with various substituents at c-, d-, the delocalization of charge density from the axial donor atom to
and meso-positions were synthesized using traditional and new
the metal and Cl resulting in the stronger binding of anionic
ligands.
1
1
microwave methodologies and then tested in the model reaction of
1,1-diphenylethylene with EDA. To complement our experimental
data, CV and DFT calculations were performed. Mainly alterations at
the c- or d-positions influence both the reaction yield and selectivity.
Introduction
Over the years vitamin B12 (1, cobalamin, Cbl) has attracted a lot
of attention mainly because of its biological role as a cofactor in
enzymatic reactions: methyl transfer, rearrangements, or
1
-3
dehalogenation (Figure 1). However, its use as a catalyst in
synthetic organic chemistry has been less explored. The
catalytic activity of cobalt corrinoids is inherently connected with
the metal ion, its redox properties, and their ability to form Co-C
bond. One of the most crucial steps in all vitamin B12 catalyzed
reactions involves the homolytic cleavage of this bond in alkyl-
cobalamins, which is influenced by the ligand structure and
reaction conditions. In the field of catalysis, the fine tuning of the
catalyst efficacy, via proper ligand design, has always been
among the top priorities. However, in the case of vitamin B12
and its derivatives, a comprehensive understanding of the role of
axial and equatorial ligands and their ligation under thermal and
photolytic conditions has not yet been fully exploited.
Figure 1. Structures of corrins 1 and 2.
We wondered whether and how functional groups present on
the periphery of the vitamin B12 corrin ring, would affect the
catalytic property of a derivative. One of the only cases, reported
by Murakami et al, of intentional modification of a vitamin B12
derived catalyst was achieved by linking c- and meso-positions
4
-6
1
4
with 1,3-diphenylenediacetal. A so called “strapped” derivative
was alkylated at the β-axial site with racemic 3-bromo-2-
methylpropionic esters. An increase in the enantioselectivity
compared to the reaction catalysed by the parent heptamethyl
cobyrinate 2 was observed. Based on the electrochemical
studies and DFT calculations, it was concluded that the
electronic state of the central cobalt ion remained unchanged
but the steric hindrance imposed by the strap effectively created
In alkyl-cobalamins, the basicity of the trans-axial ligand
corrin) weakly changes the dissociation energy of the Co-C
(
bond. However, the situation becomes more complex when the
cis-effect is additionally involved. In this regard, two main factors
should be considered: 1) modifications of the corrin ring affect
the character of the cobalt centre, and/or 2) modifications of the
peripheral groups not only affect the cobalt ion but through
interactions with substrates, for example via hydrogen bonding,
affect the catalyst’ efficiency. In this regard, NMR experiments
showed that an exchange of an axial ligand on the cobalt ion
impacts the chemical shift of the meso-proton resonance,
a
stereospecific microenvironment at the β-face of the
macrocycle. Furthermore, Zelder et al. corroborated the
influence of the peripheral groups in the substitution of the
cobalt-coordinated water molecule with the cyanide ligand in
7,8
indicating the influence of the cis-effect.
Moreover, the
15
diastereoisomerically pure aquacyanoheptmethyl cobyrinates.
comparison of meso-X-Cbl bond lengths in meso-Cl-Cbl, meso-
Kinetic studies revealed that the two faces of heptamethyl
cobyrinate (2) are indeed different due to the diverse
stereochemical environments imposed by the remote side
chains. Moreover, peripheral groups influence corrinoids’ binding
properties due to the hydrogen bonding between an axial ligand
at the β-face of the macrocycle and the carbonyl moiety at the c-
NO-Cbl, and meso-H-Cbl bearing different Co-L (L = H
CN) substituents revealed that they are different.
2
O, Me or
Marques
9
,10
[
a]
Maksymilian Karczewski, Michał Ociepa, Katarzyna Pluta, Ph.D.
Keith ó Proinsias, Prof. Dorota Gryko
Institute of Organic Chemistry Polish Academy of Sciences,
Kasprzaka 44/52, 01-224 Warsaw, Poland.
Fax: +48 22 632 66 81
E-mail: dorota.gryko@icho.edu.pl
Supporting information for this article is given via a link at the end of
the document.
1
6
side chain.
This interaction has also been reported by
1
7
O’Connor and Kräutler. In the crystal structure of spirolactone,
bearing c-ethanolamide and d-lactone, Gryko et al. observed the
existence of hydrogen bonding between the β-axial cyanide
ligand and the terminal -OH group of the c-ethanolamide
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201606059
FULL PAPER
1
8
moiety. Even though these evidences clearly suggest that
remote structural modifications of the macrocycle affect vitamin
B
newly developed methodology. It was found that utilizing
microwave irradiation for the methanolysis of vitamin B12 allowed
for a substantial decrease in the reaction time from 6 days to 40
min. and rapid generation of desired derivatives (for full
optimization and experimental details see supporting
information).
12 physicochemical properties, a study on how these changes
impact catalytic efficacy of vitamin B12 derivatives has yet to be
undertaken. Herein, the influence of modifications at the c-, d-
and meso-positions of vitamin B12 derivatives on their catalytic
efficacy in the model reaction of 1,1-diphenylethene (3) with
ethyl diazoacetate (4) is presented (Scheme 1).
All catalysts were transformed into their aqua-form 2, 10-26
((CN)(H O)Cby) to facilitate the reduction of the central cobalt
2
Ph
Ph
Ph
ion in the model reaction.
Firstly, we focused on derivatives modified at the meso-
position. As it is known that such modifications via the cis-effect,
influence the nature of the central cobalt atom. The presence
of meso-Br- (10), -Cl (11), or -NH (13) substituents in the
+
N2
CO Et
2
+
Ph
CO Et Ph
CO2Et
Ph
2
3
4
5
6
2
3
1
9
Scheme 1. Model reaction of 1,1-diphenylethene with EDA.
2
catalyst structure had little to no effect on the model reaction
yield but fluctuation in the products’ ratio (5:6) was observed
(Table 1, entry 2, 3, 5). This suggests that such modifications
affect either the rate of hydrogenation of olefin 5 (Figure 2, step
C) or the recombination rate of intermediate 8 with the catalyst
(Figure 2, step B decreased rate), both steps that heavily
influence the selectively of the studied reaction. Unfortunately,
data obtained for corrins 12 and 14 could not be used for
comparison as both catalysts were not stable under reaction
Results and Discussion
The influence of different functional groups present at the
periphery of the macrocycle on the catalytic activity of corrin
derivatives 10-26 was studied in the model reaction of 1,1-
diphenylethylene with ethyl diazoacetate (EDA, 4). This reaction
is known to be catalysed by an amphiphilic cobalamin derivative
-
cobalester giving a mixture of olefin 5 and its hydrogenated
conditions (entries 4, 6).
1
9
analogue 6 in overall 91% yield (Scheme 1). For the purpose
of our project, heptamethyl cobyrinate (2) was used as a catalyst
with the loading being decreased to 1 mol%. The reaction
furnished a mixture of products 5 and 6 with a desirable
decreased yield (61%) thus allowing for a larger gap of variability
in the yield hence giving more flexibility to our study.
Table 1. Yields and ratios for the model reaction with meso-position
[
a]
modified catalysts
Entry
Catalyst
Yield [%]
Ratio (5:6)
1
2
3
4
5
22
61
62
51
-
62
61
17:1
11:1
8:1
-
9:1
7:1
1
10
21
22
23
11
12
13
14
[
b]
23
6
[
(
a] Conditions: diphenyl ethylene (90 μL, 0.5 mmol), ethyl diazoacetate
156 μL, 1.3 mmol), catalyst (1 mol%), Zn (196 mg, 3.0 mmol), NH Cl (90
4
mg, 1.7 mmol), ACN (5 mL), rt, under light irradiation (2x300 Lm LED
warm light), 18 h, Ar atmosphere. [b] Possible reduction to compound 13.
Scheme 2. Proposed mechanism for the C-H alkylation of an olefin using a
19
B
12 catalyst.
1
9
According to the proposed mechanism (Scheme 2) post-
generation of the Co(I) species and reacting with EDA 4, radical
Subsequently, to examine the effect of the peripheral groups
a series of c- and d-modified catalysts was prepared. First,
restrained c- 15 and d-modified catalysts 16, 17 were examined.
Catalyst 15 with a lactam between the d- and meso- positions,
resulted in a significant drop in the yield of products (27%) and a
decrease in the selectivity (4:1) (Table 2, entry 1). An even more
pronounced result was obtained with c-lactam 17, the reaction
yield dropped to 32% and no selectivity was observed (entry 3).
Although these results do adhere to our theory, still there may
be some interactions between the remaining, protruding
carbonyl groups. Therefore, catalysts with no substituents at c-
7
is generated (A). Upon reacting with 1,1-diphenylethene (3)
affording intermediate 8, which subsequently undergoes
recombination with the catalyst in its +2 oxidation state
(
Co(II)form), either alkylcobalamin 9 or compound 6 (B) is
obtained. Subsequent dehydrocobaltation gives product 5, which
can also transform into compound by reacting with
6
2
0
hydridoderivative (C).
7 6
The synthesis of Cby(OMe) 2, Cby(OMe) (c-lactone) 16
and Cby(OMe)
6
(c-lactam) 17, the three main starting materials
required for the preparation of all catalysts, was performed using
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201606059
FULL PAPER
and d-positions were prepared to give a more comprehensive
ratio (Table 4, entry 2). Next, two particular amides, n-
butylamide 22 and ethanolamide 23 (entry 3 and 4) were tested
as the later one is known to interact with the cyano ligand bound
view.
Table 2. Yields and ratios for the model reaction with restrained c-/d-
[
a]
catalysts
1
8
to the cobalt ion. In both cases the isolated yield increased to
7-78%. Moreover, major differences were observed in the ratio
of products, 9:1 for catalyst 22 (entry 3) and 12:1 for catalyst 23
entry 4). Presumably, this was the result of the presence of the
7
(
terminal -OH group, hence hydrogen bonding can facilitate the
formation of desired product 5 and hinders the generation of
compound 6. Unfortunately, a complete selectivity in the studied
Entry
1
2
3
Catalyst
15
16
17
Yield [%]
Ratio (5:6)
4:1
23
27
37
32
[
b]
reaction has not yet been achieved.
4:1
1:1
Table 4. Yields and ratios for the model reaction with c- and d- modified
[
a]
catalysts
[
a] Conditions: diphenyl ethylene (90 μL, 0.5 mmol), ethyl diazoacetate (156
COR1
COR2
μL, 1.3 mmol), catalyst (1 mol%), Zn (196 mg, 3.0 mmol), NH Cl (90 mg, 1.7
4
mmol), ACN (5 mL), rt, under light irradiation (2x300 Lm LED warm light), 18
h, Ar atmospehere. [b] Possible reduction to compound 21.
2
CO Me
CONHn-Bu
N
R1 = OH
NHn-Bu
NHCH CH OH 23
N
2
1
R2 = NHn-Bu 24
22
OMe
25
2
2
Entry
Catalyst
21
22
23
24
25
Yield [%]
Ratio (5:6)
3:1
9:1
12:1
5:1
26
Surprisingly, removal of the substituent at the c-position (catalyst
2
3
4
5
6
30
78
77
53
69
18, Table 3, entry 1) did not have a major impact on the yield
(
51%), although a 19% increase in the yield was observed as
compared to c-lactam 17. In reactions catalyzed by corrins 19
and 20 (entry 2-3), lacking the d-peripheral side chain, the effect
was even more pronounced as a larger decrease in the yield,
9:1
[
a] Conditions: diphenyl ethylene (90 μL, 0.5 mmol), ethyl diazoacetate (156
μL, 1.3 mmol), catalyst (1 mol%), Zn (196 mg, 3.0 mmol), NH
4
Cl (90 mg, 1.7
4
5% and 31% respectively, and an almost complete loss in
mmol), ACN (5 mL), rt, under light irradiaton (2x300 Lm LED warm light), 18
h, Ar atmospehere.
selectivity was observed. This emphasizes the importance of the
d-side chain in the catalyst structure. Therefore, further studies
into modifying c- and d-positions to empower the catalyst
efficacy and possibility steer towards an optimal catalyst were
conducted.
As the significance of the substituent at the d-position in the
catalyst structure was confirmed (see Table 3), catalyst 25,
bearing the n-butylamide group at this position, was synthesized
and tested. Interestingly, the yield dropped to 69%, compared to
catalyst 22 (78%), but was still higher than the one obtained for
parent catalyst 2 (61%). This suggests the importance of the
distance between the amide group and the cobalt ion or the
configuration at the d-position. However, when di-n-butylamide
catalyst 24 was applied, the model reaction furnished products
with a decreased yield (53%) and selectivity (5:1) (entry 5).
Although each group influences the reaction course in a specific
manner, interactions between neighbouring groups also hinder
the catalyst. To further elaborate on this hypothesis, heptamide
26 was prepared and tested. In this case the reaction yield
increased to 71% with the highest ratio of products being
recorded (13:1) compared to all the catalysts studied.
Table 3. Obtained yields and ratios for the model reaction with nor-c- and
[
a]
d- catalysts
Entry
Catalyst
Yield [%]
Ratio (5:6)
4:1
2
2
2
5
6
7
1
2
3
18
19
20
51
45
31
4:1
2:1
[
(
a] Conditions: diphenyl ethylene (90 μL, 0.5 mmol), ethyl diazoacetate
156 μL, 1.3 mmol), catalyst (1 mol%), Zn (196 mg, 3.0 mmol), NH Cl (90
4
mg, 1.7 mmol), ACN (5 mL), rt, under light irradiation (2x300 Lm LED
warm light), 18 h, Ar atmosphere.
At this stage of the research, the best catalyst for our model
reaction possesses the original ester groups at the c- and d-
positions at the periphery of the corrin ring (catalyst 2, Table 1,
entry 1); however, any modification imposed on the catalyst only
gave a decrease in the yield and ratio of products. Since
reported data indicate that hydrogen bonding between axial
ligands and the c-side chain amide group was shown to form
stronger hydrogen bonds than with ester group, consequently
amide derivatives were prepared and tested. The replacement of
2
the c-methyl ester group with -CO H in the catalyst structure
(
catalyst 21) led to both a substantial decrease in the yield and
Figure 2. Structure of catalyst 26.
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201606059
FULL PAPER
To complement our data and further elaborate the
structure/efficacy relationship, a series of electrochemical and
computational experiments were performed.
show analogous behaviour, this can be further attested to their
yield and product ratio that vary substantially.
[
a]
Table 5. Reduction potential values [V] of synthesized catalysts
(vs.
Ag/AgCl)
(
/(H
H
2
O)(CN)Co(III)
(H
/Co(I)
2
O)Co(II)
(CN)
2
Co(III)
(CN)Co(II)
/Co(I)
-1.50
-1.51
-1.39
-1.34
-1.54
-1.53
-1.44
-1.33
-1.48
-1.57
-1.52
-1.51
-
Entry
Cat.
2
O)Co(II)
/(CN)Co(II)
-1.30
-1.30
-1.18
-1.13
-1.30
-1.27
-1.21
-1.15
-1.25
-1.35
-1.52
-1.30
-
[
b]
1
2
3
4
5
6
7
8
9
2
2
-
-
[
c]
-0.43
-0.35
-0.34
-0.39
-0.48
-0.33
-0.37
-0.62
-0.36
-0.36
-0.42
-0.39
-0.36
-0.33
-0.42
-0.46
-0.37
-0.64
-0.54
-0.53
-0.62
-
-0.56
-0.54
-0.62
-0.92
-0.91
-0.63
-0.65
-0.69
-0.64
-0.64
-0.64
-0.68
10
11
13
14
15
16
17
Figure 3. Comparison of catalysts 2 (green), 21 (purple) and 22 (red).
[
[
e]
10
11
12
13
14
15
16
17
18
18
19
e]
20
21
22
23
24
25
26
On the other hand, the voltammogram of complex 17 (entry 9)
showed not separated redox couples Co(III)/Co(II) and
Co(II)/Co(I) for their aqua forms, which is distinctively different
-
-
-1.21
-1.23
-1.31
-1.24
-1.46
-1.47
-1.58
-1.46
29
from typical cobyrinates, but similar to the redox behaviour
30
observed for cobalamins (e.g. cyanocobalamin, cobalester).
For other studied catalysts, the value of redox potentials are
varying in the range of +/- 0.1 V, indicating that in those cases
structural changes have minor influence on the redox properties
of the cobalt centre.
[
0
a] Measurements conditions: catalyst (c = 0.2 M); electrolyte (NBu
.1 M); solvent: dry, degassed acetonitrile; potential sweep rate: 100 mV/s;
4 4
ClO , c =
working electrode: GC; auxiliary electrode: Pt wire; reference electrode:
Ag/AgCl; all measurements were carried out at room temperature and under
Ar atmosphere; [b] (CN)
form of the catalyst, [e] Unusual voltammogram was recorded
2
Cby(OMe)
7
, [c] (CN)(H
2
O)Cby(OMe)
7
, [d] Dicyano
The trans effect’s influence can be exploited using DFT
calculations (considering the second step of the mechanism).
We wondered whether the electron density, as computed by
Gausian 09, localized on the central metal ion might be
3
1,32
proportional to the reaction yield.
As the Co(I) species has a
The influence of structural changes on a catalyst redox property
was studied with the means of cyclic voltammetry (Table 5). The
results clearly indicate that the incorporation of the halogen
substituent at the meso-position gave less negative values of
reduction potentials compared to heptamethyl cobyrinate 2.
pseudo square planar geometry and its two faces, α and β, are
capable of acting catalytically the absolute value of the
arithmetic mean of minimum electron density at the cobalt atom
was calculated. For highly complex molecules DFT calculations
are often performed on simplified models. Kozłowski et al.
proved that in the case of vitamin B12, a simplified structure of
cobyrinate, bereft of peripheral groups, could be used to
compute dissociation energies of the axial ligands (Figure 4).
We have additionally incorporated c- and d- moieties. For the
initial dataset, the electron densities of catalysts – 2, 10, 13, 15,
Surprisingly, the presence of strong electron donating (-NH
2
13,
entry 5) or electron withdrawing (-NO 14, entry 6) substituents
2
at this position did not change Epc substantially indicating that
the effect of the halogen on the cobalt cannot be purely
electronic. Interestingly, in the case of catalyst 14 the peak
corresponding to the redox couple Co(II)/Co(I) for the aqua form
was not observed hence Co(II) complex exists in solution mainly
in the (CN)Co(II) form. This can be explained by the fact that the
33,34
18, 20, and 22 were assigned. At first the B3LYP/6-31G(d) level
of theory was used, incorporating the solvent effect (acetonitrile)
as implemented in the PCM. As well as the LANL2DZ basis set
which takes heavy atoms, i.e. cobalt, into account. Furthermore,
BP86 and M062x functionals were also investigated.
2
incorporation of the -NO group at the meso-position induces
stronger affinity of the cobalt centre towards the cyanide ligand,
which is consistent with constant values of the complex
2
8
formation (pKCo
-
CN
)
reported by Marques.
Contrary, for
catalysts 21 and 22 (entry 13-14) the redox couples Co(III)/Co(II)
and Co(II)/Co(I) for dicyano form were not observed. Hence, the
formation of complexes 21 and 22 in the dicyano form in
acetonitrile solution is much slower in comparison to other
cobyrinates studied, which is advantageous when using mild
reducing agents (Figure 3). This could also contribute to the
increase in yield observed for catalyst 22, but the conflicting
results found for catalyst 21, bearing the c-acid moiety, further
expresses the complexity of the reaction. In the case of catalyst
24 (entry 16) having very similar structural features to 22 did not
Figure 4. Simplified and optimized structure of cobyrinates.
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201606059
FULL PAPER
The absolute value of the mean electron density (E
d
) was plotted
Table 7. Calculated electron densities using BP86/TZVP.
against the yield, assuming error of ±5% (Table 6). (Please see
supporting information for a more detailed graph.) Catalyst 21,
bearing a free carboxylic group, was exempt from this study
since it is not inert and can be present in its anion form.
Table 6. Absolute value of mean electron densities of cobalt for different
basis/set functional.
ǀE.@Co(I)I [e r-1Bohr]
Entry
Compound
gas
PCM
PCM/ex.
state
ex. state
phase
0.0301
0.0313
0.0319
0.0338
0.0333
0.0336
0.0359
0.0382
0.0383
0.0394
0.0405
0.0403
1
18
0.0437
0.0435
0.0426
0.0472
0.0475
0.0478
0.0495
0.0497
0.0542
0.0575
0.0558
0.0573
0.0429
0.0434
0.0427
0.0478
0.0469
0.0476
0.0498
0.0497
0.0540
0.0572
0.0560
0.0573
0.0301
0.0312
0.0319
0.0337
0.0339
0.0340
0.0361
0.0379
0.0382
0.0395
0.0398
0.0401
2
16
15
10
11
17
22
25
2
3
ǀE.@Co(I)I [e r-1Bohr]
4
5
Entry
Cpd
TZVP
6-31G(d)
LANL2DZ
B3LYP
6
BP86
0.0542
0.0475
0.0575
0.0426
0.0573
0.0558
0.0572
B3LYP
0.0507
0.0433
0.0517
0.0395
0.0533
0.0537
0.0527
M062x
0.0691
0.0493
0.0718
0.0562
0.0723
0.0729
0.0719
7
1
2
3
4
5
6
7
2
0.0620
0.0562
0.0673
0.0512
0.0674
0.0507
0.0670
8
10
13
15
18
20
22
9
10
11
12
13
20
18
Although the geometry of the c- and d-peripheral side chains
have previously been calculated, in our case reliable results for
catalysts possessing amide groups were not obtained. Utilizing
catalyst 23, bearing c-ethanolamide group, the conformation in
relation to electron density vs yield was examined. It was
discovered that the conformation of the c-side chain with the
nitrogen atom facing the corrin plane, was superior when
compared to an oxygen atom (see supporting information for a
detailed graph regarding conformation vs electron density).
Using the electron densities for the optimized structure a
complete plotted graph was assigned (Figure 5).
With the B3LYP functional an unusual plateau was observed
and therefore was disregarded, while employing
B3LYP/LANL2DZ a vast difference in electron densities was
found for catalysts 18 and 20 (Table 6, entry 5 and 6), which is
in contradiction to their chemical character and yields. The
combination of BP86 and M062x with LANL2DZ gave a large
error for catalyst 10 compared to other results (entry 2).
Consistent data were obtained using B3LYP/6-31G(d) or
BP86/TZVP and upon expansion of the dataset the latter proved
superior (Table 7).
DFT calculations indicate that with none of our catalyst could
furnish products 5 and 6 exceeding 80%, even with the assumed
error of 5%. In the case of catalyst 18 a larger deviation was
observed, giving a 10% error. When compared to Murakami‘s
In order to present
a more realistic view, different
environmental aspects were taken into consideration, including
optimized geometries in the gas phase, first excited state with
PCM included or solely first excited state. However, gas phase
and PCM calculations were discarded due to over or under
estimation of electron densities for catalyst 10 and 13
respectively (Table 7, entry 4 and 10). Hence, we have
concluded that the excited state optimized geometry was
paramount in describing the relationship between minimum of
the electron density and the yield.
14
work, the effect of steric bulkiness could not be considered,
since when the structures of catalyst 2 and 15 are overlaid the
angle of the d-side chain is the same for both compounds (see
supporting information for comparison of structures). Therefore,
the instability of the catalysts under the reaction conditions
should be considered. This is also true for catalyst 17, 18 and 19.
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201606059
FULL PAPER
reaction as a whole, combining the effect of catalyst modification
with the subsequent effect the catalyst has on the surrounding
reactants. This work shows only the beginning of our
investigatory journey into viewing real-life vitamin B12 catalysis.
Experimental Section
General procedure for the model reaction: Into a dry tube (30 mL
Pyrex borosilicate glass with ground socket) catalyst (1 mol%), activated
Zn (196 mg, 3.0 mmol) and NH Cl (90 mg, 107 mmol) was added with a
4
magnetic stirrer. The flask was sealed using a septa and flushed with Ar.
MeCN (5.0 mL) was added and the mixture degassed for 10 min by
bubbling Ar under sonication. Subsequently, diphenyl ethylene (90 μL,
0.5 mmol) and ethyl diazoacetate (156 μL, 1.5 mmol) were added and
the mixture irradiated with visible light from LEDs (300 Lm; warm light) for
18 h. The reaction was then diluted with DCM and filtered through a silica
plug to remove the catalyst and zinc, and then concentrated in vacuo.
Purification using flash column chromatography, 2% AcOEt in hexane
gave the desired product as a clear oil.
Figure 5. The electron density plotted against yield and Gauss fit.
Conclusions
In conclusion, vitamin B12 derivatives were prepared using
standard and new microwave methodologies, specifically
focusing on modifications at the c-, d- and meso-positions. The
Acknowledgements
hydrophobic vitamin
B12 structure/efficacy relationship was
studied on the model reaction of 1,1-diphenylethylene (3) and
EDA (4). It was found that the introduction of halogens or
electron donating/withdrawing groups at the meso-position had
little to no effect on the reaction yield, though halogenation at the
meso-position (10, 11, 12) did have an impact on the cobalt
redox properties. Thus, we assume that the reduction step has a
minor effect on the overall reaction outcome. However,
differences in the ratio of saturated and unsaturated products
were observed.
Financial support for this work was provided by the National Science
Centre (grant no: K.óP. - SONATA 2013/11/D/T5/02956 and D.G., M.K. -
OPUS 2012/07/B/ST5/02016) and the Ministry of Science and Higher
Education (M.O. grant no. 0141/DIA/2015/44). Calculations have been
carried out in the Wroclaw Centre for Networking and Supercomputing
(http://www.wcss.pl), grant no. 432.
Keywords: vitamin B12 • Co-catalysis • corrins • diazo
compounds • olefins
In the case of the B-ring peripheral groups, restraint of
either the c- or d-positions, via lactam formation, resulted in a
large drop in the yield of products 5 and 6, and a complete loss
of selectivity, highlighting the importance of the B-ring side
chains on the catalysts efficacy. The removal of either c-acetate
or d-propionate resulted in a decrease in the yield and selectivity
of the model reaction. On the other hand, the incorporation of
amide moieties at the c-position (namely ethanolamide or n-
butylamide) had a positive effect, increasing the yield and giving
selectivity close to that of the original heptamethyl cobyrinate (2)
due to possible interactions of the amide or other terminal
groups with the ligand bound to cobalt.
Furthermore, the relationship between the electron density
of the central cobalt metal and the actual yield was established
using BP86/TZVP which proved the best for calculating the
efficacy of our catalysts. Geometries of the peripheral groups
were considered, with the implementation of the excited state
geometries proving superior. The accumulated results gave a
Gauss distribution curve with a 5-10% error, depending on the
catalyst, with a possible optimum yield of 80%.
[
1] a) R. Banerjee in Chemistry and Biochemistry of Vitamin B12, John Wiley &
Sons: New York, 1999. b) B. Kräutler, B. T. Golding, D. Arigoni in
Vitamin B12 and B12-Proteins, Wiley-VCH: Weinheim, 2008.
[2] H. Shimakoshi, A. Nakazato, M. Tokunaga, K. Katagiri, K. Ariga, J.-i.
Kikuchi, Y. Hisaeda, Dalton Trans. 2003, 2308-2312.
[3] M. Giedyk, K. Goliszewska, D. Gryko, Chem. Soc. Rev. 2015, 44, 3391-
3404.
[4] T. Niimi, T. Uchida, R. Irie, T. Katsuki, Adv. Synth. Cat. 2001, 343, 79-88.
[5] J. Willkomm, N. M. Muresan, E. Reisner, Chem. Sci. 2015, 6, 2727-2736.
[6] S. Zhu, J. V. Ruppel, H. Lu, L. Wojtas, X. P. Zhang, J. Am. Chem. Soc.
2008, 130, 5042-5043.
[7] H. A. O. Hill, B. E. Mann, J. M. Pratt, R. J. P. Williams, J. Chem. Soc.
1968, 564-567.
A
[
[
8] S. M. Chemaly, Dalton Trans. 2008, 5766-5773.
9] K. L. Brown, S. Cheng, X. Zou, J. D. Zubkowski, E. J. Valente, L. Knapton,
H. M. Marques, Inorg. Chem. 1997, 36, 3666-3675.
[
10] N. Ghadimi, C. B. Perry, P. P. Govender, H. M. Marques, Inorg. Chim.
Act. 2016, 450, 269-278.
[
[
11] C. B. Perry, H. M. Marques, S. Afr. J. Chem. 2005, 9-15.
12] L. Knapton, H. M. Marques, Dalton Trans. 2005, 889-895.
[13] P. P. Govender, I. Navizet, C. B. Perry, H. M. Marques, J. Phys. Chem.
A 2013, 117, 3057-3068.
The accumulation of all results leads us to reconsider our
view on exactly how a cobalamin catalyst operates in a chemical
reaction. Even though previous reports gave us a glimpse into
the catalysts activity in a specific situation, one must view the
[
14] Y. Murakami, Y. Hisaeda, T. Ohno, H. Kohno, T. Nishioka, J. Chem. Soc.
Perkin Trans. 2 1995, 1175-1183.
[
15] K. Zhou, F. Zelder, Eur. J. Inorg. Chem. 2011, 2011, 53-57.
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201606059
FULL PAPER
[
16] a) C. Mannel-Croise, F. Zelder, Inorg. Chem. 2009, 48, 1272-1274. b) B.
Aebli, C. Männel-Croisé, F. Zelder, Inorg. Chem. 2014, 53, 2516-2520.
17] C. Kratky, G. Farber, K. Gruber, K. Wilson, Z. Dauter, H. F. Nolting, R.
Konrat, B. Kräutler, J. Am. Chem. Soc. 1995, 117, 4654−4670. K.
Venkatesan, D. Dale, D. C. Hodgkin, C. E. Nockolds, F. H. Moore, B. H.
O’Connor, Proc. R. Soc. London, Ser. A 1971, 323, 455−487.
[
[
18] K. ó Proinsias, J. L. Sessler, S. Kurcoń
674-4677.
19] M. Giedyk, K. Goliszewska, K. ó Proinsias, D. Gryko, Chem. Commun.
016, 52, 1389-1392.
́, D. Gryko, Org. Lett. 2010, 12,
4
[
2
[
[
20] H. Shimakoshi, Y. Hisaeda, ChemPlusChem, 2014, 79, 1250-1253.
21] A. Gossauer, K. P. Heise, H. Gotze, H. H. Inhoffen, Liebigs Ann. Chem.
1
972, 1480-1499.
22] A. Gossauer, K. P. Heise, H. Laas, H. H. Inhoffen, Liebigs Ann. Chem.
976, 1150-1165.
[
1
[
23] K. ó Proinsias, S. Kurcoń, D. Gryko, Eur. J. Org. Chem. 2012, 154-159.
24] I. Navizet, C. B. Perry, P. P. Govender, H. M. Marques J. Phys. Chem. B
[
2012, 116, 8836-8845.
[
25] M. Giedyk, K. ó Proinsias, S. Kurcon, I. Sharina, E. Martin, D. Gryko,
Chem. Med. Chem. 2014, 9, 2344-2350
[
[
26] S. Kurcoń, K. ó Proinsias, D. Gryko, J. Org. Chem. 2013, 78, 4115-4122.
27] T. Otten, T. Darbre, S. Cosnier, A. Lusia, J. Correia, R. Keese, Helv. Chim.
Acta 1998, 81, 1117-1126.
[
28] H. M. Marques, L. Knapton, X. Zou, K. L. Brown, Dalton Trans. 2002, 16,
3195-3200.
[
[
29] D. Lexa, J. Savéant, J. Zickler J. Am. Chem. Soc. 1980, 102, 4851-4852.
30] a) M. Giedyk, H. Shimakoshi, K. Goliszewska, D. Gryko, Y. Hisaeda
Dalton. Trans. 2016, 45, 8340-8346. b) D. Lexa, J. M Savéant, J.
Zickler J. Am. Chem. Soc. 1980, 102, 2654-2663. c) D. Lexa, J. M
Savéant Acc. Chem. Res. 1983, 16, 235-243.
[
31] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb,
J. R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A.
Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian, A. F.
Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K.
Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O.
Kitao, H. Nakai, T. Vreven, J. A. Montgomery, Jr., J. E. Peralta, F.
Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N.
Staroverov, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J.
C. Burant, S. S.Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M.
Klene, J. E.Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R.
Gomperts,R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C.
Pomelli, J. W.Ochterski, R. L. Martin, K. Morokuma, V. G. Zakrzewski,
G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels,
O. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox,
Gaussian 09 Revision D.01, Gaussian Inc. Wallingford CT 2009.
[
[
[
32] R. G. Parr, L. v. Szentp
924.
33] J. Kuta, S. Patchkovskii, M. Z. Zgierski, P. M. Kozlowski, J. Comp. Chem.
006, 27, 1429-1437.
34] A. J. Reig, K. S. Conrad, T. C. Brunold, Inorg. Chem. 2012, 51, 2867-
879.
́l y, S. Liu, J. Am. Chem. Soc. 1999, 121, 1922-
1
2
2
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201606059
FULL PAPER
Layout 2:
FULL PAPER
Co-catalysis, vitamin B12
Maksymilian Karczewski, Michał Ociepa,
Katarzyna Pluta, Keith ó Proinsias,* and
Dorota Gryko*
Vitamin B12 catalysis: Vitamin B12 derivatives modified at c-, d-, and meso- were
synthesized using new microwave methodology and tested as catalysts in the
model reaction of 1,1-diphenylethylene with EDA. Experimental results, CV
measurements and DFT calculations showed that mainly alterations at c- and d-
positions influence the catalytic efficacy of vitamin B12 derivatives.
Page No. – Page No.
Vitamin B12 catalysis - probing the
structure/efficacy relationship
*one or two words that highlight the emphasis of the paper or the field of the study
This article is protected by copyright. All rights reserved.