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New Developments in the Field of Vitamin B12 Reactions of the Cobalt Atom in Corrins and in Vitamin B12 Model Compounds.

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New Developments in the Field of Vitamin B12: Reactions of the
Cobalt Atom in Corrins and in Vitamin B12 Model Compounds
By G . N. Schrauzer[*]
Studies with vitamin B12 model compounds such as the cobaloximes provide a basis for
the understanding of the mode of action of corrinoid coenzymes in enzymatic reactions. They
also widen our knowledge of the properties and reactions of organocobalt compounds. The
present article outlines the most important nonenzymatic reactions of cobalt in vitamin B12
and in model compounds of the cobaloxime type.
1. Introduction
The last extensive report on chemical and biochemical developments in the field of vitamin B,, (cyanocobalamin) was
published in this Journal in 1964['1, shortly after CrowfootHodgkin and Lenhert demonstrated that coenzyme Bl2 (5'deoxy-5'-adenosylcobalamin) contains a direct cobalt-carbon
bond[']. This important result indicated for the first time
that organometallic reactions occur in biological systems. In
view of the complicated structure of vitamin B12 ( I ) (see
Scheme 1) it furthermore appeared reasonable to assume that
the macrocyclic ligand system modifies the properties of cobalt
significantly, enabling it to form stable Co-C bonds, for at
that time only few rather unstable compounds were known
to have Co-C-o bonds.
of vitamin BI2, and were named the "cobaloximes" to stress
their similarity to the cobalamins. In the ensuing years
numerous papers appeared in the literaturer4Jwhich confirmed
the validity of cobaloximes as vitamin B12 model compounds.
Other cobalt chelates were studied (see, e. g . L4, '1) and proposed
as alternative models (Scheme 2), but it eventually became
clear that the simple cobaloximes of type (2) simulate the
reactions of vitamin B12 most closely, both qualitatively and
quantitatively. Since they are easily prepared and the required
reagents can be found in every inorganic laboratory, none
of the other cobalt chelates studied to date have challenged
CONH,.
/
F' 'F
(31
I
LCONH,
L
(41
Scheme 1. Structure of an organocobalamin. In vitamin Blz (cyanocobalamin)
( I ) R = C N ; in coenzyme B L 2R=S-deoxy-5'-adenosyl. The ligand system
having carbon atoms 1 to I 9 and the four central nitrogen atoms is called
corrin; see ( 9 ) in Section 4.
J
(5)
(7)
In 1964 Schrauzer and K ~ h n l e [reported
~]
that the reactions
of the cobalt atom in vitamin B12 can be simulated with
much simpler complexes. The cobalt(lI1)complexes of diacetyldioxime (2)c4], which were first prepared by Tshugaev in 1907,
resemble vitamin B12 so closely in their chemical properties
that they were introduced as coordination-chemical models
p] Prof. Dr. G. N. Schrauzer
Department of chemistry, University of California at San Diego, Revelle
College
La Jolla, Calif. 92093 (USA)
Angrw. Chem. l n t . Ed. Engl.
Vol. I5 ( 1 9 7 6 ) N o . 7
Scheme 2. Structures of cobaloxime ( 2 ) and of other vitamin BIZ model
compounds ( 3 ) to (8). In a wider sense, cobaloximes can also contain
H, alkyl, or aryl [in place of CHI as in ( 2 ) ] . B=base; R =C N , CH3,
C2H5,C6H5,ere.
417
the leading position of the cobaloximes in the field of vitamin
BIZ model chemistry. Even ten years ago it was reasonable
to expect that studies with cobaloximes would play a role
in the eventual elucidation of the mechanism of action of
vitamin B12- or coenzyme B12-catalyzed enzymatic reactionsr61. There can be no doubt that this expectation has
been fulfilled, even though more work remains to be done.
This report outlines the most important properties and reactions of the cobalt atom in the cobalamins as well as in
the cobaloximes. Current theories and hypotheses concerning
biochemical mechanisms of reactions involving vitamin B12coenzymes will be discussed in a future paper.
cobalt, simply by (Co), reduced derivatives will be designated
cobaloxime(I1) or cobaloxime(1) [see eq. (b)]. All other modifications of the abbreviated nomenclature are obvious. The
axial bases in cobaloxime complexes will often not be identified
as such and simply represented by "B" (see Table 1).
3. Structure
The structure of the first organocobaloxime was determined
by LenhertI8]in 1967 and is shown in Figure 1.The observed inplane Co-N bond distances are essentially identical to those
observed in coenzyme BIZ. The Co-C bond length is also
2. Nomenclature
Extensive guidelines for the nomenclature of vitamin Blz
derivatives exist which will not be described here (for details
see, e. y.,171).The cobalamins (more precisely : cob(i1r)alamins)
contain 5,6-dimethylbenzimidazole as an additional axial
ligand, which is linked to the corrin system through a ribofuranosyl-phosphate chain (see Scheme 1). In the cobamides
the axial ligand is missing, but the ribofuranosyl-phosphate
moiety is still present. The latter may be removed by acid
hydrolysis, yielding cobinamides. For our present purposes
it is usually not necessary to distinguish cobalamins from
cobamides or cobinamides, all will be simply represented by
[Co]. The reduced forms of vitamin BIZare known as vitamin
B12, (cob(r1)alamin) and vitamin BI 2s (cob(1)alamin). The
former is a derivative of divalent cobalt, the latter of monovalent cobalt. In cyanocobalamin (vitamin Blz) and hydroxocobalamin (vitamin B12J, cobalt is trivalent [see eq. (a)]. We
shall represent cobaloximes, which also contain trivalent
Table 1. Survey of nomenclature of cobalamins and cobaloximes.
Name
Constituents
Cobalamines
Cobamides
Cobinamides
Cobaloximes
Cobalt(ll1)
Cobalt(II1)
Co halt(111) Cobalt(1il)
+
+
Suhst.
corrin
Suhst.
corrin
Suhst.
corrin
Suhst. bis(glyoxaldioxime)
+
+
+
+
Ribofuranosyl
phosphate
Ribofuranosyl
phosphate
+
=
CH,-CO,CH,
I
188
KamJ
t
PV
Fig. 1. Structure of methoxycarbonylmethyl(pyridine)cobaloxime (according
to [8], distances in A). Hydrogen atoms are not shown.
virtually the same, but the axial Co-N distance is somewhat
shorter in the cobaloxime than in the cobalamin. We concluded
from this that the cobalt in the cobaloximes might carry
a slightly greater partial positive charge than in the cobalamins; this suggestion was substantiated by LCAO-MO calculations (see Scheme 3).
+
5,6-Dimethylbenzimidazole
Base
R
R
+
+
Abbreviations used
I c0 I
or
or
or
P
($0'11)
B
or
Scheme 3. Calculated (experimental) bond distances and n-electron charge
distribution in the ground state of models of cyanocobalamin (left) and
of the corresponding cobaloxime derivative (right) [16].
4. General Considerations
Modifications
[CO"]
418
The biological activity of vitamin B I Z coenzymes must
undoubtedly be associated with the presence of cobalt, whose
oxidation-reduction potentials are modified by incorporation
into the corrin system. It can now exist not only as a diand trivalent, but also as a monovalent entity [eq. (a)]['].
Angew. Chem. Int. Ed. Engl.
/
Val. 15 (1976) No. 7
Hydroxo-
cobalamin
Vitamin B l Z a
Vitamin R,,,
Vitamin BlZr
brown
blue- g r e e n
purple
The cobaloximes behave analogously [eq. (b)Ir9.l o ]
OH
Hydroxocnbaloxime
Cobaloxlme (11)
red-bmwp
bmwn
Cobaloxime (I)
blue or blue-green
in Table 2. It may be seen that the cobalt(1) derivatives are
some of the most powerful nucleophiles known and for
this reason have been called "supernucleophiles". Although
certain cobalt(1) complexes are apparently even more nucleophilic than vitamin B1zS(cob(i)alamin),the latter is presumably
the most powerful nucleophile of Nature, especially since it
can be readily generated in the physiological pH range. The
cobalt(r)-porphyrins, on the other hand, are capable of existence only in nonaqueous media, e. g. pyridine, and decompose
in water spontaneously with evolution of hydrogen. Vitamin
Blzs and cobaloximes(~)decompose in neutral or weakly alkaline solutions (pH 10) as well [(eq. (d)], but the rates are
comparatively slow.
,--30']~ 601 -fi
H
+
Co"] +
'/z
H,
(d 1
Hydridocobalamin
In the cobalt(1) derivatives, the metal is in a spin-paired
d8 configuration. Two electrons occupy the weakly antibonding 3dZZorbital, and the resulting electron distribution is
responsible for the high nucleophilic reactivity of
cobalt(r)[' ''1. Cobalt(1) in the cobaloximes interacts with
bases, giving rise to changes in the optical absorption spectrum
and chemical reactivity. There is evidence that one molecule
of the base interacts with cobalt(1) in the axial position. This
changes the electron-distribution of the dZ2orbital as shown
in eq. (c). "Hard" bases such as OH- increase the electron
density on cobalt, unsaturated nitrogen bases lower the elec'3
tron density through d,-p, interactions. The latter effect leads
to a slight diminution of the nucleophilic reactivity. The position of vitamin B,,, and of cobalt([) derivatives of model
compounds in Pearson's Nucleophilicity Scale" 3 l is shown
Table 2. Pearson nucleopbilicities 1131 (based on CH31) of a number of
cobalt(1) derivatives and other nucleophiles.
Nucleophile [a]
nPC.rS.3"
CH3OH
CI NH3
Br1CN
CsHsS~
szo: P(C6H5)3
CsHsSe(C6Hs)aSnRhodoxime(1) [HzO or OH-]
Cobaloxime(1) [Pyridine]
Cobaloxime(1) [HzO or OH-]
Cobinamide(1) [HzO or OH-]
Vitamin Bizr
Cobalt(1)-Salen[b]
Cobalt(1)-Porphyrins
[a] Axial base components in square brackets
[b] Salen is the tetradentate ligand in (7).
Angew. Chem. I n t .
Ed. Engl. 1 V'l. I S ( 1 9 7 6 ) No. 7
0.00
4.37
5.50
5.79
1.42
6.70
9.92
6.90
8.69
ca. 10.7
ca. 11.5
13.7
13.8
14.3
14.4
14.4
ca. 14.6
ca. 14.6
The decomposition according to eq. (d) is accelerated by
noble metal catalysts, e.g. Pt; vitamin B1zs is a metastable
compound in the physiological pH range. The corresponding
Br6nsted acid hydridocobalamin is unstable in aqueous media.
It is presumably a weak acid, since the corresponding hydridocobaloximes are also only weakly dissociated. Solutions of
hydridocobalamin are obtained if vitamin B,,, (hydroxocob(rii)alamin)is reduced with zinc in glacial acetic acid. Generated under these conditions, hydridocobalamin has sufficient
life-time to be characterized by its reactions with a variety
of substrates and its absorption spectrum. Its reactivity differs
from that of vitamin B L ~ ,as
, will be outlined below (see
Section 7).
Cobalt-porphyrins do not occur in Nature, or at least have
never been isolated. We would not expect them to have any
physiological activity if only because they cannot be reduced
to, or maintained in, the Co' state in aqueous solution. This
fact may be used to explain some of the most striking differences between the structure of the corrin system ( 9 ) and
that of the porphyrins (10). Both are related biogenetically,
but in ( 9 ) rings A and D are connected through a direct
C-C bond. This causes a marked distortion of the coordination symmetry of the ligand and produces and odd-numbered
Tc-electron system which exists only as a monoanion. The
porphyrin ligand possesses an even number of constituent
atoms, is highly symmetrical and in metal complexes is present
as the dianion. These structural differences cause a weakening
of the effective coordinating power of ( 9 ) relative to (ZO),
which in turn lowers the Co"/Co' reduction potential.
Q-6
u
'*NH
p'
N-(
/
"/
The azomethine system in ( 9 ) is reasonably resistant to
reducing agents and can be hydrogenated to colorless deriva419
tives only under relatively drastic conditions. The peripheral
substituents protect the vitamin B 12 chromophore against
dehydrogenating attack. The propionamide side-chains endow
the molecule with hydrophilic character, but the various substituents also serve as points of attachment of the vitamin to
apoenzymes or transport proteins.
If it is assumed that vitamin BIZ functions biologically
at least in some cases as a nucleophile, it can be rationalized
why the central metal must be cobalt. Of all other elements,
only the rare element rhodium could replace cobalt in some
of its functions. Rhodium analogs of vitamin BIZ,e.g. a (5,6dimethylbenzimidazolyl)rhodibamide, have recently become
known[l41,but initial tests indicate biological inactivity. Investigating the reactions of “rhodoximes”, i. e. the Rh analogs
of the cobaloximes, we predicted“ that Rh-B,, derivatives
should be either biologically inactive or less active than vitamin
B12, since rhodium(1) nucleophiles are not as reactive as the
corresponding cobalt(1) derivatives. Organometallic derivatives of rhodoximes furthermore are as a rule more stable
or chemically resistant than organocobaloximes, the same
should be true for the respective rhodibamides relative to
cobamides.
Why is the 6th coordination position of cobalt blocked with
a base, such as 5,6-dimethylbenzimidazole?An at least
partial answer to this question can be given if one considers that the Co-C bond in organocorrins is susceptible to reductive cleavage through axial attack. The axial base
thus functions as a protecting group and assures that cobaltbound organic substituents such as the 5’-deoxyadenosyl residue of the coenzyme is not lost due to nonspecific interactions
with biogenic reductants.
The systematic study of other cobalt chelates did not provide
any better models of vitamin BI 2, but furnished examples
of nucleophiles with npearson values ranging between 10 and
15, i. e. supernucleophiles. Substitution of the oxime protons
by BF2 groups yielded complexes of type (3) which also
proved to be much less nucleophilic than the parent cobaloxime(1) species. A number of Schiff base complexes of cobalt
proved somewhat more nucleophilic, but offered no advantage
over the cobaloximes. The chelates ( 5 ) and (8) were found
to form dialkylcobalt derivatives‘’ 7, l81, in contrast to the
behavior of cobaloximes, and thus can no longer be regarded
as bonafide models of vitamin B I Z .Pentacyanocobalt complexes are known to form organometallic derivatives and have
therefore been temporarily regarded as vitamin BIZ
6. Reactions of Cobalt(1) Supernucleophiles
The cobalt(1) supernucleophiles react with conventional
alkylating agents to yield organocobalt complexes, the reactions are nucleophilic substitutions and occur with inversion
at the a-carbon atom[20].Epoxides and certain cyclopropane
derivatives also react with the cobalt(1)chelates. Stable organocobalt compounds are as a rule formed only if the cobaltbound carbon is primary or secondary[”]. Tertiary derivatives
are isolable only in rare instances. The cobaloxime ( 1 1 ) is
sufficientlystable to be isolated, but the corresponding derivative of vitamin B12 cannot be obtained. This suggests steric
hindrance by the corrin ligand. However, electronic effects
influence the stabilities of the organocobalt complexes as well.
5. Electronic Structure and Bonding
The striking analogies between the chemical properties of
the cobalt atom in vitamin B12 and in the cobaloximes are
primarily a consequence of a fortuitous identity of the effective
coordinating power of the four sp2-hybridized nitrogen atoms
in the otherwise unrelated ligand systems. LCAO-MO-calculations (Scheme 3)[16] confirmed this conclusion, since they
revealed a nearly identical charge distribution in the atoms
surrounding the cobalt atom. The eigenvalues and -vectors
of the axial cobalt-ligand bonds were also found to be essentially the same. However, the calculations revealed that the partial
positive charge on cobalt is somewhat higher in the cobaloximes than in vitamin B12. This causes a firmer attachment
of axial bases in the model compounds as compared to corrins
and introduces some differences in reactivity. However, the
overall orbital-stabilizing effects of the corrin ligand are by
no means specifically dependent on details of the electronic
structure of the azomethine system in the molecule, thus permitting their simulation with unrelated simpler ligands.
Nevertheless, the original selection of biacetyldioxime complexes ( 2 ) of cobalt(rI1) as vitamin B12 models was in part
fortunate, since the properties of the cobalt complexes depend
on the nature of the peripheral dioxime substituents as well.
For example, bis(benzi1dioximato)cobaltcomplexesare already
less suitable for model work, if only because their CO(I)derivatives are less nucleophilic than vitamin B z s or bis(biacety1dioximato)cobalt(~).
420
The cobalt(1) derivatives of cobaloximes form n complexes
with activated olefins, for example, with acrylonitrile (12);
they also form adducts with carbon monoxide ( 1 3 ) . There
is some evidence that vitamin Bizs also forms n complexes
with activated olefins, but these appear to be less stable than
the corresponding complexes with cobaloximes ( I ) [ ~ ~ ] .
The n-complex bound axial ligands effectively block the
cobalt(1)ion against nucleophilic attack by alkylating agents,
although the complexes are labile, and the n-bound ligands
can be readily removed, i.e. by passing argon through the
solutions. The free cobalt(r) nucleophiles are all extremely
oxygen-sensitive.They are also oxidized by N2OlZ3].The reaction with NzO is of interest as it occurs only with cobalt(I),
and not with cobalt(I1)derivatives.The specificoxidizing action
of NzO.was used as a means to detect the corrin nucleophile
in certain enzymes, as will be outlined in a future paper.
Typical reactions of vitamin BIZ%(cob(1)alamin) are shown
in Scheme 4.
Angew. Chem. I n t . Ed. Engl.
1 Vol. 1.5
(1976) N o . 7
7. Hydridocobalamin and Hydridocobaloximes
It has already been mentioned in Section 4 that the Br@nsted
acid of vitamin Bizs (hydridocobalamin) is unstable in aqueous
solution (Scheme 4). Most "hydridocobaloximes" are also unstable in water, especially if nitrogen bases occupy the 6th
coordination position. With phosphanes as axial ligands, isolable hydridocobaloximes are
Hydridocobaloximes
are weak acids with pl(,-values in the order of
Hydrido(tributy1phosphane)cobaloximeis dark blue and is surprisingly
soluble in nonpolar media, including n-hexane. The hydride
is relatively unreactive in nonpolar aprotic solution. For
example, no reaction occurs with methyl iodide, ethylene oxide,
or ethyl acrylate in dry n-hexane.
no
reaction
-
8. ElectronicStructureand Reactivity of Cobalt(I1)Derivatives
In vitamin B1zr and the cobalt(r1)derivatives of the cobaloximes the cobalt ion is in a d7 configuration, the unpaired
electron occupies the 3dZ2orbital. EPR measurements show
that the axial ligand 5,6-dimethylbenzimidazole in vitamin
Bizr is attached to cobalt[z6.27].Cobaloximes(I1) form 1 :1
and 1 :2adducts with a variety of bases['*]. The 1 : 1 adducts
are diamagnetic in the solid state, therefore suggesting a
dimeric structure with a Co-Co bond. A dimeric rhodoxime
with a Rh-Rh bond is
Vitamin Bizr shows no
tendency to dimerize, presumably for steric reasons, it also
does not generally form adducts with two molecules of base.
Vitamin BIZ, and cobaloximes(I1)react with oxygen to yield
peroxo complexes. Peroxocobalamin~30~
may be regarded as
a charge-transfer type complex. Two limiting structures can
be written, of which ( 1 4 ) has the greatest weight, as evidenced
by EPR analysis. Vitamin Blzr is a nearly reversible oxygen
carrier.
CzH.
U
no
I']
Cobaloximes(I1) react with oxygen to yield three different
compounds ( I 6)-(18). Peroxocobaloximes (1 6j in solution
show EPR spectra which are virtually identical to those of
peroxocorrins. However, cobaloximes(ir) also form diamagnetic pperoxodimers of type ( 1 7 ) . The latter tend to convert
into p-peroxoradicals ( I 8 j , presumably by way of a dispropor-
I
Scheme 4. Some reactions of the vitamin 9 1 2 cobalt(1) supernucleophile
(vitamin B , z\, cob(1)alamin). Cobaloximes(1) also undergo these reactions.
The reduction of hydroxocobalamin (vitamin Blza) with
zinc in glacial acetic acid affords solutions of hydridocobalamin[25].Hydridocobalamin differs from vitamin B,,, in that it
reacts with simple nonactivated olefins to yield alkycobalamins. With ethylene, ethylcobalamin is formed ; with propylene, isopropylcobalamin. Cycloolefins such as norbornene,
cyclooctene, and even cyclododecatriene react with hydridocorrins as well to yield secondary cycloalkyl cobalt derivatives
which were previously not readily accessible. Some of the
reactions of hydridocobalamin are summarized in Scheme 5.
Further studies with this interesting compound are presently
still in progress.
tionation reaction. Cobaloximes(r1) react with acetylene as
well to yield the compound (19j[211. They also react with
alkylating agents under certain conditions["]. On reaction
with benzyl halides, benzylcobaloximes are
the
reaction is assumed to be of a free-radical type. It is possible
that the reaction of cobaloximes(I1) with CCL [eq. (e)]["]
also involves homolytic C-CI bond cleavage.
ccq
+ 2 (CO")
-
(733
(CO)
+
Y
(CO)
d"O'
TH=CHz
Bol
dc"'
0
d o 1
O=c-CH3
r[;o']'
+
He
U
Scheme 5. Some reactions of hydridocobalamin (generated from vitamin
Biz. by reduction with zinc in glacial acetic acid).
Angew. Chem. I n r . Ed. Engl.
Vol. 15 (1976) N o . 7
Methyl radicals, generated in solution, have been shown
to react with vitamin B,,, to yield methylcobalamin. Cobaloximes(I1) act as catalysts in the reduction of cobaloximes(iii)
by carbon monoxide [eq. (f)[331].The reduction of hydroxocobalamin by carbon monoxide in aqueous solution is also
catalyzed by vitamin
Cobaloximes(i1) disproportionate in alkaline solution to
yield cobalt(m) and cobalt(1) derivatives; the corresponding
reaction of vitamin BI zr occurs more slowly. Cobaloximes(rr),
42 1
T
(Co"')
+
CO
+
2 OH@
-
9. Reactions of the Cobalt(II1) Derivatives
(COll)
(Co')'
+
CO,
+
H,O
+ Xo
but not vitamin Blzr, react with molecular hydrogen. The
reduction of cobaloximes(iI1) by H, is catalyzed by cobaloximes(n) and yields the cobalt(1) nucleophiles [eq. (g)]" 'I.
The first organocobalt derivatives of corrins['] and of cobalo x i m e ~ [were
~ ] synthesized by the reaction of the corresponding Co"' derivatives with organomagnesium halides. In
aqueous solution, organocobalt complexes can be obtained
from Co"' derivatives on reaction with carbanions, eq. (kj
may be cited as an as yet unpublished example:
OH
I
(Co"') + [NC-CH-COOC2H5]@
(k)
NC\ ,COOC,H,
CH
I
(CO)
Reaction according to eq. (g) proceeds readily even below
room temperature at 1 atm of HZand in neutral Or alkaline
buffered aqueo'Js media. This method of generating the
cobalt(1) nucleophiles or hydridocobaloximes is useful for the
synthesis of organocobalt complexes. Reacting cobaloximes(I1)
with Hz in alkaline solutions yields the cobalt(1) nucleophiles,
which react with e. g. acrylates to yield 0-alkoxycarbonylethylcobaloximes. In neutral buffered solutions hydridocobaloximes are formed as such or in-situ; their reaction with acrylic
esters affords the corresponding ~ - i s o m e r s [ ~ ~ ] .
(Co") +
'la H,
pH 10-11
(CO')'
H,C,
+ CHz=CH-COOR
s
,COOR
FH
(CO)
With monosubstituted alkynes a- or P-substituted vinylcobaloximes are formed in analogy to eq. (h).
The reaction of cobaloximes(I1) with H, in the presence of
primary amines and formaldehyde gives rise to the formation
of N-methylated amines via isolable aminomethylenecobaloximes (20) [eq. (j)][351.
This reactions shows some analogy to Wullach's aminomethylation method and can also be performed catalytically. With
thiols in place of amines, the corresponding methylthio compounds are obtained, but in this case intermediate organocobaloximes analogous to (20) could not be isolated. A complex
of type (20), with R=C6H5, reacts with NO? to yield a
residue is
compound in which the -CH2-N(NO)-C6H5
attached to cobalt. The reductive cleavage of the Co-C bond
in such complexes affords the carcinogenic N-methyl-N-nitro~oaniline'~~].
422
+ OH'
Vinyl ethers react with cobaloximes(rI1) as well as with
hydroxocobalamin in the presence of bases to yield derivatives
of formylmethylcobaloxime and -cobalamin, respectively [eq.
(lj] 1371.
-
+ (COII')
+ OR"
CHz=CH-oR
CHz-CH1oR)z
cHz-CH(oR)2
I
(CO)
(21)
The acetals (21 1 can be saponified to the corresponding
formylmethylcobalt complexes under appropriate conditions.
It is of interest that the acid-cleavage of diacetals and of
hemiacetals of formylmethylcobalamin occurs with extensive
Co-C bond cleavage. Formylmethylcobalamin was also prepared by the reaction of vitamin Bizs (cob(1)alamin) with
bromoacetaldehyde. This compound is stable in neutral
aqueous solution just as the corresponding cobaloxime derivative, both decompose in acidic media to yield acetaldehyde138.391.
Ligand-exchange reactions of cobaloximes(II1) have been
extensively investigated by many workers and will not be
discussed in any
A cobaloxime(rr1j was recently
employed for the stereospecific synthesis of N'-alkylated xanthine and hypoxanthine derivatives. The purine bases are
first attached to the Co of the cobaloxime, affording N9-coordinated adducts whose subsequent alkylation produces the
N 7 substituted alkyl purines (22) as exemplified in eq. (m)14'1.
It may be expected that cobaloximes will become useful
reagents in synthetic organic chemistry. Recently, cobaloximes
were employed as protecting groups in the synthesis of certain
amino acid derivatives[42!
10. Properties and Reactions of the Organocobalt
Compounds
Although organocobalt complexes of vitamin B I Z and of
model compounds are routinely described as cobalt(Ir1) comA n g e w . Chrm. I n t . E d . Engl. 1 Vol. 15 (1976) No. 7
plexes, this formalism can lead to misunderstandings as it
ignores the high covalency of the C O X bonds. It is more
realistic to describe the nature of the axial Co-C bonds
in terms of the limiting structures a to c; structure a is the most
important:
-
B
R@
[ C o ] CI I C O ~ ]
a
b
RO
ICo@l
C
LCAO-MO calculations indicate that the interactions of
the carbon sp3 orbital with the 3d,2, 4p,, and 4s orbitals
of cobalt are mainly responsible for bond stabilization. The
axial bonds in cobaloximes and cobalamins possess very similar energy and can be described as multicenter
The organic residue R is accordingly influenced through cobalt
by the axial base B, and vice versa. These trans effects, or
vertical conjugation effects, have indeed been detected experimentally. If the organic residue R is an sp2- or sp-hybridized carbon atom, additional interactions of the R-carbon
orbitals with the 3d,, and 3d,, orbitals of cobalt occur and
lead to a stabilization of the axial bond. The axial bond
MOs also interact to some extent with the orbitals of the
horizontal ligand systems. The axial bonds thus are slightly
delocalized over the whole molecule of the complex. The
effects of the axial groups on the horizontal ligands are not
very important chemically. They are, however, responsible
for characteristic changes of the absorption spectra, particularly of vitamin BIZ derivatives. The effects of variation of
the axial substituents on the transition energies of cobalamins
have been calculated and are in reasonable agreement with
experimental data[7.43!
tion sphere of cobalt and subsequently terminate either by
dimerization to ethane, or by hydrogen abstraction, to methane. Photolysis of the same compounds in alcoholic solvents,
particularly isopropanol, favors H-abstraction reactions and
methane is formed virtually e x c l ~ s i v e l y ~Some
~ ~ ! of the methyl
radicals are reduced under the photolysis conditions. This
explains, why CH3D is formed in varying amounts if the
methylcobaltcomplexes are photolyzed in DzO as the solvent.
The photolysis of trideuteriomethyl-cobalamin and -cobaloxime, respectively, in H,O produces ethane which consists
to 89 % of CzDs and to 11 % of CH3CD3. It appears that
ligand-methyl groups are also cleaved off during the photolysis.
If methylcobalt complexes are photolyzed in the presence
of CN- ions, methane becomes the main product. The axial
coordination of cobalt by CN- increases the electron density
of cobalt; this apparently favors the reduction of methyl radicals. The aerobic photolysis of methyl cobalt complexes is
complicated by radical-oxidation reactions. H a peroxide-type
intermediates, formaldehyde is formed as one of the major
products derived from the methyl radicals.
The methylcobalt complexes are stable thermally up to
about 170°C. They decompose at higher temperatures, during
the decomposition methyl radicals are formed which terminate
to yield methane and ethane as expected. This indicates that
the Co-C bond undergoes homolytic cleavage during thermolysis. Photolysis of methylcobaloxime in the presence of vitamin B,,, gives rise to the formation of small amounts of
methylcobalamin, the vitamin B,,, thus acts as a radical scavenger. Benzene similarly traps the methyl radicals produced
on photolysis to yield toluene.
10.2. Photolysis and Thermolysis of Higher Alkylcobalt
Complexes
10.1. Photolysis and Thermolysis of Methylcobalt Complexes
In the absorption spectra of alkylcobaloximes, bands of
weak to medium intensity are observed in the range between
350 and 470nm ( E = 1000-3000). These have been assigned
to transitions between axial bond MOS''~].Irradiation of
alkylcobaloximes with light of wavelengths between 5 0 and
350nm causes an occupation of antibonding axial bond MOs,
which induces the cleavage of the C o x bond. During the
excitation process, intermediate states of the complexes are
generated which ultimately decompose into free radicals R'
and cobaloxime(I1)fragments [eq. (n)].
The subsequent reactions of the free radicals depend on
their structure and reactivity. Methyl radicals recombine with
the cobalt(r1) fragments with high efficiency if the photolysis
is performed under strictly anaerobic conditions in water.
Accordingly, one finds that methylcobaloxime and methylcobalamin are rather resistant to photolysis under these conditions. Some of the methyl radicals diffuse out of the coordinaAngew. C h r m . I n l . Ed. Enql.
Vol. 15 ( 1 9 7 6 ) No. 7
During the photolysis of higher alkyl-cobaloximes or -cobalamins, radicals are also the primary products of Co-C bond
cleavage. However, the subsequent reactions of the organic
radicals are more complicated. Ethylcobalt complexes of vitamin B,, and of cobaloximes undergo photolysis to yield
ethylene, the cobalt(l1) fragments produced are reduced to
cobalt(1) derivatives, which in turn decompose with release
of hydrogen. The intermediate formation of the cobalt([) species was clearly demon~trated'~~-~''.
The overall process can
thus be expressed in terms of eq. (0).
Higher alkylcobalt derivatives undergo photolysis in analogy to eq. (o),but if the reactions are carried out in alcoholic
solvents instead of water alkanes are formed as well as oleIn the photolysis of alkylcobalt derivatives of salen
(7), alkanes are formed which arise from the dimerization
of two alkyl radicals. This indicates that the behavior of
alkyl radicals depends on the Co"/Co' reduction potential
of the cobalt chelates.
Ethylene is the main product of the thermolysis of ethylcobalamin and -cobaloxime, respectively, but traces of ethane and
of n-butane were also detected.
423
On aerobic photolysis of the higher alkylcobalt compounds
aldehydes and other radical oxidation products are observed.
Higher alkenylcobaloximes carrying a terminal C=C bond
in the cobalt-bound organic residue produce alkenyl radicals
on aerobic photolysis which undergo cyclization reactions
prior to the termination
Alkylperoxo radicals which
are formed during aerobic photolysis may also react with
the cobaloxime(r1) fragments to yield isolable alkylperoxocobalt complexes[47,481.The quantum yields in typical photolysis
reactions of alkylcobaloximes and -cobalamins have been
determined" 6,491. Hydridocobaloximes are formed during the
thermolysis of certain alkylcobaloximes. Isopropyl(tri-n-butylphosphane)cobaloxime decomposes on heating according to
eq. (p), possibly uia a cyclic transition state[24].
Another example of a hydridocobaloxime elimination reaction is described in ref. ['I.
nucleophiles t h e m ~ e l v e s [ ~ ~ ,Higher
~'].
alkylcobalt derivatives react with some of the nucleophiles as well, but frequently by way of P-elimination rather than nucleophilic substitution. Isopropyl(pyridine)cobaloxime reacts with tri-nbutylphosphane rapidly at 50°C to yield propylene and hydri-
do(tri-n-buty1phosphane)cobaloxime. NeopentyI(pyridine)cobaloxime, a compound which does not carry hydrogen in
the P-position, does not undergo Co-C-bond cleavage, not
even on heating with tributylphosphane to 100°C; the only
reaction which is observed is the displacement of the axially
bound pyridine by the p h ~ s p h a n e [ ~ ~ !
Electron-attracting substituents in the P-position increase the
tendency of organocobalt complexes to undergo elimination
reactions. P-Cyanoethyl~obalamin[~~]
and the corresponding
cobaloxime[211are base-sensitive and decompose reversibly
according to eq. (s)["].
CN
10.3. Photolysis and Thermolysis of Substituted AlkylcobaltComplexes
CHZ
The behavior of substituted alkylcobalt complexes on photolysis and thermolysis is determined by the oxidation-reduction
potential and constitution of the radicals which are formed
during the initial process of Co-C bond cleavage. Inductively
electron-attracting substituents in cc-position give rise to radicals whose electron affinity may be sufficient to cause oxidation
of the cobalt(I1)fragments to the cobalt(m) species. The photolysis of formylmethylcobalamin is cited as a typical example
[eq. (q)][381.Acetaldehyde and hydroxocobalamin are the only
detectable products, vitamin Bizr cannot be observed as it
is apparently immediately oxidized to vitamin BI za. Similarly,
ethyl acetate is formed in the thermolysis of ethoxycarbonylmethylcobaloxime[2 'I.
PY
@CH,-CH=O
+P
CH3CH0
Substituents in the P-position relative to cobalt influence the
photochemical behavior in several ways. Ethylene and acetaldehyde are produced during the photolysis of P-hydroxyethylcobaloxime, for example, indicating that both elimination and
rearrangement reactions take placer5'1.
PY
The reaction of organocobalt complexes with thiolate ions
is strongly pH dependent. Nucleophilic transalkylation occurs
in alkaline media at high RS- concentrations. In neutral or
weakly acidic solutions Co-C bonds are cleaved reductively
according to eq. (t)[,'I.
Reductive cleavage of Co-C bonds occurs preferentially
with organocobalt complexes carrying electronegatively substituted alkyl residues. Reductive Co-C bond cleavage reactions were also observed with alkaline CO, stannite, and with
d i t h i ~ n i t e [ ~The
~ ! reaction with CO in alkali is exemplified
for an ethylcobaloxime in eq. (u). The mechanism of Co-C
bond cleavage by CO, particularly the trans attack in eq.
(u), is supported by the observed formation of a C O adduct
of methylcobaloxime in nonaqueous solvents[59].
cH3
CH3
CH3
10.4. Chemical Cleavage of Cobalt-Carbon Bonds
The covalent Co-C bonds in the organocobalt complexes
may be cleaved by nucleophilic as well as electrophilic attack,
reductive cleavage reactions are also known. The reaction
of n-alkylcobaloximes and -cobalamins with thiolate ions[521
have been studied in greater
Kinetic measurements
indicate that they proceed by an SNZ mechanism [eq. (r)].
The methylcobaloxime derivatives also react with other nucleophiles, e.g. with C1-, Br-, I-, CN-, P(n-C,H,),, P(C,H,),,
C,H,-NR-,
Se2-[541,and also with the cobalt(1) super424
Reactive, electron-attracting substituents in P-position facilitate Co-C-bond cleavage by oxidative elimination reaction.
p-Hydroxyethylcobalamin and -cobaloxime decompose on
reaction with acids to yield ethylene and cobalt(n1) derivatives
of the parent chelates. There is good evidence that the reactions
occur uin a nonclassical ion [eq. (v)].
It is also possible to rearrange P-hydroxyisopropylcobaloxime into P-hydroxy-n-propylcobaloximeby a mechanism
related to that of eq. (v)r601.
Anyew. Chem. I n t . Ed. Engl. J Vol. 1 5 ( 1 9 7 6 ) No. 7
cobalt-organic compounds are a rule much more resistant
to solvolytic attack than simple organometallic compounds.
T o saponify ( 2 4 ) to the free acid ( 2 5 ) it is convenient to
dissolve ( 2 4 ) in conc. HzSO4 followed by dilution with water.
The Co-C bond remains intact even under these rather drastic
conditions [Eq. (z)][''1.
Cobaloximes and cobalamins with halogen in a-position
of the cobalt-bound alkyl group have not yet been isolated.
The reaction of cobaloximes(1) with 1,2-dichloroethane causes
the spontaneous evolution of ethylener6'I; the presumed intermediate, 2-chloroethylcobaloxime, is evidently quite short
lived. a-Haloalkylcobalt complexes are likewise sensitive to
alkali. In the reaction of DDT with cobaloxime(t), a complex
( 2 3 ) is formed, indicating that not only substitution of C1but also elimination of HCl took p l a ~ e [ ~ ~ , ~ ~ ] .
PY
The base-induced cleavage of 2-hydroxyalkylcobalt complexes is of interest as it produces the cobalt(1) nucleophiles
We assumed that
and aldehydes or ketones,
reaction eq. (w) is a model of the enzymatic dehydration
of ethylene glycol to acetaldehyde:
1241
1251
10.6. Organornetallic Derivatives
Cobaloximes with Co-Sn, Co-Ge, Co-Pb, Co-Si, CoSb, and Co-Bi bonds were synthesized in 1965 and described
in greater detail in 1969[65'. The compound ( 2 6 ) is formed
by the reaction of cobaloxime(1) with (C,H,),SnCl. It is stable
to air and decomposes on reaction with NaOH to yield triphenyltin hydroxide and (Co')- ; this reaction is reversible.
A homolytic cleavage of the Co-Sn bond in ( 2 6 ) occurs
on irradiation with visible light, the triphenylstannylradical
dimerizes to hexaphenyldi~tannane[~'I.Attempts to synthesize
analogous compounds of vitamin 3 1 2 have not yet been successful.
FI,
11. Concluding Remarks
( C O ' ) ~t CH,CH=O
The substitution of hydrogen by halogen in y-position
affords stable organocobalt complexes. We found some time
ago, however, that y-bromopropylcobaloxime undergoes thermolysis with formation of cyclopropane [eq. (x)]. Acylcobalamins and -cobaloximes decompose in alkali according to eq.
(y)wI 641,
~
8'
3
C=O
I
(Co) +
Olio
--+
( C O ' ) ~+ R C OOH
(y)
In the present report some of the most important reactions
of the cobalt atom in vitamin Blz and in cobaloximes have
been summarized. Most of the reactions cited may not be
surprising to the organic chemist as they are typical for the
behavior of organometallic or nucleophilic agents. It is significant, however, that the organometallic derivatives of vitamin
B I 2 and those of the model compounds possess both unusual
stability and reactivity. Vitamin BIZ appears as an ideally
designed biocatalyst; almost all of its complex structural features are necessary to assure high catalytic efficiency and
lifetime under enzymatic conditions. The fact that the reactions
of cobalt in vitamin B I Z can be simulated with much simpler
compounds is quite surprising, but can be rationalized.
Although new reactions of vitamin BIZ may be discovered
in the future, it appears highly probable that the supernucleophilic cobalt(1) derivatives are active forms of vitamin B12,
coenzymes.
10.5. Reactions of Alkylcobalt Complexes with Metal Ions
Methylcobalamin, methylcobaloxime, and higher n-alkylcobalt derivatives of both, react with mercuric ion to yield
alkylmercuric salts. The Co-C bond in methylcobalt complexes is cleaved by ions such as Au3+, TI3+, Pt2+, and
Pd", giving rise to methyl derivatives of metals which have
been isolated in some cases[65'66].The alkylcobalt derivatives
of vitamin B1 and of cobaloximes thus behave in some respects
just as typical organometallic compounds, although they
should not be regarded as Nature's Grignard reagents. The
A n g r w Chmi. Inr. Ed. Eiiyl.
/ Vo/. 15
(1Y76) N o . 7
The results described in the present report were accumulated
during the past twelve years. I wish to express my gratitude
to my past and present collaborators for their help and contributions.
Received: February 18, 1976 [A 121 IE]
German version: Angew. Chem. 88. 465 (1976)
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