SOME ASPECTS OF ORGANOCOBALT CHEMISTRY RELATED TO VITAMIN B12

PART 1. RECENT DEVELOPMENTS IN ORGANOMETALLIC CATALYSIS

SOME ASPECTS OF ORGANOCOBALT CHEMISTRY RELATED TO VITAMIN B,,*

Jack Halpern

Department of Chemistry The University of Chicago

Chicago, Illinois 60637

INTRODUCTION

The distinctive features of organocobalt chemistry are reflected in a variety of contexts, perhaps most strikingly in the particularly widespread role of organocobalt compounds in catalysis. Thus, one of the earliest reactions encompassed by the modern era of coordination and organometallic catalysis is the cobalt carbonyl-catalyzed hydroformylation of olefins (Equation l).1-3 This process, which continues to be of considerable technological importance (0x0 process), is now generally recognized as proceeding through organometallic intermediates of the type RCo(CO), and RCOCo(CO),.

HCo(CO), RCH=CHz + CO + HZ - RCHZCHZCHO

Another distinctive feature of organocobalt chemistry relates to the Occurrence of organocobalt compounds in nature and to the biochemical roles of such compounds. The X-ray determination of the structure of coenzyme B1, (5'-deoxyadenosylcobalamin) by Lenhert and Hodgkin4 in 1961 revealed an unexpected feature, namely the presence of a covalent cobalt-carbon bond (FIGURE l) , the first known example of a naturally occurring organometallic substance. This compound, as well as the naturally occurring corresponding methylcobalamin, exhibits remarkable stabilities, including resistance to decomposition by moisture and oxygen. Both of these compounds are now recognized to play important and distinctive biochemical roles5 the nature of which, while not yet fully elucidated, has led to their designation6 as '' biological Grignard reagents " and to the early recognition' of possible connections with the mechanism of cobalt carbonyl-catalyzed hydroformylation of olefins.

(organocorrinoids) are currently themes of intensive research. The field encompassed by this research is characterized by important discoveries of distinctive compounds and reactions the full elucidation of which constitutes a challenging objective that is still being vigorously pursued. The field is also remarkable for the degree to which it has brought together, for the first time, and in a highly creative and productive context, important lines of research in biochemistry and organometallic chemistry. I t is principally with the aspects of organocobalt chemistry that relate to this field that the present paper is concerned. Important recent accounts pertinent to this subject include the monograph by Pratts and the reviews by Johnson and Dodd' and by Wood and Brown.'O

The chemistry and biochemistry of organometallic derivatives of vitamin B,

* This paper is based in part upon research supported by Grant AM-13339 from the National Institute of Arthritis, Metabolism, and Digestive Diseases of the U.S. Public Health Service and Grant GP 26600X from the National Science Foundation.

2

Halpern : Organocobalt Chemistry 3

(I) R = +

NH2

FIGURE I . Structure of organocobalamins. ( I ) Methylcobalamin (R=CH3). (2) Co- enzyme B, (R=5'-deoxyadenosyl).

4 Annals New York Academy of Sciences

VITAMIN BIZ ANALOGUES

Many of the characteristic chemical properties of vitamin BIZ and its derivatives are manifested also by a variety of the other classes of cobalt compounds. Par- ticularly significant parallels include (i) the occurrence of redox series encompassing the Co(III), Co(II), and Co(l) forms of such complexes (the latter two forms corresponding to vitamin BIZ, and vitamin BIZ., respectively) and (ii) the reactions of the reduced fomis of such complexes with alkylating agents such as organic halides to form organocobalt derivatives related to organocorrinoids such as methylcobalamin and coenzyme BIZ.

The earliest examples of such vitamin BIZ analogues or "model systems" were recognized in 1964 when Halpern and Maher reported that the pentacyanocobaltate(I1) ion reacts with organic halides in aqueous solution to form stable organopentacyanocobaltate (111) species (Equation 2), while at the same time Schrauzer and Kohnle' described the alkylation of bis(dimethylg1yoximato)cobalt complexes (commonly referred to as cobaloximes) according to Equations 3 and 4 (where B is a neutral axial ligand such as water, a n amine, or a phosphine).

2C01'(CN)s3- + RX - RCO" ' (CN)~-~ + Co1''(CN)sX3- (2)

Co"'(DH)z(B)X + RMgX - RCo"'(DH)z(B) + MgXz (3)

Co'(DH)z(B)- + RX - RCo"'(DH)z(B) + X- (4) These particular analogues have been the subjects of intensive subsequent

~ t u d i e s . ~ ~ - ' ~ In addition, numerous other vitamin BIZ analogues have been recognized, encompassing a variety of ligands, notably of the Schiff-base type, such as bis(acety1acetone)ethylenediimine (BAE) and bis(salicylaldehyde)ethylenediimine (SALEN), the study of which has been advanced particularly by Costa and his coworker^.'^*^^ Organocobalt derivatives of some of these complexes are depicted in FIGURE 2.

SAWPI4 s*Lw 7,7'(CH3) SAW - - FiGuRE 2. Organocobalt derivatives of some vitamin BIZ analogues.


It would appear that many of the characteristic chemical properties of vitamin B1 and its derivatives, including the ability to form stable organocobalt compounds through reactions such as those of Equations 2-4, are not critically dependent on the precise nature of the ligands and are manifested by complexes containing ligands (e.g. C N - or SALEN) that bear littlechemical or structural resemblance to the corrin ligand system of vitamin B I Z itself. The only essential properties of the ligands seem to be the ability to stabilize all three pertinent oxidation states of cobalt (i.e., +3, +2, and + I ) and to form spin-paired complexes of cobalt in each of these oxidation states. The preferred coordination numbers of these complexes are characteristically 6 (occasionally 5) for Co(lII), 5 for Co(Il), and either 5 or 4 for Co(1).

These parallels notwithstanding, important quantitative and even qualitative differences are apparent among these different compounds and between the models and the corresponding derivatives of vitamin B1 itself. Some of these differences are summarized in TABLE I . Attention is directed particularly to the following points.

TABLE 1 COMPARISON OF SOME VITAMIN B I Z ANALOGUES*

Ligand BAE 7,7'(CHs)ZSALEN SALEN SALOPH (DH), (DO)(DOH)PN

pK,t 7.06 6.86 6.73 5.14 4.17 Log KS -1.76 - 1.42 -0.91 2.7 EI/zP -1.97 -1.80 -1.71 -1.54 -0.93

*Based on data from Costa." (Ligand designations from Figure 2). t K. for CO(LIGAND)(OH~)~+ $ K, for Co"(L1GAND) + 2CbH5NHz 9 El,* for RCo"'(L1GAND) + e-

Co(LIGAND)(OH,)(OH) + H + . Co"(LIGAND)(NHzCbH5)2.

RCo"(LIGAND), (V vs SCE in DMF). - 1. The systematic variation of the electron-donor power of the various ,ligand

systems, reflected in the trend of increasing reduction potentials of the organocobalt (RCo) derivatives as well as parallel trends of other properties, such as the acidity of coordinated water and the axial ligand binding constants of the cobalt(I1) complexes. In the context of these trends the cobalamins would appear t o fall somewhere between the Schiff base and d'ioxime compounds.

2. The basicities of the cobalt(1) species and the degree to which they are protonated in aqueous solution (Equation 5 ) vary over an enormous range as a result of differences in chargeand other ligand properties. Thus, the pK. of CO(CN)~H'-- is ca 20, whereas that of the protonated form of vitamin B I Z , is < 5 . Accordingly, for these two species, the equilibria corresponding to Equation 5 in aqueous solution lie far to the right and left, respectively. The chemistry of these systems, including the modes of reaction with organic halides, profoundly reflects this difference.

CO' + HzO a CoI'lH- -t- OH- (5)

3. Steric influences are manifested in a number of ways that are important in the present context. Thus, bulky axial ligands (e.g., B=tricyclohexylphosphine) markedly reduce the reactivities of complexes of the type Co"(DH),(B) with organic halides to form organocobalt derivatives, RCo"'(DH),(B). In the case of vitamin BIZ and its derivatives, important steric influences may be exerted by the bulky


substituents on the corrin ring. The potential steric interaction of these substituents with axial ligands is revealed by the structural features of coenzyme B i z .4 Such steric interactions may contribute to (i) the strikingly high substitution labilities of the axial ligands in ~ o b ( l l l ) a l a m i n s ~ ~ ~ ~ compared with most analogues, (ii) the formation of stable five-coordinate cobalt(II1) corrinoids, for which evidence has beem reported,'O and, perhaps most important in the present context, (iii) the weakening of cobalt-carbon bonds in organocorrinoid compounds and promotion of dissociation of such bonds. The potential importance of the latter theme for the biochemical roles of vitamin B I Z and its derivatives will be apparent from the discussions that follow.

FORMATION OF COBALT CARBON BONDS

According to the usual conventions, the oxidation state of Co in organocorrinoids and related compounds (designated as Co-R) is +3, while the organic ligand is regarded as anionic(i.e., R-). By means of these designations, three limiting processes, depicted by Equations 6-8, can be considered to lead to the formation of cobalt-carbon bonds, that is, starting from Co(IIl), Co(Il), and Co(1). The corresponding organic reagents, [R-1, [R'] and [R+], may actually be the free carbanions, radicals, or carbonium ions, respectively, or, alternatively, appropriate precursors, such as RLi, RMgX, or RCI, as in the examples depicted by Equations

LsC0"'X + [R-] - LsCo'I'R + X- (6)

LSCO" + [R'] - LsCo"'R (7)

LsCo' + [R +I - LsCo"'R (8)

2-4.

Alkylation of Cobalt(ll1)

The alkylation of transition metals by organolithium or Grignard reagents, exemplified by Equation 3, is a reaction of fairly general applicability that has considerable utility as a synthetic route to organocobalt compound^.^ In the context of this general theme mention should be made of some special cases in which Co(Il1) may be sufficiently electrophilic to undergo reactions leading directly to the formation of cobalt-carbon bonds, for example:

0 0 II I1

LsCo"' + CHJCCH, + OH- - LsCoCHzCCHs + H20 (9)

,LsCo"' + CHtcCHZ + OH- - LsCoCHzCHzOH (10)

Formation of CH,COCH,Co(SALEN)(MeOH) by the route corresponding to Equation 9 has been reported.I6 On the other hand, while the acid induced decomposition of 8-hydroxyethylcobaloximes according to the reuerse of Equation 10 [to cobaloxime(lI1) and ethylene] has been described, it has been claimed that (in contrast to the well-known corresponding hydroxymercuration of olefinsz') alkyl- cobaloximes could not be obtained from hydroxycobaloximes and olefins under a variety of conditions.22 At this stage it is unclear that the direct alkylation of cobalt(1II) (except possibly through direct R- transfer from one cobalt atom to another), plays an important role in the biosynthesis of organocorrinoids.


Alkylation of Cobalt(I)

The formation of organocorrinoids, including methylcobalamin and coenzyme B1 2 , under biological conditions almost certainly entails the alkylation of reduced forms of vitamin BIZ through routes analogous to those depicted by Equations 3 and 4. Thus, the biosynthesis of coenzyme BIZ is believed to involve the transfer-to vitamin BIzs of a deoxyadenosyl moiety derived from adenosine triphosphate ( ATP) .

Studies on the alkylation of vitamin BI zs, cobaloxime(1) and related cobalt(1) compounds by organic halides (Equation 4) have revealed reactivity patterns characteristic of nucleophilic displacement reactions, for example the reactivity sequences (second-order rate constants for CO(DH)~(PBU~)- in methanol at 25", in parentheses), CH3Br (2.2X 10' M-' sec-I) > CzH5Br (1.6) > (CH3)zCHBr (1.1 x 10-I) and CH31 ( 2 . 3 ~ 10') > CH3Br (2.2 x lo2) > CH3CI (8.5 x Among the noteworthy features of these reactions are (1) the very high nucleophilic reactivities of vitamin BIzs and related cobalt(1) compounds (ca 14 on Pearson's logarithmic nucleophility scale, compared with ca 7 for 1- or CN-), (2) the similari- ties of the nucleophilic reactivities of vitamin B1 z, and of a variety of model cobalt(1) compounds, such as Co(DH12B-, Co(SALEN)B-, Co[(DO)(DOH)pn]B, and (3) the relative insensitivity of the nucleophilic reactivities to the nature of the axial ligand, B.23

Alkylation of Cobalf(tt)

Extensive studiesL1.L4.15.24~25 in our laboratory on the class of reactions depicted by Equation 2 and on related reactions of other cobalt(I1) complexes such as CO(DH)~B and Co(SAL0PH)B (designated generally as Lsco") have revealed that these reactions usually proceed by the stepwise free radical mechanisms described by Equations 11-13.

k l 1 LsCo" + RX - L ~ C O X + R' (Rate-determining) (11)

LSCO" + R' - L ~ C O R (12)

2LsCO" + RX - L ~ C O R + LsCOX (13) Selected rate-constants for such reactions are summarized in TABLE 2 and reveal,

not unexpectedly, a reactivity pattern quite different from that for the reactions of vitamin BIZ* and related cobalt(]) compounds with organic halides. Noteworthy features of this reactivity pattern are ( I ) the increase in reactivity along the series CH3X < CzH5X < (CH&CHX and along the series RCI < RBr < RI (trends also characteristic of other halogen atom abstraction reactions), (2) increasing reactivity with increasing electron acceptor character ( p = + 1.4) of the substituent Y for the reactions of Co(DHI2(PPh3) with a series of substituted benzyl bromides, p-YC6H4CH2Br, and (3) increasing reactivity with increasing electron donor character ( p = - 1.4) of the substituent Y for the reactions of a series of complexes, C O ( D H ) ~ [ ( ~ - Y C ~ H ~ ) ~ P ] with benzyl bromide. Both the latter trends presumably reflect some degree of electron transfer from L5Co" to the organic halide in the rate-determining step through a transition state of the type [L5Cod+. . .Xd- . . . R]$. In addition to such electronic influences, the reactivity pattern of these reactions is also clearly influenced by steric factors. Thus, bulky axial ligands lower the reactivities of the Co(DH)tB complexes, the lowest reactivity among the phosphine

TA

BL

E 2

RA

TE

CO

NST

AN

TS

FOR

REA

CTI

ON

S O

F C

OB

AL

T(I

I)

CO

MPL

EXES

W

ITH

OR

GA

NIC

H

ALI

DES

A

T 25

"

L5C

o"

RX

So

lven

t kii,

Ref

. M- Ism

- '

CH

oOH

-HZO

(80

: 20)

C

HoO

H-H

20(8

0 : 2

0)

CH

sOH

-HzO

(80

: 20)

C

H3O

H-H

20(8

0 : 2

0)

CH

3OH

-Hz0

(80

: 20)

C

HjO

H-H

zO(8

0 : 2

0)

CH

jOH

-HzO

(80

: 20)

Ben

zene

B

enze

ne

Ace

tone

B

enze

ne

Ben

zene

B

enze

ne

Ben

zene

B

enze

ne

Ben

zene

B

enze

ne

Ben

zene

B

enze

ne

CHzC

12

CHZC

IZ

CH

zClz

1.0

x lo

-'

14

5.6

x lo

-' 14

1.

2 14

9.

2 14

3.

8 x

103

14

2.3

14

4.9

x 10

-4

14

7. I

15

1.1

15

4.4

x 10

-3

15

9.7

x 10

-3

15

2.1 x

10-

2 IS

3.

4 xl

O-'

I5

4.8

~

15

3.7

x lo

-'

15

2.2

x lo

-'

15

6.1

x 15

2.1

x

15

1.5

x lo

-'

IS

2.9

x 10

-3

27

5.5

~

10-3

27

2

.9~

10

-3

27

9.0

x lo

-'

27

9

J

3

5

rn 5 E R :

lu a

Y K 0 3 8 rn


complexes being exhibited by C~(DH)~P(cyclohexyl)~ despite the high basicity of this phosphine. Such steric influences are consistent with the increase in coordination number accompanying the rate-determining step.

Modifications of the reaction scheme depicted by Equations 11-13 may result either from alternative reactions of the intermediate radical R’ or from decomposition of the primary organocobalt product. Two such cases are described by the following examples :

CO(CN),~- + (CH3)2CHBr - C O ( C N ) ~ B ~ ~ - + (CH3),CH (14)

Co(CN)5’- + (CH3)zCH - Co(CN)sH + CHjCH-CHz (15)

2Co(CN)S3- + (CHdZCHBr - Co(CN),Br3- + Co(CN),H3- + CH,CH=CH, (16)

Co(CN):- + ICH,CH,CH,I - Co(CN),I’- + ICH,CH,eH, (17)

Co(CN):-ICH2CH2?HZ - [Co(CN)5CHzCH2CH21] - NCQ

2Co(CN):- + ICH,CH,CH,I - 2Co(CN),13- + H2C- CH2 (19)

Because of the very high basicity1* of CO’(CN)~~- , this ion exists in aqueous solution predominantly in the protonated form, CO(CN)~H~- . The reactivity pattern of this species with organic halides differs from those of the other cobalt(1) complexes (including vitamin B1 2.) described earlier. Instead of forming organocobalt derivatives, the reaction follows the course depicted by Equations 20-23, in which CO(CN),~- acts as a catalyst.26 From the known Co-H bond dissociation energy (ca 60 kcal/mole), reaction 21 can be estimated to be exothermic by 30-40 kcal/mole and is thus likely to be very fast.

Co(CN)S3- + RX - Co(CN)5X3- + R’ (20) R’ + Co(CN)5H3- - RH + Co(CN)S3- (21)

Co(CN),’- Co(CN)5H3- + RX - Co(CN)SX3- + RH (22)

A variant of the mechanism depicted by Equations 11-13 has been observed in the cases of the reactions of cer’ain Schiff-base cobalt(1l) complexes with strongly electron-accepting organic halides, such as p-N02C6H4CHzX.27 This mechanism, described by Equations 23-27, involves an outer-sphere electron transfer from a (presumably high-spin) six-coordinate cobalt(l1) complex, formed in a preequili- b r i m step, to the organic halide, followed by dissociation of the resulting radical anion. While the products are similar to those expected for the halogen abstraction mechanism, the rate-law k’[Co(SALEN)(MelMD)][MeIMD][RX], where MelMD = I-methylimidazole) is different. This mechanism is also distinguished by the insensitivity of the rate to the nature of the halogen atom in contrast to the marked halogen dependence ( I > Br > CI) characteristic of the halogen abstraction processes. Such electron-transfer mechanisms are uncommon and are apparently


restricted to systems in which the high-spin state of cobalt(I1) is reasonably accessible and in which the organic halide is a sufficiently strong electron acceptor.

Co"(SALEN)(MelMD) + MelMD Co'l(SALEN)(MelMD)z (23)

+ [RXI- (Rate-determining) (24)

[RXI- - R ' + X - (25) Co"(SALEN)(MelMD) + R' - Co(SALEN)(MelMD)R (26)

Co"(SALEN)(MelMD)2 + RX - Co"'(SALEN)(Mel MD), +

2Co"(SALEN)(MelMD) + MeTMD + RX - Co(SALEN)(MelMD)z + + Co(SALEN)(MelMD)R + X- (27)

Recently we have extended our studies on the alkylation of cobalt(l1) complexes by organic halides to vitamin BIZ, itself.28 In methanol solution the course of reaction appears to be similar to that previously found for other cobalt(l1) complexes, such as CO(CN),~- and CO(DH)~B, i.e.,

Biz, + RX - R' +X- BIZ(' BIZ. + X-) (Rate-determining) (28)

Biz r+R ' - R-Biz (29)

The rate law, accordingly, has the second-order form of Equation 31, the dependence of k on RX paralleling that for other cobalt(l1) complexes (TABLE 3).

TABLE 3 RATE CONSTANTS FOR REACTIONS OF VITAMIN BIZ, WITH ORGANIC HALIDES,

Methanol Solution Aqueous Solution RX k31, M-'scz-' kj1, M - ~ s K - ' k 3 2 , M-'sec-'

p-N02C6 H4CH Br p-NOzC6H4CHzI 6 CHzICOOCH3 9 x 10-4 2 x 104 CHzIC00- 3 x 10 CHzICONHz 2 x 10-4 3 x 1 0 2 CH3I 6 x 10 CHzBrCOOCH3 e 2 x 10-4 s x 10-3 CHz BrCOO- 7 x 10-4 CHCIzCOOCH3 I x 10-3 CHCIZCOO- very slow 2 x 10-4

7 x 1 0 - 2

* H. Blaser and J. Halpern, Unpublished dataaZ8

Although differences in solvent, axial bases, and so on, make exact comparisons difficult, approximately comparable kinetic data for different cobalt(l1) complexes are summarized in TABLE 4. These data suggest that the reactivity of vitamin B I z, is considerably lower than that of CO(CN),~- and falls somewherebetween that of CO(DH)~B and Co(SAL0PH)B. This is consistent with some of the other coniparisons encompassed by TABLE 1.

-d[RX]/dt = kll[vitamin BIz,I[RX] (31)

Halpern : Organocobal t Chemistry 11

111 aqueous solution, the above pattern of behavior was observed only for the reactions of vitamin BI 2 , with organic chlorides and bromides (CH2BrCOO-, CHzBrCOOCH3, CHCl,COO-, for instance). I n these cases the rate laws were similar to those in methanol (corresponding t o Equation 31), and these reactions apparently proceed according to the same mechanism-that depicted by Equations 28-30. However, for the reactions of the several iodides examined (including CH31, CHzICOOCH3, C H z I C O N H z , and CH21C00-) the behavior in aqueous

TABLE 4 COMPARISON OF REACTIVITIES OF VARIOUS COBALT(II) COMPLEXES

TOWARD ORGANIC HALIDES Second-Order

Cobalt(l1) Complex Organic Halide Solvent Rate Constant, M-I=-1

C O ( C N ) ~ ~ - p-N02C6H4CHzBr CH30H:Hz0(80: 20) 1 x 10' Co(DH)z(PPh 3) p-NO 1C6H4CH Br Benzene 4 x lo- ' Vitamin BIZ, p-NOzC6H4CHzBr CH30H 7 x 10-2 Co(SALOPH)(C,H,N) p-NOzC6H4CHzBr CH2C12 s x 10-3

solution was quite different from that in methanol. In these cases the overall stoi- chiometry was still in accord with Equation 30, but the rate-law was quite different, having the third-order form corresponding to Equation 32. The values of k lz for these reactions, which are also listed in TABLE 3, were unaffected by the addition of vitamin B, z., .

- d[RX]/dt = k3 2 [vitamin B1 ~,I21RX] (32)

This rate law is clearly incompatible with the earlier mechanisms, such as that described by Equations 28-30, deduced for the reactions of organic halides with other cobalt(I1) compounds and with vitamin BIZ, in methanol solutions. Our results are also incompatible with yet another mechanism that has previously been proposedz9 for the reactions of organic halides with vitamin BIZ, , namely disproportionation (to BIZ. and B, z,,) followed by alkylation of vitamin BIZ, (Equations 33-35). Application of the steady state approximation (to vitamin B, yields for this mechanism the rate law corresponding to Equation 36, which is incompatible with the observed rate law (Equation 32) and with the absence of any influence of added vitamin BIzp on the rate.


The mechanism that we favor for these reactions is that depicted by Equations 37-39.28 This involves the formation of a BIz,-RI complex that reacts with a second BIZ, molecule to form the products.

k37

k-37

Bizr+ RX Bizr.RX (37)

2Bi2, + RX - R - B I ~ + Biz, + X- (39) Application of the steady-state approximation to the BIZ;RX intermediate

yields the rate-law corresponding to Equation 40. Under the limiting conditions, k - 3 7 %k3s[B12,], this reduces to Equation 41 which has the same form as the observed rate law.

k3,kss[vitamin Bl2,l2[RX1 k - 3 7 + kps[vitamin BI2J --d[RX]/dt =

-d[RX]/dr = (k37k38/k- 37)[vitamin B1 z,]Z[RX] (41)

The difference between the behavior of organic iodides and that of bromides and chlorides in these reactions may reflect the, not unexpected, greater tendency of the iodides (presumably because of their greater polarizabilities) to form complexes with B i z r . The plausibility of such complexes also receives some support from the demonstrated formation of a stable I--complex of cob(I1)yrinic acid heptamethyl ester of the composition C O " . I - . C O ~ ~ , ~ ~ and from our own observation of spectral evidence for the interaction of I - with vitamin Biz, in

Still another mechanism compatible with a rate-law of the form of Equation 32 is that depicted by Equations 42 and 43, involving the reaction of RI with a dimer of vitamin BIZ; which is formed in a pre-equilibrium step. While such a mechanism cannot be excluded, it is not supported by any independent evidence of such dimer formation; nor is it clear why this mechanism should be preferred for iodides but not for bromides or chlorides.

2B121 (Bi2r)z (Rapid equilibrium) (42)

(Biz.)z + RX - R-BIz + Biz, + X- (43) In view of the degree to which the parallels between vitamin B I 2 and its model

compounds are so frequently emphasized, and the reliability of such models as guides to the chemistry of BIZ is defended, it is worth noting that the features of the relatively simple reactions of vitamin B I Z , that have just been described are not reflected in the corresponding chemistry of any of the model cobalt(l1) compounds thus far examined.

CLEAVAGE OF COBALT-CARBON BONDS

The mechanisms through which cobaltcarbon bonds are cleaved, and the factors that promote (or inhibit) such cleavage, are of considerable chemical and biochemical interest. Just as for the formation of such bonds, three limiting mechanisms of simple cleavage can be formulated corresponding to the release of Co(lll), Co(1l) or Co(1). These processes are depicted in Equations 4446, where, as previously, the symbols [R-1, [R'], and [R 'I may represent free species (corresponding


to simple dissoriafiort processes) or bound forms such as RH or RHg+ (corresponding to transfer of R- to H + and HgZ +, respectively).

CO-R - CO"'+ [R-] (44) CO-R - Co"+[R ' ] (45)

CO-R - Co '+[R+] (46)

Homolytic Cleavage

Homolytic cobalt-carbon bond cleavage may be induced photochemically or thermally, as well as by transfer of R' to a radical acceptor.

The photolability of organocobalamins is well known and has been extensively investigated. Although the overall reactions are often complex, it seems likely that at least in the majority of cases the primary photochemical process involves the homolytic cleavage of the cobalt-carbon bond to form cobalt(l1) and R' . Closely related photochemical cobalt-carbon bond cleavage processcs have been observed for certain organocobalt model compounds, notably the cobal~ximes.~' Systematic investigations of the influence of electronic and steric factors, notably those con- nected with axial ligand variation, have been described for organocobalamins, and cobinamides as well as model ~ y s t e m s . ~ ~ * ~ ~

I t seems likely that, at least in such relatively simple cases as methylcobalamin, thermolysis also entails honiolytic cobalt-carbon bond cleavage. Thus, solid methyl- cobalamine decomposes above 200" to give a mixture of methane and ethane, the products expected from initially formed methyl radical^.^' The thermal stabilities of many organocobalamins appear to be somewhat lower than those of corresponding model compounds, such as the organopentacyanocobaltate and organoco- baloxime analogues. This may reflect, in part, steric interference from the bulky substituents on the corrin ligand. A particularly striking comparison is provided by the benzyl cobalt compounds. While C6H5CHzCo(CN)53- and C6H5CHzCo- (DH)z(pyridine) are relatively stable compounds, benzylcobalamin (prepared by the reaction of vitamin BlZs with C6HsCH2Br) proved too unstable for isolation.z8 Its facile spontaneous decomposition in solution at room temperature suggests that the Co-C bond dissociation energy in benzylcobalamin is probably less than 30 kcal/mole. Allowing for the ca 20 kcal/mole resonance stabilization of the benzyl radical, the corresponding Co -C bond dissociation of ethylcobalamin (for which steric factors are likely to be comparable) can be estimated to be less than 50 kcal/niole. There is a pressing need for more extensive and more reliable thermo- dynamic data for these and related organocobalt compounds.

Several reports have recently appeared 33.34 of homolytic cobalt-carbon bond cleavage reactions involving the transfer of radicals from cobalt to radical acceptors, notably other metal atoms, such as Co(ll) and Cr(IL), e.g. Equation 47 (where TFEN =N,N'-ethylenebis-(4,4,4-trifluoro-l-methyl-3-oxobutylideneiminato) and ACEN =N,N'et hylenebis( 1 -methyl-3-oxobutylideneiminato).

CH 3Co"'(ACEN) + Co"(TFEN) - Co"(ACEN) + CHjCo"'(TFEN) (47)

Transfer of R - to Electrophiles

Electrophilic reagents that induce cleavage of cobalt-carbon bonds include halogen molecules and metal ions, such as mercury(l1) and thallium(ll1). The alkylation of mercury(l1) by organocobalt compounds was first described by


Halpern and Maher," who reported, in 1964, that CH3Co(CN)53- reacts with HgCI, in aqueous solution to form CH3HgCI. Such reactions and their analogues, for instance, the corresponding alkylations of thallium(II1) and arsenic(lII), have subsequently received considerable attention, especially following the demonstration by Wood and colleagues in 1968 that methylcobalamin was capable of effecting the synthesis of both monomethylmercury and dimethylmercury in enzymatic as well as nonenzymatic ~ystems. '~

The re~u1t . s~~ of kinetic studies in our laboratory on the alkylation and arylation of mercury(I1) by various organobis(dimethylglyoximato)cobalt(III) complexes (Equation 48) are summarized in TABLE 5.

TABLE 5 KINETIC DATA FOR THE REACTIONS OF RCO(DH)~(H~O) WITH

Hg2+ AND WITH IrC162-

R kas,* M-' SK-' k5o.t M-I SW-'

54 1 .o 1.2 x lo-' 2.2 9.4 x 10-2 1.8 very slow 8.4 x 104

p-NOzC6H4CHz 6.5 x 10-3 1.7 p-FCsHdCH2 2.8 x lo-' 1.4 x 104 C6HsCHz 7.5 x 9.0 x 103 p-CH3CsH4CHz 9.0 x 2.4 x 105 P-CHJOC~H~CHZ 1.1 x 10-1 4.0 x 105

P-FCsH4 4.0 x loz C6H5 2.5 x lo2 P-CH&H4 4.5 x 103 p-CH3OCsH4 3.0 x 104

* Rate constants for Reaction 48. Data from Ref. 36. 7 Rate constants for Reaction

The reactivity patterns are characteristic of electrophilic displacement reactions, the rate constants decreasing along the series CH3 > C2H5 >CC,H,, and with increasing electron withdrawing character of the para-substituents in the case of the benzyl- and phenylcobalt series. Hammett plots for these series yielded p values of - 1.2 and -6.3, respe~tively.'~ The latter value is close to that (-5.9) previously found for phenyl transfer between mercury(I1) ions: (p-YC6H4)zHg + HgIz +

The alkylation of mercury(1 I) by organocobalamins exhibits similar trends and appears to proceed through similar electrophilic displacement of R -, with the addit,ional complication that Hg(l1) also promotes displacement of the axial 5,6- dimethylbenzimidazole ligand by coordinating with the latter.38

The cobalt-carbon bonds in simple alkylcobalamins and related alkyl-cobalt compounds, such as methylcobalamin, are quite stable toward protonic acids. However, certain substituted (e.g. 8-hydroxy- or p-alkoxy-) organocobalamines

2p-YC&HgI.37


are readily decomposed by acids, apparently through attack at the &oxygen substituent, according to Equation 49.39 An analogous process, initiated by proto- nation of the ring oxygen and entailing elimination of the unsaturated sugar has been proposed for the acid-induced decomposition of coenzyme BI2 .40

+ CO-CHZCH~OH + H + - [COCHZCHZOH~] - CO"' + CHz-CH2 + Ha0 (49)

Oxidative Cleavage

We have recently shown4' that one-electron oxidation of organobis(dimethy1- glyoximato)cobalt(llI) compounds (for example by IrC16' -) induces cobalt-carbon bond cleavage in accord with the scheme described by Equation 50 (where X - = OH-, CI-, or D H - ) . The proportions of RX and Rz formed depend on the conditions and on the nature of R, the former being favored for R=benzyl and the latter for R = i s o p r ~ p y l . ~ ' . ~ ~

RCo(DH),(H,O) + 1rCI;-

Co"' + R'(- +Rz) (501)

[RCo(DH)z(HzO)I+ lkS0 -(:I Co" + RX (Sob)

Kinetic data for these reactions, listed in TABLE 5 , reveal a marked trend of increasing rate along the series CH3 < CzHs < (CHACH and, for p-YC6H4CHz- CO(DH)~(H~O), along the series Y=NOZ < F N H < CH3 < CH30. The Hammett p value for the latter series is - 5 . 2 (as against - 1.2 for the corresponding transfer of the same benzyl ligands to Hg2+, according to Equation 48). The implication of these trends is that the origin of the electron removed in the initial 1-electron oxidation step is effectively the R- ligand and that the resulting species is perhaps best represented by the formulation Co"l.R'.

Reductive Cleavage

Cobalt-carbon bond cleavage can also be induced by reduction of organocobalt compounds. Studies on the electrochemical reduction of [RCo[(DO)(DOH)PN]- HzO]+ complexes by have been interpreted in terms of both one- and two-electron reduction processes resulting in the release of R ' and R-, respectively, according to the scheme of Equation 51.

,z* [CoR] - C o ' + R ' (511)

H+ [CoR]- - C o ' + R - [- RH] (51b)


Reductive cleavage of cobalt-carbon bonds can also be effected chemically, for example by reduction with C044*4s or t h i o l ~ . ~ ~ The reductive cleavage by CO may be accommodated by the scheme depicted by Equations 52 and 53. Substantial evidence for intermediate carboxyl complexes similar to that postulated in this scheme (CoCOOH) has been provided by related studies on the oxidation of CO by Co"' and other metal ions.46

Heterolytic cleavage of cobalt-carbon bonds leading to the formation of cobalt(1) may also be induced by a nucleophile such as OH-, through a mechanism involving deprotonation of an activated ,!?-carbon atom together with olefin elimination, as in the example depicted by Equation 54.39,47

Co' + CH,-CHCN + H 2 0 (54)

VITAMIN B1 2 - D ~ ~ ~ ~ ~ ~ ~ ~ BIOCHEMICAL PROCESSES

The two important biologically active derivatives of vitamin B I Z , shown in FIGURE 1, are methylcobalamin and 5'-deoxyadenosylcobalamin (coenzyme B, 2).

Each of these is involved in the catalysis (together with the appropriate enzyme systems) of a distinctive class of biologically important reactions, some features of which are considered below.

Methylcobalamin- Dependent Processes

Methylcobalamin (or an enzyme-bound form thereof) is known to be. operative in the catalysis of a number of important biochemical processes including the methylation of homocysteine to methionine (Equation 59, the biosynthesis of methane, the reduction of C 0 2 to acetic acid, as well as the methylation of mercury and other metals already referred ~ O . ~ . * O

HSCH2CH2CH(NH2)COOH + Ns-Methyltetrahydrofolic acid

+ CH3SCH2CH2CH(NH2)COOH + Tetrahydrofolic acid (55) CH3-B12

Transmethylase

It is believed that in all of these reactions the incorporation of CH3 into the 'product is accomplished by transfer of CHI from an intermediate methyl cobalt

corrinoid. Such transfer may occur directly to the substrate or, alternatively,

Halpern: Organocobalt Chemistry 17

through an intermediate carrier. Thus, the biosynthesis of methionine (Equation 5 5 ) involves the transfer of CH, + from Ns-methyltetrahydrofolate to a Co(l)-corrinoid, followed by transfer of CH, + from the resulting methyl corrinoid to homocysteine to produce methionine and regenerate the Co(l)-corrinoid. The biosynthesis of acetate is believed to proceed through similar formation of a methylcorrinoid and conversion of the latter by reaction with C 0 2 to a carboxymethylcorrinoid, [Co-CH,COOH], followed by reductive cleavage to form CH,COOH and regenerate Co(l). The biosynthesis of methane has also been shown to involve methylcorrinoid intermediates. Recent evidence suggests that methyl transfer from the latter may occur as CH,’ to an intermediate coenzyme, followed by reductive demethylation of the latter.’O

The formation of highly toxic methyl mercury compounds [CH3Hg+ and (CH,),Hg] under environmental conditions has been shown to result from the methylation of mercury(I1) by methylc~rrinoids.~~ While the remethylation of the corrinoid and hence the overall catalytic cycle is enzyme-dependent, it is not clear that the actual step requiring transfer of CH3- from [CoCH,] to Hg(I1) is an enzymatic process since this reaction has been demonstrated to occur readily under nonenzyma tic conditions. 38

Coenzyme B , 2-Dependent Processes

5’-Deoxyadenosylcobalarnin (coenzyme B1 2 ) has been shown to mediate the catalysis of a variety of processes (mutase reactions), a common feature of which, depicted in Equation 56, is the intramolecular 1,2-interchange of a H-atom and another substituent (for example, OH, NH, or CH(NH,)COOH) between adjacent carbon atoms. A specific example, shown in Equation 57, is the deamination of ethanolamine, catalyzed by the enzyme ethanolamine ammonia lyase.

i t Coenzyme B1 I t -c. -Cb- b -c.-cb-

I I Enzyme I t . . X H

. . H X

H H I I I I

H2N H

Coenzyme Bla , [ 7 1 H-c-c-oH Ethanol Ammonia H-C-C-OH

H NH2 Lyase

A variety of evidence and suggestions have been advanced concerning the mechanisms of these reactions.10.48-54 Particularly significant evidence includes the following:

(1) The demonstration that the H atom that is transferred, does not exchange with the solvent but does exchange with, and become chemically equivalent to, the two H atoms of the 5’-CH2 group of the coenzyme during the course of reaction.49

(2) The demonstration that incubation of coenzyme BI , with dioldehydrase or ethanolamine ammonia lyase, together with the corresponding substrate, results in the appearance of EPR signals attributable to cobalt(l1) cobalamin and free


radical species.55 Evidence for the formation of cobalt(l1) under these conditions has also been obtained from electronic spectral changes” and from spin labeling experiment^.^^ At least in the case of the ethanolamine ammonia lyase reaction, the formation of these species, presumably through homolytic cleavage of the coenzyme Co-C bond, is sufficiently rapid to be compatible with their being intermediates in the catalytic process.

(3) Addition of a pseudo-substrate to solutions containing a combination of coenzyme B,, and one of the mutase enzymes results i n the stoichiometric formation of 5‘-deoxyadeno~ine.~**~’

In the light of this evidence we propose the mechanistic scheme depicted by FIGURE 3 for the ethanolamine ammonia lyase reaction (Equation 57). Steps 1, 2, and 5 of this scheme are derived from the mechanism for the same reaction originally proposed by Babior4* and are designed to accommodate the three specific obser- vations, (l), (2), and (3, cited above. The remaining steps are intended to rationalize the occurrence of the 1-2 rearrangement. In this connection it should be noted that, while the initial heterolytic cleavage of the Co-CH,R to form the primary RCHz+ carbonium ion is expected to be very unfavorable, the considerably enhanced stability of the oxocarbonium ion CHz(NHz)+CHOH could provide the necessary driving force for the proposed electron-transfer step (3), following the hydrogen atom transfer step (2). Conversely, the ensuing 1 ,2-NH2- shift and NH3 elimination would generate a driving force for reversal of the electron transfer (step 4). An alternative mechanism for the l’,Zshift, involving a u-m-u-rearrangement of an intermediate organometallic adduct, has recently been It is not unlikely that this feature of the mechanism will vary among the reactions of the mutase type, depending on the nature of the migrating group X.

FIGURE 3. Proposed mechanism of the coenzyme B, z-dependent ethanolaniine ammonia lyase reaction. (R==5’-deoxyadenosyl).

CONCLUDING REMARKS

The mechanisms of vitamin B1 z-dependent biochemical processes remain to be fully elucidated and are at this stage still subjects of considerable speculation and controversy. At the same time there is already a convincing body of evidence and widespread agreement about one feature of these processes, namely the break- ing and ultimate reconstitution of the cobalt-carbon bond of methyl-cobalamin or coenzyme B, during the catalytic cycle. Accordingly, studies relating to the formation and cleavage of cobalt-carbon bonds, such as those with which much of this

Halpern: Organocobalt Chemistry 19

paper has been concerned, seem highly relevant at this stage to an understanding of the chemistry and biochemistry of vitamin B 1 2 . A particularly important issue in this context concerns the mechanism of and driving force for the proposed homolytic 5’-deoxyadenosyl-cobalt bond cleavage (step 1 in the mechanism depicted by FIGURE 3) which results from the interaction of the coenzyme with the enzyme and substrate. Possible factors that may induce such cleavage are (i) steric influences resulting from conformational changes in the corrin ring, (ii) cobalt-carbon bond weakening resulting from trans-axial ligand substitution of the 5,6-dimethylbenzimidazole ligand of the coenzyme by another ligand derived from the enzyme (such as, a thiol group), or (ii i) an oxidative or reductive cleavage process leading to a 5’-deoxyadensyl radical, such as that shown by Equation 50 or 51. There is clearly a need for further studies on organocobalamins as well as analogous compounds that will contribute to a more detailed and quantitative understanding of these and related processes.

Finally, some comment seems in order about the distinctiveness of cobalt in the context of most of the chemistry that has been discussed above. The extensive studies that have been carried out on a variety of vitamin BIZ analogues suggest that many features of the chemistry of vitamin BIZ and its derivatives are exhibited also by cobalt complexes containing other ligands, some of which bear little electronic or structural resemblance to the corrin ligand system (for example, cyanide, dioximes. and Schiff bases). Although important differences among these ligand systems do exist, necessary and sufficient conditions for much of the chemistry that has been discussed, including that relatine to the formation and cleavage of cobalt- carbon bonds, appear to be met by the ability of the ligands to stabilize the +3, +2, and + 1 oxidation states of cobalt and to form low-spin complexes of cobalt in each of these oxidation states. However, there is little indication, and little reason to expect, that the role of cobalt in the context of this pattern of chemistry can be simulated by any other metal. The nature and origin of this distinctiveness of cobalt is emphasized by a comparison with its congener, rhodium. For ligands of the type under consideration complexes of Rh(1) and Rh(I1) are much less stable, relative to Rh(IIl), than are the corresponding cobalt complexes. Furthermore, whereas low-spin Co(l1) complexes such as Co(DH)’B are typically monomeric, the corresponding Rh(ll) complexes, because of the much stronger Rh-Rh bond, are almost invariably Rh-Rh bonded dimers [e.g. Rhz(DH)4(PPh3)z]58 and thus exhibit virtually none of the distinctive chemistry of low-spin Co(I1) complexes that has been described above.

The uniqueness of cobalt in the context of most of the chemistry related to vitamin BIZ contrasts with at least certain other situations involving metals in biological systems. Thus, in hydrolytic metalloenzymes such as carboxypeptidase Zn’ + can be replaced by other metal ions such as Co2 + and Mn2 + with retention, or even enhancement, of catalytic Similarly, many of the oxygen-binding characteristics of hemoglobin are presetved when the Fe atoms are replaced by C O . ~ ’ In contrast to this, it is quite unlikely that the significant features of the chemistry or biochemistry of vitamin BIZ and its derivatives can survive the replace- ment of cobalt by any other element.

REFERENCES

1 .

2. 3.

FALBE. J. 1970. Carbon Monoxide in Organic Synthesis. Springer Verlag. New York, N. Y .

PAULIK, F. E. 1972. Catal. Rev. 6: 49. ORCHIN, M. & W. RUPILIUS. 1972. Catal. Rev. 6: 85.


4. LENHERT, P. G. & D. C. HODGKIN. 1961. Nature (London). 192: 937. 5. STADTMAN, T. D. 1971. Science 171: 859, and references therein. 6. INGRAHAM, L. L. 1964. Ann. N. Y. Acad. Sci. 112:713. 7. WHITLOCK, H. W. 1964. Ann. N. Y. Acad. Sci. 112: 721. 8. PRATT, J. M. 1972. Inorganic Chemistry of Vitamin BIZ. Academic Press. New York,

9. DODD, D. & M. D. JOHNSON. 1973. Organometal. Chem. Rev. 52: I . 10. WOOD, J. M. & D. C. BROWN. 1972. Structure and Bonding 11: 47, and references

11. HALPERN, J. & J. P. MAHER. 1964. J. Amer. Chem. Soc. 86: 231 1. 12. SCHRAUZER, G. N. & J. KOHNLE. 1964. Chem. EIer. 97: 3056. 13. SCHRAUZER, G. N. 1968. Accts. Chem. Res. 1: 97. 14. CHOCK, P. B. & J. HALPERN. 1969. J. Amer. Chem. Soc. 91: 582. 15. HALPERN, J. & P. F. PHELAN. 1972. J. Amer. Chem. Soc. 94: 1881. 16. BIGOITO, A., G. COSTA, G. MESTRONI, G. PELLIZER, A. PUXEDDU, E. REISENHOFFER,

L. STEFANI, & G. TAUZHER. 1970. Inorg. Chim. Acta Rev. 4: 51. 17. COSTA, G. 1972. Pure Appl. Chem. 30: 335. 18. VENERABLE, G. D. & J. HALPERN. 1971. J. Amer. Chem. Soc. 93: 2176. 19. RANDALL, W. C. & R. A. ALBERTY. 1966. Biochem. 5: 3189. 1967. Biochem. 6: 1520. 20. FIRTH, R. A., H. A. 0. HILL, B. E. MANN, J. M. PRATT, R. G. THORP & R. J. P.

21. HALPERN, J. & H. B. TINKER. 1967. J. Amer. Chern. Soc. 89: 6427. 22. SCHRAUZER, G. N. & R. J. WINDGASSEN. 1967. J. Amer. Chem. Soc. 89: 142. 23. SCHRAUZER, G. N. & E. DEUTSCH. 1969. J. Amer. Chem. Soc. 91: 3341. 24. HALPERN, J. & J. P. MAHER. 1965. J. Amer. Chem. Soc. 87: 5361. 25. MARZILLI, L. G., P. A. MARZILLI & J. HALPERN. 1971. J Arner. Chem. SOC. 93: 1374. 26. KWIATEK, J. 1967. Catal. Rev. 1: 37. 27. MARZILLI, L. G., P. A. MARZILLI & J. HALPERN. 1970. J. Amer. Chern. Soc. 92: 5752. 28. B L ~ E R , H. & J. HALPERN. Unpublished results. 29. YAMADA, R., S. SHIMIZU & S. FUKUI. 1968. Biochem. 7: 1713. 30. WERTHEMANN, L. 1968. E. T. H. ABHANDLUNG, Juris Druck Verlag. Zurich, Switzer-

31. SCHRAUZER, G. N., J. W. SIBERT, & R. J. WINDGASSEN, 1968. J. Amer. Chem. Soc.

32. PAILES, W. H. & H. P. C. HGGENKAMP, 1968. Biochemistry 7: 4160. 33. VAN DEN BERGEN, A. & B. 0. WEST. 1971. Chem. Comm. 1971: 52. 34. ESPENSON, J. H. & J. S . SHVEIMA. 1973. J. Amer. Chem. Soc. 95:4 468. 35. WOOD, J. M., F. S. KENNEDY & C. G. ROSEN. 1968..Nature 220: 173. 36. ABLEY, P., E. R. DWKAL, & J. HALPERN. 1973. J. Amer. Chem. SOC. 95: 3166. 37. DESSY, R. E. & Y. K. LEE. 1960. J. Amer. Chem. Soc. 82: 689. 38. DE SIMONE, R. E., M. W. PENLEY, L. CHARBONNEAU, S. G. SMITH, J. M. WOOD,

H. A. 0. HILL, J. M. PRATT, S. RIDSDALE & R. J. P. WILLIAMS. 1973. Biochim. Biophys. Acta. 304: 851, and references therein.

39. HGGENKAMP, H. P. C. 1966. Fed. Roc. 25: 1623. 40. HOGENKAMP, H. P. C. & T. G. OIKAWA. 1964. J. Biol Chem. 239: 191 1. 41. ABLEY, P., E. R. DWKAL & J. HALPERN. 1972. J. Amer. Chem. SOC. 94: 659. 42. DOCKAL, E. R. & J. HALPERN. 1973. Unpublished results. 43. COSTA, G., A. PUXEDDU & E. REISENHOFER. 1971. Chem. Comm. 1971: 993. 44. COSTA, G., C. MESTRONI, T. LICARI & E. MESTRONI. 1969. Inorg. Nucl. Chem. Lett.

45. SCHRAUZER, G.N. 1973. Pure Appl. Chem. 33: 545. 46. BERCAW, J. E., L. Y. GOH & J. HALPERN. 1972. J. Amer. Chem. Soc. 94: 6534, and

47. BARNETT, R., H. P. C. HOGENKAMP & R. H. ABELES. 1966. J. Biol. Chem. 241: 3641. 48. BABIOR, B. M. 1970. J. Biol. Chem. 245: 1755, 6125. 49. ABELES, R. H. 1971. Advances Chem. Ser. 100: 346, and references therein. 50. ABELES, R. H. 1972. J. Biol. Chem. 247:4197. 51. SCHRAUZER, G. N. & SIBERT, J. W. 1970. J. Amer. Chem. Soc. 92: 1022.

N. Y.

therein.

WILLIAMS. 1968. J. Chem. Soc. (A). 1968: 2419.

land. (Cited in Ref. 8, pp. 104-106).

90: 6681.

5: 561.

references therein.


52. SILVERMAN, R. B., D. DOLPHIN & B. M . BABIOR. 1972. J. Arner. Chem. Soc. 94: 4028

53. MILLER, W. W. & J . RICHARDS. 1969. J. Amer. Chern. Soc. 91: 1498. 54. CARTY, T. J., B. M. BABIOR, & R. H. ABELES. 1971. J. Biol. Chem. 246: 6313. 55. COCKLE, S. A., H. A.O. HILL, R. J . P. WILLIAMS, S. P. DAVIES & M. A. FOSTER. 1972.

56. LAW, P. Y., D. G. BROWN, E. L. LIEN, B. M. BABIOR & J . M. WOOD. 1971. Biochemistry,

57. FINLAY, T. H., J . VALINSKY, K. SATO & R. H . ABELES. 1972. J. Biol. Chern.247:4197. 58. CAULTON, K. G. & F. A. COTTON. 1969. J. Amer. Chem. Soc. 91 : 651 7. 59. VALLEE, B. L., J. F. RIORDAN, D. S. AULD & S. A. LATT. 1970. Phil. Trans. Roy. Soc.

60. Hsu, G. C., C. A. SPILBURG, C. BULL & B. M. HOFFMAN. 1972. Proc. Nat. Acad. Sci.

R. B. SILVERMAN, & D. DOLPHIN. 1973. J. Amer. Chem. Soc. 95: 1686.

J. Amer. Chern. Soc. 94: 275.

10: 3428.

(London). B257: 215.

69: 2122.

SOME ASPECTS OF ORGANOCOBALT CHEMISTRY RELATED TO VITAMIN B12

Documents

Transcript of SOME ASPECTS OF ORGANOCOBALT CHEMISTRY RELATED TO VITAMIN B12