9 Some Mechanistic Aspects of Coenzyme B -Dependent Rearrangements Downloaded via YORK UNIV on December 13, 2018 at 19:02:41 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
12
Homolytic Cleavage of Metal-Carbon Bonds JACK HALPERN Department of Chemistry, University of Chicago, Chicago, IL 60637
A widely accepted mechanism of coenzyme B dependent rearrangements encompasses, as the initial step, the homolytic cleavage of the carbon-cobalt bond to generate the 5'-deoxyadenosyl radical. The thermodynamic and kinetic aspects of this and related processes involving the homolysis of transition metal-carbon bonds are discussed. 12
C
oenzyme B i (5'-deoxyadenosylcobalamin, abbreviated R C H — Bi ) serves as a cofactor for a variety of enzymic reactions, a common feature of which involves the 1,2-interchange of an H atom and another group (X = O H , N H , C H ( N H ) C O O H , etc.) on adjacent carbon atoms (Equation 1) (1, 2). 2
2
2
2
2
(i)
A widely accepted mechanistic interpretation of these reactions, supported by a variety of evidence from studies on the enzymic processes as well as on model systems, is depicted by Equations 2 and 3 (1, 2, 3). R C H — B 12 2
enzyme
R C H - + B 12r 2
0-8412-0514-0/80/33-191-165$05.00/0 © 1980 American Chemical Society
Dolphin et al.; Biomimetic Chemistry Advances in Chemistry; American Chemical Society: Washington, DC, 1980.
(2)
166
BIOMIMETIC CHEMISTRY
H
X
Ci
C
RCH 2
C
C
2
1
(-RCH )
2
3
X
X Ci
C
I
RCH3 2
(-RCH )
H -C -
(3)
2
2
This mechanism encompasses the following sequence of steps: (i) enzyme-induced homolysis of the C o - C bond to generate cob(II)alamin (i.e., vitamin B ) and a 5'-deoxyadenosyl radical (abbreviated R C H ) ; (ii) H-atom abstraction from the substrate to generate a substrate radical and 5'-deoxyadenosine (RCH ); (iii) rearrangement of the resulting substrate radical (through a mechanism that is not fully understood and that probably differs from substrate to substrate); and (iv) abstraction of an H atom from R C H by the rearranged radical to complete the rearrangement reaction. While the possible involvement of the cobalt complex in the substrate radical rearrangement step has been suggested (I), the evidence for this is inconclusive. At this stage it appears that the principal, if not only, role of the organometallic cofactor (i.e., of coenzyme B ) in these reactions is to serve as a precursor for an organic free radical, which presumably implies facile homolytic dissociation of the C o alkyl bond. A troublesome feature of this mechanistic interpretation is the absence of direct supporting evidence that the C o - C bond in coenzyme B (whose dissociation energy has not yet been determined) is sufficiently weak that facile homolysis under the mild conditions of the enzymic reactions is a plausible process. In fact, alkylcobalamins, including coenzyme B , exhibit considerable thermal stability and typically do not decompose at measurable rates, in the absence of light or reagents such as 0 , until fairly elevated temperatures (^ 200°C for methylcobalamin) (4). Among the possible interpretations of this behavior are: 12r
2
3
3
i2
1 2
12
2
1. The above mechanistic interpretation is incorrect and C o - C bond homolysis is not involved in coenzyme B dependent rearrangements. 2. C o - C bond weakening and homolysis is induced by interaction of the coenzyme with the enzyme (e.g., through trans-axial ligand substitution or conformational distortion of the corrin ring). 3. C o - C bond homolysis, (i.e., according to Equation 1) occurs spontaneously under mild conditions, but is reversible and, hence, is not reflected in net decomposition. 12
Dolphin et al.; Biomimetic Chemistry Advances in Chemistry; American Chemical Society: Washington, DC, 1980.
9.
HALPERN
167
Coenzyme B -Dependent Rearrangements 12
(In this case, decomposition should be induced by appropriate radical traps such as 0 . The results of numerous studies on the thermal and photochemical stabilities of alkylcobalamins as well as of model compounds are consistent with this.) (5, 6, 7, 8). 2
This chapter addresses the following themes: The estimation of the metal-alky 1 bond dissociation energies of coenzyme B and related compounds. The factors that influence metal-alkyl bond dissociation energies of organocobalamins and related compounds. Reactions between free radicals and metal complexes. The third theme is of significance in this context, not only because the proposed mechanism of coenzyme B -dependent rearrangements (Equations 2 and 3) involves the generation of organic free radicals in the presence of a metal complex (i.e., vitamin B ), but also because of the potential utility of metal complexes as radical traps in studies involving kinetic approaches to the estimation of metal-alkyl bond dissociation energies. 1 2
12
12r
Some Reactions of Free Radicals with Metal Complexes Low-spin cobalt(II) complexes characteristically react with organic halides to generate free radicals through halogen abstraction processes of the type depicted by Equation 4. Such reactions, which have been identified for pentacyanocobaltate(II) (9, 10, 11), for fois(dioximato)- and Schiffs-base-cobalt(II) complexes (12, 13, 14) as well as for vitamin B (15), are among the cleanest thermal routes for generating organic free radicals in solution, particularly for the purpose of studying the reactions of free radicals with metal complexes. 1 2 r
L C o + R—X - » L C o X + R • n
5
(4)
m
5
The overall course of reaction of pentacyanocobaltate(II) with methyl and benzyl halides is depicted by the scheme of Equations 5, 6, and 7, in which the initial halogen abstraction step is rate determining. [Co(CN) ] " + R-X 5
3
>[X-Co(CN) ] 5
[Co(CN) ] - + R 5
+R •
3
[R - C o ( C N ) ] -
3
5
(6)
3
Overall reaction: 2[Co(CN) ] - + R—X -> [X-Co(CN) ] - + [R-Co(CN) ] 5
5
(5)
3
3
5
3
(7)
For radicals containing j3-hydrogen atoms such as ethyl or isopropyl, /3-hydrogen abstraction by [Co(CN) ] " competes with com5
3
Dolphin et al.; Biomimetic Chemistry Advances in Chemistry; American Chemical Society: Washington, DC, 1980.
168
BIOMIMETIC CHEMISTRY
bination of R • and [Co(Cn ] ~ resulting in the formation of [H—Co(CN) ] " and an olefin through parallel paths as depicted below: for R = C H , kjk ~ 4 (11). 5
3
3
5
2
5
9h
[Co(CN) ] - + C H , X -> [ X — C o ( C N ) l - + C H 3
5
2
3
3
2
(8)
5
[C H -Co(CN) ] 2
5
(9a)
3
5
[Co(CN) ] - + C H 3
5
2
5
[H—Co(CN) ] " + C H = C H 3
5
2
(9b)
2
Finally, when [Co(CN) ] ~ is reacted with organic halides in the presence of [H—Co(CN) ] ~, efficient trapping of R- by H-atom abstraction from the metal hydride occurs (Equation 10), resulting in the catalytic cycle depicted by Equations 5, 10, and 11. 3
5
5
3
[Co(CN) ] - + R-X 5
-> [ X - C o ( C N ) ] - + R •
3
5
R • + [H—Co(CN) ] " —
[Co(CN) ] - + R—H
3
5
(5)
3
5
(10)
3
[ H — C o ( C N ) J - + R—X - » [ X — C o ( C N ) ] - + R—H 8
5
(11)
3
The reactions in which the free radicals (R •) are consumed in these systems (i.e., Equations 12, 13, and 14, where L M • = [Co(CN) ] " for the cases cited), are all sufficiently fast that they compete effectively with the radical-coupling process, 2R- —> R , and no formation of R can be detected. From such competition studies it can be deduced that Reactions 12, 13, and 14 must all proceed at rates that are close to diffusion-controlled and that the activation barriers for such reactions do not exceed a few kcal/mol. n
5
3
2
2
L M- + R • —» L M—R n
L Mn
(12)
n
+ R C H C H - —* L M—H 2
2
n
+ RCH=CH
2
R • + L M — H —» R — H + L M • n
n
(13) (14)
Reaction 12 is the reverse of the metal-alkyl bond dissociation process (Equation 15). Hence, the activation enthalpies (AH*) of such homolytic bond dissociation reactions are expected to be close to the corresponding bond-dissociation energies.
L M—R^>L Mn
n
+R-
(15)
As elaborated below, the facile occurrence of Reactions 13 and 14 is important in this context because of the potential usefulness of these reactions as radical trapping processes in kinetic approaches to the determination of metal-alkyl bond dissociation energies.
Dolphin et al.; Biomimetic Chemistry Advances in Chemistry; American Chemical Society: Washington, DC, 1980.
9.
HALPERN
169
Coenzyme B -Dependent Rearrangements 12
Approaches to the Estimation of Metal-Alkyl Energies
Bond-Dissociation
Few transition-metal-alkyl bond-dissociation energies are known reliably (16). Potential approaches to the estimation of such dissociation energies encompass the following: 1. Thermochemical. Application to the estimation of the enthalpy of a process such as that depicted by Equation 15 requires determination of the heats of formation of L M —R, R -, and L M •. The latter usually is not accessible to measurement although it is in the case of alkylcobalamins (where L M- corresponds to vitamin B , a stable and accessible compound). Thus, thermochemical approaches, in principle, are potentially applicable to the estimation of the C o - C bond dissociation energy in coenzyme B . However, the practical difficulties are considerable and the probable accuracy of the result is questionable. n
n
12r
n
12
2. Kinetic. This approach entails determination of the activation enthalpy (AH*) of the homolytic dissociation process depicted by Equation 15 and the identification of A H with the corresponding bond-dissociation energy (i.e., assuming that the activation energy of the reverse process, namely the recombination of L M- and R-, is small). As noted earlier, the latter assumption probably is valid generally. Successful application of this approach may be compromised by interference from other accompanying modes of decomposition or by complicating secondary reactions (including recombination to form L M—R) of the initial radical products unless the latter are scavenged efficiently by appropriate radical traps. 1
n
n
3. Equilibrium. Reactions of the type depicted by Equation 16 have been identified as synthetic routes to organocobalt compounds (17, 18). Cobalt-alkyl bonddissociation energies could be deduced from the enthalpies of such reactions if the latter could be determined, for example from the temperature dependence of the corresponding equilibrium constants. L„Co +
\
n
/
C=C
/
+iH ?±L„Co
\
2
\
/
C—C
/
\
H
4. Photochemical. Determination of the threshold wave length for the photolytic dissociation of a metal-alkyl bond yields an upper limit for the corresponding thermal bond dissociation energy (5, 19), but the assumption that the photochemical threshold approximates the bond dissociation energy does not appear to be warranted.
Dolphin et al.; Biomimetic Chemistry Advances in Chemistry; American Chemical Society: Washington, DC, 1980.
(16)
170
BIOMIMETIC CHEMISTRY
Among these alternative approaches, 1 and 2 are considered the most promising for the determination of metal-alkyl bond-dissociation energies in coenzyme B and related compounds. The application of these approaches will be elaborated below. 1 2
Transferability Energies
of Information about Metal-Alkyl
Bond-Dissociation
Failure to achieve a reliable determination of the C o - C bonddissociation energy in coenzyme B reflects significant obstacles associated with this task. Accordingly, it seems appropriate to explore indirect approaches to estimating this energy, notably through extrapolating information about metal-alkyl bond-dissociation energies in related compounds. Unfortunately, hardly any other transition-metal-alkyl bonddissociation energies are known reliably (16). Our approach has encompassed attempts to estimate such dissociation energies for a wide variety of transition-metal-alkyl compounds, including both recognizable organocobalt B analogues as well as less directly related compounds. The objectives of these studies have been twofold: to test approaches to the estimation of metal-alkyl bond-dissociation energies on appropriate test compounds with a view to applying such approaches to alkylcobalamins; and to accumulate systematic information about metal-alkyl bond-dissociation energies for a variety of organometallic compounds with a view to identifying trends from which the C o - C bond-dissociation energy of coenzyme B might be deduced by extrapolation and/or interpolation. Our studies have encompassed the following series of compounds (R—ML ), which are arranged below in order of decreasing apparent "stabilities" of the corresponding hydrides ( H — M L ) . The values in parentheses below the compounds are estimates of the M - H bond dissociation energies (kcal/mol) of the hydrides deduced from the temperature dependence and/or position of the equilibrium corresponding to Equation 17 (20, 21, 22, 23). It seems likely that, at least in the absence of steric factors, the corresponding metal-alkyl bonddissociation energies (e.g., of CH —ML ) would follow a similar trend ( D M G H = dimethylglyoxime). 1 2
1 2
1 2
n
n
3
n
2
[R— Mn(CO) ] > [R—Co(CN) ] ~ > (3=60) (57) [R_Co(DMGH) L] > 5
5
3
2
(-53)
2 ML
n
[R—Cobalamin] (=250)
+ H « ± 2 H — ML 2
n
Dolphin et al.; Biomimetic Chemistry Advances in Chemistry; American Chemical Society: Washington, DC, 1980.
(17)
9.
171
Coenzyme B -Dependent Rearrangements
HALPERN
12
Our initial studies, in the context of this approach, relate to attempts to estimate metal-alkyl bond-dissociation energies in compounds of the type R —Mn(CO) and R —Mn(CO) (PR' ). Among the reasons for this choice of compounds are the following: the C H Mn(CO) bond-dissociation energy (~ 30 kcal/mol) is one of the few transition-metal-alkyl bond-dissociation energies to have been determined to date (24); the relatively high stabilities of alkyl- and benzyl-manganese pentacarbonyl compounds (compared, for example, with the corresponding cobalamins) afford some advantages in experimental convenience; the high thermal stability and accessibility of the hydride, H—Mn(CO) , enables it to be used as a radicaltrapping agent in experiments involving kinetic approaches to the estimation of metal-alkyl bond-dissociation energies in the corresponding R—Mn(CO) compounds. 5
4
3
3
5
5
5
Kinetic Approaches to the Estimation of Metal-Alkyl Bond-Dissociation Energies C H C H — M n ( C O ) reacts cleanly with H—Mn(CO) , at rates conveniently measurable in the temperature range 40°-80°C, according to the stoichiometry of Equation 18 and the first-order rate law, Equation 19, where k (2.0 x 10" sec at 45°C) is independent of the concentration of H—Mn(CO) . Measurements of the temperature dependence of fc yield the activation parameters, A H * = 25 kcal/mol and A S * = 0 cal/(mol deg) (25). 6
5
2
5
5
5
i9
_1
5
19
1 9
19
C H C H —Mn(CO) + H—Mn(CO) —• C H C H + M n ( C O ) 6
5
2
5
5
Rate =
6
fc [C H CH — 19
6
5
5
3
2
Mn(CO) ]
2
10
(18) (19)
5
These observations imply a unimolecular rate-determining reaction of C H C H M n ( C O ) to generate an intermediate that reacts rapidly with H M n ( C O ) to form the observed products. Possible candidate reactions for the rate-determining step are: loss of C O to form C H C H M n ( C O ) ; migratory insertion rearrangement to form C H C H ( C O ) M n ( C O ) ; and homolytic M n - C bond dissociation to form C H C H - and Mn(CO) . The last possibility, which is of particular interest in this context, would lead to the mechanistic sequence of Equations 20, 21, and 22. 6
5
2
5
5
6
5
2
6
5
2
4
4
6
5
2
5
C H CH -Mn(CO) -^C H CH - + 6
5
2
5
6
5
Mn(CO)
2
C H CH - + H-Mn(CO) - ^ U C H CH + 6
5
2
5
2 Mn(CO) — 5
6
5
3
(20)
5
Mn(CO)
Mn (CO) 10 2
Dolphin et al.; Biomimetic Chemistry Advances in Chemistry; American Chemical Society: Washington, DC, 1980.
5
(21) (22)
172
BIOMIMETIC CHEMISTRY
The identification of AH\ with the C H C H - M n ( C O ) bond dissociation energy, according to this interpretation, yields a value of approximately 25 kcal/mol for the latter. This is consistent with the value expected from the thermochemically determined bonddissociation energy (—30 kcal/mol) of C H — M n ( C O ) . If this interpretation is invoked, a puzzling issue is the observation that the thermal decomposition of C H C H — M n ( C O ) , in the absence of H — M n ( C O ) (or other radical traps), is much slower than would correspond to k . This could imply that, in the absence of such radical-trapping agents, selective recombination of C H C H - and Mn(CO) to re-form C H C H — M n ( C O ) is favored relative to the self-coupling reactions to form ( C H C H ) and M n ( C O ) . The reasons for such behavior are unclear and the investigation of this and related systems is continuing. The issue is pertinent directly to the behavior of coenzyme B and other alkylcobalamins that also exhibit higher apparent thermal (and photochemical) stabilities in the absence, than in the presence, of radical-trapping agents. 6
9
5
2
3
6
5
2
5
5
5
5
l9
6
6
5
2
5
2
5
5
6
5
2
2
2
10
1 2
The direct extension of similar approaches to other systems, notably alkyl-cobalamins and related alkyl-cobalt compounds, is constrained by the instability of the corresponding hydrides, which are consequently unsuitable as radical traps. Modification of the approach to utilize other radical traps (e.g., 0 ) potentially is feasible but needs further investigation in view of possible complicating features such as reaction between the trapping agent and the parent metal-alkyl and ambiguities between homolytic dissociation and other (e.g., concerted) mechanisms (26, 27). One possible variant of the kinetic approach to the estimation of metal-alkyl bond-dissociation energies, which potentially is applicable to alkyl groups having /3-hydrogen atoms, involves hydrogen abstraction, Equation 13, as the radical-quenching step. This may be a feature of some observations that we have made on the thermal decompositions of certain organobis(dimethylglyoximato)cobalt compounds (R = C H , C H C H , C H , etc. and py = pyridine) that proceed under mild conditions (25°-80°C) according to the stoichiometry of Equation 23 and the first-order rate law, 24 (k at 25°C = 1 x 10" and 8 x 10" sec" ; A H * = 31 and 21 kcal/mol for R = C H and C H , respectively) (28). 2
3
2
6
5
6
5
7
24
4
1
24
(py)(DMGH) Co-C 2
/
\
3
6
5
R CH 3 H
[(py)(DMGH) Co(II)] + C H = C 2
/
R + £H
2
\
H
Dolphin et al.; Biomimetic Chemistry Advances in Chemistry; American Chemical Society: Washington, DC, 1980.
2
(23)
9.
HALPERN
173
Coenzyme B -Dependent Rearrangements l2
Rate = k
/
(py)(DMGH) Co—C
R CH
2
24
(24)
3
\
H A plausible mechanistic interpretation of these reactions is as follows: R
/ (py)(DMGH) Co-C
CH
2
3
\ H k
* [(py)(DMGH) Co(II)] +
C
2
/
R CH
\
H
R
[(py)(DMGH) Co—H] + C H = C 2
[(py)(DMGH) Co-H]
(25)
2
\
H
[(py)(DMGH) Co(II)] + i H
2
3
2
(26)
2
According to this interpretation, A H ' may be identified with the cobalt-alkyl bond-dissociation energies in these compounds. However, at this stage other mechanistic interpretations, such as that involving a concerted olefin elimination, cannot be excluded (29). The investigation of these systems is continuing. 2 4
Equilibrium Approaches to the Estimation of Bond-Dissociation Energies
Metal-Alkyl
We have found that in certain cases (e.g., when R = C H ) the reaction depicted in Equation 23 attains a measurable equilibrium permitting the spectrophotometric determination of the equilibrium constant, K , defined by Equation 27 (28). Measurements of the temperature dependence of K yielded corresponding values of A H ° and A S ° . For the case, C H = C H R = styrene, the following values were determined in toluene solution: K ( 2 5 ° C ) = 1.3 X 1 0 M ; AG° (25 C) = 6.7 kcal/mol; A H ° = 22.1 kcal/mol; A S ° = 52 cal/ (mol deg). The same values of K were obtained when the equilibrium was approached from the opposite direction, that is, starting with [(py)(DMGH) Co(II)], C H C H = C H and H . 6
5
27
2 7
27
27
2
_5
27
27
0
27
3/2
27
2 7
2
K
6
5
2
2
_ [(py)(DMGH) Co(II)][C H CH=CH ][H ] [(py)(DMGH) Co-CH(CH )C H ] 2
6
2
5
2
3
6
2
1/2
5
Dolphin et al.; Biomimetic Chemistry Advances in Chemistry; American Chemical Society: Washington, DC, 1980.
, K
*"
174
BIOMIMETIC CHEMISTRY
Using available data for the heats of formation of C H C H = C H [AH° (25°C) = 35.2 kcal/mol] (30) and of the C H C H C H radical [AH° (25°C) = 33 kcal/mol] (31), the C o - C bond-dissociation energy of [ ( p y ) ( D M G H ) C o — C H ( C H ) C H ] can be deduced to be 19.9 kcal/mol using the following thermochemical cycle: 6
f
6
5
5
2
3
f
2
3
6
5
AH°
[ ( p y ) ( D M G H ) C o - C H ( C H ) C H ]
