Cobalt-catalysed alkene hydrogenation: A metallacycle can explain the hydroxyl activating effect and the diastereoselectivity

Article abstract of DOI:10.1039/c8sc01315b

Bis(phosphine)cobalt dialkyl complexes have been reported to be highly active in the hydrogenation of tri-substituted alkenes bearing hydroxyl substituents. Alkene substrates containing ether, ester, or ketone substituents show minimal reactivity, indicating an activating effect of the hydroxyl group. The mechanistic details of bis(phosphine)cobalt-catalysed hydrogenation were recently evaluated computationally (X. Ma, M. Lei, J. Org. Chem. 2017, 82, 2703-2712) and a Co(0)-Co(ii) redox mechanism was proposed. However, the activating effect of the hydroxyl substituent and the accompanying high diastereoselectivity were not studied. Here we report a computational study rationalizing the role of the hydroxyl group through a key metallacycle species. The metallacycle is part of a non-redox catalytic pathway proceeding through Co(ii) intermediates throughout. The preference for alcohol over ether substrates and the high diastereoselectivity of terpinen-4-ol hydrogenation are correctly predicted in computations adopting the new pathway, whereas the alternative redox mechanism predicts ethers rather than alcohols to be more reactive substrates. Additional experimental evidence supports the role of the hydroxyl group in the metallacycle mechanism. Our work highlights the importance of employing known substrate preferences and stereoselectivities to test the validity of computationally proposed reaction pathways.

Full text of DOI:10.1039/c8sc01315b

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Cobalt-Catalysed Alkene Hydrogenation: A Metallacycle Can
Explain the Hydroxyl Activating Effect and the Diastereoselectivity
Received 00th March 20xx,
Accepted 00th XXXX 20xx
a
b
b
a,*
Glenn R. Morello , Hongyu Zhong , Paul J. Chirik , and Kathrin H. Hopmann
DOI: 10.1039/x0xx00000x
Bis(phosphine)cobalt dialkyl complexes have been reported to be highly active in the hydrogenation of tri-substituted
alkenes bearing hydroxyl substituents. Alkene substrates containing ether, ester, or ketone substituents show minimal
reactivity, indicating an activating effect of the hydroxyl group. The mechanistic details of bis(phosphine)cobalt-catalysed
hydrogenation were recently evaluated computationally (J. Org. Chem. 2017, 82, 2703) and a Co(0)-Co(II) redox
mechanism was proposed. However, the activating effect of the hydroxyl substituent and the accompanying high
diastereoselectivity were not studied. Here we report a computational study rationalizing the role of the hydroxyl group
through a key metallacycle species. The metallacycle is part of a non-redox catalytic pathway proceeding through Co(II)
intermediates throughout. The preference for alcohol over ether substrates and the high diastereoselectivity of terpinen-
www.rsc.org/
4
-ol hydrogenation are correctly predicted in computations adopting the new pathway, whereas the alternative redox
mechanism predicts ethers rather than alcohols to be more reactive substrates. Additional experimental evidence
supports the role of the hydroxyl group in the metallacyle mechanism. Our work highlights the importance of employing
known substrate preferences and stereoselectivities to test the validity of computationally proposed reaction pathways.
whereas the corresponding methyl ether displays <5% conver-
sion despite higher catalyst loading and longer reaction time
Introduction
The majority of homogeneous hydrogenation catalysts
employed today are based on precious metals such as
rhodium, ruthenium, or iridium. During the last two decades,
there has been an increasing focus on developing
hydrogenation catalysts involving more earth abundant
transition metals. Hydrogenation of alkenes or carbonyl
compounds with transition metal complexes based on iron,
cobalt, nickel, or manganese has been achieved by several
2f
(
entry 3, Fig. 1). Interestingly, hydrogenation of terpinen-4-ol
gives a high diastereoselectivity with a diastereomeric ratio
d.r.) of 99.8:0.2 (entry 2, Fig. 1). Compared to tri-substituted
(
alkenes, di-substituted terminal alkenes could be hydroge-
nated without a hydroxyl group present (entry 4, Fig. 1).
Ph2
P
CH2SiMe3
C1:
Co
groups, including those of Budzelaar,1 Chirik,2 Casey,3
Milstein,4 Hanson,5 Peters,6 Kempe,7 Morris,8 Fout9, and
P
CH SiMe
2 3
R
R''
R
R''
Ph
2
Beller.10 Despite these promising results, more efforts are
required to develop non-precious catalysts for diastereo- and
enantioselective hydrogenation reactions. To date only a
limited number of non-precious metal complexes are able to
R'
2
4 atm H , 25 C°, toluene
R'
% Conversiona
Substrate
OH
Product
OH
1
2
99% (7 h)
2
d,11,12,13
catalyse enantioselective alkene hydrogenations.
Recently, Chirik and co-workers reported bis(phosphine)co-
balt dialkyl complexes for the hydrogenation of alkenes at mild
99% (4 h)
9
9.8:0.2 d.r.
2
f
OH
OH
conditions (Fig. 1). A significant activating effect by hydroxyl
groups was observed for the cobalt catalysts. Ether, ester, or
2
f
3
4
<5% (16 h)
99% (2 h)
ketone groups did not provide such an effect. The reported
cobalt dialkyl catalyst dppeCo(CH SiMe ) C1, dppe = 1,2-
OMe
OMe
(
3 2
2
bis(diphenylphosphino)ethane) catalyses hydrogenation of
terpinen-4-ol providing 99% conversion (entry 2, Fig. 1),
a)
5% C1 for entry 1 and 3, 1% C1 for entry 2 and 4.
2
C1-catalysed alkene hydrogenation (data from ref. ).
f
Fig. 1
.
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we conclude that the intermediate formed upon H
2
coordi-
nation prefers a Co(0)-H structure over a Co(II)-dihydride
2
configuration (the dihydride is 2.6 kcal/mol higher in energy,
Fig. S1, SI). The overall hydrogenation steps of ours (Fig. 3) and
the previous redox mechanism (Fig. 2) are otherwise identical.
The rate-determining step is the formation of the alkyl-
intermediate (TS2-3R, Fig. 3), involving transfer of a hydride to
the methyl-substituted carbon (the pathway involving hydride
transfer to the other carbon has a larger barrier, Fig. S2, SI).
The alkyl-intermediate then undergoes reductive elimination
to form the alkane product (a β-H elimination pathway was
also evaluated, but is higher in energy, Fig. S3, SI).
In order to evaluate the validity of the redox mechanism,
we considered the substrate preference with this pathway. As
previously determined in experiments, terpinen-4-ol (Fig. 1,
Fig. 2. Previously proposed redox pathway for C1 (based on
results in ref. 14). A Co(0) species oxidatively adds H to form a
2
Co(II)-dihydride, followed by alkene insertion to form an alkyl entry 2) is the preferred substrate compared to its methoxy
intermediate. The alkyl undergoes reductive elimination (a) or derivative (Fig. 1, entry 3). With the redox mechanism, the
β-H elimination (b) to yield the product or alkene isomers.
overall barriers are calculated to be +23.6 kcal/mol for
terpinen-4-ol and +23.3 kcal/mol for the methoxy-derivative,
indicating a slight preference for the methoxy-substrate (Fig.
Recent computational work by Ma and Lei on C1 suggests
4
). This is in disagreement with the experimentally observed
that hydrogenation of hydroxylated tri-substituted alkenes
strong preference for the alcohol substrate (Fig. 1). The
analysis of the substrate selectivity indicates that C1-catalysed
hydrogenation may not proceed through the previously
proposed redox mechanism.
1
4
proceeds through a Co(0)-Co(II) redox mechanism (Fig. 2).
The proposed catalytic cycle starts with oxidative addition of
to a Co(0) species generating a Co(II)-dihydride, followed by
H
2
substrate insertion to give an alkyl intermediate. The inter-
mediate may undergo direct reductive elimination to yield the
product alkane and regenerate Co(0) (Fig. 2, path (a)) or may
proceed via β-hydrogen elimination to form an alkene
regioisomer, followed by substrate reinsertion and reductive
elimination (Fig. 2, path (b)). Regardless if alkene isomerization
occurs, the same product is formed and the overall pathway
involves a cycling between Co(0) and Co(II) oxidation states.
The role of the hydroxyl group was not considered in the
RO
Co
RO
Co
RO
RO
H
H
0
0
TS2ꢀ3RH
TS1ꢀ2R
H
Co
2R
Co
1
R
H2 attack
H
Hydride transfer
H
Rate- and
selectivity-
determining step
1
4
previous analysis.
Here we present computational and experimental results,
which provide novel insights into the mechanism of C1
OR
OR
-
RO
Co
catalysed directed hydrogenation. On basis of our results, we
propose that hydrogenation of hydroxylated alkenes occurs
through a non-redox reaction pathway proceeding through a
metallacycle, which is formed through activation of the
hydroxyl group. The metallacycle mechanism correctly predicts
the catalyst’s preference for hydroxylated alkenes and the high
RO
RO
H
II
0
TS3ꢀ4R
Co
4R
Co
H
3R
H
Proton transfer
diastereoselectivity observed in hydrogenation of terpinen-4- Fig. 3. Co(0)-Co(II) redox mechanism computed here for C1
-
ol.
catalysed hydrogenation of terpinen-4-ol (R = H) and its
methoxy-derivative (R = CH ). Computed energies are shown in
Fig. 4. Terpinen-4-ol prefers an alternative mechanism, Fig. 5.
3
Results and Discussion
Computational Results
Metallacycle pathway: We explored several alternative
mechanistic possibilities (Fig. S2-S4, SI), of which only the
preferred metallacycle pathway is discussed here (Fig. 5). We
propose that reaction between the precatalyst C1 and the
Redox pathway: We performed a quantum chemical analysis
of a full molecular model of C1 with different substrates using
B3LYP-D3 with the solvent model IEFPCM (for computational
details see SI). Initially, we evaluated if C1 employs a redox
mechanism (Fig. 3), similar to the mechanism proposed by Ma
substrate terpinen-4-ol under H
cobalt(monohydride)(alkoxide) species, which we suggest
constitutes the active catalyst (Fig. 5). Interestingly,
2
results in generation of a
1
4
1
M
and Lei (Fig. 2). Our redox mechanism differs slightly, as we
formation of
1
M
from the precatalyst C1 is preferred over
find that substrate coordination precedes addition of H , and
2
2
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ARTICLE
formation of the dihydride species implicated in the redox
mechanism (see Fig. S5 SI for computed energies).
undergo a hydride transfer to the double bond of the bound hydroxyl coordinating to cobalt. In the final step, another
substrate to form the metallacycle (Fig. 5, for optimised substrate molecule transfers its proton to the alkane oxygen
geometry see Fig. 6), which is -9.8 kcal/mol below (Fig. 4). TS5M), regenerating and turning over the cycle. The cobalt
Subsequent coordination of H to the metallacycle appears center has a formal oxidation state of +2 throughout (Fig. 5).
facile, with a cost of 11 kcal/mol relative to TS2-3M, Fig. 4). Although a Co(0) species in principle can be formed in one step
The barrier for H attack may be slightly underestimated, given from the Co(II) species through reductive elimination of the
that is ~1 kcal/mol higher in energy than TS2-3M. Proton substrate (TS1R-1M, Fig. 5), this transformation has a prohi-
transfer from H
(
TS3-4M, 21.3 kcal/mol relative to
M
2 , Fig. 4) and provides the
M
1 can then hydrogenated alkane, which still exhibits a deprotonated
2
M
1
M
(
1
M
2
M
2 (
2
1
M
3
M
2
M
to the alkyl carbon is the rate-limiting step bitively high barrier (36.5 kcal/mol relative to 2 , Fig. S6, SI).
HO
Selectivity-
determining step
0
Co
1
R
TS1Rꢀ1M
O
O
H
2
Co
H
Co
O
O
O
OH
H
II
II
Co
H
TS2ꢀ3M
II
II
TS1ꢀ2M
TMS
TMS
Co
H
Co
Co
1
M
2
M
3
M
2
HTMS
Hydride transfer
2
H attack
H
Precatalyst
Metallacycle
H
OH
O
O
H
O
Co
H
Co
O
O
H
H
II
OH
H
II
Co
H
O
Co
H
TS5M
Proton transfer to O
TS3ꢀ4M
H
5
M
4
M
Proton transfer to C
Rate-determining step
Fig. 5. Non-redox metallacycle mechanism proposed for bis(phosphine)cobalt-catalysed hydrogenation of terpinen-4-ol. For
details on the activation of the precatalyst, see Fig. S5, SI.
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computed barrier for redox hydrogenation of α-methylstyrene
is 19.9 kcal/mol (four possible pathways were modelled, see
SI, Fig. S7). These results are in excellent agreement with
experiment (Fig. 1), which showed 99% conversion of
terpinen-4-ol and α-methylstyrene (after 4 and 2 hours,
respectively), whereas the methoxy substrate gave <5%
conversion after 16 hours. The barrier difference of 2 kcal/mol
between terpinen-4-ol (barrier 21.3 kcal/mol) and its methoxy
derivative (barrier 23.3 kcal/mol) translates roughly to a ratio
of 97 to 3 (Table S1, SI), in good agreement with the
experimental result of 99% to <5% conversion.
Analysis of the diastereoselectivity: The product formed from
hydrogenation of terpinen-4-ol can exist as two different
i
diastereomers, which, respectively, have the Pr and methyl
Fig. 6. Optimised geometry of the metallacycle 2M, a Co(II)
open shell species (S = ½) with a planar configuration around
the cobalt atom.
substituents cis or trans to each other (Fig. 8). In our
computations, the trans-diastereomer is 1.9 kcal/mol lower in
energy than the cis-diastereomer, yet in experiment, the cis
-
diastereomer is predominantly formed, with a very high
diastereoselectivity of 99.8:0.2 (Fig. 1). This indicates that the
hydroxyl group may have a directing effect that favours
formation of the cis-isomer. We have here evaluated if the two
discussed mechanisms, the metallacycle mechanism and the
alternative redox pathway, are able to reproduce the
experimentally observed diastereoselectivity.
The calculated free energies show that the metallacycle 2
M
is facile to form and that it is the lowest-lying intermediate
computed here (Fig. 4), implying that other reaction pathways
M
must be referenced to 2 , even if the metallacycle constitutes
an off-cycle species to these. The barrier for hydrogenation of
terpinen-4-ol via the redox mechanism thus raises from 23.6
kcal/mol to 32.6 kcal/mol (TS2-3R relative to 2M, Fig. 4). The
barrier for the metallacycle mechanism is instead 21.3
kcal/mol (TS3-4M relative to 2M, Fig. 4). Although DFT protocols
1
5
may exhibit an error of some kcal/mol, we consider a
difference of 11.3 kcal/mol between the redox and the
metallacycle mechanism to be more than significant to
conclude that the metallacycle pathway is preferred for
hydrogenation of terpinen-4-ol.
cis
trans H
H
HO
HO
Predicted d.r.a
Redox mechanism
75%
100%
99.8%
25%
0.0%
0.2%
Metallacycle mechanism Predicted d.r.b
Observed d.r.c
Experiment
Analysis of the substrate preference: The metallacycle
mechanism (Fig. 5) is only accessible for substrates containing
a hydroxyl group. For other substrates, an alternative
hydrogenation mechanism must operate, which may be the
redox pathway (Fig. 3). We have compared the computed
barriers for three substrates (Fig. 7) to validate our
mechanistic proposals.
Fig. 8. Computed diastereoselectivity of C1-catalysed
hydrogenation of terpinen-4-ol, assuming redox or
metallacycle mechanism, and comparison to experiment
a
a
b
c
2f
(
Table S2, SI, Table S3, SI, data from ref. ).
In the redox mechanism as depicted in Fig. 3, the
diastereoselectivity is determined in the insertion step (TS2-3R),
where the OH substituent is oriented towards cobalt, leading
OH
OMe
Redox
to the cis-diastereomer. For formation of the trans
-
Mechanism
Metallacycle
21.3
Redox
19.9
diastereomer, we have analysed four pathways (see SI, Fig. S8-
11), and find that the lowest pathway proceeds via β-hydrogen
elimination (Fig. S10, SI). The overall barriers for formation of
the cis and trans-diastereomers via a redox pathway differ by
Computed barrier (∆G‡)
23.3
Experimental conversion
99%
<5%
99%
(
4h, 1% C1) (16h, 5% C1) (2h, 1% C1)
0
.6 kcal/mol, which corresponds to a predicted d.r. of
5(cis):25(trans) (Fig. 8, Table S2 SI).
Fig. 7. Hydrogenation barriers (kcal/mol) computed here for
three substrates and their experimental conversion (from ).
7
2
f
In the metallacycle mechanism, the diastereoselectivity is
determined in the hydride transfer step TS1-2M (Fig. 5). Due to
the strong coordination of the alkoxide oxygen, hydride
addition inevitably has to lead to formation of only the cis-pro-
duct (Fig. 8), in excellent agreement with the experimentally
observed high d.r. of 99.8(cis):0.2(trans). Formation of the
Hydrogenation of terpinen-4-ol preferably occurs via the
metallacycle pathway, with a barrier of 21.3 kcal/mol. Redox
hydrogenation of the methoxy-derivative of terpinen-4-ol has
a computed barrier of 23.3 kcal/mol, whereas the lowest
4
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trans-diastereomer would require cleavage of the cobalt-
ARTICLE
Treating precatalyst C1 with H
2
in the absence of substrate
alkoxide bond, which energetically is very costly (Table S3 SI). unveiled a catalyst deactivation pathway, which involves
We propose that in the experimental reaction, the cis formation of a catalytically inactive (dppe) Co species (Fig. S14,
-
2
diastereomer is formed via the energetically preferred SI). This observation suggests an essential role of the substrate
metallacycle mechanism, whereas the very small amount of in maintaining the catalyst in an active form.
observed trans-diastereomer (0.2%, Fig. 1) must be formed via
other mechanisms. Our computational results provide a
Conclusions
rationale for the high diastereoselectivity of the cobalt
complex C1. Interestingly, the Crabtree iridium catalyst
6
We have here reported a new mechanism for bis(phosphine)-
cobalt-catalysed hydrogenation of hydroxylated alkenes,
proceeding through an energetically low-lying metallacycle
1
provides the same diastereoselectivity with terpinen-4-ol.
However, the mechanistic details of said system are not known
so far.
M
intermediate (2 , Fig. 5). In the computational analysis, the
metallacycle mechanism correctly predicts the preference for
hydroxylated alkenes (Fig. 7) and the high diastereomeric ratio
observed in hydrogenations of terpinen-4-ol (Fig. 8). The
mechanism is further supported by experimental
investigations providing indirect evidence of a cobalt-terpinen-
Experimental Results
Hydrogenation of deuterium-labelled terpinen-4-ol (C10
8
H -OD)
afforded 1,2-H alkane with no deuterium incorporation into
2
the alkene double bond (Fig. S12, SI), consistent with the
proposed metallacycle mechanism, where proton transfer
from a second substrate to the cobalt alkoxide turns over the
catalytic cycle (TS5M, Fig. 5).
4
-ol alkoxide intermediate (Co-OR, Fig. 9).
Our computational analysis further shows that a previously
14
proposed redox mechanism
may be valid for non-
Our attempts to obtain the metallacycle intermediate
2
M
hydroxylated substrates, but is unable to explain the activating
effect and diastereoselectivity of hydroxylated alkenes. As also
reported for iron-catalysed hydrogenation of carbonyl
from different synthetic routes and to characterize it by X-ray
crystallography were unsuccessful due to strong interference
from the thermodynamically more accessible bis(ligand)cobalt
1
9
substrates, we have here shown that known substrate
selectivities provide a straightforward tool for testing the
validity of proposed mechanisms, and we suggest to always
asses these important parameters in computational studies of
reaction pathways.
1
7
species formed during isolation of cobalt complexes.
However, indirect experimental evidence suggests that a
reaction between the precatalyst dppeCo(CH SiMe C1) and
terpinen-4-ol does occur (Fig. 9). Specifically, adding five
equivalents of terpinen-4-ol to C1 in benzene-d at room
temperature resulted in protonolysis of the cobalt alkyl. The
volatile component of the reaction was distilled and analysed Conflicts of interest
2
3 2
) (
6
1
by H-NMR after 12 hours, and the protonolysis product SiMe
4
There are no conflicts to declare.
1
8
was observed. Integration suggests approximately half of the
alkyl groups in C1 reacted with terpinen-4-ol (Fig. S13, SI). This
experimental observation supports the formation of a mono-
alkoxide intermediate, in agreement with the mono-alkoxide
Acknowledgements
HZ and PJC acknowledge the U.S. National Science Foundation
species expected during the metallacycle mechanism (
). Further treatment of the non-volatile component
containing the assumed mono-alkoxy complex) with TMSI
M
1 , Fig.
(NSF) Grant Opportunities for Academic Liaison with Industry
GOALI) grant (CHE-1265988).
5
(
(
KHH acknowledges the Research Council of Norway for a
FRINATEK grant (No. 231706) and a Centre of Excellence Grant
resulted in formation of TMS-terpinen-4-ol (Fig. 9), providing
additional support for formation of an alkoxide species.
(No. 262695), the Tromsø Research Foundation (No.
TFS2016KHH) and Notur - The Norwegian Metacenter for
Computational Science for grants of computer time (No.
nn9330k and nn4654k).
Notes and references
Fig. 9. Indirect evidence for formation of an alkoxide
intermediate. Components in boxes were identified via NMR
(see SI).
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Although this reaction appears slow (12 h), it should be noted
that this is in agreement with the computed barrier for this reaction
in absence of H , 32.3 kcal/mol, which is 3 kcal/mol higher than
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Chemical Science
View Article Online
DOI: 10.1039/C8SC01315B
A new non-redox metallacycle mechanism explains the substrate preference, the
diastereoselectivity, and the hydroxyl activating effect in cobalt-catalyzed alkene
hydrogenation.