Cobalt-Catalyzed Coupling of Aryl Chlorides with Aryl Boron Esters Activated by Alkoxides

Article abstract of DOI:10.1021/acscatal.0c05557

The cobalt-catalyzed Suzuki biaryl cross-coupling of aryl chloride substrates with aryl boron reagents, activated with more commonly used bases, remained a significant unmet challenge in the race to replace platinum group metal catalysts with Earth-abundant metal alternatives. We now show that this highly desirable process can be realized using alkoxide bases, provided the right counterion is employed, strict stoichiometric control of the base is maintained with respect to the aryl boron reagent, and the correct boron ester is selected. Potassium tert-butoxide works well, but any excess of the base first inhibits and then poisons the catalyst. Lithium tert-butoxide performs very poorly, while even catalytic amounts of lithium additives also poison the catalyst. Meanwhile, a neopentane diol-based boron ester is required for best performance. As well as delivering this sought-after transformation, we have undertaken detailed mechanistic and computational investigations to probe the possible mechanism of the reaction and help explain the unexpected experimental observations.

Full text of DOI:10.1021/acscatal.0c05557

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Cobalt-Catalyzed Coupling of Aryl Chlorides with Aryl Boron Esters
Activated by Alkoxides
Sanita B. Tailor,† Mattia Manzotti,† Gavin J. Smith, Sean A. Davis, and Robin B. Bedford*
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ABSTRACT: The cobalt-catalyzed Suzuki biaryl cross-coupling of aryl chloride substrates with aryl boron reagents, activated with
more commonly used bases, remained a significant unmet challenge in the race to replace platinum group metal catalysts with Earth-
abundant metal alternatives. We now show that this highly desirable process can be realized using alkoxide bases, provided the right
counterion is employed, strict stoichiometric control of the base is maintained with respect to the aryl boron reagent, and the correct
boron ester is selected. Potassium tert-butoxide works well, but any excess of the base first inhibits and then poisons the catalyst.
Lithium tert-butoxide performs very poorly, while even catalytic amounts of lithium additives also poison the catalyst. Meanwhile, a
neopentane diol-based boron ester is required for best performance. As well as delivering this sought-after transformation, we have
undertaken detailed mechanistic and computational investigations to probe the possible mechanism of the reaction and help explain
the unexpected experimental observations.
KEYWORDS: cobalt, Suzuki, aryl chlorides, aryl boron, alkoxide
based on palladium, and these have been applied to a vast
range of processes, including the commercial synthesis of
pharmaceutical intermediates such as o-tolyl benzonitrile
(OTBN)used in the production of six different sartan-class
drugs for the treatment of hypertensionand in BASF’s
production of boscalid, a broad-spectrum fungicide.3 Despite
the unrivaled success enjoyed by palladium, its application has
serious drawbacks: palladium is expensive, scarce, and its
extraction is environmentally deleterious; in addition, the
inherent toxicity of all platinum group metals (PGMs) means
that there are stringent regulatory requirements limiting the
levels of palladium that can be present in active pharmaceutical
intermediates to the low-ppm range.4 Accordingly, there is a
drive to replace palladium and other PGMs with more benign
alternatives based on less-toxic Earth-abundant metals (EAMs)
in a range of catalytic transformations.5
INTRODUCTION
■
Biaryls are widely found in pharmaceuticals, agrochemicals,
and materials, and the Suzuki biaryl coupling reaction (Figure
1) is a powerful, robust, and widely exploited method for the
production of this structural motif.1,2 By far the most widely
used catalysts for the Suzuki reaction are homogeneous species
Of the EAMs investigated as replacements for PGMs in
cross-coupling reactions, those based on first-row transition
metals are particularly attractive due to their relatively low cost,
Received: December 18, 2020
Revised: February 24, 2021
Published: March 12, 2021
Figure 1. Suzuki biaryl cross-coupling and selected commercial
examples.
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Figure 2. Effect of varying boronate on catalytic reaction (yields determined by G. C., dodecane internal standard) and calculated relative phenyl
ion affinities (PhIA, B3LYP-D3/6-311+G**, implicit solvation by THF modeled using the CPCM; see the Supporting Information for full details).
and greater availability. Nickel6−11 and copper-catalyzed12−15
Suzuki biaryl cross-couplings are by far the most advanced.
The iron-catalyzed cross-coupling of a range of sp3-based
electrophiles with aryl boron reagents has been reported,16−22
but simple Suzuki biaryl coupling remains elusive,23−25 with
genuine examples limited so far to substrate-directed
reactions.26,27 While rare, cobalt-catalyzed Suzuki biaryl
cross-coupling reactions are known.24,28−31 Thus, aryl triflates
or activated heteroaryl halides can be reasonably readily
coupled with aryl boron esters activated with either organo-
lithium reagents or, far more desirably, alkoxide salts.28,30,31
Conversely, highly expedient, yet electronically challenging,
aryl chloride substrates have only been shown to successfully
couple when activated by harsher alkyl lithium bases.29
Resolving this dilemma would give the sought-after cobalt-
catalyzed cross-coupling of aryl chlorides with aryl boron esters
using practical bases. Accordingly, we re-examined the roles of
alkoxide salts in this reaction and found that there is a fine
balance between their ability to activate the aryl boron reagent
and their intrinsic ability to inhibit or even poison the cobalt
catalyst. We also uncovered a strong dependence of the
catalytic activity on both the nature of the diol backbone of
aryl boron ester and on the counterion of the alkoxide salt.
With these critical pieces of information at hand, we were able
to deliver the desired yet elusive biaryl cross-coupling reaction.
RESULTS AND DISCUSSION
■
Optimization Studies. The N-heterocyclic carbene ligand
IPr (introduced as its HCl salt) was used throughout the initial
optimization studies, as we had previously shown it to be
useful in the related coupling reaction of aryl boronic ester
activated by alkyl lithium reagents.29 In the first instance, we
examined the effect of varying the diolate backbone of the aryl
boronic ester on the coupling reactions outlined in Figure 2; in
particular, we were keen to see whether there is any
relationship between the intrinsic thermodynamic propensity
to transfer the aryl group from the boron center and
performance in the catalytic reaction. This was done by
examining the calculated relative phenyl ion affinities (PhIA)32
of selected examples (density functional theory, B3LYP-D3/6-
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Figure 3. Selected data for the effect of variation of type and loading (equivalents with respect to 1a loading, 1.5 equiv of boron ester 2e used
throughout) of alkali metal alkoxide and salt additives on the coupling of 1a with 2e to give 3a (see Tables S4 and S5 for further data). The reaction
with entries marked (*) employed 2.0 equiv of 2a and 5 mol % of both CoCl2 and IPr·HCl.
311+G**, implicit solvation by tetrahydrofuran (THF)
modeled using the CPCM method; see Section 10 of the
Supporting Information for full details) since this approach has
previously been shown by Ingleson and co-workers to be a
good proxy for transmetalation from boron to iron.32 The
PhIAs were determined according to the isodesmic processes
outlined in Figure 2.
derived boron ester 2m, to be an excellent reagent for transfer
of the 4-tolyl group to iron.32 Despite the significantly
increased thermodynamic propensity of 2m to transfer an
aryl group compared with 2e (compare PhIAs of 4f with 4d),
no activity was observed when this nucleophile was employed.
Taking all of the calculated relative PhIA data together with
the corresponding catalytic data, it is clear that there is no
trend between the activity and the thermodynamic propensity
of the activated aryl boron ester to transfer an aryl group.
Instead, the profound variation in the activity must lie in more
detailed kinetic considerations (see the Mechanistic Inves-
tigations section) and points strongly toward transmetalation
being the key step to control in developing the catalytic
transformation, as suggested previously by Chirik.28
As well as choosing cyclic aryl boronic ester, the correct
choice of ligand, solvent, and alkoxide salt proved to be vital to
the success of the reaction, as did the loading of the alkoxide
salt. Table S2 summarizes the results obtained with various N-
heterocyclic carbene, phosphine, imine, and amine-derived
ligands. Of those tested, IPr and SIPr proved the stand-out
ligands. Interestingly, all of the phosphines examined gave
noticeably poorer performance than the use of CoCl2 alone
which gave 11% of 3a within 24 h, accompanied by significant
amounts of homocoupled byproduct derived from the aryl
boron ester (8%)suggesting that these ligands actually
inhibit cross-coupling. The fact that some activity, albeit low
and unselective, was observed without added ligands prompted
us to question whether cobalt nanoparticles were formed under
these conditions; however, transmission electron microscopy
(TEM) analysis indicated this was not the case (see the
Supporting Information for details).
The initial reaction explored, the coupling of 4-chloroto-
luene (1a) with the pinacol boronic ester 2a activated with
KOtBu acting as the base, unfortunately yielded none of the
desired product 3a. This is in sharp contrast with the
analogous reaction using nBuLi as a base, which gave
quantitative conversion to 3a,29 despite the identical
thermodynamic propensity of the corresponding “ate” species
[PhB(OtBu)(pin)]− to transfer a phenyl group, as judged by
the calculated values for the relative PhIA. Small amounts of
the desired product 3a could be obtained by varying the α-
substituents of the five-membered diolate motif (2b and 2d). A
more profound improvement was obtained on changing from
five- to six-membered cyclic boron esters, with the boronic
ester derived from neopentane diol (2e) giving a creditable
60% yield of 3a. Notably, the calculated relative PhIA of 4d is
essentially identical to that of 4a, indicating that the absence of
activity observed with 2a activated by KOtBu is not due to any
intrinsic thermodynamic difference of the two substrates in
their ability to transfer their phenyl groups to the cobalt center.
Importantly, both 2e and 2a react in the same way with KOtBu
to give the corresponding salts K[5a] (see below) and K[5b]
(see the Supporting Information), indicating that differences in
activation cannot account for the stark variation in perform-
ance in the catalytic reaction. Again, α-substitution of the
diolate backbones of the six-membered boron esters proved
deleterious, with no activity observed with tetra-methyl-
substituted substrate 2j, and almost no activity with the
seven-membered analogue 2l.
The use of 2-MeTHF or 1,4-dioxane in place of THF as
solvent led to only a modest diminution in catalytic
performance, while the use of either acetonitrile or
dimethylformamide (DMF) led to a complete suppression of
activity (Table S1).
Ingleson and co-workers found the potassium salt 5c,
formed in situ by N-deprotonation of the dipropanolamine-
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Figure 3 summarizes selected data from a study on the
influence of various alkoxide bases and salt additives on the
coupling of 1a with 2e to give 3a (see Tables S4 and S5 for full
details). Of the alkoxides tested, tert-butoxide proved most
effective, but the reaction was surprisingly sensitive to both the
alkali metal counterion and the loading of the base. Thus,
KOtBu worked well while the sodium analogue was less
effective, and the lithium salt gave very poor activity. Critically,
contrary to common practice in Suzuki cross-coupling, the
alkoxide salt must absolutely not be used in significant excess
as this proved highly deleterious to performance. Indeed, while
increasing the loading of KOtBu from 1.5 to 1.7 equiv with
respect to the aryl chloride 1a, in reactions with 1.5 equiv of
the boron ester 2e, led to only a modest diminution in
performance, increasing to 1.8 equiv led to an almost complete
shutdown of the reaction.
boronic ester coupling partner. 1-Chloro-4-fluorobenzene
coupled well, although again the better performance was
observed if 3h was produced by swapping the substitution
patterns between the aryl chloride and the boron ester. By
contrast, both para-CF3 and ortho-F groups on the aryl
chloride gave disappointing yields of 3i and 3j, respectively.
Similarly, aryl chlorides with ketone substituents gave modest
to no yield. While the yield of 3n was only modest, this was
significantly better than the previously reported analogous
coupling with aryl boron esters activated with nBuLi, where the
cyano function is not tolerated, but not as good as reported by
Duong and co-workers for this class of substrate.29,30 In sharp
contrast with the general trend observed in palladium-catalyzed
Suzuki cross-coupling, electron-rich aryl chlorides with alkoxy
or dialkylamino groups gave reasonable to good yields of the
desired biaryls.
Heteroaryl chlorides based on pyridine or benzothiazole
were tolerated, although the latter proved to be the exception
to the more general observation that sulfur-based moieties are
not tolerated on either coupling partner. Indeed, control
reactions between 1a and 2e were poisoned by the addition of
1 equiv of either thiophene or methyl phenyl thioether.
Broadly speaking, variation in the para-substituent on the aryl
boron ester indicated somewhat surprisingly that electron-
withdrawing groups tended to give better performance than
electron-donating groups, an observation borne out by a
Hammett analysis (see the Mechanistic Investigations section).
Meanwhile, the introduction of a methoxy into the ortho-
position of the aryl nucleophile gave enhanced performance
suggesting that in this instance neighboring group participation
may play a positive role. Indeed, the effect proved sufficiently
large to overcome the poor performance associated with a
para-CF3 on the aryl chloride substrate (compare 3aa with 3i
and 3ac).
An audit of the KOtBu in the latter reaction shows that 1.5
equiv of the base are used in a quantitative reaction with the
boron ester 2e to give the potassium boronate K[5a] (see the
Supporting Information for details), the single-crystal X-ray
structure of which is shown in Figure 4, while a further 0.1
Mechanistic Investigations. Influence of the Base. As
outlined in Figure 3, both the counterion and loading of the
tert-butoxide base have a profound effect on activity. To probe
the role of the counterion further, we examined the effect of
additives on the catalytic reaction, and selected results are
shown in Figure 3 (for full results, see Table S5). It can clearly
be seen that not only does the use of LiOtBu in place of KOtBu
inhibit the reaction, the same inhibition is seen on addition of
stoichiometric or catalytic amounts of LiCl to reactions with
KOtBu acting as the base. Furthermore, the addition of
stochiometric KBr to the reaction with LiOtBu as a base does
not restore activity. Evidently lithium salts inhibit the catalysis
however introduced. Inhibition is also seen when catalytic
amounts of MgBr2, ZnBr2, or AlBr3 are added to reactions
using KOtBu as the base, while the addition of KBr or NaBr
has no real impact, ruling out the possibility of a deleterious
role played by bromide.
Figure 4. Single-crystal X-ray structure of the dimeric boronate K[5a]
showing K+−π-arene interactions. Thermal ellipsoids are set at 50%
probability and hydrogen atoms are omitted for clarity.
equiv of the base are required to deprotonate the NHC
precursor IPr·HCl. This leaves 0.2 equiv of KOtBu, or a ratio of
cobalt to free KOtBu of 1:2, sufficient to almost completely
suppress catalytic activity. Increasing the amount of the aryl
boron ester 2e to 2 equiv (using 1.8 equiv of the base) led to a
complete recovery in activity even at a lower catalyst loading
(5 mol %); meanwhile, reducing the KOtBu loading to 1.5
equiv while using 2 equiv of the boron ester led to the optimal
conditions and a yield of 3a of 71%. The mechanistic
implications will be discussed in detail later, but it is clear
from the optimization studies that both the nature of the
counterion and the relative loading of the alkoxide salt have a
profound influence on the success or otherwise of the catalytic
reaction.
Substrate Scope. With optimized conditions in hand, we
next turned our attention to the scope and limitations of the
cross-coupling reaction, and the results from this study are
summarized in Figure 5, while unsuccessful coupling reactions
are presented in the Supporting Information, Section S4.2.
Reasonable to good yields of the desired biaryl were obtained
with alkyl-substituted aryl chlorides or naphthyl chloride
substrates, although in the case of 1-phenyl naphthyl product
3f, the naphthyl group was far better introduced via the aryl
1
It is apparent from H NMR spectroscopic investigations
that there is a significant difference between how Li+ and K+
interact with the anion 5a− (see the Supporting Information
for details); meanwhile, the X-ray structure for K[5a] (Figure
4) contains K+−π interactions, which are absent in analogous
structures with lithium or sodium counterions.33−35 It is
tempting to conclude that the observed activity order for
MOtBu of K > Na > Li may be due to increasing oxophilicity of
the counterions of the boronate salt: it may be more
challenging to replace the alkali metal with the cobalt catalyst
in a transmetalation step (see below). However, the fact that
even a catalytic amount of Li+ suppresses activity suggests that
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Figure 5. Selected Suzuki cross-coupling reaction. Conditions: CoCl2 (0.025 mmol), IPr·HCl (0.025 mmol), aryl chloride (0.5 mmol), KOtBu
1
(0.75 mmol), aryl boron ester (1.0 mmol), THF (3 mL), 60 °C, and 24 h.a Determined by H NMR (1,4-C6H4-NO2 internal standard) or GC
(dodecane internal standard). * 10 mol % of precatalyst used. Unsuccessful reactions are given in the Supporting Information, Section S4.2.
the issue is more likely due to the lithium ion interacting
deleteriously with the cobalt center in addition to or instead of
simply with the boronate. One way this might occur is via
interaction of the counterion with alkoxide ligands on the
cobalt center. To probe this further, we investigated the nature
of the species formed on reacting representative cobalt species
with MOtBu salts.
The reaction of (IPr)CoCl2 (formed in situ) with 3 equiv of
KOtBu yielded the potassium salt of the NHC-free ate complex
[Co(OtBu)3]− (6−, Figure 6). A genuine sample of K[6] was
prepared according to modification of a literature method for
comparison purposes,36 by the reaction of CoCl2 with 3 equiv
of the base. It is clear that the NHC ligand is readily displaced
by a tert-butoxide ligand. No reaction was observed between
the complex K[6] with an excess of the NHC ligand.
Displacement of the NHC ligand also occurred when only 2
equiv of KOtBu were employed, giving a highly insoluble
purple product, 7, that could also be prepared by either the
reaction of CoCl2 with 2 equiv of KOtBu or [Co(N(SiMe3)2)]
with 2 equiv of tert-butanol.
The powder X-ray diffraction (XRD) pattern of 7 (Figure 7)
shows reflections at 2θ = 18.0, 31.6, 36.5, 37.0, and 41.3°.
Based on the reaction stoichiometries and the highly insoluble
nature of the product, we suggest that 7 is a polymer of
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observation that complex K[6] is an active precatalyst in the
presence IPr·HCl, giving 51% of 3a. Taken together, it is clear
that for good activity the NHC ligand is required, and that a
stoichiometric or excess of aryl boron ester is needed with
respect to total alkoxide loading to prevent catalyst
deactivation.
The previously reported single-crystal X-ray structure of
K[6] shows that the molecule is dimeric with two-terminal and
two-bridging alkoxide ligands per cobalt, with each potassium
coordinated by one of the bridging alkoxides and two of the
terminal alkoxides, one from each Co (structure type I, Figure
8).36 The structural type I was also reported for Na[6];36
Figure 6. Reactions of cobalt precursors with KOtBu (THF, r.t. 30
min).
Figure 8. Structural variation in trisalkoxide cobaltate anions with
differing metal counterions.
meanwhile, smaller, more oxophilic metals have been shown to
give structure type II in related complexes in which the metal is
coordinated by the two terminal alkoxides.37,38
1H NMR spectroscopy of a THF solution of K[6] shows
only two paramagnetically shifted butoxide peaks, 21.5 and
−37.3 ppm in a 2:1 ratio, consistent with the dimeric structure
being preserved in solution; meanwhile, the spectra of Na[6]
and Li[6] show multiple peaks for the tert-butoxide ligands,
suggesting that in the solution a variety of oligomeric species
are obtained (see Figures S37 and S38). When LiCl, MgBr2, or
ZnBr2 were added to the solutions of K[6], then once again
multiple alkoxide environments were observed; conversely, the
addition of NaBr had no effect on the spectrum. Taken
together, the NMR data suggest that while the potassium salt
cleanly gives a single species in the solution, harder, more
oxophilic cations give complex mixtures and can displace the
potassium salt. The exception is sodium which, despite giving
complex mixtures on its own, is unable to displace potassium,
suggesting weaker interaction with the alkoxides of the more
heavily aggregated species.
Figure 7. Powder XRD data for samples of 7 obtained by: (i) reaction
of CoCl2 with 2 KOtBu; (ii) reaction of (IPr)CoCl2 with 2 KOtBu;
(iii) reaction of [Co(N(SiMe3)2)2] with 2 HOtBu; and (iv) at the end
of a representative catalytic reaction, * indicates reflections due to
coprecipitated KCl.
[Co(OtBu)2] in which four-coordinate cobalt centers are
bridged by two tert-butoxide ligands. The same highly
insoluble purple precipitate is observed toward the end of
many of the catalytic transformations.
The relatively weak binding of K+ and Na+ to the cobalt
alkoxide species may well account for the observed activity
with these counterions, while the relatively strong binding of
more oxophillic cations my explain their inhibitory effect. We
cannot preclude the possibility that one or more of the
Interestingly, unlike “ligand free” CoCl2, which showed
some catalytic activityalbeit low yielding and unselective
(see above)K[6] proved not to be a viable precatalyst under
NHC-free conditions when 1.5 equiv of aryl boron ester 2e
and 1.5 equiv base (with respect to aryl chloride) were used.
However, when the amount of the boron ester was increased to
2 equiv, in the reaction catalyzed by K[6], then 24% of the
cross-coupled product was obtained along with 24% of
biphenyl. This provides clear evidence that the boron ester
can “mop up” the alkoxide even when it is coordinated to
cobalt. The inactivity of K[6] in the absence of excess 2e,
coupled with the observation that the complex does not react
with free IPr, and slowly degrades to 7 when heated with IPr·
HCl, suggests that both the ligand and one or both of the
coupling partners are required to transform 6 into a
catalytically viable intermediate. This is supported by the
1
multiple alkoxide peaks observed in the H NMR spectra
derived from heteroleptic “CoX(OtBu)” species (X = Cl, Br);
indeed, such species have been crystallographically charac-
terized previously.39−41 The H NMR spectrum of a reaction
1
between CoCl2 with only 1 equiv of KOtBu shows a single
peak at 41.5 ppm, suggestive of the formation of a mono-
alkoxide complex, 8 (Figure 6); however, it is not possible to
comment on whether this species is a neutral complex or an ate
species, nor whether it is monomeric or oligomeric, beyond
noting that the shift is in the same general region of that
observed for the terminal tert-butoxide ligands in K[6].
So far, the data do not suggest a positive role for potassium,
rather a deleterious role for more oxophilic cations; however,
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Figure 9. Kinetic investigations. Full details are given in the Supporting Information.
the explanation cannot be this straightforward. If the only role
for the cation were that it hampers reactivity, then sequestering
the cation in an appropriate crown ether would be expected to
have little or no influence on activity in the case of K+ yet
significant benefit in reactions inhibited by Li+. However, this
is not the case, addition of 1 equiv of 18-crown-6 per
potassium in a reaction with KOtBu switches off activity
(Figure 3), while the addition of 12-crown-4 in a reaction with
LiOtBu has no effect on performance.
than the boronate formed on reaction of 2a with butyllithium
and second that any catalytic manifold that requires access to
the Co(0) oxidation state can be excluded here.
Kinetic and Computational Investigations. Figure 9
summarizes the kinetic data obtained for the coupling of
chlorobenzene 1b with the preformed borate salt K[5d] using
the precatalyst IPrCoCl2, formed in situ by stirring CoCl2 with
IPr for 15 min before the start of catalysis. Interestingly, using
the mixture of preformed carbene complex and preformed
borate significantly reduced the induction period to around 20
min, with essentially no turnover observed before this point.
While the use of the initial rate method in catalytic reactions
with induction periods can be problematic, the essentially
complete lack of formation of 3h during the induction period
followed by clear regions of linear increase in the concentration
of 3h vs time (typically to between 10 and 25% conversion to
product, see Figures S5−S7) gave us reasonable confidence in
the use of this approach, when applied to the linear regions of
product growth.
Summarizing, when KOtBu is used as the base, an excess of
two or more free alkoxides per cobalt must be avoided to
prevent the formation of either the inactive ate complex K[6],
which needs to be subsequently transformed into an active
species in the presence of free NHC ligand and one or more of
the components of the catalytic reaction, or worse the
formation of the highly insoluble polymer 7, which represents
a catalyst termination process. Replacing potassium with
harder more oxophilic cations is highly deleterious to
performance.
Catalyst Activation. As can be seen in Figures S1 and S2,
the catalytic reaction is subject to an induction period of
around 190 min, during which a significant proportion of the
side-product, biphenyl (9), is produced by a homocoupling of
the nucleophilic substrate. The formation of 9 is indicative of a
reductive elimination from cobalt, and, in the absence of the
electrophile, the amount produced can be used as a proxy to
determine the lowest bulk oxidation state that can be
thermodynamically accessed on the metal under the reaction
conditions.42 Meanwhile, the time frame in which it is
produced in the absence of the electrophile can help determine
the kinetically most relevant bulk oxidation state. Here,
approximately 0.7 electrons per cobalt are released during
the reductive activation of the NHC-containing precatalyst,
corresponding to an approximately 70% conversion to an
average bulk oxidation state of Co(I) for the activated catalyst.
Examining catalytic reaction mixtures formed in the presence
or absence of the NHC ligand by TEM did not reveal the
presence of any cobalt nanoparticles (see the Supporting
Information, Section S11). We previously found that
homogeneous cobalt(0) SIPr complexes could be trapped
using alkenes and dienes when reducing the precatalyst
mixture with BuLi-activate boronates;29 however, this is not
the case here (see the Supporting Information, Section S8.1),
indicating first that the aryl boronate K[5a] is less reducing
The initial rate analysis shows that the rate of catalysis has a
slightly greater than first-order dependence (1.3) on the
concentration of the precatalyst, an observation confirmed by
variable time normalization analysis (VTNA),43 which both
showed that the same order holds true throughout a significant
proportion of the reaction and helped vindicate our application
of the initial rates method to the postinduction phase region of
catalysis. Meanwhile, a positive order dependence of
approximately 0.7 was observed for borate. Surprisingly, the
order in aryl chloride proved to be slightly negative (approx.
−0.3). Clearly, the oxidative addition of 1a is not the rate-
limiting step, while the slight negative order suggests a
secondary, inhibitory role for the substrate, possibly by the
formation of an off-cycle cobalt adduct, which might also
explain greater than first-order dependence on the concen-
tration of precatalyst. The positive order dependence on the
borate K[5d] indicates its prominent role either in the rate-
determining process or in an unfavorable equilibrium prior to
this step.
Linear free-energy analyses were performed varying the para-
substituents on both the aryl chloride and the aryl boronic
ester (Figure 10). On varying the electronics of the ester 2a, a
strongly positive value for ρ was obtained, indicating either the
build-up of negative charge or a loss of positive charge in the
rate-determining step.
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point energies were separately determined using the larger
def2-TZVP basis set, while THF solvation was accounted for
by a single-point calculation using the conductor-like polar-
izable continuum model.55 For full details, see the Supporting
Information, Section S10.
Figure 11 summarizes the key results from the computa-
tional study. For simplicity, we investigated the manifold using
the free boronate ion 6−, rather than its potassium salt. While
the mechanistic studies above indicate that the role and nature
of the alkali metal ion are critical to success, too many variables
and unknowns including speciation and highly variable levels
of solvation render realistic modeling of the role(s) of the
counterion beyond the scope of the current study. We instead
focussed more broadly on determining a representative
catalytic manifold, focussing in particular on the likely spin
states of the intermediates as well as the likely slow
transformation.
The intermediate LCoCl, IA, was used as a model for the
Co(I) species formed in situ. While we cannot rule out mono-
alkoxide-containing analogues or ate species, for simplicity, we
decided this would act as a useful and representative starting
point. Modeling the THF-containing analogues of HSIA (see
Figure S44) showed that mono-adduct HSIA(THF) was just
under 3 kcal/mol higher in energy, while neither HSIA(THF)2
nor HSIA(THF)3 converged, with both failed optimizations
indicating dissociation of one or two THF ligands, respectively.
As can be seen in Figure 11, high spin (S = 1) HSIA undergoes
coordination of chlorobenzene, 1b, to give intermediate HSIB,
followed by oxidative addition via the transition state HSTSOA
to give the intermediate spin (S = 1) Co(III) species ISIC.
Overall, this sequence is exergonic by around 3 kcal/mol
compared with the starting materials. Explicit solvation of HSIB
with 1 equiv of THF gave an intermediate HSIB(THF) that was
marginally (1.2 kcal/mol) lower in energy; however, the
analogous subsequent transition state HSTSOA(THF) could not
be located. Figure S44 outlines the analogous oxidation
addition pathway starting with the low-spin Co(I), LSIA.
Here, explicit THF coordination proved beneficial; however,
the pathway remained far too high in energy compared with
the HS route to be operative; furthermore, we were unable to
locate an appropriate transition state for oxidative addition on
this surface.
Figure 10. Linear free-energy studies.
This is distinct from transmetalation from aryl boronic acids
to palladium, which typically show a negative ρ.44,45 While
oxidative addition is not the rate-determining step, the
observed dependence of rate on the nature of the p-substituent
of the aryl chloride indicates that the rate-determining process
occurs after the oxidative addition step and that the aryl group
is a component part of the intermediate prior to the slow step.
Unlike with the aryl on the boronate, the rate does not show
a simple Hammett dependence on the p-substituent of aryl
chloride, but rather a dependence on the Creary scale,46
suggesting radical character. A radical-based reductive
elimination would show a radical stability dependence for
both aryl groups, which is clearly not the case, and can thus be
discounted, as can any other form of reductive elimination
being the slow step, as the profoundly different electronic
influences of the two aryls are essentially irreconcilable in such
a scenario: reductive elimination of aryl−aryl′ from any
intermediate Co(aryl)(aryl′) cannot give one trend for
substitution of aryl and a separate trend for the substation of
aryl′. Indeed, the data indicate that while both aryl groups are
present in an intermediate immediately prior to the rate-
determining transformation, or in equilibrium with such a
species, they are in profoundly different environments.
Subsequent steps involving Co(III) were modeled on all
three possible spin surfaces: S = 0 (low spin, LS); S = 1
(intermediate spin, IS), and S = 2 (high spin, HS). In all cases,
the intermediates and transitions states on the IS pathway were
significantly lower in energy than either the HS or LS
analogues. Meanwhile for Co(I) intermediates and transition
states, HS (S = 1) is preferred over LS (S = 0), indicating that
the catalytic cycle essentially lies entirely on the triplet
manifold.
The coordination of the “naked” borate anion 6− and
displacement of the chloride ligand in intermediate ISIC to give
ISID is unfavorable, while the subsequent transition state for
transmetalation (ISTSTM) represents the turn-over frequency-
determining transition state (TDTS).56 Subsequent reductive
elimination and product loss processes complete the cycle and
proceed smoothly on the triplet surface, with the reformation
of HSIA and liberation of product representing the turn-over
frequency-determining intermediate (TDI), which gives a
calculated energetic span of 27.9 kcal/mol for the catalytic
cycle.56
To probe the mechanism further, we undertook a computa-
tional investigation into the catalytic manifold. All calculations
were performed using Orca 4.2,47,48 employing the B3LYP
functional.49−52 with Grimme’s D3 dispersion correction with
Becke−Johnson damping53 and were accelerated by the use of
the RIJCOSX approximation.54 Intermediates and transition
states were optimized using the def2-SVP basis sets, single-
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Figure 11. Selected data from the density functional theory investigation of the proposed catalytic cycle. Further data, including alternative
pathways starting with a low-spin state for IA and the effect of explicit solvation, are presented in the Supporting Information.
The determination of ISTSTM as the TDTS marries well with
the catalytic and mechanistic observations outlined above.
Examining the structure of the TDTS, ISTSTM, it is clear that
CONCLUSIONS
■
In conclusion, we have instigated the cobalt-catalyzed Suzuki
coupling of aryl chloride substrates with aryl boron esters
reducing the size of the boron diolate ring would increase ring
strain in the Co(O)2B moiety, disfavoring the transmetalation,
consistent with the observed pronounced deleterious effect on
changing from a six- to a five-membered B-diolate. Meanwhile,
variation of both the aryl on the cobalt (derived from the aryl
chloride substrate) and the aryl on the boron center in the
activated by alkoxide bases. As has been previously
suggested,28 the challenging step in the manifold proved to
be transmetalation, but we have shown that the problems
associated with this exacting transformation can be overcome.
Key to success is (i) the correct choice of diolate residue on
the aryl boron ester, (ii) the nature of the counterion of the
alkoxide base, with potassium tert-butoxide proving to be best
under our conditions, and (iii) tight control of the
stoichiometry of the base with respect to the aryl boron
ester. As yet we have not been able to fully unpick the role(s)
of the counterion on the reaction, although it seems highly
likely from the data obtained that the counterion is required in
the formation of a boronate−cobalt cluster, a key intermediate
in the slow transmetalation step. Whether transmetalation
occurs from this point or whether solvated potassium chloride
is fully or partially extruded prior to aryl transfer has not yet
been established, although the inhibitory role of lithium
suggests that overly tight coordination of the counterion may
inhibit such a process and thus the catalytic reaction. Now that
the major obstacle to transmetalation has been cleared in the
cobalt-catalyzed Suzuki biaryl cross-coupling reaction, future
developments must focus on producing higher activity catalysts
that can act as genuine challengers to the supremacy of
palladium in the reaction.
IS
transition state TSTM would be expected to impact upon the
rate of catalysis, as observed in the kinetic and Hammett
investigations above, with quite distinct electronic influences
anticipated and obtained. The intermediate spin Co(III)
center is a triplet diradical; therefore, it is perhaps not
surprising that the relative rates associated with processes that
lead to changes in cobalt’s coordination sphere might well be
expected to display a Creary dependence on the para-
functional groups in the linear free-energy analysis. The
observed positive value for ρ obtained on varying the para-
substituents on the boron center indicate either the build-up of
negative charge or a loss of positive charge in the TDTS. This
may well reflect changes in the location of the potassium
counterion en route to the TDTS; the modeling of which is
beyond the scope of the current study.
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cross-coupling reactions of aryl boronate esters with perfluoroben-
zenes. J. Org. Chem. 2016, 81, 5789−5794.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.0c05557.
■
sı
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All experimental details, including syntheses, catalytic
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(PDF)
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the Iron-, Cobalt-, Nickel-, and Copper-Catalyzed Suzuki Biaryl
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AUTHOR INFORMATION
Corresponding Author
Robin B. Bedford − School of Chemistry, University of Bristol,
Bristol BS8 1TS, U.K.; orcid.org/0000-0002-8021-8768;
Email: r.bedford@bristol.ac.uk
■
Authors
Sanita B. Tailor − School of Chemistry, University of Bristol,
Bristol BS8 1TS, U.K.
Mattia Manzotti − School of Chemistry, University of Bristol,
Bristol BS8 1TS, U.K.; orcid.org/0000-0001-9058-8087
Gavin J. Smith − School of Chemistry, University of Bristol,
Bristol BS8 1TS, U.K.
Sean A. Davis − School of Chemistry, University of Bristol,
Bristol BS8 1TS, U.K.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.0c05557
Author Contributions
†S.B.T. and M.M. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the following for supporting the project: the
EPSRC for provision of a studentship (to S.B.T.), the
provision of a studentship through the EPSRC Centre for
Doctoral Training in Catalysis (to M.M.), and the Erasmus+
Fund of the European Union for financial support (G.J.S.).
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