Observations on transition metal free biaryl coupling: Potassium tert-butoxide alone promotes the reaction without diamine or phenanthroline catalysts

Article abstract of DOI:10.1039/c3cc49019j

Biaryl coupling (often labelled 'C-H activation') of aromatic systems can be achieved by potassium tert-butoxide alone in the absence of any amine or bipyridine catalyst (1,10-phenanthroline or N,N′-dimethylethylenediamine being the most common), previously reported to be essential. Various mechanistic studies and observations are presented which suggest that when 1,10-phenanthroline is employed as the catalyst, the alkoxide is destroyed almost immediately. The Royal Society of Chemistry 2014.

Full text of DOI:10.1039/c3cc49019j

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Observations on transition metal free biaryl
coupling: potassium tert-butoxide alone promotes
the reaction without diamine or phenanthroline
catalysts†
Cite this: Chem. Commun., 2014,
0, 2575
5
Received 26th November 2013,
Accepted 13th January 2014
J. Cuthbertson, V. J. Gray and Jonathan D. Wilden*
DOI: 10.1039/c3cc49019j
www.rsc.org/chemcomm
Biaryl coupling (often labelled ‘C–H activation’) of aromatic systems can
be achieved by potassium tert-butoxide alone in the absence of any
0
amine or bipyridine catalyst (1,10-phenanthroline or N,N -dimethyl-
ethylenediamine being the most common), previously reported to be
essential. Various mechanistic studies and observations are presented Scheme 1 TM free biaryl coupling with amine catalysis.
which suggest that when 1,10-phenanthroline is employed as the
catalyst, the alkoxide is destroyed almost immediately.
reactions due to the fact that the O–K bond is relatively weak and
supplies an essentially dissociated alkoxide anion. We therefore
8
One of the most important observations in organic chemistry in
examined the reaction of simple aryl iodides with benzene under
recent years has been the discovery that certain reactions previously
various conditions. The results are given in Table 1.
thought the preserve of transition metal catalysis (for example C–H
The results demonstrate that while amine additives may allow
1
2,3
4
5
activation, biaryl couplings, certain Heck and Sonogashira
processes) can be effected without the requirement for a transition
metal. These quite remarkable observations have raised many
questions in the academic community as to the origin of these
reactions. In some cases trace metal contaminants in coreagents
the reactions to proceed under slightly milder conditions, the
major effect can be observed without an amine ‘ligand’ or a
transition metal present in the reaction mixture. The experiments
also demonstrate the superiority of the potassium cation for
effecting these reactions. As has been previously noted, addition
6
have been shown to be the origin of the catalysis while in others a
2,3
of radical traps such as TEMPO or even prolonged exposure to
2,7
radical mechanism has been implicated. The common feature of
those reactions where a TM is not required is the requirement of
either a phenanthroline or diamine derivative to effect the catalysis Table 1 Optimisation of TM and amine-free C–H activation
2
,3
(
with phenanthroline derivatives being used most frequently). The
2
3
pioneering work of Hayashi and, Kwong and Lei which demon-
strates this is outlined in Scheme 1. Since their publications in 2010,
numerous similar approaches have followed.
We here report observations from our own laboratory, which
demonstrate that the amine or phenanthroline additive is not
an essential component of these C–H activation and biaryl
coupling reactions. In some cases the additive may improve
the rate or efficiency of the reaction but the reactions still
proceed in their absence. This paper outlines our experiments,
observations and thoughts as to why this is the case.
Our laboratory has long been interested in the reactions of alkoxy
bases and their application in TM-free processes. Our previous work
has suggested that potassium tert-butoxide undergoes sp-displacement 11
a
Entry
X
M
Additive
Temp. (1C)
Yield (%)
1
2
3
4
5
6
7
8
9
I
I
I
I
K
K
K
K
K
K
K
Na
Li
Na
Na
K
K
K
—
—
—
—
—
—
—
—
55
85
0
0
3
110
160
160
160
160
160
160
160
160
85
38
66
b
I
Br
Cl
I
I
I
I
I
I
I
6
0
2
0
65
2
—
1
0
1,10-Phen
15-Crown-5
1,10-Phen
1,10-Phen
DMEDA
DMEDA
1
1
1
1
2
3
4
5
2
160
85
160
65
53
Department of Chemistry, University College London, 20 Gordon Street, London,
WC1H 0AJ, UK. E-mail: j.wilden@ucl.ac.uk
b
I
K
67
†
Electronic supplementary information (ESI) available: Full characterisation and
a
b
analytical data is provided. See DOI: 10.1039/c3cc49019j
Isolated yields. Reaction time extended to 6 h.
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Table 2 Substrate scope in TM and amine free KOtBu mediated C–H
Table 3 Physical data for unpurified and purified 1,10-phenanthroline
activation
Theoretical
(%)
Unpurified
(m.p. 90–99 1C)
Purified
(m.p. 115–116 1C)
Element
C
H
N
79.78
4.47
15.55
72.62
4.89
14.12
78.09
4.57
16.2
a
Entry Ar–X 1a–h
Additive
Product 2a–i
Yield (%)
1
2
3
4
—
—
—
—
2a
2b
2c
2d
77
66
48
64
sodium tert-butoxide is employed (entries 5, 8, 10 and 13). We
therefore decided to examine the role of phenanthroline in these
reactions more closely.
We were at first suspicious that the quality of commercially
sourced 1,10-phenanthroline was poor. A number of different
companies supplied the reagent with a faint pink hue, which we
believed may be transition metal contaminants. Additionally the
reagent contained at least one mole of water, which could be clearly
1
5
6
—
—
2e
2f
48
observed in the H NMR spectrum. This observation was reflected in
the melting point of the material which at 90–99 1C was significantly
below the literature value of 117–118 1C and almost perfectly
matched the literature value for the hydrated species. The elemental
analysis data also suggested the hydrate. In order to rectify this, the
reagent was converted to the mesylate salt, then washed with
concentrated aqueous ammonia before recrystallisation to give the
pure material as a white crystalline solid. This material was spectro-
scopically pure, and gave satisfactory elemental analysis data along
with a melting point of 115–116 1C, in good agreement with the
literature value for the pure material (Table 3).
The first striking observation in these reactions was the immedi-
ate, exothermic and vigorous reaction between equimolar mixtures of
KOtBu and purified 1,10-phenanthroline in THF, forming a black tar.
Performing the same reaction with unpurified 1,10-phenanthroline
led to a comparatively more sluggish reaction and a pale yellow
solution after five minutes (Fig. 1). It is also noteworthy that this
reaction occurs even when the aryl iodide is omitted from the mixture.
Given these observations, we decided to specifically examine the
30
21
2
g
7
—
2
h
30
37
8
9
—
2i
1,10-Phen
DMEDA
2e
2e
81
45
1
0
a
Isolated yields.
molecular oxygen attenuates the reaction and so a radical process tert-butoxide–phenanthroline mixture by NMR spectroscopy. We
the mechanism of which will be discussed later) can be inferred. were somewhat surprised to observe that mixing equimolar
(
Having identified suitable reaction conditions for the pro- amounts of KOtBu with 1,10-phenanthroline leads to essentially
cess we then turned to examine the scope of the reaction with a complete destruction of the tert-butoxide moiety, the characteristic
variety of substrates. The results are presented in Table 2.
9H singlet at 1.2 ppm collapsing to o1H according to the spectrum
We were pleased to observe that the reaction could be integral. The signals arising from the phenanthroline molecule
effected with a variety of electron rich and electron deficient are left untouched. The same result is obtained when NaOtBu
aryl iodides and that minimal side products were observed. We and 1,10-phenanthroline are mixed except the reaction takes
were also interested to note that addition of the diamine had no ca. 5 minutes rather than a few seconds (Fig. 2).
effect on the reaction yield but (as shown in Table 1) does allow
the reaction to proceed at a much lower temperature.
Our model to explain this observation is one where the
metal ion and alkoxide for the group 1 metals are in dynamic
Along with others working in this field we have been intrigued by
the reaction mechanism of these processes. Previous postulated
mechanisms have suggested that phenanthroline acts as a bidentate
ligand for the alkali metal leading to a chelate that is capable of
undergoing electron transfer to an organic substrate to initiate a
2
radical coupling reaction with benzene.
Given that 1,10-phenanthroline is only a weak ligand for the
9
lower group 1 metal ions (due to their large ionic radius) an
alternative explanation seems likely given that the results Table 1
demonstrate that there is little advantage to employing phenanthro-
Fig. 1 Demonstration of reactivity of KOtBu when mixed with (a) com-
line with the potassium counterion but a significant advantage when mercial 1,10-phenanthroline and (b) purified 1,10-phenanthroline.
2
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Scheme 3 Collapse of pentoxide radical to give butanone and methyl
radicals.
the immediate colour change on mixing the two reagents
(Scheme 3).
This we have confirmed by analysing the mixture of potassium
pentoxide and 1,10-phenanthroline by mass spectrometry, which
suggests that butanone is a major component of the reaction
mixture. Aware of the difficulties in drawing conclusions from
the mass spectra of low molecular weight compounds we therefore
proceeded to confirm the presence of volatile, enolisable ketones in
the reaction mixture, for which additional evidence was required.
We therefore confirmed the collapse of the putative alkoxy radical
by employing the established Janovsky Test for enolisable
ketones. Addition of m-dinitrobenzene to a dilute THF solution
of the alkoxide–phenanthroline mixture resulted in an intense
purple colour, indicating that the ketone was a significant compo-
nent of the mixture (Fig. 4).
1
Fig. 2 H NMR spectrum of an equimolar mixture of 1,10-phenanthroline
and KOtBu demonstrating the collapse of the 9H singlet at 1.2 ppm.
12
Given our evidence that increased charge separation
between the metal cation and the alkoxy anion is responsible
for the increasing reducing ability of the metal alkoxide (Fig. 3),
we expected that the addition of 15-crown-5 to sodium tert-
butoxide would increase the concentration of charge separated
species and result in a reaction broadly similar to that of the
potassium analogue. Entry 11 in Table 1 demonstrates that this
is clearly not the case. A consultation of the literature however
reveals that although 15-crown-5 assists in the solvation of
sodium salts, simple stoichiometric mixtures maintain a con-
tact association with the anion, particularly when the anion is
Fig. 3 Increasing reducing power of group 1 alkoxides with increased
cationic dissociation.
equilibrium between the essentially covalent and charge separated
species. Additionally, when in the charge-separated form, the alk-
oxide can be thought of as being in equilibrium with a species that
bears a loosely bound electron (Fig. 3). At elevated temperatures this
electron can be transferred to an aryl halide to initiate the reaction.
This would tally with the work of Ashby, who demonstrated that the
alkylation of alkoxides can proceed via single electron transfer from
1
3,14
10
highly coordinating.
In this example it is unlikely therefore
the alkoxide to the alkyl halide.
that the crown ether succeeds in generating sufficient levels of
charge separated species to be synthetically useful (Fig. 5).
Presumably, once the alkoxy radical has collapsed the phenan-
throline radical anion is then capable of transferring an electron to
the aryl halide to initiate the radical coupling process. We conclude
therefore that the phenanthroline derivatives serve as a temporary
electron stock where they are sufficient electron acceptors to drive
the equilibrium towards the alkoxy radical which then collapses,
but do not hold the electron so tightly that it cannot be given up to
an organic substrate in the reactions most recently reported. This is
supported by the observation that 1,10-phenanthroline does not
appear to be consumed when mixed with potassium tert-butoxide
The addition of 1,10-phenanthroline has an effect on the two
equilibria (b) and (c) by removing the loosely bound electron
from the complex and rendering the reaction irreversible. In
the case of the lithium analogue (a), the initial equilibrium lies
far to the left and the concentration of either of the dissociated
species is too low for the reaction to be viable. The effect of
adding phenanthroline to the system not only drives the
equilibrium to the right, but by removing the loosely bound
electron leaves a highly reactive alkoxy radical (Scheme 2).
The alkoxy radical immediately collapses via a variety of
well-known decomposition pathways such as H-atom abstrac-
tion and b-scission processes to yield highly reactive methyl
1
1
radicals. The intractable mixtures of products and polymers
which result from uncontrolled radical processes accounts for
Fig. 4 (a) Reaction of m-dinitrobenzene with butanone (Janovsky Test)
Scheme 2 Effect of phenanthroline on sodium and potassium pentoxide.
and (b) (inset) purple colour indicating the positive test obtained.
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Fig. 5 Contact association of alkoxide anion with sodium cations com-
plexed by 15-crown-5.
Scheme 4 Radical processes leading to biaryl formation.
whereas the alkoxide collapses rapidly. Others have noted that of the mechanism of these reactions and the role of 1,10-phen-
alternative additives, structurally unrelated to 1,10-phenanthroline anthroline, the mechanism by which the diamines (e.g.
15
(
e.g. macrocyclic pyridone pentamers developed by Zeng ) also DMEDA) appear to facilitate these processes is still unknown.
promote the reaction in the same way. It is likely that these agents Work is underway in our laboratory to understand this mechanism
behave similarly, providing a haven for a loosely bound electron and to improve the efficiency of the reaction and will form the basis
that can then be transferred to an organic substrate. Interestingly of future communications from our laboratory.
however, Murphy and Tuttle having examined similar processes by
The authors would like to thank UCL for support via the
computational means concluded that electron transfer directly doctoral training programme in Organic Chemistry: Drug
from the alkoxide to the aryl iodide is unlikely, in contrast to our Discovery.
16
results presented here. Our results have demonstrated that a
Notes and references
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organic substrates when highly dissociated. Although many have
attempted to describe these reactions in terms of catalytic cycles,
our evidence suggests that a series of radical reactions is more
accurate (where 1,10-phenanthroline is only required when the
metal alkoxide is not sufficiently dissociated for the reaction to
proceed) (Scheme 4). This is in agreement with the conclusions of
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1
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2
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