Mechanism-Based Condition Screening for Sustainable Catalysis in Single-Electron Steps by Cyclic Voltammetry

Article abstract of DOI:10.1002/anie.201800731

A cyclic-voltammetry-based screening method for Cp₂TiX-catalyzed reactions is introduced. Our mechanism-based approach enables the study of the influence of various additives on the electrochemically generated active catalyst Cp₂TiX, which is in equilibrium with catalytically inactive [Cp₂TiX₂]^?. Thioureas and ureas are most efficient in the generation of Cp₂TiX in THF. Knowing the precise position of the equilibrium between Cp₂TiX and [Cp₂TiX₂]^? allowed us to identify reaction conditions for the bulk electrolysis of Cp₂TiX₂ complexes and for Cp₂TiX-catayzed radical arylations without having to carry out the reactions. Our time- and resource-efficient approach is of general interest for the design of catalytic reactions that proceed in single-electron steps.

Full text of DOI:10.1002/anie.201800731

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Accepted Article
Title: Mechanism-Based Condition-Screening for Sustainable Catalysis
in Single Electron Steps by Cyclic Voltammetry
Authors: Andreas Gansäuer, Theresa Liedtke, Peter Spannring, and
Ludovico Riccardi
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201800731
Angew. Chem. 10.1002/ange.201800731
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10.1002/anie.201800731
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Mechanism-Based Condition-Screening for Sustainable Catalysis
in Single Electron Steps by Cyclic Voltammetry
Theresa Liedtke, Peter Spannring, Ludovico Riccardi and Andreas Gansäuer*
Abstract: A cyclic voltammetry based screening method for Cp2TiX-
catalyzed reactions is introduced. Our mechanism-based approach
enables the study of the influence of various additives on the
electrochemically generated active catalyst Cp2TiX which is in an
equilibrium with catalytically inactive [Cp2TiX2]-. Thioureas and ureas
are most efficient in the generation of Cp2TiX in THF. The precise
knowledge of the position of the equilibrium between Cp2TiX and
[Cp2TiX2]- allows the identification of conditions for bulk electrolysis of
Cp2TiX2 complexes and for Cp2TiX-catayzed radical arylations without
having to carry out the reactions. Our time and resource efficient
approach is of general interest for the reaction design in catalysis in
single electron steps.
Here, we demonstrate the validity of this approach by identifying
conditions for the bulk electrolysis of the single electron transfer
precatalyst Cp2TiX2 (X = Cl or Br). This was achieved by CV-
monitoring[5] the efficiency of the electrochemical reduction (Eq) of
Cp2TiX2 to [Cp2TiX2]- on the one hand, and investigating the
equilibrium reaction of [Cp2TiX2]- to [Cp2TiX] + X- (Cr) as a function
of various additives on the other hand (Scheme 1, upper part).[6]
The unambiguous identification of the Cp2TiX peak was achieved
by CV experiments in which an external X- source was added to
reverse the Cr-reaction (indicated by an increase of the intensity
of the oxidation peak pertaining to [Cp2TiX2]- and a decrease of
the intensity of the oxidation peak of Cp2TiX). Additionally,
literature data was taken into account.[6] For practical applications,
the electrochemical generation of titanocene(III) reagents is of
high interest in sustainable catalysis. An ideal and at the same
time challenging reaction to prove this point is the atom-
economical titanocene(III) catalyzed radical arylation (Scheme 1,
lower part).[7] Efficient reaction conditions require the
simultaneous presence of both Cp2TiX as the active catalyst as
well as [Cp2TiX2]- as the resting-state for catalyst stability.
Therefore, the radical arylation is critically dependent on the
composition of the Cr-equilibrium.[8] For this mechanism-based
screening,[9] halide abstracting additives are added in order to
enforce a suitable Cr-equilibrium.
‘Catalysis in single electron steps’[1] or ‘metalloradical catalysis’[2]
are concepts that allow the incorporation of radical
transformations in metal catalyzed reactions. Key aspects of this
approach are oxidative additions and reductive eliminations in
single electron steps[3] that require an efficient shuttling of the
catalyst between neighboring oxidation states.
A highly attractive feature of catalysis in single electron steps is
that cyclic voltammetry (CV) is in principle ideally suited for the
pre-screening of new reagents and of efficient reaction
conditions.[4] CV allows the characterization of the composition of
redox-active compounds in solution, the study of their properties,
and the kinetics of their reactions. The data obtained within
minutes, require marginal amounts of material (0.02 mmol) and
are essential for catalyst design.
The investigated solvent was THF, as it is an excellent solvent in
many titanocene(III) catalyzed reactions[10] and allows a good
evaluation of the additive influence, as additives are crucial in this
solvent to form active catalyst at all. In our hands, the electrolysis
of Cp2TiCl2 or Cp2TiBr2 in pure THF did not occur when water and
oxygen were rigorously excluded.[11]
Scheme 1. EqCr-scheme for Cp2TiX2 investigated by cyclic voltammetry (upper
part) and example of a radical arylation reaction studied to confirm the validity
of our screening method (lower part).
Figure 1. Cyclic voltammograms (CV) of 2 mM Cp2TiCl2 (left) and 2 mM
Cp2TiBr2 (right) in 0.2 M Bu4NPF6/THF at ν = 0.2 Vs-1 (black) and 2 Vs-1 (red).
The reasons why bulk electrolysis of Cp2TiX2 (X = Cl or Br) in THF
fails can be deduced from the cyclic voltammograms (Figure 1).
At a sweep rate of ν = 0.2 Vs-1 (black traces) the only detectable
oxidation wave pertains to [Cp2TiX2]-. Even at ν = 2.0 Vs-1 (red
traces) the oxidation wave originating from Cp2TiCl is barely
visible and the oxidation of Cp2TiBr is largely outrun by formation
of [Cp2TiBr2]-. Thus, in THF halide binding by Cp2TiX is favorable.
Presumably, this coordination prevents diffusion of Cp2TiX into
the solution and thwarts bulk electrolysis. Thus, a voltammogram
showing the formation of a substantial amount of Cp2TiX together
[a]
T. Liedtke, Dr. P. Spannring, L. Riccardi, Prof. Dr. A. Gansäuer
Kekulé-Institut für Organische Chemie und Biochemie
Universität Bonn
Gerhard Domagk-Straße 1, 53121 Bonn, Germany
E-mail: andreas.gansaeuer@uni-bonn.de
Supporting information (SI) is given via a link at the end of the
document.
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with [Cp2TiX2]- should indicate a possible electrolysis. Moreover,
it foretells an efficient radical arylation because the active catalyst
and its resting state are generated in the critical Cr-equilibrium.
We investigated the electron deficient thiourea L1,[12] its urea
counterpart L2, the thiourea L3, calix[4]pyrrole L4,[14] and the
pyridinium derivatives L5 – L7[15] (Figure 2, upper part) that can
all bind halides by supramolecular interactions. They should
enable reversible X- abstraction from [Cp2TiX2]- in the pivotal Cr-
equilibrium. L1 – L4 are hydrogen bond donors and highly
appealing because the efficiency of halide binding can be fine-
tuned by their acidity and the number of hydrogen bonds available
per donor. Other potentially attractive additives are pyridinium
ions L5 – L7 that activate C-Cl bonds via coulombic interactions.
Figure 3. Titration of 0.5 to 3 eq. of L1 to Cp2TiBr2 in 0.2 M Bu4NPF6/THF
monitored by CV (recorded at ν = 2 Vs-1).
The shift of the reduction peak potential of Cp2TiBr2 to more
positive potentials (indicated by the blue arrow, Figure 3) and the
shift of the oxidation peak potential of [Cp2TiBr2]- to also more
positive potentials upon the addition of the additive demonstrating
that the additive facilitates the reduction and hampers oxidation.
This indicates formation of Cp2TiBr2*L1 and [Cp2TiBr2]-*L1 and an
activation of the Ti-Br bonds in these complexes. The situation is
closely similar for Cp2TiCl2 (see SI). However, Cp2TiBr does not
seem to coordinate to L1 because even with an excess of L1 no
additional oxidation peak was detected.Thus, the screening of
additives has shown that thiourea- and urea-additives can
significantly shift the Cr-equilibrium towards Cp2TiX. In line with
our mechanistic reasoning, this suggests that bulk electrolysis of
Cp2TiX2 with L1 – L3 should be possible and that the solutions
obtained should be active catalytic systems in the radical arylation
of epoxides. The combination of Cp2TiX2 with thioureas or ureas
represents a more benign system than the conventional radical
arylation involving reducing agents like Zn or Mn, with additives
like Coll*HCl.
To our delight, bulk electrolysis of Cp2TiBr2 and Cp2TiCl2 in THF
was successful under the conditions identified by cyclic
voltammetry. It was carried out in a divided cell set-up in the
presence of 1 eq. L1, L2, or L3 under potentiostatic conditions
(glassy carbon sponge and Pt-electrodes, -1.4 V vs. Ag/Ag+, 1-
2 h, 0.2 M Bu4NPF6/THF) at ambient temperature. The typical
lime green solutions indicative of Ti(III) formation (see SI for
details) were obtained. Subsequently, the solutions were used in
the catalytic arylation by addition of epoxide S1 (Table 1).
We probed the catalytic reactions for the influence of the catalyst,
the additive, the reaction time, the temperature and the
catalyst/additive ratio. Under conditions similar to conventional
radical arylation reactions[7a,c] (10 mol% cat. and 2 h reaction time)
our electrochemically reduced Cp2TiCl2 (catalyst A) and Cp2TiBr2
(catalyst B) rendered good results, with B outperforming A (91%
Figure 2. Investigated additives. Bottom left: CVs of Cp2TiCl2/L1 1/1 and
Cp2TiBr2/L1 1/1. Bottom right: CVs of Cp2TiBr2 with L1, L2, and L3, cat/additive
1/1. CVs were recorded in 0.2 M Bu4NPF6/THF at ν = 2 Vs-1.
We started our CV screening by studying the effect of Schreiner’s
thiourea L1 on the Cr-equilibrium for Cp2TiCl2 and Cp2TiBr2. All
voltammograms show an increase of the oxidation wave
pertaining to Cp2TiX upon addition of L1. Hence, L1 has a
profound influence on the Cr-equilibria for both Cp2TiX/[Cp2TiXl2]-
(Figure 2). The effect of L1 is more pronounced for Cp2TiBr2 than
for Cp2TiCl2 (Figure 2, left voltammograms) as indicated by the
more intense Cp2TiX oxidation wave. Thus, halide abstraction
from [Cp2TiBr2]- is more favorable and Cp2TiBr2 was used in
further pre-screening experiments.
The voltammograms of Cp2TiBr2 with L1, L2 and L3 show that the
Cr-equilibrium is dependent on the properties of additives (Figure
2, right voltammograms). L1 is more efficient in bromide binding
than L2 that is about as efficient as L3. This trend qualitatively
correlates with the additives’ pKa-values in DMSO (L1: 8.5, L2:
13.8, L3: 13.4).[12c] Calix[4]pyrrole L4[13] did not show a significant
increase of Cp2TiX formation. L5, L6, and L7[14] decomposed via
reduction and loss of benzylic radical. Hence, L4 – L7 were
excluded in further investigations. Finally, we carried out a L1-
titration on the Cr-equilibrium (Figure 3). The formation of Cp2TiBr
gradually increased upon addition of 0.5 to 2 eq. of L1 after which
the effect saturated.
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10.1002/anie.201800731
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vs. 76% yield of P1, entries 1-2). For subsequent experiments, we
used catalyst B. Changing the additive to L2 and L3 led to a
slightly less active system, yet the yields of P1 were still
satisfactory with 85 and 83%, respectively (entries 3-4). This is in
line with the voltammograms of the screening process (Figure 2),
spelling out the importance of the composition of the Cr-
equilibrium.
However, in both cases B was superior to A with respect to
catalyst loading and yield. Thus, B was used in the other
examples. The yields of the reaction depend on the B/L1 ratio.
For P4 identical yields were obtained for B/L1 = 1/1 or 1/2. S5 –
S7 containing more electron deficient arenes showed significantly
higher product yields at a B/L1 ratio of 1/1.
Table 2. Catalytic radical arylation of S2 - S8 by electrochemically reduced
Cp2TiCl2 (A), Cp2TiBr2 (B) or Cp2Ti(O3SMe)2 (C) with the aid of L1 in THF.
Table 1. Catalytic radical arylation of S1 by electrochemically reduced Cp2TiCl2
(A) and Cp2TiBr2 (B) with the aid of L1, L2 or L3 in THF.
entry
catalyst
additive
L1
t [h]
2
T [˚C]
66
yield [%][a]
76
1
2
3
4
5
6
7
8
9
A [10 mol%]
B[10 mol%]
B [10 mol%]
B [10 mol%]
B [10 mol%]
B [2.5 mol%]
B [2.5 mol%]
B [2.5 mol%]
B [2.5 mol%]
L1
2
66
91
L2
2
66
85
L3
2
66
83
L1
16
40
16
16
16
25
84
L1
66
97
L1
66
96[b]
82[b]
88[b]
For these substrates, the rearomatization of the intermediate
radical σ–complex is more difficult and, therefore, catalyst
decomposition interferes with the reaction as shown earlier.[7b]
Catalyst decomposition is prevented by a higher concentration of
[Cp2TiBr2]-, the catalyst resting state. The decrease in the B/L1
ratio leads precisely to this effect (Figure 3). This further
underlines the usefulness of our screening results.
S8 is the only substrate not suitable with Cp2TiBr2 because the
rearomatization of the radical σ–complex requires more electron
deficient complexes. It turned out that electrochemically reduced
Cp2Ti(O3SMe)2 (C) is an efficient catalyst in this case. The
electrolysis required a C/L1 ratio of 1/1 and a reaction time of 16 h
yielding P8 in 78% (Table 2).To the best of our knowledge, the
recognition of mesylate by L1 was not published before, however,
the binding of sulfate anions is known which led us to the idea to
analyze the effect of L1 on Cp2Ti(O3SMe)2.[12f] Thus, Ti-X
activation for enabling bulk-electrolysis is not confined to halides.
For the other substrates C requires longer reaction times than A
and B.
As further evidence for the application potential of our novel
system, an ‘all-in’ electrolysis experiment with 5 mmol of S1,
10 mol% of catalyst B and a B/L1 ratio of 1/1 was conducted. The
similarly high yield (81%, see Experimental) as that of the small-
scale reaction with the pre-activation of the catalyst (Table 1, entry
5) demonstrating that a one-pot procedure is the first choice to
produce product P1 on larger scale. The two step procedure is
the convenient choice if a large variety of products should be
synthesized in a small scale.
L2
66
L3
66
Reaction conditions: catalyst A or B, additive L1, L2 or L3, cat/additive =
1/1, 10 mM in THF; [a] isolated yield of P1; [b] catalyst/additive = 1/2.
The radical arylation with B also proceeds successfully at ambient
temperature, yielding 84% P1. However, 16 h reaction time is
required (entry 5). We found a functioning system with a catalyst
loading as low as 2.5 mol% at reflux. An almost quantitative yield
of P1 was obtained at equimolar B/L1 ratio after 40 h (entry 6).
Such low catalyst loadings also allow for experiments with an
excess of additive. We observed an almost quantitative P1 yield
after 16 h, at a B/L1 ratio of 1/2 (entry 7). These two examples
concur with the titration experiments with L1 (Figure 3), indicating
a higher amount of active catalyst under the latter conditions.
Likewise, B/L2 and B/L3 ratios of 1/2 lead to high yields of P1
(82% and 88%, entries 8-9), albeit slightly lower than with L1.
Thus, our mechanism based screening method indeed provides
efficient conditions for the radical arylation of S1. For S1 it is
advantageous to shift the equilibrium towards Cp2TiX by
employing an excess of L1 (2 eq. with respect to the titanocene).
Since L1 proved to be slightly more efficient as additive than L2
and L3, we carried out the study of the substrate scope in the
presence of L1. We investigated the radical arylation with the
modestly electron-rich S2 – S4, the modestly electron-poor S5 –
S7 and the electron-poor S8 (Table 2). A provided lower yields of
P2 (59%) than under identical conditions for P1 (Table 1, entry 1).
P3 was obtained in 81% yield, demonstrating that
tetrahydroquinolines are readily accessible with our system.
In summary, we have shown that our mechanism-based CV-
screening is an ideal tool for discovering conditions for bulk
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10.1002/anie.201800731
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Rev. 2008, 108, 2300-2347; c) W. E. Geiger, Coord. Chem. Rev. 2013,
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electrolysis of Cp2TiX2 and sustainable catalysis with the resulting
Cp2TiX containing solutions. This was achieved by Cp2TiX
formation from [Cp2TiX2]- through X- abstraction with thioureas
and ureas as identified by cyclic voltammetry. We believe that our
time and resource efficient CV-screening approach is of
substantial interest for reaction design in catalysis in single
electron steps.
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Experimental: The bulk electrolysis cell was equipped with a
stirring bar and Bu4NPF6 (10.7 mmol), Cp2TiBr2 (0.5 mmol),
Schreiner’s thiourea L1 (0.5 mmol), epoxide S1 (5 mmol) and
THF (50 mL) were added inside a glovebox. The electrodes were
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Stirring was continued for another 14 h. The solvent was
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Acknowledgements
We thank the Deutsche Forschungsgemeinschaft (SFB 813
‘Chemistry at Spin Centers’ and Ga 619/11-1) and the
‘Evangelisches Studienwerk Villigst’ (fellowship to T. L.)
Keywords: arylation • cyclic voltammetry• epoxide• thiourea•
titanium
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COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
T. Liedtke, P. Spannring, L. Riccardi and
A. Gansäuer *
Page No. – Page No.
Mechanism-Based Condition-
Screening for Sustainable Catalysis
in Single Electron Steps by Cyclic
Voltammetry
Catalysis with a thunderbolt through screening with cyclic voltammetry! Ti-X bond
activation by thioureas enables bulk electrolysis of Cp2TiX2 and sustainable catalysis.
This key-interaction was identified by a CV-screening method that directly observes
mechanistic aspects of the electrolysis and catalysis in single electron steps.
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