Mechanistic study of the titanocene(III)-catalyzed radical arylation of epoxides

Article abstract of DOI:10.1002/chem.201404404

An atom-economical and catalytic arylation of epoxide-derived radicals is described. The key step of the catalytic system is a sequential electron and proton transfer for the rearomatization of the radical σ-complex and catalyst regeneration. Kinetic, computational, spectroscopic, and cyclo-voltammetric investigations highlight the key issues of the reaction mechanism and catalyst stabilization by collidine hydrochloride. Studies employing radicophiles rule out the participation of cations as reactive intermediates.

Full text of DOI:10.1002/chem.201404404

DOI: 10.1002/chem.201404404
Full Paper
&
Radical Chemistry
Mechanistic Study of the Titanocene(III)-Catalyzed Radical
Arylation of Epoxides
Andreas Gansꢀuer,*[a] Daniel von Laufenberg,[a] Christian Kube,[a] Tobias Dahmen,[a]
Antonius Michelmann,[a] Maike Behlendorf,[a] Rebecca Sure,[b] Meriam Seddiqzai,[b]
Stefan Grimme,[b] Dhandapani V. Sadasivam,[c] Godfred D. Fianu,[c] and Robert A. FlowersII*[c]
Abstract: An atom-economical and catalytic arylation of ep-
oxide-derived radicals is described. The key step of the cata-
lytic system is a sequential electron and proton transfer for
the rearomatization of the radical s-complex and catalyst re-
generation. Kinetic, computational, spectroscopic, and cyclo-
voltammetric investigations highlight the key issues of the
reaction mechanism and catalyst stabilization by collidine
hydrochloride. Studies employing radicophiles rule out the
participation of cations as reactive intermediates.
Introduction
sis of tetrahydrofurans from suitably unsaturated epoxides is
another example in this field.[8]
The design of atom-economical catalytic reactions is central to
the development of sustainable reactions for use in chemical
manufacturing.[1] Free radicals are highly attractive in this re-
spect because radical generation usually proceeds under mild
conditions, and these intermediates tolerate a wide range of
functional groups and add to unsaturated functional groups in
a highly selective and predictable manner.[2,3]
The realization that single-electron oxidative additions and
reductive eliminations are key steps of these processes pro-
vides fascinating possibilities for incorporating radical chemis-
try in atom-economical catalytic radical reactions that are relat-
ed to classical organometallic catalysis.[9]
In this respect, an especially appealing target is the combi-
nation of radical additions to arenes with sequential electron-
transfer and proton-transfer processes for rearomatization
(Scheme 1). In arylations of free radicals, radical s-complexes
have been oxidized by FeIII salts (Minisci reactions)[10] or di-
lauroyl peroxide (Zard’s arene functionalizations from xan-
thates).[11]
Only a small number of atom-economical catalytic CÀC
bond-forming radical reactions have been devised. Examples
include Ru-catalyzed atom-transfer radical-addition reactions,[4]
Cu-catalyzed atom-transfer radical polymerizations,[5] and H2-
mediated metal-catalyzed radical cyclizations.[6] The fine tuning
of the catalysts’ redox properties enables the realization of
either polymerization reactions or efficient radical-addition pro-
cesses with high selectivity. The titanocene-catalyzed[7] synthe-
[a] Prof. Dr. A. Gansꢀuer, Dr. D. von Laufenberg, Dr. C. Kube, T. Dahmen,
A. Michelmann, Dr. M. Behlendorf
Kekulꢁ-Institut fꢂr Organische Chemie und Biochemie
Universitꢀt Bonn
Gerhard Domagk Strasse 1, 53121 Bonn (Germany)
E-mail: andreas.gansaeuer@uni-bonn.de
Scheme 1. General approach for the homolytic aromatic substitution.
[b] R. Sure, M. Seddiqzai, Prof. Dr. S. Grimme
Mulliken Center for Theoretical Chemistry
Institut fꢂr Physikalische Chemie und Theoretische Chemie
Universitꢀt Bonn
From a catalytic perspective, the main challenge is the use
of a reagent capable of both substrate reduction for radical
generation from a low-valent oxidation state and oxidation of
the intermediate radical s-complex in its higher-valent oxida-
tion state.
Beringstrasse 4, 53115 Bonn (Germany)
[c] Dr. D. V. Sadasivam, G. D. Fianu, Prof. Dr. R. A. FlowersII
Department of Chemistry, Lehigh University
Bethlehem, PA 18015 (USA)
Recently, we obtained data suggesting that an electron
transfer can be incorporated as a key step in the catalytic
atom-economical radical arylation (Scheme 2).[12] No stoichio-
metric amounts of an oxidant or an acid[13] were necessary. Cat-
alysis was achieved by combining radical generation from ep-
oxides with radical addition to anilines and oxidation of the re-
E-mail: rof2@lehigh.edu
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201404404. Further details of the cyclic vol-
tammetry studies, synthetic procedures, compound characterization, and
geometry optimized structures for all calculated radicals are available in
the Supporting Information.
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Results and Discussion
Rate studies were initiated to determine the kinetic order of
catalyst and substrate using the reaction shown in Table 1. Be-
cause deactivation occurred in the absence of Coll*HCl (4),[12]
studies were focused on the reaction in the presence of 4.
Rates were measured by following the decay of 1 or growth of
2. Rate orders for the reaction components were determined
using the initial-rates method. Rate studies with varying con-
centrations of 1 and 3 indicated that the rate is approximately
first order in both (see the Supporting Information).
Examination of the proposed catalytic cycle in Scheme 2
shows that there are several possible turnover-limiting steps:
initial ring opening of the epoxide, radical addition to the
arene (conversion of A to B, Scheme 2), and the regeneration
of the catalyst (conversion of B to product via C, Scheme 2). To
understand the likely turnover-limiting step, experiments were
designed to determine (or estimate) the rate of each step.
Scheme 2. Titanocene-catalyzed arylation of epoxide-derived radicals.[12]
sulting radical s-complex by TiIV to the corresponding cation.
This pivotal step is enabled by the unique properties of the ti-
tanocene (III)/(IV) redox couple.[9,14] Another key feature of the
catalytic cycle is the importance of collidine hydrochloride,
Coll*HCl (Table 1). Coll*HCl stabilized the titanocene catalyst
through the formation of a supramolecular complex.[12,15] In
this manner, catalyst deactivation was prevented by providing
access to the [Cp2TiCl2]À resting state of the catalyst.
Rate of epoxide opening by titanocene(III) complexes as
a function of ligand substitution and reagent composition
To identify the turnover-limiting step of the radical arylation, it
is essential to know the rate constant of epoxide opening by
titanocene (III) reagents. Moreover, it is important to identify
the factors affecting the rate constant, such as ligand substitu-
tion and reagent composition. The experimental results sum-
marized in Table 1 demonstrate that catalyst performance in
the radical arylation is dependent on the addition of Coll*HCl.
To highlight the differences between these reaction conditions,
the metal-reduced titanocenes with and without added
Coll*HCl will be discussed separately.
Table 1. Atom-economical catalytic aromatic substitution via radicals
(Coll*HCl=2,4,6-Me3Py*HCl).
Rate of epoxide opening and reagent composition in the ab-
sence of Coll*HCl: Previous work on Zn- and Mn-reduced alkyl
substituted titanocene(III) complexes [Zn- or Mn–(C5H4R)2TiCl2
hereafter] has shown that they exist as a monomer–dimer
equilibrium in which the composition is dependent on the
steric bulk of the substituents. With the aid of cyclic voltamme-
try (CV), it was possible to determine the redox potentials of
the titanocene(III) species generated during the CV experiment.
For Mn–Cp2TiCl2 these results are summarized in Scheme 3.
In this study, we are also interested in the dependence of
these values on ring substitution. To this end, we studied the
complexes [(C5H4CH3)2TiCl2] (5) and [(C5H4Cl)2TiCl2] (6) as two
simple ring-substituted titanocenes. Their potentials were ob-
tained by digital simulation from the corresponding CVs and
are summarized in Table 2.
3
4
Time
1:2
Yield
[%]
[mol%]
[mol%]
10
5
5
1[b]
–
–
10
5
30 min
30 min
30 min
2 h
0:100
98[a]
–
–
96[c]
25:75[a]
0:100[a]
0:100
[a] 0.1m. [b] 10 mol% Mn. [c] 0.5m. All concentrations refer to 1.
Herein, we present kinetic, computational, voltammetric,
and radical probe studies designed to clarify key aspects of
our reaction. These include the following questions: What are
the rate orders of the reaction components? What is the turn-
over-limiting step? How does the addition of Coll*HCl affect
the reagent composition and rate of epoxide opening? Can
cationic intermediates in the addition to the arene be ruled
out? Can this information be used to rationalize the effects of
ligand substitution? The results of these studies provide
a mechanism-based platform for catalytic processes with
arenes that are typically recalcitrant to homolytic substitutions.
Scheme 3. Redox potentials of the titanocene (III) species generated during
the CV of Mn–Cp2TiCl2.[16]
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Table 2. DigiSim Data[17] for the oxidation of Mn-5[18] and Mn-6.
Table 4. Rate constants for the opening of 7 by Mn-3, Mn-5, and Mn-6.
[Ti]
E0
E0
E0
E0
4
[V][a]
[Ti]
kdimer
[MÀ1 sÀ1
kmonomer
[MÀ1 sÀ1
]
1
2
3
[V][a]
[V][a]
[V][a]
]
5
6
À1.35
À1.12
À0.92
À0.49
À0.83
À0.37
À0.35
À0.23
3
5
6
0.8Æ0.1
1.8Æ0.3
0.5Æ0.1
0.3Æ0.1
0.6Æ0.1
0.13Æ0.04
[a] Potentials are measured in V vs. Fc+/Fc and can be converted to SCE
by adding 0.52 V.
Rate of epoxide opening and reagent composition in the
presence of Coll*HCl (4): The addition of 4 to Mn–(C5H4R)2TiCl2
prevents catalyst decomposition during radical arylation by for-
mation of a supramolecular adduct of [Cp2TiCl2]À and the am-
monium ion.[12,15] However, it is unclear how adduct formation
affects the monomer–dimer equilibrium. The presence of a rest-
ing state for the catalyst might even result in the reduction of
the rate of epoxide opening.
Only the monomers [(C5H4R)2TiCl] and dimers [(C5H4R)2TiCl]2
are components of Mn-3, Mn-5, and Mn-6. [(C5H4R)2Ti]+ is only
generated in the diffusion layer during sweeping. The respec-
tive equilibrium constants and monomer/dimer ratios (in solu-
tion (2 mm) in THF) were obtained by digital simulation and
are summarized in Table 3. Thus, in the absence of 4, Mn–
(C5H4R)2TiCl2 exists as a mixture of monomers and dimers.
The composition of the Mn-reduced titanocene solutions in
the presence of 4 was investigated by CV as outlined above
and is summarized in Table 5. Only the peaks corresponding to
[(C5H4R)2TiCl2]À and [(C5H4R)2TiCl] could be identified. The po-
tentials deviate only slightly from those obtained in the ab-
sence of chloride. This can be ascribed to medium effects
caused by the added hydrochloride salts. Within the limits of
accuracy of the method, neither the dimer [(C5H4R)2TiCl]2 nor
[(C5H4R)2TiCl]+ were detected.
Table 3. Monomer/dimer ratio in Mn-3,[18] Mn-5,[18] and Mn-6 solutions
(2 mm) in THF.
[Ti]
Dimer/monomer
K [MÀ1
]
5
3
6
0.8
1.5
0.4
1000
3000
375
Table 5. DigiSim Data[17] for the oxidation of Mn-3, Mn-5, and Mn-6 in
the presence of 4.
The opening of 7 under the conditions shown in Scheme 4
for the stoichiometric reaction was studied with Mn-3, Mn-5,
and Mn-6. Under pseudo-first-order conditions, with the sub-
strate in excess, the reaction rates were determined by moni-
toring the loss of the TiIII absorbance band at 800 nm, as de-
scribed by Daasbjerg and co-workers (see the Supporting In-
formation).[18]
[Ti]
E0
E0
E0
E0
4
[V][a]
1
2
3
[V][a]
[V][a]
[V][a]
3
5
6
À1.23
À1.31
À1.08
–
–
–
À0.77
À0.95
À0.58
–
–
–
[a] Potentials are measured in V vs. Fc+/Fc and can be converted to SCE
The data for these experiments are contained in Table 4. All
decays fit well to a double exponential (see the Supporting In-
formation). This finding is consistent with previous work show-
by adding 0.52 V.
The presence of Coll*HCl has a profound influence on the
monomer–dimer equilibria. For Mn-3, Mn-5, and Mn-6, the sim-
ulations indicate that within the limits of accuracy of the
method, the monomer is largely preferred over formation of
the dimer (dimer:monomer<13:87, K<100, Table 6). There-
fore, the monomer is the predominant species in solution.
Next, the kinetic analyses of the reactions of 7 with Mn-3,
Mn-5, and Mn-6 were carried out as shown in Scheme 4 in the
presence of 4 (2 equiv, Table 7). The rate data fit well to
Scheme 4. Conditions of the kinetic study of the opening of 7 by Mn-3, Mn-
5, and Mn-6 (CHD=1,4-cyclohexadiene).
ing that epoxide opening is mediated by two titanium species,
that is, the monomer and the open dimer.[18] In addition, the
rate constants for the reactions of Mn-3 and Mn-5 match those
of the previous study employing Zn-3 and Zn-5, within experi-
mental error. This clearly shows that the metal (Zn or Mn) used
to generate the TiIII species has no influence on epoxide open-
ing. As a corollary, this finding suggests that neither Zn2+ nor
Mn2+ ions are contained in the species mediating ring open-
ing.
Table 6. Monomer/dimer-ratio in Mn-3, Mn-5, and Mn-6 solutions (2 mm)
in THF in the presence of Coll*HCl.
[Ti]
Dimer/monomer
K [MÀ1
]
3
5
6
<0.15
<0.15
<0.15
<100
<100
<100
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Table 7. Rate constants (kmonomer) for the opening of 7 by Mn-3, Mn-5,
and Mn-6 in the presence of Coll*HCl (2 equiv) and observed rate con-
stants (kobs) for the reaction of 1 with Mn-3, Mn-5, and Mn-6.
[Ti]
kmonomer [MÀ1 sÀ1
]
kobs [minÀ1
]
3
5
6
0.6Æ0.1
1.1Æ0.2
0.4Æ0.1
0.57Æ0.02
0.26Æ0.01
0.85Æ0.13
a single exponential (see the Supporting Information). This in-
dicates that epoxide opening is mediated by a single species.
We suggest that this is the monomeric complex, a supposition
supported by the CV results on the composition of Mn-3, Mn-
5, and Mn-6 in the presence of Coll*HCl. The rate constant of
epoxide opening by the monomers is slightly higher (by
a factor of 2 to 3) in the presence of Coll*HCl. The rate con-
stants were obtained from total [TiIII] but because they were
determined in the presence of 4, kmonomer contains an equilibri-
um term for the complex of the titanocenes with Coll*HCl.
Because the equilibrium constants derived from CV experi-
ments are consistent with a larger portion of the monomer
formed in the presence of 4, its proportion of [TiIII] and hence
the rate constant of ring opening is higher. Under both sets of
conditions, the best reductant but weakest Lewis acid, Mn-5,
opens 7 faster than the other complexes. Mn-6, the weakest
reductant but strongest Lewis acid, is the slowest complex in
the opening of 7. Therefore, the reducing power is more rele-
vant than Lewis acidity for an efficient epoxide opening. The
different species involved in epoxide opening with and with-
out 4 are summarized in Scheme 5.
Scheme 5. Species involved in the opening of 7.
At room temperature, only the acrylate-addition product
could be detected and isolated. The intramolecular-arylation
product is favored in refluxing THF (2:9=60:40). It should be
noted that the addition to the electron-deficient acrylate is
only possible for radicals and not for cations. The experiments
in the presence of CHD also confirm the presence of radicals
because 10 can only be formed through hydrogen-atom ab-
straction by radical intermediates (intermediate A, Scheme 2).
The competition reactions of 11 with tert-butyl acrylate and
CHD are summarized in Scheme 7. Again, the use of overstoi-
chiometric amounts of Mn and 4 is of no consequence for the
outcome of the arylation. Compared to the reactions of 1, the
calculations[20] suggest that the radical arylation should be less
competitive for 11 due to the methyl substituent on N.
This is indeed the case for radical reduction and for acrylate
addition at reflux in THF. Our recently described epoxide re-
duction (via intramolecular HAT from a TiÀH bond), which does
not require the presence of Mn or 4, is much faster than aryla-
tion (Scheme 7, last example).[23]
Rate of radical addition to the arene
There have been a limited number of studies to determine the
absolute rate constants of radical additions to arenes. These
were mostly carried out in studies of the Minisci reaction.[19]
The butyl radical adds to benzene with a rate constant of
about 4ꢂ102 mÀ1 sÀ1 at 798C. The addition to substituted ani-
lines was only studied computationally for relatively simple
model systems.[20] The rate constants (4ꢂ102 to 4ꢂ103 sÀ1) are
lower than those of the 5-exo cyclization[21] but are still in the
range of useful processes.
To exclude the presence of cationic intermediates in our re-
action and to experimentally estimate the rate of radical addi-
tion to anilines, we reacted 1 and 11 in the presence of either
1,4-cyclohexadiene or tert-butyl acrylate.[22] Both reagents have
been employed as radical traps in titanocene catalyzed epox-
ide openings.[14a,b] These reactions require overstoichiometric
amounts of Mn and Coll*HCl for complete conversion. There-
fore, 1 and 11 were subjected to the same conditions, without
the radical traps, to ensure comparability of the reactions. The
results are summarized in Schemes 6 and 7.
Finally, the competition between the 5-exo cyclization and
addition to the arene was investigated with 15. As highlighted
in Scheme 8, only 16 (47%), the product of the 5-exo cycliza-
tion, and 17 (28%) could be isolated.
The tetrahydrofuran moiety of 17 is formed by a homolytic
substitution at a TiÀO bond.[8] Because no product of the radi-
Without 1,4-cyclohexadiene (CHD) or acrylate, only 2 is
formed in essentially quantitative yield. Thus, overstoichiomet-
ric amounts of Mn or Coll*HCl lead to essentially identical re-
sults as those obtained under our optimized conditions.[12]
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Scheme 6. Competition experiments involving 1 and radical addition to the
arene or radical trapping.
cal arylation was detected, the 5-exo cyclization[7a,d,21,22b,24] is
much faster than radical addition to the arene.
In summary, the competition experiments show that, al-
though radical addition to anilines is substantially slower than
5-exo cyclizations or radical additions to acrylates (for the addi-
tion of the tert-butyl radical to methyl acrylate, k=1.1ꢂ
106 mÀ1 sÀ1 at room temperature),[25] the addition can compete
with the hydrogen-atom abstraction of tertiary radicals from
CHD (kꢀ104 mÀ1 sÀ1 at 290 K for the reaction between CHD
and the tert-butyl radical).[26] Consistent with previous calcula-
tions, our results suggest that the intramolecular addition of
radicals to anilines has rate constants in the range of 102–
104 sÀ1 at temperatures above 408C. Since the rate constant
for epoxide opening is lower, radical addition can be ruled out
as the potential turnover-limiting step. The addition of radicals
to aniline derivatives investigated here are likely to be as fast
as titanocene-catalyzed 4-exo and 3-exo cyclizations.[27]
Scheme 7. Competition reactions with 1.
Scheme 8. Competition of radical arylation and 5-exo cyclization in THF.
Oxidation of radical s-complex and rearomatization through
deprotonation
To probe whether electron transfer is rate-limiting, additional
kinetic studies for the conversion of 1 to 2 were carried out
with catalysts 3–5 (Scheme 9). If this step is turnover-limiting,
it should be facilitated by electron-withdrawing substituents
on the cyclopentadienyl ligands. As a consequence, the stron-
gest oxidant (6) should lead to the fastest reaction, whereas 5
should lead to the slowest process.
The final steps in the proposed catalytic cycle are the back
electron transfer from the radical s-complex to TiIV (conversion
of B to C shown in Scheme 2) and the proton transfer from
the cationic s-complex to the pending alkoxide that liberates
the final product.
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homolytic cleavage was observed. This is consistent with Way-
mouth’s observations that Cp2TiIVÀO bonds derived from alkox-
ides are strong and unlikely to homolytically cleave under our
reaction conditions.
One interesting feature was the change in the intermediate
formed upon the addition of Coll*HCl to [Cp2TiCl(OEt)]. The CÀ
H wag of this compound is observed at 808 cmÀ1. Upon addi-
tion of Coll*HCl, there was an immediate shift to 820 cmÀ1.
This is consistent with the formation of [Cp2TiCl2] (see the Sup-
porting Information). This finding shows that protonation and
subsequent cleavage of the TiÀO bond is a rapid process.
Scheme 9. Conditions for the kinetic study of the reaction with Mn-3, Mn-5,
and Mn-6.
The rate constants (kobs) for the reactions of 1 with Mn-3,
Mn-5, and Mn-6 are shown in Table 7.
The results show that 6 leads to the fastest turnover, fol-
lowed by 3, with 5 leading to the slowest rate. It is important
to compare these data with the observed rate constants of ep-
oxide opening in Table 5. For epoxide opening, 6 results in the
slowest reaction and 5 in the fastest process. Moreover, epox-
ide opening is substantially faster with reactions progressing
over a range of several seconds at room temperature, whereas
the arylation takes place over the timeframe of several minutes
in refluxing THF. Overall, these data are consistent with the
back electron transfer to the metal being the turnover-limiting
step, not epoxide opening or radical addition to the arene.
Finally, to explore the possibility of proton transfer to the
alkoxide as being a potential turnover-limiting step, further ki-
netic studies were carried out with 1 containing perdeuterated
phenyl groups. If this step is turnover-limiting, a substantial ki-
netic isotope effect is expected. The kH/kD value obtained for
this reaction is 1.1Æ0.1.[28] This finding strongly suggests that
the final proton transfer leading to rearomatization is not turn-
over-limiting (see the Supporting Information).
Observation of catalyst regeneration
The oxidation of the radical s-complex and aromatization
through protonation of the TiÀO bond results in the regenera-
tion of the catalytically active titanocene(III) species. Previously,
we found that the IR band of the CÀH wag of the cyclopenta-
dienyl ligand is sensitive to the oxidation state of Ti.[12] As
a consequence, the two different oxidation states of Ti can be
distinguished experimentally. In situ monitoring of the reaction
by IR spectroscopy enabled observation of the active catalyst
TiIII at 798–800 cmÀ1, the pre-catalyst TiIV at 820–825 cmÀ1, and
growth of the product at 1385 cmÀ1. When epoxide is added
to the reaction mixture, the initial decay of [TiIII] is observed
and, as the reaction progresses, the regeneration of [TiIII] can
be followed (Figure 1). It is important to note that the regener-
ation of TiIII is concomitant with conversion of 1 to 2, but its
formation is not instantaneous.
An alternative progression of events, that is, TiÀO bond ho-
molysis in the intermediate radical s-complex and H-atom
transfer to the O-centered radical (Scheme 9), might also be
possible. Previous work by Waymouth and co-workers have
shown that titanium–oxygen bonds derived from TEMPO can
be cleaved under the reaction conditions described herein, but
more stable precursors derived from alkoxides could not.[29]
To determine whether homolytic cleavage of the TiÀO bond
was possible under our conditions, [Cp2TiIVCl(OEt)] was pre-
pared[30] and subjected to reaction conditions in the presence
and absence of Coll*HCl (Scheme 10). In situ monitoring of the
reaction by IR spectroscopy enabled us to determine whether
cleavage occurred because the CÀH wag of titanocene(III)
occurs at 798–800 cmÀ1, whereas the titanocene(IV) is found in
the range of 820–825 cmÀ1. After refluxing for up to 3 h, no
Figure 1. Conversion of 1 to 2 and regeneration of [TiIII] in THF at 608C, fol-
lowed by in situ IR monitoring. [1]=28 mm; [3]=5.7 mm; [4]=11.5 mm. The
CÀH wag of the Cp ligand in the TiIV precatalyst occurs at 821 cmÀ1 and at
798 cmÀ1 for the TiIII catalyst. The loss of peak height in [TiIII] is a conse-
quence of dilution upon addition of a solution of 1 to initiate the reaction.
Overall, the competition experiments and the in situ moni-
toring of [TiIII] are consistent with the generation of [Cp2TiCl],
which acts as a reductive electron-transfer reagent. By reduc-
tive epoxide opening, radicals are generated as key intermedi-
ates under the reaction conditions. The IR experiments also
support the proposed oxidation of radical s-complexes to the
classical cationic s-complexes by electron transfer to the pend-
ant TiIV, as evidenced by the regeneration of [TiIII].
Scheme 10. TiÀO homolysis as an unlikely alternative for rearomatization.
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Computational study of radical arylation
The overall reaction is highly exothermic at 339 K (DHoverall =
À35.7 and À34.2 kcalmolÀ1) as a consequence of the release
of the epoxide’s ring strain. Epoxide opening and radical addi-
tion together are exothermic by 13.8 and 8.5 kcalmolÀ1. From
these values, the enthalpy of the rearomatization by electron
and proton transfer, DHET,PT, can be calculated as À21.8 and
À25.7 kcalmolÀ1. The calculations on the ET step did not con-
verge for B and model systems gave largely varying results de-
pending on the functionals employed. The discrepancies are
a result of the inaccuracies in describing the electron transfer
from the highly delocalized SOMO of the radical s-complex to
the localized d-orbital of titanium, due to the so-called self-in-
teraction error in most contemporary functionals.[53] Unfortu-
nately, this implies that the intramolecular PT step also cannot
be treated computationally.
Computational methods: All DFT calculations were performed
with the TURBOMOLE 6.6 suite of programs.[31] The geometry
optimizations were carried out using the TPSS density func-
tional[32] along with the polarized triple-zeta def2-TZVP basis
set.[33] Single-point energies were obtained on the B3LYP,[34–36]
PW6B95,[37] and M06-2X[38] level, together with the extended
quadruple-zeta basis set def2-QZVP.[33] In all DFT calculations
the resolution-of-identity (RI) approximation for the Coulomb
integrals[39] with matching default auxiliary basis sets[40] was ap-
plied. For integration of the exchange correlation contribution,
the numerical quadrature grid m4 was employed for B3LYP
and PW6B95 and grid 5 for M06-2X. For all DFT calculations
the D3 dispersion-correction scheme,[41] applying the Becke–
Johnson (BJ) damping,[42–44] was used.
Nevertheless, the enthalpy of the PT step can be estimated
from the intermolecular model reaction shown in Scheme 12.
Computations of the harmonic vibrational frequencies were
performed numerically using SNF version 2.2.1[45] Thermal cor-
rections from energy to enthalpy were obtained by a coupled
rigid-rotor-harmonic-oscillator approximation for each mole-
cule in the gas phase.[46] The TPSS vibrational frequencies were
used unscaled.
The COSMO-RS continuum solvation model[47,48] was used as
implemented in COSMOtherm 2012[49] to obtain all solvation
enthalpies. Single-point calculations employing the default
BP86[50,51]/def-TZVP[52] level of theory were performed on the
optimized gas-phase geometries for each molecules. The solva-
tion contribution was then added to the gas-phase enthalpies.
Only the B3LYP and PW6B95 values are discussed in the fol-
lowing because the M06-2X SCF calculations did not converge
for A and C of Scheme 11. For all other reactions the M06-2X
values are given in the Supporting Information.
Scheme 12. Thermodynamics of the model rearomatization at 339 K in THF
on the B3LYP-D3/def2-QZVP and PW6B95-D3/def2-QZVP (in brackets) level
of theory.
Based on these results, a value of À35 to 40 kcalmolÀ1 for
DHPT of the catalytic cycle (Scheme 11) can be assumed. DHET,
shown in Scheme 11, can then be estimated to be about
+15 kcalmolÀ1. In agreement with the conclusion from the
synthetic and kinetic studies, the computational analysis is
consistent with a turnover-limiting ET step.
Mechanistic alternatives: As outlined above, the homolysis of
the TiÀO bond in B (Scheme 10) is a potential alternative to
rearomatization. To provide further evidence in addition to the
experiment, the bond dissociation energies (BDEs) of the
simple model titanocene complexes (Scheme 13) were calculat-
ed.
Scheme 11. Thermodynamics of the [Cp2TiCl]-catalyzed reaction of 1 to 2 at
339 K in THF on the B3LYP-D3/def2-QZVP and PW6B95-D3/def2-QZVP (in
brackets) level of theory.
Thermodynamics of radical arylation: To obtain the overall
enthalpy of the radical arylation, and of each step, we compu-
tationally investigated the [Cp2TiCl]-catalyzed reaction of 1 to 2
at 339 K in THF (Scheme 11).
Scheme 13. Investigation of the BDE of TiÀO bonds at 339 K in THF on the
B3LYP-D3/def2-QZVP and PW6B95-D3/def2-QZVP (in brackets) level of
theory.
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The results amply demonstrate that the TiÀO bond in titano-
cene(IV) alkoxides is too strong for a homolytic cleavage at
608C in agreement with the kinetic study. Therefore, the mech-
anism for rearomatization depicted in Scheme 10 seems rather
unlikely. In addition, the low BDE for the TEMPO derivative is in
agreement with a previous study and highlights the quality of
our calculations.[29]
Table 8. Optimization of the reaction of 18.
[Ti]
[mol%]
4
Conv.
[%]
19:20
19
[%]
[mol%]
5, 3
5, 3
5, 3
10, 6
10
20
50
20
44
53
62
95
48:52
75:25
77:23
>95:<5
14
30
39
70
Finally, a direct aryl titanation from radical B may also
appear to be a mechanistic possibility. To this end the reac-
tions of [Cp2TiCl(OEt)] with benzene and dimethyl aniline were
investigated computationally as a model (Scheme 14). The cal-
culations indicate that the aryl titanation is an unfavorable pro-
cess. Certainly, it should not be able to compete with an intra-
molecular radical addition.
quantitative and highly selective formation of 19. We attribute
this clean reaction to the efficient oxidation of the intermedi-
ate radical s-complex. The isolated yield of 19 is satisfactory.
We also investigated the more easily-cleaved benzyl carba-
mates as an N-protecting group (Scheme 16).[54] Isolated yields
of the protected indolines were high, except for 22d, which
decomposes somewhat during SiO2 purification.
Scheme 14. Thermodynamics of aryl titanations at 339 K in THF on the
B3LYP-D3/def2-QZVP and PW6B95-D3/def2-QZVP (in brackets) level of
theory.
Scheme 16. Preparation of Z-protected indolines.
Synthetic work
Carbamate-substituted anilines are especially interesting sub-
strates for our reaction because the free indolines can be ob-
tained after deprotection. However, the oxidation of the radical
s-complex should be more difficult than for 1 because of the
electron-withdrawing nature of the carbamate group. As
shown in Scheme 15, for model epoxide 18, the reaction is crit-
To obtain the free amines, the carbamate group was re-
moved by catalytic hydrogenation (Scheme 17).
Indolines 23a–c were obtained in reasonable yields over
two steps. As shown above, the lower yield of 23d is a conse-
quence of its increased instability during SiO2 chromatography.
Scheme 15. Reaction of 18 in the absence of 4.
Scheme 17. Radical arylation and hydrogenative removal of the Z-protecting
group.
ical, and not only because of the slow oxidation. In the ab-
sence of 4, the desired product 19 was only obtained in a dis-
appointingly low yield of 18%, because 18 readily decomposes
to give 20. This was also confirmed independently by reacting
18 with ZnCl2. The experiments to improve the performance of
the reaction are summarized in Table 8.
Conclusion
Overall, the mechanistic studies presented above in concert
with previous work enables clarification of several key steps as
shown in the catalytic cycle (Scheme 18).
These results highlight that Mn-3 is not a suitable system for
clean transformation of 18 to 19. The addition of 4 improves
conversion of 18, but the formation of 20 is not efficiently sup-
pressed. Gratifyingly, the use of Mn-6 results in an almost
Reduction of [Cp2TiCl2] leads to the formation of a mono-
mer–dimer equilibrium of [Cp2TiCl]. The presence of Coll*HCl
disrupts the monomer–dimer equilibrium through the forma-
tion of an equilibrium mixture of monomeric titanocene and
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Scheme 18. Mechanism of the Titanocene-catalyzed arylation of epoxide-de-
rived radicals in the presence of Coll*HCl.
a complex between Coll*HCl and the titanocene, which we
propose to be the resting state. After radical generation, the
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B to the pendant TiIV is the turnover-limiting step that leads to
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Acknowledgements
We gratefully acknowledge generous support by the SFB 813
Chemistry at Spin Centers. T.D. was supported by the Jꢃrgen
Manchot Stiftung and Studienstiftung des Deutschen Volkes,
and A.M. by the Hans-Bçckler-Stiftung. R.A.F. thanks the US Na-
tional Science Foundation (CHE-1123815) for support of the
work at Lehigh University.
Keywords: arylation · cyclic voltammetry · DFT · epoxides ·
radicals · titanium
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Received: July 14, 2014
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ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Full Paper
FULL PAPER
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Radical Chemistry
A. Gansꢀuer,* D. von Laufenberg, C. Kube,
T. Dahmen, A. Michelmann,
M. Behlendorf, R. Sure, M. Seddiqzai,
S. Grimme, D. V. Sadasivam, G. D. Fianu,
R. A. FlowersII*
&& – &&
Catalytic arylations the radical way:
The mechanistic intricacies of an atom-
economical and catalytic method for
radical arylation have been unraveled.
The key step of the catalytic cycle is an
electron transfer from a radical to the ti-
tanocene catalyst.
Mechanistic Study of the
Titanocene(III)-Catalyzed Radical
Arylation of Epoxides
Chem. Eur. J. 2014, 20, 1 – 11
www.chemeurj.org
11
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ