Mechanism of the TiIII-Catalyzed Acyloin-Type Umpolung: A Catalyst-Controlled Radical Reaction

Article abstract of DOI:10.1021/jacs.5b09223

The titanium(III)-catalyzed cross-coupling between ketones and nitriles provides an efficient stereoselective synthesis of α-hydroxyketones. A detailed mechanistic investigation of this reaction is presented, which involves a combination of several methods such as EPR, ESI-MS, X-ray, in situ IR kinetics, and DFT calculations. Our findings reveal that C-C bond formation is turnover-limiting and occurs by a catalyst-controlled radical combination involving two titanium(III) species. The resting state is identified as a cationic titanocene-nitrile complex and the beneficial effect of added Et₃N·HCl on yield and enantioselectivity is elucidated: chloride coordination initiates the radical coupling. The results are fundamental for the understanding of titanium(III)-catalysis and of relevance for other metal-catalyzed radical reactions. Our conclusions might apply to a number of reductive coupling reactions for which conventional mechanisms were proposed before.

Full text of DOI:10.1021/jacs.5b09223

Article
pubs.acs.org/JACS
Mechanism of the TiIII-Catalyzed Acyloin-Type Umpolung: A Catalyst-
Controlled Radical Reaction
Jan Streuff,*,† Markus Feurer,† Georg Frey,† Alberto Steffani,† Sylwia Kacprzak,‡ Jens Weweler,†
Leonardus H. Leijendekker,† Daniel Kratzert,§ and Dietmar A. Plattner†
‡
§
†Institut fur Organische Chemie, Institut fur Physikalische Chemie, and Institut fur Anorganische und Analytische Chemie,
̈
̈
̈
Albert-Ludwigs-Universitat Freiburg, Albertstr. 21, 79104 Freiburg, Germany
̈
S
* Supporting Information
ABSTRACT: The titanium(III)-catalyzed cross-coupling be-
tween ketones and nitriles provides an efficient stereoselective
synthesis of α-hydroxyketones. A detailed mechanistic
investigation of this reaction is presented, which involves a
combination of several methods such as EPR, ESI-MS, X-ray,
in situ IR kinetics, and DFT calculations. Our findings reveal
that C−C bond formation is turnover-limiting and occurs by a
catalyst-controlled radical combination involving two titanium-
(III) species. The resting state is identified as a cationic
titanocene-nitrile complex and the beneficial effect of added
Et3N·HCl on yield and enantioselectivity is elucidated:
chloride coordination initiates the radical coupling. The results are fundamental for the understanding of titanium(III)-catalysis
and of relevance for other metal-catalyzed radical reactions. Our conclusions might apply to a number of reductive coupling
reactions for which conventional mechanisms were proposed before.
INTRODUCTION
■
The development of catalytic C−C bond forming reactions is
one of the central topics of synthetic organic chemistry.1 Over
the past years, reductive cross-coupling reactions have gained
increasing attention since they enable new connections under
often mild reaction conditions starting from readily available
substrates.2 Among them are so-called reductive umpolung
reactions that forge molecules with functionalization in even
bond distances from two similarly polarized carbon frag-
ments.3−5 Recently, transition metal catalyzed protocols have
evolved that allow the control of the chemo- and stereo-
selectivity in such transformations.5 In particular, titanium(III)
catalysis is superior for achieving high selectivity in pinacol
couplings and related reactions.6−8 Importantly, these titanium-
(III) catalyzes are radical reactions that proceed under full
catalyst control of stereo- regio- and chemoselectivity, which is
a striking advantage over classical free radical reactions.
However, the usually heterogeneous reaction mixtures and
the presence of open-shell systems make them notoriously
difficult to examine. In particular, the mechanism of the
titanium(III)-catalyzed pinacol coupling has been subject of a
longstanding debate.9
unusual and deserved further investigation. Afterward, a more
general cross-coupling with substituted titanocene 2 as catalyst
was established, which enabled the modular synthesis of linear
α-hydroxyketones from readily available precursors such as
acetophenone (PhCOMe) and benzyl cyanide (BnCN)
(eq 2).10c To understand the features of this titanium(III)-
catalyzed acyloin-type coupling, a mechanistic investigation was
envisioned, but the previously faced difficulties had to be
overcome. To this end, we applied a combined approach of
EPR, online ESI-MS, in situ IR, and DFT investigations as well
as stoichiometric experiments that allowed the examination of
such difficult cases in unprecedented mechanistic detail. The
We recently advanced the concept of catalytic reductive
umpolung toward cross-coupling reactions, for which only few
examples existed in the literature.6,10,11 An asymmetric
reductive radical cyclization of ketonitriles was developed that
led to enantioenriched α-hydroxyketones in the presence of
chiral ansa-titanocene 1 (eq 1).10e,12 The addition of Et3N·HCl
had a remarkable influence on the enantioselectivity, which was
Received: August 31, 2015
© XXXX American Chemical Society
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results gave valuable insight into the nature of titanium(III)-
catalyzed C−C forming processes and could become relevant
for radical reactions catalyzed by other metals as well.
In the past, several scenarios were proposed for titanium(III)-
mediated or -catalyzed reductive umpolung reactions involving
carbonyls.5,6 Hence, one of the key goals of this study was the
elucidation of the nature of the central C−C bond forming
event using the title reaction as example. The C−C coupling
reaction shown in eq 2 could for example take place at a single
titanium(III) center coordinating (a) only to the ketone12,13 or
(b) coordinating ketone and nitrile, which would lead to the
formation of either a neutral- or a cationic nitrogen-centered
radical, respectively (Scheme 1).
wave EPR spectra of three samples were recorded in both
frozen (110 K) and liquid states (220 K): (a) a solution of Zn-
reduced 2 and acetophenone in THF, (b) a solution of Zn-
reduced 2 and benzyl cyanide in THF, and (c) the reaction
mixture as shown in eq 2. For all the mixtures and at both
temperatures, intense signals originating from titanium(III)
species were observed. The isotropic hyperfine features from
the coupling to 47Ti and 49Ti isotopes with I = 5/2 and I = 7/2,
respectively, were well resolved in the spectra measured for
liquid-state samples. Since most spectra revealed signals from
multiple titanium(III) components, the tentative assignment of
the signals was based on DFT-calculated EPR parameters.22
Sample (a) recorded at 220 K showed the presence of two
titanium(III)-species and the main features of the isotropic
signals were satisfactorily reproduced considering two compo-
nents with giso of 1.981 and 1.979 (see Figure S1, Supporting
Information).22 In contrast, the signal of a frozen solution of
sample (a) was dominated only by a single titanium(III) species
with the g-tensor principal values gx = 1.958, gy = 1.982, and gz
= 2.003 resulting in giso = 1.981 (Figure 1). Based on the
Scheme 1. Selected Possible C−C Forming Pathways
Alternatively, a second titanium(III) species could coordinate
to the nitrile, leading to a bimolecular pathway (c) via a radical
combination, avoiding the formation of high-energy N-radical
intermediates.10c,14 A Ti−N and Ti−O cleavage followed by
imine hydrolysis during workup would then form the
hydroxyketone product.
Before the discussion of the results of this study, it is
important to note that the composition of the titanium(III)
species in solution is strongly influenced by the reaction
conditions: coordinating molecules such as acetonitrile or water
solvate the chloride ligands leading to cationic titanium
species.15−17 Reduction of Cp2TiCl2 with zinc dust in THF,
on the other hand, leads to a mixture of a monomeric
[Cp2TiCl] and its chloride bridged dimer [(Cp2TiCl)2]
without the formation of cationic [Cp2Ti]+ or Zn-bridged
dimers.18 The dimerization, however, is drastically reduced with
bulkier titanocenes.18a Hydrochloride additives such as coll·HCl
(coll = 2,4,6-collidine) or Et3N·HCl lead instead to the
formation of a coordination complex of [Cp2TiCl] and the
hydrochloride.8l,19 Due to this complexity, one of the major
challenges was to elucidate the actual nature of the
intermediates of the acyloin-type cross-coupling. Thus, the
following fundamental questions were raised: (1) Is the
reaction a titanium(III)-catalyzed process? (2) Are cationic
intermediates involved? (3) Which is the rate-determining step?
(4) What is the nature of the C−C bond forming event, and are
two titanium(III)-species involved? (5) What are the roles of
the additives, especially the hydrochloride?
Figure 1. Continuous-wave EPR spectrum of Zn-reduced 2 in THF
with added PhCOMe (sample (a)) at X-band (9.404 GHz) at 110 K
(solid line). Simulated spectrum (dashed line). Experimental
conditions: microwave power, 1.99 mW; magnetic-field modulation
amplitude, 0.1 mT (100 kHz modulation frequency); time constant,
40.96 ms.
comparison of the parameters from the fit with literature data
and the computed g-tensor principal values, this signal was
assigned to [(EtCp)2TiCl] (3).22 However, a cationic TiIII-
acetophenone complex [(EtCp)2Ti(PhCOMe)]+ (4) could
also be a possible choice: considering the typical computational
errors observed in previous calculations of EPR parameters,8h
giso = 1.980 as calculated for 4 (with gx = 1.950 gy = 1.991, gz=
2.001) did not deviate strongly from the values obtained from
the fit to the experimental data. The second species, with giso
=
1.979 that was formed only at 220 K could not be assigned by
comparison with calculated values for neutral or cationic
titanium(III) complexes that could potentially be present under
these conditions.22 We propose that the titanium(III) complex
which we observed at 110 K (giso = 1.981) decomposed to this
second species (giso = 1.979) during the time required for
thawing and thermal equilibration of the sample. Importantly, a
sample (a) prepared in the presence of an excess of Zn or Mn
still showed the characteristic titanium(III) signal with
unchanged intensity, which spoke against a further reduction
to titanium(II) in the presence of a large excess of the
reductant. Therefore, a potential Ti(II)-pathway was ruled out
for this coupling.9a
EPR SPECTROSCOPY
■
The investigation was started with EPR spectroscopy with the
goal to confirm the presence of titanium(III) in the catalysis
shown in eq 2. EPR is the method of choice to detect and
investigate paramagnetic metal centers. Previously, bis-
(cyclopentadienyl)-titanium(III) species such as [Cp2TiCl]
and [Cp2Ti(THF)]+ had been investigated by EPR spectros-
copy, which facilitated the analysis.8h,17,20,21 Hence, continuous-
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Figure 2. Continuous-wave EPR-spectra of Zn-reduced 2 in THF with
added BnCN (sample (b)), and the reaction mixture of the catalytic
reaction (sample (c)) at X-band (9.404 GHz) at 220 K (solid lines).
Simulated spectra (dashed lines). Experimental conditions: microwave
power, 1.99 mW; magnetic-field modulation amplitude, 0.1 mT (100
kHz modulation frequency); time constant, 40.96 ms.
The isotropic signal of sample (b) comprised three
titanium(III)-components of nearly equal intensities with giso
= 1.979 (identical to the unknown species observed for liquid-
state sample (a)), giso = 1.984 (which could not be assigned),
and giso = 1.990 (Figure 2). The last matched perfectly the giso
value calculated for the cationic bis-acetonitrile complex
[(EtCp)2Ti(BnCN)2]+ (5).22 The relative intensities of the
components changed between the spectra of liquid and frozen
samples, indicating that a reaction set in upon thawing of the
sample (see Figure S2, Supporting Information). The isotropic
spectrum of sample (c) also comprised three signals (Figure 2)
with nearly the same giso values as those found for sample (b)
but with very different relative intensities. The most intense
signal was centered at giso = 1.990. However, a reliable fit of the
data was hampered by the presence of multiple Ti(III)-
components in both samples (b) and (c).
Figure 3. In situ ESI-MS spectra showing cationic intermediates.
Table 1. Assignment of MS Peaks
Overall, the above-discussed data confirmed the presence of
titanium(III) under our reaction conditions and indicated the
formation of a cationic bis-benzylcyanide complex. The
complexity of the mixtures, prevented further assignments.
ESI-MS INVESTIGATIONS
■
With the goal to further reveal the nature of the titanium(III)
intermediates present under catalytic conditions, we then
performed a series of electrospray MS (ESI-MS) experiments of
the reaction mixtures in an online fashion. The actual reaction
mixtures were directly transferred from a sealed flask to the
electrospray source using a PEEK capillary.22,23 In this way,
cationic species present in the solution could be detected and
characterized. For the studies at hand, we employed the 4-
methyl substituted acetophenone (p-TolCOMe) and benzyl
cyanide to circumvent the overlap of certain mass peaks. An
overall concentration of 0.1 M was applied and the catalyst
loading was increased to 50 mol %. These “dilute conditions”
facilitated the detection of cationic species, in particular
substrate-titanocenium complexes, and led to stable, reprodu-
cible spectra.22
The spectrum of the catalytic reaction mixture (Figure 3a)
showed the presence of several titanocenium intermediates m/z
306.0, 351.0, 368.0, 423.1, 468.1, and 485.1 that were
structurally assigned and characterized by collision-induced
dissociation (CID) (Table 1).24 Since fragmentation of these
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complexes could be induced at relatively low collision energies
(with an onset of ca. 5 eV lab frame) it is safe to assume the
ligands were bound coordinatively to the titanium center as
shown for the dinitrile complex 5 and the mixed complex 13
(Scheme 2). In all cases, [(EtCp)2Ti]+ (14) remained as the
others and ourselves.23 Performing the coupling with an N-
methylpyrrolidinium tagged acetophenone, it was first ensured
in an independent experiment that the desired hydroxyketone
−
was formed. It turned out to be crucial to use the PF6
counterion in order to increase the substrate solubility and to
prevent catalyst inhibition by a high local halide concen-
tration.22 Despite extensive experimentation and various
modifications of the charge-tag, none of the species 17−19
shown in Figure 4 could be detected. Only the benzyl cyanide
and THF complexes 5, 8, 10, 12, the charge-tagged substrate
itself, and the charged imine were detected in the online ESI-
MS experiments.22
Scheme 2. CID Characterization of Selected Intermediates
m/z 468, 485, and 486
These findings led us to the conclusion that cationic
substrate-titanium(III) complexes were indeed present in
solution and represented resting states of the catalyst.
Furthermore, the formation of product chelate 15 occurred
only with added Et3N·HCl. Since the corresponding charge-
tagged neutral chelate was not detected in absence of Et3N·
HCl, this confirmed that the preceding C−C bond formation
required the presence of this additive. Subsequent detitanation-
silylation of this intermediate was significantly faster since this
chelate was not observed in the catalytic mixture.
ISOLATION OF A CATALYST RESTING STATE
■
Crystallization experiments were undertaken to isolate a
potential resting state using authentic reaction mixtures with
50 mol % catalyst loading in absence of TMSCl. The titanium
precursor was changed to [Cp2TiCl2] to facilitate crystalliza-
tion, which was carried out at −17 °C from toluene under
argon atmosphere (Scheme 3). The cationic bis-benzylcyanide
ionic metal species after dissociation. In addition, ammonium
species 6 and 7 emerging from Et3N·HCl and importantly, the
protonated, silylated imine (9) were identified. The species m/z
487.1 was a byproduct that only occurred under the dilute
conditions and was not a product of the titanium(III)-catalyzed
coupling.22
Subsequently, an identical experiment was carried out in
absence of TMSCl (Figure 3b). While the titanocenium
complexes 5, 8, and 10−13 were all greatly diminished in
their intensities, a new ion with m/z 486 was detected as the
main species. It was assigned the protonated titanocene-
product chelate 15: fragmentation of m/z 486 sets in at a much
higher collision energy of about 40 eV and proceeded via the
loss of a benzyl radical (m/z 91), thus leading to radical cation
16 with m/z 395 (Scheme 2, bottom).
a
Scheme 3. X-ray Structure of Catalyst Resting State 20
This pattern was further confirmed by employing acetophe-
nones and benzyl cyanides with different aromatic substitu-
ents.22 Finally, the experiment was repeated in absence of
TMSCl and Et3N·HCl. Here, only the previously identified
titanocenium complexes of acetophenone, benzyl cyanide and
THF were observed. The product chelate with m/z 486 was
not detected.
The presence of neutral species in solution that were not
detectable in the previous experiments was probed with a
charge-tagged substrate (Figure 4) as demonstrated earlier by
a
Thermal ellipsoids drawn at 50% probability level. Disordered
toluene molecules were omitted for clarity. Selected bond lengths (Å)
and angles (deg): Ti(1)−N(1) 2.1709(15), Ti(1)−N(2) 2.1564(14),
N(1)−C(11) 1.144(2), N(2)−C(19) 1.138(2), N(3)−Zn(1)
2.1053(14), N(1)−Ti(1)−N(2) 83.78(6), Cp(1)-Ti(1)-Cp(2)
135.725.
titanocene 20 was obtained, which was the unsubstituted
version of the resting state identified in the ESI-MS
experiments. Complex 20 was unambigously characterized by
X-ray analysis. The counterion was a triethylamine-stabilized
trichlorozincate, which could have emerged from the
abstraction of Cl− from the titanium in the presence of benzyl
Figure 4. Chloride-containing titanocene intermediates could not be
detected with a charge-tagged acetophenone.
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cyanide and ZnCl2.9c,17,18b,c Along these lines, it was possible to
isolate and characterize [HNEt3][Zn(Et3N)Cl3] (21) via X-ray
analysis, which apparently constituted a byproduct of our cross-
coupling reactions, from a similar experiment with only two
equivalents of benzyl cyanide.22
We monitored reactions with varying amounts of TMSCl (2.0,
1.5, and 1.1 equiv) (Figure 5a), and an almost identical curve
The bis-benzylcyanide complex 20 was previously described
in the literature as not isolable due to its tendency to dimerize
rapidly.25 In a third attempt to isolate 20, [Cp2TiCl] in THF
(generated by reduction with Zn followed by filtration) was
treated with 2 equiv of benzyl cyanide at room temperature (eq
3). Indeed, crystallization at −17 °C then afforded the
literature-known bis-titanated 1,2-diimine 22.25 At this lower
nitrile-catalyst ratio of 2:1, solvation of the remaining chloride
by the nitrile was apparently less favorable. Although 22 had
been characterized previously, this X-ray analysis was of crucial
importance to confirm its formation under conditions that were
very similar to those of our reductive acyloin-type coupling.
This led to the following conclusions:
(1) C−C bond formation did not occur from the cationic
bis-benzyl cyanide complex, but from the neutral chloride
complex [Cp2Ti(BnCN) (Cl)] (23), which was in equilibrium
with 20 as earlier proposed by Rehbaum and Thiele (eq 4).25
The requirement of a coordinating chloride was further
supported by an earlier study of pinacol couplings in aqueous
media,26 and our ESI-MS experiments.
Figure 5. Plots of fraction conversion of [PhCOMe] vs time. (a)
Varying amounts of TMSCl. (b) Varying amounts of Et3N·HCl. The
asterisk (*) marks the standard reaction conditions from eq 2.
was observed for the reactions up to ∼80% conversion, which
confirmed a zeroth order dependence in TMSCl as our MS
experiments had suggested. A reaction run with only 1.1 equiv
became slower at this point, indicating a change in the rate-
determining step at low TMSCl amounts. A similar scenario
was observed for reactions run with varying amounts of
Et3N·HCl. Here, it was important to note that 2.0 equiv of
hydrochloride additive were required to maintain a high
reaction rate until full completion was achieved (Figure 5b).
Thus, the reaction was zeroth order in TMSCl as well as
Et3N·HCl, which simplified eq 5 to eq 6.
(2) Two titanium species were likely involved in the C−C
bond forming proccess as indicated by the crystal structure of
the dichlorotitanated diimine 22.
It should be noted that this titanium(III)-promoted reaction
was therefore completely different from recently published
titanium(II)-mediated nitrile−nitrile couplings.27
rate ∝ [2]a[PhCOMe]b[BnCN]c
(6)
With the assumption that [2]a remained constant, the
determination of the reaction order in acetophenone was
then possible by plotting rate × [PhCOMe]−b vs [BnCN] at
different excess of [BnCN] over [PhCOMe] (varied equiv-
alents of PhCOMe) and altering b until an overlap of the curves
was achieved. This way, the order of the reaction in
acetophenone was determined to be b = 0.6.22 In a similar
fashion, a plot of rate × [BnCN]−c vs [PhCOMe] using the
same data set, revealed an order in BnCN of c ≈ − 3.22 The
plot in Figure 6 of rate × [BnCN]3 vs [PhCOMe]0.6 showing
overlaying curves in a straight line confirmed these results.
A possible interpretation of these unusual findings was a
double Michaelis−Menten situation:28e The product forming
species A and B emerged each from kinetically close equilibria
with the bis-benzyl cyanide resting state as shown in Scheme 4.
REACTION PROGRESS KINETIC ANALYSIS
■
To gain deeper insight into the reaction mechanism, a reaction
progress kinetic analysis of the reaction in eq 2 was undertaken
using in situ IR spectroscopy.28 This allowed us to identify the
rate-determining step, the rate equation and changes in the
reaction order over the reaction course. The consumption of
acetophenone (ν = 1689 cm−1) as well as the buildup of the α-
silyloxyimine product (ν = 1645 cm−1) could be followed
precisely.22 The former was found suitable for the monitoring
of reaction kinetics after calibration. Then, the determination of
the order in catalyst, acetophenone, benzyl cyanide, hydro-
chloride, and TMS chloride was carried out, all of which could
potentially contribute to the rate (eq 5).
rate ∝ [2]a[PhCOMe]b[BnCN]c[Et3N·HCl]d[TMSCl]e
(5)
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Figure 6. Graphical rate equation verifying a 0.6th order in PhCOMe
and −3rd order in BnCN.
Scheme 4. Rationale for the Observed Orders
However, regarding the complex situation and the likely
involvement of other cationic species, a full elucidation of the
situation would require a detailed analysis that was beyond the
scope of this work.
Then, the reaction was examined at different catalyst
loadings. A plot of reaction rate vs [PhCOMe] revealed that
the order of the reaction changed dramatically depending on
the catalyst amount and the reaction progress (Figure 7a). For
higher catalyst loadings an increasingly dominant initiation
period was observed and the maximum reaction rate was
achieved with 20 mol % of 2 at ∼50% conversion. We
attributed this initiation period to an increased formation of
(catalytically inactive) titanocene(III) dimers at such high
catalyst concentrations (eq 7).22 Previously, it was shown that
Figure 7. Determination of reaction order in catalyst. Plots of (a) rate
vs [PhCOMe] and (b) rate × [2]−1.6 vs [PhCOMe] of reactions at
varying catalyst loading.
[HNEt3][Zn(Et3N)Cl3] from the reaction of [Zn(THF)2Cl2]
with Et3N·HCl and Et3N.
(2) The titanium(III)-catalyzed acyloin-type coupling was a
complex case of catalyst saturation kinetics with a rate-limiting
bimolecular C−C formation from two different substrate-
catalyst complexes. Acetophenone and benzyl cyanide com-
peted for the coordination to the titanium center in a pre-
equilibrium situation. The negative order in BnCN was further
in agreement with a nonproductive (off-cycle) resting state
such as 5.
(3) The observed 1.6th order in catalyst and the initiation
time were the results of a bimolecular reaction and a
nonproductive (off-cycle) dimer formation of the catalyst,
which increased with the catalyst loading.
substituted titanocene(III)-chlorides have a significantly lower
tendency to dimerize than [Cp2TiCl].18a Consequently, a
standard reaction run with 10 mol % [Cp2TiCl2] as catalyst,
showed an increased initiation period.22 The reaction with only
5 mol % of 2, on the other hand, did not exhibit an initiation
time and followed a first overall reaction order over the whole
reaction course, indicating a change in the rate-determining
step at low catalyst loadings. From the plots of rate × [2]−a vs
[PhCOMe], a reasonable overlap of the curves was achieved for
the second half of the reaction for a = 1.6 (Figure 7b). This was
in agreement with a second order reaction and the above-
mentioned off-cycle formation of dimers, reducing the observed
order in catalyst from 2 to 1.6.
From these results, the following conclusions were drawn:
(1) Protonation and silylation of the product were not rate-
determining. However, 2 equiv of Et3N·HCl was required to
achieve full conversion. The first was attributed to the
protonation of the Ti−N bond of the product chelate. The
second equivalent was likely required due to the formation of
HAMMETT ANALYSIS AND ACTIVATION
PARAMETERS
■
To further support our conclusions, an investigation of the
electronic influence of the substrate on the catalysis and the
determination of the activation enthalpy and entropy was
undertaken. A Hammett-analysis showed a dependence of the
reaction rate on the electronic properties of the acetophe-
none.22 Interestingly, a value of ρ = 0.81 was obtained, which
showed that electron-poor acetophenones reacted significantly
faster than electron-rich ones. This was in agreement with our
conclusion that C−C bond formation proceeds via a chloride-
coordinated acetophenone complex: chloride coordination to
titanium-acetophenone complexes with more electron-with-
drawing acetophenone ligands would be facilitated. In addition,
electron-poor ketones would be reduced more easily and
should therefore be better substrates in general. The preference
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for C−C coupling from the chloride complex was supported by
a DFT-calculation of the conversion of [Cp2Ti(BnCN)
(PhCOMe)]+ (24) into [Cp2Ti(PhCOMe) (Cl)] (25) by a
chloride transfer from Et3N·HCl on the PW6B9529-D330-
COSMO31/def2-QZVP32//TPSS33-D3-COSMO/def2-
TZVP32-level using the TURBOMOLE V6.5 package.22,34 It
was found that the chloride complex had a significantly
increased spin density at the carbonyl carbon, which would lead
to an increased reactivity toward a C−C bond forming radical
reaction at this carbon (eq 8).22 This was in agreement with the
titanium(III)-substrate chelate was detected as main species.
Upon addition of Et3N·HCl, a comparably stable cationic
chelate of the protonated product with a titanium(IV)-center
was observed as sole species.22
Then, the influence of the amount of the hydrochloride
additive on the yield and the enantioselectivity of the
cyclization reaction was investigated (Figure 8). Although
expected increase of the reduction potential of the titanocene
upon chloride coordination and thus a higher performance of
the catalyst. The influence of the redox potential of titanocenes
on the performance in redox reactions was discussed
previously.8b,9c,19,35 The chloride transfer, however, was found
to be endergonic and thus, the equilibrium was on the side of
the thermodynamically favored cationic species. This explained
the requirement of a high chloride concentration to induce C−
C bond formation and also why the chloride complex remained
elusive in our ESI-MS experiments. The electronic influence of
the nitrile was briefly examined as well, but side-reactions were
observed with varying benzonitriles and no appropriate data
could be obtained. For para-substituted benzyl cyanides, no
influence was observed.22 The activation parameters for the
rate-limiting step were determined from an Eyring-plot with
data from IR-monitored experiments at different temper-
atures.22 A positive, but low activation enthalpy and a
considerable negative activation entropy were obtained
(Table 2). This was in agreement with a highly ordered
Figure 8. Influence of Et3N·HCl amount on yield and enantiomeric
excess of the cyclization in eq 1.
product formation was already observed in absence of the
hydrochloride, the addition of 0.5 equiv Et3N·HCl increased
the reaction yield significantly. Higher amounts diminished the
yield again and the addition of 3.0 equiv Et3N·HCl almost
inhibited the reaction. Importantly, the enantiomeric excess
increased in an almost linear fashion upon further addition of
Et3N·HCl (up to 91% ee at 3.0 equiv Et3N·HCl). Thus,
chloride coordination directly affected the enantioselectivity-
determining C−C bond formation.
The scenario shown in Scheme 5 provided a plausible
rationale for this observed additive effect. Two equivalents of
Scheme 5. Proposed Scenario for the Observed Dependence
of Yield and Enantioselectivity on the Hydrochloride
Amount
Table 2. Experimental Activation Parameters
parameter
value
ΔH⧧
10.2 kcal mol−1
−45.5 cal mol−1 K−1
23.8 kcal mol−1
2.4 × 10−5 s−1
ΔS⧧
ΔG⧧,298.15K
k
transition state suffering from steric repulsion as well as a
bimolecular reaction in form of a radical combination of two
titanium(III)-complexes. From these values, ΔG⧧,298.15K = 23.8
kcal mol−1 and a rate constant of k = 2.4 × 10−5 s−1 were
calculated that matched our kinetic data at that temperature.
Interestingly, this reaction seemed to be significantly slower
than related titanium(III)-catalyzed epoxide opening
reactions.7e,18a
titanium catalyst coordinated the substrate and two pathways to
the product existed. At low chloride concentrations, the first
path was followed, in which the product was formed from a bis-
titanium complex A containing one cationic titanium species.
Because of the reduced reactivity toward a radical combination
(see above), the product formation was slow in this case and a
low enantioselectivity was obtained. At higher chloride
concentrations (>0.5 equiv Et3N·HCl), a second path became
available that proceeded via a neutral dichloro-bistitanium
complex B. The C−C bond formation was faster due to a
THE ASYMMETRIC CYCLIZATION REACTION
■
The asymmetric cyclization with enantiopure ansa-titanocene
catalyst 1 (eq 1) was examined as well in order to fully
understand the role of the hydrochloride additive and to
confirm that a second order C−C formation was also present in
the intramolecular case.
First, ESI-MS analyses of the reaction mixture were carried
out and the results were identical to the intermolecular
reaction: in absence of Et3N·HCl and TMSCl, a cationic
G
DOI: 10.1021/jacs.5b09223
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
a
higher spin-density at the carbonyl carbon and the increased
reduction potential of the catalyst. The additionally coordinated
chloride led to a more rigid transition state, which was
expressed in a high enantioselectivity. At too high chloride
concentrations (>3 equiv), however, a titanocene(III)-hydro-
chloride complex C was formed. As noted in the introduction,
hydrochloride adducts were known to stabilize the catalyst but
also to represented inactive catalyst species.8l,19 Due to charge-
repulsion, a C−C bond formation involving two cationic
complexes was ruled out.
Scheme 6. Catalytic Cycle Summarizing the Results
Finally, the asymmetric cyclization exhibited a case of
asymmetric amplification, which was concluded from a positive
nonlinear effect that was determined from reactions with
varying enantiopurity of the catalyst (Figure 9).36 This
a
Species detected by ESI-MS were highlighted in blue, and inhibiting
b
pathways were drawn in gray. Ar = p-tolyl.
complex equilibrium situation existed prior to the C−C
formation.
The results are fundamental for the understanding of related
titanium(III)-catalyzed C−C couplings and the design of future
titanium catalyzes will benefit from this study. The counterion
could provide a feasible platform for the fine-tuning of the
catalyst properties that is complementary to the often executed
optimization of the titanocene backbone.8a,b,9c,19,35 Further-
more, bimetallic catalysts containing appropriately linked
titanocenes could lead to a superior performance in reductive
C−C couplings such as the title reaction.
In a broader perspective, our results will be valuable for the
development of other catalyst-controlled radical reactions.
Furthermore, a similar bimolecular radical combination
mechanism could be present in a number of cases that
exhibited superior catalyst control of the chemo-, regio-, and
stereochemistry. This includes reductive couplings catalyzed by
other metals such as V, Cr, Fe, Co, Ni, Zr, Ru, In, Sn, Pb, Ce,
Yb, and importantly Sm that take place under related
conditions.5 In addition, a number of reductive couplings that
were proposed to be Mn/Mn+2-catalyzed processes could in fact
involve open-shell species as was previously suggested for
certain cobalt catalyzed reactions.37 The combined approach
presented here could provide important insight in these cases
and find application in the mechanistic investigation of other
complex reactions that are heterogeneous, require multiple
additives, or involve radical intermediates.
Figure 9. Nonlinear effect observed in the asymmetric cyclization of
eq 1. The data was fitted using the ML2 model (red line).
unambiguously confirmed the second order catalyst depend-
ence of the C−C bond forming event in the asymmetric
cyclization reaction. Using the ML2 model for the coordination
of two equivalents of catalyst to one substrate (here: M =
substrate, L = catalyst), a fit was obtained from which the values
K = 3.74 and g = 0.13 were extracted.22 The value of K being
close to 4 indicated an almost statistical distribution for the
coordination of the catalyst enantiomers to the substrate
[2(R,R):(R,R)/(S,S):2(S,S) = 1:2:1]. The substrate complexed
by two identical (homochiral) catalyst enantiomers reacted
about 1/g = 7.7 times faster than the substrate coordinated by
two catalyst enantiomers of opposite absolute configuration.
CONCLUSIONS
■
The titanium(III)-catalyzed acyloin-type cross-coupling of
ketones and nitriles as shown in eqs 1 and 2 was investigated
by a combination of methods including EPR, ESI-MS, kinetic
studies, X-ray analysis, and DFT calculations. Through this
combined approach, the C−C bond formation was identified to
be the rate-determining key step and it was revealed that it
proceeds via a radical combination involving two titanium(III)
catalyst species (Scheme 6). This radical combination led to the
observed catalyst control of the selectivity and circumvented
free radical intermediates. Cationic complexes of the ketone
and nitrile reagents represented catalyst resting states, but their
role was intriguing: although such cationic species were the
only observable titanium complexes in solution, they were not
productive. Instead, product formation occurred from neutral
chloride complexes, which explained the positive influence of
Et3N·HCl on yield and enantioselectivity. Ketone and nitrile
competed for coordination to the titanium(III), and thus, a
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.5b09223.
■
S
Materials and methods for EPR, in situ ESI-MS, in situ
IR experiments, and computational details; additional
experimental results and DFT calculations; NMR spectra
of new compounds and HPLC reports (PDF)
X-ray crystallographic data for 20·toluene (CIF)
X-ray crystallographic data for 21 (CIF)
H
DOI: 10.1021/jacs.5b09223
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Rosales, A.; Oltra, J. E. Chem. - Eur. J. 2012, 18, 14479−14486.
X-ray crystallographic data for 22 (CIF)
́
(k) Jimenez, T.; Morcillo, S. P.; Martín-Lasanta, A.; Collado-Sanz, D.;
Car
́
denas, D. J.; Gansauer, A.; Justicia, J.; Cuerva, J. M. Chem. - Eur. J.
̈
AUTHOR INFORMATION
Corresponding Author
*jan.streuff@ocbc.uni-freiburg.de
■
2012, 18, 12825−12833. (l) Gansauer, A.; Behlendorf, M.; von
Laufenberg, D.; Fleckhaus, A.; Kube, C.; Sadasivam, D. V.; Flowers, R.
̈
A., II Angew. Chem., Int. Ed. 2012, 51, 4739−4742. (m) Gansauer, A.;
̈
Klatte, M.; Brandle, G. M.; Friedrich, J. Angew. Chem., Int. Ed. 2012,
̈
Notes
51, 8891−8894. (n) Gansauer, A.; Otte, M.; Shi, L. J. Am. Chem. Soc.
̈
The authors declare no competing financial interest.
2011, 133, 416−417. (o) Kosal, A. D.; Ashfeld, B. L. Org. Lett. 2010,
12, 44−47.
ACKNOWLEDGMENTS
■
́
(9) (a) Rosales, A.; Munoz-Bascon, J.; Roldan-Molina, E.; Castaneda,
̃
̃
We gratefully acknowledge generous financial support by the
Fonds der Chemischen Industrie (Dozentenpreis and Liebig-
Fellowship to JS) and the Deutsche Forschungsgemeinschaft,
DFG (STR 1150/3-1, STR 1150/6-1, STR 1150/7-1). We
furthermore thank Prof. Stefan Weber for his support and
access to EPR equipment.
M. A.; Padial, N. M.; Gansauer, A.; Rodríguez-García, I.; Oltra, J. E. J.
̈
Org. Chem. 2014, 79, 7672−7676. (b) Paradas, M.; Campana, A. G.;
̃
́
Estev
́
ez, R. E.; Alvarez de Cienfuegos, L.; Jimen
́
ez, T.; Robles, R.;
Cuerva, J. M.; Oltra, J. E. J. Org. Chem. 2009, 74, 3616−3619.
(c) Enemærke, R. J.; Larsen, J.; Hjøllund, G. H.; Skrydstrup, T.;
Daasbjerg, K. Organometallics 2005, 24, 1252−1262. (d) Yamamoto,
Y.; Hattori, R.; Miwa, T.; Nakagai, Y.-i.; Kubota, T.; Yamamoto, C.;
Okamoto, Y.; Itoh, K. J. Org. Chem. 2001, 66, 3865−3870. (e) Dunlap,
M. S.; Nicholas, K. M. J. Organomet. Chem. 2001, 630, 125−131.
REFERENCES
■
(1) Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A.,
Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004.
(f) Gansauer, A.; Moschioni, M.; Bauer, D. Eur. J. Org. Chem. 1998,
̈
1998, 1923−1927. (g) Wirth, T. Angew. Chem., Int. Ed. Engl. 1996, 35,
(2) (a) Jeganmohan, M.; Cheng, C.-H. Chem. - Eur. J. 2008, 14,
10876−10886. (b) Metal-Catalyzed Reductive C-C Bond Formation;
Krische, M. J., Ed.; Springer: Berlin, 2007. (c) Montgomery, J. Angew.
Chem., Int. Ed. 2004, 43, 3890−3908.
(3) (a) Seebach, D. Angew. Chem., Int. Ed. Engl. 1979, 18, 239−258.
(b) Fittig, R. Justus Liebigs Ann. Chem. 1859, 110, 23−45.
61−63.
(10) (a) Frey, G.; Hausmann, J. N.; Streuff, J. Chem. - Eur. J. 2015,
21, 5693−5696. (b) Bichovski, P.; Haas, T. M.; Kratzert, D.; Streuff, J.
Chem. - Eur. J. 2015, 21, 2339−2342. (c) Feurer, M.; Frey, G.; Luu, H.-
T.; Kratzert, D.; Streuff, J. Chem. Commun. 2014, 50, 5370−5372.
(d) Frey, G.; Luu, H.-T.; Bichovski, P.; Feurer, M.; Streuff, J. Angew.
Chem., Int. Ed. 2013, 52, 7131−7134. (e) Streuff, J.; Feurer, M.;
Bichovski, P.; Frey, G.; Gellrich, U. Angew. Chem., Int. Ed. 2012, 51,
8661−8664. (f) Streuff, J. Chem. - Eur. J. 2011, 17, 5507−5510.
(4) Catalytic umpolung reactions and other cross-electrophile
couplings are a highly topical research area: (a) Ackerman, L. K. G.;
Lovell, M. M.; Weix, D. J. Nature 2015, 524, 454−457. (b) Wu, Y.;
Hu, L.; Li, Z.; Deng, L. Nature 2015, 523, 445−450. (c) Lo, J. C.; Gui,
J.; Yabe, Y.; Pan, C.-M.; Baran, P. S. Nature 2014, 516, 343−348.
(5) (a) Streuff, J. Synthesis 2013, 45, 281−307. (b) Hirao, T. Top.
(11) (a) Estev
́
ez, R. E.; Oller-Lop
́
ez, J. L.; Robles, R.; Melgarejo, C.
R.; Gansauer, A.; Cuerva, J. M.; Oltra, J. E. Org. Lett. 2006, 8, 5433−
̈
5436. (b) Groth, U.; Jung, M.; Vogel, T. Chem. - Eur. J. 2005, 11,
3127−3135. (c) Jung, M.; Groth, U. Synlett 2002, 2015−2018.
(d) Boeckman, R. K., Jr.; Hudack, R. A., Jr. J. Org. Chem. 1998, 63,
3524−3525. (e) Corey, E. J.; Zheng, G. Z. Tetrahedron Lett. 1997, 38,
2045−2048.
Curr. Chem. 2007, 279, 53−75. (c) Gansauer, A.; Bluhm, H. Chem.
̈
Rev. 2000, 100, 2771−2788. See also: (d) Knappke, C. E. I; Grupe, S.;
Gartner, D.; Corpet, M.; Gosmini, C.; von Wangelin, A. J. Chem. - Eur.
̈
J. 2014, 20, 6828−6842. (e) Everson, D. A.; Weix, D. J. J. Org. Chem.
2014, 79, 4793−4798.
(12) See also: Zhou, L.; Hirao, T. Tetrahedron 2001, 57, 6927−6933.
(13) It should be noted that the unpaired electron is in part located at
the titanium and at the carbonyl carbon (see also eq 8). This can be
illustrated by the following two mesomeric forms:
(6) Streuff, J. Chem. Rec. 2014, 14, 1100−1113.
(7) For selected reviews on low-valent titanium chemistry, see:
́
(a) Morcillo, S. P.; Miguel, D.; Campana, A. G.; Alvarez de
̃
Cienfuegos, L.; Justicia, J.; Cuerva, J. M. Org. Chem. Front. 2014, 1,
15−33. (b) Rossi, B.; Prosperini, S.; Pastori, N.; Clerici, A.; Punta, C.
Molecules 2012, 17, 14700−14732. (c) Gansauer, A.; Shi, L.; Otte, M.;
̈
Huth, I.; Rosales, A.; Sancho-Sanz, I.; Padial, N. M.; Oltra, J. E. Top.
Curr. Chem. 2011, 320, 93−120. (d) Gansauer, A.; Fan, C.-A.; Keller,
̈
(14) (a) Fernan
P.; Rubio Gonzal
(b) Fernandez-Mateos, A.; Herrero Teijon
Rabanedo Clemente, R.; Rubio Gonzalez, R. J. Org. Chem. 2007, 72,
́
dez-Mateos, A.; Encinas Madrazo, S.; Herrero Teijon
ez, R. J. Org. Chem. 2009, 74, 3913−3918.
, P.; Mateos Buron, L.;
́
,
F.; Karbaum, P. Chem. - Eur. J. 2007, 13, 8084−8090. (e) Gansauer, A.;
̈
́
Justicia, J.; Fan, C.-A.; Worgull, D.; Piestert, F. Top. Curr. Chem. 2007,
́
́
́
279, 25−52. (f) Furstner, A.; Bogdanovic,
́
B. Angew. Chem., Int. Ed.
̈
́
Engl. 1996, 35, 2442−2469.
(8) For selected recent works on TiIII-catalysis, see: (a) Gansauer, A.;
Hildebrandt, S.; Michelmann, A.; Dahmen, T.; von Laufenberg, D.;
9973−9982. (c) Yamamoto, Y.; Matsumi, D.; Hattori, R.; Itoh, K. J.
Org. Chem. 1999, 64, 3224−3229. (d) Yamamoto, Y.; Matsumi, D.;
Itoh, K. Chem. Commun. 1998, 875−876.
̈
Kube, C.; Fianu, G. D.; Flowers, R. A., II Angew. Chem., Int. Ed. 2015,
(15) Markovich, G.; Perera, L.; Berkowitz, M. L.; Cheshnovsky, O. J.
Chem. Phys. 1996, 105, 2675−2685.
54, 7003−7006. (b) Gansauer, A.; von Laufenberg, D.; Kube, C.;
̈
Dahmen, T.; Michelmann, A.; Behlendorf, M.; Sure, R.; Seddiqzai, M.;
Grimme, S.; Sadasivam, D. V.; Fianu, G. D.; Flowers, R. A., II Chem. -
Eur. J. 2015, 21, 280−289. (c) Zhao, Y.; Weix, D. J. J. Am. Chem. Soc.
(16) (a) Gansauer, A.; Behlendorf, M.; Cangonul, A.; Kube, C.;
̈
̈
̈
Cuerva, J. M.; Friedrich, J.; van Gastel, M. Angew. Chem., Int. Ed. 2012,
51, 3266−3270. (b) Burgmayer, S. J. N. J. Chem. Educ. 1998, 75, 460.
(c) Billinger, P. N.; Claire, P. P. K.; Collins, H.; Willey, G. R. Inorg.
Chim. Acta 1988, 149, 63−67. (d) Coutts, R. S. P.; Kautzner, B.;
Wailes, P. C. Aust. J. Chem. 1969, 22, 1137−1141.
2015, 137, 3237−3240. (d) Mar
́
quez, I. R.; Miguel, D.; Millan
́
, A.;
Marcos, M. L.; de Cienfuegos, L. A.; Campana, A. G.; Cuerva, J. M. J.
̃
Org. Chem. 2014, 79, 1529−1541. (e) Morcillo, S. P.; Martínez-
́
Peragon
́
, A.; Jakoby, V.; Mota, A. J.; Kube, C.; Justicia, J.; Cuerva, J.
̈
(17) Seewald, P. A.; White, G. S.; Stephan, D. W. Can. J. Chem. 1988,
66, 1147−1152.
(18) (a) Daasbjerg, K.; Svith, H.; Grimme, S.; Gerenkamp, M.;
M.; Gansauer, A. Chem. Commun. 2014, 50, 2211−2213. (f) Munoz-
̃
́
́ ́
Bascon, J.; Hernandez-Cervantes, C.; Padial, N. M.; Alvarez-Corral,
M.; Rosales, A.; Rodríguez-García, I.; Oltra, J. E. Chem. - Eur. J. 2014,
20, 801−810. (g) Campos, C. A.; Gianino, J. B.; Ashfeld, B. L. Org.
Muck-Lichtenfeld, C.; Gansauer, A.; Barchuk, A.; Keller, F. Angew.
̈
̈
Chem., Int. Ed. 2006, 45, 2041−2044. (b) Enemærke, R. J.; Larsen, J.;
Skrydstrup, T.; Daasbjerg, K. Organometallics 2004, 23, 1866−1874.
(c) Enemærke, R. J.; Larsen, J.; Skrydstrup, T.; Daasbjerg, K. J. Am.
Chem. Soc. 2004, 126, 7853−7864. (d) Coutts, R. S. P.; Wailes, P. C.;
Lett. 2013, 15, 2656−2659. (h) Cangonul, A.; Behlendorf, M.;
̈
̈
Gansauer, A.; van Gastel, M. Inorg. Chem. 2013, 52, 11859−11866.
̈
(i) Gianino, J. B.; Ashfeld, B. L. J. Am. Chem. Soc. 2012, 134, 18217−
́
́
18220. (j) Munoz-Bascon, J.; Sancho-Sanz, I.; Alvarez-Manzaneda, E.;
̃
I
DOI: 10.1021/jacs.5b09223
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Martin, R. L. J. Organomet. Chem. 1973, 47, 375−382. (e) Vonk, C. G.
J. Cryst. Mol. Struct. 1973, 3, 201−207. (f) Salzmann, J.-J. Helv. Chim.
Acta 1968, 51, 526−529.
(37) Wang, L.-C.; Jang, H.-Y.; Roh, Y.; Lynch, V.; Schultz, A. J.;
Wang, X.; Krische, M. J. J. Am. Chem. Soc. 2002, 124, 9448−9453.
(19) Gansauer, A.; Kube, C.; Daasbjerg, K.; Sure, R.; Grimme, S.;
̈
Fianu, G. D.; Sadasivam, D. V.; Flowers, R. A., II J. Am. Chem. Soc.
2014, 136, 1663−1671.
(20) Samuel, E.; Vedel, J. Organometallics 1989, 8, 237−241.
(21) See also: (a) Kessler, M.; Schuler, S.; Hollmann, D.; Klahn, M.;
̈
Beweries, T.; Spannenberg, A.; Bruckner, A.; Rosenthal, U. Angew.
̈
Chem., Int. Ed. 2012, 51, 6272−6275. (b) Kessler, M.; Hansen, S.;
Hollmann, D.; Klahn, M.; Beweries, T.; Spannenberg, A.; Bruckner, A.;
̈
Rosenthal, U. Eur. J. Inorg. Chem. 2011, 2011, 627−631.
(22) See the Supporting Information.
(23) (a) Gellrich, U.; Meißner, A.; Steffani, A.; Kahny, M.; Drexler,
̈
H.-J.; Heller, D.; Plattner, D. A.; Breit, B. J. Am. Chem. Soc. 2014, 136,
1097−1104. (b) Vikse, K. L.; Ahmadi, Z.; Luo, J.; van der Wal, N.;
Daze, K.; Taylor, N.; McIndoe, J. S. Int. J. Mass Spectrom. 2012, 323−
324, 8−13. (c) Beierlein, C. H.; Breit, B.; Paz Schmidt, R. A.; Plattner,
D. A. Organometallics 2010, 29, 2521−2532. (d) Chisholm, D. M.;
McIndoe, J. S. Dalton Trans. 2008, 3933−3945.
(24) These titanocenium complexes were also present in a 0.5 M
reaction with 10 mol % catalyst; however, their intensity was drastically
reduced. Instead, the protonated imine product, a titanocenium-Et3N·
HCl adduct and a product complex of (EtCp)2TiCl2 were the major
peaks. See ref 22.
(25) (a) Rehbaum, F.; Thiele, K.-H.; Trojanov, S. I. J. Organomet.
Chem. 1991, 410, 327−333. (b) De Boer, E. J. M.; Teuben, J. H. J.
Organomet. Chem. 1978, 153, 53−57. (c) De Boer, E. J. M.; Teuben, J.
H. J. Organomet. Chem. 1977, 140, 41−45.
(26) Barden, M. C.; Schwartz, J. J. Am. Chem. Soc. 1996, 118, 5484−
5485.
(27) (a) Becker, L.; Arndt, P.; Spannenberg, A.; Jiao, H.; Rosenthal,
U. Angew. Chem., Int. Ed. 2015, 54, 5523−5526. (b) Becker, L.; Arndt,
P.; Jiao, H.; Spannenberg, A.; Rosenthal, U. Angew. Chem., Int. Ed.
2013, 52, 11396−11400.
(28) For excellent references on this topic, see: (a) Blackmond, D. G.
J. Am. Chem. Soc. 2015, 137, 10852−10866. (b) Scott, M.; Sud, A.;
Boess, E.; Klussmann, M. J. Org. Chem. 2014, 79, 12033−12040.
(c) Mathew, J. S.; Klussmann, M.; Iwamura, H.; Valera, F.; Futran, A.;
Emanuelsson, E. A. C.; Blackmond, D. G. J. Org. Chem. 2006, 71,
4711−4722. (d) Blackmond, D. G. Angew. Chem., Int. Ed. 2005, 44,
4302−4320. (e) Nielsen, L. P. C.; Stevenson, C. P.; Blackmond, D. G.;
Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 1360−1362. (f) Singh, U.
K.; Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc.
2002, 124, 14104−14114.
(29) Zhao, Y.; Truhlar, D. G. J. Phys. Chem. A 2005, 109, 5656−5667.
(30) Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. J. Chem. Phys.
2010, 132, 154104.
(31) Klamt, A.; Schuurmann, G. J. Chem. Soc., Perkin Trans. 2 1993,
̈
̈
799−805.
(32) Weigend, F.; Ahlrichs, R. Phys. Chem. Chem. Phys. 2005, 7,
3297−3305.
(33) Tao, J.; Perdew, J. P.; Staroverov, V. N.; Scuseria, G. E. Phys.
Rev. Lett. 2003, 91, 146401.
(34) Ahlrichs, R.; Armbruster, M. K.; Bar, M.; Baron, H.-P.;
̈
Bauernschmitt, R.; Crawford, N.; Deglmann, P.; Ehrig, M.; Eichkorn,
K.; Elliott, S.; Furche, F.; Haase, F.; Haser, M.; Hattig, C.; Hellweg, A.;
̈
̈
Horn, H.; Huber, C.; Huniar, U.; Kattannek, M.; Kolmel, C.; Kollwitz,
̈
̈
M.; May, K.; Nava, P.; Ochsenfeld, C.; Ohm, H.; Patzelt, H.;
Rappoport, D.; Rubner, O.; Schafer, A.; Schneider, U.; Sierka, M.;
̈
Treutler, O.; Unterreiner, B.; von Arnim, M.; Weigend, F.; Weis, P.;
Weiss, H. TURBOMOLE v6.5 2013, University of Karlsruhe and
Forschungszentrum Karlsruhe GmbH: Karlsruhe, Germany, 1989−
2007; http://www.turbomole.com.
(35) Gansauer, A.; Fleckhaus, A.; Lafont, M. A.; Okkel, A.; Kotsis, K.;
̈
Anoop, A.; Neese, F. J. Am. Chem. Soc. 2009, 131, 16989−16999.
(36) Girard, C.; Kagan, H. B. Angew. Chem., Int. Ed. 1998, 37, 2922−
2959.
J
DOI: 10.1021/jacs.5b09223
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX