Demystifying Cp2Ti(H)Cl and Its Enigmatic Role in the Reactions of Epoxides with Cp2TiCl

Article abstract of DOI:10.1021/acs.organomet.8b00793

The role of Cp₂Ti(H)Cl in the reactions of Cp₂TiCl with trisubstituted epoxides has been investigated in a combined experimental and computational study. Although Cp₂Ti(H)Cl has generally been regarded as a robust species, its decomposition to Cp₂TiCl and molecular hydrogen was found to be exothermic (ΔG = -11 kcal/mol when the effects of THF solvation are considered). In laboratory studies, Cp₂Ti(H)Cl was generated using the reaction of 1,2-epoxy-1-methylcyclohexane with Cp₂TiCl as a model. Rapid evolution of hydrogen gas was demonstrated, indicating that Cp₂Ti(H)Cl is indeed a thermally unstable molecule, which undergoes intermolecular reductive elimination of hydrogen under the reaction conditions. The stoichiometry of the reaction (Cp₂TiCl:epoxide = 1:1) and the quantity of hydrogen produced (1 mol per 2 mol of epoxide) is consistent with this assertion. The diminished yield of allylic alcohol from these reactions under the conditions of protic versus aprotic catalysis can be understood in terms of the predominant titanium(III) present in solution. Under the conditions of protic catalysis, Cp₂TiCl complexes with collidine hydrochloride and the titanium(III) center is less available for "cross-disproportionation" with carbon-centered radicals; this leads to byproducts from radical capture by hydrogen atom transfer, resulting in a saturated alcohol.

Full text of DOI:10.1021/acs.organomet.8b00793

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pubs.acs.org/Organometallics
Cite This: Organometallics XXXX, XXX, XXX−XXX
Demystifying Cp2Ti(H)Cl and Its Enigmatic Role in the Reactions of
Epoxides with Cp2TiCl
†
‡
,‡
Jonathan Gordon,† Sven Hildebrandt,‡ Kendra R. Dewese, Sven Klare, Andreas Gansauer,*
̈
T. V. RajanBabu,*,† and William A. Nugent*,†
†Department of Chemistry and Biochemistry, The Ohio State University, 100 West 18th Avenue, Columbus, Ohio 43210, United
States
‡
́
Kekule-Institut fur Organische Chemie und Biochemie, Universitat Bonn, Gerhard-Domagk-Straße 1, 53121 Bonn, Germany
̈
̈
S
* Supporting Information
ABSTRACT: The role of Cp2Ti(H)Cl in the reactions of Cp2TiCl with
trisubstituted epoxides has been investigated in a combined experimental and
computational study. Although Cp2Ti(H)Cl has generally been regarded as a
robust species, its decomposition to Cp2TiCl and molecular hydrogen was
found to be exothermic (ΔG = −11 kcal/mol when the effects of THF solvation
are considered). In laboratory studies, Cp2Ti(H)Cl was generated using the
reaction of 1,2-epoxy-1-methylcyclohexane with Cp2TiCl as a model. Rapid
evolution of hydrogen gas was demonstrated, indicating that Cp2Ti(H)Cl is indeed a thermally unstable molecule, which
undergoes intermolecular reductive elimination of hydrogen under the reaction conditions. The stoichiometry of the reaction
(Cp2TiCl:epoxide = 1:1) and the quantity of hydrogen produced (1 mol per 2 mol of epoxide) is consistent with this assertion.
The diminished yield of allylic alcohol from these reactions under the conditions of protic versus aprotic catalysis can be
understood in terms of the predominant titanium(III) present in solution. Under the conditions of protic catalysis, Cp2TiCl
complexes with collidine hydrochloride and the titanium(III) center is less available for “cross-disproportionation” with carbon-
centered radicals; this leads to byproducts from radical capture by hydrogen atom transfer, resulting in a saturated alcohol.
dienyl)titanium hydride chloride, has been synthesized and is
stable in the solid state and in THF solution.10,11
Cp2TiCl is a broadly useful reagent in organic syn-
thesis.12−14 Cp2TiCl is usually generated in situ by reduction
of Cp2TiCl2 with a metal powder, typically zinc or manganese
as shown in eq 1. We are particularly interested in the role of 1
in the reactions of Cp2TiCl with trisubstituted epoxides.
INTRODUCTION
■
Titanocene hydride chloride (1) is an enigmatic molecule in
organometallic chemistry: often invoked but never observed.
On the one hand, 1 has been proposed as an intermediate in
reactions as diverse as ethylene polymerization1 and the
aminolysis of N-acyl carbamates.2 In particular, 1 is implicated
as a product of the reaction between tertiary alkyl radicals and
the titanium(III) reagent Cp2TiCl.3−5 Because of the expect-
ation that 1 is a robust organometallic species, there has been
concern that its formation might be an impediment in catalytic
reactions using substoichiometric amounts of Cp2TiCl.
Specialized protocols have been developed to address this
supposed issue.3,4
2 Cp2TiCl2 + M → 2 Cp2TiCl + MCl2
M = Zn, Mn
(1)
It is instructive to first consider the reaction of Cp2TiCl with
the simple monosubstituted epoxide 2 in the presence of a
hydrogen atom donor Q−H. (Examples of such donors
include 1,4-cyclohexadiene and tert-butanethiol.) When it is
run under stoichiometric conditions,15 the reaction proceeds as
shown in Scheme 1. Initial homolysis of one epoxide C−O
bond results in formation of the β-titanoxy radical 3. The
carbon-centered radical 3 abstracts hydrogen from Q−H to
afford alkoxide 4. Alkoxide 4 is then hydrolyzed in a separate
step with dilute aqueous acid to afford the free alcohol.
In order to carry out such reactions in a catalytic manner,
one must address the fact that titanium(IV) alkoxide 4 cannot
be directly reduced to the +3 oxidation state. It is essential to
first convert the alkoxide back to Cp2TiCl2 so that it may once
On the other hand, 1 has never been isolated or even
observed in situ. Attempts to prepare 1 by treatment of
Cp2TiCl2 with hydride reagents have instead consistently
afforded the titanium(III) complex Cp2TiCl.6,7 In contrast,
zirconocene hydride chloride, Cp2Zr(H)Cl (Schwartz’s
reagent) is a thermally stable organometallic compound with
many useful applications in organic synthesis.8,9 Interestingly,
the permethylated analogue of 1, bis(pentamethylcyclopenta-
Received: October 29, 2018
© XXXX American Chemical Society
A
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Scheme 1. Cp2TiCl-Mediated Opening of an Epoxide in the
Presence of Hydrogen Atom Donor Q−H
involve the combination of 7 with Cp2TiCl to afford a 3°
organotitanium complex, followed by β-hydride eliminatio-
n.21,23a See the Supporting Information for a more detailed
discussion; however, this distinction does not affect the
conclusions of the current paper.)
Reactions of this type provide an efficient means for the
isomerization of trisubstituted epoxides to allylic alcohols.
Moreover, the loss of a β-hydrogen atom has also been
observed as a radical termination step in other reactions of
epoxides with Cp2TiCl that give rise to a 3° alkyl radical.
Examples include cyclization of epoxyolefins,20,24 transannular
cyclizations,25,26 and the cascade cyclization of epoxypo-
lyenes.4,24
again be reduced according to eq 1. In one approach, this is
accomplished by the use of a buffered Brønsted acid, most
often 2,4,6-collidininium hydrochloride (coll·HCl).16,17 When
stoichiometric amounts of coll·HCl and metal reductant with a
substoichiometric amount of Cp2TiCl2 as precatalyst are used,
a catalytic cycle can be achieved as shown in Scheme 2.
β-Scission of hydrogen and reduction by hydrogen
abstraction are sometimes observed as competitive processes,
as is the case in Scheme 4. When Bermejo and Sandoval
Scheme 2. Protic Catalysis of Ti(III)-Mediated Epoxide
Ring Opening (TiIV = Cp2ClTi−)
Scheme 4. Effect of Mode of Addition on Reduction vs β-
Hydrogen Scission
Scheme 3. Formation of Allylic Alcohols via Cp2TiCl-
Mediated Opening of Trisubstituted Epoxide
carried out the stoichiometric reaction of epoxide 10 with
Cp2TiCl (2.2 equiv), they discovered that different products
were favored depending on the order of addition of the
reactants (Scheme 4).21 When a 0.5 M solution of 10 in THF
was added dropwise to a 0.1 M solution of Cp2TiCl in THF
(normal addition), the predominant product was 11 derived
from β-scission of hydrogen. When the order of addition was
reversed (inverse addition) so that Cp2TiCl was added to
epoxide, the principal product was the saturated alcohol 12.
Inverse addition results in a very low instantaneous
concentration of Ti(III), which disfavors mixed disproportio-
nation. This suggests that the kinetic order in titanium(III) for
the product-forming step is higher for the formation of 11 than
for 12 and provides evidence for the requirement for a second
equivalent of Ti(III) in the β-scission of hydrogen.
A different reaction path emerges when a trisubstituted
epoxide such as 6 reacts with Cp2TiCl. In Scheme 3, the initial
C−O bond homolysis gives rise to the tertiary alkyl radical 7.
In the absence of a hydrogen atom donor, the observed
product after hydrolysis is a mixture of allylic alcohols 9a and
9b. Examples of this type of reaction began to appear in the
late 1990s,18−20 and the transformation was subsequently
explored in detail by Bermejo and Sandoval.21
In Scheme 3, the reaction between the radical 7 and
Cp2TiCl affords both 1 and either alkene 8a or 8b, depending
on which β-hydrogen atom is transferred to Cp2TiCl. This
type of process is proposed to proceed via a “mixed
disproportionation” between the carbon-centered radical 7
and the “titanium-centered radical” Cp2TiCl, in which a β-
hydrogen atom is abstracted by the Ti(III) reagent.22 This is
illustrated for the major pathway leading to 8a in eq 2.
(Alternatively, formation of Cp2Ti(H)Cl has been suggested to
With few exceptions,3 the Ti(III)-mediated rearrangement
of trisubstituted epoxides to allylic alcohols has not been
carried out under protic catalytic conditions. This is consistent
with the prevailing view that Cp2Ti(H)Cl is a robust species
that would not readily react with coll·HCl to regenerate
Cp2TiCl2.4,5 To address this issue, Takahashi and co-workers
proposed the use of triethylborane as an additive to promote
the reduction of Cp2Ti(H)Cl.3 In another approach, Barrero
and co-workers introduced an alternative catalytic protocol,
which proceeds under aprotic conditions.26 The coll·HCl that
is used in protic catalysis is replaced with a combination of
chlorotrimethylsilane and 2,4,6-collidine. Under these con-
ditions, the titanium alkoxide product will be converted to the
corresponding trimethylsilyl ether, regenerating Cp2TiCl2, as
illustrated for alkoxide 8a in eq 3.
B
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which decomposes rapidly in THF solution at room temper-
ature. A practical consequence of this fact is that it should not
be necessary to employ 2 or 3 equiv of Cp2TiCl in the
conversion of trisubstituted epoxides to allylic alcohols as is the
general practice.21,22 The second equivalent of Cp2TiCl is
unnecessary, since half of the reagent would be converted to
Cp2Ti(H)Cl which then decomposes, regenerating Cp2TiCl.
In fact, we have confirmed this experimentally (see Table 3,
entry 1).
The observed instability of 1 stands in contrast to the known
stability of its sterically encumbered pentamethylcyclopenta-
dienyl (Cp*) analogue. Treatment of (Cp*)2TiH with lead(II)
chloride results in oxidation of titanium to the +4 oxidation
state and affords (Cp*)2Ti(H)Cl.10 The analogue
(PhC5Me4)2Ti(H)Cl was similarly prepared.11
It is reasonable to assume that decomposition of Cp2Ti(H)
Cl follows a bimolecular pathway because of the requirement
that H2 is generated in this process. A unimolecular pathway
would require formation of atomic hydrogen, which is a high-
energy intermediate.28 Moreover, if formed, atomic hydrogen
would be expected to rapidly abstract hydrogen from the
solvent THF, which would not be consistent with the observed
stoichiometry. A bimolecular pathway also helps to explain the
kinetic stability of sterically hindered (Cp*)2Ti(H)Cl.
The calculations in Table 1 compare the energetics of the
decomposition process in THF for three different complexes at
In addition, it has been proposed that chlorotrimethylsilane
is able to regenerate Cp2TiCl2 from Cp2Ti(H)Cl according to
eq 4.4 This reaction is presumed to proceed by σ-bond
metathesis and produces Me3SiH as a coproduct (although no
evidence for the formation of Me3SiH has been reported).
Cp2Ti(H)Cl + Me3SiCl → Cp2TiCl2 + Me3SiH
(4)
Aprotic catalysis of titanium(III)-mediated epoxide opening
has been successfully applied not only to simple reactions such
as the rearrangement of trisubstituted epoxides but also to an
array of cyclization and polycyclization reactions. A compelling
example is the transannular cyclization of the simple
germacrolide derivative in eq 5, which affords (after desilylative
workup) a useful bicyclic product as a single stereoisomer in
68% isolated yield.27
RESULTS AND DISCUSSION
■
The fact that Cp2Ti(H)Cl has never been isolated caused us to
wonder whether this complex is in actuality thermally stable.
To address this question, we first examined the stability of 1
using DFT calculations. These studies revealed that the
decomposition of Cp2Ti(H)Cl to Cp2TiCl and molecular
hydrogen in THF (eq 6) is in fact exothermic (ΔG = −9.4
kcal/mol at the PW6B95-D3 level of theory). The effects of
explicit THF solvation were not included in this preliminary
study.
Table 1. Calculated Thermodynamic Parameters for
Cp2Ti(H)Cl → Cp2TiCl + 1/2H2
ΔE
ΔG
ΔGsolv
a
complex
Cp2TiHCl
level
(kcal/mol) (kcal/mol) (kcal/mol)
B3LYP-D3
PW6B95-D3
B3LYP-D3
PW6B95-D3
B3LYP-D3
PW6B95-D3
−3.25
−4.00
−4.25
−5.12
−2.68
−3.36
−8.95
−9.70
−10.06
−10.93
−8.77
−8.62
−9.37
−11.06
−11.93
−7.96
(ClC5H4)2TiHCl
Cp2Ti(H)Cl → Cp2TiCl + 1/2H2
(6)
Cp*2TiHCl
−9.45
−8.63
With this preliminary computational result in hand, we
proceeded to the laboratory for a closer examination of
Scheme 3. A 0.33 M solution of Cp2TiCl was prepared by
stirring a solution of Cp2TiCl2 (2.0 mmol) with excess zinc
dust (6 mmol) in THF (6.0 mL). To this solution was added a
solution of 1-methylcyclohexene oxide (2.0 mmol) in THF
(2.0 mL) over the course of several minutes. During the
addition, vigorous evolution of gas was observed. Rapid gas
evolution ceased after 5 min. At this point the volume of gas
produced could be determined by gas buret; after correction to
standard temperature and pressure it corresponded to the
release of 0.94 mmol of gas. The identity of the gas was
confirmed to be hydrogen by gas chromatography.
a
B3LYP-D3-COSMO-RS/def2-QZVP//TPSS-D3/def2-TZVP in
THF at 298.15 K or PW6B95-D3-COSMO-RS/def2-QZVP//TPSS-
D3/def2-TZVP in THF at 298.15 K.
two different levels of theory but ignore the specific effects of
THF solvation. The ΔGsolv term in the last column employs
the COSMO-RS solvation model to incorporate the overall
effect of the solvent (dielectric constant, etc.) but does not
include explicit THF coordination. Table 1 suggests that,
independent of substitution on the cyclopentadienyl rings, the
decomposition of the hydridochloride complexes is exother-
mic.
GLC analysis after quenching with dilute acid indicated that
the allylic alcohols 9a and 9b were formed in a 5:1 ratio
(Scheme 3). Their identity was confirmed by GC-MS followed
by isolation and spectroscopic analysis of the mixture. The
combined yield of 9a and 9b was shown by GLC versus an
internal standard to be 1.88 mmol (94%). These data show
that the stoichiometry for the overall transformation is best
described by eq 7.
On comparison of the various complexes, differences in ΔG
arise primarily from differences in the change in electronic
energy ΔE. The other contributions to ΔG (entropy and zero-
point energy) are essentially constant for all complexes. The
order of stability of the three complexes is consistent with their
expected redox potentials. The electron-withdrawing chlorine
atoms in (ClC5H4)2Ti(H)Cl significantly destabilize that
complex relative to the parent Cp2Ti(H)Cl. The electron-
donating methyl groups of (Cp*)2Ti(H)Cl stabilize it relative
to Cp2Ti(H)Cl.
On the basis of these experiments it appears that the Ti(IV)-
intermediate Cp2Ti(H)Cl is in fact an unstable compound
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However, the results in Table 1 are problematic in that the
decomposition of (Cp*)2Ti(H)Cl is predicted to be favorable.
For this reason, we carried out additional calculations
incorporating explicit THF solvation. It has been noted
previously that explicit calculation of solvent molecules
coordinating to a titanium(III) center can provide more
reasonable energies.33 (Cp2TiCl exists in THF solution as a
equilibrating mixture of monomeric Cp2TiCl(THF) and its
dimer. For simplicity, we consider only the monomer and do
not expect this simplification to significantly affect our
conclusions.) These results are summarized in Table 2.
cycle under protic conditions. To clarify this situation, we
returned to the laboratory to examine the reaction of epoxide 6
under the conditions of protic catalysis.
In these experiments, zinc powder was employed as
stoichiometric reductant and 2,4,6-collidine hydrochloride as
buffered Brønsted acid. All of the reactions in Table 3 were
Table 3. Product Distribution from Eq 8 under
Stoichiometric Conditions versus Protic Catalysis
a b
,
Cp2TiCl2
(equiv)
coll·HCl
(equiv)
entry
solvent 9 (%) 13 (%) 14 (%)
c
1
1.00
0.25
0.25
0.25
0.00
1.50
1.50
1.50
THF
THF
Et2O
toluene
100
44
71
0
53
24
24
0
3
5
9
Table 2. Calculated Thermodynamics for Cp2TiHCl + THF
→ Cp2Tl(THF)Cl + 1/2H2
2
3
d
4
67
ΔE
ΔG
ΔGsolv
a
a
complex
Cp2TiHCl
level
(kcal/mol) (kcal/mol} (kcal/mol)
Reaction conditions 0.25 M, room temperature, 3.0 equiv of Zn, 20
b
h unless otherwise indicated. Product ratios determined by GC-MS
B3LYP-D3
PW6B95-D3
B3LYP-D3
PW6B95-D3
B3LYP-D3
PW6B95-D3
−15.25
−16.30
−16.25
−17.03
−7.54
−6.60
−7.65
−7.52
−8.30
+2.19
+1.09
−10.50
−11.55
−11.67
−12.45
−0.04
c
and NMR. Reaction complete in 15 min; gas evolution observed.
d
Reaction complete after 2.5 h.
(ClC5H4)2TiHCl
carried out under similar conditions (THF, 20 h, room
temperature, and 0.25 M except as otherwise indicated). When
a substoichiometric amount of Cp2TiCl2 was utilized, in
addition to the allylic alcohols 9, the 2-methylcyclohexanols
cis- and trans-13 and 2-methylcyclohexanone 14 were also
produced, as shown in eq 8.
Cp*2TiHCl
−8.64
−1.15
a
B3LYP-D3-COSMO-RS/def2-QZVP//TPSS-D3/def2-TZVP in
THF at 298.15 K or PW6B95-D3-COSMO-RS/def2-QZVP//TPSS-
D3/def2-TZVP in THF at 298.15 K.
The data in Table 2 indicate that decomposition of
Cp2Ti(H)Cl and (ClC5H4)2Ti(H)Cl are further promoted
by the effect of THF solvation. Explicit solvation of the
titanium atom is possible and has the expected effect
(quenching of Lewis acidity).
When entries 1 and 2 in Table 3 are compared, it is evident
that the diminished yield of allylic alcohols 9 under protic
catalytic conditions is not due to a failure of catalytic turnover,
since complete conversion of epoxide 6 is achieved in each
case. Instead, a new pathway arises under protic catalytic
conditions, in which a significant proportion of the starting
epoxide is converted to the reduction product, alcohols 13.
This change in product distribution was also observed
(although to a lesser extent) when the THF solvent was
replaced with diethyl ether or toluene (entries 3 and 4). We
suggest that this result is related to the fact that, in the
presence of excess coll·HCl (especially in THF), titanium(III)
is largely present as complex 15. Recent studies have
underscored the importance of complex 15 in stabilizing
titanium(III) during protic catalytic reactions.29
Interestingly, the data in Table 2 indicate that decom-
position of (Cp*)2Ti(H)Cl is approximately thermoneutral in
THF solution. At first glance, it may seem strange that explicit
solvation is actually unfavorable in the case of (Cp*)2Ti(H)Cl.
However, in this case the THF is not strongly bonded in the
(Cp*)2TiCl product and in a sense Ti is actually not solvated.
We suggest that decomposition of (Cp*)2Ti(H)Cl is not
observed in THF solution due to both kinetic and
thermodynamic factors. The extreme steric bulk of the Cp*
ligands precludes the necessary bimolecular pathway required
for decomposition. In addition, there is little or no driving
force for decomposition of (Cp*)2Ti(H)Cl to (Cp*)2TiCl and
H2.
Thus, the instability of Cp2Ti(H)Cl is confirmed both in the
laboratory and by computations. It seems unlikely that the σ-
bond metathesis in eq 4 plays a role in the mechanism of
aprotic catalysis. In fact, our calculations suggest that eq 4 is
approximately thermoneutral. The calculated ΔG value is
−0.18 kcal/mol at the PW6B95-D3 level. Given that no
experimental evidence for the formation of Me3SiH has been
reported,4 σ-bond metathesis (eq 4) does not seem to be
operating. Therefore, we limited our calculations to the
thermodynamic features of both processes. Clearly, the H2
formation is largely favored thermodynamically. The higher
driving force seems to lead to a faster H2 formation.
The role of 15 in other reactions of epoxides with Ti(III)
has been delineated using cyclic voltammetry, kinetics, and
computational studies.30 It was shown that reversible
formation of 15 diminishes the concentration of active
Cp2TiCl reagent, suppressing radical trapping by Ti(III) and
therefore increasing radical lifetime. In reactions such as
reduction to the corresponding alcohol or inter- or intra-
molecular addition, trapping of intermediate radicals by
Cp2TiCl is an undesired intermolecular side reaction and
consequently the formation of 15 has a beneficial effect.
Aprotic catalysis has been successfully employed for the
rearrangement of trisubstituted epoxides to allylic alcohols. In
contrast, there is a single report where this transformation was
attempted under the conditions of protic catalysis.3 It is not
clear whether this situation simply reflects the assumption that
the formation of Cp2Ti(H)Cl would interrupt the catalytic
D
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Scheme 5. Possible Sources of Hydrogen Atoms in Saturated Alcohols 13
However, mixed disproportionation (eq 2) requires interaction
of the carbon-centered radical 7 with the active Cp2TiCl
species. The above results suggest that, in the presence of
excess coll·HCl, reaction of radical 7 with Ti(III) is inhibited.
Consequently, the extent of mixed disproportionation is
diminished and reduction of 7 by hydrogen atom abstraction
increases.
This raises the following question: what is the source of
hydrogen in the formation of reduction product 13? That is to
say, what is serving as the hydrogen atom donor Q−H in
Scheme 2? We considered five possible candidates: (1) the N−
H hydrogen atom of 15, (2) the α-hydrogen of solvent THF,
(3) the methyl hydrogen of collidine, (4) the Ti−H hydrogen
atom of Cp2Ti(H)Cl, and (5) disproportionation between two
β-titanoxy radicals to give one molecule each of 9 and 13.
These possibilities are illustrated in Scheme 5.31
The first possibility requires that the N−H bond of coll·HCl
is activated (weakened) by coordination to titanium(III). This
type of activation would be consistent with recent discoveries
regarding the activation of heteroatom−hydrogen bonds by
Ti(III). It has been shown that the O−H hydrogen of
water,25,32,33 the O−H hydrogen of methanol,34 and the N−H
hydrogen of amides35−37 can all be activated as hydrogen atom
donors when they are complexed to Cp2TiCl.
The second possibility is that the α-hydrogen atoms in
solvent THF are being abstracted by the intermediate β-
titanoxy radicals. It can be noted that the BDE for the α-
hydrogen of THF is 92 kcal/mol38 and these hydrogens might
arguably be further activated when THF is coordinated to
Ti(III).
which we expect will be less reactive as a hydrogen atom
donor. However, as the reaction proceeds, more and more of
the hydrochloride is converted to the free base. It has been
noted that when collidine is added to the stoichiometric
reactions of trisubstituted epoxides with Cp2TiCl, β-scission is
greatly diminished and reduction via hydrogen abstraction is
instead observed.23b
Fourth, it is conceivable that Cp2Ti(H)Cl is functioning as a
hydrogen transfer agent. The instantaneous concentration of
Cp2Ti(H)Cl will be low due to the fact that a substoichio-
metric amount of titanium is utilized and especially due to the
rapid decomposition of Cp2Ti(H)Cl under the reaction
conditions. Balanced against this, the reaction of a carbon-
centered radical with Cp2Ti(H)Cl results in the replacement of
a weak Ti−H bond with a far more stable C−H bond and the
process should be highly exothermic. For example, we
calculated ΔG for the reaction of radical 7 (see Scheme 3)
with Cp2Ti(H)Cl. At the PW6B95-D3 level of theory, after
correction for the effect of bulk THF solvent, ΔG = −48 kcal/
mol for this process. (See the Supporting Information for
details.)
Fifth, the final possibility would be disproportionation
between two β-titanoxy groups. This process would necessarily
produce equal amounts of unsaturated alcohols 9 and saturated
alcohols 13.
In an effort to determine the identity of the hydrogen atom
donor, isotopic labeling studies were carried out using
isotopically labeled THF-d8, collidine deuteriochloride, or
both. These studies might militate in favor of or against
possibilities 1 and 2.
The third candidate would be the “benzylic” methyl groups
on 2,4,6-collidine. The concentration of collidine is low in
comparison to that of THF, but HAT from collidine benefits
from a statistical factor of nine benzylic hydrogens per
molecule. We are unaware of any reported BDE data for the
C−H bonds of 2,4,6-collidine. However, the BDE for 2-
picoline has been estimated to be 87.2 kcal/mol and that for 4-
picoline as 86.5 kcal/mol.39 It might be argued that electron
release from multiple methyl groups in collidine would further
lower this number. In the early stages of a protic catalytic
reaction, collidine will be present as its hydrochloride salt,
Table 4 summarizes GC-MS studies of the cis-13 obtained
when eq 8 was carried out. The observed (M + 1)/M ratios
were adjusted for the 7.8% contribution to M + 1 from natural-
abundance 13C. Up to 26% deuterium incorporation was
observed when the reaction was carried out in THF-d8 using
coll·DCl as the buffered acid.
The location of the isotopic label in cis-13 produced in these
experiments was confirmed to be the tertiary (methyl-bearing)
1
carbon using 600 MHz H NMR. The resonance for the
tertiary hydrogen was located using a combination of COSY,
HSQC, and 1D-decoupling and appears as a multiplet in the δ
E
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of reactions where β-scission is an undesired side reaction.44 In
particular, we note that the reduction of certain trisubstituted
epoxides to the corresponding alcohol under protic catalysis is
a clean and high-yielding transformation. For example, the
reduction of epoxide 16 in eq 9 affords the secondary alcohol
Table 4. GC-MS Results for Deuterium Labeling Studies
D incorporation
a
b
entry
sample
authentic cis-10
(M + 1)/M
(%)
1
2
0.072
0.087
0
1
cis-10 prepared using coll·HCl in
THF-d8
3
4
cis-10 prepared using coll·DCl in
0.25
0.46
14
26
protio THF
cis-10 prepared using coll·DCl in
THF-d8
a
Ratio of m/z 115 to m/z 114 before correction for 7.8% contribution
b
from 13C. Calculated as % D = (ratio − 0.078)/(1.00 + ratio).
17 in 86% yield as a 2:1 mixture of diastereomers using just 5%
of Cp2TiCl2 as catalyst.45 In this reaction, 1,4-cyclohexadiene
functions as the hydrogen atom donor.
1.61−1.64 region. The tertiary hydrogen resonance itself is
poorly resolved due to overlapping resonances, which
interferes with integration. However, the associated methyl
resonance proved more useful. In protio-cis-13 the methyl
group appears as a doublet (J = 6.8 Hz) at δ 0.94 ppm. For
deuterium-labeled cis-10 this resonance collapses to a singlet,
which exhibits the expected40 upfield isotopic shift to 0.93
ppm. Integration of these peaks was consistent with the results
of GC-MS analysis.
Since the labeling studies in Table 4 account for only 26% of
the saturated alcohol, the remaining hydrogen must originate
from a source other than THF-d8 or coll·DCl. The remaining
candidates are the methyl hydrogen atoms of collidine, the
hydride of Cp2Ti(H)Cl, or direct disproportionation between
β-titanoxy radicals. Distinguishing between these possibilities
must await additional isotopic labeling studies: e.g., labeling of
the epoxide (and indeed the final two possibilities would be
difficult to distinguish on the basis of labeling studies).
We believe that our results are best understood in terms of
the different titanium(III) species present in solution during
protic catalysis versus stoichiometric conditions (or aprotic
catalysis). Under stoichiometric conditions, Ti(III) is mainly
present as Cp2TiCl(THF).41,42 The weakly coordinated THF
ligand is readily displaced so that titanium(III) is available for
cross-disproportionation with a β-titanoxy radical such as 7.
However, in protic catalysis, Ti(III) is complexed with coll·
HCl in the form of 15.30,43 The titanium(III) is not as readily
available to trap the intermediate β-titanoxy radical. Therefore,
carbon-centered radical 7 survives and is ultimately quenched
by hydrogen abstraction.
Earlier we noted that the order of addition of epoxide and
Ti(III) affected the products formed from epoxide 10. We
observed a similar, though considerably smaller, effect in the
stoichiometric reaction of epoxide 6 with Cp2TiCl. The ratio
of the products of reduction (cis-13 + trans-13) to the products
of H atom loss (9a + 9b + 14) was different depending on the
mode of addition. Normal addition under stoichiometric
conditions gave less of the reduction product (ratio = 0.11) in
comparison with reverse addition of Cp2TiCl to the epoxide
(ratio = 0.29). The corresponding ratio for the catalytic
reactions was 0.39, although the reaction conditions are not
strictly comparable, with excess coll·HCl also being present in
the catalytic reactions. It is not clear why the magnitude of this
effect is lower for epoxide 6 versus epoxide 10, but presumably
it reflects the greater steric encumbrance of 10.
Finally, several attempts were made to observe Cp2Ti(H)Cl,
generated according to Scheme 3, using in situ infrared
spectrometry. We hoped to observe the ν(Ti−H) band in the
1600 cm−1 region by analogy to the strong band observed at
1605 cm−1 for Cp*2Ti(H)Cl.46 However, rapid gas evolution
disrupted the operation of the IR detector of the spectrometer.
It is noteworthy that gas evolution was rapid even when the
reaction was carried out at −40 °C.
CONCLUSIONS
■
The combination of experimental work and computations used
in this study has provided a series of surprises and has several
practical consequences. The conventional wisdom that Cp2Ti-
(H)Cl is a robust species that resists reduction to the Ti(III)
oxidation state is not correct. In contrast, Cp2Ti(H)Cl
spontaneously decomposes to regenerate Cp2TiCl and
molecular hydrogen. The failure of protic catalytic conditions
to cleanly promote the conversion of trisubstituted epoxides to
allylic alcohols is the result of competing hydrogen atom
transfer rather than an interruption in catalyst turnover.
Aprotic catalysis does not require the putative σ-bond
metathesis of Cp2Ti(H)Cl with Me3SiCl. The stoichiometric
reactions of trisubstituted epoxides with Cp2TiCl have
previously been carried out using 2 or 3 equiv of the
titanium(III) reagent. Our results demonstrate that a single
equivalent of Cp2TiCl will suffice. (Nevertheless, it appears
prudent to use a ca. 20% excess of Cp2TiCl to avoid potential
side reactions when the titanium(III) concentration becomes
very low near the end of the reaction.) The previously
undocumented, rapid evolution of hydrogen may represent a
safety concern for emerging large-scale applications of this
chemistry.47
The fundamental difference between protic and aprotic
catalysis of the reaction of Cp2TiCl with epoxides is the form
of Ti(III) that is present. In aprotic catalysis, Ti(III) is present
as Cp2TiCl(THF) where the titanium(III) center is available
to participate in reactions with carbon-centered radicals. In
protic catalysis, Cp2TiCl and coll·HCl form the stable complex
15, which less readily reacts with carbon-centered radicals. For
these reasons, protic and aprotic catalysis of these reactions are
in fact complementary protocols. Aprotic catalysis will
generally prove superior when scission of β-hydrogen or
deoxygenation is the desired termination step. Protic catalysis
will be advantageous when reduction of the epoxide via
hydrogen atom transfer is desired, especially with an added
hydrogen atom donor such as 1,4-cyclohexadiene.
It is evident that aprotic catalysis will be superior to protic
catalysis when the desired termination step from Ti(III)-
catalyzed epoxide ring opening is β-scission of hydrogen.
However, it is worth reiterating that the diminished reactivity
of 15 as a hydrogen atom acceptor can be beneficial for types
F
DOI: 10.1021/acs.organomet.8b00793
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
deuterium chloride (96% D) in ether solution (9.0 mL, 9.0 mmol, 1.2
equiv). A white solid precipitate formed immediately and was stirred
for several minutes. The remaining Et2O was decanted and removed
with a syringe through the septum. The solid was washed with Et2O
(3 × 10 mL) and decanted using a syringe. The flask was then
returned to the glovebox and the remaining Et2O was removed under
vacuum to yield coll·DCl (0.996 g, 83% yield). The deuterium
content was established to be ca. 90% by integration of the residual
EXPERIMENTAL SECTION
■
Reaction of Cp2TiCl with 1,2-Epoxy-1-methylcyclohexane
(6). Titanocene dichloride (0.498 g, 2.00 mmol) and zinc dust (0.393
g, 6.00 mmol) were placed in a Schlenk flask which was then flushed
with argon. To the flask were added THF (6.0 mL) and tert-butyl
methyl ether (238 mL, 0.177 g, 2.00 mmol) as an internal standard.
The mixture was stirred for 30 min at which time the initial red color
had discharged to lime green. The flask was closed to argon, and a
thin tube was fed from the flask into an inverted buret filled with
water (see photograph in the Supporting Information). A solution of
epoxide (0.225 g, 2.00 mmol) in 1.5 mL of THF was added slowly,
and as gas evolved, it bubbled into the buret to displace 22.4 mL of
water. The reaction was quenched with 2.5 mL of saturated aqueous
sodium hydrogen carbonate. Gas chromatographic analysis indicated
the formation of allylic alcohols 9a and 9b (1.88 mmol) in a 5:1 ratio.
The solution was filtered over Celite and rinsed with THF and was
subjected to flash chromatography (4/1 pentane/diethyl ether).
CDCl3 was added to the residue and removed at reduced pressure to
obtain an approximately 3/2 mixture of 2-methylenecyclohexan-1-ol
(9a; major) and 2-methylcyclohex-2-en-1-ol (9b; minor) free of
residual solvents. NMR analysis and comparison with literature
data48,49 allowed the assignment of the spectra as follows. For the
major product 9a: 1H NMR (400 MHz, CDCl3) δ 4.90 (s, 1H), 4.77
(s, 1H), 4.09−4.13 (m, 1H), 2.41−2.45 (m, 1H), 1.94−1.53 (m, 8H);
13C NMR (100 MHz, CDCl3) δ 151.6, 105.0, 72.7, 36.7, 33.5, 27.7,
1
1
NH resonance in the H NMR at δ 17.3 ppm. H NMR (600 MHz,
CDCl3): δ 2.52 (s, 6H), 2.90 (s, 3H), 7.20 (s, 2H). 13C NMR (151
MHz, CDCl3): δ 19.3, 22.1, 125.2, 153, 157.9.
Procedure for Isotopic Labeling Studies in Table 4. In a N2-
filled glovebox an oven-dried Schlenk flask (or a 20 mL screw-capped
vial for small-scale reactions) equipped with a stir bar was charged
with collidine·DCl (238 mg, 1.5 equiv) or collidine·HCl (235 mg, 1.5
equiv), activated Zn (199 mg, 3 equiv), and Cp2TiCl2 (62 mg, 0.25
equiv), after which was added distilled THF or THF-d8 (4 mL, to
make a 0.25 M solution in epoxide). The greenish turbid solution was
stirred for 15 min before 1,2-epoxy-1-methylcyclohexane (124 μL,
1.00 mmol, 1 equiv, density = 0.905 g mL−1) was added via a
microsyringe. The solution showed a slight reddish color, and gas
evolution was observed. After it was stirred for 1 h, the reaction
mixture was quenched with saturated NH4Cl (4 mL) and extracted
with Et2O. The yellow solution was filtered over a pad of silica and
eluted with Et2O (100 mL), and the solvent was evaporated under
reduced pressure to obtain the crude product, which was analyzed by
GC-MS (HP-5MS 5% phenyl methyl silicone (HP-5) capillary
column, 30 m length, 250 μm diameter, 0.25 μm film thickness, 35 °C
5 min, 5°/min to 250 °C and hold 2 min). The relative intensities for
the M and M + 1 peaks were determined by integrating the total ion
current for the cis-10 molecular ion (retention time 3.39 min) at m/z
114 and 115. For details of the determination of isotopic composition
of products, see the Supporting Information.
23.8; GC-MS m/z 112.10 ([M+]), calcd for C7H12O 112.09. For the
1
minor product 9b: H NMR (400 MHz, CDCl3) δ 5.56 (br s, 1H),
4.00 (t, J = 4.4 Hz) (m, 1H), 1.94−1.53 (m, 10H); 13C NMR (100
MHz, CDCl3) δ 135.3, 125.5, 68.5, 32.2, 25.4, 20.6, 18.1; GC-MS m/
z 112.10 ([M+]), calcd for C7H12O 112.09.
Procedure for Catalytic Reactions in Table 3. In a Schlenk
tube, 2,4,6-collidinium chloride (1.50 equiv) was sublimed in vacuo
with careful heating. After they were cooled to room temperature, the
solids were flushed with argon and transferred back to the bottom of
the flask. Zn powder (3.00 equiv) and Cp2TiCl2 (0.05 to 1.00 equiv)
were added, and the solids were evacuated and flushed with argon
three times. Dry THF (substrate 0.25 M) was added via syringe, and
the reaction mixture was stirred for 15 min at room temperature. The
solution turned green within minutes. 1,2-Epoxy-1-methylcyclohexane
(1.00 equiv) was added via syringe, and the reaction mixture was
stirred under argon at room temperature for the indicated time.
Saturated aqueous NH4Cl solution was added (100% v/v THF), and
the aqueous phase was extracted with ethyl acetate three times. The
combined yellow organic phase was filtered through a short silica pad.
The solvent was removed under reduced pressure (not below 150
mbar at 40 °C, due to volatility of the substrate and products) to yield
the crude product, which was subjected to GC-MS analysis.
Computational Details. DFT calculations were carried out with
the TURBOMOLE 7.0 program package.51 Geometries were first
optimized at the TPSS52-D353,54/def2-TZVP55 level of theory. Final
reaction free energy values were obtained through single-point
calculations on the PW6B9556-D3 or B3LYP57,58-D3 level in the
gas phase. Solvation contributions to ΔG were included using the
COSMO-RS continuum solvation model.59,60 For a full description of
the computational methods and data, see the Supporting Information.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.8b00793.
A sample of the product obtained under the conditions of Table 3,
entry 2, was carefully chromatographed on silica using 10% ether in
pentane to collect various fractions for identifications. The order of
elution was as follows: cis-13 Me at δ 0.939 (J = 6.6 Hz), α-H at δ
3.77; 9a, α-H at δ 4.089; 9b α-H at δ 3.987; trans-13, Me at δ 1.004 (J
= 6.6 Hz), α-H at δ 3.10. The ketone 14 and the cis-13 and trans-13
alcohols were further confirmed by coinjection in the GC with
authentic samples. Samples of the saturated alcohols were obtained by
NaBH4 reduction of the commercially available 14 (ratio of cis-13 to
trans-13 42:58). Pure samples of cis-13 and trans-13 were isolated by
careful column chromatography on silica gel using 20/1 pentane/
ether as eluent. Spectra for cis-13 and trans-13 match those in the
literature.50 The C2-H in cis-13 was identified by 1H COSY and
decoupling experiments. Irradiation of the CH3 (δ 0.939) doublet
shows simplification of the multiplet centered around δ 1.61−1.64.
Conversely, decoupling of the broad peak at δ 1.63 causes the CH3
signal to appear as a singlet. See Supporting Information for details.
Preparation of Collidine Deuteriochloride for Isotopic
Labeling Studies. A Schlenk flask equipped with a stir bar was
charged with 2,4,6-collidine (1 mL, 7.57 mmol, d = 0.917 g/mL, 1
equiv) in a N2 filled glovebox before transferring to the Schlenk line.
Diethyl ether (5 mL) was added followed by a commercial 1 M
General experimental details, preparation of 6 and
1
authentic cis- and trans-13, H and 13C NMR data,
GC-MS chromatograms, mechanistic discussion of β-
hydrogen scission, and complete computational details
(PDF)
Cartesian coordinates for optimized structures (XYZ)
AUTHOR INFORMATION
Corresponding Authors
*E-mail for A.G.: andreas.gansaeuer@uni-bonn.de.
*E-mail for T.V.R.: rajanbabu.1@osu.edu.
*E-mail for W.A.N.: nugent.60@osu.edu.
■
ORCID
Sven Hildebrandt: 0000-0001-9196-7070
̈
Andreas Gansauer: 0000-0003-2622-6369
T. V. RajanBabu: 0000-0001-8515-3740
Notes
The authors declare no competing financial interest.
G
DOI: 10.1021/acs.organomet.8b00793
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
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ACKNOWLEDGMENTS
■
We gratefully acknowledge the SFB 813 (“Chemistry at Spin
Centers”) and Ga-619/12-1 for support to A.G. and the U.S.
National Institutes of Health (R01 GM108762) and NSF
(CHE-1362095) for support to T.V.R. S.H. and S.K. thank the
̈
Jurgen Manchot Stiftung for doctoral fellowships. J.G. and
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I
DOI: 10.1021/acs.organomet.8b00793
Organometallics XXXX, XXX, XXX−XXX