Electronic selectivity tuning in titanium(III)-catalyzed acetylene cross-dimerization reactions

Article abstract of DOI:10.1021/om201008k

The reactivity of open-shell titanium(III) complexes in organometallic catalysis is associated with many open questions, in particular regarding the electronic structure of catalytic intermediates and transition states. The unpaired electron density in principle allows for radical-type reactivity, while at the same time empty d orbitals allow more traditional cis-coordination insertion pathways. In this paper we investigated the (Cp*) ₂Ti^III-catalyzed cross-dimerization of aliphatic and aromatic acetylenes, focusing on the reactivity of two different aliphatic acetylenes with a series of different aromatic acetylenes. The applied aliphatic acetylenes 1a (4-methylpent-1-yne) and 1b (N,N-dimethyl-N-propargylamine) have the same size but different electron-accepting abilities. The better I-accepting substrate 1b shows a higher reactivity and selectivity than substrate 1a in the studied cross-dimerization reactions. Stronger I back-donation from the titanium-localized SOMO to the substrate thus seems to be a reasonable explanation for the improved selectivity of substrate 1b. DFT calculations indeed suggest a stronger binding of substrate 1b as compared to that of 1a in the selectivity-determining steps of the reaction, thus leading to faster insertions and higher selectivities with substrate 1b.

Full text of DOI:10.1021/om201008k

Communication
pubs.acs.org/Organometallics
Electronic Selectivity Tuning in Titanium(III)-Catalyzed Acetylene
Cross-Dimerization Reactions
Gennady V. Oshovsky,*,†,‡ Bart Hessen,‡ Joost N. H. Reek,† and Bas de Bruin*,†
†Supramolecular and Homogeneous Catalysis Group, van’t Hoff Institute for Molecular Sciences, University of Amsterdam,
Science Park 904, 1098 XH Amsterdam, The Netherlands
‡Department of Molecular Inorganic Chemistry, Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG,
Groningen, The Netherlands
S
* Supporting Information
ABSTRACT: The reactivity of open-shell titanium(III) complexes in organo-
metallic catalysis is associated with many open questions, in particular regarding
the electronic structure of catalytic intermediates and transition states. The
unpaired electron density in principle allows for radical-type reactivity, while at
the same time empty d orbitals allow more traditional cis-coordination
insertion pathways. In this paper we investigated the (Cp*)2TiIII-catalyzed
cross-dimerization of aliphatic and aromatic acetylenes, focusing on the
reactivity of two different aliphatic acetylenes with a series of different aromatic acetylenes. The applied aliphatic acetylenes 1a
(4-methylpent-1-yne) and 1b (N,N-dimethyl-N-propargylamine) have the same size but different electron-accepting abilities.
The better π-accepting substrate 1b shows a higher reactivity and selectivity than substrate 1a in the studied cross-dimerization
reactions. Stronger π back-donation from the titanium-localized SOMO to the substrate thus seems to be a reasonable
explanation for the improved selectivity of substrate 1b. DFT calculations indeed suggest a stronger binding of substrate 1b as
compared to that of 1a in the selectivity-determining steps of the reaction, thus leading to faster insertions and higher selectivities
with substrate 1b.
π-conjugated building blocks in organic synthesis.5 The
atalytic organometallic reactions are dominated by the
1
Cclosed-shell reactivity of diamagnetic species.
While
reports on the open-shell organometallic reactivity of titanium(III)
compounds in catalysis dates back to the early era of Ziegler
and Natta, our current understanding of these reactions is still
rather limited and is associated with many open questions
regarding the electronic structure of the catalytic intermediates
and transition states. In this perspective we became interested
in the catalytic reactivity of Cp2TiIII-type compounds. While the
reactivity of these compounds should in many ways resemble
that of their closed-shell Cp2TiIV analogues, their unpaired spin
density and highly reducing nature also makes them capable of
promoting selective radical-type transformations (such as
cyclization reactions induced by radical ring opening of
epoxides2). We thus wondered if Cp2TiIII-type compounds
have a general preference for radical pathways or perhaps allow
a more subtle participation of the singly occupied molecular
orbital (SOMO) in tuning the selectivity of catalytic reactions
following cis-coordination reactivity. Our interest in SOMO
participation in the reactivity and selectivity tuning of catalytic
reactions is further inspired by SOMO organocatalysis, which
recently opened a new research area.3 For these reasons we
decided to study the effect of different substrates on the
selectivity of Cp*2TiIII-catalyzed cross-dimerization reactions of
acetylenes in a combined experimental and computational
study.
homodimerization reaction has been extensively studied, but
the much more challenging selective cross-dimerization of two
different alkynes has received much less attention.4,6 This is an
intrinsically difficult reaction, due to several possible competing
reactions leading to regio- and stereoisomers as well as
competing cross-dimerization and homodimerization.5
The catalyst we used in this study is TiIII complex 3,7 which is
an analogue of the Nakamura catalyst (Cp*2TiCl2/PriMgCl).4
We used this catalyst for the cross-dimerization between
aliphatic 1 and aromatic 2 acetylenes leading to 1,3-enynes
(Scheme 1).
Scheme 1. TiIII-Catalyzed Acetylene Head-to-Tail Cross-
Dimerization
Selective catalytic dimerization of alkynes is a synthetically
Received: October 19, 2011
Published: October 31, 2011
useful procedure to obtain enynes,4 which are versatile
© 2011 American Chemical Society
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Selectivity tuning in homogeneous catalysis generally
involves a subtle tuning of steric and electronic factors.
Separating steric and electronic influences is not always trivial,
and therefore we decided to study the comparative reactivity of
the substrates 1a (4-methylpent-1-yne) and 1b (N,N-dimethyl-
N-propargylamine) (Figure 1), which have similar steric
Table 1. Results of the Acetylene Cross-Dimerization Reactions
Figure 1. Aliphatic acetylenes 1a and 1b used in catalytic screening.
features but clearly different electronic properties (see the
Supporting Information).8
Statistical dimerization would produce the products 4−7 in
equal amounts (25% each); however, formation of the cross-
dimerization products 4 and the homodimerization products 5
is favored due to a significant difference in CH acidity and
shape between aromatic and aliphatic acetylenes.4 For example,
the reaction between 1a and 2a leads to a distribution of
products in which 4aa and 5 are clearly favored over 7 (4aa,
47%; 5, 26.5% (Ar = 2-thienyl); 7, 0%). As a logical
consequence of the fact that 2 is consumed more quickly
than 1 (due to formation of 5), a substantial amount of the
homodimerization product 6 (26.5% (Alk = Pr-i)) is formed as
a side product at the end of the reaction.
Comparison of the acetylenes 1a and 1b in the TiIII-catalyzed
cross-dimerization reactions with the aromatic acetylenes 2a−g
(Table 1) revealed a much higher reactivity and selectivity for
the nitrogen-containing substrate 1b in all cases. The reaction
with this acetylene is much faster and allows a lower catalyst
loading for the reaction to reach completion (for example, the
cross-dimerizations with acetylene 1b need 2 mol % of catalyst
A to complete the reaction in less than 10 min; under similar
conditions, cross-dimerizations with 1a require 5 mol % of A
and 1 h reaction time to completion). A detailed kinetic study
also demonstrated a clearly higher reactivity of acetylene 1b
compared to that of 1a (see the Supporting Information).
The higher selectivity of 1b is best illustrated by the
comparative reactions of 1a and 1b in the cross-dimerization
reaction with 3-thienylacetylene (2a). A tremendous improve-
ment of the selectivity is observed for 1b (from 47% to 93%;
see Table 1, entries 1 and 2). The increase in the selectivity is
evidenced by 1H NMR spectroscopy in the range δ ∼5−6 ppm
showing the 1,3-enyne methylene protons (Figure S9,
Supporting Information).
To see whether the Brønsted basicity of the amine in 1b has
any influence on the selectivity, the cross-dimerization between
2a and 1a was carried out in the presence of 1.5 equiv of tri-
ethylamine or butyldimethylamine (with respect to substrate 1a).
Clearly, this had no positive influence on the selectivity toward
cross-dimerization (46−49%, as in the base-free case). This
shows that, in contrast with late-transition-metal-catalyzed
acetylene cross-dimerization reactions,9 the higher basicity of
the reaction medium is not responsible for the increased
selectivity of 1b compared to 1a.
The influence of the change in the reactivity of the aliphatic
acetylenes on the improvement of the selectivity can be
understood from the reaction mechanism (Scheme 2). DFT
calculations at the BP86/def-TZVP level (Table 2) helped us to
evaluate and expand the mechanism originally proposed by
a
b
1
Selectivity (in C6D6), determined from H NMR spectra. Isolated
yield (reaction in pentane).
Nakamura.4 This study revealed a logical energetic profile and
some interesting new catalytic intermediates. The acetylene
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densities at Ti >60%). We thus found no indications for any
true ligand-radical behavior in the reaction mechanism of this
system.
Scheme 2. Proposed Mechanisms of the Cross-Dimerization
of Acetylenes (R = Alkyl) and Competitive Acetylene Homo-
Dimerization (R = Aryl)
The computed gas-phase free energy profile (Table 2)
reveals moderate TS1 and TS2 barriers, in good agreement
with relatively fast reactions under the experimental conditions.
The σ-bond metathesis half-cycle D−A is always favored by
aromatic acetylenes, which are more CH-acidic than the
aliphatic species. Therefore, the formation of isomeric acetylene
cross-dimer 7 (via the protonation of D by aliphatic acetylenes)
is negligible. The formation of aliphatic acetylene homodimer 6,
which includes the protonation of complex D by aliphatic
acetylenes, is very slow and is only relevant after the complete
consumption of the aromatic acetylene.11
Considering the above mechanism, the overall selectivity of
the reaction is determined by the relative formation rates of
only two species: the acetylene cross-dimer 4 versus aromatic
acetylene homodimer 5. This selectivity is determined entirely
by the acetylene insertion half-cycle A−D. The TS1 free energy
barrier (Table 2) for homocoupling of phenylacetylene 2b is
about 2 kcal mol−1 higher than the TS1 barrier for cross-
dimerization between 2b and the aliphatic acetylene 1a. This is
enough to explain the experimentally observed basic selectivity
of 63% (Table 1). Moving from 1a to the more reactive
N-acetylene 1b results in a further decrease of the TS1 barrier.
Cross-dimerization between 2b and 1b has a roughly 4 kcal
mol−1 lower barrier than the homocoupling of phenylacetylene
2b. The DFT data are thus in good agreement with the
experimental results and seem to provide a decent explanation
for the increased selectivity on going from 1a (63%) to 1b
(99%).
Table 2. Free Energies of the Catalytic Intermediates
(ΔG°298 K, kcal mol−1) on the Basis of DFT Calculations
(BP86/def-TZVP)
The computed higher reactivity of 1b stems from the
stabilization of its LUMO (CC π* orbital) compared to the
higher energy LUMO of 1a (see the Supporting Information).
This results in a stronger π coordination of substrate 1b in
intermediate B (see Table 2; for a comparison of computed
relative bond lengths and bond orders, see Table S2 in the
Supporting Information). The different metal−substrate
interaction strengths between 1a and 1b in this intermediate
appear to be determined by the nature of the SOMO, which
mainly reflects the metal to ligand π back-donation component
of the Ti−acetylene interaction (Figure 2). The lower energy of
(cross)-dimerization reaction basically consists of two main
processes: acetylene insertion into the Ti−C bond of the
acetylide intermediate A (steps A−D) and a σ-bond metathesis
process which eliminates the product and regenerates the
catalyst (steps D−A).8
The reaction starts with the formation of the active catalyst
permethyltitano(III)cene acetylide10 A from the TiIII−fulvene
precatalyst 3 and an acetylenic C−H acid (the typical reaction
pathway of the complex 3 with Brønsted acids). The active
catalyst A (Scheme 2) then reacts with another acetylene by
insertion of the π-cis-coordinated substrate (B) into the Ti−C
bond of the acetylide ligand (migratory insertion via transition
state TS1) to form C, which rearranges to form the Ti−vinyl
derivative D.
Release of the product by net protonation of the Ti−C bond
in D by an aromatic acetylene proceeds via formation of the σ
complex E followed by σ-bond metathesis (transition state
TS2), which regenerates A and completes the catalytic cycle.4
Although the calculated spin densities are partly delocalized
over their π-conjugated organic ligands, the intermediates B−E
are best described as metal-centered radicals (Mulliken spin
Figure 2. SOMO of intermediate B (left) and transition state TS1
(right) with substrate 1b.
the LUMO of 1b (compared to that of 1a) leads to stronger
π back-donation from the Ti-based SOMO in intermediate B
and transition state TS1, and this lowers the insertion barrier of
substrate 1b as compared to that of 1a (see Figure 2 and Table 2).
The unpaired electron in the SOMO of these TiIII catalysts thus
seems to be actively involved in tuning the selectivity of these
catalytic acetylene dimerization reactions (for an analysis of the
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2010, 132, 10891. (d) Dzik, W. I.; van der Vlugt, J. I.; Reek, J. N. H.;
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Tables S1 and S2 in the Supporting Information).
The above electronic effects can be combined with steric
tuning to improve the selectivity of the acetylene cross-
dimerization reaction further. To demonstrate this, we
increased the steric bulk of the aromatic acetylenes 2. The
results are presented in Table 1. A significant improvement of
the selectivity is observed, thus providing convenient catalytic
routes to a number of synthetically useful 1,3-enynes.12 The
steric effect is most pronounced for the least reactive (and thus
initially less selective) substrate 1a. For example, in the case of
the nonbulky phenylacetylenes 2b−d cross-dimerization with
1a leads to a moderate selectivity in the range between 53 and
83%, while the use of the sterically more demanding
o-substituted aromatic acetylenes 2e−g increases the selectivity
to 99% (Table 1, entries 9, 11, and 13). Some of these
selectivities are almost as high as those obtained in the reactions
with acetylene 1b. However, the cross-dimerization reactions
using 1b are always more selective than those employing 1a
(Table 1, entries 2, 4, 6, 8, 10, 12, and 14), and the combination
of steric and electronic effects gives access to almost absolute
selectivities in the reactions of 1b with the bulky acetylenes
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catalyzed cross-dimerization of acetylenes can be tuned by
subtle electronic effects. In this substrate-directed reaction,13
the different electronic properties of the acetylene substrates 1a
(4-methylpent-1-yne) and 1b (N,N-dimethyl-N-propargyl-
amine) have a large influence, and the use of 1b leads to
stronger Ti−substrate interactions in the rate- and selectivity-
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in 1b on its π*-antibonding CC orbitals (lower LUMO
energy), thus leading to stronger π back-donation interactions
from the titanium-based SOMO. This leads to faster reactions
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ASSOCIATED CONTENT
* Supporting Information
Text, tables, and figures giving experimental and computational
details, NMR spectra, and a kinetic study. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: G.V.Oshovsky@uva.nl (G.V.O.); B.deBruin@uva.nl
(B.d.B.).
■
Sorum, M. T.; Chan, C.; Harms, A. E.; Ruhter, G. J. Am. Chem. Soc.
̈
ACKNOWLEDGMENTS
■
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Zhang, F.-M.; Wang, A.-X.; Yuan, D.-Y. Chem. Commun. 2009, 2706.
(h) Trost, B. M.; Lumb, J.-P.; Azzarelli, J. M. J. Am. Chem. Soc. 2011,
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This work was supported by the Council for Chemical Sciences
of The Netherlands Organization for Scientific Research (CW-
NWO; G.V.O.) and by the European Research Council (Grant
Agreement 202886; B.d.B.).
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