Pyridine Wingtip in [Pd(Py-tzNHC)2]2+ Complex Is a Proton Shuttle in the Catalytic Hydroamination of Alkynes

Article abstract of DOI:10.1021/acs.orglett.0c00203

The cationic palladium(II) complex 1 of pyridyl-mesoionic carbene ligand catalyzes Markovnikov-selective intermolecular hydroamination between anilines and terminal alkynes into the corresponding imines. The reaction proceeds at room temperature, in the a

Full text of DOI:10.1021/acs.orglett.0c00203

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Letter
Pyridine Wingtip in [Pd(Py-tzNHC)2]2+ Complex Is a Proton Shuttle in
the Catalytic Hydroamination of Alkynes
#
#
̌
Miha Virant, Mateja Mihelac, Martin Gazvoda,* Andrej E. Cotman, Anja Frantar, Balazs Pinter,*
̌
and Janez Kosmrlj*
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ABSTRACT: The cationic palladium(II) complex 1 of pyridyl-
mesoionic carbene ligand catalyzes Markovnikov-selective intermo-
lecular hydroamination between anilines and terminal alkynes into
the corresponding imines. The reaction proceeds at room temper-
ature, in the absence of additives, with exquisite selectivity and
diverse functional group tolerance. The key intrinsic feature of the
catalyst is the pyridine wingtip confined to the proximity of the
alkynophilic metal active site, which mimics the function of enzyme-
like architectures by assisting entropically favored proton transfers.
igands that provide additional functions beyond their
traditional spectator roles are becoming increasingly
functionality in the proximity of the metal, enabling a proton-
transfer process.
To test this hypothesis and its potential utility, the
intermolecular hydroamination of terminal acetylenes 2 with
anilines 3 (Figure 2) was chosen as a model reaction, as it
would likely benefit from such a combination of metal/base
centers given the multiple proton transfers involved.
Numerous catalysts based on different metals have been
developed to promote the intermolecular catalytic hydro-
amination of terminal acetylenes.5 Palladium catalysis is rare in
hydroamination of terminal alkynes and mostly comprises the
examples developed by the groups of Schmidt,6 Huynh,7 Cao,8
and Biffis.9 These catalysts operate at elevated temperatures
(80−100 °C) and require additives (TfOH, AgOTf). The
hydroamination is sometimes accompanied by undesired side
reactions like cyclotrimerization of alkyne component,
consequently requiring a large excess of this reagent.
L
important in transition-metal catalysis.1 A metal−ligand
cooperation concept has been realized by bifunctional ligands,
mostly by establishing control of a catalytic process through
weak catalyst−substrate interactions.2 Examples where the
pyridine fragment of such a bifunctional ligand assists the
catalytic process by a proton transfer are emerging and have
been demonstrated with ruthenium3a,b and iridium3c catalysts.
In palladium catalysis, proton shuttle has been rationalized by
an SCS indenediide pincer complex.3d
A palladium(II) complex [Pd(Py-tzNHC)2]2+ 2BF4 (1,
−
Figure 1)4 was sought ideal for the metal−ligand cooperation
To assess the utility of 1, phenylacetylene 2a and (2,6-
dimethyl)aniline 3a were selected as model substrates. The test
reaction was conducted in toluene at room temperature. The
selection of this solvent was based on previously documented
good performance, albeit the reported transformations took
place at substantially higher temperatures (100 °C).7,8
Monitoring the course of the reaction revealed slow formation
Figure 1. Complexes 1 (R = CH3) and 1′ (R = H). X = BF4.
process. While pyridyl-1,2,3-triazol-5-ylidene (Py-tzNHC)
strongly stabilizes the metal through the mesoionic triazolyli-
dene (tz) NHC dent, the more labile pyridine wingtip could
play a dual role. By coordination, it internally stabilizes the
metal center throughout the preparation of the complex and,
more importantly, in the resting state of the catalytic cycle.
Upon dissociation, it should expose the Lewis acidic metal
center to enable substrates to enter the reactive zone and
initiate the catalytic cycle while acting as a local Lewis base
Received: January 14, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00203
© XXXX American Chemical Society
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Figure 3. No hydroamination occurs with complex A or B.
the pyridine wingtip of the iPEPPSI ligand indeed plays an
explicit role in the overall function of catalyst.
To expose the role of the pyridine wingtip in this catalytic
process we scrutinized the mechanism of hydroamination to
generate imine product 4b using solution-state density
functional theory (DFT) simulations carried out using DFT
as implemented in ORCA 4.0.1.2, employing the method
PBE0-D3/def2-SV(P)/RIJCOSX/Grid4,GridX4 for geometry
optimizations and PBE0-D3/def2-TZVPP/Grid5,GridX5 for
single-point calculations (Supporting Information).10 Solvation
energies in dichloromethane as solvent were computed with
the latter computational method, using the SMD implicit
solvation model. In our in silico investigation we used slightly
truncated model of the complex with 4-tolyl replaced by
phenyl group (1′, Figure 1). The methyl substituents, relatively
far from the metal center and without significant electronic
effects, do not affect the general catalytic properties of the
[Pd(Py-tzNHC)] system and overall energy barriers. Addi-
tional details of computational investigations are provided in
the Supporting Information. The energy profile of the most
likely pathway for the catalytic formation of the imine (4b)
from phenylacetylene (2a) and aniline (3b) together with a
schematic description of the operative mechanism is illustrated
in Figures 4 and 5. In addition, Figure 5 highlights five
Figure 2. Substrate scope of Pd-catalyzed intermolecular hydro-
amination. Conversion and isolated percent yields.
a
b
of the desired imine 4a. This promising finding prompted us to
screen through the reaction parameters including other
solvents, substrates ratios, catalyst loading, and concentrations.
This analysis revealed that 1 mol % loading of 1 efficiently
promoted hydroamination of phenylacetylene 2a (1.2 equiv)
with (2,6-dimethyl)aniline 3a (1.0 equiv, 0.5 M) in dichloro-
methane. Within 24 h at room temperature, the conversion
exclusively to the Markovnikov product 4a was 83%. Besides
4a, unreacted aniline 3a (17%) and the excess amounts of
acetylene 2a, without any side product, could be detected as
1
judged by H NMR analysis of the crude reaction mixture.
Using these optimal reaction conditions along with some-
what higher catalyst loadings of 2 mol % to ensure higher
conversions, we examined the substrate scope of the reaction.
As shown in Figure 2, a variety of functional groups is tolerated
including hydroxyl (as phenol), methoxy (anisole), methyl,
trifluoromethyl, ester, chlorine, bromine, and a CC double
bond in isopropenyl group. Sterically demanding anilines also
react well. Excellent results were obtained with acetylene and
aniline coupling partners having electron-releasing groups,
whereas the presence of electron-deficient substituents slightly
eroded the conversions (Figure 2). No isomeric anti-
1
Markovnikov imine could be detected by H NMR analyses
of the crude reaction mixtures in any of these experiments.
To gauge the direct involvement of the pyridine wingtip into
the hydroamination process, we performed the same reaction
as described above by using [Pd(ImNHC)] complex A and
[Pd(Ph-tzNHC)] complex B. In the latter, the ligand strongly
resembles Py-tzNHC in 1 with the pyridine wingtip being
replaced by phenyl (Figure 3). In contrast to 1, the pyridine
and NHC parts are not bound together in A and B, allowing
the complete dissociation of pyridine from the metal upon
engaging in a reaction. No product formation could be
observed in the reaction of 2a and 3a after 24 h in the presence
of these complexes, neither in dichloromethane at room
temperature nor in toluene at 100 °C. This striking difference
between the activities of 1 and complexes A and B implies that
Figure 4. Proposed reaction pathway.
chemically well-identifiable subprocesses, starting with C−N
bond formation and terminating with imine dissociation.
Competing processes and less likely alternative mechanisms for
some of these subprocesses are also discussed in detail in the
Supporting Information, together with other pathways that
were ruled out due to being unreasonably high in energy.
As expected, and previously proposed for the catalytic
hydroamination reactions,5 the operative pathway begins with
B
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transfer, then again, to the pyridine wingtip forming another
transient intermediate with pyridinium functionality (10).
Traversing TS10/11, shown in Figures 4 and 5, the proton of the
pyridinium moiety is transferred to the terminal CH2 group
forming the imine−palladium complex 11. The two-step
process from 9 to 11 is virtually identical to a conventional
base-catalyzed imine−enamine tautomerism, but the role of
the base is played by the pyridine wingtip of the Py-tzNHC
ligand.
Finally, the extrusion of the imine product 4b and the
simultaneous regeneration of catalyst 1′ occurs traversing a tbp
transition state, TS4b+1′, characterizing a classical associative
interchange ligand substitution of the imine to the pyridine
side arm. The overall reaction is exergonic by about −23 kcal
mol−1.
Figure 5. Computational energy trajectory.
Evident from the mechanisms of enamine to imine
tautomerization and first proton-transfer steps is the explicit
role of pyridine in the discovered catalytic reactivity of 1.
Namely, the moderate basicity of pyridine opens low energy
reaction channels for the former proton transfer processes
through stable pyridinium-containing intermediates, 7 and 10,
with solution-state relative stability of about 2 kcal mol−1 to
free reactants.
acetylene coordination to the catalyst (1′) forming the adduct
5 (Figures 4 and 5). In order to accommodate the acetylene
substrate in the first coordination sphere of a stable square-
planar arrangement, one of the pyridine side arms
decoordinates from the Pd(II) center in 5, allowing tight
binding of acetylene to the metal. Although unbound, as being
tethered to the mesoionic NHC ring, this pyridine remains in
the proximity (<5.0 Å) of the metal forming together a
multicenter reactive zone comprising a Lewis base and an acid
center. This replacement of the pyridine by the incoming
acetylene takes place through an associative interchange
process traversing the tbp transition state TS5 with solution-
state Gibbs free energy of 11.7 kcal mol−1. The η2 binding of
acetylene to palladium via one of its π bonds activates its
carbon atoms toward nucleophilic attack facilitating direct
carbon−nitrogen bond formation with the amine substrate.
The tell-tale structure of the corresponding transition state
(TS6), displayed in Figures 4 and 5, conforms to the expected
electronic transitions, namely, binding to the metal through an
electron rich carbon meanwhile accepting the lone-pair of the
amine at the electron deficient carbon center. This C−N bond
formation process is associated with an activation barrier of
about 23 kcal mol−1, which is surmountable under standard
conditions. While the direct product of this step, complex 6, is
not particularly stable (8.5 kcal mol−1), a subsequent
intramolecular proton transfer stabilizes the system.
This proton transfer takes place between the secondary
ammonium fragment formed upon C−N bond formation and
the liberated pyridine side arm leading to intermediate 7 with
an amine substrate and a pyridinium group. A thermodynami-
cally rather stable enamine complex, 8, is formed upon passing
of this pyridinium proton to the carbanion center of the
substrate. Both of these proton transfer events are elementary
processes associated with a low activation barrier of ∼5−7 kcal
mol−1 to the preceding intermediates and, accordingly, are
facile transformations under the experimental conditions. The
structure of TS6/7 (Figures 4 and 5) is evidence that the
pyridine side arm has an ideal distance and arrangement to
engage in structurally unconfined proton-transfer processes.
To generate the imine product (4b) from the enamine
substrate in 8, a formal imine−enamine tautomerism needs to
take place along the reaction coordinate. Our simulations
imply that such a tautomerism is most effective if the enamine
substrate binds to the metal through its amine (N)
functionality rather than via its CC (C) π bond. The
requisite C/N coordination switch of the enamine substrate
may easily occur in a single step, through TS8/9. The
tautomerization process begins from complex 9 with a proton
An experimental mechanistic investigation comprising
kinetics and KIE studies provides support for the key features
of our mechanistic proposal; a method of initial rates for the
model reaction between phenylacetylene 2a and (2,6-
dimethyl)aniline 3a revealed orders of 0.5 in acetylene, 0.3
in aniline, and 1.4 in complex 1. In addition, the use of
deuterated (2,6-dimethyl)aniline (PhND2, 3a-d2) leads to a
primary KIE of 2.1, whereas the use of PhCCD (2a-d)
results in the absence of primary KIE (1.1). These observations
are intuitive to interpret by an early pre-equilibrium (1′ + 2a =
5) and a late rate-determining proton-transfer process. Indeed,
the imine−enamine tautomerism, i.e., going from 8 to 11, is
associated with an apparent, rate-determining barrier of 25 kcal
mol−1 centered by TS10/11 and representing proton transfer
between the pyridinium group and the terminal CH2 group,
giving rise to the observed primary KIE when using 3a-d2. The
structure of this rate determining TS accounts for the modest
primary kinetic effect when deuterium is transferredthe
effect is moderate in comparison to typical KIEs of 5−6
because the structure and bonding of 8 and TS10/11 is
significantly different. While the approximate first-order
kinetics in the catalyst agrees with a metal-mediated
tautomerization process, the dependence of the rate also on
the concentrations of acetylene (0.5) and aniline (0.3) is best
explained by the slightly uphill pre-equilibrium process
between catalyst 1′ and acetylene (2a) to form adduct 5 and
subsequent C−N bond formation with aniline. Accordingly,
these experimental observations are in conceptual agreement
with the key features of the mechanism established computa-
tionally.
In conclusion, we have demonstrated that beyond mere
stabilization and activation of the (pre)catalyst’s metal center,
the pyridyl-mesoionic carbene ligand in palladium complex
−
[Pd(Py-tzNHC)2]2+ 2BF4 efficiently assists the metal along
the reaction trajectory in enzyme-like proton transfer events. In
transition-metal catalysis, the examples in which the hemi-
labiltiy of ligands is related to their catalytic properties are still
scarce, and to the best of our knowledge, this is the first
demonstration of pyridine-assisted proton shuttle in palladium
catalysis. We believe this case study is another step toward the
C
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development of novel catalytic systems that are based on these
principles.
at the Faculty of Chemistry and Chemical Technology
University of Ljubljana for HRMS analyses.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00203.
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AUTHOR INFORMATION
Corresponding Authors
■
Martin Gazvoda − Faculty of Chemistry and Chemical
Technology, University of Ljubljana, SI-1000 Ljubljana,
Slovenia; orcid.org/0000-0003-3421-0682;
Email: martin.gazvoda@fkkt.uni-lj.si
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Balazs Pinter − Departamento de Quımica, Universidad Tecnica
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́
Federico Santa Marıa, 2390123 Valparaıso, Chile;
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̌
Janez Kosmrlj − Faculty of Chemistry and Chemical
Technology, University of Ljubljana, SI-1000 Ljubljana,
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Departamento de Quımica, Universidad Tecnica Federico Santa
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Mateja Mihelac − Faculty of Chemistry and Chemical
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Andrej E. Cotman − Faculty of Chemistry and Chemical
Technology, University of Ljubljana, SI-1000 Ljubljana,
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Anja Frantar − Faculty of Chemistry and Chemical Technology,
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00203
Author Contributions
#M.V. and M.M. contributed equally.
Funding
The Slovenian Research Agency (Research Core Funding
Grant P1-0230, Project J1-8147, Project J1-9166, and Young
Researcher Grant to M.V. including support for his 6-months
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́
stay at the Universidad Tecnico Federico Santa Maria), the
Ministry of Education, Science and Sport, Republic of Slovenia
(PhD Scholarship to M.M.), and the Department of Chemistry
of UTFSM are gratefully acknowledged for financial support.
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Notes
The authors declare no competing financial interest.
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on complexation and catalytic activities of NHC complexes. Dalton
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ACKNOWLEDGMENTS
CCTVal is acknowledged for the computational resources and
Dr. Damijana Urankar from the Research Infrastructure Centre
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