Reaction Mechanism of Pd-Catalyzed “CO-Free” Carbonylation Reaction Uncovered by In Situ Spectroscopy: The Formyl Mechanism

Article abstract of DOI:10.1002/anie.202011152

“CO-free” carbonylation reactions, where synthesis gas (CO/H₂) is substituted by C1 surrogate molecules like formaldehyde or formic acid, have received widespread attention in homogeneous catalysis lately. Although a broad range of organics is available via this method, still relatively little is known about the precise reaction mechanism. In this work, we used in situ nuclear magnetic resonance (NMR) spectroscopy to unravel the mechanism of the alkoxycarbonylation of alkenes using different surrogate molecules. In contrast to previous hypotheses no carbon monoxide could be found during the reaction. Instead the reaction proceeds via the C?H activation of in situ generated methyl formate. On the basis of quantitative NMR experiments, a kinetic model involving all major intermediates is built which enables the knowledge-driven optimization of the reaction. Finally, a new reaction mechanism is proposed on the basis of in situ observed Pd-hydride, Pd-formyl and Pd-acyl species.

Full text of DOI:10.1002/anie.202011152

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Accepted Article
Title: Reaction Mechanism of Pd-catalyzed "CO-free" Carbonylation
Reaction Uncovered by In‑situ Spectroscopy: The Formyl
Mechanism
Authors: Robert Geitner, Andrei Gurinov, Tianbai Huang, Stefan
Kupfer, Stefanie Graefe, and Bert Marc Weckhuysen
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Reaction Mechanism of Pd-catalyzed “CO-free” Carbonylation
Reaction Uncovered by In-situ Spectroscopy: The Formyl
Mechanism
Robert Geitner,[a] Andrei Gurinov,[b] Tianbai Huang[c], Stephan Kupfer[c], Stefanie Gräfe[c] and Bert M.
Weckhuysen*[a]
Abstract: “CO-free” carbonylation reactions, where synthesis gas
(CO/H2) is substituted by C1 surrogate molecules like formaldehyde
or formic acid, have received wide spread attention in homogeneous
catalysis lately. Although a broad range of organics is available via
this method, still relatively little is known about the precise reaction
mechanism. In this work, we used in-situ nuclear magnetic resonance
(NMR) spectroscopy to unravel the mechanism of the
alkoxycarbonylation of alkenes using different surrogate molecules. In
contrast to previous hypotheses no carbon monoxide could be found
during the reaction. Instead the reaction proceeds via the C-H
activation of in-situ generated methyl formate. On the basis of
quantitative NMR experiments, a kinetic model involving all major
intermediates is built which enables the knowledge-driven
optimization of the reaction. Finally, a new reaction mechanism is
proposed on the basis of in-situ observed Pd-hydride, Pd-formyl and
Pd-acyl species.
pharmaceutical products.[6] Often, “CO-free” carbonylations are
catalyzed by phosphine complexes of late transition metals (i.e.,
Pd, Rh, Ru or Ir).[4]
Although “CO-free” carbonylation reactions have been
successfully applied in organic synthesis[8] relatively little is known
about the precise reaction mechanism and the associated
catalytic cycle.[2,9,10,11] One of the main scientific questions that
arises is whether CO is generated in-situ or not. If CO gas is
generated from the surrogate molecule then the “CO-free”
carbonylation reaction should proceed in the same way as a
traditional carbonylation using synthesis gas.[12] If another
reaction intermediate is formed, the reaction mechanism of a “CO-
free” carbonylation could deviate from the established mechanism.
Rosales et al.[13] elaborated on this hypothesis by investigating the
Rh-catalyzed carbonylation of 1-hexene with synthesis gas and
formaldehyde and found that the selectivity of the reaction
changed when formaldehyde was used. This observation hints at
the possibility that “CO-free” carbonylations have a different
reaction mechanism than traditional carbonylation reactions,
which goes beyond a simple surrogate decomposition reaction.
However, in contrast to the study by Rosales et al., other studies
focusing mainly on the ligand optimization and substrate scope of
Carbonylation reactions for the production of carbonyl
compounds are an important part of industrial and academic
chemistry and one of the prime examples of the successful
application of homogeneous catalysis.[1] “CO-free” carbonylations
are a special type of reaction where the toxic CO gas is
substituted by less harmful surrogate molecules, like
formaldehyde or formic acid, and have received increasing
attention in recent years as potential building blocks for a carbon-
neutral circular economy.[2,3,4–6] These surrogate molecules are
easier to handle on a small scale than a comparable synthesis
gas (a mixture of CO and H2) feedstock thus enabling a
decentralized chemical industry. It comes as no surprise that this
type of carbonylation has been used to synthesize a wide variety
of organics ranging from industrially relevant carboxylic acids[7] to
“CO-free”
carbonylation
reactions
hypothesized
that
formaldehyde and formic acid are decomposed into CO
molecules, which are sequentially used in an alkoxy carbonylation
of alkenes. This hypothesis is supported by experiments, which
reveal the release of CO when no substrate is present.[5]
[a]
Dr. R. Geitner, Prof. Dr. B.M. Weckhuysen
Inorganic Chemistry and Catalysis Group, Debye Institute for
Nanomaterials Science, Utrecht University, Universiteitsweg 99,
3584 CG Utrecht (The Netherlands).
E-mail: b.m.weckhuysen@uu.nl
[b]
[c]
Dr. A. Gurinov
NMR Spectroscopy group, Bijvoet Center for Biomolecular
Research, Utrecht University, Padualaan 8, 3584 CH Utrecht (The
Netherlands).
T. Huang, Dr. S. Kupfer, Prof. Dr. S. Gräfe
Institute for Physical Chemistry and Abbe Center of Photonics,
Friedrich Schiller University Jena, Helmholtzweg 4, 07743 Jena
(Germany).
Scheme 1. The model reaction studied in this work: Pd-catalyzed
alkoxycarbonylation of 1-octene with 13C-PFA, methyl formate, formic acid or
phenyl formate in d4-MeOH.
These contradicting results prompted the idea that reaction
mechanisms based on CO, as well as based on other, CO-
equivalent species such as formyl groups are possible.[2] As
Supporting information for this article is given via a link at the end of
the document.
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discussed, only a few reports have focused on the mechanistic
investigation of “CO-free” carbonylation reactions and those that
do often do not apply molecular techniques[14] but rather employ
macroscopic approaches, e.g. varying reactant ratios or ligand
systems.[2,10,11,13] Such a lack of mechanistic insight into this
important class of carbonylation reactions prompted us to
investigate the reaction mechanism of “CO-free” carbonylations
on the molecular level using both ex-situ and in-situ NMR
spectroscopy. NMR spectroscopy is a powerful technique that
enables quantification of multiple species at the same time while
also providing significant chemical information to identify
unknown intermediates.[15]
of industrial application. Furthermore, by using isotope labelled
chemicals it becomes possible to selectively track specific
molecular groups over the course of the reaction. Especially the
application of 13C-PFA is very beneficial to follow the track of the
most relevant carbon atoms.
Figure 1a shows ex-situ 1H NMR spectra of the studied
carbonylation reaction using 13C-PFA (see also Figures S1-8). As
1
expected, the H-NMR spectra are dominated by the signals of
1-octene in the alkyl region and at 5.41 ppm as well as the signals
of MeOH at 3.35 and 4.91 ppm. When having a more detailed look
it is possible to identify the intermediates H213C(OMe)(OH) (MM;
4.65 ppm)[18] H213C(OMe)2 (DMM, 4.53 ppm)[19], HCOOMe (MF,
8.07 ppm), the product methyl nonanoate (2.28 and 3.64 ppm),
the precatalyst activator p-toluenesulfonic acid (TsOH; 2.36, 7.21
2+
and 7.70 ppm) and the protonated ligand LH2 (7.48 and
7.74 ppm). Under the present conditions DMM is stable,
indicating that it acts as a deactivation product rather than an
intermediate.
As can be expected from the experimental design, the
formaldehyde (hemi)formals MM and DMMshow 1J(C-H) coupling.
The same is partly true for MF where both a singlet and a doublet
at 8.07 ppm (1J(C-H) = 226.6 Hz) are observed. The reason why
13C-MF is not exclusively observed is due to a hydrogenation-
dehydrogenation equilibrium between formaldehyde and MeOH.
Part of the solvent is dehydrogenated to form 12C-formaldehyde
and consequently 12C-MF. The equilibrium was previously
observed[20] and is also visible in the 1J(C-D) coupling patterns in
ex-situ 13C spectra (see Figures S6).
The surprising result of the ex-situ 1H NMR study is that MF is
the key intermediate in the carbonylation reaction and that the
reaction sequence for the relevant carbon atom is PFA → MM →
MF + 1-octene → methyl nonanoate. A similar reaction sequence
can be observed when MF is used directly (see Figures S9-18).
When formic acid (FA) or phenyl formate are used as cosubstrate,
they undergo acidic transesterification with MeOH to form MF
(see Figures S19-34). Furthermore, the 13C spectra show the
formation of CO2 (126.1 ppm) as a side product. Surprisingly, and
in contrast to previous hypotheses,[5,20] no CO formation was
detected. This is especially remarkable for phenyl formate which
is known to easily decompose into CO and phenol.[21]
To exclude the possibility that CO gas is only formed at 100 °C
and is thus not visible under ex-situ conditions, in-situ NMR
experiments were performed (see Figures S35-42). When having
a look at the carbonyl region of the in-situ 13C spectra (Figure 1b)
it becomes clear that no CO signal is visible even under in-situ
conditions. Thus, it can be concluded that the “CO-free”
carbonylation of 1-octene is indeed completely CO-free, at least
within the NMR time scale (limit of detection for CO in MeOH: 4
Figure 1. a) Selected ex-situ 1H NMR spectra measured in d4-MeOH. b)
Selected in-situ 13C NMR spectra in the carbonyl region. Importantly no CO
signal (181 - 185 ppm[16]) is observed. c) Scheme illustrating the species
considered for the microkinetic model, their possible reaction pathways and the
respective kinetic rate constants. d-e) Data points and kinetic fits of MM (blue),
MF (green), 1-octene (orange) and methyl nonanoate (red) based on the time-
dependent concentrations extracted from ex-situ 1H NMR spectra (signals
annotated in a)).
ppm, see SI for details). In
a control experiment, the
In this work, we have chosen to focus on the alkoxy
carbonylation of 1-octene using 13C-paraformaldehyde (13C-PFA),
methyl formate, formic acid or phenyl formate in d4-methanol
(d4-MeOH) applying the homogeneous catalyst [Pd(dtbpx)] (dtbpx
= 1,2-Bis(di-tert-butylphosphino)xylene, L) as a model reaction
(see Scheme 1). The chosen model reaction is a good example
of “CO-free” carbonylation reactions as 1-octene is a chemical
commonly processed in industry while dtbpx also finds application
in industry. The associated product, methyl nonanoate, is used as
a flavoring.[17] The chosen reaction thus generalizes well in terms
decomposition of 13C-MF without 1-octene was studied (see
Figure S43). In this case CO is formed and bound in the form of
[Pd(dtbpx)(CO)] (Pd1). Neither Pd1 nor pure CO is observable
when 1-octene is present. This experiment proves that NMR
spectroscopy is a suitable technique to study the appearance of
CO containing species and that our experiments are in line with
results obtained earlier via gas chromatography.[5]
In a second stage of the study, we were interested in a
microkinetic model involving all intermediates to improve the
speed of the reaction. As the concentration of PFA is not available
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from liquid state NMR we applied in-situ Raman spectroscopy to
extract its depolymerization kinetics at 100 °C.[22] With the
depolymerization rate constant at hand, we built a microkinetic
model based on quantitative in-situ Raman and ex-situ NMR
experiments (Figure 1c). The experimental concentration profiles
were fitted by varying the kinetic rate constants k1-k5 and solving
the underlying system of differential equations (see SI for details).
The concentration profiles predicted by the microkinetic model fit
the experimental data nicely (see Figure 1d,e and Figure S44).
Although a direct comparison of the extracted kinetic rate
constants is difficult because the micro reactions are of different
order, the model shows that under the present experimental
conditions (i.e., excess of 1-octene and low concentration of MF)
the formation of methyl nonanoate from MF and 1-octene seems
to be the rate determining step in the reaction. In line with this
result, the reaction is significantly faster (done in under 2 h, see
Figures S11, S21 and S29) when MF, FA or phenyl formate are
used directly as the concentration of MF is much higher in
Scheme 2. All species in boxes were directly observed in this study. Their characteristic NMR signals are given. a) Protonation and coordination chemistry of dtbpx.
b) Proposed formyl mechanism for the hydroesterification of 1-octene using PFA, MF, FA or phenyl formate as carbonyl source. The key steps are the
depolymerization of PFA into formaldehyde (I), the C-H activation of formaldehyde to form methyl formate (II), the C-H activation of methyl formate (III) and the
reductive elimination to form methyl nonanoate (IV).
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Scheme 3. Reaction sequences and their respective Gibbs free energies and activation energies for the insertion (red and orange) as well as the CO2 and CO
decomposition pathways (green and blue) as calculated by DFT (see SI for computational protocol).
these cases.
To get further insight into the catalytically active species
[Pd(dtbpx)]. A similar reaction with Pd-acyl groups was previously
reported.[26] MF is again C-H activated by [Pd(dtbpx)] to form Pd8
(III). From there either a deactivation to CO2 is possible or the fast
insertion of 1-octene into the Pd-H bond to form
[Pd(dtbpx)(COOMe)(C8H17)] or the slow decomposition into CO.
Finally, a reductive elimination reaction takes place to form methyl
nonanoate (IV). Based on this mechanism the reaction can be
described as an hydroesterification rather than an
alkoxycarbonylation. Our experiments prove that this reaction
mechanism is very general as the most important C1 CO-
surrogate molecules (PFA, FA and MF) and phenyl formate follow
this mechanism. As no major decomposition of the ligand system
was observed, we assume that the formation of insoluble Pd black
is the main deactivation pathway for the catalyst system. The
formation of Pd black is visible after 18 h.
In the final stage of our work, we used quantum chemical
simulations, i.e. density functional theory (DFT, see SI for details),
to validate the proposed mechanism. In particular, emphasis was
set on modeling the key step of the C-H activation of MF and the
possible subsequent reactions; details are shown in Scheme 3 as
well as in Figure S49 and Table S2. The DFT calculations reveal
that insertion of an alkene into the Pd-H bond (III to IVa) is
ex-situ 31P NMR experiments were performed. Even at the
beginning of the reaction a variety of phosphorous containing
species can be found in the reaction solution. By synthesizing the
reaction mixture step by step it became possible to identify
[Pd(dtbpx)(MeOH)2]2+ (Pd2) and [Pd(η2-CP-dtbpx-H)(η2-OTs)]+
(Pd3) as the main Pd species at the beginning of the reaction
which are formed from [Pd2(η4-CP-dtbpx)(µ-OAc)2]2 (Pd4) and
[Pd(η2-CP-dtbpx)(η2-OAc)] (Pd5) when MeOH and TsOH are
added (see Scheme 2a and Figure S45-48). Furthermore, it
comes as no surprise that the main phosphorous containing
species are the mono and bis protonated ligands LH+ and LH2
2+
as dtbpx and TsOH are used in excess. During the reaction
[Pd(dtbpx)(µ-H)]2 (Pd6), [Pd(dtbpx)(CHO)(H)]+ (Pd7) and
[Pd(dtbpx)(C(O)OMe)(H)]+ (Pd8) can be identified based on their
distinct NMR signals (see Scheme 2 and Table S1). Pd6 features
a hydride signal which is split into a quintet (43 Hz, see
Figure S17) which can be explained by the presence of 4
magnetically equivalent P atoms.[23] Pd7 and Pd8 are only
observable under in-situ conditions and are characterized by
distinct 13C signals at 245 and 177 ppm, respectively. Pd7 is – to
the best of our knowledge – the first report of a Pd-formyl complex. energetically favored over the insertion into the Pd-C bond (III to
Based on the quadruple reaction cycles proposed by Beller et
al.[20], the mechanistic insights of Clegg et al.[24,25] as well as our
results, we propose a new reaction mechanism for Pd-catalyzed
“CO-free” carbonylations of alkenes (see Scheme 2b). To
differentiate it from the older hydride and methoxy carbonylation
cycles[24] we suggest to call it the formyl mechanism.
The reaction starts with the depolymerization of PFA to
formaldehyde (I), which subsequently reacts with MeOH to form
MM and DMM. MM and DMM can both undergo C-H activation
but only MM can easily eliminate MeOH to form Pd7 (II). DMM
would need to eliminate MeOMe which is not possible. The formyl
group then reacts with abundant MeOH to form the key
intermediate MF and Pd6 which eliminates H2 to regenerate
IVb) (ΔGǂ = 28.2 kJ mol-1 and ΔGǂ = 156.0 kJ mol-1). Compared
to the two insertion pathways, the decomposition of MF to either
CO or CO2 is thermodynamically favored (ΔG = -38.9/ΔH
= -78.9 kJ mol-1 (III-CO) or ΔG = -121.9/ΔH = -147.7 kJ mol-1 III-
CO2), respectively), but the activation energies for the
decompositions (ΔGǂ = 118.0 and ΔGǂ = 227.7 kJ mol-1) are
much higher compared to the activation energies of the insertion.
Comparison of the two decomposition pathways reveals that CO2
formation is thermodynamically favored over the formation of CO
(ΔG = -130.8/ΔH = -102.8 kJ mol-1 for free CO2 (V-CO2) and
ΔG = 48.5/ΔH = 93.4 kJ mol-1 for free CO (V-CO), respectively)
but CO formation is kinetically favored (ΔGǂ = 227.7 kJ mol-1 for II
to III-CO2 and ΔGǂ = 118.0 kJ mol-1 for II to III-CO, respectively).
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At first, the lower activation energy for the CO formation, as
predicted by DFT, are contradicted by our experimental
observation where no CO formation was observed. However, if
for some unknown reason CO is still formed and instantaneously
consumed, the coordination of CO and subsequent insertion into
the Pd-C bond are energetically possible (see Figure S49,
ΔGǂ = 59.8 kJ mol-1 and ΔGǂ = 15.6 kJ mol-1, respectively) but
the final elimination of the methyl ester has a high activation
energy barrier (ΔGǂ = 141.1 kJ mol-1). Concluding from the DFT
calculations – and in line with our experimental observations – we
favor the idea of the C-H activation of MF followed by direct
insertion of 1-octene into the Pd-H bond at Pd8 and the
subsequent elimination of the product.
In conclusion, we have presented a detailed mechanistic
investigation of “CO-free” carbonylation reactions using in-situ
spectroscopy and quantum chemical simulations. Based on the
NMR experiments, methyl formate could be identified as the key
intermediate independent of the starting material. Based on this
information a microkinetic model, involving all intermediates, was
developed and a new reaction mechanism was proposed based
on the identification of many Pd-dtbpx complexes. A highlight is
the first direct observation of a Pd-formyl complex. The
experimental findings were supported by DFT calculations on the
key steps of the proposed reaction mechanism. Importantly, this
study showed that no CO is formed during the “CO-free”
hydroesterification of alkenes.
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Acknowledgements
R.G. gratefully acknowledges a Research Scholarship from the
German Research Foundation under the grant number
GE3112/2-1. The authors would like to thank Johan Jastrzebski
(Utrecht University) for assistance during the ex-situ NMR
measurements and the Organic Chemistry and Catalysis group at
Utrecht University for NMR measurement time. The authors thank
Hugo van Ingen and Marc Baldus for valuable advice on the NMR
experiments. A.G. is supported by uNMR-NL, an NWO-funded
National Roadmap Large-Scale Facility grant for the Netherlands
(grant no. 184.032.207). Matthias Beller is acknowledged for
helpful discussion throughout the project.
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1840.
Keywords: Carbonylation • In-situ spectroscopy • Kinetics •
Palladium • Reaction mechanism
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1326–1327.
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Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Understanding reaction mechanisms
is crucial to knowledge-driven catalyst
design. Here, NMR spectroscopy and
DFT are combined to unravel the
mechanism of “CO-free”
Robert Geitner, Andrei Gurinov, Tianbai
Huang, Stephan Kupfer, Stefanie Gräfe
and Bert M. Weckhuysen*
Page No. – Page No.
hydroesterifications. Methyl formate is
found to be the key intermediate in
this Pd-catalyzed reaction. This is
supported by the first observation of a
Pd-formyl species.
Reaction Mechanism of Pd-catalyzed
“CO-free” Carbonylation Reaction
Uncovered by In-situ Spectroscopy:
The Formyl Mechanism
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