Highly Recoverable Pd(II) Catalysts for the Mizoroki-Heck Reaction Based on N-Heterocyclic Carbenes and Poly(benzyl ether) Dendrons

Article abstract of DOI:10.1021/acs.organomet.8b00295

Two series of bis(imidazolylidene)palladium complexes of general formula [PdBr₂(NHC)₂] have been prepared. The molecular weight of the complexes was enlarged by bonding poly(benzyl ether) dendrons of increasing size (G0 to G3) at the nitrogen atom of the NHC ligands. Complexes 1-4 contain monodentate NHC ligands coordinated in a trans mode, whereas complexes 9-12 contain a chelating ethylene-bridged bis(NHC) ligand. The complexes were recovered from the product stream of a Mizoroki-Heck reaction by nanofiltration through thermally and chemically stable ceramic membranes. The recoverability is better for larger complexes and chelate ligands. In particular, chelate G3 complex 12 maintained a constant activity during the 13 recovery cycles performed, affording an accumulated turnover number (TON) of 13a€000. On average, around 99.5% of the metal is recovered in each recovery cycle, and contamination by palladium is only 3 mg per kg of product. Several models to explain the efficiency of the recovery are discussed.

Full text of DOI:10.1021/acs.organomet.8b00295

Article
Cite This: Organometallics XXXX, XXX, XXX−XXX
Highly Recoverable Pd(II) Catalysts for the Mizoroki−Heck Reaction
Based on N‑Heterocyclic Carbenes and Poly(benzyl ether) Dendrons
Alba Ortiz, Pilar Gomez-Sal, Juan C. Flores,* and Ernesto de Jesus*
́
́
Departamento de Química Organ
de Alcala, Alcala de Henares, Madrid 28871, Spain
ica y de Química Inorganica, Instituto de Investigacion Química “Andres M. del Río”, Universidad
́ ́ ́ ́
́
́
*
S Supporting Information
ABSTRACT: Two series of bis(imidazolylidene)palladium
complexes of general formula [PdBr (NHC) ] have been
2
2
prepared. The molecular weight of the complexes was enlarged
by bonding poly(benzyl ether) dendrons of increasing size (G0
to G3) at the nitrogen atom of the NHC ligands. Complexes
1
−4 contain monodentate NHC ligands coordinated in a trans
mode, whereas complexes 9−12 contain a chelating ethylene-
bridged bis(NHC) ligand. The complexes were recovered from
the product stream of a Mizoroki−Heck reaction by nano-
filtration through thermally and chemically stable ceramic
membranes. The recoverability is better for larger complexes
and chelate ligands. In particular, chelate G3 complex 12
maintained a constant activity during the 13 recovery cycles performed, affording an accumulated turnover number (TON) of
3 000. On average, around 99.5% of the metal is recovered in each recovery cycle, and contamination by palladium is only 3
mg per kg of product. Several models to explain the efficiency of the recovery are discussed.
1
INTRODUCTION
difference between the catalyst to be retained and the
■
1
molecules permeating the membrane (substrates and prod-
ucts). As such, the viability of separation may require
molecular weight enlargement of the catalyst (MWE
The Mizoroki−Heck (MH) reaction is one of the most
powerful and versatile palladium-catalyzed reactions for the
formation of C−C bonds, with widespread applications in
11
2
3
catalyst) using linear or hyperbranched polymers, dendrons
academic laboratories or on an industrial scale. An illustrative
example of the consolidated position of Pd-catalyzed couplings
in the pharma industry is that they represented 20% of the
reactions employed by GlaxoSmithKline in 2010 to discover
12
or dendrimers, or other large substituents. Retention
mechanisms involve both size exclusion and physicochemical
13
interactions of the solute with the membrane. As such, the
separation efficiency can be affected by the chemical
composition of the membrane and solution (solvent, additives,
salts, and other byproducts formed in the reaction, etc.) and
has to be evaluated under actual operating conditions. The
correct choice of membrane material is also critical for
successful separation. In this regard, the thermal, mechanical,
and chemical stability and long-term durability of ceramic
membranes gives them an initial advantage for OSN
applications compared to polymeric membranes (although
4
clinical candidates for respiratory diseases. Together with the
cost of palladium, the need to meet strict specification5s
concerning the metal content of products, particularly drugs,
is one of the main drawbacks of C−C couplings. An increase in
catalyst productivity to reduce Pd loadings from the typical
mol % level to the ppm or ppb level would therefore remove
6
these price and contamination concerns. In this regard,
numerous efforts are being directed to add recyclability to the
highly active homogeneous catalysts developed for C−C
14
the latter are currently cheaper to produce). Ceramic
7
coupling reactions.
membranes tend to be somewhat less efficient in apolar
solvents due to their hydrophilic nature but can be operated at
the high temperatures often required for continuous operation
and, in contrast to polymeric membranes, do not undergo
swelling in contact with organic solvents.
Strategies used for catalyst recovery most often confine
catalyst and substrates/products in different phases, thereby
reducing the advantages of the homogeneous process (activity,
selectivity) or introducing operational difficulties. In this
regard, organic solvent nanofiltration (OSN) is an attractive
8
OSN technologies have demonstrated their suitability for the
15
approach for the recycling of soluble organometallic catalysts
given the availability of membranes resistant to solvents. As
removal of Pd residues after a single MH reaction, thus
9
no phase transition or biphasic operation is required, OSN
reduces energy usage, is operationally simple and easy to scale-
up, and can be operated under continuous flow conditions.
However, efficient separation needs a large enough size
Special Issue: In Honor of the Career of Ernesto Carmona
Received: May 7, 2018
10
©
XXXX American Chemical Society
A
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a
allowing the isolation of products with a purity that meets the
Scheme 1. Synthesis of Bis(carbene) Pd(II) Complexes
16,5
specifications of the ICH guidelines.
Their suitability for
catalyst recycling has also been proven by examples in which
the Pd catalyst has been reutilized after OSN separation in
1
2b,17
18
batch
or continuous mode. Nevertheless, the highest
productivity achieved in OSN recyclings (around 30−40 μmol
of metal per mol of product, excluding the metal remaining in
18b
the reactor at the end of the experiment)
is not optimal
compared with other alternatives. The catalysts tested in these
experiments were mostly conventional Pd complexes of
relatively small size which, in practice, were insufficiently
retained by the membrane. Even when molecular weight
enlarged catalysts are used, metal leaching from the MWE
ligand, which reduces recoverability, and decomposition, which
19
prevents reusability, still tend to limit their recyclability.
When Herrmann and co-workers described the use of
bis(NHC)−Pd(II) complexes (NHC = N-heterocyclic carbene
20
ligand) as catalysts for the MH reaction for the first time,
they observed that these catalysts did not undergo degradation
by Pd(0) metal deposition, in contrast to the usual behavior of
most catalysts in C−C coupling reactions. Further studies
showed that cis-chelating bis-NHC ligands were particularly
21,22
suitable as stable MH catalysts.
The strength of the ligand
coordination to the metal center is one of the keys to the
23
success of NHC complexes in catalysis. For this reason, there
is an increasing interest in immobilizing transition metal
compounds to solid supports using N-heterocyclic carbene
2
4
ligands. Consequently, the development of NHC Pd
complexes for OSN recovery seems a natural, although
17b,25
relatively unexplored, alternative.
Herein we describe the synthesis of monodentate and
chelate bis(NHC)−Pd(II) complexes, the molecular weight of
which has been enlarged by bonding dendritic poly(benzyl
2
6
ether) substituents of increasing size at the nitrogen atoms of
the NHC ligand. In a previous paper, we showed that the
palladium site of related bis(NHC) complexes was not
significantly congested by dendritic poly(benzyl ether)
27
substituents up to the third generation. The semirigid and
three-dimensional structure of these dendrons should facilitate
retention of the catalyst by the membrane. In addition, for one
of these catalysts, we report quantitative conversions and Pd
losses of less than 5 μmol per mol of product in the MH
reaction used as model after 13 recovery cycles using ceramic
membranes. Although the stability of the bis(NHC)−Pd(II)
complexes and the good retention of the largest complexes
form the basis for these findings, we also discuss several
scenarios that might explain the results observed.
a
(
a) Synthesis of monoligated bis(NHC) complexes 1−4. (b)
Synthesis of imidazolium bromides 5−8. (c) Synthesis of chelate
bis(NHC) complexes 9−12.
solvents such as acetone, dimethylformamide (dmf), or
tetrahydrofuran, and insoluble in alkanes. Their solubility in
aromatic solvents increases with generation number. The trans
arrangement of the NHC ligands is supported by the single H
resonance observed for the N-bonded methylene protons (the
two protons of each group are expected to be diastereotopic in
cis isomers). The chemical shifts of around 170−171 ppm for
the carbenic carbon are also consistent with a trans
configuration since these resonances appear at lower
RESULTS AND DISCUSSION
■
1
Synthesis of Complexes. We first prepared the series of
bis(carbene) complexes 1−4 containing benzylic substituents
of increasing molecular weight at the monodentate NHC
28
ligand (Frec
́
het dendrons G0 to G3). Synthesis involved
2
2
reaction of (η :η -1,5-cyclooctadiene)dibromidopalladium(II)
27b
with the appropriate silver(I) NHC complex
in dichloro-
2
8a−c,29
methane at room temperature following the procedure
reported previously by us for related [PdBr (NHC) ]
frequencies for cis arrangements (157−165 ppm).
The
molecular structures of G0 and G1 complexes 1 and 2, which
were determined by X-ray diffraction methods (Figure 1),
show that the NHC rings are tilted between 68 and 72°
relative to the square-planar metal coordination plane. The
Pd−C (2.036(8) Å for 1 and 2.01(2) Å for 2) and Pd−Br
distances (2.394(1) and 2.458(3) Å) are within the ranges
reported for other trans-[PdBr (NHC) ] complexes in the
2
2
2
7a
dendrimers (Scheme 1a).
The bis(NHC) palladium
complexes were isolated in high yields (in general >85%) as
analytically pure white or pale-yellow solids. They were
characterized by NMR and IR spectroscopy and ESI mass
spectrometry (see Experimental Section for details). The
complexes are air-stable, soluble in chlorinated and polar
2
2
B
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lium bromides with palladium(II) acetate in dmso (Scheme
1
c). The procedure was based on a well-known method
reported by Herrmann and co-workers for the synthesis of
PdX (NHC) ] chelates and requires adequate control of the
[
2
2
20c,31
temperature ramp to attain good yields.
These complexes
were obtained as spectroscopically and analytically pure yellow
solids in yields of around 90%, irrespective of the dendritic
generation. Special care was taken to remove any trace of Pd
colloids by filtration of the solutions through a column of
+
kieselguhr. The expected monopositive ions [M − Br] were
observed in the ESI(+)-TOF mass spectra. Full synthetic and
characterization details are given in the Experimental Section.
Due to the chelate-type coordination of the bidentate ligand,
the endo and exo protons of the ethylene bridge are chemically
1
nonequivalent (see a partial view of the H NMR spectrum of
G1 complex 10 in Figure 2a). The two CH protons are also
2
diastereotopic in the methylene groups of the Gn substituents.
Figure 1. Molecular structures of complexes 1 (G0, top) and 2 (G1,
bottom). Selected bond lengths (Å) and angles (deg) for 1: Pd−
Br(1), 2.3939(13); Pd−C(1), 2.032(8); C(1)−N(1), 1.369(11);
C(1)−N(2), 1.369(11); C(1)−Pd−Br(1), 91.4(2); C(1)−Pd−
Br(1′), 88.6(2); Br(1)−Pd−Br(1′), 180; C(1)−Pd−C(1′), 180;
N(1)−C(1)−N(2), 103.8(7). Selected bond lengths (Å) and angles
(
deg) for 2 [distances and angles for the second independent unit
present in the crystal structure are given in brackets]: Pd−Br(1),
2
.4589(10) [2.4626(11)]; Pd−C(1), 2.018(9) [2.035(9)]; C(1)−
N(1), 1.382(11) [1.324(11)]; C(1)−N(2), 1.361(10) [1.380(10)];
C(1)−Pd−Br(1), 89.2(3) [90.1(3)]; C(1)−Pd−Br(1′), 90.8(3)
[
89.9(3)]; Br(1)−Pd−Br(1′), 180; C(1)−Pd−C(1′), 180.
Cambridge Structural Database (CSD): Pd−NHC 1.99−2.05
Å (mean 2.02 Å), Pd−Br 2.38−2.50 Å (mean 2.44 Å),
respectively.
Preparation of the bis(imidazolium) salts 5−8 started with
the synthesis of 1,2-di(1H-imidazol-1-yl)ethane by reaction
between imidazol and 1,2-dichloroethane (Scheme 1b).
Although the method previously described employed 1,2-
3
0
dibromoethane, we found that the use of 1,2-dichloroethane
reduced formation of the 1-vinylimidazole byproduct and
increased the yield of 1,2-di(1H-imidazol-1-yl)ethane to 65%
on a 10 g preparative scale. Subsequent reaction of this
compound with 2 equiv of the corresponding Gn−Br dendron
in acetone at 60 °C afforded 5−8 in almost quantitative yields
after a reaction time ranging from 0.5 to 3 h (larger dendrimers
required longer reaction times). The volume of acetone
employed as solvent in the reaction was critical for isolation of
the pure products in high yields as precipitation of the
bis(imidazolium) bromides favored completion of the reaction,
thereby avoiding the need for further purification steps. Any
trace of 1,2-di(1H-imidazol-1-yl)ethane contaminating the
precipitate was removed by washing the solid with hexane.
Salts 5−8 are highly hygroscopic, soluble in chlorinated
solvents, and quite insoluble in most other solvents. Intense
peaks corresponding to the expected mono- or dipositive ions
1
Figure 2. (a) Partial view of the H NMR spectrum of G1 complex
1
0, showing the protons for the three types of methylene group. The
red lines correspond to the spectrum simulated for the AA’XX’ system
formed by the ethylene bridge protons ( J = J = 5.5 Hz, J =
AX′
15.5 Hz, J = 8 Hz). (b) Molecular structure of 10. Selected bond
2
2
3
AA′
XX′
3
−
AX′
lengths (Å) and angles (deg): Pd−Br(1), 2.4960(6); Pd−Br(2),
+
2+
(
[M − Br] or [M − 2Br] ) were observed by ESI(+)-TOF
2
.4863(6); Pd−C(1A), 1.970(4); Pd−C(1B), 1.969(4); C(1A)−Pd−
mass spectrometry.
Br(1), 91.03(11); C(1B)−Pd−Br(2), 94.09(11); C(1A)−Pd−C(1B),
84.14(16); Br(1)−Pd−Br(2), 92.23(2); C(1A)−Pd−Br(2),
168.53(12); C(1B)−Pd−Br(1), 170.49(11).
The series of chelate bis(carbene) complexes, 9−12, was
synthesized by direct reaction of the corresponding imidazo-
C
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Despite this, the chemical shift differences between protons of
the same CH become progressively smaller on going from the
2
inner to the outer dendron layers. The chemical shifts of
around 160 ppm for the carbenic carbon are within the usual
28a−c,29
range for a cis arrangement (157−165 ppm).
The
molecular structure of G1 complex 10 (see Figure 2b) shows
the boatlike conformation of the seven-membered palladacycle,
with a C(1A)−Pd−C(1B) angle of 84.1(1)°. The Pd−C (1.97
Å) and Pd−Br distances (2.49 Å) almost match the mean
distances found in chelate or monodentate cis-[PdBr (NHC) ]
2
2
complexes (1.98 and 2.48 Å, respectively; CSD database
search). The internal aryl groups of the dendritic branches are
arranged almost in parallel (angle between planes of 2.7°) with
centroid−centroid and centroid−plane distances (3.875 and
3
.431 Å, respectively) suggesting the existence of π interactions
32
between these face-to-face oriented aromatic rings.
Evaluation of the Dendronized Pd−NHC Complexes
in the MH Reaction. The MH coupling between para-
iodotoluene and methyl acrylate was selected as model
reaction for this study (Scheme 2). All reactions were
Scheme 2. Model MH Reaction Tested Using Complexes
a
1−4 and 9−12 as Catalysts
Figure 3. Kinetic profiles for (a) monodentate complexes 1−4 and
(
2.
b) chelate complexes 9−12 under the conditions specified in Scheme
a
Conditions: para-iodotoluene (0.50 mmol), methyl acrylate (0.60
mmol), triethylamine (0.6 mmol), Pd complex (0.5 μmol),
naphthalene (internal standard, 0.50 mmol), and DMF (5 mL).
time employed to complete the reactions was highly dependent
on the catalyst concerned (ranging from 4.5 h for G2 complex
11 to 36 h for G3 complex 12), thus reflecting the irregular
trend of the reaction rates in the initial period as regards the
dendrimer generation (G0 < G1 < G2 > G3). Similar
irregularities in the reaction kinetics of a series of dendritic
catalysts are frequent and can be explained by the opposite
effect of increasing dendron size on the protection of the active
performed at 130 °C in dmf, with catalyst loadings of 0.1
mol %, and afforded exclusively methyl (E)-4-methylcinna-
mate. Naphthalene was used as internal standard when
monitoring the reaction by gas chromatography (GC). Several
precautions were taken to avoid misleading results. Thus,
experiments were performed in duplicate, reaction vessels
6b
36
cleaned with aqua regia to remove any Pd residue, and blank
tests routinely run to discard contamination of substrates,
sites and their accessibility.
Reactions with chelate complexes 9−12 were completed in
around 8−10 h, except for the largest G3 complex. Conversion
versus time plots show a typical sigmoid shape, with an
induction period of around 4 h for G0 catalyst 9 and somewhat
shorter for the larger catalysts (Figure 3b). Such induction
periods are associated with formation of the Pd(0) active
33
bases, or solvents with traces of Pd. As the real performance
of the catalysts might be affected by contamination with traces
of simple Pd(II) salts, which can be very active in MH
3
4
reactions, several experiments were performed in which the
catalyst solutions were pretreated with a Pd(II) scavenger,
namely, poly(4-vinylpyridine) (PVPy), and filtered before
1
d,37
species from the Pd(II) precursor
in a process in which the
3
5
1d,38
use. The kinetic profiles obtained using these pretreated
triethylamine and olefin are potential reductants.
In
catalysts were identical to those obtained without treatment
accordance with this, we observed a drastic reduction in the
induction period when the catalyst was incubated in the
presence of methyl acrylate and triethylamine at 130 °C for 3.5
h prior to the catalytic reaction (Figure 4). Preincubation with
only the olefin also reduced the induction period, although the
reaction rate was slower in this case, whereas preincubation
with only triethylamine had no apparent effect on the
induction period (Figure S4). The turnover frequencies
(TOF) determined at initial reaction times under preincuba-
tion conditions (Figure 4) show an effect of dendritic
generation on the catalytic activity (G0 < G1 < G2 > G3)
that follows a trend similar to that discussed above for the
monodentate complexes.
(
Figure S3).
A common feature of all the reactions tested here is that Pd
deposits or colloids were never detected by visual or TEM
analysis of the solutions, either during the reaction or after
completion of the process. This apparent absence of
degradation for bis-NHC catalysts was already noted by
2
0a,b
Herrmann and co-workers in their seminal studies.
Notable differences were, however, observed between the
kinetic profiles of monodentate and chelate complexes. The
conversion versus time plots for monodentate complexes 1−4
are relatively complex, with several differentiated phases,
namely, an initial period of around 2 h of elevated catalytic
activity, a second period in which the reaction is apparently
almost stopped, and a third period of slow evolution (Figure
The evolution of 9 in dmf-d in the presence of methyl
7
acrylate and triethylamine (2 equiv of each) was monitored by
1
3
a). This behavior is indicative of the probable involvement of
H NMR spectroscopy in an attempt to gain information on
different catalytic species over the course of the reaction. The
the precatalyst incubation process. Complex 9 remained largely
D
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Figure S6 for the analogous plots of 10−12). The profiles
obtained in the successive reloading cycles of a given catalyst
coincide, thus indicating the marked stability of the catalytic
system. Moreover, the induction periods are shorter in the
reloading cycles, as can be clearly observed for 9 in Figure 5.
40
As previously observed for similar catalysts, the addition of
an ammonium halide produces a comparable effect on the
induction periods and the reloading cycles are initiated in the
presence of the [NEt H]I formed during the initial cycle of the
3
MH reaction. After the induction period, the catalytic rates are
slightly dependent on the type of cycle and tend to increase in
the following order: initial cycle performed without catalyst
preincubation < reloading cycles < initial cycle with
preincubation. The catalytic system also seems quite stable
in the case of nonchelate bis(NHC) complexes 1−4, for which
similar conversions are measured at 2 and 24 h in the initial
and successive reloading cycles (Table S2).
Figure 4. Comparison of the kinetic profiles for the chelate complexes
9
−12 after preincubation of the catalysts with methyl acrylate and
triethylamine. Lines represent the data fitting to a sigmoidal curve and
are given as a guide to the eyes. The insert gives TOF values
calculated at 40% conversion.
As will be highlighted at the end of this section, the results
disclosed in the preceding paragraphs can be interpreted in
several ways. However, the absence of formation of palladium
deposits, which contrasts with the behavior frequently
observed for other Pd precursors, and the sustained activity
over the various reloading cycles suggest that the above NHC
complexes form homogeneous catalytic systems that might be
suitable for recovery by nanofiltration techniques.
unaltered when this mixture was heated for 3 h at 130 °C (see
Figures S5a,b). The presence of two new minor resonances
(
doublet at 6.85 ppm and singlet at 5.02 ppm), which
correspond to an NHC Pd complex that diffuses at a rate
comparable to that of 9 (evidenced by a DOSY experiment)
should, however, be noted. The formation of this complex is
probably a key step in the activation of 9, although all efforts to
identify it have failed thus far. Subsequent addition of aryl
iodide (1 equiv) did not produce any apparent change in the
mixture, except for formation of the biaryl coupling product
Recycling Experiments. Recycling experiments were
performed using the nanofiltration setup described in Figure
S7. For operational simplicity, a cell for dead-end filtration was
selected to demonstrate the proof of principle as cross-flow
membrane devices require a more sophisticated setup that is
not mandatory at this testing level. The filtration unit was
equipped with commercially available ceramic membranes
comprising a zirconia/titania selective layer. These membranes
resisted the complete set of recovery runs performed with each
catalyst without apparent degradation. In contrast, several
commercially available “organic solvent resistant” polymeric
membranes used in preliminary tests had to be replaced after
every recovery cycle due to evident damage. A practical
limitation of the dead-end cell is that it uses disk (flat)
membranes. Ceramic membranes with a disk geometry are
commercially available with only relatively high-molecular-
weight cutoffs (MWCO ≥ 1000 Da), while the ceramic
membranes with tubular geometries used industrially are
(
Figure S5c). These results are consistent with initial
observations that highlighted the recovery of important
amounts of the bis(NHC) precursors in MH reactions
performed at high temperature under conditions similar to
3
9
those used here. The important point here is that these
results point to the activation of only a small fraction of the
bis(NHC) precursors under these conditions.
Since the MH reactions occurred without apparent
degradation of the catalysts, the reusability of complexes 9−
1
2 was subsequently analyzed performing several reloading
experiments. After completing the initial reaction cycle, the
concentration of para-iodotoluene, methyl acrylate, and
triethylamine was restored by adding fresh reagents, and the
reaction was restarted without intermediate separation of the
products. The kinetic profiles for the initial cycle and four
reloading cycles of G0 catalyst 9 are compared in Figure 5 (see
14,41
available starting from MWCOs of a few hundred daltons.
The MWCO is defined as the minimum molecular weight of a
42
solute that is 90% retained by a given membrane. Reactions
were performed in batch mode in a conventional glass pressure
tube and transferred to the nanofiltration cell at the end of
every catalytic cycle. The cell was pressurized to obtain a flow
through the membrane of approximately 10 mL/min. Around
9
1
0% of the reaction mixture was filtered, and the remaining
0% was returned to the glass reactor and combined with
solvent and reactants to restore the initial conditions.
Recycling experiments were performed with complexes 10−
2, all of which have molecular weights above the nominal
1
MWCO of the membrane. Reactions were continued for
exactly the same time in all successive cycles for a given
catalyst, except for the initial cycle, which lasted longer (see the
Experimental Section for details). The dendritic generation of
the precatalyst had a clear effect on the evolution of the
catalytic conversions over the successive recovery cycles
(Figure 6a). Thus, while conversions abruptly fell to 50% in
the second cycle for 10, they remained above 80% for seven
Figure 5. Kinetic profiles for G0 chelate complex 9 during the initial
cycle, four consecutive reloading cycles, and the initial cycle after
preincubation of the catalyst. Conversions were measured by GC and
are referenced to the amount of aryl iodide added in each reaction
cycle.
E
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is a poor approach for assessing the recoverability of a
19
catalyst. Consequently, in addition to Pd content analysis, we
also evaluated the recoverability of 12 by determining the
kinetic profiles for several of the recovery cycles (Figure 7).
These experiments showed that the catalytic activity is almost
constant over the recovery cycles.
Figure 7. Kinetic profiles obtained by CG for the G3 chelate complex
1
3 at the initial cycle and four recovery cycles (2, 3, 10, and 13) in the
nanofiltration experiments.
Figure 6. (a) Conversions obtained in the recovery experiments after
reaction for 7 h (for 10 and 11) and 12 h (for 12) [reaction times in
the initial cycle were 12 and 16 h, respectively]. (b) Dashed lines
represent the evolution of Pd content over the successive recovery
cycles for 11 (●) and 12 (△) determined from the amount of Pd
found in the corresponding permeate. The solid line represents the
calculated evolution of Pd content for complex 12 determined from
the membrane rejection constant determined for the complex in pure
dimethylformamide (99.8%, see the Supporting Information). Pd
content is given as μmol of Pd per mol of para-iodotoluene added in
each cycle. The palladium content was quantified by ICP-MS analysis,
as described in the Supporting Information.
From an operational point of view, it is also important to
note that the ceramic membrane did not retain the ammonium
iodide formed in the reaction (Figure S8). Poor permeation of
salts through polymeric membranes often means that these
salts accumulate, thus resulting in their precipitation in the
17a,18b
reactor and introducing operational complications.
A final recovery experiment was performed with mono-
dentate G2 complex 3. However, although the molecular
weight of this complex (3309.80 Da) is close to that of chelate
G3 complex 12 (3580.08), the conversions obtained with 3
decreased below 80% after only four recovery cycles (Figure
S11). The recoverability of this monodentate bis-carbene
complex is even superseded by that of G2 chelate complex 11
despite the much smaller size of the latter. This result
highlights the potential influence of the design on the
recoverability of a catalyst.
cycles in the case of 11. For the largest precatalyst 12, almost
complete conversions were observed for the 13 cycles
performed before we decided to stop the experiment (Figure
6
a). The evolution of the Pd content over the successive
recovery cycles (dashed lines in Figure 6b; quantified by ICP-
MS analysis) shows that the better performance obtained with
the largest precatalyst is a reflection of the lower permeation of
the membrane to the Pd species present in the reaction
mixture in this case. One observation that we are currently
unable to explain is the marked Pd leaching observed in the
first recovery cycle. Possible contamination of the starting
precatalyst with low molecular weight Pd species is unlikely
considering the accurate elemental analyses and the
precautions taken in the experimental procedure (as described
above). The solid line in the upper part of Figure 6b represents
the expected evolution of the Pd content in a solution of G3
complex 12 in pure dimethylformamide submitted to several
cycles of nanofiltration recovery (the trace was determined
from the membrane rejection value of 99.8% measured for the
complex in a single experiment in the same solvent; see the
Supporting Information for details). The close similarity
between the slopes of the experimental and calculated curves
of Pd content for complex 12 from the second recovery cycle
means that permeation of the Pd species present in the
catalytic mixture is similar to what would be expected for
complexes that essentially retain the structure of complex 12.
As noted by Gladysz, the widespread use of product yield,
conversion or turnover numbers (TON) as a function of cycle
Interpretation of the Recycling Experiments. We have
shown above that Pd complexes with bidentate NHC ligands
of enlarged molecular weight are homogeneous catalysts for
the MH reaction that can be efficiently recovered using
nanofiltration techniques. In particular, the initial activity of
complex 12 was maintained after 13 recovery cycles, affording
an accumulated turnover number (TON) of 13 000 at an
−
1
average turnover frequency (TOF) of 80 h (Figure S10).
Moreover, the initial Pd loading is just 0.1 mol %, and 99.5% of
the metal is recovered, on average, in each recovery cycle
(except for the first). As such, Pd wastage is as low as 5 μmol
per mol of product, and a theoretical TON of 200 000 could
potentially be attained using 12 in a continuous reactor. The
concentration of palladium in the product (5 μmol per mol of
product or, in other words, 3 mg per kg of product) is, for
instance, within the safe concentration limit recommended by
5
ICH for orally administered drugs.
Despite the high recoverability demonstrated by complex
12, the nature of the retained species, the nature of the
activated species, and the nature of the dormant species remain
to be clarified. The starting point is the nature of the real
catalyst. The MH coupling of activated substrates can be
promoted by very small (homeopathic) amounts of ligand-free
1d,43
Pd catalysts (single atoms or small clusters).
In addition,
F
DOI: 10.1021/acs.organomet.8b00295
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
complexes catalyzing MH reactions at high temperature are
often merely reservoirs that decompose under catalytic
conditions to deliver ligand-free Pd atoms to the reaction
eliminate the NHC ligand by reductive coupling with the
49
organyl or hydride ligands. The lack of detection of Pd
nanoparticles during or at the end of the reaction should be
remembered here. For instance, analysis of the bulk solution
for samples of 9 taken at 40 and 100% conversion by dynamic
light scattering (DLS) demonstrated the absence of aggregates
above the detection limit of 0.6 nm. In addition, none of the
aggregates localized by TEM microscopy contained palladium
(energy-dispersive X-ray spectroscopy analysis, EDS). The
most conclusive evidence against this scenario is nevertheless
the clear correlation observed between recoverability and size
of the catalytic precursor.
3
5c,37a,44
medium.
Aggregation of Pd to produce metal nano-
particles and eventually Pd black deposits is a normal evolution
of the ligand-free Pd(0) species involved in the catalytic cycle.
However, there is some agreement with the hypothesis that the
MH reaction is homogeneously catalyzed in solution
4
5
irrespective of the Pd metal precatalyst and that Pd
aggregates may also be involved in the catalysis as metal
4
6
reservoirs. In this respect, we ran two classic tests intended to
distinguish between homogeneous and heterogeneous cata-
3
3e,47
lysis.
Of these, the mercury test was inconclusive. Thus, a
Scenario B. Activation of the catalytic precursor occurs
basically after decoordination of the NHC ligand, with the
unaltered precursor being recovered in this scenario. The
rejection of (small) ligand-free Pd species by the membrane
seems unlikely (and aggregation to give larger particles has not
been observed). To explain the elevated recoverability of the
G3 catalyst, it has to be assumed that the fraction of precursor
activated in each catalytic cycle is very small (maximum 0.5%
of the initially added complex). This quantity of ligand-free Pd
species might, however, be sufficient to justify the activity
observed in the MH reaction. In this scenario, the reaction
kinetics should be dependent on the rate of metal leaching
from the precursor. In the recovery experiments, the naked Pd
species are removed, and the stability of the reaction kinetics in
different catalytic cycles for G3 catalyst 12 (Figure 7) can be
easily understood. The main weakness of scenario B is that
naked Pd species should accumulate in the successive
reloading experiments. Consequently, either the reaction rate
should increase or the formation of Pd deposits should be
observed. This contradiction can be solved by making the
drop of mercury was added to the reaction mixture at 20%
conversion, but the reaction continued to a conversion of
around 70% and then stopped (Figure S12). In addition, the
reliability of the mercury test has been questioned with
homogeneous Pd−catalyzed reactions because Pd(0) inter-
mediates can react with Hg, thereby poisoning the
47b,c,48
homogeneous catalyst.
The Collman test is based on
the difficulty of large aggregates to diffuse into the polymeric
matrix of a substrate anchored to a polymer (for this test, 4-
iodobenzoate groups were attached to a Wang resin). The
observation of reactivity under similar conditions to those
employed for soluble substrates, as was the case for the two
catalysts tested here (9 and 12; see the Supporting Information
for details), is considered a symptom of homogeneous
catalysis. It should also be noted at this point that the high
reproducibility of the kinetic profiles observed in the above
reactions is more typical of homogeneous catalysis. Evidence
for or against several possible scenarios involving NHC-ligated
complexes, ligand-free species, and metal aggregates (Scheme
3
), in which the possibility of MH catalysis by Pd nanoparticles
(
undemonstrated) assumption that NHC decoordination can
has not been considered for the reasons indicated above, is
analyzed below.
be reversed at the end of the catalytic reaction.
Scenario C. The NHC ligand remains coordinated in the
active species formed during the catalytic cycle and in the
dormant species formed between recovery cycles. This is the
simplest scenario and explains most of the observations
Scheme 3. Several Simplified Scenarios for Interpretation of
the Recovery Experiments
50
discussed in this report. As pointed out by Gladysz, the
induction period in the recovery cycles suggests that the
catalyst is not being recycled in its active form.
CONCLUSIONS
■
Herein we have reported the recovery of Pd catalysts in a
model MH reaction by means of organic solvent nanofiltration
techniques (OSN). A strategy was designed on the basis of the
strong coordination of monodentate or chelate NHC ligands
to the Pd center, the size of which was enlarged by the
attachment of poly(benzyl ether) dendrons. We have found
that the recoverability is better for larger complexes and
chelate ligands. In particular, chelate G3 complex 12
maintained a constant activity during the 13 recovery cycles
performed, at the end of which the reactor conserved almost
90% of the initial Pd content. As a consequence, contamination
of the coupling product with palladium was very low (3 mg per
kg of product, below international specifications for orally
administered drugs). In addition, catalyst separation was
performed using ceramic membranes, which are very stable
to organic solvents and under astringent reaction conditions (a
feature highly desirable for continuous flow operation). These
results are encouraging and permit us to anticipate the viability
of implementing the process under continuous flow operation,
Scenario A. Marked decomposition of the NHC precursor
results in the liberation of naked Pd species, which are the real
active species. In the presence of an excess of olefin and amine,
Pd(0) species are prevalent in solution at the end of the
reaction, and their aggregation might produce metal nano-
particles that would be easily recovered due to their high
molecular weight. Detachment of palladium from the NHC
complexes can be favored under MH conditions because
(
NHC) Pd(II) aryl, alkenyl, or hydride intermediates can
x
G
DOI: 10.1021/acs.organomet.8b00295
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
OCH Ph), 5.48 (s, 8H, NCH Ar), 6.39 (t, JH,H = 2.3 Hz, 4H, p-
2 2
4
with the practical advantage that OSN technologies are easily
adaptable to both micro- or large-scale syntheses.
G0
4
G0
Ar ), 6,46 (d, J
Ar , o-Ar , and Imz), 7.22−7.36 (m, 80H, Ph). C{ H} NMR
= 2.3 Hz, 8H, o-Ar ), 6.55−6.58 (m, 28H, p-
H,H
G1
G1
13 1
Although several scenarios have been analyzed to explain
these results, further studies are needed to disclose the basis of
the high recyclability of the bis(NHC) complexes. Preformed
complexes enlarged with (expensive) dendrons are surely not
the ideal approach to obtain catalysts for practical applications.
However, these well-defined molecular catalysts working under
homogeneous conditions can be studied using the powerful
techniques available to the molecular chemist. Recovery
mechanisms are often poorly understood due to the difficulties
associated with poorly defined catalytic systems working in a
heterogeneous catalytic medium.
(
CDCl ): δ 54.2 (CH ), 69.8 (OCH Ar), 69.9 (OCH Ph), 101.46 (p-
3
2
2
2
G1
G0
G1
G0
Ar ), 102.1 (p-Ar ), 106.3 (o-Ar ), 107.1 (o-Ar ), 121.2 (Imz−
C ), 127,5 and 128,5 (o- and m-Ph), 127.0 (p-Ph), 136.8 (ipso-Ph),
1
1
CNC), 1294 (m, C−O−C ), 1154 and 1053 cm (s, C−O−C ). MS
(ESI -TOF in CH Cl /MeOH/NH HCOO 5 mM): m/z 3148.18
4
,5
G0
G1
G1
G0
38.6 (ipso-Ar ), 139.3 (ipso-Ar ), 159.9 (m-Ar ), 160.0 (m-Ar ),
2
69.7 (Imz−C ). IR (KBr): ν 1595 and 1451 (s, C−Carom), 1497 (s,
−
1
as
s
+
2
2
4
+
[M − 2Br + H] (calcd 3148.18).
G3
Bis(1,3-bis{3,5-bis[ω-octahydro-dendro -(oxymethyleneben-
z e n e - 1 , 3 , 5 - t ri y l) -α - y l ] be n z y l } im id a z o l- 2 - y l id e n e ) -
dibromidopalladium(II) (4). [PdBr (cod)] (0.016 g, 0.043 mmol)
2
and [AgBr(1,3-bis(G3)imidazol-2-ylidene)] (0.290 g, 0.0851 mmol).
Yield: 199 mg (70%). Anal. Calcd (%) for C426H368N O Br Pd
4
56
2
EXPERIMENTAL SECTION
(6705.70): C, 76.30; H, 5.53; N, 0.84. Found: C, 76.10; H, 5.41; N,
■
1
G1
2
6
0.95. H NMR (CDCl
3
): δ 4.66 (s, 16H, OCH
2
Ar ) 4.72 (s, 32H,
General Procedures and Materials. Gn−Br dendrimers,
G2
5
1
OCH Ar ), 4.81 (s, 64H, OCH Ph), 5.42 (s, 8H, NCH Ar), 6.35
2
2
2
[
PdBr (cod)], and (1,3-bis(Gn)imidazol-2-ylidene)bromidosilver-
2
G0
G1
2
7b
(broad d, 8H, o-Ar ), 6.39 (broad t, 8H, p-Ar ), 6.43 (broad t, 20H,
(
I)
were prepared as described in the literature. Other general
G0,G2
G1,G2
p-Ar
1
(
1
(
1
1
), 6.53 (broad d, 52H, o-Ar
and Imz), 7.15−7.26 (m,
procedures and materials, and the modified procedure for the
synthesis of 1,2-di(1H-imidazol-1-yl)ethane, are described in the
Supporting Information. The following abbreviations/notations are
used: Imz refers to the imidazole ring, Ph refers to terminal, and Ar
refers to internal aromatic rings in poly(benzyl ether) dendrons, and
ipso refers to the first ring-position on going from the azole ligand.
1
3
1
60H, Ph). C{ H} NMR (CDCl ): δ 54.4 (CH ), 69.7
3
2
G2
G1
G0,G1,G2
OCH Ar ), 69.9 (OCH Ar and OCH Ph), 101.5 (p-Ar
),
2
2
2
G1,G2
G0
4,5
06.4 (o-Ar
), 106.9 (o-Ar ), 121.4 (Imz−C ), 127.5 and 128.5
G0
o- and m-Ph), 127.8 (p-Ph), 136.7 (ipso-Ph), 138.7 (ipso-Ar ),
39.2 (ipso-Ar ), 139.3 (ipso-Ar ), 159.8 (m-Ar ), 159.9 (m-Ar ),
59.7 (m-Ar ), 169.8 (Imz−C ). IR (KBr): ν 1595 and 1451 (s, C−
G1
G2
G1
G2
G0
2
Preparation of Complexes trans-[PdBr (NHC) ] (1−4).
2
2
−1
C
), 1497 (s, CNC), 1294 (m, C−O−C ), 1151 and 1052 cm (s,
arom
as
[
PdBr (cod)] was added to a Schlenk tube containing a solution of
2
+
C−O−C ). MS (ESI -TOF in CH Cl /MeOH/NH HCOO 5 mM):
s
2
2
4
the appropriate [AgBr(NHC)] complex in dichloromethane (25 mL).
The reaction mixture was then stirred at room temperature for 1 h
1), 3 h (2 and 3), or 6 h (4). The suspension was subsequently
+
m/z 6541.52 [M − 2Br + H] (calcd 6541.52).
Synthesis of Bis(imidazolium) Bromides (5−8). A solution of
,2-di(1H-imidazol-1-yl)ethane and benzyl bromide in acetone was
(
1
filtered, the solution evaporated to dryness under vacuum, and the
residue washed with hexane (3 × 15 mL) and dried under vacuum.
Complexes 1−4 were isolated as white or pale-yellow solids. Complex
stirred at 60 °C for the time specified for each compound. Once this
reaction time passed, the white precipitate was separated by filtration
and dried under vacuum. Any trace of 1,2-di(1H-imidazol-1-yl)ethane
remaining in the final product was removed by successive washings
with hexane.
4
was purified by chromatography over silica gel using dichloro-
methane/ethyl acetate (1:1) as the eluent.
Bis(1,3-bis(benzyl)imidazol-2-ylidene)dibromidopalladium(II)
1
,1′-Bis(benzyl)-3,3′-(ethane-1,2-diyl)diimidazolium Dibromide
(
1). [PdBr (cod)] (0.376 g, 1.00 mmol) and [AgBr(1,3-bis(G0)-
2
(
5). 1,2-Di(1H-imidazol-1-yl)ethane (0.500 g, 3.08 mmol), benzyl
imidazol-2-ylidene)] (0.877 g, 2.01 mmol). Yield: 689 mg (90%).
Anal. Calcd (%) for C H Br N Pd (762.87): C, 53.53; H, 4.23; N,
bromide (0.73 mL, 6.16 mmol), and acetone (15 mL). Reaction time:
30 min. Yield: 1.55 g (100%). Anal. Calcd (%) for C H N Br
2
3
4
32
2
4
1
7
8
8
1
.34. Found: C, 52.95; H, 4.25; N, 7.16. H NMR (CDCl ): δ 5.70 (s,
22 24
4
3
(
504.27): C 52.40; H 4.80; N 11.11%. Found: C 52.15; H 4.58; N
H, CH ), 6.62 (s, 4H, Imz), 7.26−7.28 (m, 12H, Ph), 7.41−7.43 (m,
2
1
13
1
4,5
11.24%. H NMR (dmso-d ): δ 4.71 (s, 4H, CH CH ), 5.41 (s, 4H,
H, Ph). C{ H} NMR (CD Cl ): δ 55.1 (CH ), 121.7 (Imz−C ),
6 2 2
2
2
2
4
or5
CH ), 7.34−7.40 (m, 10H, Ph), 7.68 (s, 2H, Imz−H ), 7.81 (s, 2H,
28.7 and 129.3 (o- and m-Ph), 129.1 (p-Ph), 136.9 (ipso-Ph), 170.7
2
4
or5
2
13
1
2
Imz−H ), 9.26 (s, 2H, Imz−H ). C{ H} NMR (dmso-d ): δ 47.9
(
Imz−C ). IR (KBr pellet): ν 1603 and 1454 (s, C−Carom), 1495
6
4,5
−
1
+
(CH CH ), 51.5 (CH ), 122.4 (Imz−C ), 127.7 (m-Ph), 128.3 (p-
cm (s, CNC). MS (ESI -TOF in CH Cl /MeOH/NH HCOO 5
2
2
2
2
2
4
2
+
Ph), 128.4 (o-Ph), 133.9 (ipso-Ph), 136.2 (Imz−C ). IR (KBr): ν
mM): m/z 681.08 [M − Br] (calcd 681.08).
−
1
+
G1
1
557 and 1454 (s, CC), 1497 cm (m, CNC). MS (ESI -TOF,
Bis(1,3-bis{3,5-bis[ω-dihydro-dendro -(oxymethylenebenzene-
,3,5-triyl)-α-yl]benzyl}imidazol-2-ylidene)dibromidopalladium(II)
+
1
(
dmso): m/z 423.12 [M − Br] (calcd 423.12).
G1
2). [PdBr (cod)] (0.043 g, 0.11 mmol) and [AgBr(1,3-bis(G1)-
1,1′-Bis(3,5-bis[ω-dihydro-dendro -(oxymethylenebenzene-
2
imidazol-2-ylidene)] (0.200 g, 0.232 mmol). Yield: 160 mg (90%).
Anal. Calcd (%) for C H N O Br Pd (1611.85): C, 67.06; H, 5.00;
1,3,5-triyl)-α-yl]benzyl)-3,3′-(ethane-1,2-diyl)diimidazolium Dibro-
mide (6). 1,2-Di(1H-imidazol-1-yl)ethane (1.02 g, 6.30 mmol), G1−
Br (4.82 g, 12.6 mmol), and acetone (50 mL). Reaction time: 2.5 h.
9
0
80
4
8
2
1
N, 3.48. Found: C, 66.64; H, 5.00; N, 3.58. H NMR (CDCl ): δ 4.88
3
4
(
s, 16H, OCH Ph), 5.60 (s, 8H, NCH Ar), 6.45 (t, J = 2.2 Hz,
Yield: 5.84 g (100%). Anal. Calcd (%) for C50
C 64.66; H 5.21; N 6.03%. Found: C 64.61; H 4.82; N 5.89%. H
NMR (dmso-d ): δ 4.66 (s, 4H, CH CH ), 5.03 (s, 8H, OCH Ph),
5.25 (s, 4H, NCH Ar), 6.61 (broad s, 6H, o-Ar and p-Ar), 7.30−7.35
(m, 20H, Ph), 7.65 (s, 2H, Imz−H ), 7.73 (s, 2H, Imz−H ), 9.33
H N O Br (928.75):
48 4 4 2
2
2
H,H
4
,5
4
1
4
7
7
H, p-Ar), 6.62 (s, 4H, Imz−H ), 6.71 (t, J = 2.2 Hz, 8H, o-Ar),
H,H
13 1
.25−7.30 (m, 40H, Ph). C{ H} NMR (CDCl ): δ 54.6 (CH ),
6
2
2
2
3
2
4
,5
0.1 (OCH Ph), 102.1 (p-Ar), 107.4 (o-Ar), 121.3 (Imz−C ), 127.6
2
2
4
or5
4or5
and 128,4 (o- and m-Ph), 127.8 (p-Ph), 136.7 (ipso-Ph), 138.4 (ipso-
2
2
13
1
Ar), 160.1 (m-Ar), 169.7 (Imz−C ). IR (KBr): ν 1595 and 1452 (s,
(s, 2H, Imz−H ). C{ H} NMR (dmso-d
): δ 47.9 (CH CH ), 51.5
6 2 2
C−C ), 1497 (s, CNC), 1294 (m, C−O−C ), 1152 and 1058
(NCH Ar), 68.9 (OCH Ph), 100.9 (p-Ar), 104.1 (o-Ar), 122.3 (Imz−
C ), 127.7 (m-Ph), 127.4 (p-Ph), 127.9 (o-Ph), 136.0 (ipso- Ar),
2
2
arom
as
−
1
+
4,5
cm (s, C−O−C ). MS (ESI -TOF in CH Cl /MeOH/NH HCOO
s
2
2
4
+
+
2
5
1
mM): m/z 1626.37 [M + NH ] , 1451.52 [M − 2Br + H] (calcd
136.1 (ipso-Ph), 136.2 (Imz−C ), 159.3(m-Ar). IR (KBr): ν 1598 and
4
451.51).
1444 (s, CC), 1497 (m, CNC), 1302 (m, C−O−Cas), 1164 and
G2
−1
+
Bis(1,3-bis{3,5-bis[ω-tetrahydro-dendro -(oxymethyleneben-
1058 cm (s, C−O−C
s
). MS (ESI -TOF, dmso): m/z 847.29 [M −
+
z e n e - 1 , 3 , 5 - t r iy l ) - α- y l ] b e n z y l} i m i d a z o l - 2 -y l i d e n e ) -
Br] (calcd 847.29).
G2
dibromidopalladium(II) (3). [PdBr (cod)] (0.022 g, 0.059 mmol)
2
1,1′-Bis(3,5-bis[ω-tetrahydro-dendro -(oxymethylenebenzene-
1,3,5-triyl)-α-yl]benzyl)-3,3′-(ethane-1,2-diyl)diimidazolium Dibro-
mide (7). 1,2-Di(1H-imidazol-1-yl)ethane (250 mg, 1.54 mmol),
G2−Br (2.49 g, 3.08 mmol), and acetone (30 mL). Reaction time: 7.0
h. Yield: 2.66 g (97%). Anal. Calcd (%) for C H N O Br
2
and [AgBr(1,3-bis(G2)imidazol-2-ylidene)] (0.200 g, 0.117 mmol).
Yield: 164 mg (85%). Anal. Calcd (%) for C202H176Br N O Pd
2
4
24
(
1
3309.80): C, 73.30; H, 5.36; N, 1.69; Found: C, 72.22; H, 5.44; N,
1
G1
.83. H NMR (CDCl ): δ 4.76 (s, 16H, OCH Ar ), 4.89 (s, 32H,
3
2
106 96
4
12
H
DOI: 10.1021/acs.organomet.8b00295
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
(
3
1777.72): C 71.61; H 5.44; N 3.15%. Found: C 71.31; H 5.52; N
1595 and 1452 (s, CC), 1497 (m, CNC), 1319 (m, C−O−C ),
as
1
−1
+
.23%. H NMR (dmso-d ): δ 4.66 (s, 4H, CH CH ), 4.98 (s, 8H,
1152 and 1058 cm (s, C−O−C ). MS (ESI -TOF, CH Cl /
6
2
2
s
2
2
G1
+
OCH Ar ), 5.04 (s, 16H, OCH Ph), 5.26 (s, 4H, NCH Ar), 6.56−
6
MeOH/HCOONH 5 mM): m/z 951.17 [M − Br] (calcd 951.17).
2
2
2
4
G0,G1
G2
.68 (m, 18H, Ar
), 7.27−7.40 (m, 40H, Ph), 7.65 (s, 2H, Imz−
), 7.76 (s, 2H, Imz−H ), 9.20 (s, 2H, Imz−H ). C{ H}
(1,1′-Bis(3,5-bis[ω-tetrahydro-dendro -(oxymethylenebenzene-
4or5
4or5
2
13
1
H
1,3,5-triyl)-α-yl]benzyl)-3,3′-methylenediimidazol-2,2′-diyliden)-
dibromidopalladium(II) (11). Pd(OAc) (63 mg, 0.28 mmol), 7 (500
NMR (dmso-d ): δ 47.9 (CH CH ), 51.5 (NCH Ar), 68.7
2
6
2
2
2
G1,G2
G0,G1,G2
mg, 0.28 mmol), and dmso (3 mL). Yield: 474 mg (90%). Anal. Calcd
(%) for C106H N O PdBr (1882.13): C 67.64; H 5.03; N 2.98%.
(
Ar
OCH Ar
and OCH Ph), 100.4 (p-Ar
), 105.9 (o-
2
2
G0,G1,G2
4,5
), 122.5 (Imz−C ), 127.1 (m-Ph), 127.3 (p-Ph), 127.8
94
4
12
2
1
G0,G1
2
G2
Found: C 67.37; H 4.90; N 3.21%. H NMR (CDCl ): δ 4.14 (m, 2H,
(
o-Ph), 136.2 (ipso-Ar
and Imz−C ), 138.3 (ipso-Ar ), 138.6
). IR (KBr): ν 1589 and 1453 (s, C
3
G0,G1,G2
CHHCHH), 4.80 (m, 8H, OCHHAr), 4.89 (m, 16H, OCHHPh),
(ipso-Ph), 158.9 (m-Ar
2
−
1
4.97 (d, 2H, J = 14.4, NCHHAr), 5.32 (overlapping resonances,
C), 1497 (m, CNC), 1295 (m, C−O−C ), 1110 and 1076 cm (s,
H,H
as
G0
+
2+
4H, CHHCHH and NCHHAr), 6.40 (t, 2H, p-Ar ), 6.42 (d, 4H, o-
Ar ), 6.47 (t, 4H, J = 2.0, p-Ar ), 6.55 (overlapping d; 8H, J
C−O−C ). MS (ESI -TOF, dmso): m/z 808.35 [M − 2Br] (calcd
s
G0
3
G1
3
1
616.70).
,1′-Bis(3,5-bis[ω-octahydro-dendro -(oxymethylenebenzene-
H,H
H,H
G1
3
G3
= 2.0, o-Ar ; 2H, Imz), 6.66 (d, 2H, J = 1.9, Imz), 7.25−7.38 (m,
13 1
1
H,H
1
,3,5-triyl)-α-yl]benzyl)-3,3′-(ethane-1,2-diyl)diimidazolium Dibro-
40H, Ph). C{ H} NMR (CDCl
3
): δ 47.9 (CH
2
CH
2
), 54.7
G1
G1
4,5
mide (8). 1,2-Di(1H-imidazol-1-yl)ethane (19.6 mg, 0.12 mmol),
G3−Br (400 mg, 0.24 mmol), and acetone (10 mL). Reaction time:
(NCH Ar), 70.0 (OCH Ar and OCH Ph), 101.4 (p-Ar ), 103.3
(p-Ar ), 106.4 (o-Ar ), 107.5 (o-Ar ), 122.2 (Imz−C ), 127.6
(m-Ph), 128.0 (p-Ph), 128.5 (o-Ph), 136.7 (ipso-Ph), 139.0 (ipso-
2
2
2
G0
G1
G0
1
7.0 h. The solid thus obtained was washed with hexane until any
G0
G1
G1
G0
trace of 1,2-di(1H-imidazol-1-yl)ethane was removed (3 × 15 mL).
Yield: 1.68 g (84%). Anal. Calcd (%) for C218H192N O Br
(
2
OCH Ar ), 5.00 (s, 48H, OCH Ar and OCH Ph), 5.24 (s, 4H,
NCH Ar), 6.56−6.64 (m, 42H, Ar
7
Ar ), 139.9 (ipso-Ar ), 159.9 (m-Ar ), 160.05 (m-Ar and Imz−
2
C ). IR (KBr): ν 1595 and 1451 (s, CC), 1497 (m, CNC), 1321
4
28
2
−
1
+
3475.68): C 75.33; H 5.57; N 1.61%. Found: C 74.43; H 5.23; N
(m, C−O−C ), 1153 and 1053 cm (s, C−O−C ). MS (ESI -TOF,
as
s
1
+
.05%. H NMR (dmso-d ): δ 4.64 (s, 4H, CH CH ), 4.95 (s, 8H,
CH
2
Cl
2
/MeOH/HCOONH
4
5 mM): m/z 1799.51 [M − Br] (calcd
6
2
2
G1
G2
1799.51).
2
2
2
G0,G1,G2
G3
), 7.20−7.35 (m, 80H, Ph),
(1,1′-Bis(3,5-bis[ω-octahydro-dendro -(oxymethylenebenzene-
2
4or5
4or5
.63 (s, 2H, Imz−H ), 7.74 (s, 2H, Imz−H ), 9.21 (s, 2H, Imz−
1,3,5-triyl)-α-yl]benzyl)-3,3′-methylenediimidazol-2,2′-diyliden)-
2 13 1
dibromidopalladium(II) (12). Pd(OAc) (9 mg, 0.041 mmol), 8 (145
H ). C{ H} NMR (dmso-d ): δ 47.9 (CH CH ), 52.5 (NCH Ar),
2
6
2
2
2
G1
G1
G0
mg, 0.041 mmol), and dmso (1.5 mL). Yield: 133 g (89%). Anal.
Calcd (%) for C218H190N O Br Pd (3580.08): C 73.14; H 5.35; N
6
8.8 (OCH Ar , OCH Ph), 100.4 (p-Ar ), 100.9 (p-Ar ), 106.0
2 2
G1
G0
4,5
(o-Ar ), 107.1 (o-Ar ), 122.3 (Imz−C ), 127.1 (m- and p-Ph),
4
28
2
1
G0,G1
2
1.56%. Found: C 73.32; H 5.62; N 1.82%. H NMR (CDCl ): δ
1
27.8 (o-Ph), 136.30 (ipso-Ar
59.0(m-Ar
and Imz−C ), 138.4 (ipso-Ph),
3
G0,G1
3.84−4.00 (m, 2H, CHHCHH), 4.69−5.10 (m, 58H, NCHHAr,
1
). IR (KBr): ν 1596 and 1451 (s, CC), 1497 (m,
G1,G2
−
1
OCH Ar
, and OCH Ph), 5.11−5.42 (m, 4H, NCHHAr and
CNC), 1298 (m, C−O−C ), 1158 and 1054 cm (s, C−O−C ). MS
(
2
2
a
s
s
G0 G0
+
+
CHHCHH), 6.35 (broad s, 2H, p-Ar ), 6.39 (broad s, 4H, o-Ar ),
ESI -TOF, dmso): m/z 3392.29 [M − Br] (calcd 13392.29).
Preparation of Complexes [PdBr (NHC NHC)] (9−12). A
G1
G2
∧
6.42 (broad s, 4H, p-Ar ), 6.48 (broad s, 8H, p-Ar ), 6.54 (broad s,
2
G1
G2
8
2
H, o-Ar ), 6.58 (broad s, 18H, o-Ar and Imz−H), 6.61 (broad s,
mixture of Pd(OAc) and the corresponding bis(imidazolium)
2
13 1
H, Imz), 7.23−7.34 (m, 80 H, Ph). C{ H} NMR (CDCl ): δ 47.9
bromide was dissolved in dmso and heated at 50 °C for 2 h. The
temperature was then increased to 110 °C at a rate of 0.5 °C/min and
maintained at 110 °C for 1 h. The greenish solution was subsequently
filtered through kieselguhr, and the column washed with dichloro-
methane (2 × 5 mL). The dmso and dichloromethane filtrates were
combined and evaporated to dryness under vacuum. After dissolution
of the residue in dichloromethane (10 mL) and addition of hexane
3
G1,G2
(
CH CH ), 54.7 (NCH Ar), 69.7 (OCH Ar
), 69.9 (OCH Ph),
), 107.5 (o-Ar ),
2
2
2
2
2
G1,G2
G0
G1,G2
G0
1
01.5 (p-Ar
), 102.7 (p-Ar ), 106.3 (o-Ar
4
,5
1
24.6 (Imz−C ), 127.5 (m-Ph), 128.0 (p-Ph), 128.5 (o-Ph), 136.7
G2,G3
G0
G1
G2
(
ipso-Ar
), 139.1 (ipso-Ar ), 139.3 (ipso-Ar ), 159.9 (m-Ar ),
G0,G1
2
1
60.05 (m-Ar
and Imz−C ). IR (KBr): ν 1596 and 1451 (s, C
−
1
C), 1497 (m, CNC), 1299 (m, C−O−C ), 1158 and 1052 cm (s,
as
+
C−O−C ). MS (ESI -TOF, CH Cl /MeOH/HCOONH 5 mM):
(
15 mL), the precipitate was separated by filtration and dried under
s
2
2
4
+
m/z 3496.18 [M − Br] (calcd 3496.18).
vacuum to give corresponding complex 9−12 as a yellow solid.
Catalytic and Recovery Studies. MH Reaction. Methyl acrylate
0.90 mL, 10 mmol), para-iodotoluene (1.83 g, 8.5 mmol),
(
1,1′-Bis(benzyl)-3,3′-methylenediimidazol-2,2′-diyliden)-
(
dibromidopalladium(II) (9). Pd(OAc) (86 mg, 0.38 mmol), 5 (193
mg, 0.38 mmol), and dmso (1.2 mL). Yield: 215 mg (93%). Anal.
Calcd (%) for C H N PdBr (608.66): C 43.41; H 3.64; N 9.20%.
Found: C 43.77; H 3.57; N 9.58%. H NMR (CDCl ): δ 4.60 (m, 2H,
CHHCHH), 5.25 (d, 2H, J
NCHHPh), 5.60 (m, 2H, CHHCHH), 6.76 (d, 2H, J = 2.0, Imz),
7
δ 47.8 (CH CH ), 54.7 (NCH Ph), 122.2 (Imz−C ), 124.9 (Imz−
C
2
triethylamine (1.39 mL, 10 mmol), and naphthalene (1.08 g, 8.5
mmol) were dissolved in dmf (50.0 mL). An aliquot of this solution
22
22
4
2
1
(
3 mL) was then transferred to a glass ampule together with 1 mL of a
3
2
freshly prepared solution of the corresponding catalyst (25 μmol) in
dmf (50 mL). The overall reaction volume was completed with an
additional amount of dmf (1 mL). The reaction time was started
when the ampule was introduced into a silicone bath previously
warmed to 130 °C. The reaction progress was monitored by gas
chromatography, using the added naphthalene as an internal
reference. At the end of the reaction, the volatiles were removed in
vacuo, the residue extracted with dichloromethane (20 mL), and the
= 14.8, NCHHAr), 5.59 (d, 2H,
H,H
3
H,H
1
3
1
.12 (d, 2H, Imz), 7.23−7.37 (m, 10H, Ph). C{ H} NMR (CDCl ):
3
4or5
2
2
2
4or5
), 128.4 (m-Ph), 128.6 (p-Ph), 128.9 (o-Ph), 135.4 (ipso-Ph),
2
−1
1
(
59.4 (Imz−C ). IR (KBr): ν 1557 and 1454 (s, CC), 1497 cm
+
m, CNC). MS (ESI -TOF, CH Cl /MeOH/HCOONH 5 mM):
2
2
4
+
m/z 527.01 [M − Br] (calcd 527.01).
G1
(
1,1′-Bis(3,5-bis[ω-dihydro-dendro -(oxymethylenebenzene-
organic phase washed with water (3 × 15 mL), dried over MgSO4,
and evaporated to dryness. The methyl (2E)-3-(4-methyl)-
phenylprop-2-enoate product thus obtained was weighed and the
yield compared with that measured by GC.
Recovery Procedure. The MH reactions were performed as
specified above in pressure ampules of 250 mL fitted with a J.
Young valve. The ampules were filled with a dmf solution (100 mL)
of methyl acrylate (1.083 mL, 12.0 mmol), para-iodotoluene (2.202 g,
10.0 mmol), triethylamine (1.674 mL, 12.0 mmol), and naphthalene
(1.296 g, 10 mmol) as internal standard, and the corresponding
catalyst (10 μmol) in dmf (50 mL). The solution was stirred at 130
°C for 12 h (for 3, 10, and 11) or 16 h (for 12) in the initial cycle,
and for 7 h (for 3, 10, and 11) or 12 h (for 12) in successive cycles.
The solution was then transferred into the nanofiltration cell under
1
,3,5-triyl)-α-yl]benzyl)-3,3′-methylenediimidazol-2,2′-diyliden)-
dibromidopalladium(II) (10). Pd(OAc) (97 mg, 0.43 mmol), 6 (400
2
mg, 0.43 mmol), and dmso (2.3 mL). Yield: 408 mg (92%). Anal.
Calcd (%) for C H N O Br Pd (1033.15): C 58.13; H 4.49; N
5
0
46
4
4
2
1
5
.42%. Found: C 57.78; H 4.69; N 5.60%. H NMR (CDCl ): δ 4.48
3
2
(
m, 2H, CHHCHH), 4.89 (d, 4H, J = 11.7, OCHHPh), 4.97 (d,
H,H
2
4
H, OCHHPh), 5.17 (d, 2H, J = 14.5, NCHHAr), 5.43 (d, 2H,
H,H
NCHHAr), 5.48 (m, 2H, CHHCHH), 6.50 (broad s, 6H, o- and p-
3
Ar), 6.62 (d, 2H, J = 2.2, Imz), 6.89 (d, 2H, Imz), 7.27−7.31 (m,
2
H,H
1
3
1
0H, Ph). C{ H} NMR (CDCl ): δ 47.7 (CH CH ), 54.6
3 2 2
(
(
NCH Ar), 70.1 (OCH Ph), 101.7 (p-Ar), 107.8 (o-Ar), 122.2
2
2
4,5
Imz−C ), 127.7 (m-Ph), 128.0 (p-Ph), 128.5 (o-Ph), 136.5 (ipso-
2
Ph), 137.7 (ipso-Ar), 159.2 (m-Ar) 160.2 (Imz−C ). IR (KBr): ν
I
DOI: 10.1021/acs.organomet.8b00295
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
argon. Under continuous stirring, the cell was pressurized with argon
at 1.5 bar to obtain a flow through the 90 cm diameter membrane of
approximately 10 mL/min. The permeate was collected under argon
in a Schlenk tube to a volume of 70 mL. Then, dmf (70 mL) was
subsequently added to the retentate in the cell, and a further 70 mL of
solution was filtered under continuous stirring. The result of this two-
step filtration procedure is that around 90% of the initial reaction
mixture was filtered. The two permeate fractions collected in each
recovery cycle were combined and evaporated to dryness. The solid
residue was weighed and a small fraction separated for analysis of the
Pd content. The remaining solid was extracted with dichloromethane
*E-mail: ernesto.dejesus@uah.es.
ORCID
Pilar Gom
́
ez-Sal: 0000-0002-9279-210X
Juan C. Flores: 0000-0001-6356-555X
: 0000-0001-8101-1358
Ernesto de Jesus
Notes
́
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(
50 mL), and the organic phase was washed with water (3 × 30 mL),
This work was supported by the Spanish Ministerio de
dried over MgSO , and evaporated to dryness. The methyl (2E)-3-(4-
4
́
Economia, Industria y Competitividad (projects CTQ2014-
methyl)phenylprop-2-enoate product thus obtained was weighed and
analyzed by 1H NMR. The retentate was again transferred to a
pressure ampule and a new load of substrates, triethylamine, internal
standard, and solvent was added (to complete an overall volume of
5
5005-P and CTQ2017-85203-P). A.M.O. is grateful to the
Spanish Ministerio de Educacion, Cultura y Deporte for an
FPU Doctoral Fellowship. Dedicated to Professor Ernesto
Carmona on the occasion of his 70th birthday.
́
1
00 mL). The procedure was then repeated.
X-ray Crystallographic Studies. Suitable single crystals of 1, 2, and
0 were obtained by the following methods: slow evaporation of a
1
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Corresponding Authors
E-mail: juanc.flores@uah.es.
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*
J
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