Hydroformylation of Alkenes in a Planetary Ball Mill: From Additive-Controlled Reactivity to Supramolecular Control of Regioselectivity

Article abstract of DOI:10.1002/anie.201705467

The Rh-catalyzed hydroformylation of aromatic-substituted alkenes is performed in a planetary ball mill under CO/H₂ pressure. The dispersion of the substrate molecules and the Rh-catalyst into the grinding jar is ensured by saccharides: methyl-α-d-glucopyranoside, acyclic dextrins, or cyclodextrins (CDs, cyclic oligosaccharides). The reaction affords the exclusive formation of aldehydes whatever the saccharide. Acyclic saccharides disperse the components within the solid mixture leading to high conversions of alkenes. However, they showed typical selectivity for α-aldehyde products. If CDs are the dispersing additive, the steric hindrance exerted by the CDs on the primary coordination sphere of the metal modifies the selectivity so that the β-aldehydes were also formed in non-negligible proportions. Such through-space control via hydrophobic effects over reactivity and regioselectivity reveals the potential of such solventless process for catalysis in solid state.

Full text of DOI:10.1002/anie.201705467

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Communications
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International Edition: DOI: 10.1002/anie.201705467
German Edition: DOI: 10.1002/ange.201705467
Hydroformylation by Mechanosynthesis
Hydroformylation of Alkenes in a Planetary Ball Mill: from Additive-
Controlled Reactivity to Supramolecular Control of Regioselectivity
Kꢀvin Cousin, Stꢀphane Menuel, Eric Monflier, and Frꢀdꢀric Hapiot*
Abstract: The Rh-catalyzed hydroformylation of aromatic-
substituted alkenes is performed in a planetary ball mill under
CO/H2 pressure. The dispersion of the substrate molecules and
the Rh-catalyst into the grinding jar is ensured by saccharides:
methyl-a-d-glucopyranoside, acyclic dextrins, or cyclodextrins
(CDs, cyclic oligosaccharides). The reaction affords the
exclusive formation of aldehydes whatever the saccharide.
Acyclic saccharides disperse the components within the solid
mixture leading to high conversions of alkenes. However, they
showed typical selectivity for a-aldehyde products. If CDs are
the dispersing additive, the steric hindrance exerted by the CDs
on the primary coordination sphere of the metal modifies the
selectivity so that the b-aldehydes were also formed in non-
negligible proportions. Such through-space control via hydro-
phobic effects over reactivity and regioselectivity reveals the
potential of such solventless process for catalysis in solid state.
compel terminal alkenes to react preferentially by their
terminal carbon, leading to very high regioselectivity toward
linear aldehyde.[14]
Recently, focus has been in controlling selectivity of
organic reactions under solventless ball-milling conditions.[15]
Concurrently with works of Cravotto et al.,[16,17] we showed
that regioselective mono-2-O-tosylation of the secondary face
of CDs proceeds quantitatively upon grinding on very short
reaction times (ca. 1 min) via supramolecular means, the
reactant (tosylimidazole) being included into the CD
cavity.[18] Similarly, highly selective processes were identified
in the mechanically-activated Au-catalyzed reduction of
nitroarenes in the presence of CDs.[19] On the basis of the
aforementioned results, we sought to assess the potential of
CDs to control both the chemo- and regioselectivity of the
hydroformylation reaction under CO/H2 pressure under
mechanochemical activation. To our knowledge, nothing has
been published so far on the hydroformylation of alkenes in
the solid state under ball-milling conditions. In fact, very few
has been reported so far on the mechanochemical activation
of catalytic reactions using a pressurized ball mill.[20,21]
Reported herein is the ball-milled Rh-catalyzed hydroformy-
lation of alkenes to the corresponding aldehydes under CO/
H2 pressure in the presence of saccharide additives such as
methyl-a-d-glucopyranoside (1a), acyclic dextrins (1b, mal-
todextrins 6D, degree of polymerization = 20)[22] and CDs of
different cavity size (1c–e, Figure 1). The saccharides have
been chosen for their high temperature of fusion (1688C for
T
ransition-metal-catalyzed hydroformylation of alkenes rep-
resents one of the most important approaches to aldehydes.
Since the seminal studies from Roelen,[1] a range of improve-
ments have been made to produce aldehydes in excellent
yields at operatively convenient conditions of pressures and
temperatures.[2] Over the years, research has focused on the
design of catalysts consisting of transition metals stabilized by
specialized ligands, to increase chemo-, regio-, and enantio-
selectivities.[3] Countless first-sphere ligands are now available
for regioselective control in hydroformylation of terminal and
internal alkenes.[4–7] Concurrently, a supramolecular approach
has been developed aiming at controlling site-selective
reactions via secondary interactions.[8] Cooperative ligand
systems have thus demonstrated that supramolecular inter-
actions between substrate and ligand can result in non-
covalent substrate preorganization around the active catalytic
site. In this context, one of the most developed approach
relies on hydrogen bonding between the ligand and the
substrate.[9–13] However, the substrate preorganization in
hydroformylation reactions could also be achieved through
hydrophobic effects. For example, we showed that bidentate
ligands and cyclodextrins (CDs, cyclic oligosaccharides con-
sisting of glucopyranose units) supramolecularly interact to
[*] K. Cousin, Dr. S. Menuel, Prof. Dr. Ing. E. Monflier, Prof. Dr. F. Hapiot
Univ. Artois, CNRS, Centrale Lille, ENSCL
Univ. Lille, UMR 8181, Unitꢀ de Catalyse et de Chimie du Solide
(UCCS)
62300 Lens (France)
E-mail: frederic.hapiot@univ-artois.fr
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201705467.
Figure 1. Selected saccharides and substrates.
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1a, and > 2508C for 1b and CDs) which ensures that the
catalytic process takes place at the solid state. The role of
saccharides in favoring and orienting the course of the
mechanically activated hydroformylation reaction is espe-
cially highlighted.
To begin with, we demonstrated that the hydrido-Rh
precursor could be synthesized under mechanochemical
conditions. As described for many other organometallic
complexes,[23] ball milling allowed for the straightforward
synthesis of the HRh(CO)(PPh3)3 complex, as confirmed on
the basis of 1H and 31P NMR spectroscopy (Figure 2 and
Figure 3). The hydrido-Rh species was identified at À9.8 ppm
on the 1H NMR spectrum and the Rh-P bond was revealed by
minute (rpm) for 4 h. The HRh(CO)(PPh3)3 catalyst was
generated in situ by mixing Rh(CO)2(acac) (acac = acetyla-
cetonate) with 5 equiv PPh3 under 220 psi CO/H2 (1:1)
pressure in the presence of saccharide. Considering 1a as an
additive led to remarkable 100% conversion of 2a (Table 1,
entry 1) and 100% chemoselectivity in aldehydes, as deter-
Table 1: Optimization of the reaction conditions.[a]
Entry
Additive
Conv. [%][b]
Aldehyde
sel. [%][b]
3a/3b[b]
1
2
3
4
5
1a
1b
1c
1d
1e
100
79
38
54
67
100
100
100
100
100
10.0
10.0
4.5
2.0
3.2
[a] Reagents and Conditions: Rh(CO)2(acac) (3.7 mmol), PPh3
(18.5 mmol), 2a (1.8 mmol), additive (1.8 mmol), CO/H2 (1:1) (220 psi),
rotation speed (850 rpm), 4 h. [b] determined by NMR spectroscopy.
1
mined by H NMR spectroscopy. The a-aldehyde (3a) was
mainly formed (10 times more than the b-aldehyde (3b),
Table 1), in line with what was typically observed in solution
for the hydroformylation of aromatic-substituted alkenes.[24,25]
The preference for 3a resulted from the formation of
a rhodium a-arylalkyl intermediate stabilized by p-benzyl
interaction.[26] Thus, the high proportion of 3a suggested that
the in situ formation of the rhodium a-arylalkyl intermediate
also took place at the solid state under ball-milling conditions.
This experiment alone validated the approach of hydro-
formylation under ball-milling conditions.
Figure 2. 1H NMR spectra of a) commercial HRh(CO)(PPh3)3 and b) a
mixture of Rh(CO)2(acac) (0.16 mmol), PPh3 (0.78 mmol), and a-CD
(2.06 mmol) after 1 h ball-milling under 15 bar CO/H2 (1:1) in
[D6]DMSO at 258C.
The same reaction was then carried out by using the
acyclic dextrin 1b as additive. Because of its helicoidal
structure and extended binding site,[27] 1b can bind to 2a
resulting in a reduced diffusion of 2a and lower 79%
conversion (entry 2). Here again, 2a was exclusively con-
verted into aldehydes and the 3a/3b ratio remained
unchanged (Table 1). Grinding 2a in the presence of a-CD
(1c) gave 38% conversion and 100% chemoselectivity
towards aldehydes (entry 3). The moderate conversion
likely resulted from the formation of host-guest complexes
between the naphthyl moiety of 2a and the CD cavity,[28]
which slowed down the diffusion of 2a within the solid
mixture. This result was in line with our previous observations
about the poor ability of 1c to diffuse aromatic substrates in
AuNP-catalyzed reduction under ball-milling conditions.[19]
Interestingly, while the conversion was negatively affected by
1c, significant effects were measured on the regioselectivity.
The proportion of 3b significantly increased (Table 1,
entry 3), suggesting that the cyclic structure of 1c slightly
affected the rhodium a-arylalkyl intermediate in the solid
state. However, the cavity of 1c being too narrow to include
the entire naphthalene ring,[29] the discriminating effect to 3b
was limited. The negative effect on the conversion of 2a was
Figure 3. 31P NMR spectra of a) commercial HRh(CO)(PPh3)3 and b) a
mixture of Rh(CO)2(acac) (0.16 mmol), PPh3 (0.78 mmol), and a-CD
(2.06 mmol) after 1 h ball-milling under 15 bar CO/H2 (1:1) in
[D6]DMSO at 258C. TPP=PPh3.
the doublet at 40.0 ppm (1JRh-P = 154.9 Hz) in the 31P NMR
spectrum. The chemical shift and coupling constant values
were in line with those of the commercial product. Note that
the formation of hydrido-Rh complex in solution during the
NMR analysis should be discarded in that the medium was
free of H2 in the NMR tube.
The first catalytic test began with the Rh-catalyzed
hydroformylation of 2-vinylnaphtalene (2a) as a model sub-
strate in a planetary ball mill rotating at 850 rounds per
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less pronounced using b-CD (1d) as an additive (54%,
and 1b illustrated the formation of CD/substrate inclusion
Table 1) probably because of better dynamics of exchange
between 2a and the larger cavity of 1d compared to 1c.[30]
In terms of regioselectivity, a deeper penetration of 2a
into the cavity of 1d explained the lower 3a/3b ratio of 2.0
(33% of 3b). Upon inclusion of 2a, the bulky rigid structure
of 1d repelled the Rh-catalyst to the less hindered b-position
(Figure 4). The formation of the rhodium a-arylalkyl inter-
complexes. Upon inclusion into the CDsꢀ cavity, the diffusion
of the substrate throughout the solid mixture slowed down,
which logically resulted in lower catalytic activity.
We then tried to intensify the discriminating effect of 1d
by optimizing the catalytic parameters. Varying the CO/H2
pressure from 75 to 220 psi did not significantly change the
conversion. The rotation speed, for its part, affected both the
catalytic activity and the regioselectivity. By increasing the
rotation speed from 350 to 850 rpm under 220 psi CO/H2, the
conversion increased from 6% to 54% and the percentage of
b-aldehyde increased from 9% to 36%.[32] This clearly
indicated that the energy transfer resulting from friction and
shocks of the balls onto the reactor walls favored the inclusion
process of 2a into the cavity of 1d. In terms of regioselectivity,
the Rh-catalyst was more prone to react favorably on the less
hindered position of the vinyl group upon inclusion, resulting
in higher proportion of 3b. Changing the nature of the ligand
(Figure 5) also gave interesting results (Table 2). The best
conversion was obtained using TPFP (Table 2, entry 5). The
electron-withdrawing effects of the F atoms probably allowed
for a rapid de-coordination of TPFP from the Rh-center to
form catalytically active low-phosphine coordinated Rh-
complexes.
Figure 4. Schematic representation of the influence of the molecular
recognition between 2a and the CD cavity of 1c and 1d on the
regioselectivity of the hydroformylation under ball-milling conditions.
mediate was then disfavored, resulting in higher proportion of
3b. These observations were substantiated by experiments
carried out with g-CD (1e) as additive. Compared to 1c and
1d, the conversion was higher (67%, Table 1, entry 5) using
1e as its wider cavity promoted higher dynamics of exchange
of 2a and its corresponding aldehydes throughout the solid
mixture. However, the percentage of 3b decreased (24%)
compared to that obtained for 1d. Indeed, as 2a was less
constrained by the more flexible structure of 1e, the imperfect
preorganization of 2a around the active catalytic site resulted
in lower percentage of 3b.
We then conducted a comparative study to determine the
contribution of amorphization and complexation under ball
milling conditions. To do so, differential scanning calorimetry
(DSC) analysis was performed on co-grinded mixtures of 2a
and saccharides (Supporting Information) to assess the
encapsulation efficiency (EE%).[31] While EE% is based on
thermodynamic data (especially enthalpy, see Supporting
Information), its variation with time gives indications on the
rate of the amorphization and/or encapsulation processes.
More precisely, from the variations of EE% values at
different grinding times, we estimated the ability of 1a to
amorphize 2a (no inclusion complex in that case), and the
ability of 1b, 1c, 1d, or 1e to form inclusion complexes with
2a in the solid state. Hypothesizing that the amorphization
contribution was similar for all saccharides, the higher EE%
measured at a given grinding time for CDs with respect to 1a
Figure 5. Selected phosphines and phosphite.
Table 2: Influence of the ligand on the hydroformylation of 2a under ball-
milling conditions in the presence of 1d.[a]
Entry
Phosphine
Conv
[%][b]
Aldehyde
sel. [%][b]
3a/3b[b]
1
2
3
4
5
6
–
PPh3
TPPTS
TPTP
TPFP
0
54
4
38
67
35
100
100
100
100
100
100
–
2
10
3.3
2.5
1.1
BIPHEPHOS
[a] Reagents and Conditions: Rh(CO)2(acac) (3.7 mmol), PPh3
(18.5 mmol), 2a (1.8 mmol), additive (1.8 mmol), CO/H2 (1:1) (220 psi),
rotation speed (850 rpm), 4 h. [b] determined by NMR spectroscopy.
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In terms of regioselectivity, the best regioselectivities were
obtained using BIPHEPHOS, a bidentate ligand BIPHE-
PHOS well-known to favor the reactivity of terminal alkene
carbons.[3,12]
ever the nature of the saccharide, as aldehydes were
exclusively formed during the course of the reaction. Acyclic
saccharides greatly favor the diffusion of the substrate within
the solid mixture while cyclic saccharides, such as CDs, act as
transient second-sphere ligand around the catalyst center with
noncovalent structure-directing effects. They modify the
regioselectivity via through-space control and favor hydro-
formylation at the less-hindered position of the vinyl function.
The effect could be amplified by using bulky bidentate
ligands, such as BIPHEPHOS. This is the first example of
saccharide-assisted selectivity control under solvent-free ball-
milling conditions. These unprecedented results pave the road
to further developments of catalytic processes with high
catalytic activity and unusual selectivity in the solid state.
In that case, 3a and 3b were obtained in almost equal
proportions (Table 2, entry 6). The low 3a/3b ratio reflected
the tendency of the bulky BIPHEPHOS-based Rh-catalyst to
orient the hydroformylation towards the two vinyl carbons in
a balanced way. Actually, the steric effects of both 1d and
BIPHEPHOS probably operate in conjunction (Figure 4).
The formation of the bidentate Rh-complex derived from
BIPHEPHOS under ball-milling conditions was unambigu-
ously demonstrated by NMR measurement (Supporting
information).
Once the proof-of-concept was complete with 2a as
a model substrate, we examined the substrate scope of the
reaction, and the results are shown in Table 3. Compared to
Acknowledgements
We thank Dr. N. Kania and D. Prevost for technical
assistance. Chevreul Institute (FR 2638), Ministꢁre de lꢂEn-
seignement Supꢃrieur et de la Recherche, Rꢃgion Nord—Pas
de Calais, and FEDER are acknowledged for supporting and
funding partially this work.
Table 3: Substrate scope of the hydroformylation reaction.[a]
Entry
Substrate
Additive
Conv[b]
[%]
Aldehyde
sel. [%][b]
a/b[b]
1
2
3
4
5
6
7
8
2b
2b
2b
2b
2b
2c
2c
2c
2c
2c
2d
2d
2d
2d
2d
1a
1b
1c
1d
1e
1a
1b
1c
1d
1e
1a
1b
1c
1d
1e
82
100
24
27
24
100
100
27
24
23
9
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
6.2
10
5
2
Conflict of interest
3.3
n.d.
n.d.
3.3
2
3.3
100
100
10
5
The authors declare no conflict of interest.
9
Keywords: cyclodextrins · hydroformylation ·
mechanosynthesis · regioselectivity · supramolecular chemistry
10
11
12
13
14
15
20
10
4
3
2
[a] Conditions: Rh(CO)2(acetylacetonate) (3.7 mmol), TPP (18.5 mmol),
substrate (1.8 mmol), additive (1.8 mmol), CO/H2 (1:1) (200 psi),
rotation speed (850 rpm), 4 h. [b] determined by NMR spectroscopy;
n.d.= not determined.
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4
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Accepted manuscript online: July 3, 2017
Version of record online: && &&, &&&&
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Communications
Hydroformylation by Mechanosynthesis
K. Cousin, S. Menuel, E. Monflier,
F. Hapiot*
&&&& — &&&&
Hydroformylation of Alkenes in
a Planetary Ball Mill: from Additive-
Controlled Reactivity to Supramolecular
Control of Regioselectivity
Ground sugar: The rhodium-catalyzed
hydroformylation of aromatic-substituted
alkenes is efficiently performed in a plan-
etary ball mill under CO/H2 pressure. It
gives aldehydes in high chemoselectivity
and with modification of the regioselec-
tivity to the less-preferred b-aldehydes.
6
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